Details for Patent: 6,555,581

Summary for Patent: 6,555,581

Title:	Levothyroxine compositions and methods
Abstract:	The present invention generally relates to stable pharmaceutical compositions, and methods of making and administering such compositions. In one aspect, the invention features stabilized pharmaceutical compositions that include pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs), preferably in an immediate release solid dosage form. Also provided are methods for making and using such immediate release and stabilized compositions.
Inventor(s):	G. Andrew Franz, Elaine A. Strauss, Philip A. DiMenna, Rocco L. Gemma
Assignee:	King Pharmaceuticals Research and Development Inc
Application Number:	US10/077,677
Patent Claim Types: see list of patent claims	Composition; Formulation; Dosage form;

United States Patent 6,555,581 (Levothyroxine) Scope, Claim Coverage, and Competitive Patent Landscape

Executive summary: U.S. Patent 6,555,581 claims a stable, solid immediate-release oral levothyroxine (T4) formulation for thyroid disorders built around a specific excipient system: β-form microcrystalline cellulose (flat needle-shape, defined bulk density and low conductivity), controlled disintegrant load (including croscarmellose salt), and performance targets tied to rapid dissolution, tight potency-loss stability, and “essentially sugar-free” composition constraints. Downstream claim coverage is broad on: levothyroxine salt type (unspecified within the claim), excipient selection/amount ranges, and tablet physical variants (non-granular; hardness/surface area; beveled/scored/raised-violin tablet geometry). It is narrower on: the β-MCC physical/physicochemical profile plus quantified PK/dissolution/stability windows (claims 2-10 and 25) that can be used as hard design-around tripwires.

What this patent is protecting (at a glance)

• Product type: solid, immediate-release, oral levothyroxine-containing composition/tablet
• Core excipient: β-form microcrystalline cellulose with defined morphology and properties (flat needle-shapes; bulk density 0.10–0.23 g/cm³; conductivity <200 μS/cm)
• Disintegrant: 0.5–30 wt%; at least one embodiment locks to croscarmellose salt
• Performance constraints:
  • Dissolution: ≥90 wt% levothyroxine dissolves in <5 min (or <2.5 min in claim 2)
  • Stability: potency loss ≤0.3% per month for ≥18 months (and ≤0.2% per month in claim 25)
  • Sugar-free: essentially sugar-free
• Optional downstream measurable PK windows: T4 Cmax/Cmax windows, T3 Cmax, Tmax windows, AUC windows (claims 3-10)

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What does U.S. Patent 6,555,581 claim about levothyroxine immediate-release compositions?

Direct scope answer: The patent covers a specific formulation architecture for oral levothyroxine salts where the composition meets three coupled criteria: (i) a defined amount of levothyroxine salt, (ii) β-form MCC with specified physicochemical attributes used at ≥50 wt%, and (iii) sufficient disintegrant at 0.5–30 wt%, while achieving rapid dissolution, limited potency loss, and essentially sugar-free status.

Claim 1 is the independent anchor (composition-level)

Claim 1 requires:

1. Levothyroxine salt content: 0.00005 wt% to 5 wt%
2. β-form microcrystalline cellulose particles: ≥50 wt% with:
   • generally flat needle-shapes
   • bulk density 0.10–0.23 g/cm³
   • conductivity <200 μS/cm
3. Disintegrating agent: 0.5–30 wt%
4. Must satisfy all performance conditions:
   • (1) ≥90 wt% levothyroxine salt dissolves in <5 minutes in aqueous solution
   • (2) potency loss ≤0.3% per month for ≥18 months
   • (3) essentially sugar-free

Claim 25 is a second independent composition variant (stricter stability)

Claim 25 repeats the same architecture but tightens stability:

• potency loss on average ≤0.2% per month for ≥18 months
• maintains dissolution ≥90 wt% in <5 minutes and essentially sugar-free

Practical consequence: A candidate manufacturer that meets excipient profile and dissolution but has higher average potency loss may still avoid infringement of claim 1 but risk infringement of claim 25 if the stability is within that tighter band (and vice versa).

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What excipient characteristics of β-form microcrystalline cellulose define infringement risk in 6,555,581?

Direct scope answer: The patent’s infringement hinge is the use of β-form microcrystalline cellulose with a specific morphology and measured properties. Even if MCC is “microcrystalline cellulose,” a generic MCC grade that does not meet the β form designation, or does not hit bulk density and conductivity thresholds, can fall outside the claim.

Key β-MCC limitations (hard design-around targets)

• β-form MCC (crucial polymorph/form requirement)
• particle shape: generally flat needle-shapes
• bulk density: 0.10–0.23 g/cm³ (and claim 12 narrows further: 0.17–0.23 g/cm³)
• conductivity: <200 μS/cm

Claim 11 and 13 add processing constraints that may reduce avoidance opportunities

• Claim 11: composition is non-granular
• Claim 13: formulated as a tablet

Even if the excipient profile matches, switching to a granulated process could avoid claim 11 (though claim 1 and 25 do not require non-granularity).

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How fast must levothyroxine dissolve under 6,555,581 and what dissolution windows create liability?

Direct scope answer: Claim 1 requires rapid dissolution and claims 2 narrows that further.

• Claim 1: ≥90 wt% dissolves in <5 minutes
• Claim 2: same, but <2.5 minutes

Design-around logic: A formulation that uses different excipient system but still contains β-MCC that meets the excipient constraints could still infringe if dissolution is within the windows. Avoidance typically requires either:

• failing the β-MCC property/morphology requirement, or
• missing the dissolution performance requirement, or
• missing sugar-free / stability requirements (see below).

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What stability and sugar-free requirements protect the commercial value of 6,555,581?

Direct scope answer: The patent protects not only the recipe but measured chemical performance: potency loss and “essentially sugar-free.”

Stability bands

• Claim 1: potency loss ≤0.3% per month for ≥18 months
• Claim 25: potency loss on average ≤0.2% per month for ≥18 months

“Essentially sugar-free”

• Claim 1 and claim 25 both require the composition to be essentially sugar-free.

Design-around logic: If a formulation adds non-sugar components that nonetheless qualify as “sugars” under the patent’s interpretive frame (or relies on excipients that contribute to sugars), it can fall outside this limitation. Conversely, typical excipient selections that are non-sugar may still infringe if other features are met.

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What tablet form-factor limitations are claimed in 6,555,581 (hardness, geometry, scoring, beveling)?

Direct scope answer: The patent contains multiple dependent claims that narrow to tablet embodiments with mechanical/geometry constraints. These claims are likely to be asserted when an accused product is a tablet that matches these physical specs.

Dependent tablet claims (coverage expansion)

• Claim 13: formulated as a tablet
• Claim 14: tablet total hardness 5–15 KP
• Claim 15: tablet surface area 0.9–15 in²
• Claim 16: tablet is beveled
• Claim 17: tablet is scored
• Claim 18: tablet has a raised violin configuration

Claim 23 gives a tablet composition with quantified amounts

Claim 23 specifies:

• Levothyroxine sodium: 0.01 mg to 0.8 mg
• β-MCC: 100–110 mg meeting β-MCC properties
• Croscarmellose sodium: 25–50 mg
• Magnesium stearate: 0.5–5 mg
• plus the same dissolution (<5 min), stability (≤0.3%/month for ≥18 months), and essentially sugar-free requirements

Practical consequence: Claim 23 narrows to a tablet with defined excipient weights and disintegrant selection, which can be useful for pinpointing specific product strengths if an accused product aligns with these dose ranges.

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How do the PK parameter claims (Cmax, Tmax, AUC) expand 6,555,581’s enforceable scope?

Direct scope answer: Claims 3–10 add additional performance metrics. These are not merely “preferences”: they create an extra infringement path if the accused product’s clinical/lab PK readouts fall inside the listed windows.

T4 and T3 PK windows in claims 3–10

• Claim 3 (T4 Cmax): 10–20 μg/dL
• Claim 4 (T4 Cmax): 12–16 μg/dL
• Claim 5 (T3 Cmax): 0.1–10 ng/mL
• Claim 6 (T3 Cmax): 0.5–2 ng/mL
• Claim 7 (T4 Tmax): 1–3 hours
• Claim 8 (T3 Tmax): 12–16 hours
• Claim 9 (T4 AUC(0-t)): 500–550 μg-hour/dL
• Claim 10 (T3 AUC(0-t)): 20–60 ng-hour/mL

Enforcement posture: These PK-dependent claims typically require evidence of measured PK similarity, often through clinical bridging studies or comparative analytical/clinical testing.

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What formulation impurity limits are included, and how do they constrain a design-around?

Direct scope answer: The patent includes impurity thresholds that can disqualify formulations with higher total impurity levels.

• Claim 19: less than 10% total impurities
• Claim 20: less than 5% total impurities

Design-around logic: A formulation could remain within excipient and performance windows but still avoid if it exceeds these impurity thresholds. In practice, manufacturers target low impurities, so this is not a typical design-around lever unless driven by product-specific constraints.

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Which disintegrant and excipient add-ons are explicitly claimed (croscarmellose; coloring agents; magnesium stearate)?

Direct scope answer: The patent explicitly locks at least one disintegrant embodiment to croscarmellose salt and includes embodiments with coloring agents.

Disintegrant specificity

• Claim 21: disintegrant is croscarmellose salt
• Claim 23: croscarmellose sodium 25–50 mg

Colorants

• Claim 22: includes at least one pharmaceutically acceptable coloring agent
• Claim 24: tablet of claim 23 further includes coloring agent

Lubricant

• Claim 23: magnesium stearate 0.5–5 mg

Design-around logic: If an accused product uses a non-croscarmellose disintegrant, it may avoid claim 21 and claim 23’s specific embodiment while still being at risk under claim 1’s broader “disintegrating agent” range (0.5–30 wt%). The broad claim 1 only requires a disintegrant, not croscarmellose, so disintegrant substitution alone is not a guaranteed carve-out.

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How many distinct infringement “paths” exist in 6,555,581 based on the claim set?

Direct scope answer: The claim set supports multiple infringement routes: excipient-and-performance (claim 1/25), tablet-specific physical specs (claims 13–18), tablet weight composition and disintegrant/lubricant embodiment (claim 23), and PK-based windows (claims 3–10).

Infringement path map

1. Composition architecture route (most central):
   • claim 1 / claim 25: β-MCC definition + dissolution + potency stability + essentially sugar-free
2. Time-to-dissolve tightening route:
   • claim 2: dissolution <2.5 min
3. PK window route:
   • claims 3–10: Cmax/Tmax/AUC fall into specified bands
4. Tablet physical attribute route:
   • claims 13–18: hardness, surface area, beveled/scored/raised violin
5. Specific weight embodiment route:
   • claim 23: levothyroxine sodium mg dose with specific β-MCC mg and croscarmellose mg and magnesium stearate mg, plus performance constraints
6. Impurity route:
   • claims 19–20: total impurity percentage bands
7. Excipients add-on route:
   • claim 22/24 (coloring agents)
   • claim 21 (croscarmellose salt)

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What is the most realistic design-around strategy under 6,555,581 given the claim language?

Direct scope answer: The most reliable design-arounds are those that attack the β-MCC form/physicochemical profile or fail the hard performance constraints (dissolution and/or potency stability), because those are embedded throughout the independent claims.

High-value design-around levers

• Use a non-β-form MCC (breaks the “β-form” limitation)
• Fail β-MCC conductivity or bulk density window (≥50 wt% MCC only matters if it meets the defined profile)
• Fail dissolution time performance (≥90 wt% dissolves in <5 min or <2.5 min)
• Fail potency loss limits (≤0.3%/month vs ≤0.2%/month)
• Avoid “essentially sugar-free” compliance if the formulation otherwise matches (less common in practice)
• Fail PK windows if pursuing a clinical/bridging carve-out (requires operational control and can be hard)

Lower-value levers (often not decisive)

• Changing tablet geometry (bevel/score/raised violin): claim 1 still covers composition even if geometry differs.
• Avoiding croscarmellose: helps only against the dependent claims that lock to croscarmellose; claim 1 only needs a disintegrant.
• Adjusting hardness/surface area: depends on whether the accused product matches those dependent claims.

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How does claim 23 (tablet composition with specific mg amounts) affect generic and competitor risk?

Direct scope answer: Claim 23 increases evidentiary leverage against specific strengths/products because it includes exact component mass ranges and a defined disintegrant/lubricant system, in addition to dissolution and stability.

Claim 23 is a “fingerprint” embodiment

• Levothyroxine sodium 0.01–0.8 mg
• β-MCC 100–110 mg
• croscarmellose sodium 25–50 mg
• magnesium stearate 0.5–5 mg
• performance: ≥90 wt% dissolves in <5 min; potency loss ≤0.3%/month for ≥18 months; sugar-free

Litigation relevance: If an accused generic or reformulation has a tablet composition that aligns with these mg ranges and performance, claim 23 becomes a strong assertion candidate even if geometry-dependent claims are not met.

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What formulation and method decisions matter for infringement exposure?

Direct scope answer: Under 6,555,581, infringement turns on what the product contains and what it does (dissolution, potency stability, and sugar-free status). Manufacturing process matters only where expressly claimed.

• Non-granular (claim 11): process carve-out if the accused product is granulated, but claim 1/25 do not require non-granular.
• Tablet geometry claims (claims 16–18): could be avoided by changing tablet tooling and design, but composition claims remain.

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Key takeaways

• U.S. Patent 6,555,581 protects a β-form microcrystalline cellulose-based immediate-release levothyroxine formulation with strict measured performance targets.
• The β-MCC definition (β form + flat needle-shape + bulk density + conductivity) is the central technical constraint and the best design-around starting point.
• Independent claims are performance-coupled: dissolution (<5 min for ≥90 wt%), stability (≤0.3%/month or ≤0.2%/month), and essentially sugar-free.
• Dependent claims extend coverage into: tighter dissolution (<2.5 min), PK window ranges (T4/T3 Cmax/Tmax/AUC), tablet physical specs, and a specific mg composition embodiment (claim 23) with croscarmellose sodium and magnesium stearate.
• Geometry, colorants, and impurities can matter for dependent-claim alignment but are usually secondary to β-MCC and performance constraints.

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FAQs

1) Which claim elements are most difficult for a generic manufacturer to change without failing dissolution or stability targets?
The β-form MCC requirements and the dissolution and potency-loss performance bands are the main constraints.

2) Does switching from croscarmellose sodium to another disintegrant fully avoid infringement?
Not against claim 1/25 because they only require “disintegrating agent” within a range; it may avoid only croscarmellose-locked dependent claims.

3) Can tablet geometry differences avoid liability under this patent?
Not for the composition claims (claim 1/25). Geometry changes mainly affect dependent claims 16–18 and 14–15.

4) How do the PK claims change the evidentiary burden in litigation?
They require demonstrating that the accused product’s T4/T3 Cmax, Tmax, and AUC fall within the stated windows.

5) What is the role of the impurity percentage claims in infringement strategy?
They can support arguments against dependent claims if the accused formulation exceeds total impurity thresholds; routine quality targets often keep impurities low, making this less of a practical carve-out.

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References (APA)

No external sources were provided or cited in the prompt; therefore no reference list can be compiled without introducing uncited material.

Drugs Protected by US Patent 6,555,581

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

International Family Members for US Patent 6,555,581

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2002240394
Australia	2002258397
Australia	2002332507
Australia	2002341555