US 12364691

I'll verify the patent's status and check for any litigation, then summarize from the authoritative full text provided.

Let me attempt to pull the actual claim set to ground the independent-claim summary.

US 12,364,691 B2 — Verification Summary

Verification status: Confirmed as an existing, granted, currently-active US patent. Matches the number exactly as given (US 12,364,691 B2; application US 17/824,421). No similar-but-different number was substituted.

Note on scope of my search: I was able to confirm bibliographic data, Orange Book listing, and the text of claims 1–2. I did not find any Court of Appeals for the Federal Circuit (CAFC) 2026 docket activity for this patent. That is a negative finding from search, not proof of absence — see the "Litigation / docket" section below.

1. Bibliographic data

Continuity chain (from the specification itself): a continuation of Ser. No. 16/012,372 → Ser. No. 15/664,930 (abandoned) → Ser. No. 15/241,128 (now US 9,717,724, issued Aug. 1, 2017) → a continuation-in-part of Ser. No. 14,406,776 (now US 9,452,162, issued Sep. 27, 2016), which is the §371 national phase of PCT/US2013/045495.

⚠️ Expiration-date discrepancy (flagged, not reconciled): Google Patents shows an adjusted expiration of 2034-02-22 (i.e., inclusive of patent term adjustment), whereas FDA Orange Book aggregators (TheraRadar, GreyB/Pharsight, PharmaCompass) list June 12, 2033, which is the nominal 20-year date from the June 12, 2013 PCT filing. These are consistent with each other only if the 2033 date is the nominal date and 2034-02-22 is the PTA-adjusted date. I cannot independently verify the PTA calculation from the sources retrieved.

2. Abstract (verbatim)

"Provided are methods for treating pancreatic cancer in a patient by administering liposomal irinotecan (MM-398) alone or in combination with additional therapeutic agents. In one embodiment, the liposomal irinotecan (MM-398) is co-administered with 5-fluorouracil and leucovorin."

3. Independent-claim overview (plain language)

Important caveat: The full claim set was not available to me in its entirety. I verified the verbatim text of claim 1 and part of claim 2 via DrugPatentWatch's claim reproduction. The remaining independent claims below are described from the patent's own Summary of the Invention section, and I cannot confirm their claim numbers or exact wording — treat those as probable, not verified.

Claim 1 (verified verbatim in substance) — the NAPOLI-1 combination regimen as a locked-down method claim

Claim 1 is a method of treating metastatic adenocarcinoma of the pancreas in human patients after disease progression following gemcitabine-based therapy, with a specific treated-patient population (Karnofsky Performance Status ≥ 70, albumin ≥ 3 g/dL, serum bilirubin within normal range). It requires intravenous administration of three things — liposomal irinotecan, leucovorin, and 5-FU — in a 2-week repeating cycle, where:

• (a) the liposomal irinotecan is given on day 1 by 90-minute infusion as irinotecan sucrose octasulfate salt liposome injection, in an irinotecan-moiety amount equivalent to 80 mg/m² of irinotecan hydrochloride trihydrate;
• (b) leucovorin is 200 mg/m² of the (l) form, or 400 mg/m² of (l+d) leucovorin, infused over 30 minutes;
• (c) 5-FU is a total dose of 2,400 mg/m² infused over 46 hours;
• (d) no other antineoplastic agent is administered for the pancreatic cancer beyond the liposomal irinotecan of (a) and the 5-FU of (c) — i.e., a closed/negative limitation excluding gemcitabine and everything else;

and the claim closes with product-by-structure limitations on the liposome itself: a unilamellar lipid bilayer vesicle of approximately 80–140 nm diameter encapsulating an aqueous space containing irinotecan complexed in a gelated/precipitated state as a salt with sucrose octasulfate; membrane composed of 3 molar parts DSPC, 2 molar parts cholesterol, and 0.015 molar parts PEG2000-DSPE; and an irinotecan entity-to-lipid weight ratio of 0.5:1.

Plain-language read: "Treat gemcitabine-refractory metastatic pancreatic cancer with the specific NAPOLI-1 MM-398 + 5-FU + leucovorin regimen, in reasonably fit patients, using this specific liposome, and don't add any other anticancer drug."

Claim 2 (verified): depends from claim 1 and specifies that the human patients are not homozygous for UGT1A1*28.

Probable further independent claims (from the Summary; numbering unverified)

• Monotherapy method, q3w: treating pancreatic cancer with liposomal irinotecan in 3-week cycles, 120 mg/m² on day 1, except that patients homozygous for UGT1A1*28 receive 80 mg/m² in cycle 1 (optionally escalating by 20 mg/m² per cycle up to 120 mg/m²).
• Combination method, q2w (UGT1A1-stratified): co-administering liposomal irinotecan + 5-FU + leucovorin in 2-week cycles, where non-homozygous patients get 80 mg/m², and UGT1A1*28 homozygotes get 60 mg/m² in cycle 1 rising to 60–80 mg/m² thereafter; 5-FU 2400 mg/m²; leucovorin 200 mg/m² (l) or 400 mg/m² (l+d).
• Formulation-for-use claim (Swiss-type/"formulation of liposomal irinotecan for co-administration"): the same q2w combination parameters framed as a liposomal irinotecan formulation for use with 5-FU/LV.
• Kit claims: a kit comprising a dose of liposomal irinotecan (and in another aspect, doses of all three agents) with instructions for the disclosed dosing.
• Tumor-vascularity method: improving chemotherapy outcomes by administering irinotecan sucrose octasulfate salt liposome injection in an amount effective to increase tumor vascularity, plus concomitant administration of a non-irinotecan chemotherapy agent.
• Composition-for-use counterpart: irinotecan sucrose octasulfate salt liposome injection for concomitant administration of (1) an amount effective to increase tumor vascularity and (2) an effective amount of a non-irinotecan chemotherapy agent.

4. Technical substance (one paragraph)

The patent covers the nal-IRI (nanoliposomal irinotecan, MM-398 / Onivyde) regimen for gemcitabine-refractory metastatic pancreatic adenocarcinoma. The specification supports three pillars: (i) preclinical data — superior anti-tumor activity in the orthotopic L3.6pl pancreatic model (Fig. 1), a ~20-fold increase in tumor SN-38 AUC versus free irinotecan (Fig. 2), dose-dependent reduction of the hypoxia marker CAIX (Fig. 3), and increased perfusion of Hoechst dye (Fig. 4); (ii) pharmacokinetics — prolonged total-irinotecan half-life (~21–48 h), much higher Cmax/AUC for total irinotecan versus free drug, but lower SN-38 Cmax, and the observation that SN-38 Cmax scales proportionally with dose while SN-38 AUC scales less than proportionally (the asserted basis for a widened therapeutic index and for dose-adjustment methods); and (iii) the NAPOLI-1 Phase 3 results — median OS 6.1 months for MM-398+5-FU/LV vs. 5-FU/LV control (per-protocol population 8.9 months), with the most common grade ≥3 TEAEs being neutropenia, fatigue, diarrhea, and vomiting, plus the UGT1A1*28 dose-reduction rationale.

5. Litigation / docket status

• District court: Google Patents' litigation record (sourced from Unified Patents) lists a US case filed in the District of New Jersey, case 1:25-cv-13647. Darts-ip separately flags "first worldwide family litigation" for family 57601636. Consistent with a Hatch-Waxman/ANDA dispute over an Orange Book-listed patent, but I have not confirmed the parties, the asserted claims, or the current posture from a primary docket source.
• Federal Circuit (CAFC), 2026: No CAFC docket activity for this patent was found. I searched specifically for CAFC 2026 activity tied to this number and retrieved nothing on point. Because district-court cases filed in 2025 would in the ordinary course not yet be at the Federal Circuit, the absence of a CAFC docket is unsurprising — but I want to be explicit that this is a negative search result, not confirmation of no CAFC involvement. Google Patents, Justia, and the FDA/Orange Book aggregators do not, by themselves, provide a complete Federal Circuit docket.
• PTAB: Multiple PTAB petition documents surfaced in search that discuss a "Bayever" specification (e.g., "Bayever's Example 7 discloses dosing modifications … depending on a patient's UGT1A1*28 [status]") and the Ko Phase II PEP02 reference, which strongly suggests post-grant proceedings (IPR/PGR) touching this patent family. I could not confirm the specific PTAB case number or patent from the retrieved snippets, so I am flagging this as a lead rather than a verified fact.

6. Explicit uncertainties

1. Total claim count and the full independent-claim set are unknown to me. Only claims 1 and 2 were verified textually; the Summary-derived independent claims may be numbered differently and may have been amended during prosecution.
2. The patent's own text has apparent typographical errors that I am reproducing literally rather than correcting: "an affective amount of liposomal irinotecan" (Summary), "(5) 4,11-diethyl…" for the irinotecan stereodescriptor (should conventionally read (S)), and "t serv" vs. "t surv" mixed usage.
3. The expiration date is unresolved (2033-06-12 nominal vs. 2034-02-22 adjusted) — see the discrepancy flagged above.
4. The district-court case number 1:25-cv-13647 and the PTAB leads are second-hand. I did not retrieve the complaint, the PTAB petition caption, or a CAFC docket directly.

Sources consulted: the authoritative full patent text at https://patents.google.com/patent/[US12364691B2](/patent/US12364691B2)/en (including its "Family has litigation" entries pointing to https://portal.unifiedpatents.com/litigation/New%20Jersey%20District%20Court/case/1%3A25-cv-13647 and https://patents.darts-ip.com/?family=57601636); claim text via https://www.drugpatentwatch.com/p/patent-claims/[12364691](/patent/12364691); Orange Book listing data via https://theraradar.com/drugs/onivyde/patents/ and https://pharsight.greyb.com/ingredient/irinotecan-hydrochloride; family/specification cross-check against EP 2 861 210 B1 and US 9,452,162 B2.

I'll search for litigation involving US patent 12364691.

Let me search for the specific New Jersey case identified in the patent record.

Let me check for any additional cases or IPR proceedings involving this patent.

Litigation Involving U.S. Patent No. 12,364,691

Based on searches of Google Patents' litigation links, the Unified Patents portal, Justia Dockets, and litigation/news coverage, I found one (1) lawsuit asserting U.S. Patent No. 12,364,691 (the "'691 patent"). Note that I interpreted the number literally as 12,364,691; results referencing other numbers (e.g., 6,771,646; 10,130,646; the "646" patents) are unrelated and were disregarded.

Case 1 — Ipsen Biopharmaceuticals, Inc. et al. v. Conjupro Biotherapeutics, Inc. et al.

Procedural history and current status:

• The '691 patent was listed in the Orange Book against Ipsen's NDA No. 207793 for Onivyde® (irinotecan liposome injection). Source: Google Patents family/litigation data (portal.unifiedpatents.com litigation link to the N.J. case).
• This was the third infringement action Ipsen filed against the Conjupro/CSPC defendants over the Onivyde patent family, following:
  • C.A. No. 24-4991 (D.N.J.), filed April 15, 2024 (asserting U.S. Pat. Nos. 8,329,213; 9,339,497; 9,364,473; 9,452,162; 9,492,442; 9,717,724; 10,980,795; and 11,369,597 — i.e., not the '691 patent, which had not yet issued).
  • C.A. No. 24-8723 (D.N.J.), filed August 23, 2024 (asserting U.S. Pat. No. 12,059,497), consolidated with 24-4991 on October 18, 2024.
• August 21, 2025: The Court issued a text order consolidating Docket Nos. 24-4991 and 25-13647, and set a Markman hearing for February 19, 2026 (Camden).
• September 5, 2025: Order (Chief Judge Bumb) consolidating Civil Action Nos. 24-4991 and 25-13647 and directing the Clerk to administratively terminate the 25-13647 docket; the '691 claims now proceed within the consolidated action.
• Defendants' answer/counterclaims: Defendants denied infringement and alleged the '691 patent is invalid under 35 U.S.C. §§ 101, 102, 103 and/or 112; also asserted affirmative defenses of non-infringement, failure to state a claim, prosecution history estoppel, limitation on costs under § 288, and equitable defenses. They also filed counterclaims seeking declaratory judgments of non-infringement/invalidity.
• Outcome: No final judgment or settlement reflected in the sources reviewed. The matter remains pending in the consolidated D.N.J. action as of the last docket activity retrieved (September 9, 2025). The scheduled February 19, 2026 Markman hearing post-dates the last docket snapshot I could retrieve, so I cannot confirm whether it went forward or what was decided.

Related proceedings (NOT against the '691 patent — provided for context)

• IPR2025-00505 (PTAB): CSPC Pharmaceutical Group Limited et al. v. Ipsen Biopharm Ltd., challenging U.S. Pat. No. 11,344,552 (a different, related Ipsen patent) — instituted August 14, 2025.
• IPR2025-01531 (PTAB): Apotex Inc. v. Ipsen Biopharm Ltd., also challenging U.S. Pat. No. 11,344,552, seeking joinder to IPR2025-00505.

I found no IPR, PGR, or other PTAB proceeding directed specifically at U.S. Pat. No. 12,364,691 in the sources reviewed.

Caveats and confidence notes

1. A significant discrepancy exists in one source. An Apotex joinder motion (IPR2025-01531) states that "On December 20, 2024, Patent Owner filed a complaint against Conjupro Biotherapeutics, Inc. … Case No. 1:25-cv-13647 … asserting infringement of the '552 patent." That statement conflicts with (a) the D.N.J. docket, which shows 25-13647 was filed July 22, 2025, and (b) the defendants' own counterclaims, which identify 25-13647 as the action asserting the '691 patent. I have treated the latter (docket + case documents) as controlling and flag the IPR-motion text as likely erroneous or conflated. Per the strict-interpretation rule, I am not "correcting" any number — I am reporting the conflict.
2. The Google Patents page lists only a single litigation link for this family (the N.J. case) and a Darts-IP "first worldwide family litigation filed" link (family 57601636), which points to the same U.S. case.
3. My searches did not surface any additional U.S. or foreign suits naming the '691 patent specifically, but I cannot rule out very recent filings (post-dating the latest retrievable docket data) that are not yet indexed. This should not be treated as a comprehensive or cleared freedom-to-operate search.

Would you like me to attempt to pull the most recent PACER docket entries for the consolidated 24-4991 action or the February 2026 Markman outcome?

I'll start by searching for PTAB proceedings on this patent and its family members.

Let me search the patent family more specifically.

Let me search specifically for the '691 patent and related 2025-2026 proceedings.

Proceedings overview

Total AIA trial proceedings on US 12,364,691: 0. The canonical source — the USPTO Open Data Portal "PTAB proceedings on file" block supplied with this task — returns no IPR, PGR, or CBM for this patent, and my independent web searches surfaced no petition, institution decision, or Final Written Decision naming the '691 patent. Breakdown by status therefore is: active 0 / claims invalidated 0 / claims sustained 0 / settled 0 / institution denied 0.

Bottom line for a defendant: the "0" is not the same as "the patent is clean." It means the '691 patent is untested at the PTAB, not that it has survived anything. Nothing has been canceled, nothing has been sustained, and no claim has been construed by the Board. Anyone asserting the '691 patent today is asserting a patent that has never been through an AIA trial — which cuts both ways: the claims are intact and there is no § 315(e) estoppel to exploit, but there is also no FWD you can point to, pro or con.

Two important caveats that shape the real defensive picture:

1. The '691 patent is brand new. It issued 2025-07-22 from application 17/824,421 (filed 2022-05-25), a continuation in the Bayever/MM‑398 chain claiming priority to 2012-06-13. Its IPR eligibility window under § 311(c) opened on 2026-04-22 (nine months post-grant), i.e., roughly five months before today. A petition filed today would be timely as to a new petitioner with no § 315(b) service history.
2. The same patent family is already under PTAB attack — just on sibling patents. Petitions have been filed against U.S. 11,344,552 ('552, the NALIRIFOX/liposomal‑irinotecan + oxaliplatin patent) by both CSPC Pharmaceutical Group / CSPC Ouyi / Conjupro Biotherapeutics and by Apotex, Inc. I found an Apotex petition on '552 (IPR2025‑01531) and a CSPC IPR on '552, plus a CSPC challenge to the '473 patent. None of these reaches the '691 claims, and I could not confirm the CSPC '552 proceeding number from public sources — treat that number as unverified.

Proceedings on US 12,364,691

None. There is no proceeding to describe.

Per the operating rule in the prompt, the default is "no PTAB activity on file," and nothing in my searches displaced that default. I will not invent a proceeding number, panel, or disposition.

Adjacent-family AIA activity (NOT proceedings on the '691 patent — context only)

I list these only because a defendant will encounter them and should not confuse them with '691 exposure.

IPR2025-01531 — Apotex, Inc. v. Ipsen Biopharm Ltd.

• Type: Inter Partes Review
• Patent challenged: U.S. 11,344,552 — not the '691 patent
• Status: Preliminary stage. Patent Owner's Preliminary Response on file; Notice of Filing Date Accorded entered 2025-09-23.
• Petition grounds: Obviousness under § 103, claims 1–15, over Conroy, Conroy Protocol, Conroy Appendix, Mahaseth, Bayever, Saif, Ko, Cantore (Ground 1); plus Masi and Ginocchi (Ground 2); plus Carnevale and Dean (Ground 3). The claims are directed to liposomal irinotecan 60 mg/m² + oxaliplatin 60 mg/m² + leucovorin + 5‑FU 2400 mg/m² q2w.
• Institution decision: none found on the public record I retrieved.
• Defensive value for '691: minimal. The § 315(e) estoppel that may attach to Apotex runs to the '552 patent, not to claims of '691.

CSPC / Conjupro IPR(s) on the '552 (and '473) patents

• Type: Inter Partes Review
• Patent challenged: U.S. 11,344,552 ('552) — and separately the '473 patent. Not the '691 patent.
• Status: Appears to have been instituted, at least as to '552 — Ipsen's later Apotex POPR refers to "the Director's finding, in the CSPC IPR, that the prior art discloses critical claim limitations." I could not retrieve the proceeding number, the institution date, or the panel. Flagging this as an open item to verify on PTAB E2E, not as a confirmed fact.
• Note: The March 26, 2025 Director's Memorandum on PTAB workload management is invoked in that docket, so institution was Director-controlled.
• Defensive value for '691: The reference set (Conroy 2011 NEJM/FOLFIRINOX; Mahaseth; Saif; Ko; Cantore; Masi; Ginocchi) is portable in principle, but the timing problem described below is severe.

No PGR is possible on the '691 patent. Its earliest priority is 2012-06-13, before the 2013-03-16 AIA effective date, so the PGR window (which closed ~2026-04-22 anyway) was never available. CBM is unavailable — it sunset 2020-09-16, and a method-of-treatment claim is not a covered business method.

Strategic summary

Claim status: everything is UNTESTED. No claim of US 12,364,691 has been canceled, narrowed, or confirmed by the PTAB. From the claim text published for the '691 patent, independent claim 1 is directed to treating metastatic pancreatic adenocarcinoma post-gemcitabine, in patients with KPS ≥ 70, albumin ≥ 3 g/dL and normal bilirubin, with intravenous irinotecan sucrose octasulfate liposome (90-minute infusion, irinotecan moiety equivalent to 80 mg/m² irinotecan HCl trihydrate) + leucovorin (200 mg/m² (l) form or 400 mg/m² (l+d)) + 5‑FU 2,400 mg/m² over 46 h on a 2‑week cycle, with no other antineoplastic agent, and closed by structural limitations — unilamellar 80–140 nm vesicle, DSPC:cholesterol:PEG2000‑DSPE at 3:2:0.015 molar parts, irinotecan:lipid weight ratio 0.5:1. Dependent claims add non‑UGT1A128 status (claim 2) and administration sequence (claim 3), and a further independent claim (claim 4) addresses the UGT1A128‑homozygous 60 mg/m² first-cycle population. Because none of this has been construed in an AIA trial, there is no Board claim construction and no FWD reasoning to borrow. (Source: drugpatentwatch claim text for 12,364,691 — secondary source; verify against the granted patent at patents.google.com/patent/US12364691/en.)

Estoppel landscape. No § 315(e)(2) estoppel has attached to any claim of the '691 patent, because estoppel requires an IPR that reaches a final written decision, and no such IPR exists here. Any estoppel running against CSPC, Conjupro, or Apotex from the '552 or '473 proceedings is patent-specific — it bars them from re-running, in a later civil action or ITC proceeding, grounds they raised or reasonably could have raised as to those claims of those patents. It does not bar them (or anyone else) from raising prior art against the '691 claims. For a defendant new to the fight, the entire § 102/§ 103 field is open.

The critical timing trap — and likely why there are no '691 IPRs. The '691 patent was asserted against Conjupro/CSPC in Ipsen Biopharmaceuticals, Inc. v. Conjupro Biotherapeutics, Inc., D.N.J. No. 1:25-cv-13647 (filed 2025-07-22; consolidated with the earlier 1:24-cv-04991 action in which 12,364,691 was also named in the patent schedule). Conjupro's answer there admits the '691 patent issued on 2025-07-22 but "den[ies] that the '691 patent was duly and legally issued," and counterclaims for declaratory judgment of invalidity and non-infringement under §§ 101, 102, 103 and/or 112, plus prosecution history estoppel, inequitable conduct/unenforceability and laches-flavored equitable defenses. See njdc25cv13647A.pdf and njdc25cv13647C.pdf; Unified Patents litigation record. Under § 315(b), the one-year clock for those served defendants ran from service of the '691 complaint — i.e., it likely expired on or about 2026-07-22, before today. If that reading is right, the parties closest to the invalidity case have already lost their IPR window on '691 and are confined to district court under § 282. A new petitioner (another ANDA filer, a different manufacturer, or a defensive aggregator) faces no such bar. This is a § 315(b) inference from public docket dates, not a Board ruling — verify the actual service dates before relying on it.

Pattern signals. (i) Ipsen is a serial enforcer on this family: one complaint in 2024 (1:24-cv-04991), a second in 2024 (1:24-cv-8723), and a third on 2025-07-22 (1:25-cv-13647), all consolidated in D.N.J. before Judge Bumb. (ii) The same petitioner group (CSPC/CSPC Ouyi/Conjupro) has both litigated and petitioned, and Apotex has separately petitioned — so the family is a magnet for AIA challenges even though '691 itself is untouched. (iii) I found no Unified Patents-style defensive-aggregator IPR on any patent in this family; the Google Patents page's "Family has litigation" flag routes to Unified's litigation database, not to a Unified-filed IPR — do not misread it as aggregator activity. (iv) No Federal Circuit appeal exists as to '691, because there is no FWD to appeal. (v) Foreign parallel proceedings are adverse and worth reading as a preview: the EPO Boards of Appeal revoked EP 2 861 210 (T 2963/19, decision 2022-03-18, opponent Teva) on inventive step, and EP 3 337 478 (T 2308/23, opponent Generics [UK]) turned on the same family's liposomal‑irinotecan combination claims. Those decisions are persuasive context for a § 103 attack in the U.S.

Recommended next steps

1. Confirm zero on PTAB E2E before you brief anything. Search the '691 patent number at PTAB E2E / Patent Trial and Appeal Board End-to-End (and the PTAB Decisions site). I found no proceeding, and ODP's structured feed reports none, but a petition filed in the last few months may not yet be indexed. There is no FWD to link to — because there is none.
2. If you are a new defendant/ANDA filer: you are inside the IPR window and should be the one to move. The window opened 2026-04-22. There is no § 315(b) bar, no § 315(e) estoppel against you, and no adverse FWD to overcome. The obviousness theories that the Board has already found sufficient to institute against the sibling '552 patent — the FOLFIRINOX/Conroy line plus the "replace free irinotecan with MM‑398" motivation cases (Saif, Ko) — are the natural starting point, and the '691 patent's added structural limitations (80–140 nm unilamellar vesicle; 3:2:0.015 DSPC/chol/PEG2000‑DSPE; 0.5:1 drug:lipid) point to a second, independent attack grounded in the liposome-formulation art (e.g., the WO 2005/107712 / Hermes lineage the specification itself cites).
3. Watch the priority/effective-filing-date issue. The '552 proceedings show the Board taking seriously the argument that claims limited to clinical efficacy lose the earlier priority benefit. '691's claim 1 closes on structural/pharmacokinetic parameters rather than an efficacy statement, but the same § 112(a) written-description attack on the 2012/2013 priority chain — and any resulting move of the effective filing date past the 2013-03-14 provisional — changes the entire prior-art field (it would make the family's own Bayever publication, to the extent it predates the new date, available). That is the single highest-leverage issue to develop.
4. Do not over-rely on the sibling-patent estoppel. § 315(e)(2) estoppel from the '552/'473 IPRs does not travel to the '691 claims. If you are a privy of a petitioner in those proceedings, you still have the full prior-art field open against '691 — but assume Patent Owner will argue privity-based estoppel arguments to complicate it.
5. Use the district court as your forum-of-record while the PTAB stays empty. Conjupro/CSPC's counterclaims in 1:25-cv-13647 already tee up §§ 101/102/103/112 and inequitable conduct. Statutory disclaimer, § 282 defenses, and the EPO revocations (T 2963/19; T 2308/23) are your live assets. If an IPR is filed by anyone, note the statutory milestones: institution decision within six months of the petition's filing date, and a Final Written Decision within one year of institution (§ 316(a)(11)), extendable to 18 months for good cause.

Sources cited: US 12,364,691 on Google Patents · DrugPatentWatch claim text, 12,364,691 · DrugPatentWatch litigation record, 1:24-cv-04991 · Conjupro answer/counterclaims, 1:25-cv-13647 · Ipsen complaint, 1:25-cv-13647 · Apotex POPR, IPR2025-01531 ('552) · EPO T 2963/19 (EP 2 861 210 revoked) · EPO T 2308/23 (EP 3 337 478) · Unified Patents litigation record

Confidence statement: I have high confidence that no AIA trial proceeding has been instituted or decided on US 12,364,691 — that is what the ODP feed says and what my searches show. I have lower confidence in the negative that no petition has been filed within the last few months and simply not yet indexed. I could not confirm the proceeding number, dates, or panel for the CSPC IPR against the '552 patent, and I have not verified the actual service dates that drive the § 315(b) analysis for 1:25-cv-13647; both should be checked at the source before you rely on them.

I'll research the assignment chain, corporate history, and litigation for US 12364691.

Let me dig into the assignment records, the Ipsen–Merrimack transaction, and the litigation details.

Let me try to pin down the actual reel/frame numbers and correspondents, plus inventor backgrounds.

Assignment & Ownership Analysis — US 12,364,691 B2

Patent: US 12,364,691 B2 — "Methods for treating pancreatic cancer using combination therapies"
App. No.: 17/824,421 (filed 2022-05-25; issued 2025-07-22)
Priority: 2012-06-13 (provisional 61/659,211) via PCT/US2013/045495
Family/Orange Book: Family 57601636; listed against NDA 207793 (Onivyde®) with use code U-1848; Google Patents lists adjusted expiration 2034-02-22.

Retrieval note (applies to the timeline section). I was able to retrieve the USPTO assignment recordation events (via the Google Patents legal-events feed), which show two assignments, both recorded 2023-01-27. I was not able to load the Assignment Center abstract of title directly, and the search results did not disclose the reel/frame numbers, execution dates, or correspondent-of-record for either document. Those fields are marked "not retrieved" below rather than guessed. Reel/frame and correspondent should be confirmed at the Assignment Center before this memo is relied on.

Inventors

All seven are the named inventors on the face of the patent, and all seven appear as assignors in the 2023-01-27 inventor→Merrimack recordation. The subject matter (MM-398/nal-IRI, the NAPOLI-1 clinical program) is Merrimack's own development program, so this is a classic single-employer inventor group. I could not independently verify each inventor's title/employment from a primary source in this session.

Unusual patterns — partial flag, not a finding. There is a documented corporate-level exodus rather than an inventor-level one: Merrimack eliminated its CEO in October 2016, cut ~20% of staff, shut down the MM-302 breast-cancer program in December 2016, and after the Ipsen asset sale reduced headcount from >400 to ~80 (Boston Business Journal, 2017-05-31). Whether any individual named inventor left within 12 months of filing is not determinable from the sources retrieved, and in any event the departures post-date the 2012–2013 filing by several years — so this does not fit the "pre-fire-sale inventor exodus" template.

Original assignee

Merrimack Pharmaceuticals, Inc. (Cambridge, Massachusetts; NASDAQ: MACK) is the original assignee named on the issued patent.

• Product embodying the claims: Yes — Merrimack developed and obtained FDA approval (October 2015) for Onivyde® (irinotecan liposome injection), MM-398, the liposomal irinotecan recited in the claims, indicated with 5-FU/leucovorin after gemcitabine failure. Merrimack was launching and selling it at the time of the asset sale.
• Primary line of business: Clinical-stage oncology biopharmaceutical company ("network biology" drug developer); Onivyde was its only commercial product.
• Current status: Functionally dissolved/wound up. Merrimack sold Onivyde plus a generic Doxil asset to Ipsen (announced 2017-01-09; closed 2017-04-03) for $575M upfront + up to $450M milestones; sold MM-121/MM-111 to 14ner Oncology (May 2019); terminated essentially all staff by June 2019 and reorganized itself into a milestone-collection vehicle. Following a final ~$225M Ipsen milestone triggered by the February 2024 FDA approval of the NALIRIFOX first-line regimen, Merrimack announced dissolution and distributed the proceeds as a cash dividend. No Chapter 7/11 filing was located — the asset sale was an out-of-court APA, not a bankruptcy sale.

Assignment timeline

Two assignment documents are of record. Both were recorded 2023-01-27, i.e., during prosecution of application 17/824,421 — roughly six years after the Ipsen transaction closed and roughly fifteen months before the first infringement suit.

• Execution date not retrieved / recorded 2023-01-27 — Reel/frame not retrieved

  • Conveyance: Assignment of assignors' interest (per Google Patents legal events: "ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS)")
  • Assignor: KIM, Jaeyeon; NIYIKIZA, Clet; MOYO, Victor; BAYEVER, Eliel; FITZGERALD, Jonathan Basil; DHINDSA, Navreet; LAIVINS, Peter (all inventors)
  • Assignee: MERRIMACK PHARMACEUTICALS, INC.
  • Correspondent: not retrieved
  • Context: Inventor-to-employer assignment perfecting title in the newly filed continuation; routine employment/confirmation recordation, not a transfer to a third party.

• Execution date not retrieved / recorded 2023-01-27 — Reel/frame not retrieved

  • Conveyance: Assignment of assignors' interest ("ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS)")
  • Assignor: MERRIMACK PHARMACEUTICALS, INC.
  • Assignee: IPSEN BIOPHARM LTD.
  • Correspondent: not retrieved
  • Context: Confirmatory recording of the 2017 corporate asset-purchase transfer (Onivyde transaction announced 2017-01-09, closed 2017-04-03, $575M upfront) against this continuation case. The gap between the 2017 deal closing and the 2023 recordation is administrative, not a new acquisition.

No other recorded assignments were identified. In particular, there is no separate security agreement, merger, change-of-name, or license recordation surfaced for this patent, and no post-issuance transfer. Caveat: because I could not open the Assignment Center abstract directly, I cannot rule out additional recorded documents (e.g., a security interest or release) that Google's legal-events feed does not surface.

Timeline diagram

timeline
    title Ownership of US 12364691
    2012 : Priority filing by Merrimack
    2013 : PCT application filed
    2017 : Ipsen buys Merrimack oncology assets
    2022 : Continuation application filed
    2023 : Inventors assign to Merrimack recorded
         : Merrimack assigns to Ipsen Biopharm recorded
    2025 : Patent issues July 22
         : Ipsen sues Conjupro and CSPC

NPE / troll-pattern signals

1. Shell-entity transfer — NOT PRESENT. The 2023-01-27 recordation moves the patent from Merrimack Pharmaceuticals, Inc. to Ipsen Biopharm Ltd, the UK operating subsidiary of Ipsen S.A. (Euronext Paris: IPN), a public specialty-pharma group with ~€1.6B+ in sales. The assignee name carries no "IP / Holdings / Ventures / Licensing" suffix, and the entity commercializes the patented product (Onivyde). This is an operating-company-to-operating-company asset sale.

2. Known asserter in the chain — NOT PRESENT. Neither Merrimack nor Ipsen Biopharm appears on the NPE lists named in the brief (Acacia, Marathon, Intellectual Ventures, IPNav, Wi-LAN, Conversant/Mosaid, Vringo, Pendrell, Innovatio, MPHJ, Lumen View, Round Rock, Document Generation Corp, Spangenberg entities). The only litigation of record is a branded-vs-generic ANDA action: Ipsen Biopharmaceuticals, Inc. et al. v. Conjupro Biotherapeutics, Inc., CSPC Pharmaceutical Group Limited, and CSPC Ouyi Pharmaceutical Co., Ltd., D.N.J. No. 1:25-cv-13647 (filed 2025-07-22, Nature of Suit 835 — ANDA).

3. Repeat correspondent across the chain — UNCLEAR / not assessable. Both the inventor→Merrimack and Merrimack→Ipsen documents were recorded on the same day (2023-01-27), which is consistent with a single firm preparing and filing both recordations as one chain-of-title package. However, I could not retrieve the correspondent of record for either document, so I cannot name the attorney/firm, cannot test recurrence across this chain or other patents, and cannot cross-check against any Unified Patents/RPX/Patent Progress assertion list. This signal is unresolved on the evidence available — it is not evidence of anything either way.

4. Cascading transfers — NOT PRESENT. The chain comprises only two links, both recorded on the same date. There is no sequence of chained LLCs, no shared registered-agent address, and no common-principal pattern. The intervening 2017→2023 gap reflects the timing of an asset-sale recordation, not rapid serial flipping.

5. Pre-litigation transfer — NOT PRESENT. The most recent recorded assignment is dated 2023-01-27, while the first infringement suit naming Ipsen's patents was filed 2024-04-15 (C.A. 24-4991) and the suit naming this patent was filed 2025-07-22 (C.A. 25-13647) — the same day the patent issued. The ownership transfer therefore precedes the first assertion by roughly 15 months and is not a within-6-month pre-suit transfer.

6. Bankruptcy fire-sale — NOT PRESENT (but note distressed-sale context). Merrimack's sale of Onivyde was a distressed but solvent out-of-court asset purchase, driven by the October 2016 restructuring, the December 2016 MM-302 failure, and debt pressure (its $175M senior secured notes were redeemed from proceeds). Related convertible-note litigation (Wells Fargo Bank, N.A. v. Merrimack Pharmaceuticals, Inc., Del. Ch.) settled in October 2017. No Chapter 7 or Chapter 11 filing by Merrimack was located, so the classic Kodak/Nortel/Polaroid template does not apply.

7. Privateering — NOT PRESENT. The ultimate parent (Ipsen) is itself the plaintiff asserting the patent against generic ANDA filers; there is no operating company hiding behind a proxy NPE. Ipsen is enforcing its own Orange Book-listed product.

8. Defensive aggregator (anti-NPE) — NOT PRESENT. The chain does not terminate at RPX, AST, LOT Network, Unified Patents, or OIN. It terminates at an operating pharmaceutical company that is actively asserting.

Additional observation (not one of the eight signals): the family shows ongoing continuation activity by the brand owner — US20230088999A1 (this case), US20240342162A1 (from 18/613,633, filed 2024-03-22) and US20260000666A1 (from 19/234,798, filed 2025-06-11) — i.e., a deliberate Orange Book patent-stack extension strategy. That is normal brand-side lifecycle management, not an NPE pattern.

Verdict

Operating-company assertion.

Ipsen Biopharm Ltd (current assignee per the 2023-01-27 Merrimack→Ipsen recordation) is the operating subsidiary of publicly traded Ipsen S.A., markets the patented product as Onivyde® (NDA 207793), and is asserting US 12,364,691 against ANDA filers Conjupro/CSPC in D.N.J. 1:25-cv-13647 — genuine generic competitors, not a licensing shell monetizing a paper portfolio. The chain is a two-link, single-employer-to-acquirer sequence (inventors → Merrimack → Ipsen) with no shell LLCs, no known asserter, no defensive aggregator, and no within-6-month pre-suit transfer; the only unresolved signal is signal 3 (correspondent recurrence), which is unresolved solely because the correspondent field was not retrievable, not because of any adverse evidence.

Verification links:

• USPTO Assignment Center (search "12364691"): https://assignmentcenter.uspto.gov/
• Google Patents legal events for US 12,364,691 B2: https://patents.google.com/patent/[US12364691B2](/patent/US12364691B2)/en
• Docket for the assertion: https://dockets.justia.com/docket/new-jersey/njdce/1:2025cv13647/[579995](/patent/579995)

Two items to close out before relying on this memo: (a) pull the reel/frame and correspondent of record for both 2023-01-27 documents from Assignment Center — the correspondent is the field most likely to change the analysis if it unexpectedly points at a known assertion firm; and (b) confirm whether any security-interest, release, or change-of-name recordations exist for this patent that Google's legal-events feed did not surface.

I'll research US patent 12364691 and its cited prior art references. Let me start with several searches.

Let me look for the specific cited references sections.

Let me look for the actual "Patent Citations" and "Non-Patent Citations" lists on the patent's face and prosecution history.

US 12,364,691 B2 — Prior-Art Citation Analysis

1. Identification (as returned by the search)

Search results for "12364691" also returned several unrelated documents (an SEC Form 24F‑2NT item, a Honeywell inventor list, unrelated chemical patents). Those are literal‑string false positives and are excluded.

2. Important caveat on the citation record

⚠️ I could not retrieve a verbatim image of the "References Cited" table printed on the face of US 12,364,691 B2. The full patent text supplied to me omits the front‑page citation table, and my searches returned Google Patents "similar/cited documents" mappings rather than the certified list. The reference set below is therefore a best‑available reconstruction drawn from:

• the U.S. patent‑document citation list of the closely related sibling patent US 11,369,597 (same specification, same family), and
• Google Patents' cited/citing mappings around US 12,364,691 B2 and its family, and
• documents cited inside the specification itself.

Treat inventor names, dates and § 102 assignments below as indicative, not certified. Where I could not verify a reference's contents I say so explicitly rather than guessing.

3. Patent citations and their § 102 relevance

3A. Liposomal drug‑delivery / formulation patents (relevant to the "liposomal irinotecan (MM‑398)" limitation)

3B. The patentee's own pancreatic‑cancer method patents (same family)

Analytical note: Because these are commonly owned, same‑specification continuations, they are ordinarily not § 102 prior art to US 12,364,691 ("by another" / "same invention"). They matter for statutory or non‑statutory double patenting and as § 103 starting points, not anticipation.

3C. Other cited U.S. documents

4. Foreign / PCT citations

5. Non‑patent literature cited in the specification itself

6. Bottom line — strongest § 102 candidates

1. WO 2003/013536 A2 (UGT1A1‑based irinotecan dosing) — the only third‑party reference that arguably reaches a dose‑modification limitation (the UGT1A1*28‑homozygote reduced‑dose element).
2. WO 2005/107712 A1 / US 8,147,867 family — reaches the liposomal irinotecan (irinotecan sucrose octasulfate) composition elements, but not the pancreatic q2w/q3w treatment method as a whole; because Merrimack/Ipsen is the common owner, expect ODP/§ 103 rather than clean § 102.
3. NAPOLI‑1 (Lancet 2016) — the pivotal § 102(a)(1)/§ 102(b) exposure only for claims lacking 2012/2013 priority support (the 2‑week combination regimen was added by later amendment).
4. The Bayever et al. family (US 9,339,497 / 9,364,473 / 9,452,162 / 9,492,442 / 9,717,724 / 10,980,795) — same‑family continuations: double‑patenting/§ 103 references, not anticipatory art.
5. Every other citation (Hong/Drummond/Tardi/Janoff/Benz liposome patents; Schoeberl, Marks, Anderson, Okabe) is § 103 background at most for the method‑of‑treatment claims.

7. Explicit limitations of this analysis

• I did not obtain a certified copy of the "References Cited" table on the face of US 12,364,691 B2; the list above is reconstructed from the sibling patent US 11,369,597, Google Patents mapping data, and the specification's own citations. A USPTO PatentCenter / Global Dossier pull of the 17/824,421 file wrapper (Form PTO‑892 / PTO‑1449) would be needed to certify the exact cited set.
• Claim‑number mapping is inferred from the patent's SUMMARY and Definitions (the q3w monotherapy claim with the 120 mg/m² / 80 mg/m² UGT1A1 split; the q2w triple‑combination claim with 80/60 mg/m² liposomal irinotecan + 2,400 mg/m² 5‑FU + 200/400 mg/m² leucovorin; plus kit and formulation claims). The verbatim granted claim set was not present in the supplied text, so "which claim" statements should be confirmed against the issued claims.
• One reference (US 9,616,081, Okabe) was listed but its content could not be verified in this search; I have not assigned it a § 102 position.

Obviousness Analysis — U.S. Patent 12,364,691 B2 (35 U.S.C. § 103)

Important sourcing caveat first (per your rules): I was unable to load the literal "Prior Art"/"Citations" table rendered on the Google Patents page for US 12,364,691 B2 in this session. What I could verify are (a) the patent text you supplied, (b) the family's related publications and their art-of-record (US 9,339,497; US 10,980,795; US 11,369,597; US 11,344,552; WO 2013/188586), and (c) the prosecution/opposition/IPR records for that family. The reference set below therefore reflects the art that is common to this family's file histories rather than a pixel-exact copy of the '691 page's citation table. Where I extrapolate, I say so.

1. Threshold: what is (and is not) prior art to the '691 patent

• Effective priority date: 2012-06-13 (provisional 61/659,211), with a possible 2013-03-14 date (61/784,382) for CIP-added subject matter. The application is a continuation (16/012,372 ← 15/664,930 ← 15/241,128 ← 14/406,776 ← PCT/US2013/045495).
• Because all claims appear entitled to pre-3/16/2013 priority, the pre-AIA §§ 102/103 regime most likely governs. Art must predate the 2012 priority date (§ 102(a)/(e)) or the § 102(b) critical date.
• Critical trap: Bayever (WO 2013/188586 / US 9,339,497) is the priority document of this very family and is therefore not prior art to the '691 patent. It was cited as prior art ("Ex. 1006") in the IPRs against sibling US 11,344,552, because that patent's effective filing date is 2015-08-21. Anyone re-running the Conroy + Bayever combination from the '552 IPR would be committing error as to '691.

2. The claim scope that must be met (from the patent's own summary)

Independent-type subject matter of '691 covers:

1. Combination method: co-administer liposomal irinotecan + 5-FU + leucovorin, ≥ 1 cycle of 2 weeks, wherein each cycle: (a) liposomal irinotecan 80 mg/m² (salt) on day 1 — 60 mg/m² in cycle 1 if UGT1A1*28 homozygous; (b) 5-FU 2400 mg/m²; (c) leucovorin 200 mg/m² (l-form) or 400 mg/m² (l+d racemate).
2. Monotherapy method: liposomal irinotecan alone, 3-week cycle, 120 mg/m², with 80 mg/m² in cycle 1 for UGT1A1*28 homozygotes.
3. Formulation-for-use claim of liposomal irinotecan for the above co-administration.
4. Kits containing the dose(s) plus instructions.
5. Dependent features: 90-min IV infusion of liposomal irinotecan; 46-h 5-FU infusion; 30-min leucovorin infusion; sequence nal-IRI → LV → 5-FU; premedication with dexamethasone/5-HT3 antagonist; exocrine pancreatic cancer subtypes; and the "increase tumor vascularity" aspect (irinotecan sucrose octasulfate liposomes + a second chemotherapeutic).

Caveat: the issued claim wording is not in the text supplied to me; the above is reconstructed from the patent's Summary/Definitions. Exact wording matters for the § 103 mapping.

3. Level of ordinary skill

A POSA here is a medical oncologist or clinical pharmacologist with an M.D. or Ph.D. and several years' experience in GI-oncology drug development, familiar with (i) irinotecan pharmacology (prodrug → SN-38, UGT1A1 glucuronidation), (ii) liposomal/nanoparticle drug delivery and its PK consequences, and (iii) the FOLFIRI/FOLFIRINOX literature.

4. The prior art references

(R8-R11 and R13 are the kind of formulation/pharmacogenetics references that populate the "Citations" block of every member of this family; I verified their family linkage from the citation tables of US 10,350,201 / US 7,846,473, where US 12,364,691 B2 appears as a citing/similar document.)

5. Grounds of rejection

Ground 1 (primary): R1 + R3 + R4 + R6 — the core combination claims

• R1 teaches the exact three-drug concept (liposomal irinotecan + 5-FU/LV) in a human solid-tumor Phase I.
• R3 teaches that the same agent is active in the exact claimed disease (gemcitabine-refractory metastatic pancreatic cancer).
• R4 supplies, expressly, the claimed 5-FU/LV backbone values (leucovorin 400 mg/m²; 5-FU 2400 mg/m² over 46 h) and the q2w cycle, in metastatic pancreatic cancer.
• R6 supplies the UGT1A1*28 genotype-directed dose-reduction step for irinotecan.

Motivation / rationales (KSR, MPEP 2143(I)-(III)):

1. Same field, same problem. All four references address irinotecan-based therapy of advanced/refractory pancreatic or GI cancer. The '691 specification itself concedes the unmet need ("dearth of effective therapies") — a classical motivation framed by the inventors' own acknowledgment.
2. Combining prior-art elements to achieve an expected additive effect. 5-FU/LV was the recognized standard backbone for gemcitabine-refractory pancreatic cancer; the inventors merely add a known active irinotecan formulation to it, exactly as FOLFIRI/FOLFIRINOX adds irinotecan to 5-FU/LV.
3. Dose selection is routine optimization of a disclosed parameter. R1's combination Phase I brackets the 80 mg/m² (salt)/q2w dose; R4 fixes 2400 mg/m²/46 h and LV 400 mg/m². Per In re Boesch / In re Aller, discovering optimum values of a result-effective variable within a disclosed range is not inventive.
4. Genotype-directed dose reduction is label-directed, not inventive. R6 and R13 teach that UGT1A1*28 homozygotes should start lower. Applying the label's precaution to the new regimen is the definition of obviousness according to In re Beattie / MPEP 2144.02 (following a known, published safety guidance).

Reasonable expectation of success: high. Each component was individually known to be efficacious and tolerable in this disease, the combination had already been shown safe in R1, and the mechanism (topoisomerase-I inhibition + thymidylate synthase inhibition) was well understood and non-overlapping in toxicity profile.

Ground 2: R4 + R5 + R7 + R6 — "substitute nal-IRI for free irinotecan"

• R4/R5 teach the irinotecan + LV + 5-FU regimen and its q2w schedule; R7 teaches that encapsulating irinotecan in sucrose-octasulfate liposomes markedly prolongs exposure, concentrates SN-38 intratumorally and improves the therapeutic index relative to free irinotecan.
• Rationale: substitution of a known, improved formulation of a known drug in a known regimen, to obtain the predictable benefit of better PK/tolerability (KSR; In re Merck, "improved formulation of a known drug"). The '691 claims recite nothing about the liposome beyond sucrose octasulfate nal-IRI, which R7 discloses.

Ground 3: R8 or R9 (Alza) + R1/R3 + R4

Where WO 2008/079240 and WO 2008/070009 both teach liposome-encapsulated topoisomerase inhibitors (including irinotecan) for treating solid tumors, including combinations with other cytotoxics, they supply the "liposomal irinotecan for tumor therapy" element. Combined with R1/R3/R4, the same combination follows.

Ground 4: R12 (+R1) — the "increase tumor vascularity" aspect

Baker (R12) is essentially anticipatory-of-the-concept art: it expressly discloses that liposomal irinotecan ("Imophore C" / nanoliposomal irinotecan) alters tumor vascular function and enhances the distribution/delivery of 5-fluorouracil. A claim to "administering an amount of irinotecan sucrose octasulfate salt liposome injection effective to increase tumor vascularity and concomitantly administering an effective amount of a chemotherapy agent other than irinotecan" reads directly on R12's teaching, giving a § 102/§ 103 rejection that would be very hard to overcome.

Dependent claims

• 90-min nal-IRI infusion / 46-h 5-FU / 30-min LV: 46-h 5-FU and LV doses come from R4/R5; infusion durations are routine, result-effective variables (cf. the '552 IPR institution decision, which found such timing "a subject of routine optimization within the POSA's skill," grounded in Bayever's infusion-rate guidance).
• Sequence nal-IRI → LV → 5-FU: the LV-before-5-FU order is FOLFIRI/FOLFIRINOX practice (R4/R5); ordering nal-IRI first is routine and, per the '552 institution decision, obvious.
• Premedication with dexamethasone/5-HT3 antagonist: standard antiemetic/preadministration practice; the prescribing-information art (R6 and equivalents) teaches it.
• Exocrine pancreatic subtypes: the indication itself is metastatic pancreatic adenocarcinoma; listing histologic subtypes adds no structural or process difference.
• Kits: KSR permits treating a kit-for-a-known-combination as an obvious assembly of known components with instructions; nothing unexpected in a kit.

6. What the patent owner will argue (and the strength of it)

1. Unexpected results / secondary considerations. The NAPOLI-1 data recited in the specification (median OS 6.1 vs 4.2 months, HR 0.67; ORR 16% vs 1%) would be marshalled as an unexpected survival benefit. The counter is that the closest prior art (R1 + R3 + R4) already leads to a combination of two active agents with distinct mechanisms, so an additive survival gain over 5-FU/LV is expected, not surprising. (In the sibling '552 IPRs, Apotex/CSPC argued exactly this, invoking Nichetti and Nevala-Plagemann to show the patentee's "superiority" story was not statistically robust; the PTAB's ultimate resolution on the sibling patents does not control '691, but the reasoning is transferable.)
2. No teaching to combine with liposomal (as opposed to free) irinotecan. Weak where R7 (Drummond) and R1 (PEP02 + 5-FU/LV) are on the record.
3. Specific 80 mg/m² (salt) figure as non-obvious. Vulnerable, because R1's Phase I combination data and the patent's own admission set the MTD at 80 mg/m².
4. Teaching away / toxicity concerns. Predictable counterargument (toxicity of irinotecan combos) but generally insufficient post-KSR absent evidence of actual discouragement.

The most defensible position for the patentee is that the specific, closed combination of three agents at three specific doses on a q2w schedule in the post-gemcitabine mPAC population, with genotype-stratified starting doses, produced a clinical result (survival benefit in a uniformly fatal disease) that a POSA would not have predicted with confidence — i.e., reasonable-expectation-of-success and unexpected-results arguments, not the art-coverage arguments.

7. Conclusion

On the art of record, claims 1-type combination subject matter (and their dependent features) is prima facie obvious over:

R1 (Chen 2010) + R3 (Ko 2011) + R4 (Conroy 2011) + R6 (Camptosar label), optionally further in view of R5 (Douillard 2000) and R7 (Drummond 2006).

and the tumor-vascularity aspect is even more clearly obvious over R12 (Baker 2008) alone or in view of R1. The strongest rebuttal available to Ipsen is objective evidence of unexpected efficacy (the NAPOLI-1 results) plus a narrowed, dose-specific claim scope — precisely the ground on which this family has been litigated. Note also the pending New Jersey District Court case 1:25-cv-13647 (family litigation per the Google Patents page) and parallel PTAB activity against sibling patents, which indicate this issue is being actively contested.

Confidence/limitations: (i) I could not directly read the '691 page's own "Prior Art" citation table; the reference set is reconstructed from family art-of-record and is likely substantially congruent but not guaranteed identical. (ii) The claim text is reconstructed from the patent's summary; the exact issued claims should be confirmed against the USPTO PatentCenter copy before relying on this analysis. (iii) Do not use "Bayever/WO 2013/188586" as prior art against '691 — it shares the 2012-06-13 priority and is not prior art.