United States Drug Patent 7,101,576: Claim Scope, Orange Book Status, and Megestrol Patent Landscape

U.S. Patent No. 7,101,576 protected once-daily administration of a nanoparticulate megestrol acetate oral suspension for treating anorexia, cachexia, or loss of body mass. The patent focused on the formulation and pharmacokinetic profile associated with Megace ES, rather than on megestrol acetate as an active pharmaceutical ingredient.

The principal commercial combination was:

Megestrol acetate dose: approximately 40 mg to 800 mg in approximately 5 mL
Nanoparticulate megestrol particles: effective average particle size below approximately 2,000 nm
Surface stabilizer associated with the particles
Once-daily administration
Reduced food effect, measured through Cmax, Tmax, or AUC
Treatment of wasting associated with HIV/AIDS or cancer

The patent issued September 5, 2006, and its listed term ended in approximately late 2021. It is therefore no longer an enforceable barrier to generic entry based solely on this patent. The patent remains commercially important as the core U.S. patent associated with the Megace ES nanoparticulate formulation.

What patents protect Megace ES and nanoparticulate megestrol acetate?

U.S. Patent 7,101,576 is a method-of-treatment patent covering administration of a specific megestrol acetate formulation to patients with wasting-related conditions. It does not claim every megestrol acetate formulation or every use of megestrol acetate.

Core claim architecture

Claim group	Subject matter	Main limitation
Claims 1-3	Independent method claim and disease-specific dependents	Once-daily nanoparticulate megestrol acetate suspension with no substantial fed/fasted Cmax difference
Claims 4-5	Alternative independent method claim	Fed/fasted Cmax difference below specified thresholds
Claims 6-8	Pharmacokinetic dependents	Tmax, Cmax, and AUC limitations
Claims 9-10	Disease-specific dependents	Cancer, HIV, or AIDS-associated wasting
Claims 11-15	Exposure and timing dependents	Tmax, Cmax, and plasma concentration thresholds
Claims 16-17	Surface-stabilizer dependents	Broad stabilizer classes and an extensive named list
Claims 18-20	PK dependents of claim 4	Tmax, Cmax, and AUC limitations
Claims 21-31	Disease, PK, and stabilizer dependents of claim 4	Replication of limitations applied to the second independent claim

Claims 1 and 4 are the commercial center of gravity. A product or prescribing method would need to satisfy the limitations of one of those claims and all applicable limitations incorporated from them.

What are the essential limitations of U.S. Patent 7,101,576?

A potentially infringing method must involve more than administration of megestrol acetate for weight gain. The principal limitations are cumulative.

1. A therapeutic indication involving loss of body mass

The patient must suffer from anorexia, cachexia, or loss of body mass. Claims 2, 3, 9, 10, and 21-24 narrow the indication to wasting associated with HIV, AIDS, or cancer.

The claims are directed to treatment of a patient, not merely to the sale of a bottle of suspension. That distinction is relevant to method-of-use enforcement and induced-infringement theories.

2. A liquid oral suspension

The formulation must be administered as an oral suspension in an approximately 5 mL dose. The dose range is approximately 40 mg to 800 mg of megestrol acetate.

The wording is broad enough to encompass a 625 mg/5 mL product, the strength associated with Megace ES. It also covers other concentrations if the administered amount and approximate volume fall within the claim parameters.

3. Nanoparticulate megestrol acetate

The megestrol particles must have an effective average particle size below approximately 2,000 nm. This is a central structural limitation.

The claim does not require a single narrow particle-size range. A formulation with particles averaging below 2,000 nm could fall within the claim, subject to the other limitations. The phrase "effective average particle size" creates a measurement and claim-construction issue because particle-size results can vary depending on analytical method, sample preparation, and whether the reported value is a number, volume, or intensity average.

4. A surface stabilizer

At least one surface stabilizer must be associated with the particle surface. Claims 16 and 30 cover nonionic, cationic, ionic, and zwitterionic surfactants. Claims 17 and 31 list a large number of specific materials, including:

Hydroxypropyl methylcellulose
Hydroxypropylcellulose
Polyvinylpyrrolidone
Sodium lauryl sulfate
Poloxamers and poloxamines
Polyethylene glycols
Polyvinyl alcohol
Cellulosics
Phospholipids
Lecithin
Chitosan
Quaternary ammonium compounds
Cationic polymers
Various glucosides and alkyl surfactants

The stabilizer need not be limited to one named excipient. The independent claims require at least one stabilizer, while the dependent claims provide broader categorical and specific alternatives.

5. Once-daily administration

The claimed method requires once-daily administration. A formulation administered twice daily would not literally satisfy this limitation, although infringement analysis could involve claim construction or equivalents depending on the facts.

This limitation was commercially relevant because conventional Megace products included dosing regimens that differed from the once-daily Megace ES presentation.

6. Reduced food effect

Claims 1 and 4 distinguish the formulation through fed-versus-fasted pharmacokinetics.

Claim 1 requires no substantial difference in megestrol Cmax between:

A fasted state, defined as no food for at least the prior 10 hours; and
A fed state, defined as a high-calorie meal within approximately 30 minutes of dosing.

Claim 4 uses quantitative alternatives, including a fed/fasted Cmax difference below approximately 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, or 3%.

The claims therefore combine formulation identity with human pharmacokinetic performance. A generic applicant could challenge the patent by arguing that its formulation does not meet the particle-size, stabilizer, dosing, or fed/fasted PK limitations.

How do the independent claims differ?

Issue	Claim 1	Claim 4
Formulation	Nanoparticulate megestrol acetate suspension	Same
Dose	Approximately 40-800 mg in approximately 5 mL	Same
Particle size	Below approximately 2,000 nm	Same
Administration	Once daily	Once daily
Fed/fasted requirement	No substantial difference in Cmax	Quantified Cmax difference below a listed threshold
Proof burden	Requires interpretation of "no substantial difference"	Requires selecting and proving a quantitative threshold

Claim 1 may be broader in wording because "no substantial difference" is not assigned a single numerical cutoff. Claim 4 provides numerical alternatives but may create a more direct evidentiary record. A challenger would likely contest whether the selected threshold is met in a statistically and clinically reliable manner.

What formulations are protected by U.S. Patent 7,101,576?

The patent potentially covers a liquid oral suspension containing nanoparticulate megestrol acetate with a stabilizer, administered once daily at a dose of approximately 40 mg to 800 mg in approximately 5 mL, where the resulting formulation demonstrates the claimed PK behavior.

A formulation is more likely to fall within the technical scope when it has the following profile:

Feature	Claimed profile
Active ingredient	Megestrol acetate
Dosage form	Oral suspension
Dose volume	Approximately 5 mL
Dose amount	Approximately 40-800 mg
Particle size	Effective average size below approximately 2,000 nm
Stabilization	Surface-associated stabilizer
Dosing frequency	Once daily
Clinical use	Anorexia, cachexia, or loss of body mass
PK	Limited fed/fasted change in Cmax, Tmax, or AUC

The patent does not expressly require a specific stabilizer, manufacturing process, excipient ratio, viscosity, preservative system, container, flavor system, or branded product name. Those omissions reduce the usefulness of a simple excipient-design-around strategy if a competing product retains the same nanoparticle and PK profile.

How strong is the patent estate for megestrol acetate?

The estate was strong against a product that intentionally reproduced the Megace ES design. It was materially weaker against products using a different formulation platform or a different dosing method.

Strengths

The claims combine several commercially identifiable limitations.
Megace ES was itself associated with a 625 mg/5 mL nanoparticulate suspension.
The claims cover both qualitative and quantitative fed/fasted PK outcomes.
The broad stabilizer language limits reliance on a single excipient substitution.
Claims 1 and 4 provide alternative infringement theories.

Vulnerabilities

The patent claims methods, not the active ingredient generally.
"About," "no substantial difference," "effective average particle size," and "associated with the surface" invite claim-construction disputes.
Cmax, Tmax, and AUC limitations require human pharmacokinetic evidence.
The claims depend on a particular patient use and once-daily administration.
The large stabilizer list may face written-description, enablement, or obviousness scrutiny for combinations not specifically supported by the specification.
The patent term has ended, eliminating prospective infringement risk from this patent.

The patent’s historical value was higher than its current blocking value. For present development programs, the main risk is not enforcement of U.S. Patent 7,101,576 but potential coverage by later formulation, manufacturing, regulatory, or foreign patents.

When did U.S. Patent 7,101,576 lose exclusivity?

The patent’s 20-year term ran from its effective U.S. nonprovisional filing date, subject to any patent-term adjustment and applicable regulatory extensions. Public patent and Orange Book records associate the patent with an expiration date in late 2021. The patent is expired as of 2026.

Milestone	Date or period
Patent issued	September 5, 2006
Megace ES FDA approval	2005
Listed patent term	Approximately late 2021
Current enforceability	Expired
Biosimilar exclusivity	Not applicable

Patent expiration does not erase the patent’s historical relevance to earlier ANDA certifications, litigation, or settlements. It does remove the ordinary basis for an injunction against current U.S. commercial activity.

What is the Orange Book status of Megace ES?

Megace ES was approved by FDA under NDA 021778 as megestrol acetate oral suspension at 625 mg/5 mL. U.S. Patent 7,101,576 was listed in the FDA Orange Book for the product and was the principal formulation-related patent associated with the product’s regulatory exclusivity profile (FDA, 2024).

The listing covered a patent connected to the approved drug product or method of use. It did not create a separate patent on all megestrol acetate products.

Megestrol acetate is a small-molecule drug. Biosimilar rules do not apply. Competitive products would ordinarily use the ANDA pathway if they sought approval as generic equivalents, with patent certifications under section 505(j) of the Federal Food, Drug, and Cosmetic Act.

Which companies challenged Megace ES exclusivity?

The principal competitive pathway was an ANDA challenge to the listed patent. Generic applicants could submit:

A Paragraph III certification accepting delayed approval until patent expiration;
A Paragraph IV certification asserting that the patent was invalid, unenforceable, or not infringed; or
A section viii statement carving out a patented method of use, where permitted.

A Paragraph IV filing would create a potential 45-day period for the NDA holder or patent owner to file suit and trigger a statutory stay of approval. The patent’s expiration ultimately reduced the value of continued litigation and allowed approval pathways to proceed after the statutory barriers ended.

The patent record alone does not establish the complete identity of every ANDA applicant, the terms of any private settlement, or the final disposition of each litigation matter. Those facts must be separated from the patent’s intrinsic scope.

What patent litigation affects U.S. Patent 7,101,576?

Historically, litigation risk centered on whether a proposed generic suspension reproduced the patented nanoparticulate formulation and the claimed pharmacokinetic behavior.

The most important litigation questions would have been:

Whether the ANDA product contained particles below 2,000 nm.
Whether an excipient qualified as a surface stabilizer.
Whether the proposed labeling induced once-daily treatment for wasting.
Whether the product met the fed/fasted Cmax limitations.
Whether the patent was invalid for anticipation or obviousness.
Whether the asserted claims were enabled across the breadth of the stabilizer list.

Because the patent has expired, there is no current forward-looking injunction risk under U.S. Patent 7,101,576. Any remaining disputes would concern past damages, contractual obligations, or historical settlement rights rather than future exclusion from the U.S. market.

Are there formulation or manufacturing barriers after patent expiration?

Patent expiration does not make Megace ES technically simple to reproduce. A competitor still must address:

Nanoparticle milling or precipitation technology
Particle-size distribution control
Stabilizer adsorption and physical stability
Sedimentation and redispersibility
Dose uniformity throughout the bottle
Suspension viscosity
Preservative and microbial-control systems
Scale-up and equipment qualification
Comparative dissolution and bioavailability
Fed/fasted pharmacokinetic performance
Labeling and pharmaceutical equivalence

These are regulatory and manufacturing barriers rather than continuing rights under the expired patent. A generic product could attempt to avoid the patent’s historical claim scope through a non-nanoparticulate formulation, a different concentration, a different dosing schedule, or a different release and absorption profile. Each approach would require FDA support and may create new development risks.

How does Megace ES compare with conventional megestrol acetate products?

Attribute	Conventional megestrol acetate suspension	Megace ES-type formulation
Particle technology	Conventional micronized or larger particles	Nanoparticulate particles
Food effect	More pronounced potential variability	Designed to reduce fed/fasted variability
Dose presentation	Often lower concentration or larger volume	625 mg/5 mL commercial strength
Dosing objective	May require different daily regimen	Once daily
Patent relevance	Generally outside the core combination	Directly aligned with U.S. 7,101,576
Regulatory pathway	Generic or legacy NDA pathway	ANDA or product-specific regulatory pathway

The patent’s commercial distinction was the combination of high-concentration oral suspension, nanoparticle size reduction, once-daily use, and reduced food effect.

What generic entry risks exist for megestrol acetate?

The expired patent creates no continuing U.S. exclusivity barrier by itself. Current risk assessment should focus on:

Later patents owned by the NDA holder, technology supplier, or formulation manufacturer
Regulatory exclusivity or exclusivity associated with a later approved product
Trade secrets involving nanoparticle manufacturing
Contractual supply or licensing restrictions
Product-specific FDA requirements
Foreign patents with different expiration dates
State-law and commercial issues unrelated to patent validity

In the United States, a generic applicant that does not rely on the patented formulation can generally avoid the principal technical limitations of the expired patent. A product that reproduces the Megace ES formulation may still face historical patent documentation issues, but not a current injunction based on this patent.

Key Takeaways

U.S. Patent 7,101,576 covered a method of treating wasting with once-daily nanoparticulate megestrol acetate suspension.
The core formulation required particles below approximately 2,000 nm and at least one surface stabilizer.
The claims also required a dose of approximately 40 mg to 800 mg in approximately 5 mL.
Reduced fed/fasted Cmax, Tmax, or AUC variability was a major claim limitation.
The patent was closely associated with Megace ES, an FDA-approved 625 mg/5 mL oral suspension.
It was a method-of-use and formulation-performance patent, not a basic compound patent.
The patent term ended in approximately late 2021 and no longer blocks current U.S. generic entry.
Biosimilar risk is irrelevant because megestrol acetate is a small molecule.
Current commercial risk should be assessed against later patents, manufacturing know-how, FDA requirements, and foreign rights.

FAQs

Does U.S. Patent 7,101,576 cover all megestrol acetate oral suspensions?

No. It requires a specific combination of dose, oral-suspension volume, nanoparticulate size, surface stabilizer, once-daily administration, wasting-related treatment, and pharmacokinetic performance.

Does a 625 mg/5 mL megestrol acetate product automatically infringe the patent?

No. The concentration alone is insufficient. The product and method must also satisfy the nanoparticle, stabilizer, dosing, indication, and PK limitations.

Is Megace ES protected by a biologic patent or biosimilar exclusivity?

No. Megace ES contains megestrol acetate, a small-molecule active ingredient. Generic competition uses the ANDA framework rather than the biosimilar pathway.

Can a generic avoid the historical patent by using particles larger than 2,000 nm?

Potentially, because particle size below approximately 2,000 nm is a central limitation. The product would still need to satisfy FDA requirements for quality, bioavailability, dose uniformity, and therapeutic equivalence.

Does expiration of U.S. Patent 7,101,576 eliminate all global exclusivity risk?

No. U.S. expiration eliminates the blocking effect of that U.S. patent. Foreign patents, later continuation or improvement patents, trade secrets, contractual restrictions, and regulatory exclusivities may have different terms and geographic scope.

References

U.S. Patent No. 7,101,576. (2006). Nanoparticulate megestrol acetate formulations. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: The Orange Book. FDA.
U.S. Food and Drug Administration. (2005). Megace ES prescribing information. FDA-approved labeling for megestrol acetate oral suspension, NDA 021778.
United States Code, 35 U.S.C. §§ 154, 156. Patent term and patent-term extension provisions.
United States Code, 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	539737	⤷ Start Trial
Australia	2003230885	⤷ Start Trial
Australia	2003231071	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 7,101,576

Summary for Patent: 7,101,576