US Patent 5,114,923 Landscape and Claim Scope: natriuretic peptide analogs, R1/R2 substituents, and US infringement risk
US Patent 5,114,923 is a peptide-claims-centered estate focused on a specific natriuretic-activity peptide core (Cys-Phe-Gly-Arg-Arg-Leu-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Leu-Gly-Cys) with defined variability at two termini through (i) an R1 substituent selected from an attachment scheme and (ii) C-terminal R2 options including lysine-based and short peptide/carboxamide variants. Claim 2 and Claim 3 extend protection to pharmaceutical compositions and methods for inducing natriuresis, diuresis, and/or vasodilation via administration of the claimed peptide. Claim 4 narrows to a specific R1/R2 combination.
What patents protect natriuretic peptide analogs with this exact core in the US?
Core scope in 5,114,923
- The protected “active” structure is a peptide of natriuretic activity having the formula:
- R1 – Cys – Phe – Gly – Arg – Arg – Leu – Asp – Arg – Ile – Gly – Ser – Leu – Ser – Gly – Leu – Gly – Cys – R2
- Variability is concentrated at:
- N-terminus via R1, selected from a terminal/sequence selection set shown in the patent’s schematic (“R1 selected from ##STR11##”).
- C-terminus via R2, defined as OH, NH2, NHR’, NR’R’’ (lower alkyl 1-4C) and, in specific enumerated alternatives, lysine-derived residues:
- “R2 is Lys”
- “Lys-Val”
- “Lys-Val-Leu”
- “Lys-Val-Leu-Arg”
- “Lys-Val-Leu-Arg-Arg”
- “Lys-Val-Leu-Arg-Arg-His”
- or the amides of the above (NH2, NHR’, NR’R’’).
Claim-type coverage
- Product (peptide): Claim 1.
- Formulation (composition): Claim 2.
- Use (method of treatment): Claim 3.
- Specific sub-genus (fixed R1/R2): Claim 4.
How broad is claim 1’s peptide formula and where are the real boundaries?
Claim 1 is a structured genus with two modifiable ends.
The middle portion is fixed down to residue identity and order:
- Cys–Phe–Gly–Arg–Arg–Leu–Asp–Arg–Ile–Gly–Ser–Leu–Ser–Gly–Leu–Gly–Cys
Boundary 1: the middle 18-ish residue “core” is not optional
- Any substituted, deleted, or reordered residues in the core likely remove literal coverage because the formula explicitly fixes the sequence from the first Cys to the terminal Cys.
Boundary 2: R1’s selection set controls N-terminal alternatives
- R1 is “selected from ##STR11##” and additionally described as including:
- “wherein R3 is the 102 amino acid sequence shown as positions 1–99 for the human protein in FIG. 6, or a C-terminal portion thereof”
- Practically, this makes R1 a function of:
- whether the patent defines an “attachment” of a sequence portion to the N-terminus of the core, and
- which contiguous C-terminal subsegments are permitted as R3.
Boundary 3: R2 enumerations create multiple sub-genuses
R2 options include:
-
Simple terminus
- OH (free acid)
- NH2 (primary amide)
- NHR’ or NR’R’’ where R’ and R’’ are independently lower alkyl (C1–C4)
-
Lysine-based extension series
- Lys
- Lys-Val
- Lys-Val-Leu
- Lys-Val-Leu-Arg
- Lys-Val-Leu-Arg-Arg
- Lys-Val-Leu-Arg-Arg-His
- and the corresponding amide versions of those Lys-terminated extensions
Key legal risk point
- Many competitive natriuretic peptide analogs fail literal infringement if they:
- change core residues (middle sequence),
- change C-terminal tail beyond those enumerated (or replace Lys-tail with different capping groups),
- or attach a different N-terminal scaffold than the defined R1/R3 selection set.
What does R1 “102 amino acid sequence shown as positions 1–99” likely mean for claim construction?
Claim 1 ties R1 to a “102 amino acid sequence shown as positions 1–99 for the human protein in FIG. 6, or a C-terminal portion thereof.” That language is a typical attempt to claim:
- peptides that use a portion of a known human precursor/processing product, and/or
- peptides that preserve biologically relevant N-terminal residues.
Practical claim mapping
- If the FIG. 6 sequence corresponds to a known human natriuretic proprotein fragment, then R1 likely includes one of:
- the exact N-terminal fragment up to position 99, or
- a C-terminal portion of that fragment.
Enforcement implications
- Literal infringement will turn on:
- the exact residues used at the N-terminus,
- whether the N-terminal fragment is “a C-terminal portion thereof” (contiguous subsequence question),
- and whether competitor designs use non-overlapping N-terminal residue sets.
What patents protect pharmaceutical compositions and methods of inducing natriuresis/diuresis/vasodilation?
Claim 2 (composition)
- “A pharmaceutical composition for inducing natriuresis, diuresis and/or vasodilation… comprises an effective amount of the peptide of claim 1 in admixture with a suitable pharmaceutical excipient.”
- This is broad in excipient selection and does not add technical limitations beyond:
- effective amount
- admixture with a “suitable pharmaceutical excipient.”
Infringement boundary
- The composition claim is likely derivative from Claim 1:
- if a product does not include a peptide falling within Claim 1, Claim 2 is typically not reached.
Claim 3 (method of treatment)
- “administering to said subject in need… an effective amount of the peptide of claim 1 or a pharmaceutical composition thereof.”
Infringement boundary
- Similar dependency on Claim 1 peptide coverage.
- The method claim targets therapeutic effect categories:
- natriuresis
- diuresis
- vasodilation
- Competitors who develop peptide analogs that do not meet the “natriuretic activity” premise or do not literally practice the defined peptide may avoid literal method coverage.
What does claim 4 narrow, and why does it matter for competitive freedom-to-operate?
Claim 4 is a fixed sub-genus
- “The peptide of claim 1 wherein R1 is Ser-Pro-Lys-Met-Val-Gln-Gly-Ser-Gly and R2 is Lys-Val-Leu-Arg-Arg-His or the amide thereof.”
This claim does two things:
- It anchors at least one commercially plausible endpoint tail (Lys-Val-Leu-Arg-Arg-His and its amide).
- It locks an N-terminal peptide segment with high specificity.
Enforcement value
- Claim 4 can be used as:
- a narrower fallback in litigation if Claim 1 is challenged on breadth or indefiniteness arguments, and
- a more direct comparison target against specific candidate sequences.
Competitive risk
- If a competitor’s lead candidate matches the claim 4 exact R1 and R2, they face higher odds of literal infringement even if the broader R1 selection in Claim 1 is disputed.
Where are the likely “design-around” routes for natriuretic peptide competitors?
Design-around strategies against 5,114,923 typically focus on breaking one of three dependencies:
- Core sequence mismatch
- Change one or more residues in:
- Cys-Phe-Gly-Arg-Arg-Leu-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Leu-Gly-Cys
- This is the cleanest path to avoid literal coverage.
- Tail mismatch at R2
- Avoid the enumerated R2 series:
- OH / NH2 / NHR’ / NR’R’’ (lower alkyl C1–C4)
- Lys and Lys-Val, Lys-Val-Leu, Lys-Val-Leu-Arg, Lys-Val-Leu-Arg-Arg, Lys-Val-Leu-Arg-Arg-His
- and amide versions of the above
- N-terminal scaffold mismatch at R1
- Use an N-terminal fragment not within the “selected from ##STR11##” set or not conforming to the “R3 … positions 1–99 … or a C-terminal portion thereof” limitation.
- Claim 4 also provides a very specific N-terminal fragment that can be targeted for non-infringing selection.
What is the expected relationship between this patent and later follow-on patents?
Without the patent’s full specification (including the disclosed R1 attachment options under ##STR11## and the detailed description of FIG. 6) and without a jurisdictional family list, it is not possible to enumerate a complete follow-on US filing chain. A full landscape requires:
- a family document list,
- related continuations/divisionals,
- and citing/cited patent network data.
No reliable landscape can be produced from the provided claim excerpt alone.
When did US 5,114,923 expire and how does that affect generic entry risk?
No expiration, priority, or term-adjustment data is provided in the prompt, so the exclusivity timeline cannot be stated with accuracy. Patent term (and any extensions) depends on:
- priority date,
- filing date,
- prosecution history and any adjustments,
- and whether the patent is subject to PTA/PTA, pediatric exclusivity, or other term modifiers.
This cannot be derived from claim text.
What Orange Book status and FDA pathway issues apply to 5,114,923?
This claim set does not identify:
- the specific marketed drug,
- the listed active ingredient name,
- the dosage form,
- or the NDA/ANDA/BLA it corresponds to.
Orange Book status is product-specific and cannot be correctly assigned from claim language alone.
Key takeaways
- US 5,114,923 protects a natriuretic-activity peptide defined by a fixed internal core sequence (from Cys through the terminal Cys) and defined terminal variability at N-terminus (R1) and C-terminus (R2).
- Claim 2 and Claim 3 extend protection to any pharmaceutical composition and any method of administration that uses the Claim 1 peptide (effective amount with suitable excipients; administration to induce natriuresis/diuresis/vasodilation).
- Claim 4 is a high-specificity sub-genus that materially raises infringement risk if a candidate matches its exact R1 (Ser-Pro-Lys-Met-Val-Gln-Gly-Ser-Gly) and R2 (Lys-Val-Leu-Arg-Arg-His or corresponding amide).
- Design-around most plausibly relies on changing the fixed internal core, using an R2 tail outside the enumerated Lys-based series and capping set, or using an R1/N-terminal scaffold outside the defined “##STR11##” and FIG. 6 sequence portion.
FAQs
1) Does changing the Cys-Phe-Gly-Arg-Arg-Leu-Asp sequence avoid infringement of Claim 1?
Yes, because Claim 1 fixes the core residues in order; altering any core residue likely removes literal coverage.
2) Are free acid (OH) and primary amide (NH2) covered at the peptide’s C-terminus?
Yes, both are explicitly included under R2, along with secondary/tertiary amide forms using lower alkyl (C1–C4).
3) If a competitor uses Lys-Val-Leu-Arg-Arg-His but with a non-amide cap, is it covered?
Only if the non-amide cap still matches an R2 option enumerated in Claim 1; claim 4 specifically includes amide or Lys-Val-Leu-Arg-Arg-His as R2.
4) Can a pharmaceutical composition infringe Claim 2 without practicing the method in Claim 3?
Potentially, because Claim 2 is a product/composition claim and does not require method proof, but it still depends on using a Claim 1 peptide.
5) Is it possible to avoid both composition and method claims while still using a natriuretic peptide concept?
Yes by using a peptide that falls outside Claim 1’s defined structure, since both Claims 2 and 3 are tethered to “the peptide of claim 1.”
References
- US Patent 5,114,923.
