DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/03/2026 has been entered.
Claim Status
Applicant’s reply filed on 06/03/2026 is acknowledged. Claims 1 and 13 have been amended.
Claims 1, 7, 10-11, 13, 16, 24, 26, 35-37, 41, and 43 are pending and under examination.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 7, 10-11, 13, 16, 24, 26, 35-36, 41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Olsen (WO2019/005636A2, published 01/03/2019, cited in IDS filed 08/09/2022) in view of Karachaliou (Expert Rev Respir Med. 2019 Oct;13(10):1019-1028, cited in PTO-892 06/03/2025) and Floc’h (Mol Cancer Ther. 2018 May;17(5):885-896), as evidenced by “Zilovertamab,” MedChemExpress (accessed 05/27/2025, cited in PTO-892 06/03/2025) and Kaufmann (WO2021/155180A1, published 08/05/2021, cited in PTO-892 06/03/2025).
Regarding claims 1 and 10-11 Olsen teaches the following:
Anti-ROR1 monoclonal antibodies, antigen binding portions thereof, therapeutic compositions thereof, and/or nucleic acid encoding the same (page 3, paragraph 2).
The antibody includes antagonists (page 7, paragraph 4).
A method of treating a subject with cancer using the disclosed anti-ROR1 antibody and co-administering an effective amount of a therapeutic agent such as a growth inhibitory agent, osimertinib, a small molecule, third-generation EGFR inhibitor. (page 5, paragraphs 6-7, Claims 4, 28, 29).
Treatment of cancer cells with humanized anti-ROR1 antibody, specifically, UC-961 (p. 1-2), which is a synonym for cirmutuzumab, as evidenced by MedChemExpress. Further evidenced by WO2021155180, Kaufmann, cirmtuzumab comprises instant SEQ ID NOs: 7 and 8, comprising CDR SEQ ID NOs: 1-6 (see sequence alignments below). Therefore, the cirmtuzumab (UC-961) taught by Olsen necessarily comprises instant SEQ ID NOs:1-8.
SEQ ID NO:7 cirmtuzumab variable heavy domain aligned with
BJQ49849
ID BJQ49849 standard; protein; 446 AA.
AC BJQ49849;
DT 02-SEP-2021 (first entry)
DE Anti-ROR1 humanized antibody cirmtuzumab VH, SEQ ID:7.
Ntrkr1 tyrosine kinase receptor; ROR1 antigen; cancer; cirmtuzumab;
cytostatic; heavy chain variable region; humanized antibody; therapeutic;
tyrosine kinase-like orphan receptor 1.
OS Unidentified.
PN WO2021155180-A1.
PD 05-AUG-2021.
PF 29-JAN-2021; 2021WO-US015749.
PR 30-JAN-2020; 2020US-0968121P.
PR 16-APR-2020; 2020US-0011036P.
PA (ONCT-) ONCTERNAL THERAPEUTICS INC.
PI Kaufmann G;
DR WPI; 2021-903373/069.
Treating cancer e.g. renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, stomach cancer, or cervical cancer in mammal or human, by administering epidermal growth
factor receptor inhibitor and tyrosine kinase-like orphan receptor 1 antagonist.
Claim 10; SEQ ID NO 7; 92pp; English.
SQ Sequence 446 AA;
ALIGNMENT:
Query Match 100.0%; Score 2404; Length 446;
Best Local Similarity 100.0%;
Matches 446; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSY 60
Qy 61 NQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGWYYFDYWGHGTLVTVSSASTK120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGWYYFDYWGHGTLVTVSSASTK120
Qy 121 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS180
Qy 181 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF240
Qy 241 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR300
Qy 301 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN360
Qy 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN420
Qy 421 VFSCSVMHEALHNHYTQKSLSLSPGK 446
||||||||||||||||||||||||||
Db 421 VFSCSVMHEALHNHYTQKSLSLSPGK 446
SEQ ID NO:8 light chain variable region cirmtuzumab:
BJQ49850
ID BJQ49850 standard; protein; 214 AA.
AC BJQ49850;
DT 02-SEP-2021 (first entry)
DE Anti-ROR1 humanized antibody cirmtuzumab VL, SEQ ID:8.
Ntrkr1 tyrosine kinase receptor; ROR1 antigen; cancer; cirmtuzumab;
cytostatic; humanized antibody; light chain variable region; therapeutic; tyrosine kinase-like orphan receptor 1.
PN WO2021155180-A1.
PD 05-AUG-2021.
PF 29-JAN-2021; 2021WO-US015749.
PR 30-JAN-2020; 2020US-0968121P.
PR 16-APR-2020; 2020US-0011036P.
PA (ONCT-) ONCTERNAL THERAPEUTICS INC.
PI Kaufmann G;
DR WPI; 2021-903373/069.
Treating cancer e.g. renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, stomach cancer, or cervical cancer in mammal or human, by administering epidermal growth factor receptor inhibitor and tyrosine kinase-like orphan receptor 1 antagonist.
PS Claim 10; SEQ ID NO 8; 92pp; English.
SQ Sequence 214 AA;
ALIGNMENT:
Query Match 100.0%; Score 1119; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGSTLQSGIPP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGSTLQSGIPP 60
Qy 61 RFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEIKRTVAAPSVFIFPP120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEIKRTVAAPSVFIFPP120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Regarding claim 7, Olsen teaches the ROR1 antibody antigen-binding fragment is a Fv, Fab, F(ab’)2, or a scFv (page 3, paragraph 1, Claim 8).
Regarding claim 16, Olsen teaches reagents are administered concurrently, which indicates separately (page 13, paragraph 3).
Regarding claim 24, Olsen teaches a method of treating a subject with cancer by co-administering an anti-ROR1 antibody and an effective amount a pharmaceutical composition of the EGFR inhibitor, osimertinib (page 5, paragraphs 6-7). Olsen teaches the compositions may be administered in the form of a solid composition, including pills which may be administered orally (page 12, paragraph 6).
Regarding claim 26, Olsen teaches the pharmaceutical compositions of the anti-ROR1 antibody may be administered intravenously (page 12-13).
Regarding claim 35, Olsen teaches the anti-ROR1 antibody binds specifically to human ROR1 (Summary, Claim 1). Olsen teaches the subject receiving treatment may be a human (page 5, paragraph 8).
Regarding claim 36, Olsen teaches the disclosed anti-ROR1 antibody can be used to treat a variety of cancers including breast cancer, colorectal cancer, pancreatic cancer, non-small lung cell cancer, glioma, esophaphageal cancer (page 5, paragraph 5).
Regarding claim 41, Olsen teaches the disclosed anti-ROR1 antibody can be used to treat non-small cell lung cancer (page 5, paragraph 5).
Regarding claim 43, Olsen teaches the disclosed anti-ROR1 antibody can be used to treat breast cancer (page 5, paragraph 5).
The disclosure of Olsen does not teach: (1) the specific combination of an EGFR inhibitor and an anti-ROR1 antibody, (2) that the subject is afflicted with a cancer that comprises a mutated EGFR gene or that (3) the mutated EGFR gene comprises an L858R mutation in the EGFR protein or an exon 20 insertion in the EGFR gene.
The deficiencies are taught by Karachaliou and Floc’h.
Karachaliou:
Karachaliou teaches therapeutic strategies to overcome resistance to erlotinib (EGFR TKI) in non-small cell lung cancer patients.
Regarding claim 1, pertaining to the limitation that the combined treatment is administered to a subject with cancer that comprises and EGFR mutation, Karachaliou teaches a combination treatment of EGFR tyrosine kinase inhibitors (TKI) and ROR1 inhibitors to overcome resistance to erlotinib in non-small cell lung cancer patients (Table 1).
Regarding claim 13, wherein said mutated EGFR further comprises a mutation resulting in a T790M mutation, Karachaliou teaches osimertinib is a third-generation EGFR TKI that is selective for T790M resistance mutations, and is approved for patients with tumors expressing T790M mutation in the tissue (page 2, paragraph 3). Osimertinib has FDA approval for non-small cell lung cancer patients, and is superior to other EGFR inhibitors such as erlotinib in EGFR-mutant NSCLC patients, who carry the T790M mutation (page 2, paragraph 4).
Karachaliou teaches ROR1 is expressed in a variety of cancers. Karachaliou teaches examining ROR1 in patients from the EURTAC clinical trial NCT00446225. Karachaliou discloses higher ROR1 expression had a negative impact on progression-free survival in erlotinib treated patients, and also teaches that the ROR1 inhibitor, cirmtuzumab, has been proven to be safe and effective (page 5, paragraph 2).
Floc’h:
Floc’h is directed to assessing the activity of osimertinib in EGFR exon 20 insertion NSCLC (Abstract). Floc’h teaches that EGFR exon 20 insertion are generally not responsive to 1st and 2nd generation EGFR inhibitors and point to in vitro data indicating that 3rd generation inhibitor osimertinib could be potent against some exon 20 insertion cancers (Pg. 2, Bottom paragraph, entire paragraph). Floc’h demonstrates that osimertinib inhibits tumor growth more effectively than afatinib in EGFR exon 20 insertion in vivo xenograft models. Once-daily administration of 25 mg/kg of osimertinib induced significant tumor growth inhibition in two different exon 20 insertion xenograft models when compared to the control group (Pg. 10, Bottom paragraph, entire paragraph, and Fig. 3A–B).
Regarding claim 1, pertaining to the limitation that the mutated EGFR gene is an exon 20 insertion mutation, Floc’h teaches that some tumors expressing exon 20 insertion mutation in the EGFR gene are responsive to treatment with osimertinib (see Fig. 3A-B).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to: (1) administer to a subject in need the EGFR inhibitor osimertinib and the ROR1 antagonist cirmtuzumab (2) to administer the combination treatment to a subject afflicted with cancer that has a mutated EGFR gene, and (3) wherein the mutation is an exon 20 insertion mutation. One would have been motivated to and have a reasonable expectation of success for the following reasons: (1) Olsen teaches administering ROR1 antagonist antibodies to treat cancer and teaches coadministration with an EGFR inhibitor such as osimertinib, (2) Karachaliou suggests a combination treatment of osimertinib and ROR1 inhibitors in non-small cell lung cancer patients with the EGFR mutations, (3) Karachilou provides motivation for combining ROR1 inhibitor cirmtuzumab and a superior EGFR inhibitor, osimerintib, and (4) Karachilou successfully demonstrates tumor growth inhibition with ROR1 knockdown in NSCLC EGFR mutation positive patients and (6) Floc’h teaches many EGFR exon 20 insertion mutations are responsive to osimertinib treatment.
Claims 1, 7, 10-11, 13, 16, 24, 26, 35-37, 41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Olsen (WO2019/005636A2, published 01/03/2019, cited in IDS filed 08/09/2022) in view of Karachaliou (Expert Rev Respir Med. 2019 Oct;13(10):1019-1028, cited in PTO-892 06/03/2025) and Floc’h (Mol Cancer Ther. 2018 May;17(5):885-896), as applied to claims 1, 7, 10-11, 13, 16, 24, 26, 35-36, 41, and 43 above, and further in view of Altunel (JCO Precis Oncol. 2018 Nov;2:1-7).
The teachings of the combined references are set forth above. Olsen teaches treating NSCLC, breast cancer and colorectal cancer (page 5, paragraph 5).
The combined references do not teach treating colon adenocarcinoma or exemplify treating breast cancer and NSCLC.
Regarding claim 37, Altunel teaches the EGFR T790 mutation is a commonly found mutation in patients with non-small-cell lung cancer. Altunel also teaches characterizing EGFR T790M mutant tumor in a patient presenting with breast, lung, colon, and rectal cancer (page 1, column 2). Altunel teaches histologic and molecular characterization of the breast, colon, and lung tumors of the patient revealed T790M mutation in all three of the cancers (Figure 1). Altunel also discloses testing of osimertinib in T790M mutation-positive cancers by generating patient-derived xenografts and found that the PDX tumors were sensitive to Osimertinib, suggesting that the EGFR T790 mutation in colorectal cancer shows similar biologic features with non-small cell lung cancer (Figure 3, page 4).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to administer an EGFR inhibitor and an ROR1 antagonist to a subject in need to treat NSCLC, colon adenocarcinoma and breast cancer.
One would have been motivated to and have a reasonable expectation of success given: 1) The combined references teach administering an EGFR inhibitor and an ROR1 antagonist to treat cancer with an EGFR mutation, including T790 mutation, 2) Altunel discloses NSCLC, colon cancer and breast cancer with positive T790 mutation, and 3) Altunel successfully demonstrates inhibiting a T790M mutation positive tumor by treating with Osimertinib. One would have a reasonable expectation of success in using the claimed method of treatment, administering a combination of EGFR inhibitor and ROR1 antagonist to treat other cancers with similar biologic features, such as colon adenocarcinoma and breast cancer.
Response to Applicant’s Remarks
Applicant's arguments filed 06/03/2026 have been fully considered but they are not persuasive.
The applicant argues the combination of osimertinib and the claimed antibody displays an unexpected increase in efficacy compared to either alone. The claims have been amended to recite “wherein said subject is afflicted with a cancer that comprises a mutated EGFR gene, wherein the mutated EGFR gene comprises a mutation resulting in an L858R mutation in the EGFR protein, or an exon 20 insertion mutation in the EGFR gene” which the applicant alleges is representative of the scope of the demonstrated unexpected results. (Remarks 5-6).
In response, the Examiner acknowledges that the applicant has presented unexpected results pertaining to the effect of co-administration of osimertinib and the claimed antibody in the context of a xenograft model of NSCLC generated with the cell line LU0858, which has an EGFR L858R mutation. Table 4 shows UC961 antibody monotherapy (Group 2) inhibited tumor growth by 13.3% compared to vehicle control, osimertinib monotherapy (Group 3) inhibited tumor growth by 32.2%, and the combination treatment inhibited tumor growth by 51.0% which was greater than the sum of each monotherapy.
Pertaining to synergy with combination treatment in the context of an exon 20 insertion mutation the in the EGFR gene, the data presented does not show synergy as compared to vehicle control. In the UC962 exon 20 insertion mutation xenograft model, the combined treatment had a tumor growth inhibition less than the additive effect of each monotherapy. Table 7 shows UC962 antibody monotherapy (Group 2, 10 mg/kg) inhibited tumor growth by 33.1%, osimertinib monotherapy (Group 5, 20 mg/kg) inhibited tumor growth by 51.8%, whereas the combination treatment (Group 6) was 77.4%. In this particular model, it appears that that tumor with an exon 20 insertion was responsive to osimertinib monotherapy treatment.
Further pertaining to the limitation that the mutated EGFR gene comprises an exon 20 insertion, the art teaches heterogeneity in the known NSCLC-associated exon 20 insertions. For example, Bai (Cancer Treat Rev. 2023 Nov;120:102605) teaches: “Ex20ins mutations are heterogeneous in nature and include in-frame insertions or duplications of 3–21 base pairs (1–7 AAs). EGFR Ex20ins mutations are reported to occur either toward the C terminal of the C-helix or in the loop that immediately follows it. Ex20ins mutations in the αC-helix are more classical-like mutations, which are predicted to be phosphate-binding loop (P-loop) and αC-helix compressing mutations. EGFR ex20ins occurring in the C-terminal loop of the αC-helix (ex20ins-L) are considered to be a distinct subgroup, and these are further classified into 2 molecular subtypes: near- (AA767–772) and far-loop (AA773–775) ex20ins” (Pg. 2, Right column Lines 3-12).
The importance of this heterogeneity is that the location and nature of the exon 20 insertion affects susceptibility to tyrosine kinase treatment. Cardona (Cancer Cell. 2022 Jul 11;40(7):705-708) teaches that exon 20 insertions in the αC-helix (for example, an FQEA insertion at A763 [A763insFQEA]) are pansensitive to EGFR TKIs, while those in the loop following the αC-helix (A767-C775) are not (Pg. 705, Right column Lines3-6, continued on Pg. 707 lines 1-3).
In all, the applicant has not shown unexpected results pertaining to treating cancer with a mutated EGFR gene comprising an exon 20 insertion. The results in the disclosure show that that the exon 20 insertion EGFR cancer was responsive to osimertinib monotherapy, which aligns with the art that teaches certain exon 20 insertions many mutations are responsive to osimertinib.
Because the combination treatment would be obvious and the showing of unexpected results does not align with the scope of the claims, namely the limitation wherein the cancer has an exon 20 insertion EGFR, the updated 35 U.S.C. 103 rejections above will be maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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