# US Patent 8,835,505: Claim Scope, Patent Landscape, Exclusivity and Generic-Entry Risk for Esmolol Premix Products
US Patent No. 8,835,505 protects a sterile, premixed esmolol hydrochloride solution in a non-PVC flexible container, with defined pH, ethanol and propylene glycol or glycerin concentrations, and terminal heat-moist sterilization. The broadest independent composition claim requires the combination of formulation chemistry, container characteristics and sterilization status. The patent also includes method-of-use and manufacturing claims.
The principal commercial risk is concentrated in claim 1. A competing product that uses the same esmolol concentration range, pH range, co-solvent system, non-PVC container and terminal sterilization process could face literal infringement exposure. Products using different solvents, pH, container materials or aseptic rather than terminal sterilization may reduce risk, although the dependent claims and potential doctrine-of-equivalents arguments remain relevant.
What does US Patent 8,835,505 protect?
The patent claims an esmolol hydrochloride injectable product with five central technical elements:
| Claim element |
Required limitation in claim 1 |
| Active ingredient |
Esmolol hydrochloride |
| Esmolol concentration |
5 to 22.5 mg/mL |
| Solution pH |
4.5 to 5.5 |
| Co-solvents |
0.1% to 3% w/v ethanol and 0.1% to 3% w/v propylene glycol or glycerin |
| Container and processing |
Sealed non-PVC flexible plastic container, heat-moist sterilized |
The claimed product is not limited to one specific commercial bag size, dose volume or administration rate. Its scope is defined primarily by formulation ranges, packaging material and sterilization treatment.
The active ingredient is identified by its chemical name and by the common name esmolol hydrochloride. Because esmolol hydrochloride is an established active pharmaceutical ingredient, the likely patent value is in the formulation and container-processing combination rather than in the molecule itself.
How should claim 1 be construed?
Claim 1 is a product claim directed to a finished sterile pharmaceutical product. Each limitation must be present in the accused product for literal infringement.
Esmolol concentration
The claim requires 5 to 22.5 mg/mL. This range covers common premixed esmolol concentrations, including products around 10 mg/mL and 20 mg/mL. A product above 22.5 mg/mL would fall outside the literal range, subject to any applicable doctrine-of-equivalents analysis.
The concentration limitation is technically significant because esmolol formulations can present stability, degradation and container-compatibility issues at commercially useful concentrations. The claim is not limited to a single concentration, so a generic manufacturer cannot avoid the claim merely by selecting a different strength within the claimed range.
pH range
The required solution pH is 4.5 to 5.5. The range is narrow enough to create a meaningful design-around option. A product maintained outside that range may avoid literal infringement, but the practical formulation consequences must be assessed because pH affects esmolol stability, impurity formation and tolerability.
Ethanol and propylene glycol or glycerin
Claim 1 requires both:
- Ethyl alcohol at 0.1% to 3% w/v; and
- Propylene glycol or glycerin at 0.1% to 3% w/v.
A formulation containing ethanol but no propylene glycol or glycerin would not meet claim 1. The same applies to a formulation containing propylene glycol or glycerin but no ethanol. The claim requires the combination.
The use of "one of propylene glycol or glycerin" creates two covered alternatives. A product using both propylene glycol and glycerin would likely still satisfy the claim if at least one is within the claimed range, although the precise construction could depend on the intrinsic record and prosecution history.
Non-PVC flexible container
The container limitation is central. Claim 1 requires a non-PVC flexible plastic container. A glass vial, rigid plastic vial or PVC bag is outside the literal scope of this limitation.
The claim does not require a particular polymer in its independent form. Claims 2 and 3 narrow the container construction to multilayer polyolefin-based films and identify polypropylene, cycloolefin, polyethylene and copolymerized ethylene-vinyl acetate as possible materials.
Heat-moist sterilization
The product must be sealed and heat-moist sterilized for a period sufficient to render it sterile. Claim 13 and its dependents confirm that the claimed manufacturing process includes autoclaving, with dependent claim 15 specifying 110°C to 130°C for 7 to 60 minutes.
The product claim therefore appears directed to a terminally sterilized finished product, not merely a formulation that could be sterilized. A product manufactured entirely by aseptic processing may present a non-infringement position against claims requiring heat-moist sterilization, although the product claim's interpretation should be tested against the prosecution history.
What do the dependent claims add?
| Claims |
Added subject matter |
Commercial significance |
| 2-4 |
Multilayer non-PVC films, tubing ports and closure systems suitable for terminal sterilization |
Targets the complete bag and administration system |
| 3 |
Polypropylene, cycloolefin, polyethylene and ethylene-vinyl acetate materials |
Narrows the polymer scope |
| 5-7 |
Acetate, tartrate, malate, fumarate, sodium acetate and sodium tartrate buffers |
Provides formulation-specific fallback positions |
| 8 |
Esmolol concentration of 10 to 30 mg/mL |
Creates a drafting and scope issue because claim 1 ends at 22.5 mg/mL |
| 9-10 |
Propylene glycol or glycerin |
Separates the two co-solvent alternatives |
| 11 |
Stability after autoclaving, related ester limits, co-solvent range and an ethylene-vinyl acetate inner layer |
Adds quality and container-performance limitations |
| 12 |
Treatment of bradycardia or hypotension in computerized cardiac tomography |
Method-of-use claim |
| 13-18 |
Preparation, sealing and autoclaving methods |
Process claims covering terminal sterilization |
Claim 8 is internally unusual. Claim 1 limits esmolol to 5 to 22.5 mg/mL, while claim 8 recites 10 to 30 mg/mL. Read as a dependent claim, the operative intersection would ordinarily be 10 to 22.5 mg/mL. The 22.5 to 30 mg/mL portion does not independently satisfy claim 1. This drafting issue could affect claim construction and validity analysis.
Claim 11 also contains apparent textual defects, including duplicated numbering and a grammatically incomplete stability limitation. Courts generally construe claims using the entire intrinsic record, but serious indefiniteness issues may arise if the scope cannot be determined with reasonable certainty under 35 U.S.C. §112(b).
What formulations are protected by US 8,835,505?
The strongest literal coverage is directed to a formulation with the following profile:
| Parameter |
Covered profile |
| Esmolol hydrochloride |
5-22.5 mg/mL |
| pH |
4.5-5.5 |
| Ethanol |
0.1%-3% w/v |
| Second co-solvent |
0.1%-3% w/v propylene glycol or glycerin |
| Buffer |
Any buffering agent maintaining the claimed pH |
| Container |
Sealed, non-PVC, flexible plastic |
| Sterilization |
Terminal heat-moist sterilization |
Claims 5 through 7 give specific buffer alternatives. Sodium acetate and sodium tartrate are expressly covered. The independent claim does not limit the buffer to those substances, provided the buffer maintains the pH within the required range.
The patent does not appear, from the supplied claims, to require a particular antioxidant, preservative, tonicity agent, dosage volume or infusion rate. Those characteristics could be commercially important but do not independently define the claimed invention.
How strong is the patent estate?
The patent has moderate formulation and packaging strength but a narrower enforcement profile than a basic active-ingredient patent.
Strengths
- It covers a commercially practical concentration range.
- It combines formulation and container limitations, making simple formulation comparison insufficient.
- It expressly covers non-PVC flexible containers used in terminal sterilization.
- It includes composition, manufacturing and treatment claims.
- The formulation limitations are objectively measurable through product testing.
- The container and sterilization requirements can be confirmed through regulatory records, batch documentation and physical inspection.
Weaknesses
- The claim requires a specific combination of ethanol and propylene glycol or glycerin.
- The pH range provides a potential formulation design-around.
- Aseptic processing may avoid the heat-moist sterilization limitation.
- The claim language contains apparent inconsistencies in claims 8 and 11.
- Claim 12 may face written-description, enablement or indefiniteness challenges because of the computerized cardiac tomography limitation.
- The patent does not, on the supplied claim text, cover every esmolol injection, every premixed bag or every non-PVC container.
The patent's enforceability would depend heavily on its prosecution history, including amendments, examiner objections, cited prior art and any disclaimer or terminal-disclaimer record. The claims alone support a scope analysis but do not establish validity or freedom to operate.
When does US 8,835,505 lose exclusivity?
A US patent normally expires 20 years after the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers and other statutory modifications. The issue date, September 16, 2014, does not determine the expiration date. See 35 U.S.C. §154.
The supplied claim text does not identify the earliest nonprovisional filing date or any patent-term adjustment. An exact expiration date therefore cannot be established from the claims alone. Any commercial exclusivity assessment should use the USPTO Patent Center term data and the official patent record rather than an issue-date calculation. [1]
FDA regulatory exclusivity is separate from patent protection. Esmolol hydrochloride is an established injectable active ingredient, and any applicable new-drug exclusivity would depend on the approved product, supplement, formulation approval and FDA exclusivity record. Patent expiration and FDA exclusivity should not be treated as interchangeable.
What is the Orange Book status of US 8,835,505?
Orange Book listing depends on whether the patent owner or NDA holder submitted the patent for an approved drug product and whether the patent claims the drug, drug product or an approved method of use under FDA listing standards. Process-only claims generally are not Orange Book-listed. [2]
The supplied claims include:
- A drug product in a particular container;
- Formulation limitations;
- Sterilization-related product characteristics;
- Manufacturing methods; and
- A method-of-use claim.
The product claims could potentially qualify for listing if they read on the approved drug product. The manufacturing claims generally would not provide the same Orange Book basis. A current listing determination must be made from the FDA Orange Book patent table for the relevant esmolol hydrochloride NDA and ANDA products.
An Orange Book listing would increase Paragraph IV litigation risk because an ANDA applicant would need to certify against the listed patent. A nonlisted patent could still support infringement litigation, but it would not necessarily create the same statutory ANDA stay or notice consequences.
Which companies are challenging the patent?
The claim text does not identify any Paragraph IV challenger, ANDA applicant, district-court action, or settlement agreement. A reliable challenger analysis requires matching:
- FDA ANDA certifications;
- Paragraph IV notices;
- District-court docket filings;
- Patent-owner enforcement actions;
- Any 30-month stay;
- Settlement or license terms; and
- Final FDA approval dates.
Those events cannot be inferred from the claims. The relevant public records are FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, USPTO Patent Center and federal court dockets. [1-3]
What generic launch risks exist?
A generic or 505(b)(2) applicant faces the highest risk when its proposed product has all of the following characteristics:
- Esmolol hydrochloride at 5 to 22.5 mg/mL;
- pH between 4.5 and 5.5;
- Ethanol and propylene glycol or glycerin within the claimed ranges;
- A sealed non-PVC flexible bag;
- Terminal autoclave or other heat-moist sterilization; and
- A polymer film or port construction covered by claims 2 through 4 or 11.
Potential design-around pathways include:
| Design-around variable |
Possible effect |
| Use a glass vial or rigid container |
Avoids the flexible non-PVC container limitation |
| Use PVC or another excluded container |
Creates regulatory and extractables considerations but may avoid the claimed container |
| Remove ethanol |
Avoids the conjunctive solvent requirement |
| Use a different co-solvent system |
May avoid claims 1, 9 and 10 |
| Adjust pH outside 4.5-5.5 |
May avoid claim 1, subject to product stability |
| Use aseptic processing |
May avoid process limitations requiring heat-moist sterilization |
| Use a concentration above 22.5 mg/mL |
May avoid the independent concentration range |
| Use a different inner contact layer |
May avoid claims 2, 3 and 11 |
These options can create new regulatory, stability or manufacturing problems. A design-around that avoids the patent may still require a new formulation development program and FDA comparability work.
What manufacturing and IP barriers matter most?
The principal technical barrier is terminal sterilization of an alcohol-containing esmolol solution in a flexible non-PVC container. The claimed invention links:
- Solvent composition;
- pH control;
- Polymer compatibility;
- Port and closure performance;
- Autoclave exposure;
- Esmolol assay retention; and
- Related ester impurity control.
Claim 11 is particularly directed to post-autoclave performance, including less than a 2% decrease in esmolol concentration and related esmolol esters below about 0.5%. Those limitations could be difficult to prove from public product information but could become important in discovery through batch records, stability data and regulatory submissions.
The manufacturing claims also create potential risk for contract manufacturers. A company may face contributory or induced-infringement theories if it supplies a formulation or container system specifically intended for a claimed terminally sterilized esmolol product.
How does this patent compare with molecule and method-of-use patents?
| Patent category |
Relevance to esmolol premix competition |
| Active-ingredient patent |
Low if the esmolol molecule is off-patent |
| Formulation patent |
High; this patent is principally in this category |
| Container patent |
High for non-PVC flexible bags and multilayer films |
| Manufacturing patent |
High where terminal sterilization is required |
| Method-of-use patent |
Narrower; depends on the claimed cardiac tomography use |
| Regulatory exclusivity |
Product-specific and separate from patent rights |
| Biosimilar protection |
Generally not applicable because esmolol is a chemically synthesized small molecule |
Biosimilar risk is therefore not the relevant competitive framework. Esmolol products compete through ANDA or, in some cases, 505(b)(2) pathways rather than the biologics price competition framework.
Key Takeaways
- US 8,835,505 is directed to a terminally sterilized esmolol hydrochloride premix in a non-PVC flexible plastic container.
- Claim 1 requires the combination of esmolol, pH 4.5-5.5, ethanol, propylene glycol or glycerin, sealed packaging and heat-moist sterilization.
- Claims 2-4 and 11 strengthen coverage around multilayer films, ports, closures, ethylene-vinyl acetate contact layers and post-autoclave stability.
- Claim 8 appears internally inconsistent because its 10-30 mg/mL range exceeds claim 1's 22.5 mg/mL upper limit.
- Claim 11 contains apparent drafting defects that could support an indefiniteness or claim-construction challenge.
- Claim 12 is narrower and may present written-description or enablement issues.
- The exact patent expiration date cannot be derived from the supplied claims and must be confirmed through the USPTO term record.
- Orange Book relevance depends on whether the product claims were submitted for listing against the applicable esmolol NDA.
- The principal generic design-around opportunities involve solvent composition, pH, container format, polymer selection and aseptic versus terminal sterilization.
- No Paragraph IV challenger, litigation matter or settlement can be identified from the claim text alone.
FAQs About US Patent 8,835,505
Does US 8,835,505 cover all esmolol hydrochloride injections?
No. The claims require specific formulation, pH, container and sterilization characteristics. Esmolol products outside those limitations may not infringe literally.
Can a generic avoid the patent by using a glass vial?
A glass vial would generally avoid the non-PVC flexible plastic container limitation in claim 1, but the complete product and manufacturing process must still be assessed against every asserted claim.
Does the patent cover an aseptically filled esmolol bag?
Not necessarily. The independent product claim requires heat-moist sterilization, and the manufacturing claims expressly require that process. The prosecution history and product evidence would control the final analysis.
Is US 8,835,505 a biosimilar patent?
No. Esmolol hydrochloride is a chemically synthesized small molecule. Generic-drug pathways, not biosimilar pathways, are the relevant competitive framework.
Can a patent expiration date be calculated from the 2014 issue date?
No. US patent term generally runs from the earliest effective nonprovisional filing date, not the issue date. Patent-term adjustment, terminal disclaimers and other statutory factors may change the result. [1]
References
- United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. https://www.uspto.gov/patents/laws/patent-term-adjustment
- U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book
- United States Code. (2024). 35 U.S.C. §§ 154, 271, 282; 21 U.S.C. § 355. https://uscode.house.gov/
