US Patent 8,815,258: Claim Scope, Exclusivity, and Glycopyrrolate/Formoterol Patent Landscape
US Patent No. 8,815,258 protects a pulmonary-disease treatment method using a pressurized metered-dose inhaler containing a co-suspension of glycopyrrolate and formoterol particles with respirable phospholipid suspending particles. The broadest claim is not limited to a named commercial product, but it requires a specific formulation architecture, active-ingredient combination, particle association, and administration method.
The patent is most relevant to inhaled long-acting muscarinic antagonist/long-acting beta2-agonist, or LAMA/LABA, products such as glycopyrrolate/formoterol inhalers. Its strongest commercial relevance is to products using Pearl Therapeutics’ or AstraZeneca’s co-suspension technology, including Bevespi Aerosphere and potentially related triple-therapy products depending on formulation and claim coverage.
What does US Patent 8,815,258 claim?
Claim 1 requires all of the following:
| Claim element |
Required limitation |
| Dosage form |
Metered-dose inhaler |
| Formulation |
Pharmaceutically acceptable co-suspension |
| Propellant |
Propellant free of co-solvents and solubilizing agents |
| First active |
Respirable glycopyrrolate species, including salts, esters or isomers |
| Second active |
Respirable formoterol species, including salts, esters or isomers |
| Suspending material |
Respirable dry particulate phospholipid |
| Solubility |
Suspending particles substantially insoluble in the propellant |
| Ratio |
Suspending particles to total active particles above 1:1 and up to 200:1 |
| Administration |
Aerosol administration through actuation of the inhaler |
| Therapeutic result |
Delivery of therapeutically effective glycopyrrolate and formoterol amounts |
The claim is a method claim, not a pure composition claim. Infringement therefore generally requires use of a qualifying inhaler to treat a patient. Manufacturing or selling the inhaler may support inducement or contributory-infringement theories, but those theories depend on the product’s instructions, formulation, and intended use.
How broad is claim 1?
Claim 1 is technologically broad but structurally constrained.
It covers more than one specific glycopyrrolate salt or formoterol salt. The claim expressly reaches pharmaceutically acceptable salts, esters and isomers. Dependent claims narrow the scope to crystalline glycopyrrolate bromide and crystalline formoterol fumarate.
The central limitation is the co-suspension. A conventional suspension in which the active ingredients are suspended directly in propellant may fall outside the claim if it lacks the required dry particulate phospholipid suspending particles. Conversely, a product using phospholipid particles as a stabilizing or carrier phase may present a closer infringement risk even if the commercial formulation uses different active-particle sizes or a different device.
The ratio limitation is unusually important. Claim 1 covers a suspending-particle-to-active-particle mass ratio above 1:1 and up to 200:1. Claims 5 and 6 provide more specific ratio ranges, including:
- Above approximately 1.5:1 and up to 5:1
- Up to 10:1, 15:1, 20:1, 30:1 and 50:1
- Up to 100:1, 150:1 and 200:1
- Between approximately 10:1 and 200:1
- Between approximately 15:1 and 60:1
- Between approximately 15:1 and 170:1
- Between approximately 60:1 and 200:1
A competing formulation with a ratio of 1:1 or less would not meet the express ratio requirement. A formulation above 200:1 would also fall outside claim 1 as written, although it could still implicate other patents or doctrine-of-equivalents arguments.
What formulations are protected by US 8,815,258?
The patent protects a platform formulation rather than only a single drug product.
Glycopyrrolate and formoterol combinations
The most commercially relevant embodiment uses:
- Glycopyrrolate bromide, chemically identified in the claims as 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide
- Formoterol fumarate
- A hydrofluoroalkane propellant
- Dry phospholipid particles
- A metered-dose inhaler
Claims 41 through 43 specifically recite crystalline glycopyrrolate and formoterol fumarate particles. Claims 54 and 55 narrow the salts to glycopyrrolate bromide and formoterol fumarate.
Triple therapy
Claims 3 and 4 extend the formulation to a third active species consisting of a corticosteroid. The listed corticosteroids include:
- Beclomethasone
- Budesonide
- Ciclesonide
- Flunisolide
- Fluticasone
- Methylprednisolone
- Mometasone
- Prednisone
- Triamcinolone
Claim 4 specifically identifies budesonide. This creates potential relevance to inhaled corticosteroid/LAMA/LABA products, including budesonide/glycopyrrolate/formoterol combinations, if the commercial formulation satisfies the remaining co-suspension limitations.
Phospholipid suspending particles
Claim 9 identifies a particularly important embodiment using:
- 1,2-distearoyl-sn-glycero-3-phosphocholine, or DSPC
- Calcium chloride
Claim 8 covers perforated microstructures. These limitations point to engineered porous or perforated phospholipid particles rather than ordinary micronized excipient material.
What are the most commercially important dependent claims?
Claims 41 through 57 provide the closest connection to a commercial glycopyrrolate/formoterol product.
| Claims |
Commercial significance |
| 41 |
Crystalline glycopyrrolate bromide embodiment |
| 42 |
Crystalline formoterol fumarate embodiment |
| 43 |
Combination of the two crystalline active ingredients |
| 44 |
At least 50% by volume of active particles at optical diameter of 5 micrometers or less |
| 45 |
Suspending-particle concentration of approximately 1-15 mg/mL |
| 46 |
Suspending-particle MMAD ranges |
| 47 |
Volume median optical diameter ranges |
| 48 |
No visible separation under centrifugation-induced buoyancy forces |
| 49-52 |
Twice-daily dosing and maximum delivered amounts |
| 53-57 |
Salt, ester, isomer and crystalline-particle definitions |
Claims 49 through 52 establish dose ceilings rather than a single required dose. They cover administration up to twice daily with no more than:
- 150 micrograms glycopyrrolate and 12 micrograms formoterol
- 100 micrograms glycopyrrolate and 12 micrograms formoterol
- 80 micrograms glycopyrrolate and 12 micrograms formoterol
- 50 micrograms glycopyrrolate and 12 micrograms formoterol
A product using higher doses could avoid those dependent claims but would remain exposed to claim 1 if all broad formulation and administration limitations were satisfied.
Does the patent cover clinical efficacy results?
Yes. Claims 11 through 40 add pharmacodynamic and clinical-response limitations, principally involving forced expiratory volume in one second, or FEV1, and inspiratory capacity.
The claims cover:
- At least 150 mL, 200 mL, 250 mL, 300 mL or 350 mL FEV1 improvement
- Achievement within 30 minutes, one hour or 1.5 hours
- Persistence for up to 4, 6, 8, 10 or 12 hours
- A 10% or greater FEV1 increase in at least 50%, 60%, 70% or 80% of patients
- FEV1 area under the curve from zero to 12 hours
- At least 70 mL, 80 mL or 90 mL improvement over a single-active-agent composition
- Inspiratory-capacity improvements of at least 100 mL, 200 mL, 300 mL or 350 mL
These limitations can narrow infringement disputes but create validity and proof issues. A patentee would need to establish that the accused administration produces the claimed clinical result, or that the result is inherent in the accused method. Claims requiring statistical patient-population outcomes may be more difficult to enforce against a generic or follow-on product unless the product label or clinical data directly supports the claimed result.
Which products are most likely to be relevant?
Bevespi Aerosphere
Bevespi Aerosphere contains glycopyrrolate and formoterol fumarate and is approved for maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease. The FDA-approved product uses a pressurized metered-dose inhaler and HFA propellant, making it technically aligned with several limitations in US 8,815,258.[2]
The commercial product is associated with Pearl Therapeutics, later acquired by AstraZeneca. The product’s formulation and device patent estate includes separate patents directed to compositions, inhaler systems, particle engineering, and combination therapy. US 8,815,258 should therefore be analyzed as one member of a broader patent portfolio, not as the sole exclusivity right for Bevespi.
Breztri Aerosphere
Breztri Aerosphere contains budesonide, glycopyrrolate and formoterol fumarate. The product is relevant to claims 3 and 4 because those claims add a corticosteroid, including budesonide, to the two-active co-suspension.[3]
A commercial triple-therapy formulation may implicate US 8,815,258 only if it also satisfies the phospholipid-particle, propellant, ratio, particle-association and administration limitations. Separate patents may provide stronger protection for the specific triple combination, dose strengths, formulation, inhaler and manufacturing process.
Other LAMA/LABA products
The patent is less directly relevant to products using:
- Dry-powder inhalers rather than metered-dose inhalers
- Nebulized solutions
- Solubilized active ingredients
- Formulations without particulate phospholipid suspending agents
- Devices using a different propellant architecture
- Glycopyrrolate/formoterol products that do not meet the stated particle-ratio limitations
The active-ingredient combination alone is not enough for infringement.
What is the Orange Book status of US 8,815,258?
Orange Book status is product-specific. A patent can be technically relevant to a drug without appearing as a listed patent for that drug, and a listed patent may cover a method of use, formulation or device rather than the active ingredient itself.[4]
For Bevespi Aerosphere and Breztri Aerosphere, the relevant Orange Book analysis must distinguish:
- Patents listed for the product’s approved formulation
- Patents listed for the inhaler device
- Method-of-use patents
- Patents covering the active ingredient or salt
- Patent-term extensions or pediatric exclusivity
- Delisted, expired or superseded patents
US 8,815,258 should not be treated as an Orange Book barrier solely because its claims recite glycopyrrolate and formoterol. The decisive questions are whether it was listed for the relevant product, whether the listed claims correspond to the FDA-approved use, and whether the patent remains unexpired.
When does US 8,815,258 lose exclusivity?
The patent issued on August 26, 2014. Its enforceable term is generally governed by 35 U.S.C. §§ 154 and 156, calculated from the earliest effective nonprovisional priority date, subject to patent-term adjustment, terminal disclaimers and any patent-term extension.[1]
The claims supplied do not identify:
- The earliest priority application
- Patent-term adjustment
- Terminal disclaimer status
- Patent-term extension
- Any disclaimer or reexamination certificate
Accordingly, the issue date alone does not establish the legally operative expiration date. A 20-year term calculation based only on the grant date would be incorrect. The controlling date must be taken from the USPTO patent-term record and the continuity data for US 8,815,258.
The practical exclusivity analysis should use three separate dates:
| Date |
Relevance |
| Patent expiration |
End of enforceable patent rights, subject to statutory adjustments |
| FDA regulatory exclusivity expiration |
End of NCE, clinical-investigation or pediatric exclusivity |
| Orange Book-listed patent date |
Date relevant to ANDA certification and potential litigation |
These dates are not interchangeable.
What Paragraph IV risks exist for generic glycopyrrolate/formoterol inhalers?
A generic applicant filing an ANDA for a product referencing Bevespi would likely need to address listed patents through Paragraph I, II, III or IV certifications under the Hatch-Waxman framework.[5]
A Paragraph IV challenge could target several limitations:
Formulation design-around
The applicant could attempt to avoid the claim by using:
- No phospholipid suspending particles
- A different suspending excipient
- A co-solvent or solubilizing agent, if clinically acceptable
- A suspending-particle ratio outside the claimed range
- A soluble or partially soluble carrier system
- A different inhaler architecture
- A dry-powder or nebulized product
Particle and crystallinity challenge
Claims 41 through 47 may be challenged by changing:
- Crystalline versus amorphous active material
- Optical diameter
- Aerodynamic diameter
- Particle concentration
- Phospholipid morphology
- Calcium chloride content
A design-around must account for claim construction and equivalence. Small process changes may not avoid a broad independent claim if the resulting product still satisfies its express limitations.
Clinical-result limitations
Claims 11 through 40 may present a lower-probability but fact-intensive enforcement theory. Generic labels often seek the same therapeutic indication and dosing regimen as the reference product. If the generic product necessarily produces the claimed FEV1 response, the patentee may argue inherent infringement. The generic applicant would likely respond that the claims require proof of a particular measured clinical outcome and that the label does not affirmatively instruct users to achieve that result.
How strong is the patent estate?
US 8,815,258 has moderate-to-strong technical relevance where the accused product uses the same co-suspension architecture, but its enforceability depends heavily on claim construction and prosecution history.
Strengths
- Claim 1 covers both glycopyrrolate and formoterol in one method.
- The claim reaches multiple salts, esters and isomers.
- The phospholipid-particle concept is a meaningful formulation limitation.
- Dependent claims identify commercially plausible glycopyrrolate bromide and formoterol fumarate embodiments.
- The claims cover both dual and triple therapy.
- Ratio and particle-association limitations may map closely to proprietary formulation specifications.
Weaknesses
- Claim 1 requires numerous cumulative limitations.
- The patent does not claim every glycopyrrolate/formoterol inhaler.
- Clinical-response claims may be difficult to prove in an infringement case.
- Terms such as "substantially insoluble," "respirable," "therapeutically effective," "clinically significant," and "no visible separation" may generate claim-construction disputes.
- Some dependent claims contain apparent drafting defects, including an incomplete numerical range in claim 46 and grammatical errors in several particle-size limitations.
- Patent validity may be tested against earlier co-suspension, phospholipid-particle, HFA and inhaler references.
What manufacturing and intellectual-property barriers does the patent create?
The manufacturing barrier is more important than the active-ingredient barrier.
A competitor may obtain glycopyrrolate bromide and formoterol fumarate as pharmaceutical ingredients. The harder technical problem is reproducing a stable, homogeneous HFA suspension with:
- Controlled particle size
- Stable association between active particles and phospholipid particles
- No visible separation
- Consistent valve delivery
- Reproducible emitted dose
- Suitable aerodynamic performance
- Acceptable shelf life
- Consistent lung deposition
The claimed DSPC/calcium chloride system and particle-ratio ranges may therefore operate as process and formulation barriers even when a competitor designs around the literal claim language. Separate patents may cover manufacturing steps, filling processes, valve systems and device components.
Which companies are challenging the patent?
The supplied claim text does not identify a Paragraph IV notice, ANDA filer, district-court case or settlement agreement involving US 8,815,258. No company should be identified as a challenger solely from the patent claims.
For commercial diligence, the relevant records are:
- FDA Paragraph IV litigation listings
- District Court filings under 21 U.S.C. § 355(j)
- Patent Trial and Appeal Board proceedings
- Orange Book product-specific listings
- ANDA approval letters and tentative approvals
- Public settlement agreements involving AstraZeneca, Pearl Therapeutics or generic inhaler manufacturers
A patent-level challenge and a product-level challenge are different. A company may challenge a related Bevespi patent without directly challenging US 8,815,258.
Key Takeaways
- US 8,815,258 is a method patent directed to a glycopyrrolate/formoterol co-suspension delivered through a metered-dose inhaler.
- The key limitations are the HFA-type propellant, dry particulate phospholipid suspending particles, active-particle ratio above 1:1 and up to 200:1, and therapeutic administration.
- The patent reaches glycopyrrolate bromide/formoterol fumarate and, through dependent claims, budesonide-containing triple therapy.
- Bevespi Aerosphere is the clearest commercial product for analysis; Breztri Aerosphere is relevant to the budesonide-dependent claims.
- The patent does not automatically cover every glycopyrrolate/formoterol inhaler.
- Claims requiring FEV1, inspiratory-capacity or population-response outcomes are narrower and more difficult to enforce than the formulation-focused claims.
- Exact patent expiration requires the USPTO continuity, patent-term-adjustment and terminal-disclaimer records.
- Orange Book listing must be verified at the product level and cannot be inferred from the patent’s active ingredients alone.
- The principal generic design-around opportunities involve the suspending material, particle ratio, propellant system, particle morphology and inhaler architecture.
- The broader commercial barrier is likely the combined formulation, device and manufacturing portfolio rather than US 8,815,258 standing alone.
FAQs
Does US 8,815,258 cover glycopyrrolate/formoterol tablets?
No. The claims require a metered-dose inhaler and respirable aerosol co-suspension. Oral tablets, capsules and non-inhaled dosage forms fall outside the claim scope.
Does the patent cover nebulized glycopyrrolate and formoterol?
Not on the supplied claims. A nebulized solution or suspension would not ordinarily satisfy the metered-dose-inhaler and aerosol-actuation limitations.
Is DSPC mandatory under claim 1?
No. Claim 1 broadly requires dry particulate phospholipid material. DSPC and calcium chloride are recited in dependent claim 9 and are not required by claim 1.
Can a product avoid claim 1 by using formoterol fumarate and a different glycopyrrolate salt?
Not necessarily. Claim 1 covers pharmaceutically acceptable salts, esters and isomers of both active agents. Changing the salt may avoid narrower dependent claims but may not avoid the independent claim.
Does the patent protect the Bevespi brand name or inhaler device by itself?
No. US 8,815,258 protects a treatment method meeting the claimed formulation and administration limitations. Trademark, device, formulation, manufacturing and other product patents must be analyzed separately.
References
- United States Patent and Trademark Office. (2014). U.S. Patent No. 8,815,258, Methods and compositions for treating pulmonary diseases.
- U.S. Food and Drug Administration. (2016). Bevespi Aerosphere prescribing information.
- U.S. Food and Drug Administration. (2020). Breztri Aerosphere prescribing information.
- U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
- Drug Price Competition and Patent Term Restoration Act of 1984, 21 U.S.C. § 355(j); 35 U.S.C. §§ 154, 156.
