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Patent landscape, scope, and claims: |
United States Patent 10,835,578: CNP branched-polymer prodrugs with reversible linker
United States Drug Patent 10,835,578 claims a class of CNP (C-type natriuretic peptide) prodrugs in which the active CNP moiety (-D) is released by cleavage of a reversible prodrug linker (-L1-) from a polymeric carrier (-Z) that is branched (10 kDa up to 250 kDa, depending on dependent claim), where the carrier attaches to the CNP through a chemical bond or spacer (-L2-).
The patent’s practical scope is defined less by specific peptide sequences and more by the architecture:
- CNP moiety (-D): includes specific sequences (e.g., SEQ ID NO:24/25/30), and at least one explicit attachment site (lysine side-chain at position 26 in SEQ ID NO:24).
- Reversible prodrug linker (-L1-): covalently and reversibly conjugates -L1- to -D; cleavage releases -D in free form.
- Attachment between polymer and linker (-L2-): chemical bond or spacer.
- Branched polymer carrier (-Z): branched polymer MW >= 10 kDa (with multiple dependent molecular weight windows) attached to a ring moiety of -D.
- Polymer branching rules: 1-6 branching points; each branching point selected from -N<, -CH<, >C<; polymer substituent blocks described by extensive formulae.
What do the independent claims cover (Claim 1 architecture)?
Claim 1: Core structural limitations
Claim 1 requires the following, in combination:
- Prodrug composition
- “A CNP prodrug or a pharmaceutically acceptable salt thereof comprising a CNP moiety -D” (Claim 1).
- Two-stage linkage
- Carrier moiety -Z is conjugated through -L2- to a reversible prodrug linker moiety -L1-.
- -L1- is covalently and reversibly conjugated to -D.
- Cleavage of -L1- releases -D in its free form (Claim 1).
- Nature of the attachment between -Z and -L1
- -L2- is a chemical bond or spacer (Claim 1).
- Carrier is branched polymer and MW threshold
- “-Z comprises a branched polymer having a molecular weight of at least 10 kDa attached to a ring moiety of -D” (Claim 1).
Claim 1 therefore reads as:
- A branched-polymer CNP prodrug with a reversible cleavable linker that liberates free CNP after cleavage of -L1-, with attachment to polymer governed by -L2- and with polymer attached to a ring feature of the CNP scaffold.
Immediate scope consequences
- A competitor must avoid both:
- a branched polymer carrier with MW meeting the stated thresholds, and/or
- a reversible covalent linker arrangement cleaving to free CNP via -L1-,
- and/or the specified topology where polymer is attached through -L2- to -L1- which is reversibly conjugated to -D.
- The claim language is broad on -Z substituent identity (extensive formulae in dependent claims), but narrow on the high-level structural motifs (branched polymer carrier, reversible cleavable -L1-, CNP ring attachment).
How do dependent claims narrow -Z (branched polymer parameters)?
Branching points and branching types
- Claim 2: -Z has one to six branching points.
- Claim 3: each branching point is independently selected from -N<, -CH<, >C<.
This constrains the prodrug to polymers whose branching conforms to those atom-level branching designators.
Molecular weight ranges
- Claim 4: -Z MW ranges 10 kDa to 80 kDa (inclusive).
- Claim 14: -Z is about 40 kDa.
- Claim 19: -Z MW ranges 10 to 250 kDa.
- Claim 20: -Z MW ranges 12 to 100 kDa.
Read-through for landscape:
- The specification and claim set appear to cover multiple polymer MW “bands” used for PK modulation. A product with polymer MW outside some of these bands may still fall under Claim 1 if only the >=10 kDa requirement is met, but the strongest dependent coverage occurs within the listed windows.
Polymer structural formulae: claimed variability is high
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Claim 5 adds that -Z further comprises a moiety (formula not provided in the user text beyond “wherein -Z further comprises a moiety”).
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Claim 6: -Z comprises a moiety “of formula (a)” with:
- branching point parameter BPa = -N<, -CR<, >C<
- branching index a (0 or 1 depending on BPa)
- substituent segments -Sa-, -Sa′-, -Sa″-, -Sa′″- = chemical bond or C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl
- optional interruptions and extensive functional group allowances (alkyl/alkenyl/alkynyl interrupted by groups including -T- aromatic/heteroaromatic segments and carbonyl/sulfonamide/sulfonyl/sulfide-like linkages)
- optional substitution on -R1 with wide substituent classes (halogen, cyano, nitro, carboxylate/alkoxy/amides/sulfonamides and heteroatom-containing moieties)
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Claim 7: -Z is of formula (f) with analogous structural freedoms:
- BPf and f similarly tied to branching point identity
- -Sf- segments = chemical bond or C1-50 alkyl, etc.
- interruption groups largely overlap with Claim 6’s list
- includes polymeric submoieties -Pa′, -Pa″, -Pa′″ as “polymeric moiety.”
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Claim 15: -Z is of formula (h) where each -Zc has c1 integer 200 to 250.
Key landscape inference: broad polymer chemistry with hard topology constraints
The patent tolerates extensive chemical diversity in the polymer side chains and interruptions, which makes design-around via “different polymer chemistry” insufficient. The highest-value design-around is structural:
- avoid branched polymer architecture as defined,
- avoid the reversible cleavable linker that releases free CNP,
- avoid attachment topology where polymer is linked through -L2- to reversible linker -L1- conjugated to the CNP moiety.
How do dependent claims narrow -D (CNP peptide definition and attachment point)?
Defined sequences
- Claim 8: -D has the sequence of SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:30.
- Claim 16: -D has SEQ ID NO:24.
- Claim 17: -D is SEQ ID NO:24 and -L1- is conjugated to the amine functional group of the side chain of lysine at position 26 of SEQ ID NO:24.
Attachment to amino acid residues or backbone
- Claim 9: -D is conjugated:
- to the side chain of an amino acid residue of the ring moiety of -D, or
- to the backbone of the ring moiety.
Landscape implication:
- If a competitor uses the same peptide scaffold (-D in the claim sense) but attaches the cleavable linker to a different site than the “ring moiety” definition, they may reduce likelihood of Claim 8/16/17-specific coverage, but Claim 1 still broadly covers -D as a CNP moiety with a ring moiety attachment to -Z via the linker scheme.
How do dependent claims cover formulation and therapeutic use?
Pharmaceutical composition
- Claim 10: pharmaceutical composition includes at least one prodrug/salt of Claim 1 plus at least one excipient.
Method-of-treatment: very broad disease set
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Claim 11: method of treating, controlling, delaying, or preventing disease treatable with CNP by administering therapeutically effective amount of Claim 1 prodrug or composition.
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Claim 12: disease list includes, among others:
- achondroplasia, hypochondroplasia, short stature, dwarfism
- osteochondrodysplasias (thanatophoric dysplasia, osteogenesis imperfecta, etc.)
- skeletal dysplasias and craniofacial syndromes
- neurofibromatosis, Legius syndrome, LEOPARD syndrome, Noonan syndrome
- SHOX deficiency, idiopathic short stature, growth hormone deficiency
- osteoarthritis
- cleidocranial dysostosis, craniosynostosis
- multiple limb and skeletal phenotypes (dactyly, brachydactyly, syndactyly, polydactyly, etc.)
- hypophosphatemic rickets, Jaffe-Lichtenstein syndrome
- connective tissue disorders (Marfan syndrome, McCune-Albright syndrome)
- osteopetrosis and osteopoikilosis
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Claim 13: disease is specifically achondroplasia.
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Claim 18: disease includes Muenke, Crouzon, Apert, Jackson-Weiss, Pfeiffer, or Crouzonodermoskeletal syndrome.
Landscape note:
- The patent claims broad “CNP treatable diseases” plus specific skeletal indication subsets, which strengthens enforceability against method-of-use competition where the prodrug is otherwise within scope.
Independent claim coverage vs dependent claim “rings” (what is most enforceable)?
A useful way to map scope is to separate:
- Architecture elements in Claim 1 (core enforceability), and
- Prodrug subtype restrictions in dependent claims (narrow but valuable fallback positions).
Claim 1: hardest-to-evade elements
- CNP prodrug in which -L1- cleavage releases free CNP.
- Reversible conjugation between -L1- and -D.
- Branched polymer carrier -Z with MW at least 10 kDa.
- Polymer attached to a “ring moiety” of -D, with conjugation through -L2- to -L1-.
Claim 2-4 and 14: second-tier enforceability
- Branching points 1-6 and branching atom types.
- MW windows (10-80; about 40 kDa).
- These provide multiple “capture ranges” if a competitor’s polymer MW and branching structure fall into a claimed band.
Claim 6-7 and 15: chemical-detail fallback
- The expansive formulae define polymer substitution patterns and interruptions.
- These are often enforceable if the competitor’s polymer matches the described formula families, but they also reduce the odds that entirely different polymer architectures are within the same dependent claim.
Claim 8/16/17 and 9: peptide attachment fallback
- SEQ ID NO:24/25/30 coverage.
- Lysine-26 specific linkage in SEQ ID NO:24 provides a strong positional fallback.
Patent landscape view: how this claim set positions around design-arounds
Without prosecution history and without the patent family’s continuity, the most actionable landscape analysis is a design-space matrix based on the claim motifs.
1) Design-around targeting reversible cleavage (-L1-)
To avoid Claim 1, a competitor can aim to:
- remove “reversible” covalent prodrug linker behavior that cleaves to release free CNP; or
- switch from cleavable conjugate prodrug mechanism to a different activation mode.
However, the claim is defined by cleavage releasing -D in free form, so non-cleavable or non-releasing modalities likely miss.
2) Design-around targeting branched polymer carrier (-Z)
Claim 1 requires a “branched polymer” with MW at least 10 kDa. Options:
- use a linear polymer (no branching points of the type captured by -N<, -CH<, >C<) to target failure of the “branched polymer” requirement.
- use a polymer below the MW threshold (though Claim 1 explicitly needs >=10 kDa for -Z).
3) Design-around targeting topology (attachment through -L2- to -L1-)
Even with a branched polymer and cleavable linker, competitors must match topology:
- -Z is conjugated through -L2- to -L1-,
- where -L1- is reversibly conjugated to -D.
A different attachment scheme that does not route through the “-L2- to -L1- to -D” chain may reduce risk.
4) Design-around targeting CNP ring moiety attachment
If the CNP moiety is attached outside a “ring moiety” definition, or uses a different CNP scaffold outside SEQ ID coverage, dependent claims narrow but Claim 1 might still read on the “CNP moiety -D” concept if the ring feature and conjugation topology remain.
5) Method-of-use considerations
If a competitor’s molecule is outside Claim 1, method-of-use claims become less relevant. If it is within Claim 1, the broad disease list in Claim 12 makes it harder to avoid infringement by changing indication unless the disease is outside “diseases treatable with CNP” as construed.
Scope map table: what each claim layer covers
| Claim |
Coverage focus |
Key enforceability levers |
| 1 |
Core prodrug architecture |
Reversible linker (-L1-) cleaves to free CNP; carrier (-Z) is branched polymer MW >= 10 kDa; -Z to -L1- via -L2-; polymer attached to ring moiety of -D |
| 2 |
Branch quantity |
1-6 branching points |
| 3 |
Branch chemistry |
Branching points limited to -N<, -CH<, >C< |
| 4 |
Polymer MW window |
10-80 kDa |
| 5 |
Polymer includes additional moiety |
(Not fully specified in provided text) |
| 6 |
Polymer formula (a) |
Broad substitution and interruption rules; branching framework BPa |
| 7 |
Polymer formula (f) |
Broad substitution and interruption rules; branching framework BPf |
| 8 |
Peptide sequences |
SEQ ID NO:24/25/30 |
| 9 |
Attachment location options |
Side chain of amino acid residue of ring moiety or backbone of ring moiety |
| 10 |
Formulation |
Prodrug plus excipient |
| 11 |
Method-of-use |
Treat/control/delay/prevent diseases treatable with CNP via administration |
| 12 |
Indication list |
Broad skeletal and related indications |
| 13 |
Specific indication |
Achondroplasia |
| 14 |
Polymer MW specific |
about 40 kDa |
| 15 |
Polymer formula (h) |
Each -Zc has c1 200-250 |
| 16 |
Specific peptide sequence |
SEQ ID NO:24 |
| 17 |
Specific conjugation site |
-L1- to amine of lysine side chain at position 26 of SEQ ID NO:24 |
| 18 |
Additional indications |
Muenke, Crouzon, Apert, Jackson-Weiss, Pfeiffer, Crouzonodermoskeletal |
| 19 |
Polymer MW expanded |
10-250 kDa |
| 20 |
Polymer MW window |
12-100 kDa |
Business implications for IP strategy and competitive R&D
If you are developing a CNP prodrug
The most risk-sensitive design constraints are those embedded in Claim 1:
- A branched polymer (not merely a polymer with pendant groups) with MW >=10 kDa.
- A reversible cleavable conjugate linker (-L1-) whose cleavage yields free CNP.
- Conjugation pathway -Z to -L1- through -L2-, and -L1- to -D.
If you are evaluating freedom to operate for polymer variations
- Changing polymer side chain chemistry (where -Sa-, -Sf-, interruptions, and substituents are adjustable) is unlikely to avoid Claim 1 if the carrier remains branched and meets MW thresholds and topology remains.
- The higher-leverage differentiation is to disrupt:
- branch architecture,
- reversibility/cleavage mechanism,
- or attachment topology.
If you are evaluating indication strategy
- The disease list in Claim 12 is extensive, and Claim 11 already covers any disease “which can be treated with CNP,” which can be interpreted broadly.
- A competitor changing therapeutic target within skeletal dysplasia and related growth/craniofacial indications has high overlap risk.
Key Takeaways
- 10,835,578 claims CNP prodrugs built on a fixed topology: branched polymer carrier (-Z) attached through -L2- to a reversible cleavable linker (-L1-), where -L1- cleavage releases free CNP (-D).
- Branching and MW are enforceable: -Z must be branched and at least 10 kDa, with dependent coverage spanning 10-80 kDa, about 40 kDa, 12-100 kDa, and 10-250 kDa.
- The patent allows broad chemical variability in polymer moieties (multiple formula families), but the claim set is structurally anchored by reversibility/cleavability and branched polymer topology.
- Dependent claims add specific peptide sequences (SEQ ID NO:24/25/30) and an explicit lysine-26 attachment site in SEQ ID NO:24.
- Method-of-use claims cover a wide skeletal and related disease set, with explicit focus on achondroplasia and multiple craniofacial syndromes.
FAQs
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What is the central inventive concept in 10,835,578?
A CNP prodrug where a branched polymer carrier is linked via a spacer (-L2-) to a reversible cleavable linker (-L1-) that releases free CNP after cleavage.
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What makes the patent hard to design around?
Claim 1 requires, in combination: branched polymer (MW >=10 kDa), reversible cleavable -L1-, and a specific conjugation pathway -Z to -L1- via -L2- with polymer attached to a ring moiety of the CNP.
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Do dependent claims materially constrain the polymer chemistry?
They constrain it in detail (formula families), but enforceability likely hinges most on whether the competitor matches the branched polymer architecture and MW windows, since polymer side-chain chemistry is heavily parameterized.
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Are peptide sequences a major scope limiter?
No for Claim 1, which broadly covers a CNP moiety (-D). Dependent claims narrow with SEQ ID NO:24/25/30, and one dependent claim specifies lysine-26 conjugation.
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What therapeutic areas are explicitly covered?
Skeletal dysplasias and related growth and craniofacial conditions, including achondroplasia and multiple craniosynostosis syndromes, plus broader categories listed in Claim 12.
References
[1] U.S. Patent 10,835,578 (claims provided in prompt text).
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