Executive summary
US Patent 10,369,114 is built around a single platform mechanism: cargo-loaded vesicles whose surface layer is made of cholesteryl esters (cholesterol + C8–C26 fatty acids) that (i) enable vesicles to cross cell membranes intact and (ii) trigger intracellular payload release via cholesteryl ester hydrolase (CEH). The claim set expands from core product composition (intracellular delivery with at least 2× or 10× intracellular exposure thresholds) into route-specific embodiments (oral, parenteral, topical and other routes), dosing-form packaging (capsules/tablets, optional enteric coating), and manufacturing steps (non-polar solvent mixing/sonication, vesicle volume occupancy 10%–96%). The legal risk profile is driven by how broad the payload and route language is, how functionally defined the cholesteryl ester “surface layer” is (including “passive or facilitated diffusion” and CEH-triggered release), and how strongly the specification likely ties the mechanism to the “WAP-8924A / WAP-8294A” antibiotic examples and peptide/protein payload classes.
What claims does US Patent 10,369,114 cover for cholesteryl-ester vesicle drug delivery?
Core independent claim (Claim 1) coverage
Claim 1 covers a pharmaceutical composition containing a “population of cargo-loaded vesicles” where:
- Payload location: at least one pharmaceutically active agent is encapsulated in the core.
- Surface trigger chemistry: the vesicle surface layer comprises cholesteryl ester(s) derived from cholesterol and a C8–C26 fatty acid.
- Intact entry requirement: cholesteryl ester(s) “enable intact vesicles to pass through cell membranes” by passive or facilitated diffusion and “arrive in an intact form in the cytoplasm.”
- Intracellular release mechanism: payload release occurs in the cytoplasm by intracellular CEH action on the surface layer.
- Exposure improvement: intracellular concentration of the active agent is ≥ 2× versus the active agent without vesicles (a comparative performance claim).
Claim 1 is a mechanism-and-outcome patent
The claim mixes (i) structural/chemical surface specification (cholesteryl ester from specific fatty acid range), (ii) functional transport and release language (intact cytoplasmic delivery, CEH-triggered release), and (iii) a quantitative efficacy delta (≥2× intracellular concentration). This is the center of gravity for infringement analysis: a competitor can design around by (a) using a different trigger lipids chemistry, (b) altering release trigger away from CEH on the surface layer, or (c) failing the stated intracellular exposure threshold in a defined biological context.
What dependent claims expand claim 1 into route, dosage, and target-cell handling?
Oral delivery and intestinal cell handling (Claims 2, 3, 11, 29)
- Claim 2 adds oral-specific constraints: vesicles are stable to stomach acid and are not broken by cholesteryl ester transporters on the surface of duodenal enterocytes during absorption. Vesicles enter duodenal enterocytes intact, enter the chylomicron pathway, produce “transformed chylomicrons,” and the active agent is not detected by enterocytes during passage.
- Claim 3 adds packaging: capsule, optionally enterically coated, to release at one or more GI locations.
- Claim 11 is another oral-centric independent cluster: enterically coated tablet/capsule with intestinal-location release. It adds:
- Neutral-surface vesicle with core payload and surface layer of non-ionic cholesteryl esters (explicitly “non-ionic”).
- Mass ratio of active agent : cholesteryl ester 4:96 to 96:4.
- A broad performance window: vesicles deliver active within cells to ≥ 2× to as high as 1000× versus oral administration of active not in vesicles.
- Claim 29 narrows to “oral administration to the duodenum” with the chylomicron/enterocyte intact constraint and lists payload exemplars including WAP-8924A, peptide/protein agents, ceftaroline, vancomycin, bevacizumab, trastuzumab, adalimumab, and anti-PCSK-9 mAbs.
Other administration routes (Claim 8)
Claim 8 covers adaptation for topical, IV, subcutaneous, oral, inhalation, intravaginal administration. This extends potential coverage to non-oral modalities, even though the strongest specificity is in oral embodiments.
Chylomicron receptor binding and uptake (Claim 4)
- Claim 4 requires chylomicrons loaded with cargo-loaded vesicles to bind to cell surface APO receptors. After binding, the cell takes intact vesicles into cytoplasm; CEH releases payload.
Intravenous/subcutaneous release and exposure thresholds (Claims 6–7, 21, 22)
- Claim 6: for IV/SC injection, mass ratio active : cholesteryl ester 4:96 to 96:4 and payload intracellular concentration ≥ 10× without vesicles.
- Claim 7: specifies intracellular concentration between 10 and 100×.
- Claim 21 is a parenteral composition claim echoing Claim 6 performance but keeps broader language: CEH acts on surface layer post-administration to drive intracellular concentrations “substantially greater” than without vesicles.
- Claim 22 expands payload class for claim 21: hydrophilic small molecules, peptides, proteins, polypeptides, nucleotides.
Payload type breadth (Claims 9, 22, 23)
- Claim 9: hydrophilic peptide/protein/polypeptide/polynucleotide.
- Claim 22: adds hydrophilic small molecules and nucleotide classes.
What manufacturing and parameter claims are included? (Claims 12–13, 15–20, 20, 12, 13)
Vesicle sizing (Claim 13)
- Vesicle diameter: 100 nm to 10,000 nm.
Vesicle volume occupancy (Claims 12, 15, 20)
- Claim 12: unilamellar vesicles where 10% to 96% of vesicle volume is occupied by payload.
- Claim 15 and Claim 20 recite manufacturing steps and again tie payload occupancy to 10%–96%:
- Dissolve/mix cholesteryl esters in non-polar solvent.
- Evaporate non-polar solvent on inner surface of round bottom flask.
- Add aqueous mixture with active agent; continuously sonicating.
- Form homogeneous dispersion during sonication.
- Claim 20 adds a specific sequence: removing non-polar solvent under vacuum while introducing aqueous phase, then mixing while removing vesicles and maintaining 10%–96% occupancy.
How specific are the payload examples inside the claim set? (Claims 16–19, 23–30)
Broad agent lists with explicit named proteins/peptides (Claims 16, 23, 29)
- Claim 16 lists GLP-1 agents (liraglutide, dulaglutide, semaglutide, lixisenatide, albiglutide), GLP-2, insulin types, growth hormone/prolactin, oxytocin, calcitonin, etc.
- Claim 23 mirrors those categories for a composition depending from claim 11.
Antibiotics and “WAP” compounds (Claims 24–28, 25, 28–30)
- Claim 24: antibiotic is a lipopeptide antibiotic.
- Claim 25: payload is WAP-8294A.
- Claim 26–27: antibiotic is an antibiotic; further lipopeptide antibiotic restriction.
- Claim 28: payload is WAP-8924A.
- Claim 30: composition under claim 29 where payload is WAP-8924A.
Monoclonal antibodies list explosion (Claim 19)
Claim 19 lists an extensive panel of monoclonal antibodies and related names, including adalimumab, bevacizumab, trastuzumab, pembrolizumab, and many others, plus entries that look like historical development names. This increases capture for mAb therapeutics but also creates interpretive questions for claim scope: a competitor would need the cholesteryl-ester vesicle format and intracellular release mechanism, not just a listed payload.
Binary “GLP-1 + insulin + metabolism inhibitor” combination (Claim 18)
Claim 18 requires GLP-1 plus insulin and optionally an inhibitor of intracellular metabolism of one/both. This is a niche but potentially valuable combination coverage.
What design choices create infringement risk for cholesteryl-ester vesicle compositions under US 10,369,114?
1) Surface layer chemistry: cholesteryl ester of C8–C26 fatty acids
Infringement hinges on whether the competitor uses cholesteryl esters within the specified fatty acid carbon range (C8–C26). A close variant risk is high if the competitor uses similar sterol ester structures but changes one element:
- different fatty acid chain length outside C8–C26
- using sterol derivatives that are not cholesteryl esters
- using a different lipid with CEH cleavage not tied to the surface layer cholesteryl esters
2) Release mechanism: CEH action on the surface layer
The claims repeatedly require release “by the intracellular action of cholesteryl ester hydrolase on the surface layer.” That creates a potential escape route: use a vesicle where CEH is not the cleavage trigger or release is driven by a different intracellular process (pH change, enzymatic cleavage at a different site, membrane destabilization that does not require CEH cleavage of a surface cholesteryl ester).
3) Transport requirement: intact cytoplasmic arrival
Claim 1 requires intact vesicles to arrive in cytoplasm. Competitors using vesicles that rupture during uptake and deliver payload via endosomal escape may fall outside the explicit “intact vesicles” language, unless the competitor can still show “intact” arrival and release mechanism alignment.
4) Quantitative intracellular exposure thresholds
- Claim 1: at least 2×
- Claim 5: at least 10× (for ratio-adjusted embodiment)
- Claim 6: at least 10× for IV/SC
- Claim 7: 10–100× range
- Claim 11: oral delivery to ≥2× to as high as 1000×
These comparative thresholds are a frequent litigation focal point: even if chemical structure and mechanism match, an accused product may argue the intracellular exposure does not meet the required delta in the relevant assay context.
5) Oral stability and enterocyte non-disruption by cholesteryl ester transporters
Claim 2 and Claim 29 introduce a highly specific GI absorption limitation: vesicles must be stable to stomach acid and not broken by cholesteryl ester transporters on duodenal enterocytes. Any formulation that increases transporter-mediated processing could weaken infringement if “not broken” is interpreted strictly.
What patent estate questions matter around US Patent 10,369,114: priority, coverage map, and claim bottlenecks?
Where the claim set is broad
- Platform structure: cholesteryl ester surface layer with a specified fatty acid range.
- Platform function: CEH-triggered release intracellularly.
- Broad payload categories: hydrophilic peptides/proteins/polypeptides/nucleotides, plus hydrophilic small molecules (in dependent scope).
- Broad routes (Claim 8) and multiple dosage form accommodations (capsule/tablet; optional enteric coating; intestinal-release locations).
Where claims become bottlenecked
- Oral uptake via chylomicron transformation and APO receptor binding (Claims 2, 4, 29).
- CEH mechanism is repeated but not accompanied by explicit biochemical details beyond “intracellular action” on the surface layer.
- “Intact vesicles” arrival in cytoplasm could be contested with internalization assays showing vesicle rupture.
- Quantitative intracellular concentration multipliers.
How WAP-8924A and WAP-8294A increase leverage
Named antibiotic payloads in dependent claims narrow novelty tie points and can strengthen enforceability where the specification supports those examples. They also allow focused infringement theories against developers using those specific antibiotics in a cholesteryl-ester vesicle format.
What are likely non-infringement and obviousness vectors against US 10,369,114?
Potential non-infringement vectors
- Use sterol esters not within C8–C26.
- Replace CEH cleavage with alternative intracellular release triggers (e.g., enzyme cleavable linkers where the enzyme is not CEH).
- Show vesicle rupture or non-intact cytoplasmic delivery as a factual counter to claim interpretation of “intact vesicles.”
- For oral embodiments, show vesicles are broken by cholesteryl ester transporters on duodenal enterocytes or that the payload is detected during enterocyte passage.
Potential validity vectors
Without the full prosecution history, the primary predictable validity issues in this claim class are:
- Functional broadness: mechanism and performance thresholds could be attacked as indefinite or as lacking adequate support if the specification does not cover the full payload and route range.
- Obviousness over liposome/vesicle and sterol ester delivery prior art: cholesteryl ester prodrug or delivery concepts, and membrane-crossing lipid systems, can be combined with vesicle encapsulation and intracellular enzyme-triggered release theories.
- Written description/enablement: the claim set names many therapeutic proteins and a long list of mAbs while also covering general payload types. If breadth is not supported with enabling disclosure for each class at claimed exposure multiples, it can become a vulnerability.
How to map infringement risk by product feature (operational scoring template)
| Accused product feature |
Match to US 10,369,114 requirement |
Infringement impact |
| Vesicle surface contains cholesteryl ester(s) from cholesterol + C8–C26 fatty acids |
Claim 1, 11, 21 |
High if exact or close chemical scope met |
| Payload encapsulated in vesicle core |
Claim 1 |
High |
| CEH triggers release by acting on surface cholesteryl esters |
Claim 1, 21 |
High; strongest mechanism element |
| Intact vesicle reaches cytoplasm and releases there |
Claim 1 |
Medium to high; factual and assay-dependent |
| IV/SC or oral use; route adapted |
Claims 6, 8, 2/3/11/29 |
Medium to high; route-specific claim limitations matter |
| Oral: stable to stomach acid and not broken by duodenal enterocyte cholesteryl ester transporters; chylomicron transformation |
Claim 2, 4, 29 |
High only for oral versions; otherwise avoids that claim path |
| Exposure metric met (≥2× or ≥10× etc.) |
Claims 1/5/6/7/11 |
High if litigated; requires data alignment to claimed comparisons |
| Payload is one of listed classes or specific examples (WAP-8924A etc.) |
Claims 9, 16–20, 23–30 |
Medium; affects dependent claim capture and potential secondary enforcement |
What litigation strategy issues typically follow from this claim structure?
Claim construction pressure points
- “Intact vesicles” and “pass through cell membranes… arrive in cytoplasm” will trigger disputes about what internalization and rupture states count.
- “Cholesteryl ester hydrolase” linkage to “surface layer” is a claim construction and evidence issue.
- “Not detected by enterocytes” and “not broken by cholesteryl ester transporters” are oral-specific and likely depend on the assay and what constitutes detection/breaking.
Evidentiary needs
- Bench or in vitro cellular uptake assays plus intracellular concentration quantification.
- For oral embodiments, GI and enterocyte processing evidence consistent with chylomicron formation and non-detection.
Key Takeaways
- US 10,369,114 covers a cholesteryl-ester-surfaced vesicle platform designed to deliver core payload into cytoplasm intact, with release driven by CEH acting on the surface layer.
- Independent claim coverage is broad on structure and functional outcome, with quantitative intracellular exposure thresholds anchoring performance.
- Dependent claims add high-specificity oral absorption requirements (stability in stomach, avoidance of duodenal enterocyte transporter-mediated breakdown, chylomicron transformation, and APO receptor binding).
- Manufacturing claims focus on non-polar solvent processing and sonication to form vesicles, with payload occupancy in a 10%–96% range.
- Named payload dependencies, including WAP-8294A and WAP-8924A and an expansive mAb list, can increase enforcement leverage if accused products use those drugs inside the claimed vesicle system.
FAQs
1) Does US 10,369,114 require that the pharmaceutically active agent be hydrophilic?
Claims 1 and several dependents cover hydrophilic peptides/proteins/polypeptides/polynucleotides; Claim 22 explicitly includes hydrophilic small molecules. The strongest explicit hydrophilicity requirement appears in the payload-type dependent language.
2) What vesicle size range is claimed in US 10,369,114?
Vesicle diameter is claimed at 100 nm to 10,000 nm (Claim 13).
3) What oral formulation constraints are imposed by the patent?
Oral embodiments require stability to stomach acid and resistance to breakdown by cholesteryl ester transporters on duodenal enterocytes, with intact vesicle entry, chylomicron transformation, and non-detection of the active agent during enterocyte passage (Claims 2 and 29).
4) Is intracellular release tied to CEH in every major claim path?
The central mechanism is repeated across composition claims, including Claim 1 and Claim 21, where release occurs via intracellular CEH action on the surface cholesteryl esters.
5) What manufacturing method is claimed for producing the vesicles?
A solvent-dissolution and solvent-removal step followed by aqueous introduction and sonication to form a homogenous vesicle dispersion, with payload occupying 10%–96% of vesicle volume (Claims 15 and 20).
References (APA)
- United States Patent No. 10,369,114. (n.d.). Pharmaceutical composition and methods for delivering agents using cholesteryl ester-coated cargo-loaded vesicles.
