United States Patent 11,224,661: What the Claims Actually Cover and How the Landscape Closes In
US Patent 11,224,661 claims a controlled-release CNP agonist that is engineered for extended stability in an in vitro neural endopeptidase (NEP) degradation assay and for slow release of the active peptide in free form under physiological conditions without enzymes. The patent’s protected subject matter is narrow in one respect (it is centered on a specific CNP “ring moiety” defined by SEQ ID NO:96 with a disulfide-constrained amino-acid framework), but broad in another (it covers conjugation to either water-soluble or water-insoluble polymers via a physiology-cleavable linker and gives multiple ranges of functional performance).
What is claimed (core independent claim 1)?
Claim 1 structure
Claim 1 is written as a structural-functional combination:
- Controlled-release CNP agonist
- Contains a CNP moiety (-D) comprising a ring moiety with:
- An amino acid sequence SEQ ID NO:96, with a specific permissible edit:
- “methionine at position 11 of SEQ ID NO:96 can be substituted with asparagine”
- The ring moiety is “between two cysteine residues forming a disulfide bridge”
- The ring moiety is conjugated to a polymer via a linker that is:
- cleavable under physiological conditions in the absence of enzymes
- has a half-life of up to six months
- The polymer is either:
- water-soluble and branched, at least 10 kDa, or
- water-insoluble (no kDa minimum stated in claim 1 for the water-insoluble branch)
- Release mechanism:
- The system “releases -D in its free form (D-H)”
- Performance requirement:
- The controlled-release agonist has an at least 5-fold longer degradation half-life in an in vitro NEP degradation assay than the corresponding released D-H
In practical terms, claim 1 requires a peptide ring fragment (SEQ ID NO:96-based, disulfide constrained, with a specific Met-to-Asn allowance) tethered to a polymer through a non-enzymatic, physiological-cleavable linker that yields slow, sustained liberation of free D-H and improves NEP proteolytic stability by at least a factor of 5.
Functional gates that define infringement risk
Claim 1 is not satisfied by any polymer conjugate to CNP fragments. It is gated by measurable criteria:
- Linker cleavage: occurs under physiological conditions without enzymes
- Linker half-life: “up to six months”
- Release profile: controlled-release; D-H produced
- NEP stability boost: at least 5-fold longer degradation half-life vs. the corresponding released D-H
That last element (NEP assay ratio) is a key “landscape filter”: most CNP-polymer conjugates that do not demonstrate that specific NEP-stability improvement will fall outside claim 1 even if they release peptide.
How dependent claims narrow the release and polymer parameters (claims 2–13)
Release conditions and timing (claims 2, 9–11)
These claims lock in assay conditions and enforce minimum release half-lives:
- Claim 2: releases D-H in aqueous buffer pH 7.4 at 37°C
- release half-life of at least 6 hours
- Claim 9: release half-life at least 24 hours
- Claim 10: release half-life at least 48 hours
- Claim 11: release half-life at least 168 hours
The dependency structure matters: claim 2 sets a baseline, and claims 9–11 define progressively longer release.
Infringement relevance: even if a product uses the right peptide ring and linker chemistry, failing to hit one of these release-half-life thresholds under pH 7.4 / 37°C can defeat the corresponding narrower claim.
CNP-38 embodiment (claim 3)
- Claim 3 specifies the CNP agonist is CNP-38.
Given claim 1’s “ring moiety” framing, claim 3 is a concrete embodiment that ties the protected peptide region to a known CNP length/specification used in the art.
Water-soluble vs water-insoluble polymer (claims 4–5)
- Claim 4: polymer and controlled-release CNP agonist are water-insoluble
- Claim 5: polymer and controlled-release CNP agonist are water-soluble
This gives the patentee two broad pathways: either the conjugate forms an insoluble reservoir-type system, or stays soluble while still using a cleavable linker.
Formulation (claim 6)
- Claim 6: a pharmaceutical composition comprising the controlled-release agonist plus at least one excipient.
This provides coverage for formulation variants built around the claimed conjugate.
NEP degradation half-life multiples (claims 7–8)
- Claim 7: at least 15-fold longer degradation half-life than corresponding released D-H
- Claim 8: at least 25-fold longer degradation half-life than corresponding released D-H
These are performance tiers above the independent claim’s “at least 5-fold” requirement.
Infringement relevance: a competitor could potentially design a conjugate that improves NEP stability by 5x but not 15x; that would avoid claims 7–8 while still implicating claim 1.
Polymer molecular weight floors for branched soluble polymers (claims 12–13)
- Claim 12: polymer is a branched polymer MW at least 20 kDa
- Claim 13: polymer is a branched polymer MW at least 30 kDa
These claims only apply to the branched polymer configuration and materially reduce the design space for any soluble-branched systems that use lower MW polymers.
What is the real claim scope: “design-around” pressure points
1) Peptide definition is constrained but not fully rigid
Claim 1 is tied to a “ring moiety” sequence SEQ ID NO:96 (with one permitted substitution: Met11 → Asn). That is relatively strict: most alternate ring constructs or different cyclized CNP fragments will not read on “having the amino acid sequence of SEQ ID NO:96.”
However, the patent explicitly allows a single substitution, which gives some flexibility for manufacturing, analogs, or alternate peptide synthesis routes.
2) The disulfide-bridge constraint matters
The claim requires a ring between two cysteines forming a disulfide bridge. Systems using alternate cyclization chemistries or non-disulfide constraints likely fall outside claim 1.
3) The release mechanism is “non-enzymatic cleavage under physiological conditions”
This is a practical boundary against:
- purely enzyme-cleaved prodrug linkers
- systems that depend on NEP or other proteases to trigger release
- systems where release is solely diffusion-controlled without cleavage under physiological conditions
4) NEP assay ratio is a quantitative boundary
The patent’s functional requirement (5x, 15x, 25x) is a direct design constraint. A competitor can build a slower-release conjugate but still fail the NEP stability gate if the active peptide is not sufficiently shielded from NEP attack, or if cleavage exposes D-H too rapidly.
5) Polymer architecture and solubility define two lanes
Water-soluble branched polymers have explicit kDa floors in dependent claims (20 and 30 kDa). Water-insoluble configurations do not state the same explicit MW minima in claim 1.
How this claim set maps to typical CNP-polymer conjugate design space
Likely covered product archetypes
A product infringes claim 1 if it has the following combination:
- CNP agonist active region is a SEQ ID NO:96 ring moiety with a disulfide bridge
- The ring moiety is tethered to a cleavable polymer linker that works under physiological conditions without enzymes and has up to six months linker half-life
- The conjugate releases free D-H
- In NEP assay, degradation half-life of the conjugate is ≥5x that of released D-H
Where design-around could fail (scope pressure)
- “Covalent stability” alone is not enough if free D-H release occurs too fast or NEP degradation is not improved by the required factor.
- Linkers that require enzymes to cleave may avoid the “in absence of enzymes” requirement, but only if release is not achievable under physiological conditions absent enzymes.
- Polymer MW reductions may avoid claims 12–13 if only lower MW soluble branched polymers are used, but they still face claim 1 unless the release and NEP criteria break.
Claim-by-claim infringement logic (condensed)
| Claim |
What must be true (in addition to claim 1) |
Key quantitative thresholds |
| 1 |
Core conjugate + non-enzymatic physiological cleavage + NEP stability improvement ≥5x |
NEP degradation half-life ≥5-fold vs released D-H |
| 2 |
Release as D-H at pH 7.4, 37°C |
Release half-life ≥6 hours |
| 3 |
CNP agonist is CNP-38 |
None beyond embodiment |
| 4 |
Water-insoluble polymer/conjugate |
None explicit |
| 5 |
Water-soluble polymer/conjugate |
None explicit |
| 6 |
Pharmaceutical composition with excipient |
None explicit |
| 7 |
Higher NEP improvement tier |
NEP degradation half-life ≥15-fold |
| 8 |
Higher NEP improvement tier |
NEP degradation half-life ≥25-fold |
| 9 |
Longer release |
Release half-life ≥24 hours |
| 10 |
Longer release |
Release half-life ≥48 hours |
| 11 |
Longest release |
Release half-life ≥168 hours |
| 12 |
Branched polymer MW floor |
≥20 kDa |
| 13 |
Branched polymer MW floor |
≥30 kDa |
Patent landscape read-across: what this portfolio likely blocks (and where it likely leaves gaps)
Because the prompt provides only the US 11,224,661 claim text (and not the rest of the family data), the landscape analysis below is limited to what can be inferred from the claim scope itself: what competitors must avoid to stay outside these claims.
1) The patent most directly blocks “CNP ring fragment + polymer + physiological non-enzymatic cleavage + NEP protection”
Any competitor system that:
- uses the SEQ ID NO:96 ring moiety (or the Met11 to Asn variant),
- uses a disulfide ring between cysteines,
- and demonstrates the specific NEP degradation half-life boost,
is in the direct claim capture zone.
2) Performance thresholds are the second line of defense
Even if the peptide chemistry differs slightly, a competitor may still fall into claim scope if their engineered conjugate meets the same structural language and the same functional NEP ratio. The quantitative NEP thresholds make “partial compliance” a risky strategy for freedom-to-operate.
3) Polymer architecture creates corridor-like avoidance zones
- If a competitor uses water-soluble branched polymers below 20 kDa, it can avoid claims 12–13 while still potentially implicating claim 1.
- If a competitor uses water-insoluble polymer forms but their release profile is too fast (not meeting claim 2/9/10/11 thresholds), they can avoid those narrower claims while still implicating claim 1.
4) Release without enzymes is a key carve-off for some linker classes
Linkers cleaved only by enzyme activity can avoid the “in absence of enzymes” language. But if the linker exhibits significant non-enzymatic cleavage under physiological conditions, that avoidance may fail.
5) The landscape effect is strongest for NEP-targeted stabilization approaches
The claim is explicitly anchored to an in vitro NEP degradation assay. Competitors whose development is based on other protease models or in vivo-only stabilization claims will still need NEP assay data that clears the 5x/15x/25x gates to argue “no infringement,” and those data may already exist from development.
Key Takeaways
- US 11,224,661 claims a polymer-conjugated CNP ring moiety defined by SEQ ID NO:96 with a Met11→Asn allowance, constrained by a disulfide bridge, and released as free D-H.
- The patent requires a physiologically cleavable linker that works without enzymes and provides up to six months linker half-life.
- The boundary for infringement is not only structure but a quantitative functional performance in an in vitro NEP degradation assay: ≥5x (claim 1), with higher tiers of ≥15x and ≥25x (claims 7–8).
- Dependent claims set measurable release half-life floors at pH 7.4 and 37°C: ≥6 hours, ≥24 hours, ≥48 hours, and ≥168 hours (claims 2, 9–11).
- Polymer design is partitioned by water-soluble vs water-insoluble, and for water-soluble branched polymers, MW floors are ≥20 kDa and ≥30 kDa (claims 12–13).
FAQs
1) Does claim 1 cover both water-soluble and water-insoluble polymer systems?
Yes. Claim 1 expressly includes either a water-soluble branched polymer (≥10 kDa) or a water-insoluble polymer.
2) What is the minimum NEP protection requirement to fall into claim 1?
At least a 5-fold longer degradation half-life in an in vitro NEP degradation assay compared with the corresponding released D-H.
3) What release half-life ranges are explicitly claimed?
At pH 7.4 and 37°C, the dependent claims require release half-life of at least 6 hours (claim 2), 24 hours (claim 9), 48 hours (claim 10), and 168 hours (claim 11).
4) Is Met11→Asn the only tolerated sequence variation?
Within the claim language, the only explicit tolerance stated is substituting the methionine at position 11 of SEQ ID NO:96 with asparagine.
5) What does claim 3 add beyond claim 1?
Claim 3 narrows the agonist to CNP-38.
References
[1] United States Patent 11,224,661. Claims provided in prompt (Claim 1–13 text).
