Details for Patent: 6,423,686

Summary for Patent: 6,423,686

Title:	LHRH antagonist peptides
Abstract:	Methods of treating a subject having a disorder associated with LHRH activity are disclosed
Inventor(s):	Roger W. Roeske
Assignee:	Indiana University Research and Technology Corp
Application Number:	US08/973,378
Patent Claim Types: see list of patent claims	Compound;

Executive summary: US Patent 6,423,686 (LHRH analogues) and what its claims practically cover

US 6,423,686 is a composition-of-matter patent for LHRH (GnRH) analogues defined by a highly structured peptide “variable residues” framework, plus narrower dependent claim carve-outs for specific side-chain substitutions (including D-amino acid variants, cyclized/blocked N-termini such as pyro-Glu and acylated forms) and select performance assay thresholds (antiovulatory efficacy in rats and histamine-release ED50). The independent claims are written to read broadly across a large combinatorial space of analogues by allowing “analogues thereof” at each position and covering pharmaceutically acceptable salts. Dependent claims 12-13 narrow to specific residue identity at position F (D-asparagine or D-glutamine). Claims 14-18 add a functional/effect limitation based on antiovulatory activity in rats (threshold inhibition at doses down to 1–5 μg/rat) and an additional histamine-release potency threshold (ED50 in μg/mL).

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What claims are in US Patent 6,423,686 for LHRH analogues?

Core claim architecture: A–B–C–D–E–F–G–H—I–J (10-mer) and A–B–C–D–E–F–G–H—I (9-mer) LHRH analogue scaffolds, plus variants with an alternative “B–C–D–…” numbering scheme (claims 11). Claims 3–10 expand the allowed residue identities at each position, including alternative aromatic, basic, and N-terminal capping/activation chemistries.

Independent claim 1

• Structure: A—B—C—D—E—F—G—H—I—J
• Length: 10 residues
• Residue sets (examples exactly as provided):
  • A: D-Glu, L-Glu, or analogue
  • B: D-His, L-His, or analogue
  • C: D-Trp, L-Trp, or analogue
  • D: D-Ser, L-Ser, or analogue
  • E: D-Tyr, L-Tyr, or analogue
  • F: D-Asn, L-Asn, D-Gln, or L-Gln
  • G: D-Leu, L-Leu, or analogue
  • H: D-Arg, L-Arg, or analogue
  • I: D-Pro, L-Pro, or analogue
  • J: D-Gly, L-Gly, or analogue
• Coverage: “or pharmaceutically acceptable salt thereof”

Practical scope implication: Claim 1 is broad because each position permits “or an analogue thereof” (except F is explicitly limited to Asn/Gln stereochemistry choices). The claim is composition-focused; it does not require a specific dosing regimen or formulation.

Independent claim 2

• Structure: A—B—C—D—E—F—G—H—I
• Length: 9 residues (drops J)
• Residue sets: Same pattern as claim 1 except no terminal J position.
• Coverage: pharmaceutically acceptable salts

Independent claim 3

• Structure: A—B—C—D—E—F—G—H—I—J
• Length: 10 residues
• Residue sets shifted to include additional N-terminal/side-chain variants
  • A: pyro-Glu, Ac-Nal, Ac-Qal, Ac-Sar, Ac-Pal, or analogue
  • B: His or 4-Cl-Phe, or analogue
  • C: Trp, Pal, Nal, Nal-Pal(N—O), or Trp (as written), or analogue
  • D: Ser or analogue
  • E: N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg, Ile, or analogue
  • F: Asn or Gln
  • G: Leu or Trp (or analogue)
  • H: Lys(iPr), Gln, Met, or Arg (or analogue)
  • I: Pro (or analogue)
  • J: Gly-NH2 or Ala-NH2 (or analogue)
• Coverage: salts

Practical scope implication: Claim 3 is materially broader than claim 1 in where it allows substitution variety (multiple chemically distinct options at A, B, C, E, H, and the C-terminus options J being amide forms).

Dependent claim 4

• Adds a narrower sub-set of claim 3 with explicit choices at multiple positions, including:
  • A: pyro-Glu or Ac-Nal/Ac-Qal/Ac-Sar/Ac-Pal
  • B: His or 4-Cl-Phe
  • C: Trp/Pal/Nal/L-Nal-Pal(N—O)
  • D: Ser
  • E: N-Me-Ala or Tyr or N-Me-Tyr or Ser or Lys(iPr) or 4-Cl-Phe or His or Asn or Met or Ala or Arg or Ile
  • F: Asn
  • G: Leu or Trp
  • H: Lys(iPr) or Gln or Met or Arg
  • I: Pro
  • J: Gly-NH2 or Ala-NH2
• Coverage: salts

Independent claim 5

• Structure: A—B—C—D—E—F—G—H—I
• Length: 9 residues
• Uses the same A/B/C/D/E/F/G/H/I residue sets as claim 3 (with 9-mer missing J).

Dependent claim 6

• Narrows claim 5 similarly to claim 4, with explicit selection at C and F:
  • C is among Trp/Pal/Nal/L-Nal-Pal(N—O)/Trp (as written)
  • F is Asn
• Other residues remain in the permitted sets.

Independent claim 7

• Structure: A—B—C—D—E—F—G—H—I—J

• Length: 10 residues

• Key difference vs claims 1/3: includes explicitly D-amino acid variants at multiple positions and D-amide/side-chain choices:

  • A: pyro-Glu or Ac-D-Nal/Ac-D-Qal/Ac-Sar/Ac-D-Pal (or analogue)
  • B: His or 4-Cl-D-Phe (or analogue)
  • C: Trp, D-Pal, D-Nal, L-Nal-D-Pal(N—O), or D-Trp
  • D: Ser
  • E: N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg, Ile (or analogue)
  • F: D-Asn or D-Gln
  • G: Leu or Trp
  • H: Lys(iPr), Gln, Met, or Arg
  • I: Pro
  • J: Gly-NH2 or D-Ala-NH2

• salts

Practical scope implication: Claim 7 focuses on stereochemical enrichment (D-amino acids at key positions including N-terminal acylated Nal/Qal/Pal variants and F as D-Asn or D-Gln). It can overlap with specific known GnRH analog design patterns.

Dependent claim 8

• Narrows claim 7 by fixing:
  • C: Trp or D-Pal or D-Nal or L-Nal-D-Pal(N—O) or D-Trp
  • F: D-Asn

Independent claim 9

• Structure: A—B—C—D—E—F—G—H—I
• Length: 9 residues
• D-oriented residue sets similar to claim 7 (no J).

Dependent claim 10

• Narrows claim 9 with:
  • C selection and F fixed to D-Asn.

Independent claim 11

• Structure: B—C—D—E—F—G—H—I—J
• Length: 9 residues (A omitted; alternative numbering)
• Residue sets match the claim 1-style stereochemical/analog options but explicitly:
  • B: D-His/L-His
  • C: D-Trp/L-Trp
  • D: D-Ser/L-Ser
  • E: D-Tyr/L-Tyr
  • F: D-Asn/L-Asn/D-Gln/L-Gln
  • G: D-Leu/L-Leu
  • H: D-Arg/L-Arg
  • I: D-Pro/L-Pro
  • J: D-Gly/L-Gly

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How do dependent claims narrow residue F (D-asparagine vs D-glutamine)?

Claim 12

• “The LHRH analogue … wherein F is D-asparagine.”
• Tethers to claims 1, 2, 3, 5, 7, 9, or 11 (as written).

Claim 13

• “... wherein F is D-glutamine.”
• Also tethered to claims 1, 2, 3, 5, 7, 9, or 11.

Scope impact: These two dependent claims create discrete infringement targets: a defendant analogue that uses the same 9- or 10-mer scaffold but substitutes F with D-Asn or D-Gln can fall into narrower bins even if other positions are within “analogues thereof.”

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What functional limitations does US 6,423,686 impose (rat antiovulatory and histamine release)?

Claim 14 (key performance limitation)

• Adds assay-dependent efficacy and tolerability:
  • Antiovulation: inhibits ovulation in at least 50% of treated rats in a “standard rat antiovulatory assay”
  • Dose: 5 μg/rat
  • Histamine-release ED50: at least 3 μg/mL

Claiming strategy: This is a “property” limitation, tying patent scope to biological performance. In infringement analysis, it can become both a benefit (clear boundary for a candidate compound) and a litigation friction point (assay conditions, comparability, reproducibility, and whether a competitor’s compound meets the same thresholds).

Claims 15–16 (dose tightening)

• Claim 15: ≥50% inhibition at 2 μg/rat
• Claim 16: ≥50% inhibition at 1 μg/rat

Claims 17–18 (histamine ED50 tightening)

• Claim 17: histamine ED50 ≥ 5 μg/mL
• Claim 18: histamine ED50 ≥ 10 μg/mL

Scope impact: These dependent claims are hierarchical. A compound that meets the strictest thresholds can satisfy multiple dependent claims; a compound that meets only the lower threshold can still fall within claim 14 if it satisfies 5 μg/rat and ED50 ≥3 μg/mL.

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What parts of the claim set create the broadest “design-around” risk?

Largest “infringement surface area” (breadth drivers)

1. Independent composition claims with “analogues thereof” at multiple positions (notably claims 1, 2, 5, 9, 11; and also in the residue lists of claim 3/4/6/7/8/10).
2. Salt coverage (explicit “pharmaceutically acceptable salt” in each claim recited).
3. Dual-length coverage (9-mer and 10-mer families).
4. Multi-variant residue identity (especially claims 3/5/7/9 with alternate capping groups, aromatic substitutions such as 4-Cl-Phe, and multiple N-terminal forms like pyro-Glu and acylated Nal/Qal/Pal variants).

Narrowest infringement gates (where design-arounds concentrate)

1. F residue identity when targeting claims 12 or 13 (D-Asn vs D-Gln).
2. Functional thresholds when targeting claims 14–18 (dose-response and ED50 histamine-release thresholds).

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What is the patent landscape for US 6,423,686 in practice?

Patent estate mapping limitations from the prompt: Only the claim text is provided. No filing data, publication number, assignee, jurisdictional family members, prosecution history, or expiration/litigation details are included. Without those bibliographic and legal-status elements, a complete landscape (other U.S. family members; continuation divisions; related patents on specific marketed GnRH analogs; Orange Book listing relationships) cannot be produced.

However, the claim set itself indicates the likely competitive adjacency:

• LHRH analogue patents typically cluster around:
  • core decapeptide (or nonapeptide) scaffolds,
  • N-terminal modifications (e.g., pyro-Glu; acylated substitutions),
  • side-chain stereochemistry (D-amino acids),
  • C-terminal amidation (Gly-NH2 / Ala-NH2),
  • and sometimes performance/tolerability profiles (including histamine release).

US 6,423,686’s inclusion of both structural residue permutations and explicit histamine-release ED50/antiovulatory thresholds suggests it can overlap with competitors that pursue similar efficacy and reduced histamine-related side effects.

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How strong is the patent claim set as “blocking coverage” for competitor GnRH analogues?

Strength indicators inside the provided claims

• Composition-of-matter breadth: independent claims enumerate large residue sets and allow “analogues thereof,” which can capture many close variants without requiring exact residue matches.
• Multiple independent claim families: claims exist for 9-mer and 10-mer versions and for an alternative numbering scheme (claim 11), increasing the chance that a competitor analogue matches at least one structural expression.
• Fallback narrowing exists: dependent claims 12-13 and 14-18 provide additional fallback layers that can be asserted even if the strictest structural match is disputed.

Weakness indicators embedded in claim language

• Assay-defined limitations (claims 14-18): enforceability and infringement proof can turn on assay comparability and meeting the precise numeric thresholds.
• “Analogue thereof” breadth can cut both ways: it expands coverage but also creates claim construction disputes about what qualifies as an “analogue” for each residue position.

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Key Takeaways

• US 6,423,686 claims LHRH analogues using a modular peptide scaffold with broad structural coverage across 9-mer and 10-mer forms and salts.
• The core infringement risk is driven by independent claims with wide residue options plus “analogues thereof” language.
• The most targeted narrowing occurs at:
  • residue F (claims 12 and 13): D-asparagine vs D-glutamine, and
  • functional thresholds (claims 14–18): rat antiovulation inhibition at 5, 2, and 1 μg/rat and histamine-release ED50 cutoffs of at least 3, 5, and 10 μg/mL.
• A competitor’s best design-around path, based on the text alone, would be to avoid matching the specific scaffold expressions (including C-terminal amide choices) and to fail at least one of the dependent property thresholds if those are asserted.

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FAQs

1. Can a 9-mer LHRH analogue infringe US 6,423,686 if it lacks the J position?
   Yes, claims 2, 5, 9, and 11 cover 9-residue formats that omit J in the structural expression.

2. Does the patent cover both D- and L-amino acids at key positions?
   Yes. Claims include explicit D/L options and “analogue thereof” language across multiple residues, with additional D-enrichment in claims 7–10 and F restricted to D-Asn or D-Gln.

3. What is the role of pharmaceutically acceptable salts in infringement?
   The claims expressly cover salts of the claimed LHRH analogues, so a salt form is within claim scope if the underlying peptide matches.

4. What numeric thresholds are used for functional efficacy and histamine release?
   Antiovulation: ≥50% inhibition at 5 μg/rat (claim 14) and tightened to 2 μg/rat (claim 15) and 1 μg/rat (claim 16). Histamine release ED50: ≥3 μg/mL (claim 14) tightened to ≥5 μg/mL (claim 17) and ≥10 μg/mL (claim 18).

5. Is residue F the best dependent-claim hook for narrowing?
   Yes. Claims 12 and 13 explicitly limit F to D-asparagine or D-glutamine, creating a clear structural discriminator within the broader independent claim space.

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References

No references included because the prompt provides only claim text and does not provide patent bibliographic identifiers, assignee, publication/application numbers, prosecution history, litigation records, or any external source citations.

Drugs Protected by US Patent 6,423,686

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 6,423,686

PCT Information
PCT Filed	June 07, 1996	PCT Application Number:	PCT/US96/09852
PCT Publication Date:	December 19, 1996	PCT Publication Number:	WO96/40757

International Family Members for US Patent 6,423,686

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0794961		91225	Luxembourg
European Patent Office	0794961		CA 2011 00004	Denmark
European Patent Office	0794961		C300484	Netherlands
European Patent Office	0794961		91857	Luxembourg
European Patent Office	0794961		11C0015	France
European Patent Office	0794961		1190014-9	Sweden