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 .
Claim Status
Applicant’s reply filed on 10/31/2025 is acknowledged. Claims 1, 7, 10, 11, 13, 37, 41, and 43 have been amended. Claims 2-4, 6, 9, and 12 are cancelled.
Claims 1, 5, 7, 10, 11, 13, 16, 24, 26, 35-37, 41, and 43 are pending and under examination.
Objections/Rejections Withdrawn
The following objections and rejection are withdrawn in view of amendments filed 10/31/2025:
The objection to claim 10 for informalities.
The rejection of claims 1-7, 9-13, 16, 24, 26, 35-37, 41, and 43 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The rejection of claims 1-7, 9, 10, 11, 16, 24, 26, 35, 36, 41, and 43 under 35 U.S.C. 102(a)(2) as being anticipated by WO2019005636A2, Olsen et al, published January 3, 2019, as evidenced by “Zilovertamab,” MedChemExpress, accessed May 27, 2025 and WO2021155180, Kaufmann.
Rejections Maintained
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, 5, 7, 10-11, 13, 16, 24, 26, 35-36, 41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019005636A2, Olsen et al in view of “Characterising acquired resistance to erlotinib in non-small cell lung cancer patients,” Karachaliou et al, published August 19, 2019, and “ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer patients with the EGFR T790M mutation,” Karachaliou et al, published June 3, 2014, as evidenced by “Zilovertamab,” MedChemExpress, accessed May 27, 2025, and WO2021155180, Kaufmann.
Regarding claims 1, 5, 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 a mutation resulting in a T790M mutation or an L858R mutation in the EGFR protein or an exon-20 insertion in the EGFR gene.
The deficiencies are taught by Karachaliou (2019) and Karachaliou (2014).
Karachaliou (2019) teaches therapeutic strategies to overcome resistance to erlotinib (EGFR TKI) in non-small cell lung cancer patients.
Regarding claim 1, 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, Karachaliou teaches osimertinib is a third-generation EGFR TKI that is selective for both EGFR and 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).
Karachaliou (2014) discloses the relationship between ROR1 and EGFR mutations by studying ROR1 mRNA expression in pretreatment tumor samples from patients in the EURTAC clinical trial, and suggests ROR1 as a novel therapeutic target for non-small-cell lung cancer patients with EGFR mutation (page 122). Karachaliou teaches 60% of patients expressed the EGFR T790M mutation pretreatment with the EGFR inhibitor (page 123, paragraph 2). Karachaliou teaches ROR1 knockdown inhibited the growth of NCI-H1975 cells harboring both EGFR L858R and T790M mutations (Background).
It would have been prima facie obvious to a person of ordinary skill in the art before the invention was filed to administer to a subject in need, a therapeutically effective amount of an epidermal growth factor receptor (EGFR) inhibitor and a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist to treat cancer, wherein the EGFR inhibitor is osimertinib and the ROR1 antagonist is cirmtuzumab.
One would have been motivated to and have a reasonable expectation of success given: 1) Olsen teaches administering ROR1 antagonist antibodies to treat cancer and co-administering an EGFR inhibitor, osimertinib, 2) Olsen teaches cirmtuzumab (UC-961) is a known antagonistic ROR1 antibody that treats cancer cells; 3) Karachaliou suggests a combination treatment of osimertinib and ROR1 inhibitors in non-small cell lung cancer patients with the EGFR mutation T790M, 4) Karachilou provides motivation for combining ROR1 inhibitor cirmtuzumab and a superior EGFR inhibitor, osimerintib, and 5) Karachilou successfully demonstrates inhibiting tumor growth with ROR1 knockdown in non-small cell lung cancer EGFR mutation positive patients.
Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019005636A2, Olsen et al, as applied to claims 1-7, 9-13, 16, 24, 26, 35, 36, 41, and 43 above, in view of “Characterising acquired resistance to erlotinib in non-small cell lung cancer patients,” Karachaliou et al, published August 19, 2019, and “ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer patients with the EGFR T790M mutation,” Karachaliou et al, published June 3, 2014, as evidenced by “Zilovertamab,” MedChemExpress, accessed May 27, 2025, WO2021155180, Kaufmann, and further in view of WO2018227023A1, Thompson et al, published December 13, 2018.
The teachings of the combined references are set forth above. Although the combined references teach cirmtuzumab that inherently comprises instant SEQ ID NOs:1-8, the combined references do not disclose SEQ ID NOs 7 and 8, comprising CDR SEQ ID NOs: 1-6.
Thompson teaches cirmtuzumab comprises instant SEQ ID NOs:7 and 8, comprising CDR SEQ ID NOs:1-6 (see sequence alignments below).
It would have been prima facie obvious for a person of ordinary skill in the art to use the EGFR inhibitor, cirmtuzumab, comprising SEQ ID NOs: 7-8 to treat cancer in a subject in need thereof.
One of ordinary skill in the art would have been motivated to and have a reasonable expectation of success given: 1) The combined references teach administering cirmtuzumab to treat cancer in a subject in need thereof, and 2) Thompson teaches cirmtuzumab, comprising the instantly claimed sequences comprising the heavy chain and light chain variable chain regions. One of ordinary skill in the art would have been motivated to use the already known sequences of cirmtuzumab as disclosed by Thompson.
SEQ ID NO:7 light chain variable region cirmtuzumab
BFX03011
ID BFX03011 standard; protein; 214 AA.
AC BFX03011;
DT 07-FEB-2019 (first entry)
DE Anti-ROR1 tumor antibody cirmtuzumab light chain SEQ: 471.
KW ROR1; antibody therapy; breast tumor; cancer; cirmtuzumab;
KW colorectal tumor; cytostatic; immunoconjugate; light chain; lung tumor;
KW monoclonal antibody; pancreas tumor; prophylactic to disease;
KW receptor tyrosine kinase-like orphan receptor 1; renal cell carcinoma;
KW solid tumor; stomach tumor; therapeutic.
OS Homo sapiens.
CC PN WO2018227023-A1.
CC PD 13-DEC-2018.
CC PF 07-JUN-2018; 2018WO-US036560.
PR 07-JUN-2017; 2017US-0516667P.
CC PA (SILV-) SILVERBACK THERAPEUTICS INC.
CC PI Thompson PA, Edris B, Coburn CA, Baum PR;
DR WPI; 2018-99838Y/02.
CC PT New immune-modulatory conjugate comprising antibody construct comprising antigen binding domain and crystallizable fragment domain, proteolysis targeting module and linker, useful for treating cancer e.g. breast cancer.
CC PS Disclosure; SEQ ID NO 471; 372pp; 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 RFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
SEQ ID NO:8 heavy chain variable region cirmtuzumab
BFX03006
ID BFX03006 standard; protein; 446 AA
AC BFX03006;
DT 07-FEB-2019 (first entry)
DE Anti-ROR1 tumor antibody cirmtuzumab heavy chain SEQ: 466.
KW ROR1; antibody therapy; breast tumor; cancer; cirmtuzumab;
KW colorectal tumor; cytostatic; heavy chain; immunoconjugate; lung tumor;
KW monoclonal antibody; pancreas tumor; prophylactic to disease;
KW receptor tyrosine kinase-like orphan receptor 1; renal cell carcinoma;
KW solid tumor; stomach tumor; therapeutic.
OS Homo sapiens.
CC PN WO2018227023-A1.
CC PD 13-DEC-2018.
CC PF 07-JUN-2018; 2018WO-US036560.
PR 07-JUN-2017; 2017US-0516667P.
CC PA (SILV-) SILVERBACK THERAPEUTICS INC.
CC PI Thompson PA, Edris B, Coburn CA, Baum PR;
DR WPI; 2018-99838Y/02.
SQ Sequence 446 AA;
ALIGNMENT:
Query Match 99.8%; Score 2398; Length 446;
Best Local Similarity 99.6%;
Matches 444; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSY 60
Qy 61 NQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGWYYFDYWGHGTLVTVSSASTK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGWYYFDYWGHGTLVTVSSASTK 120
Qy 121 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 180
Qy 181 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF 240
Qy 241 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 300
Qy 301 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||:|:|||
Db 301 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 360
Qy 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 420
Qy 421 VFSCSVMHEALHNHYTQKSLSLSPGK 446
||||||||||||||||||||||||||
Db 421 VFSCSVMHEALHNHYTQKSLSLSPGK 446
Claims 1, 5, 7, 10-11, 13, 16, 24, 26, 35-37, 41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019005636A2, Olsen et al, as applied to claims 1, 5, 7, 10-11, 13, 16, 24, 26, 35, 36, 41, and 43 above, in view of “Characterising acquired resistance to erlotinib in non-small cell lung cancer patients,” Karachaliou et al, published August 19, 2019, and “ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer patients with the EGFR T790M mutation,” Karachaliou et al, published June 3, 2014, as evidenced by “Zilovertamab,” MedChemExpress, accessed May 27, 2025, WO2021155180, Kaufmann, and further in view of “Characterization of the Epidermal Growth Factor Receptor T790M Mutation in Colorectal Cancer,” Altunel et al, published December 21, 2018.
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 a person of ordinary skill in the art at the time the invention was filed 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 Arguments
Applicant's arguments filed 31 October 2025 have been fully considered but they are not persuasive.
I. The applicant submits a person of skill in the art, using Olsen, would have not reasonable expectation of success in creating an effective combination for treatment of cancer that comprises a mutated EGFR gene. Disclosure of a cancer that comprises a mutated EGFR gene is noticeably absent from Olsen, and Olsen provides no expectation of success as to treatment of an EGFR mutant cancer. Moreover, Olsen's disclosure of cirmtuzumab is constrained to the background on ROR1 antibodies, and provides no rationale or expectation of success with combining cirmtuzumab with an EGFR inhibitor. Instead, Olsen's disclosure of any EGFR inhibitor is limited to a long laundry list of unrelated "therapeutic agents," while providing no enabling disclosure relating ROR1 antibodies and these "therapeutic agents". (Remarks, Pg. 5-7)
In response, the 35 U.S.C. 102 rejection has been withdrawn and the 35 U.S.C. 103 rejection is maintained. This addresses the deficiency of Olsen in teaching treatment of cancer that comprises a mutated EGFR gene. The 35 U.S.C. 103 rejection also maintains that it would be obvious to co-administer an EGFR inhibitor with a ROR1 antagonist as complementary anti-cancer agents. It is standard in the art to co-administer known anti-cancer therapeutics. In this situation, it is known that ROR1 is implicated in resistance to anti-EGFR treatment and thus intervention in the ROR1 pathway using previously described anti-ROR1 antagonists would be obvious.
II. The applicant submits that taken together, the cited references, alone or in combination, do not provide a reasonable expectation of success for the combination of the instant claimed methods.
Pertaining to Karachaliou (2019), the applicant argues that the disclosure provides a multitude of possible speculative combinations that may be effective at treating a variety of different resistance strategies. In regards to ROR1, Karachaliou (2019) posits that "ROR1 directed therapies can enhance the efficacy of erlotinib Karachaliou (2019) at p. 5, left column)." However, a person of skill in the art, based on the disclosure of ROR1, would not expect that using a third generation EFGR inhibitor (as claimed), as opposed to erlotinib would be successful at treatment of cancer that comprises a mutated EGFR gene. (Remarks, Pg. 7)
Pertaining to Karachaliou (2014), the applicant argues that the disclosure is similarly directed to first-generation EFGR inhibitors and ROR1 further bolsters this lack of reasonable expectation success by noting that "a major limitation of our study is the small number of patients with sufficient archival tumor tissue for ROR1 mRNA expression. (Karachaliou (2014) at p. 129, emphasis added). Moreover, Karachaliou (2014) at most provides review of a study to ROR1 expression knockdowns in relation to erlotinib (see e.g., p.123 right column), and not of ROR1 antagonists, such as required by the instant claims. As these represent distinct molecular mechanisms of controlling ROR1, there is no reasonable expectation that an antibody based ROR1 antagonist, especially in combination with a different EGFR inhibitor, would be successful. (Remarks, Pg. 7)
In response, Table 1 of Karachaliou (2019) points to the use of third generation EGFR TKI osimertinib and the use of EGFR TKIs + ROR1 inhibitors as a potential therapeutic strategy. The Office disagrees with the characterization of Table 1 as “a multitude of possible speculative combinations” as it only provides 20 potential therapeutic strategies and is specifically directed to strategies that overcome the well-documented issue of EGFR TKI resistance. Further, Karachaliou (2019) plainly teaches ROR1 expression has negative impact on PFS in patients treated with EGFR inhibitors (Pg. 5, Left column, Full paragraph 2). As there is no indication that ROR1 antagonists would not work similarly with third generation TKIs as they do with first generation, one having ordinary skill in the art would still be motivated to use the combination in a treatment method. Therefore, it would indeed be obvious to one having ordinary skill in the art to combine EGFR inhibitors with anti-ROR1 antibodies.
Karachaliou (2014) may not provide an absolute expectation of success, but does indeed provide a reasonable expectation of success in combining the treatments to arrive at the instantly claimed methods. The applicant emphasizes that Krachaliou (2014) is directed to a study of ROR1 expression knockdown and not antagonism, however, expression knockdown of genes in a patient is not therapeutically relevant. The results do point to interventions that are therapeutically relevant, namely, inhibition through antagonist antibodies. Though the mechanisms of action are distinct, researchers readily extrapolate gene knockdown data to clinically relevant therapies with a reasonable expectation of success in doing so.
Conclusions
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646