Details for Patent: 9,040,088

Summary for Patent: 9,040,088

Title:	Nanoparticulate megestrol formulations
Abstract:	The present invention is directed to nanoparticulate compositions comprising megestrol. The megestrol particles of the composition have an effective average particle size of less than about 2000 nm.
Inventor(s):	Douglas Hovey, John Pruitt, Tuula Ryde
Assignee:	Alkermes Pharma Ireland Ltd
Application Number:	US14/536,517
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,040,088
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

Executive summary US Drug Patent 9,040,088 claims a once-daily oral megestrol acetate (MA) suspension for increasing body mass in anorexia, cachexia, or loss of body mass, where the MA is formulated as nanoparticulate particles with tightly defined particle-size distributions (by % fractions) and at least one surface stabilizer on the particle surface, and where food effect is minimized after a single dose by defining a fed vs fasted Cmax equivalence (fasted = no food for ≥10 hours; fed = high-calorie meal within ~30 minutes). Independent claim 1 is anchored to 40–800 mg MA per ~5 mL, about 80% of particles between 250 nm and 50 nm, and no substantial Cmax difference fed vs fasted. Dependent claims narrow (i) the particle-size distribution, (ii) target etiologies (HIV/AIDS; cancer), and (iii) pharmacokinetic performance ranges (Tmax/Cmax/AUC and quantitative thresholds). The claim set is largely formulation-and-performance defined, making infringement analysis depend on (a) measured particle size distribution and stabilizer association, and (b) measured fed/fasted Cmax relationship using the defined dosing conditions.

Important note on scope inference from provided text This analysis is limited to the claim language you supplied for US 9,040,088. Patent-landscape and claim-scope conclusions below are drawn directly from those claim terms: nanoparticle fractions, stabilizer classes/examples, dosing volume/concentration, and fed/fasted bioequivalence to Cmax.

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US Patent 9,040,088 scope and claim construction: what does “no substantial difference in Cmax fed vs fasted” mean

Short answer: The independent method claims require that, after a single administration, Cmax of megestrol is not substantially different between a defined fasted regimen and a defined fed regimen.

How the claim defines fed vs fasted (hard gating)

• Fasted state: subject has no food for at least the previous 10 hours
• Fed state: subject has a high-calorie meal within ~30 minutes of dosing

This ties infringement to a specific study design or to clinical conditions that reproduce those definitions. If an accused product is tested in a different fasted window or different fed timing, the metric may not map cleanly to “substantial difference” as claimed.

What “no substantial difference” is trying to capture

The independent claim 1 uses qualitative language (“no substantial difference”), while dependent claim 5 provides an explicit quantitative framing of Tmax difference with enumerated bands (“less than about X%”). Dependent claims do not give the same explicit percent bands for Cmax difference, but claim 1 still requires Cmax equivalence in the fed vs fasted comparison.

Practical claim construction signals from the dependent set

• The patent’s strategy is to claim reduced food effect via nanoparticulate MA plus stabilizer.
• The dependent claims show the same approach is used for other PK variables:
  • Tmax difference is numerically bounded (claim 5)
  • AUC difference is numerically bounded (claim 7)
  • Cmax magnitude is numerically bounded (claims 9–12 and claim 6 via relative Cmax vs a standard MA composition)

Infringement test implication for Cmax equivalence

To assess infringement risk, the key is not only whether an accused product is nanoparticulate and stabilized, but whether it achieves the claimed fed vs fasted Cmax relationship under the defined conditions after single administration.

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What particle size ranges and % distributions are protected in US 9,040,088

Short answer: Claim 1 requires a specific distribution: ~80% between 250 nm and 50 nm. Claim 16/23 require different split distributions (different ways of tying “% of particles” to the end points). These distributions are core to infringement.

Claim 1 particle distribution (independent)

• MA particles where about 80% of particles are between about 250 nm and about 50 nm
• At least one surface stabilizer is associated with particle surface

Interpreting “between 250 nm and 50 nm” implies a single interval (50–250 nm). The claim does not define whether particles are counted by number, volume, or mass; infringement assessment will depend on the patent’s implied metrology, but your text does not supply that. Still, the endpoints and % fraction are explicit.

Claim 16 particle distribution (independent alternative)

• About 90% of particles are ≤250 nm
• About 10% are ≤50 nm
• At least one surface stabilizer is associated with the surface

This is not the same as “80% between 250 and 50.” It allows a different population shape: a majority under 250 nm with a minority at or below 50 nm.

Claim 23 particle distribution (independent alternative with a different definition)

• Particle size constraints are expressed in an unusual way:
  • “about 90%… have a size ≤250 nm”
  • and “about 90%… have a size ≥50 nm”
• Plus once daily and fed/fasted Cmax equivalence.

This wording can be read as internally constraining the distribution’s lower bound while also constraining the upper bound, but it is presented as two overlapping “about 90%” statements. It increases reliance on how “about” and the specific measurement method define particle distribution.

Dependent tightening on distribution

• Claim 2 narrows claim 1 distribution to:
  • ~80% between 230 nm and 70 nm
• Claim 17 tightens claim 16 distribution to:
  • ~90% ≤230 nm
  • and ~10% ≤70 nm
• Claim 24 tightens claim 23 similarly:
  • ~90% ≤230 nm
  • and ~90% ≥70 nm

Why these fractions matter competitively

A generic or alternative formulation can avoid literal claim 1 by shifting particle-size distribution fractions so that it does not meet the “about 80% between 50–250 nm” requirement. Conversely, it can still infringe if it is within “about” tolerances and still meets the fed/fasted Cmax condition.

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What surface stabilizers are covered by the patent: claim lists and scope

Short answer: The claims require a surface stabilizer associated with the nanoparticle surface, and they explicitly list stabilizers spanning cellulose derivatives, PVP, anionic surfactants, and enzyme/protein and block-like/ethylene oxide polymers.

Stabilizer classes (general)

• Nonionic surfactants
• Cationic surfactants
• Ionic surfactants
• Zwitterionic surfactants

This is broad enough to cover many pharmaceutical excipients if they are used as stabilizers and are “associated with the surface” of the MA particles.

Example stabilizers explicitly listed (claim 13/14/20/21/28/29 sets)

• hydroxypropyl methylcellulose
• hydroxypropylcellulose
• polyvinylpyrrolidone
• sodium lauryl sulfate
• dioctylsulfosuccinate
• polyoxyethylene alkyl ethers / polyoxyethylene sorbitan fatty acid esters (note spacing issues in the text)
• 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde
• lysozyme
• random copolymers of vinyl pyrrolidone and vinyl acetate

Narrowing dependent claim set (two-stabilizer emphasis)

• Claim 15 / 22 / 29: stabilizer selected from:
  • hydroxypropyl methylcellulose
  • dioctylsulfosuccinate
  • combination thereof

This indicates the patent’s claim set is structured to capture both broad formulation choices and specific “preferred” embodiments.

Key scope risk for competitors

If a competitor uses a stabilizer that is not listed but is argued to fall within the stabilizer classes, infringement depends on whether the formulation meets both:

1. “surface stabilizer associated with particle surface,” and
2. the enumerated nanoparticle size distribution and fed/fasted Cmax equivalence.

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What dose and dosage form constraints define the “megestrol acetate oral suspension”

Short answer: The formulation is constrained by MA dose range and dosing volume: 40–800 mg in about 5 mL per dose delivered once daily.

Core formulation constraint (claim 1)

• MA dose: about 40 mg to about 800 mg
• in about a 5 mL dose
• once daily

This effectively limits claim scope to a specific oral suspension format and daily exposure regime. Products that are tablets, capsules, or different suspension volumes might avoid literal coverage even if nanoparticulate.

Independent claim variants maintain the same dose/volume constraint

Claims 16 and 23 retain:

• 40–800 mg MA
• in about 5 mL
• once daily while changing particle distribution language.

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What clinical indications and patient subgroups are expressly claimed

Short answer: The method is framed for anorexia, cachexia, or loss of body mass, with dependent claims specifying HIV/AIDS and cancer.

Baseline population (independent)

• human patient suffering from:
  • anorexia
  • cachexia
  • loss of body mass

Dependent indications (claims 3–4; 18–19; 25–26)

• associated with HIV or AIDS
• associated with cancer

For product design and enforcement, these dependent claim legs matter because the generic’s label and prescribing use matter in method-of-use infringement: a generic may be used broadly off-label, but litigation in the US often focuses on the intended/indicated use and label language.

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How the patent claims food-effect performance: Tmax, AUC, and Cmax thresholds

Short answer: The claims lock down multiple PK outcomes to reduce the chance that a nanoparticle MA formulation still behaves differently under fed vs fasted.

Tmax difference (claim 5)

Claim 5 quantifies the fed vs fasted mean Tmax difference and selects it from:

• less than about 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, and 3%

This provides a mechanism to connect food-effect reduction to measurable time shift.

AUC difference (claim 7)

Claim 7 defines fed vs fasted absorption (AUC) difference selectable from:

• less than about 35%, 30%, 25%, 20%, 15%, 10%, 5%, 3%

Cmax equivalence in independent claim (claims 1/16/23)

The independent claims require:

• after a single administration:
• no substantial difference in Cmax between fed and fasted

Cmax magnitude vs non-nanoparticulate reference (claim 6)

Claim 6 requires a relative Cmax threshold compared to a “standard commercial, non-nanoparticulate composition of megestrol” at the same dosage:

• Cmax of nanoparticulate formulation is selected from:

  • 5%, >10%, >15%, ... up to >150% of the mean Cmax of standard

This is a major enforcement lever: it ties infringement not only to absolute PK outcomes but also to a comparative baseline.

Absolute Cmax and timing thresholds (claims 9–12)

• Claim 9: Cmax at least ~700 ng/mL
• Claim 10: Cmax at least ~700 ng/mL and attained in <5 hours
• Claim 11: Cmax at least ~400 ng/mL and attained in <5 hours
• Claim 12: mean Cmax ~300 to ~2000 ng/mL after a single dose in fasted state

These provide numerical windows that can be tested in a head-to-head bioequivalence style study.

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Which claim set is most likely to be asserted: claims 1 vs 16 vs 23

Short answer: The infringement “entry points” are three independent method claim structures that differ mainly in particle distribution language while sharing the same dosing, suspension format, surface stabilizer association, and fed/fasted Cmax condition.

Claim 1 “80% in 50–250 nm interval”

Best fit if the nanoparticle size distribution is centered in the 50–250 nm band and the bulk fraction is ~80% in that interval.

Claim 16 “90% ≤250 nm with 10% ≤50 nm”

Best fit if the product has a bimodal or skewed distribution with a small fraction at or below 50 nm and a majority below 250 nm.

Claim 23 “90% ≤250 nm and 90% ≥50 nm (as written)”

Best fit if the product’s distribution is constrained on both ends with the specific “about 90%” overlaps matching the claim text as construed and measured.

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US patent landscape around US 9,040,088: how it typically clusters in enforcement

Short answer: Based on claim content, the estate is expected to sit at the intersection of:

• nanoparticle drug formulation patents (size distribution and stabilizer)
• food-effect reduction
• oral MA suspension process/formulation IP
• method-of-use claims for cachexia/anorexia indications

However: with only the claims provided (no publication number, no family members, no assignee, no priority dates, no listed references), a complete US landscape mapping (continuations, continuations-in-part, related patents, Orange Book entries, or litigation docket linkages) cannot be produced from the supplied information.

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Generic entry risks: what design-arounds would most likely avoid literal infringement

Short answer: Literal avoidance most plausibly comes from breaking one of the three core pillars:

1. particle-size distribution fractions and endpoints,
2. absence/different type of “surface stabilizer associated with surface,” and/or
3. achieving “no substantial Cmax difference” under the defined fed vs fasted regimens.

1) Shift particle distribution fractions

Examples of potential avoidance strategies using the claim’s own structure:

• adjust the fraction of particles in the claimed size interval so it is no longer “about 80% between 250 and 50 nm,” or so that it no longer matches the dependent tighter bands (230–70 nm) where asserted
• alter the fraction of particles below the ≤50 nm or ≤70 nm thresholds required by claims 16/17/24

2) Remove or change the stabilizer association mechanism

• The claims require at least one surface stabilizer associated with the particle surface.
• If a competitor uses a different stabilization method that is not “surface stabilizer” as construed (e.g., bulk matrix immobilization rather than surface association), it could move out of literal scope.
• Claims include many listed stabilizers, but the classes are broad; the safe design around would need both a different physical association and failure to meet particle sizing/fed effect requirements.

3) Maintain food-effect differences in Cmax

Even with nanoparticle MA and stabilizer, the independent claims require no substantial Cmax difference fed vs fasted after a single dose.

• If an accused product produces a measurable Cmax shift under the claim’s fed vs fasted definitions, it may avoid independent claim 1/16/23 literal coverage.

4) Change dosage format or dosing volume

The claim constrains “about 5 mL dose” and “once daily.”

• A different dosage form or different suspension volume could avoid literal coverage even if nanoparticle MA is used.

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Key takeaways

• US 9,040,088 is a method-of-use claim set that is formulation-and-performance defined: nanoparticulate megestrol acetate oral suspension with defined dose/volume, surface stabilizer on particle surfaces, and minimized fed vs fasted Cmax differences after a single administration.
• Core infringement triggers are:
  • particle size distribution fractions (claim 1: ~80% between ~50–250 nm; claim 16: ~90% ≤250 nm with ~10% ≤50 nm; claim 23 wording as provided),
  • surface stabilizer association (broad classes plus explicit examples), and
  • food-effect on Cmax under ≥10-hour fast and high-calorie meal within ~30 minutes.
• Dependent claims provide additional “guardrails” tied to patient etiology (HIV/AIDS; cancer) and PK metrics (Tmax, AUC, absolute Cmax, and Cmax relative to standard non-nanoparticulate MA).

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FAQs

1. What would most likely determine literal infringement of US 9,040,088 for a nanoparticulate megestrol acetate suspension?
   The product’s measured particle-size distribution fractions, presence of a surface stabilizer associated with particle surface, and achievement of the claimed fed vs fasted “no substantial Cmax difference” after a single dose under the stated fed/fasted definitions.

2. Do the dependent claims on HIV/AIDS or cancer expand scope beyond the baseline anorexia-cachexia-loss-of-body-mass method?
   They add specific patient-etiology limitations that narrow applicability of those dependent claims to HIV/AIDS- or cancer-associated conditions.

3. How do the claims reduce design-around by numerical PK thresholds?
   They include quantitative criteria for Tmax difference, AUC difference, and absolute/relative Cmax thresholds, enabling enforcement based on measurable bioavailability and food-effect outcomes.

4. Can a competitor avoid infringement by using a different surface stabilizer not listed in the examples?
   Literal avoidance depends on whether the stabilizer is still a surface stabilizer associated with particle surface and whether other core limitations (particle distribution and fed/fasted Cmax equivalence) are also met; claim scope includes stabilizer classes beyond the explicit examples.

5. Is the 5 mL dosing volume a strict requirement for infringement?
   It is part of the claim requirement (“about 5 mL dose”), so a materially different suspension volume or dosage form would likely affect literal alignment with the claim limitations.

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References (APA)

1. United States Patent 9,040,088. (Claims text provided in prompt).

Drugs Protected by US Patent 9,040,088

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 9,040,088

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	539737
Australia	2003230885
Australia	2003231071
Australia	2006262144
Brazil	PI0612665