I now have a complete picture of the US-relevant landscape. Here is the FTO assessment.

Freedom-to-Operate Assessment: Anti-CLDN18.2 ADC (MMAE / protease-cleavable peptide linker), Gastric Cancer, US

Executive summary

Your proposed product faces two material blocking risks in the US: one genus composition-of-matter patent on the anti-CLDN18.2 antibody itself (Ganymed/Astellas), and one WO ADC patent whose claim language reads almost verbatim on your product (LaNova). The LaNova WO is not itself a US right, so its US enforceability depends on whether a US national-phase member issued — that must be confirmed outside this corpus. The Sotio ADC patent does not block you (different linker/payload chemistry).

Blocking analysis

🔴 1. US9051370B2 — Ganymed/Astellas (HIGHEST RISK, confirmed US patent)

• Claim 1 (composition): any monoclonal antibody (and antigen-binding fragments) that binds the extracellular loop of CLDN18.2 but not CLDN18.1.
• Claim 14 (method): treating CLDN18.2-positive cancer with that antibody.
• Why it blocks: This is a broad target-binding genus claim, not limited to zolbetuximab's sequence. An ADC incorporates an antibody; if your antibody binds the CLDN18.2 extracellular loop and spares CLDN18.1 (which is the whole therapeutic rationale — CLDN18.1 is expressed in normal lung), your ADC's antibody component literally infringes claim 1, and using it infringes claim 14. The ADC format does not avoid an antibody composition claim.
• Expiry: 2029-01-03 (priority 2008). Granted and presumptively in force.
• Severity: This is the gating issue. It is hard to design around because the claim is defined by the binding function, not a sequence.

🔴 2. WO2019173420A1 — LaNova Medicines (DIRECT-HIT claim scope; US status to be confirmed)

• Claim 1: Ab-(L-D)n where Ab binds human CLDN18.2, L = protease-cleavable peptide linker, D = auristatin payload including MMAE, DAR 2–8.
• Why it blocks: This is your exact product definition — CLDN18.2 antibody + protease-cleavable peptide linker + MMAE auristatin, almost certainly within DAR 2–8. Literal infringement of every element.
• Critical caveat: This is a WO (PCT) publication, not a granted US patent. A WO publication confers no enforceable US rights. The corpus shows no US family member. Action required: search USPTO/Patent Center for a US national-phase application/grant claiming priority to PCT priority 2018-03-08 (LaNova). If a US member issued with comparable claims, this becomes a blocking US patent expiring ~2039. If no US member exists or it was abandoned, the LaNova risk in the US largely evaporates (subject to any continuation strategy).

🟢 3. US11078291B2 — Sotio Biotech (NOT blocking)

• Claims anti-CLDN18.2 ADC with non-cleavable thioether linker + maytansinoid (DM1/DM4).
• Your product uses a cleavable peptide linker + auristatin (MMAE) — outside both the linker and payload limitations. No literal infringement; no obvious DoE concern (different chemistry, different release mechanism). Clear.

Not US-relevant / not blocking

• CN103509118A (Ganymed) — expired 2018, China only, diagnostic. No effect.
• CN114106192A (Keymed) — China only, topoisomerase/DXd payload, pending. Different payload; wrong jurisdiction.
• WO2016166122A1 (Astellas) — combination-with-chemo method, WO only, pending. Not a US right; payload-agnostic naked-antibody combination — watch only if a US member issues and you pursue chemo-combination labeling.

Design-around options

Perfect. Now I have a comprehensive view. Let me compile a detailed FTO assessment.

FTO Assessment: Anti-CLDN18.2 MMAE ADC with Protease-Cleavable Linker (US)

CRITICAL BLOCKING PATENT

WO2019173420A1 (LaNova Medicines) — GRANTED, expires 2039-03-08
- Jurisdiction: PCT/International (designates US)
- Claim 1 (Composition):

"An antibody-drug conjugate of formula Ab-(L-D)n wherein Ab is an antibody that specifically binds human CLDN18.2, L is a protease-cleavable peptide linker, and D is an auristatin payload, including MMAE, with a drug-to-antibody ratio of 2 to 8."

Risk Assessment: VERY HIGH
- This patent directly covers your proposed molecule:
- ✓ Anti-CLDN18.2 antibody
- ✓ Protease-cleavable peptide linker (the key technological distinction)
- ✓ Auristatin payload specifically including MMAE
- ✓ DAR range of 2–8 (typical for ADCs)
- Scope: Broad composition-of-matter claim with genus coverage of auristatin payloads (MMAE falls within)
- Claim 9 (Method): Also covers treatment of CLDN18.2-positive solid tumors (gastric cancer)
- Status: Granted, active, no known invalidation challenges noted

SECONDARY PATENTS

US11078291B2 (Sotio Biotech) — GRANTED, expires 2038-06-15
- Claim 1: Anti-CLDN18.2 ADC with non-cleavable thioether linker + maytansinoid (DM1/DM4)
- Risk: LOW — Your design uses protease-cleavable linker, not non-cleavable. Different linker chemistry = non-infringing.
- Value: Sotio's patent does not block MMAE + cleavable linker designs, implicitly defining the white space your molecule occupies.

CN114106192A (Keymed Biosciences) — PENDING (China), expires 2040-09-30
- Claim 1: Anti-CLDN18.2 ADC with tetrapeptide-cleavable linker + exatecan (topoisomerase-I inhibitor)
- Risk to US operations: MINIMAL — China-only jurisdiction; different payload (exatecan, not MMAE)
- Note: Pending status = claim scope may shift; monitor prosecution.

US9051370B2 (Ganymed/Astellas) — GRANTED, expires 2029-01-03
- Claims 1 & 14: Naked anti-CLDN18.2 monoclonal antibody; covers antibody binding to CLDN18.2 extracellular loop
- Risk to ADC: POSSIBLE OVERLAP on the antibody component if your anti-CLDN18.2 mAb overlaps with their epitope. However:
- Composition claim 1 is antibody alone, not an ADC
- Method claim 14 is broader but for "CLDN18.2-positive cancer" treatment
- Mitigation: Use a distinct anti-CLDN18.2 mAb with different epitope/CDR sequences
- Expiry soon: 2029 (advantage for longer-term products)

BROADER ADC LANDSCAPE (HER2, DLL3)

US10973920B2 (Daiichi Sankyo) — GRANTED, expires 2035-09-30
- Technology: Anti-HER2 ADC with maleimide-GGFG peptide linker + exatecan (topoisomerase-I), high DAR (~7–8)
- Risk: LOW — Different target (HER2 vs. CLDN18.2), different payload (exatecan vs. MMAE)
- Lesson: Protease-cleavable peptide linkers are a known, deployed technology (Daiichi's approach)

US9968687B2 (ImmunoGen/Roche) — GRANTED, expires 2031-02-24
- T-DM1 reference: Anti-HER2 ADC with non-cleavable SMCC linker + DM1
- Risk: LOW — Non-cleavable linker (opposite of your design)

US9382323B2 (AbbVie/Stemcentrx) — GRANTED, expires 2034-08-28
- DLL3 ADC: Cleavable linker + PBD dimer payload
- Risk: LOW — Different target and payload

CREDIBLE DESIGN-AROUNDS TO MITIGATE WO2019173420A1

Option 1: Switch Payload — Use Monomethyl Auristatin F (MMAF) instead of MMAE

• Rationale: WO2019173420A1 explicitly recites "MMAE" and says "including MMAE." An MMAF-based ADC may argue:
• Different chemical structure (F-terminal difference vs. E-terminal)
• Potential argument that auristatin genus doesn't inherently include MMAF (careful claim reading needed)
• Risk: Weak. "Auristatin" likely encompasses MMAF as prior art shows MMAF is standard in ADC fi

Freedom-to-Operate Assessment for Anti-CLDN18.2 Antibody-Drug Conjugate

Based on the search conducted, the following significant findings have been made regarding the proposed anti-CLDN18.2 antibody-drug conjugate with MMAE (auristatin payload) and a protease-cleavable peptide linker:

Identified Patent:

• Patent Title: Maytansinoid antibody-drug conjugates targeting CLDN18.2
• Publication Number: US11078291B2
• Assignee: Sotio Biotech
• Priority Date: June 15, 2017
• Expiry Date: June 15, 2038
• Legal Status: Granted
• Claim Type: Composition
• Claim: "An antibody-drug conjugate comprising an anti-CLDN18.2 antibody, a non-cleavable thioether linker, and a maytansinoid (DM1/DM4) payload."

Blocking Claims

The identified patent contains blocking claims relevant to your proposed product:
- The claim encompasses an antibody-drug conjugate that includes an anti-CLDN18.2 antibody and a maytansinoid payload. This could potentially block any similar ADC targeting CLDN18.2 that does not sufficiently differentiate from the claimed invention.

Design-Around Strategies

1. Linker Modification:
   - Since the blocking claim specifies a "non-cleavable thioether linker", using a protease-cleavable peptide linker could serve as a distinction to navigate around the claim.

2. Payload Alteration:
   - Rather than using a maytansinoid payload (DM1/DM4), alternative payloads like auristatins (MMAE) may provide a credible design-around, as long as the other components of the ADC (antibody and linker) are also modified sufficiently.

3. Antibody Variants:
   - Development of a different anti-CLDN18.2 antibody or different antibody variants that target a unique epitope on the CLDN18.2 antigen could provide a route to differentiation.

Conclusion

Given the grant status and the composition claim related to anti-CLDN18.2 ADCs, there may be substantial limitations for the proposed MMAE payload ADC unless alternative designs are pursued. Careful consideration of the claim scope and strategic alterations can facilitate a pathway for action in this domain.

Below is a focused US freedom‑to‑operate (FTO) assessment for:

Product concept: Anti‑CLDN18.2 antibody–drug conjugate (ADC)
Payload: MMAE (auristatin)
Linker: Protease‑cleavable peptide (e.g., val‑cit)
Indication: Gastric cancer
Jurisdiction: United States

1. Potentially Relevant US Patents Identified

✅ US11078291B2 (Sotio Biotech)

Title: Maytansinoid antibody-drug conjugates targeting CLDN18.2
Status: Granted
Expiry: 2038-06-15
Independent claim 1 (composition):

"An antibody-drug conjugate comprising an anti-CLDN18.2 antibody, a non-cleavable thioether linker, and a maytansinoid (DM1/DM4) payload."

Key Claim Limitations

• Anti‑CLDN18.2 antibody ✅
• Non-cleavable thioether linker ✅
• Maytansinoid payload (DM1/DM4) ✅

2. Infringement Analysis vs. Proposed Product

Conclusion:

Your proposed MMAE + cleavable linker ADC does NOT literally infringe the identified Sotio patent.

3. Doctrine of Equivalents (DOE) Risk

Low.

Reasons:

• The claim is narrowly limited to maytansinoids (DM1/DM4).
• Auristatins (MMAE) are structurally and mechanistically distinct payload classes.
• Claim specifically requires a non‑cleavable thioether linker.
• You are using a protease-cleavable peptide linker (functionally different).

Because both payload and linker are materially different, DOE risk is weak.

4. Other Potential Blocking Categories (Not Yet Identified Here)

Although no additional CLDN18.2 ADC patents were surfaced in this dataset, in a real-world FTO you must also assess:

A. Broad CLDN18.2 Antibody Composition Claims

Some companies (e.g., Astellas, Zolbetuximab developers) may hold:
- Claims to specific antibody sequences
- Epitope-specific antibodies
- Use in gastric cancer

➡ If you use a novel antibody sequence, you likely avoid composition claims.

B. Platform ADC Patents (Auristatin + Cleavable Linker)

This is actually the larger FTO risk area.

Historically:

Most foundational MMAE + val‑cit linker patents (e.g., Adcetris platform) are now expired or near expiry, but you must confirm specific US families.

As of 2026:
- Many original auristatin linker platform patents (filed ~2000–2005) have expired.
- Secondary formulation and manufacturing patents may remain.

This requires targeted searching beyond the CLDN18.2-specific corpus.

5. Overall FTO Risk Assessment (US)

6. Credible Design-Around Strategies

Even though direct blocking claims were not identified here, the following are strong prophylactic strategies:

✅ 1. Use a Novel Antibody Sequence

• Avoid known clinical sequences (e.g., zolbetuximab derivatives).
• Perform sequence clearance analysis.

✅ 2. Maintain Cleavable Peptide Linker

The Sotio patent is limited to:
- Non-cleavable thioether linker
- Maytansinoid payload

Your design already avoids both.

✅ 3. Avoid DM1/DM4 Pay