Details for Patent: 8,617,599

Summary for Patent: 8,617,599

Title:	Modified release compositions comprising tacrolimus
Abstract:	A modified release composition comprising tacrolimus releases less than 20% w/w of the active ingredient within 0.5 hours when subjected to an in vitro dissolution test using USP Paddle method and using 0.1 N HCl as dissolution medium and has increased bioavailability by effectively reducing or even avoiding the effects of CYP3A4 metabolism. The modified composition may be coated with an enteric coating; and/or may comprise a solid dispersion or a solid solution of tacrolimus in a hydrophilic or water-miscible vehicle and one or more modifying release agents; and/or may comprise a solid dispersion or a solid solution of tacrolimus in an amphiphilic or hydrophobic vehicle and optionally one or more modifying release agents.
Inventor(s):	Per Holm, Tomas Norling
Assignee:	Veloxis Pharmaceuticals Inc
Application Number:	US13/167,095
Patent Claim Types: see list of patent claims	Composition; Formulation; Dosage form;

US Patent 8,617,599 Landscape: Scope, Claim Coverage, and Blocking Position for Oral Extended-Release Tacrolimus

US 8,617,599 claims oral extended-release (ER) tacrolimus compositions defined by (i) an in vitro dissolution performance metric (USP paddle, 50 rpm, 900 mL medium with 0.005% hydroxypropylcellulose at pH 4.5), (ii) release limits (≤62% released in 15 hours; dependent claim tiers at ≤60% and ≤50%), (iii) optional vehicle/carrier architecture (hydrophilic or water-miscible vehicles, poloxamer and PEG embodiments, solid carriers like lactose), and (iv) performance-related pharmacokinetic language (AUC fed/fasted ≥0.9) and route/form-factor (compressed tablet). The estate is narrow in “what is required” (dissolution test result under specific conditions) but broad in “how it can be achieved” through multiple candidate modifying release agents and vehicles.

Because the independent claim is anchored to a specific dissolution test outcome, most design-arounds hinge on changing one of four levers: dissolution test conditions, measured release threshold (percent released in 15 hours), vehicle/release-agent system selection that changes release kinetics, or form factor/particle architecture that affects release behavior.

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What does US Patent 8,617,599 claim for oral extended-release tacrolimus?

Core answer: It claims ER oral tacrolimus compositions that release at most 62% of tacrolimus in 15 hours using a USP Paddle in vitro dissolution test at defined conditions, with optional constraints on excipients/vehicles and optional PK-related criteria.

Independent claim 1: Dissolution-bound definition

Claim 1 recites an oral ER pharmaceutical composition comprising:

• Tacrolimus (therapeutically effective amount)
• One or more modifying release agents
• Release metric constraint: “releases at most 62% of tacrolimus within 15 hours”
• In vitro test conditions (explicit):
  • USP Paddle
  • 50 rpm
  • 900 mL aqueous medium
  • 0.005% hydroxypropylcellulose (HPC/HPC-like)
  • adjusted to pH 4.5

Implication: The patent is defined less by a specific polymer chemistry and more by a performance outcome in a particular dissolution apparatus and medium. That structure creates both (a) enforceability strength for products that match the release curve in that exact test and (b) design-around opportunities by shifting the measured release profile away from the ≤62% boundary or by using different release behavior that is compliant in vivo even if the in vitro test differs.

Dependent claims 2 and 3: tighter release thresholds

• Claim 2: ≤60% released in 15 hours (same dissolution test conditions)
• Claim 3: ≤50% released in 15 hours

These establish a graded claim ladder. Any product landing between 50% and 60% (or between 60% and 62%) can remain within a portion of the dependent coverage depending on its measured release.

Dependent claim 4: AUC fed/fasted ratio

• Claim 4: composition provides an AUCfed/AUCfasted ≥ 0.9

This is a functional PK criterion tied to fed versus fasted exposure behavior. It is not tied to the in vitro dissolution test directly, creating a second infringement axis for products that meet dissolution limits but fail the PK criterion, and vice versa.

Dependent claim 5: pH independent release

• Claim 5: composition provides pH independent release

This is a functional property, typically implying consistent release across pH range. In enforcement, the “how demonstrated” details become crucial, but the claim text itself requires the property.

Claims 6–10: vehicle architecture and PEG/poloxamer embodiments

Claim 6 adds a vehicle system:

• Tacrolimus is dispersed or dissolved in a hydrophilic or water-miscible vehicle

Claim 7 lists candidate vehicles, including:

• PEG, polyoxyethylene oxide, poloxamer, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glyceride, and mixtures.

Claim 8 specifies:

• vehicle comprises poloxamer

Claim 9 specifies:

• vehicle comprises poloxamer and polyethylene glycol

Claim 10 adds a quantitative ratio:

• PEG : poloxamer by weight = 1:3 to 10:1

Implication: The independent claim does not force poloxamer/PEG, but these dependents create narrower “preferred” coverage lanes that may be easier to map to specific product formulations used in the market.

Claims 11–12: solid carrier option

• Claim 11: further comprising a solid carrier
• Claim 12: solid carrier is lactose

This means lactose-based solid carrier formulations sit within additional claim protection.

Claim 13: broad modifying release agent genus

Claim 13 lists multiple release-agent candidates, including:

• HPMC, HPC, methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose
• poloxamers
• polyoxyethylene stearates
• poly-s-caprolactone
• PVP and PVP-PVA copolymer
• polymethacrylic polymers
• PVA
• poly(ethylene oxide) (PED)

Implication: The modifying release agent limitation is broad in species coverage. That reduces the value of choosing a “different polymer” as a design-around unless it also shifts dissolution release kinetics beyond the ≤62% threshold under the specific USP paddle test.

Claims 14–15: particles and compressed tablet form

• Claim 14: composition comprises tacrolimus-containing particles
• Claim 15: composition is a compressed tablet

These can matter for infringement scope if a competitor uses granules/capsules or different dosage forms, though claim 1 already covers “composition” generally as oral ER.

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Is there a second independent claim path that narrows vehicle requirements?

Yes. The patent includes additional independent-style coverage that explicitly requires poloxamer in the vehicle.

Claim 16: Poloxamer-required vehicle plus dissolution limit

Claim 16 requires:

• tacrolimus in a vehicle + modifying release agents
• vehicle comprises poloxamer
• dissolution performance: ≤62% in 15 hours under the same USP paddle test conditions (pH 4.5; 0.005% hydroxypropylcellulose; 50 rpm; 900 mL)

This claim is narrower than claim 1 in excipient architecture, but still performance-defined.

Claim 18: PEG (MW range) + poloxamer + lactose/solid carrier style

Claim 18 requires:

• vehicle comprises PEG (MW 1,000 to 35,000) and poloxamer
• includes a solid carrier
• dissolution performance: ≤62% within 15 hours under the same test conditions

This is a more “formulation-specific” gate.

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What specific dissolution test conditions control the infringement trigger?

The in vitro dissolution test is the primary gate for the core claims. The claim language specifies:

• Method: USP Paddle
• Speed: 50 rpm
• Volume: 900 mL
• Medium: aqueous with 0.005% hydroxypropylcellulose
• pH: 4.5
• Time window: 15 hours
• Endpoint: % tacrolimus released (≤62%; with dependent thresholds ≤60% and ≤50%)

Why this matters for scope

• If a competitor’s product is tested under identical conditions and releases more than 62% by 15 hours, it may fall outside independent claim 1 and related dissolution-linked dependents.
• If release is compliant (≤62%), then attention shifts to additional requirements in dependent claims:
  • PK fed/fasted ratio (AUCfed/AUCfasted ≥0.9)
  • pH independent release
  • vehicle composition (poloxamer-only; PEG+poloxamer with MW and ratio ranges)
  • solid carrier (lactose)
  • dosage form (compressed tablet)

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How broad is the polymer and excipient coverage?

Modifying release agent genus: broad

Claim 13 enumerates multiple polymers that qualify as “one or more modifying release agents,” including both hydrophilic and hydrophobic-release modifiers (e.g., HPMC/HPC/cellulose derivatives, methacrylic polymers, polyesters/caprolactone, PVP/PVP-PVA, PVA, and PEG-like systems).

Result: Choosing a different polymer still often meets the claim’s agent limitation as long as it functions as a “modifying release agent” and does not push release kinetics above the dissolution thresholds.

Vehicle genus: broad

Claim 7 is also broad: multiple hydrophilic or water-miscible vehicles qualify, including PEG and poloxamer.

But vehicle sub-ranges are narrower

• Claim 10: PEG-to-poloxamer ratio 1:3 to 10:1
• Claim 18: PEG MW 1,000–35,000

So excipient breadth exists at the independent claim level but narrows in dependent lanes.

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What is the functional PK and performance coverage (AUC fed/fasted, pH independence)?

AUCfed/AUCfasted ≥ 0.9 (Claim 4)

This introduces an infringement basis that is not purely in vitro. For ER tacrolimus, fed/fasted exposure variability is clinically relevant. The claim turns that into a measurable threshold.

Practical enforcement risk for challengers: Even if a product meets the dissolution release boundary, it still must satisfy the in vivo fed/fasted exposure ratio if claim 4 is asserted against it.

pH independent release (Claim 5)

This adds a property requirement typically assessed across dissolution conditions of varying pH. Because claim 5 does not provide the exact pH range, infringement will depend on how the product’s release profile is characterized against the asserted “pH independence” standard.

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What formulations are explicitly covered? (vehicle and carrier permutations)

The patent’s claim set maps to a set of formulation archetypes:

Archetype A: “Dissolution-compliant” ER tacrolimus + modifying release agent

• Meets ≤62% released in 15 hours (USP paddle conditions)
• Contains at least one modifying release agent from the claimed genus

This is the broadest coverage.

Archetype B: Poloxamer vehicle

• Tacrolimus dispersed or dissolved in poloxamer vehicle
• Meets ≤62% released in 15 hours
• Modifying release agents included

Archetype C: PEG + poloxamer vehicle (with PEG MW and carrier)

• PEG (MW 1,000 to 35,000) + poloxamer vehicle
• Solid carrier included
• Meets ≤62% released in 15 hours

Archetype D: PEG/poloxamer weight ratio window

• PEG-to-poloxamer = 1:3 to 10:1 by weight
• Meets dissolution metric from claim 1

Archetype E: Lactose solid carrier

• Solid carrier is lactose
• Combined with the independent claim dissolution constraints

Archetype F: Compressed tablet form

• ER tacrolimus composition in tablet form
• Combined with the independent claim dissolution constraints

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How many distinct claim “coverage buckets” exist?

From the provided claim text, the coverage buckets are:

1. Dissolution gate only (claim 1)
2. Dissolution tighter thresholds (claims 2–3)
3. PK fed/fasted gate (claim 4)
4. pH independence gate (claim 5)
5. Vehicle/dispersed-dissolved gate (claim 6)
6. Vehicle genus (claim 7)
7. Poloxamer-only vehicle (claim 8, plus claim 16)
8. Poloxamer + PEG vehicle (claim 9)
9. PEG:poloxamer ratio (claim 10)
10. Solid carrier (claim 11) including lactose (claim 12)
11. Modifying release agent genus (claim 13)
12. Particle-based compositions (claim 14)
13. Compressed tablets (claim 15)
14. Poloxamer-required independent path (claim 16)
15. PEG MW-limited + poloxamer + solid carrier path (claim 18)
16. Dissolution thresholds tied to these dependent/independent paths (claims 17 and 19)

This structure matters for freedom-to-operate: even if a competitor designs around the dissolution gate, it can still be exposed if it matches a dependent formulation bucket.

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What generic entry risks exist for ER tacrolimus under this patent scope?

High-risk scenario

A generic/ANDA product:

• targets ER tacrolimus release control to match known reference dissolution behavior
• uses hydroxypropylcellulose-modified dissolution characteristics
• uses poloxamer and PEG vehicles
• lands within ≤62% (or tighter) release at 15 hours under the claimed test

Such a product can satisfy claim 1 and multiple dependent claims simultaneously.

Key design-around risk

The claims are not limited to a single excipient. A generic that uses different polymers still may meet the “modifying release agent” limitation in claim 13. That makes “switch polymer” a weak design-around unless it also moves dissolution beyond the ≤62% threshold.

Form-factor risk

If a competitor’s ER product is not compressed tablet (capsule instead), claim 15 may be avoided, but claim 1 still covers “composition.” So form-factor workarounds likely reduce only a slice of dependent exposure.

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What are the most plausible design-arounds based on the claim language?

These are the lever points embedded in the claim text:

1. Shift dissolution behavior above the boundary

   • Ensure >62% released within 15 hours in the specific USP paddle test conditions.
   • This is the most direct route out of claim 1, and it also avoids dependent claims 2–3.

2. Change dissolution test outcome by changing the formulation’s release kinetics

   • Even if the excipient set remains in the claimed genus, release kinetics must be pushed beyond the thresholds.

3. Miss dependent-property requirements

   • If dissolution is compliant but fed/fasted AUC ratio fails (claim 4), that narrows infringement depending on asserted claims.
   • If “pH independent release” is not met (claim 5), that narrows dependent coverage.

4. Miss dependent vehicle architecture

   • Avoid poloxamer-only vehicle (claim 16, claim 8).
   • Avoid PEG MW 1,000–35,000 with poloxamer (claim 18).
   • Avoid PEG:poloxamer ratio window 1:3 to 10:1 (claim 10).
   • Avoid lactose solid carrier (claim 12).

These do not remove exposure to claim 1 unless dissolution remains noncompliant, but they reduce the claim stack vulnerability.

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Patent landscape context: what this claim set suggests about related blocking patents

From claim structure alone, the estate is likely focused on ER tacrolimus “release-controlled” formulations rather than molecular modifications (tacrolimus itself is not inventive here). The claim language points to a formulation technology cluster around:

• in vitro dissolution-controlled ER profiles
• polymer/modifying-release agent systems
• vehicles such as poloxamer and PEG
• performance metrics like fed/fasted AUC and pH robustness

That typically correlates with a surrounding body of patents covering:

• additional dissolution endpoints (different media, paddle speed, time windows)
• specific excipient combinations and ratios
• manufacturing/process parameters that produce distinct particle size and release kinetics
• PK-related correlations between dissolution and exposure

Without the broader family listing, litigation docketing, and Orange Book entries for the referenced tacrolimus product, only the internal claim logic can be mapped here.

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Does US 8,617,599 likely read on FDA-approved ER tacrolimus products?

The claims describe “oral ER tacrolimus” compositions, which suggests coverage of marketed ER tacrolimus dosage forms that:

• use hydrophilic vehicles and cellulosic or related modifying release polymers
• target controlled release over a 15-hour window with dissolution behavior in acidic medium (pH 4.5) with 0.005% hydroxypropylcellulose
• aim for reduced food effect (AUC fed/fasted near unity) and pH-independent behavior

Read-across is most plausible if the reference product or its known generics tune release in exactly this pH 4.5/USP paddle scenario and employ poloxamer and/or PEG within the claimed ranges. Market-read across depends on formulation disclosure and dissolution testing results from the relevant NDA/ANDA product labels and bioequivalence/CMC packages.

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How strong is the patent estate for oral ER tacrolimus based on scope?

Within the provided claim set, enforceability strength is tied to the test endpoint.

• Strength: claims are performance-defined and include explicit dissolution parameters, which can reduce ambiguity in infringement testing when the opposing product is evaluated under the same conditions.
• Weakness: the endpoint is narrow in time and apparatus/medium specification. If a competitor’s formulation is tuned to different dissolution profiles that still achieve ER in vivo but changes the in vitro threshold, claim 1 can be avoided.

Overall: The patent is best viewed as a “dissolution-anchored” formulation barrier with multiple dependent lanes capturing common excipient patterns (cellulose derivatives, poloxamer/PEG, lactose carrier) and performance refinements (fed/fasted AUC, pH independence).

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Key Takeaways

• US 8,617,599’s main infringement trigger is a specific dissolution outcome: ≤62% tacrolimus released in 15 hours using USP paddle, 50 rpm, 900 mL, pH 4.5, 0.005% hydroxypropylcellulose.
• Dependent claims tighten release (≤60% and ≤50%) and add property requirements like AUCfed/AUCfasted ≥0.9 and pH independent release.
• Excipients are broad at genus level (modifying release agents and hydrophilic vehicles), but narrow in key dependent buckets (poloxamer vehicle; PEG+poloxamer with PEG MW 1,000–35,000; PEG:poloxamer ratio 1:3 to 10:1; lactose carrier).
• Design-arounds should prioritize dissolution boundary shifting over swapping excipients, since claim 13 covers many common ER tacrolimus polymers.
• Risk stacking is high when a competitor matches both the dissolution endpoint and common excipient architectures (poloxamer/PEG and lactose carrier).

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FAQs

1. What happens if a product releases 63% within 15 hours in the USP paddle test?

It falls outside the dissolution requirement of claim 1 and the dependent dissolution thresholds tied to ≤62%, ≤60%, and ≤50% (assuming the same test conditions).

2. Can a tacrolimus ER formulation still infringe claim 4 if its dissolution is compliant but AUC fed/fasted is <0.9?

Yes, if claim 4 is asserted, because AUC fed/fasted is an independent functional criterion. Whether it infringes depends on measured fed/fasted AUC results.

3. Does claim 1 require poloxamer or PEG?

No. Claim 1 only requires tacrolimus, modifying release agents, and the dissolution endpoint. Poloxamer and PEG appear in dependent claims.

4. Is lactose required to infringe US 8,617,599?

No. Lactose is specific to dependent claim 12 (solid carrier is lactose).

5. What formulation changes most directly avoid the independent claim 1 dissolution gate?

Changes that alter tacrolimus release kinetics so that >62% is released within 15 hours under the claimed USP paddle conditions.

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References

No external sources were provided or cited.

Drugs Protected by US Patent 8,617,599

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: 8,617,599

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

International Family Members for US Patent 8,617,599

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