Details for Patent: 6,440,458

Summary for Patent: 6,440,458

Title:	Sustained release preparations
Abstract:	Providing an oral formulation of a macrolide compound where the dissolution of the macrolide compound is under sustained release; and a sustained-release formulation containing a composition in solid solution, where the macrolide compound is present at an amorphous state in a solid base.
Inventor(s):	Kazunari Yamashita, Eiji Hashimoto, Yukihiro Nomura, Fumio Shimojo, Shigeki Tamura, Takeo Hirose, Satoshi Ueda, Takashi Saitoh, Rinta Ibuki, Toshio Ideno
Assignee:	Astellas Pharma Inc
Application Number:	US09/403,787
Patent Claim Types: see list of patent claims	Composition; Formulation; Dosage form;

Scope and Claims Review for US Patent 6,440,458 (Tacrolimus Sustained-Release Solid Dispersion)
US 6,440,458 claims a sustained-release tacrolimus (or hydrate) oral formulation where tacrolimus is in an amorphous solid dispersion state embedded in specific water-insoluble polymers, with dissolution behavior defined by JP dissolution testing conditions (hydroxypropyl cellulose test solution at pH 4.5). The claims narrow further by polymer identity (ethylcellulose or methacrylate copolymers), tacrolimus:polymer weight ratios, solid dispersion particle size (≤350 μm, and ≤250 μm in dependent claims), inclusion of specific excipients (lactose and/or calcium hydrogen phosphate), and optional blending with a water-soluble polymer (hydroxypropylmethyl cellulose, HPMC).

What does US 6,440,458 claim for sustained-release tacrolimus formulations?

Core claim center of gravity: Claim 1 defines an amorphous-state tacrolimus-containing solid dispersion in a water-insoluble polymer matrix, characterized by a dissolution time window measured as T63.2% using Japanese Pharmacopoeia (JP) 13th edition Dissolution Test No. 2 (puddle method, 50 rpm) with a specific test medium and pH.

Claim 1 elements (independent claim structure)

Claim 1 is a multi-parameter product-by-process and product-characterization combination:

1. Formulation type: “A sustained-release formulation.”
2. Active: tacrolimus or its hydrate.
3. Dissolution performance metric: T63.2% (time required for 63.2% of the maximum amount to dissolve).
   • Range: 0.7 to 15 hours (Claim 1).
4. Measurement framework: JP 13th edition, Dissolution Test No. 2 (Puddle method, 50 rpm).
5. Test solution: aqueous 0.005% hydroxypropyl cellulose solution adjusted to pH 4.5.
6. Composition requirement: includes a solid dispersion composition in which
   • tacrolimus (or hydrate) is present in an amorphous state in a water-insoluble polymer.

Practical scope implication: An accused product must (a) be sustained release as a formulation category, (b) contain tacrolimus/amorphous tacrolimus hydrate, (c) have that amorphous state in a water-insoluble polymer system, and (d) meet the dissolution window under the exact JP test conditions described.

Claim 1 is tightly anchored to amorphous dispersion and the specific JP dissolution method

Many tacrolimus sustained-release systems exist (microcapsules, coatings, polymer matrices). Claim 1 does not cover just any sustained-release tacrolimus. It requires the performance to be tied to T63.2% under JP paddle/puddle method No. 2 at pH 4.5 using 0.005% hydroxypropyl cellulose.

The claim also requires solid dispersion and amorphous state in a water-insoluble polymer. That is a functional characterization that typically translates into analytical proof (e.g., XRPD loss of crystallinity, DSC amorphous signature), though the claim as written is framed as compositional state.

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How are dissolution parameters and JP test conditions limiting for US 6,440,458?

Answer: Dissolution testing is a claim limitation, not a mere specification. The accused formulation must land inside the T63.2% window under the JP 13th edition Dissolution Test No. 2, 50 rpm, pH 4.5 in 0.005% hydroxypropyl cellulose.

T63.2% ranges provided by dependent claims

• Claim 10: T63.2% = 1.3 to 8.2 hours
• Claim 11: T63.2% = 2 to 5 hours

Scope stratification:

• Claim 1 (broadest dissolution window): 0.7 to 15 hours
• Claim 10 narrows to midrange dissolution kinetics
• Claim 11 narrows further to a tighter dissolution window

If a product is engineered for fast dissolution (T63.2% near the lower bound) or very slow dissolution (near or above upper bound), it may fall outside the dependent windows but could still be within Claim 1 if the tested value remains between 0.7 and 15 hours.

pH and medium choices are claim-anchoring

The test medium is not generic. It is:

• 0.005% hydroxypropyl cellulose
• adjusted to pH 4.5 This creates a strong basis to distinguish products that behave differently at pH 4.5 or in cellulose-based media.

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What polymer systems does US 6,440,458 cover (and what is excluded)?

Answer: Claim 1 broadly requires water-insoluble polymer, but Claim 3 narrows the species list to ethylcellulose or methacrylate copolymers.

Water-insoluble polymer (Claim 1 general; Claim 3 specific)

• Claim 1: “water-insoluble polymer” (species not enumerated)
• Claim 3: “ethylcellulose or methacrylate copolymers”

Implications for claim coverage:

• Products using ethylcellulose or methacrylate copolymers squarely fit Claim 3 (if other limitations are met).
• Products using other water-insoluble polymers may still fit Claim 1 if the polymer qualifies as “water-insoluble” and all other limitations are met, but they avoid Claim 3’s enumerated polymer restriction in many litigation frameworks.

Optional water-soluble polymer blend

• Claim 6: water-soluble polymer is mixed with water-insoluble polymer
• Claim 7: water-soluble polymer is hydroxypropylmethyl cellulose (HPMC)
• Claim 8: tacrolimus : HPMC weight ratio 1 to 0.2–0.4

Implication: Claim 6–9 creates a second “sub-design space” where insoluble polymer is not the only polymer component. The formulation includes an HPMC blend, with a defined weight ratio.

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What excipients and particle-size limits are required by the dependent claims?

Answer: The patent adds specific excipient and solid dispersion particle size limits that materially narrow infringement risk for formulations that deviate.

Lactose and calcium hydrogen phosphate excipient limits

• Claim 4: solid dispersion composition characterized by:
  • lactose or calcium hydrogen phosphate present as excipient and/or lubricant
  • particle size ≤350 μm

This is a key narrowing layer. If a formulation uses neither lactose nor calcium hydrogen phosphate (or uses them outside the “excipient and/or lubricant” role), Claim 4 and its downstream dependents become harder to satisfy.

Further narrowing: lactose + smaller particle size + specific amorphous host polymer

• Claim 5: depends on Claim 4 and adds:
  • tacrolimus/amorphous state is in ethylcellulose
  • lactose contained as excipient
  • particle size ≤250 μm

This is a highly specific commercial design profile: ethylcellulose host polymer, lactose excipient, and a reduced particle-size specification.

Particle size as a litigation fault line

Particle size requirements are among the most operationally fragile claim features because they depend on processing and measurement method. Under typical infringement practice, the parties will focus on:

• how particle size is measured (laser diffraction versus sieving versus microscopy-based methods),
• batch consistency,
• and whether the measured distribution satisfies ≤250 μm or ≤350 μm.

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What weight-ratio limits for tacrolimus-to-polymer are claimed?

Answer: The patent includes explicit weight ratio windows in dependent claims, which can be used to engineer around if the formulation ratio changes dissolution behavior.

Tacrolimus-to-water-insoluble polymer ratio

• Claim 2: tacrolimus to water-insoluble polymer weight ratio is
  • 1 to 0.1–5

This is a broad ratio range. It is not a tight formulation spec and may be difficult to engineer around without impacting dissolution and release.

Tacrolimus-to-HPMC ratio

• Claim 8: tacrolimus to HPMC weight ratio
  • 1 to 0.2–0.4

This is narrower than Claim 2 and becomes relevant only if HPMC is used as the water-soluble polymer (Claim 7).

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What dosage forms are included? Does the claim cover capsules, tablets, and powders?

Answer: Yes, the patent explicitly covers multiple physical forms.

• Claim 12: formulation is in the form of:
  • powder, fine powder, granule, tablet, or capsule

This is commercially broad, capturing typical oral sustained-release formats. It does not suggest a limitation to coated dosage forms, but it does not prevent formulation-by-processing differences as long as composition and performance limitations are met.

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How strong is the claim scope for infringement risk analysis (broad vs narrow layers)?

Answer: US 6,440,458 has a two-tier scope: (1) a broad independent framework defined by amorphous tacrolimus in water-insoluble solid dispersion and dissolution kinetics, then (2) narrow dependent refinements tied to polymer identities, particle size, excipients, and optional HPMC blending.

Scope ladder

• Tier A (Independent Claim 1):
  • sustained-release
  • tacrolimus or hydrate
  • solid dispersion with amorphous tacrolimus in water-insoluble polymer
  • T63.2% 0.7–15 hours under JP test conditions
• Tier B (Dependent constraints):
  • Claim 3: ethylcellulose or methacrylate copolymers
  • Claim 4–5: lactose/calcium hydrogen phosphate and particle size ≤350 or ≤250 μm
  • Claim 6–9: optional HPMC blend and ratio, plus particle size and amorphous state in mixed insoluble/soluble polymer systems

Engineering around opportunities (claim-feature level):

• Shift dissolution kinetics so T63.2% falls outside 0.7–15 hours under the specific JP medium/pH.
• Avoid “amorphous state in water-insoluble polymer” by using a crystalline state or different solid-state form in the host matrix.
• Use a water-insoluble polymer that is disputed as “water-insoluble,” while also changing solid dispersion design and dissolution behavior.
• Change excipient selection away from lactose or calcium hydrogen phosphate (to avoid Claim 4/5).
• Change particle size distribution above thresholds (≤350 μm or ≤250 μm).
• If using HPMC, shift HPMC ratio outside Claim 8 and change dispersion composition logic that Claim 9 ties to.

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What is the patent landscape for US 6,440,458 (how it is likely positioned in the tacrolimus IP universe)?

Answer: Based on the claim language, the patent fits into a common tacrolimus formulation IP theme: amorphous solid dispersion plus polymer-based sustained release, measured against Japanese dissolution conditions, with excipient and particle size specifications.

Likely competitive overlap categories (without mapping to specific other patents)

US 6,440,458’s claim framing typically intersects with neighboring classes of patents used in practice:

1. Amorphous tacrolimus / solid dispersion patents (focused on solid-state form, stabilization, and dissolution)
2. Polymer matrix sustained-release patents (focused on polymer selection, coating matrices, and release kinetics)
3. Polymer blend and ratio patents (insoluble polymer plus HPMC-type soluble polymer systems)
4. Particle-size and excipient specification patents (spray-dried dispersion attributes, lactose role as excipient/lubricant)
5. Dissolution-method-specific patents (claiming JP dissolution metrics like T63.2% at pH 4.5)

Business takeaway: For freedom-to-operate, the practical question is whether a candidate tacrolimus sustained-release product uses (a) amorphous tacrolimus solid dispersion in a water-insoluble polymer and (b) hits the JP dissolution metric. If the product deviates on solid-state form, host polymer class, excipient selection, or particle size, the infringement analysis changes materially.

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What patent-claim elements are most likely to drive validity or non-infringement arguments?

Answer: In litigation, these claim components are usually the highest-friction features:

1. Amorphous state requirement
   • Proof requires analytical characterization tied to “amorphous state in water-insoluble polymer.”
2. Solid dispersion definition
   • Dispute can focus on whether the formulation qualifies as a solid dispersion and how it is prepared.
3. Dissolution performance defined by T63.2% under a specific JP method
   • Non-infringement defenses can focus on testing method reproduction.
4. Particle size cutoffs (≤350 μm, ≤250 μm)
   • Particle-size distribution and measurement method become central.
5. Excipient role (lactose/calcium hydrogen phosphate as excipient/lubricant)
   • If these excipients are absent or used differently, dependent claims narrow quickly.
6. Polymer identities and ratios (Claim 3, Claim 8)
   • Formulation ratios and polymer selection affect both performance and whether dependent claims read on the product.

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Are method-of-use claims present in US 6,440,458?

Answer: The provided claims are product claims limited to sustained-release formulation composition and dissolution characteristics. No method-of-use, dosing regimen, or therapeutic use limitations appear in the claim text provided.

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What generic entry risks exist for tacrolimus sustained-release products relative to this patent?

Answer: The risk concentrates on products that are engineered to match the claimed formulation archetype:

• amorphous tacrolimus solid dispersion,
• water-insoluble polymer matrix,
• JP dissolution metric alignment at pH 4.5 using hydroxypropyl cellulose medium,
• with particle size and excipient choices resembling the dependent claim profiles.

A generic or follow-on product that changes the solid-state form (e.g., crystalline predominance), changes polymer system, or moves T63.2% outside the claimed bounds under the specified test conditions is less likely to read directly on Claim 1. Dependent claims add further narrowing opportunities by particle size and excipient selection.

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How does the claim language translate into an actionable claim “checklist” for FTO or infringement testing?

Answer: The checklist below maps claim limitations to testable formulation parameters.

Claim 1 checklist (direct alignment test)

• Tacrolimus or tacrolimus hydrate present
• Sustained-release formulation
• Solid dispersion composition
• Tacrolimus in an amorphous state
• Amorphous tacrolimus is present in a water-insoluble polymer
• Dissolution test:
  • JP 13 Dissolution Test No. 2, puddle method, 50 rpm
  • medium: aqueous 0.005% hydroxypropyl cellulose, pH 4.5
  • T63.2% is 0.7 to 15 hours

Dependent claim checklist (only if targeting tighter read-across)

• Claim 2: tacrolimus : water-insoluble polymer weight ratio 1 : 0.1–5
• Claim 3: water-insoluble polymer is ethylcellulose or methacrylate copolymer
• Claim 4: lactose or calcium hydrogen phosphate present as excipient/lubricant; particle size ≤350 μm
• Claim 5: ethylcellulose host; lactose present; particle size ≤250 μm
• Claim 6–8: HPMC present; tacrolimus : HPMC weight ratio 1 : 0.2–0.4
• Claim 9: amorphous tacrolimus in mixture of ethylcellulose + HPMC; lactose present; particle size ≤250 μm
• Claim 10–11: tighten T63.2% ranges
• Claim 12: dosage form listed (powder, granule, tablet, capsule, etc.)

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Key Takeaways

• US 6,440,458 is anchored on amorphous-state tacrolimus solid dispersions in water-insoluble polymers plus JP-specific dissolution kinetics via T63.2%.
• Claim 1 is broad on dissolution (0.7–15 hours) and on water-insoluble polymer identity, but narrow on amorphous state and solid dispersion plus the specific JP dissolution test conditions.
• Dependent claims add material narrowing via polymer identity (ethylcellulose/methacrylate copolymers), excipient selection (lactose or calcium hydrogen phosphate), and particle size cutoffs (≤350 μm and ≤250 μm), plus optional HPMC blending and specific weight ratios.
• The most litigation-relevant fault lines are typically solid-state characterization, dissolution testing under the claimed method, and particle size/excipient adherence.

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FAQs

1. What test drives infringement for this patent’s dissolution limitation?
The infringement-relevant metric is T63.2% measured under JP 13 Dissolution Test No. 2 (puddle method, 50 rpm) using 0.005% hydroxypropyl cellulose at pH 4.5.

2. Does the patent cover tacrolimus hydrates?
Yes. Claim 1 expressly covers “tacrolimus or its hydrate.”

3. Are ethylcellulose-only systems covered?
Yes. Claim 3 covers ethylcellulose, and Claim 5 ties amorphous tacrolimus to ethylcellulose plus lactose and tighter particle-size limits.

4. Can a formulation avoid infringement by changing excipients?
Changing away from lactose and/or calcium hydrogen phosphate is a pathway to avoid dependent-claim scope (Claims 4–5 and related dependents), assuming other limitations are also not met.

5. Is HPMC required?
No. HPMC appears only in dependent claims (Claims 6–9). Claim 1 does not require HPMC.

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References

1. U.S. Patent 6,440,458.

Drugs Protected by US Patent 6,440,458

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: 6,440,458

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

PCT Information
PCT Filed	March 25, 1999	PCT Application Number:	PCT/JP99/01499
PCT Publication Date:	October 07, 1999	PCT Publication Number:	WO99/49863

International Family Members for US Patent 6,440,458

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	023299
Austria	269075
Austria	464900