Details for Patent: 8,431,155

Which drugs does patent 8,431,155 protect, and when does it expire?

Patent 8,431,155 protects CYCLOSET and is included in one NDA.

This patent has twenty-four patent family members in twelve countries.

Summary for Patent: 8,431,155

Title:	Bromocriptine formulations
Abstract:	The present application describes pharmaceutical formulations of bromocriptine mesylate and methods of manufacturing and using such formulations. The formulations are useful for improving glycemic control in the treatment of type 2 diabetes.
Inventor(s):	Anthony H. Cincotta, Craig Michael Bowe, Paul Clark Stearns, Laura Jean Weston
Assignee:	Veroscience LLC
Application Number:	US13/460,452
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Device; Dosage form;

United States Patent 8,431,155 (Bromocriptine Mesylate Micronized Tablets): Scope, Claim Boundaries, and US Patent Estate Impact for Diabetes Glycemic Control

Executive summary: US 8,431,155 is tightly focused on a solid oral tablet of micronized bromocriptine mesylate with very specific particle-size and dissolution performance limits in 0.1 N HCl (USP <711>/USP Apparatus 2, 50 rpm, 500 mL, 37°C), plus linked pharmacokinetic (Tmax) target ranges. The independent claim set captures (i) the product (tablet) (ii) manufacturing (micronize + blend + compress with uniform distribution and the same performance targets) and (iii) use for type 2 diabetes glycemic control via oral administration of the tablet. The claim strategy uses numeric constraints to narrow design-around paths, but also creates clear non-infringement hooks: shifting dissolution release kinetics, exceeding the particle-size thresholds, or changing the release testing setup can move an accused product outside claim boundaries.

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What is the scope of US Patent 8,431,155 claims for micronized bromocriptine mesylate tablets?

Short answer: The patent claims a tablet in which micronized bromocriptine mesylate meets a defined particle-size distribution (Dv90 < ~10 µm; limited fraction < ~1 µm), and the tablet’s dissolution profile in USP Apparatus 2 at 37°C in 0.1 N HCl must fall within specific time-based release bounds. The claims also recite oral administration to improve glycemic control in type 2 diabetes, tying the tablet to a method-of-use.

Claim architecture and dependency map

From the claim text provided, the estate is structured as follows:

• Product claim (independent): Claim 1 (and a later independent-like set via Claim 22)
• Product narrowers: Claims 2, 3, 4, 5, 6, 23, 24, 25, 26, 27, 28
• Manufacturing methods:
  • Independent: Claim 7
  • Narrowers/alternatives: Claims 8–13
  • Independent-like alternate: Claims 14–18 (includes “determining” equivalent particle size distribution and optional “processing prior to said determining”)
• Methods of treatment (independent-like):
  • Claims 19–21 (treatment using claim 1, 7-prepared tablet, or 14-prepared tablet)
  • Claim 29 (treatment using claim 22-prepared tablet)

Core technical limitations that define infringement risk

These are the “hard gates” embedded across claims:

1. Dose floor

   • Tablet contains micronized bromocriptine mesylate in an amount providing ≥ ~0.8 mg bromocriptine per tablet (Claims 1, 7, 14, 22).
   • Narrower at a specific dose: ~0.8 mg/tablet (Claims 2, 8, 15, 28).

2. Particle-size distribution (micronization boundary)

   • Dv90 < ~10 µm (Claims 1, 7, 14, 22).
   • Not more than ~20% of bromocriptine mesylate has particle size < ~1 µm (Claims 1, 7, 14, 22).
   • Additional refinements:
     • Dv90 < ~5 µm (Claim 3).
     • Dv99 < ~15 µm (Claims 4, 23).
     • Claim 22 adds span constraint: volume-based span ~2 or lower (Claim 22).

3. Dissolution profile in acid under USP Apparatus 2 conditions

   • Testing setup is repeatedly fixed:
     • USP Apparatus Type 2 (Paddle)
     • 50 rpm
     • 500 mL of 0.1 N HCl
     • 37°C
   • Dissolution bounds in Claim 1 / Claim 7 / Claim 11 / Claim 25:
     • At ~7 min: ≤ ~50% released
     • At ~10 min: ≤ ~75% released
     • At ~30 min: ≥ ~90% released
   • Alternative dissolution in Claim 5 / Claim 10 / Claim 14 set / Claim 22 set:
     • At ~20 min: ≥ ~90% released
     • (Claim 22 set keeps ≥ ~90% at ~30 min and adds tighter particle span limits.)

4. Pharmacokinetic profile link (Tmax)

   • For “six tablets to adult subjects”:
     • Fasting: Tmax ~30–60 min
     • High-fat fed: Tmax ~90–120 min
   • Narrower PK parameters:
     • Claim 27 adds Cmax about 100 pg/mL.

What claim language actually forces testing/engineering alignment

The patent is not claiming “micronized bromocriptine” in the abstract. It claims tablets where microstructure (particle-size distribution) and performance (dissolution kinetics and PK timing) are simultaneously met. If a generic or licensee reproduces particle size but misses the dissolution release curve, it can avoid claim 1/22 product scope. Conversely, if it hits dissolution but violates the particle-size distributions (Dv90, fraction <1 µm, span, Dv99), it can also avoid.

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Which independent claims matter most for freedom-to-operate around US 8,431,155?

Short answer: The key infringement buckets are:

• Claim 1 (tablet with specific particle size + dissolution timing bounds)
• Claim 7 (manufacturing method producing that tablet)
• Claim 14 (manufacturing method framed via “determining equivalent particle size distribution” + blending + compressing + dissolution target)
• Claim 22 (tablet variant with span constraint and dissolution/Pk linkage)

Practical significance for FTO

• A product-maker can be directly accused under a product claim (Claims 1 or 22) if their tablets inherently meet the numeric dissolution and particle-size constraints.
• Even if a manufacturer argues formulation differences, a plaintiff often attacks in-process controls and incoming particle testing because Claims 7/14 recite manufacturing steps and particle-size distribution equivalence.
• A generic can also be targeted via use claims (Claims 19–21 and 29) if its label or clinical use aligns with “improving glycemic control in type 2 diabetes” using the claimed tablet.

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How do the particle-size distribution limits in US 8,431,155 constrain design-around strategies?

Short answer: The patent constrains both the coarse upper tail (Dv90) and the fine tail (fraction under 1 µm), plus in Claim 22 the distribution width (span) and in some dependent claims the Dv99.

Quantitative boundaries and likely measurement sensitivity

Key thresholds embedded:

• Dv90 < 10 µm (Claims 1, 7, 14, 22)
• ≤ 20% below 1 µm (Claims 1, 7, 14, 22)
• Dv90 < 5 µm (Claim 3)
• Dv99 < 15 µm (Claims 4, 23)
• Span ≤ 2 (Claim 22)
• “Volume-based particle size distribution” appears explicitly in Claim 22 (span).

Measurement risk: In litigation, particle-size infringement often turns on:

• the measurement method (laser diffraction vs sieving, dry vs wet obscuration)
• whether “Dv90” is measured as a volume-based distribution consistent with the claim’s stated basis (Claim 22 is explicit; other claims do not state “volume-based” in the text you provided).

Even without asserting measurement details, the numeric constraints make the claim estate highly testable and enforceable through expert analysis of incoming raw material and finished blends.

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What dissolution profile does US 8,431,155 require, and how do the claim variants differ?

Short answer: The core dissolution tests are fixed to an acid paddle method, and the patent has two dissolution “profiles” appearing in the claim set.

Dissolution profile A: slower early release, complete by 30 minutes

Applicable in Claims 1, 7, 11, 22? (Claim 22 specifies 90% by 30 min but also changes particle span scope), 25.

• ≤ 50% released at ~7 minutes
• ≤ 75% released at ~10 minutes
• ≥ 90% released at ~30 minutes

This profile supports a sustained/controlled early release in acid while achieving near-complete release by 30 minutes.

Dissolution profile B: rapid achievement of 90% by 20 minutes

Applicable in Claims 5, 10 (and aligned with some manufacturing language in Claim 7 set alternatives).

• ≥ 90% released at ~20 minutes

This variant can be interpreted as requiring a faster release profile than dissolution A.

Claim 22 dissolution: retains ≥90% by 30 minutes

Claim 22 retains:

• ≥ 90% released at ~30 minutes (and combines with span constraint).

So Claim 22 tightens the particle-size distribution using span and keeps a late-time dissolution performance criterion.

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Does US 8,431,155 cover pharmacokinetic (Tmax/Cmax) performance, or only dissolution?

Short answer: It covers both. The product claims link particle size and dissolution to Tmax ranges (Claims 6, 12, 26) and in one dependent claim to Cmax (Claim 27).

PK constraints embedded in tablet scope

• Fasting Tmax: 30–60 min
• High-fat fed Tmax: 90–120 min
• PK tested after administration of six tablets in adults.

Claim 27 adds:

• Cmax ~100 pg/mL

Infringement implications for generics

Because PK is not always tested for ANDA bioequivalence submissions at a granularity matching these ranges, litigants may:

• treat PK as a performance indicator tied to the formulation’s dissolution/particle properties, or
• argue inherent meeting if formulation and dissolution match.

From a design-around standpoint, changing excipients or the tableting process can move dissolution timing and PK timing, creating an additional non-infringement path beyond particle size alone.

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What manufacturing steps and process controls does US 8,431,155 claim for bromocriptine mesylate tablets?

Short answer: The manufacturing claims require processing to a defined micronized particle size, blending to achieve substantially even distribution, and compressing to form tablets that meet the dissolution criteria.

Claim 7 manufacturing method (micronize + blend + compress)

• Process bromocriptine mesylate to reduce average particle size to:
  • Dv90 < 10 µm
  • ≤ 20% < 1 µm
• Blend with excipients to achieve substantially evenly distributed bromocriptine.
• Compress to form tablet.
• Tablet meets:
  • ≥ 0.8 mg bromocriptine per tablet
  • dissolution profile with ≥ 90% released at 30 minutes (and Claim 11 adds the early time limits).

Claim 14 manufacturing method (equivalent distribution by “determining”)

Claim 14 is process-flexible in a way that can matter in evidence framing:

• “determining that bromocriptine mesylate has a particle size distribution equivalent to a volume-based particle size distribution with Dv90 < 10 µm and ≤ 20% < 1 µm”
• Blend and compress similarly to produce dissolution-conforming tablets.

Claim 16 adds:

• the method can include processing prior to determining.

Claim 18 adds:

• transfer from blending apparatus via transfer unit to a tableting apparatus for compressing tablets with substantially uniform bromocriptine content.

Design-around implications

Manufacturers seeking to avoid the method claims can attempt to show:

• they do not micronize to the claimed particle size distributions,
• they do not achieve “substantially evenly distributed” bromocriptine in the blend,
• their tablet dissolution kinetics fall outside the specified bounds.

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What US 8,431,155 method-of-treatment claims cover for type 2 diabetes?

Short answer: The method claims are directed to oral administration of the claimed tablet for improving glycemic control in type 2 diabetes. These are dependent on the product/manufacturing scope of Claims 1/7/14/22.

Treatment claim set

• Claim 19: administer a tablet according to Claim 1
• Claim 20: prepare using Claim 7 and provide for oral administration
• Claim 21: prepare using Claim 14 and provide for oral administration
• Claim 29: administer a tablet according to Claim 22

Litigation relevance

If an accused generic’s label and indications cover type 2 diabetes glycemic control, use claims can become a secondary enforcement lever. Even where direct infringement hinges on label use rather than formulation, plaintiffs often pair use claims with strong product evidence (particle and dissolution).

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How strong is the patent estate for this technology space based on claim tightness?

Short answer: The estate is strong at the claim level because it uses multiple orthogonal numeric constraints (particle size tail metrics + span + dissolution timepoints + PK timing). These are difficult to “accidentally” meet while changing the product meaningfully.

Strength drivers

1. Multiple numeric gates
   • Dv90, fraction <1 µm, span, Dv99, dissolution timepoints, Tmax ranges.
2. Defined test method
   • USP Apparatus 2, 50 rpm, 0.1 N HCl, 500 mL, 37°C.
3. Manufacturing nexus
   • process steps tied to particle distribution and blend uniformity.

Strength vulnerabilities

The same tightness can create exploitable differences:

• a challenger can aim to miss the early-time dissolution constraints (7/10-minute caps) while still reaching ≥90% by 30 minutes,
• or miss the particle-size thresholds while maintaining dissolution via formulation changes,
• or target non-infringing dissolution pathways implied by the alternative dissolution bound (≥90% by 20 minutes) depending on which claim is asserted.

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What generic entry risks exist for bromocriptine mesylate tablets under US 8,431,155?

Short answer: Risk concentrates on any product that:

• uses micronized bromocriptine meeting the Dv90 and <1 µm fraction limits, and
• achieves the specified USP 2 acid dissolution kinetics, and
• is positioned for type 2 diabetes glycemic control.

High-risk design space

• Tablets targeting early dissolution suppression (≤50% at 7 min; ≤75% at 10 min) and near-complete release by 30 min.
• Formulations using micronized bromocriptine with narrow span (Claim 22) and controlled fine fraction (≤20% <1 µm).

Lower-risk entry points

• Products with particle distributions exceeding:
  • Dv90 <10 µm (too broad coarse tail), or
  • fine fraction >20% below 1 µm,
  • span >2 (Claim 22 constraint).
• Dissolution profiles that violate the early-time caps (Claims 1/11/25) or otherwise fail to hit the required ≥90% at the specified timepoints.

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What US patent estate and Orange Book exposure should be expected for this specific claim set?

Short answer: A complete landscape requires the actual Orange Book listing and citation set for the assignee(s) and the marketed bromocriptine mesylate product(s). The claim text alone does not identify the listed NDA, listed patent numbers, or expiration dates.

Because no NDA/Orange Book data is provided in the prompt and this analysis must be complete and accurate, no specific Orange Book status, expiration dates, or Paragraph IV exposure can be stated for US 8,431,155 from the provided information.

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Key Takeaways

• US 8,431,155 claims a micronized bromocriptine mesylate tablet with tight numeric constraints on particle size distribution (Dv90 <10 µm; ≤20% <1 µm; plus Claim 22 span ≤2 and dependent Dv99 <15 µm).
• The tablet must meet acid dissolution performance under fixed USP Apparatus 2 conditions with defined timepoint release limits (including the specific early caps at ~7 and ~10 minutes in Claim 1/11/25).
• Manufacturing claims cover processing to the claimed particle size, blending for uniform distribution, and compressing into tablets that meet the dissolution targets.
• Method-of-treatment claims cover oral administration for improving glycemic control in type 2 diabetes, tied to the claimed tablet forms.
• The claim strategy creates clear non-infringement routes via particle-size threshold failure and/or dissolution timepoint failure, with PK ranges acting as an additional performance linkage.

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FAQs

1. Can a tablet avoid infringement by matching Dv90 but exceeding the “not more than 20% <1 µm” fine fraction limit?
2. How do the 7- and 10-minute dissolution caps in Claim 1 affect generic formulation design versus just meeting the 30-minute ≥90% release target?
3. If a generic hits “≥90% released at 20 minutes,” does that automatically avoid the Claim 1 dissolution profile?
4. How does the Claim 22 span constraint (≤ about 2) change the particle-size acceptance criteria compared with Claim 1’s Dv90 and <1 µm fraction limits?
5. If an ANDA product matches dissolution but deviates on Tmax (fasted or high-fat), does the claim set still present a direct product infringement pathway?

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References

No external sources were cited because the prompt provided only the claim text and did not include bibliographic details (publication/filing dates, assignee, NDA linkage, Orange Book listings, or prosecution history) needed for accurate patent-landscape citation.

Drugs Protected by US Patent 8,431,155

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Veroscience	CYCLOSET	bromocriptine mesylate	TABLET;ORAL	020866-001	May 5, 2009		RX	Yes	Yes			Y			IMPROVEMENT OF GLYCEMIC CONTROL IN INDIVIDUALS WITH TYPE 2 DIABETES

International Family Members for US Patent 8,431,155

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	091351
Australia	2013256558
Australia	2016202572
Australia	2018203021
Brazil	112014027087