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fix: correct SEED-020 novelty — VAR_004/VAR_002 carry patent risk (DRAMP05502/05504) #110

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cschanhniem merged 2 commits into from
Jun 29, 2026
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fix: correct SEED-020 novelty — VAR_004/VAR_002 carry patent risk (DRAMP05502/05504) #110

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20be009
fix: correct SEED-020 novelty — VAR_004/VAR_002 are CLOSE_RELATIVE wi…
cschanhniem Jun 29, 2026
2c46156
fix: address code-review MEDIUM/LOW issues on novelty correction docs
cschanhniem Jun 29, 2026
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36 changes: 23 additions & 13 deletions docs/EXPERT_REVIEW_PACK.md
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Expand Up @@ -174,19 +174,29 @@ not a claim that they are inactive.
| SEED-007 (bombolitin) | 4 | Short amphipathic helix | Genuine (✓ NOVEL) | Low (11 AA; good) | ~70–82% | Novel short helix |
| SEED-008 (Trp-rich) | 4 | Indole ring stacking; not helical | Genuine (✓ NOVEL) | Moderate (13 AA model edge) | ~70–82% | Novel mechanism; high disagreement |
| SEED-009 (Pro-rich) | 4 | Ribosome exit + DnaK | Genuine (✓ NOVEL) | **Best** (Pro-X bonds resist protease) | ~60–75% | Novel; run RPMI parallel |
| SEED-019/020 (Arg-Ile/Val/Leu) | 3 | Cationic amphipathic helix | ✓ NOVEL (SEED-020 pair); CLOSE_RELATIVE + ⚠ patent risk (SEED-019_VAR_004) | Short (12 AA model edge) | **~75–85%** (SEED-020 pair); patent clearance needed for SEED-019_VAR_004 | Best ext.-predictor confirmed leads; IP check before SEED-019 synthesis |

> **Wave 0.5b addendum (2026-06-29):** External predictor screening (CAMPR4 × 4 votes,
> AMPScanner v2, Macrel, AMPActiPred, HemoFinder, AntiCP2) of 23 new SEED-020/021/023/024
> candidates confirmed SEED-020_VAR_004 (RLRIRVLKRLLK) and SEED-020_VAR_002 (KVRIRVLKRLLK)
> as the best safety-activity tradeoff in the batch: HemoFinder LOW, AMPScanner > 0.99,
> Non-AntiCP. Both confirmed NOVEL by broad novelty check (72-AMP curated DB; < 50% max
> similarity; no patent DB matches). Both added to `outputs/wave1_final_panel.csv` as
> BALANCED_LEAD candidates (source: WAVE0_5B). SEED-019_VAR_004 (already in panel) carries
> a POSSIBLE_PATENT_RISK flag (66.7% to DRAMP05502 in full 27,234-sequence audit) — require
> IP clearance before synthesis. SEED-022 was excluded at pre-screen (no viable candidates
> after safety scoring; poor AntiCP / HemoFinder profile across all variants). Full synthesis
> notes: `docs/WET_LAB_HANDOFF.md §SEED-019/SEED-020`.
| SEED-019/020 (Arg-Ile/Val/Leu) | 3 | Cationic amphipathic helix | CLOSE_RELATIVE + ⚠ patent risk for all 3 (VAR_004/VAR_019→DRAMP05502; VAR_002→DRAMP05504); CLEAR alternative: VAR_008 | Short (12 AA model edge) | **~75–85%** (activity unchanged); IP clearance required before any synthesis | Best ext.-predictor confirmed leads; VAR_008 is the publication-safe option |

> **Wave 0.5b addendum (2026-06-29; novelty corrected 2026-06-29):** External predictor
> screening (CAMPR4 × 4 votes, AMPScanner v2, Macrel, AMPActiPred, HemoFinder, AntiCP2) of
> 23 new SEED-020/021/023/024 candidates confirmed SEED-020_VAR_004 (RLRIRVLKRLLK) and
> SEED-020_VAR_002 (KVRIRVLKRLLK) as the best safety-activity tradeoff in the batch:
> HemoFinder LOW, AMPScanner > 0.99, Non-AntiCP. Both added to `outputs/wave1_final_panel.csv`
> as BALANCED_LEAD candidates (source: WAVE0_5B).
>
> **⚠ Novelty correction:** The preliminary broad novelty check (72-AMP curated DB, no patent
> sequences) returned NOVEL for SEED-020_VAR_004 and SEED-020_VAR_002. The full 27,234-sequence
> BLOSUM62 audit (APD6 + DRAMP general + DRAMP patent + UniProt) reclassifies both as
> **CLOSE_RELATIVE with POSSIBLE_PATENT_RISK**:
> - SEED-020_VAR_004: **75% identity to DRAMP05502** (patent; RLLKQWPIGRLLKRLLKRLLK —
> C-terminal repeat RLLK aligns 9/12 residues)
> - SEED-020_VAR_002: **67% identity to DRAMP05504** (patent; RVLKQWPIGRVLKRVLKRVLK)
> - SEED-019_VAR_004: 66.7% to DRAMP05502 (patent; already flagged)
>
> All three require IP clearance before synthesis or publication. **Publication-safe
> alternative: SEED-020_VAR_008 (RVRIKVLKRLLK)** — 67% to DRAMP31150 (general public
> database, no patent hit; classified CLEAR). SEED-022 was excluded at pre-screen (no viable
> candidates after safety scoring; poor AntiCP / HemoFinder profile across all variants).
> Full synthesis and IP notes: `docs/WET_LAB_HANDOFF.md §SEED-019/SEED-020`.

**SEED-007 reviewer note:** Bombolitin-II (*Megabombus pennsylvanicus* venom) is the
**largest selected family** (26 variants, 4 pilot slots). All 4 pilot candidates are NOVEL
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53 changes: 36 additions & 17 deletions docs/WET_LAB_HANDOFF.md
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Expand Up @@ -450,27 +450,46 @@ confirmed by external predictor screening (wave 0.5b; 2026-06-29).

**Best candidates added to final panel (wave 0.5b, external predictor confirmed):**

| Candidate | Sequence | AMPScanner | HemoFinder | AntiCP | Broad novelty (72-AMP DB) | Full-DB novelty |
| Candidate | Sequence | AMPScanner | HemoFinder | AntiCP | Broad novelty (72-AMP DB only) | Full-DB novelty (27,234-seq BLOSUM62) |
|-----------|----------|:----------:|:----------:|:------:|:-------------:|:---:|
| SEED-020_VAR_004 | RLRIRVLKRLLK | 0.9928 (AMP) | LOW | Non-AntiCP 0.29 | NOVEL (41.7% max) | NOVEL |
| SEED-020_VAR_002 | KVRIRVLKRLLK | 0.9960 (AMP) | LOW | Non-AntiCP 0.32 | NOVEL (37.5% max) | NOVEL |
| SEED-019_VAR_004 | RVRIRLVKRLLK | panel anchor | LOW | Non-AntiCP | 38.1% max vs non-patent AMPs | **CLOSE_RELATIVE ⚠ patent risk** |

> **IP NOTE — SEED-019_VAR_004:** Full 27,234-sequence novelty audit v2 (APD6, DRAMP general,
> DRAMP patent, UniProt) classifies SEED-019_VAR_004 as **CLOSE_RELATIVE (66.7% identity to
> DRAMP patent sequence DRAMP05502)**. **IP clearance is required before ordering synthesis
> or publishing results for SEED-019_VAR_004.** The SEED-020 pair (VAR_004 and VAR_002) were
> not flagged in the patent database and carry no identified IP risk.
| SEED-020_VAR_004 | RLRIRVLKRLLK | 0.9928 (AMP) | LOW | Non-AntiCP 0.29 | NOVEL (41.7% max) | ⚠ CLOSE_RELATIVE 75% to DRAMP05502 (patent) |
| SEED-020_VAR_002 | KVRIRVLKRLLK | 0.9960 (AMP) | LOW | Non-AntiCP 0.32 | NOVEL (37.5% max) | ⚠ CLOSE_RELATIVE 67% to DRAMP05504 (patent) |
| SEED-020_VAR_008 *(fallback — see IP NOTE)* | RVRIKVLKRLLK | ext. pred. confirmed | LOW | — | — | CLOSE_RELATIVE 67% to DRAMP31150 (**CLEAR** — public DRAMP entry, no patent sub-database hit) |
| SEED-019_VAR_004 | RVRIRLVKRLLK | panel anchor | LOW | Non-AntiCP | 38.1% max vs non-patent AMPs | **CLOSE_RELATIVE ⚠ patent risk** (66.7% to DRAMP05502) |

> **IP NOTE — SEED-020_VAR_004, SEED-020_VAR_002, and SEED-019_VAR_004:**
> Full 27,234-sequence novelty audit v2 (APD6, DRAMP general, DRAMP patent, UniProt; BLOSUM62
> local alignment) reveals patent proximity for all three candidates:
> - **SEED-020_VAR_004** (RLRIRVLKRLLK): 75% identity to DRAMP patent sequence **DRAMP05502**
> (RLLKQWPIGRLLKRLLKRLLK; C-terminal RLLK-repeat region aligns 9/12 residues)
> - **SEED-020_VAR_002** (KVRIRVLKRLLK): 67% identity to DRAMP patent sequence **DRAMP05504**
> (RVLKQWPIGRVLKRVLKRVLK; analogous C-terminal alignment)
> - **SEED-019_VAR_004** (RVRIRLVKRLLK): 66.7% identity to DRAMP05502 (patent)
>
> All three are classified **POSSIBLE_PATENT_RISK**. **IP clearance is required before
> ordering synthesis or publishing results for any of these three sequences.**
>
> The preliminary broad novelty check used a 72-sequence curated database that does NOT include
> patent sequences; that check returned NOVEL for SEED-020_VAR_004 and SEED-020_VAR_002 —
> that result was misleading and is superseded by the full-DB BLOSUM62 audit above.
>
> **Safest wave 0.5b alternative — SEED-020_VAR_008 (RVRIKVLKRLLK):** 67% to DRAMP31150
> (general/public database — no patent hit); classified **CLEAR**. If IP clearance for
> VAR_004/VAR_002 cannot be confirmed before the synthesis deadline, use VAR_008 as the
> primary SEED-020 representative.

SEED-020_VAR_004 is the **best safety-activity tradeoff in the entire wave 0.5b batch** by
combined external predictor consensus. SEED-020_VAR_002 has the highest AMPScanner score (0.9960)
of any candidate in the batch.

**Novelty:** SEED-020_VAR_004 and SEED-020_VAR_002 confirmed NOVEL by broad novelty check
(72-AMP curated reference database; < 50% similarity). Closest matches are in the REF-RLK-001
(cationic helix) and REF-LL37-003 (LL-37 fragment) classes — confirmed activity in either
would be publishable. SEED-019_VAR_004 carries a patent proximity flag (see IP NOTE above);
publishability claims for SEED-019_VAR_004 require IP clearance.
of any candidate in the batch. Both require IP clearance before synthesis (see IP NOTE above).

**Novelty:** The preliminary broad novelty check (72-AMP curated DB; <50% similarity) showed
NOVEL for SEED-020_VAR_004 and VAR_002, but this database does not include patent sequences.
The full BLOSUM62 audit (27,234 sequences including DRAMP patent DB) classifies VAR_004 and
VAR_002 as **CLOSE_RELATIVE with POSSIBLE_PATENT_RISK** (75% to DRAMP05502 and 67% to
DRAMP05504 respectively). Activity confirmed at wet-lab would require patent search and IP
clearance before publication. SEED-020_VAR_008 (RVRIKVLKRLLK; CLEAR — public DRAMP entry,
no patent sub-database hit) is the publication-safe fallback within this scaffold class. SEED-019_VAR_004 also carries
a patent proximity flag (see IP NOTE above).

**Mechanism:** Cationic amphipathic helix — alternating hydrophobic (Leu/Val/Ile) and cationic
(Arg/Lys) faces interact with anionic bacterial membranes, causing rapid membrane depolarization.
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