DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicants remarks were filed July 9, 2026. Applicants state that Claim 66 was amended and claim 73 was newly added. However, no claim amendments were submitted. Previously, claims 58 and 66-67 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions. Claims 4-9, 11, 13-17, 26-31, 35, 39-57, 59-65 and 68-72 were canceled.
3. It is noted that Applicants assessment of claims 19-24 is correct. Claims 19-24 are not allowed.
Maintained Grounds for Rejection
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
4. Claims 1-3, 10, 12,18, 32-34 and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Babb et al., (US 20180134794 published May 17, 2018; priority to Nov. 16, 2016) in view of Jarkowski et al., (WO 2022248478 published Dec. 12, 2022; priority to May 24, 2022). Documents available on Google Patents.
The claims are drawn to a method of treating non-small cell lung cancer (NSCLC), reducing NSCLC tumor growth, and or causing regression of NSCLC in a subject suffering from a tumor harboring a MET alteration, the method comprising administering to the subject a dose of about 250 to 2000 mg of a bispecific antibody comprising: a first antigen-binding domain (D1) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 9; and a second antigen-binding domain (D2) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 5 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 9; wherein D1 specifically binds a first epitope of human MET; and wherein D2 specifically binds a second epitope of human MET.
Babb et al., disclose antibodies and bispecific antigen-binding molecules that bind MET and methods of use thereof. The bispecific antigen-binding molecules comprise a first and a second antigen-binding domain, wherein the first and second antigen-binding domains bind to two different (preferably non-overlapping) epitopes of the extracellular domain of human MET [abstract]. The methods comprise administering to a subject in need thereof a therapeutic composition comprising an anti-MET antibody or a MET×MET bispecific antigen-binding molecule (e.g., an anti-MET comprising any of the HCVR/LCVR or CDR sequences as set forth in Table 1 herein, or a MET×MET bispecific antigen-binding molecule comprising any of the D1 and D2 components as set forth in Table 5 herein). The therapeutic composition can comprise any of the anti-MET antibodies or MET×MET bispecific antigen-binding molecules disclosed herein, and a pharmaceutically acceptable carrier or diluent [para 226]. The treatment, and/or amelioration of any disease or disorder associated with or mediated by MET expression, signaling or activity, or treatable by blocking the interaction between MET and HGF, or otherwise inhibiting MET activity and/or signaling, and/or promoting receptor internalization and/or decreasing cell surface receptor number [para 0227]. For example, anti-MET antibodies and MET×MET bispecific antigen-binding molecules of the present disclosure are useful for the treatment of tumors that express (or overexpress) MET. In certain embodiments, the anti-MET antibodies and MET×MET bispecific antigen-binding molecules are used to treat lung cancer such as non-small cell lung cancer [NSCLC] [para 228].
In some embodiments, Ab is an anti-MET antibody comprising the CDRs within the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 82/138. In some embodiments, Ab is an anti-MET antibody comprising the HCVR amino acid sequence of SEQ ID NO: 82 and the LCVR amino acid sequence of SEQ ID NO: 138 [para 149]. In some embodiments, Ab is a MET×MET bispecific antigen-binding protein comprising the CDRs within the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the CDRs within the D2-HCVR amino acid sequence of SEQ ID NO: 82. In some aspects, the MET×MET bispecific antigen-binding protein further comprises the CDRs within the LCVR amino acid sequence of SEQ ID NO: 138. In some embodiments, Ab is a MET×MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the D2-HCVR amino acid sequence of SEQ ID NO: 82. The MET×MET bispecific antigen-binding protein further comprises the LCVR amino acid sequence of SEQ ID NO: 138 [para 150]. It is noted, that Babb et al’s SEQ ID NO; 138 corresponds to instantly claimed SEQ ID NO: 9; SEQ ID NO; 82 corresponds to instantly claimed SEQ ID NO:5; and SEQ ID NO; 58 corresponds to instantly claimed SEQ ID NO:1. The bispecific antigen-binding molecules, which comprise a first antigen-binding domain (D1) which specifically binds a first epitope of human MET and a second antigen-binding domain (D2) which specifically binds a second epitope of human MET, may be referred to herein as “MET×MET bispecific antibodies,” “MET×MET,” or other related terminology [para 69]. Thus teaching claim 1. MET and/or HGF overexpression, activation, or amplification has been shown to be involved in non-small cell lung carcinoma (NSCLC). MET amplification is thought to be a key driver of oncogenesis in NSCLCs malignancies. In addition, mutations resulting in exon 14 deletion of MET have been described as oncogenic drivers in a subset of NSCLC. Preclinical data implicate MET signaling in resistance to targeted therapies in multiple tumor types, such as NSCLC [para 5]. Thus teaching claims 2 and 3.
Samples that can be used in MET diagnostic assays according to the present disclosure include any tissue or fluid sample obtainable from a patient. Generally, levels of MET in a particular sample obtained from a healthy patient (e.g., a patient not afflicted with a disease or condition associated with abnormal MET levels or activity) will be measured to initially establish a baseline, or standard, level of MET. This baseline level of MET can then be compared against the levels of MET measured in samples obtained from individuals suspected of having a MET-related disease or condition [para 239]. Thus describing instant claim 10. With respect to instant claim 12.
Babb et al., describe the additional therapeutically active component(s), e.g., any of the agents listed above or derivatives thereof, may be administered just prior to, concurrent with, or shortly after the administration of an anti-MET antibody or MET×MET bispecific antigen-binding molecule [para 235]. Thus teaching claim 12. The administered medicines include antivirals, antibiotics, analgesics, corticosteroids, steroids, oxygen, antioxidants, COX inhibitors, cardioprotectants, metal chelators, IFN-gamma, and/or NSAIDs [para 234]. Example 18 teach subcutaneous administration; thus describing claim 33. According to certain embodiments, multiple doses of an anti-MET antibody or MET×MET bispecific antigen-binding molecule (or a pharmaceutical composition comprising a combination of an anti-MET antibody or MET×MET bispecific antigen-binding molecule and any of the additional therapeutically active agents mentioned herein) may be administered to a subject over a defined time course. The methods according to this aspect comprise sequentially administering to a subject multiple doses of an anti-MET antibody or MET×MET bispecific antigen-binding molecule provided herein. As used herein, “sequentially administering” means that each dose of antibody is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months) [para 236].
Similar results were obtained for the MET amplified human papillary adenocarcinoma NCI-H820 cell line (Bean et al., “MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to getfitnib or erlotinib,” Proc. Natl. Acad. Sci. 2007 Dec. 26, 104(52): 20932-20937) [para 279]. See Example 10. Additionally, treatment of SNU5 cells with MET×MET bispecific antibodies induced more potent degradation of MET than treatment with the bivalent monospecific anti-MET antibody (H4H13312P2) (FIG. 10, panel B), monovalent MET antibody or control hFc. Treatment of SNU5 cells with the MET×MET bispecific antibody inhibited downstream effectors of the MET pathway. Similar results were obtained for the MET amplified non-small cell lung cancer adenocarcinoma cell line NCI-H1993 (Kubo et al., “MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors,” Int. J. Cancer 2009 Apr. 15; 124(8): 1778-1784).
Example 26 shows in vivo efficacy against patient derived NSCLC tumors. Treatment of NSCLC tumors induced regression of tumor size relative to the beginning of treatment. Data are provided in Table 31 [para 342]. Thus teaching the regression of instant claim 36. Example 13. A MET×MET Bispecific Antibody Induces MET Degradation, Inhibits Pathway Activity, and Inhibits Tumor Growth More Potently than Monospecific Antibodies in EBC-1 Cells. Tumor growth was monitored for 30 days post-implantation and tumor volume (mm3) was measured for each experimental group over time. The results are depicted in Table 16 and FIG. 12, which shows that the MET×MET bispecific antibody significantly inhibits the growth of EBC-1 tumors [para 290]. See also Example 14. Thus teaching instant claims 36-38.
MET and/or HGF overexpression, activation, or amplification has been shown to be involved in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thyroid, breast, head and neck, colon and kidney carcinomas [para 5]. MET amplification is thought to be a key driver of oncogenesis in NSCLCs and oesophagogastric malignancies. In addition, mutations resulting in exon 14 deletion of MET have been described as oncogenic drivers in a subset of NSCLC. Tumor cell lines having MET gene amplification are highly dependent on MET for growth and survival. Preclinical data implicate MET signaling in resistance to targeted therapies in multiple tumor types, such as NSCLC, colorectal cancer, and head and neck squamous-cell carcinoma (HNSCC) [para 5]. For example, anti-MET antibodies and MET×MET bispecific antigen-binding molecules of the present disclosure are useful for the treatment of tumors that express (or overexpress) MET. For example, the anti-MET antibodies and MET×MET bispecific antigen-binding molecules may be used to treat primary and/or metastatic tumors, head and neck cancer (e.g., head and neck squamous cell carcinoma [HNSCC], lung cancer (e.g., non-small cell lung cancer [NSCLC]) [para 228]. Example 8 teach assays using both SNU5 and the non-small cell lung cancer (NSCLC) cell line EBC-1 [para 271]. Example 9 teach the effect of a MET×MET bispecific antibody on the MET pathway in human lung adenosquamous carcinoma cells was assessed in vitro [para 276]. Example 15. A MET×MET Bispecific Antibody does not Induce Growth of NCI-H596 Lung Cancer Cells In Vitro. Therefore, Babb et al., teach a method of treating NSCLC, reducing tumor growth and/or regression.
Alignment of SEQ ID NO:1
D BFH16676 standard; protein; 121 AA.
AC BFH16676;
XX
DT 28-JUN-2018 (first entry)
DE Anti-MET monoclonal antibody (H4H13306P2) HCVR region, SEQ 58.
XX
KW HGF protein; HGF receptor; Hepatocyte growth factor ligand;
KW Hepatocyte growth factor receptor; MET protein;
KW Met tyrosine kinase receptor; antibody therapy; cancer; cytostatic;
KW heavy chain variable region; immunoconjugate; monoclonal antibody;
KW prophylactic to disease; therapeutic.
XX
OS Homo sapiens.
XX
CC PN US2018134794-A1.
CC PD 17-MAY-2018.
CC PF 15-NOV-2017; 2017US-00814095.
XX
PR 16-NOV-2016; 2016US-0423068P.
PR 31-MAR-2017; 2017US-0479516P.
XX
CC PA (REGN ) REGENERON PHARM INC.
CC PI Babb R, Chen G, Daly C, Dasilva J, Macdonald D;
XX
DR WPI; 2018-38096Q/37.
DR N-PSDB; BFH16675.
XX
CC PT Bispecific antigen-binding molecule comprises first antigen-binding
CC PT domain, and second antigen-binding domain, where first and second antigen
CC PT -binding domain specifically binds first and second epitope of human MET,
CC PT respectively.
XX
CC PS Claim 12; SEQ ID NO 58; 140pp; English.
XX
CC 138The present invention relates to a novel bispecific antigen-binding
CC molecule, useful for treating or preventing cancer in a subject. The
CC bispecific antibody comprises a first antigen-binding domain (D1) and
CC second antigen-binding domain (D2) specifically binding to an epitope of
CC a human hepatocyte growth factor receptor (MET). The bispecific antibody
CC comprises a heavy chain variable region (HCVR) and light chain variable
CC region (LCVR) with their corresponding complementarity determining
CC regions (CDRs). The invention further claims: (1) a pharmaceutical
CC composition comprising the bispecific antibody; (2) a method for treating
CC cancer in a subject; (3) a method for treating cancer, reducing tumor
CC growth, and/or causing tumor regression in a subject; and (4) a method
CC for preparing an antibody-drug conjugate. The bispecific antibody is
CC useful for treating cancer in the subject suffering from tumor harbouring
CC a MET genetic alteration and/or tumor whose growth is driven by an
CC autocrine hepatocyte growth factor (HGF) signalling. The present sequence
CC is a anti-MET (receptor tyrosine kinase, HGF receptor, scatter factor
CC (SF)) monoclonal antibody HCVR region, which can be useful for treating
CC or preventing cancer in a subject.
XX
SQ Sequence 121 AA;
Query Match 100.0%; Score 651; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGTSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGITWNSYNIDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGTSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGITWNSYNIDY 60
Qy 61 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDDDYSNYVYFDYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDDDYSNYVYFDYWGQGTLVTVS 120
Qy 121 S 121
|
Db 121 S 121
Alignment of SEQ ID NO:5
ID BFH16700 standard; protein; 117 AA.
AC BFH16700;
XX
DT 28-JUN-2018 (first entry)
XX
DE Anti-MET monoclonal antibody (H4H13312P2) HCVR region, SEQ 82.
XX
KW HGF protein; HGF receptor; Hepatocyte growth factor ligand;
KW Hepatocyte growth factor receptor; MET protein;
KW Met tyrosine kinase receptor; antibody therapy; cancer; cytostatic;
KW heavy chain variable region; immunoconjugate; monoclonal antibody;
KW prophylactic to disease; therapeutic.
XX
OS Homo sapiens.
XX
CC PN US2018134794-A1.
CC PD 17-MAY-2018.
CC PF 15-NOV-2017; 2017US-00814095.
XX
PR 16-NOV-2016; 2016US-0423068P.
PR 31-MAR-2017; 2017US-0479516P.
CC PA (REGN ) REGENERON PHARM INC.
CC PI Babb R, Chen G, Daly C, Dasilva J, Macdonald D;
XX
DR WPI; 2018-38096Q/37.
DR N-PSDB; BFH16699.
XX
CC PT Bispecific antigen-binding molecule comprises first antigen-binding
CC PT domain, and second antigen-binding domain, where first and second antigen
CC PT -binding domain specifically binds first and second epitope of human MET,
CC PT respectively.
XX
CC PS Claim 17; SEQ ID NO 82; 140pp; English.
XX
CC The present invention relates to a novel bispecific antigen-binding
CC molecule, useful for treating or preventing cancer in a subject. The
CC bispecific antibody comprises a first antigen-binding domain (D1) and
CC second antigen-binding domain (D2) specifically binding to an epitope of
CC a human hepatocyte growth factor receptor (MET). The bispecific antibody
CC comprises a heavy chain variable region (HCVR) and light chain variable
CC region (LCVR) with their corresponding complementarity determining
CC regions (CDRs). The invention further claims: (1) a pharmaceutical
CC composition comprising the bispecific antibody; (2) a method for treating
CC cancer in a subject; (3) a method for treating cancer, reducing tumor
CC growth, and/or causing tumor regression in a subject; and (4) a method
CC for preparing an antibody-drug conjugate. The bispecific antibody is
CC useful for treating cancer in the subject suffering from tumor harbouring
CC a MET genetic alteration and/or tumor whose growth is driven by an
CC autocrine hepatocyte growth factor (HGF) signalling. The present sequence
CC is a anti-MET (receptor tyrosine kinase, HGF receptor, scatter factor
CC (SF)) monoclonal antibody HCVR region, which can be useful for treating
CC or preventing cancer in a subject.
XX
SQ Sequence 117 AA;
Query Match 100.0%; Score 611; Length 117;
Best Local Similarity 100.0%;
Matches 117; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFIVTTNYMTWLRQAPGKGLEWVSLIYSSGHTYYA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFIVTTNYMTWLRQAPGKGLEWVSLIYSSGHTYYA 60
Qy 61 DSVKGRFTISRHNSKNTLYLQMDSLRAEDTAVYYCASAFAADVFDIWGQGTMVTVSS 117
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSVKGRFTISRHNSKNTLYLQMDSLRAEDTAVYYCASAFAADVFDIWGQGTMVTVSS 117
Alignment of SEQ ID NO:9
ID BFH16756 standard; protein; 108 AA.
AC BFH16756;
XX
DT 28-JUN-2018 (first entry)
XX
DE Anti-MET monoclonal antibody LCVR region, SEQ 138.
XX
KW HGF protein; HGF receptor; Hepatocyte growth factor ligand;
KW Hepatocyte growth factor receptor; MET protein;
KW Met tyrosine kinase receptor; antibody therapy; cancer; cytostatic;
KW immunoconjugate; light chain variable region; monoclonal antibody;
KW prophylactic to disease; therapeutic.
XX
OS Homo sapiens.
XX
CC PN US2018134794-A1.
CC PD 17-MAY-2018.
CC PF 15-NOV-2017; 2017US-00814095.
XX
PR 16-NOV-2016; 2016US-0423068P.
PR 31-MAR-2017; 2017US-0479516P.
XX
CC PA (REGN ) REGENERON PHARM INC.
CC PI Babb R, Chen G, Daly C, Dasilva J, Macdonald D;
XX
DR WPI; 2018-38096Q/37.
DR N-PSDB; BFH16755.
XX
CC PT Bispecific antigen-binding molecule comprises first antigen-binding
CC PT domain, and second antigen-binding domain, where first and second antigen
CC PT -binding domain specifically binds first and second epitope of human MET,
CC PT respectively.
XX
CC PS Claim 12; SEQ ID NO 138; 140pp; English.
XX
CC The present invention relates to a novel bispecific antigen-binding
CC molecule, useful for treating or preventing cancer in a subject. The
CC bispecific antibody comprises a first antigen-binding domain (D1) and
CC second antigen-binding domain (D2) specifically binding to an epitope of
CC a human hepatocyte growth factor receptor (MET). The bispecific antibody
CC comprises a heavy chain variable region (HCVR) and light chain variable
CC region (LCVR) with their corresponding complementarity determining
CC regions (CDRs). The invention further claims: (1) a pharmaceutical
CC composition comprising the bispecific antibody; (2) a method for treating
CC cancer in a subject; (3) a method for treating cancer, reducing tumor
CC growth, and/or causing tumor regression in a subject; and (4) a method
CC for preparing an antibody-drug conjugate. The bispecific antibody is
CC useful for treating cancer in the subject suffering from tumor harbouring
CC a MET genetic alteration and/or tumor whose growth is driven by an
CC autocrine hepatocyte growth factor (HGF) signalling. The present sequence
CC is a anti-MET (receptor tyrosine kinase, HGF receptor, scatter factor
CC (SF)) monoclonal antibody LCVR region, which can be useful for treating
CC or preventing cancer in a subject.
ALIGNMENT:
Query Match 100.0%; Score 553; Length 108;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK 108
Jarkowski et al., teach methods for treating locally advanced unresectable non-small- cell lung cancer (NSCLC) with an antibody concurrently with chemoradiation therapy (cCRT) [abstract]. It will be appreciated that, although not precluded, treating a disorder, disease, or condition does not require that the disorder, disease, or condition or associated symptoms be completely eliminated. In particular embodiments relating to NSCLC [para 47]. In some embodiments, the interval between doses can be every three weeks [para 56]. Thus teaching claim 34. in some embodiments, the patient is administered one or more doses of antibody or an antigen-binding fragment thereof, wherein the dose is a fixed dose of 1500 mg thus teaching claims 1 and 32]. The antibody or an antigen-binding fragment thereof can be administered by subcutaneous injection [para 60].
Therefore, it would have been prima facie obvious at the time of applicants invention to modify the method for treating NSCLC as taught by Babb et al., to incorporate the administration amounts and schedule as taught by Jarkowski et al., into Babb et al., treatment of NSCLC in order to achieve tumor regression when using bispecific antibodies. One of ordinary skill in the art would have had a reasonable expectation of success by incorporating Jarkowski et al., dosing routine for treating NSCLC into Babb et al, method of treating NSCLC which improves anti-cancer drugs that potently block both ligand-dependent and ligand-independent MET signaling. Moreover, no more than routine skill would have been required to modify the treatment dosing schedule in order to treat and/or ameliorate NSCLC by blocking the interaction between MET and HGF, or otherwise inhibiting MET activity and/or signaling, and/or promoting receptor internalization and/or decreasing cell surface receptor number.
It is noted, that while the references recites administration at 2000mg; neither reference specifically recite the 2000mg. Regarding the specific amount recited in the instant claim, MPEP 2144.05 states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)."
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a method of treating NSCLC, where there is no change in the respective function of the bispecific antibodies; thus the combination would have yielded a reasonable expectation or success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
5. Applicant's arguments filed July 9, 2026 have been fully considered but they are not persuasive. Applicants argue that Babb et al., does not disclose treatment of patients with NSCLC harboring these MET alterations by administering the antibody defined in the pending claims at the doses described in the claims. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Applicants are reminded that reduction to practice argument is not persuasive because Babb teach NSCLC treatment with the MET X MET bispecific antibody.
Contrary to Applicants arguments, Babb et al., shows the in vivo One of ordinary skill in the art would have had a reasonable expectation of success by incorporating Jarkowski et al., dosing routine for treating NSCLC into Babb et al, method of treating NSCLC which improves anti-cancer drugs that potently block both ligand-dependent and ligand-independent MET signaling. Treatment of tumors induced regression of tumor size relative to the beginning of treatment. Data are provided in Table 31. Babb et al., teach assays using both SNU5 and the non-small cell lung cancer (NSCLC) cell line EBC-1 [para 271]. Example 13 teach a MET×MET Bispecific Antibody Induces MET Degradation, Inhibits Pathway Activity, and Inhibits Tumor Growth More Potently than Monospecific Antibodies in EBC-1 Cells. Tumor growth was monitored for 30 days post-implantation and tumor volume (mm3) was measured for each experimental group over time. The results shows that the MET×MET bispecific antibody significantly inhibits the growth of EBC-1 tumors [para 290]. See also Example 14. Therefore, Babb et al., clearly shows the in vivo efficacy against patient derived NSCLC tumors resulting from administration. Moreover, Jarkowski et al., teach treating locally advanced unresectable non-small- cell lung cancer (NSCLC) with an antibody concurrently with chemoradiation therapy (cCRT). Thus, one of ordinary skill in the art would have had a reasonable expectation of success by incorporating Jarkowski et al., dosing routine for treating NSCLC into Babb et al, method of treating NSCLC which improves anti-cancer drugs that potently block both ligand-dependent and ligand-independent MET signaling.
Applicants argue that Jarkowski does not teach any treatment or administration with a MET x MET bispecific antibody effective treatment of patients with NSCLC. In response to applicant's arguments against the Jarkowski reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, it would have been prima facie obvious at the time of applicants invention to modify the method for treating NSCLC as taught by Babb et al., to incorporate the administration amounts and schedule as taught by Jarkowski et al., into Babb et al., treatment of NSCLC in order to achieve tumor regression when using bispecific antibodies.
Applicants argue that teachings related to one antibody cannot be extrapolated to a different antibody. However, Babb teach the instantly claimed bispecific antibody. Therefore the different antibody argument is not found persuasive when Babb teach the instantly claimed antibody. Furthermore, Babb et al., describe administration of an anti-MET antibody or MET×MET bispecific antigen-binding molecule; along with multiple doses of an anti-MET antibody or MET×MET bispecific antigen-binding molecule (or a pharmaceutical composition comprising a combination of an anti-MET antibody or MET×MET bispecific antigen-binding molecule and any of the additional therapeutically active agents mentioned herein) may be administered to a subject over a defined time course. Babb teach treatment of NSCLC tumors with the bispecific antibody induced regression of tumor size relative to the beginning of treatment. Applicants attention is directed to MPEP section 2123 which teaches that patents are relevant as prior art for all they contain, “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir.1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). Therefore applicant’s argument is not persuasive especially when considering Babb teach the administration of the bispecific antibody is successful in reducing NSCLC tumor size.
Applicants argue that REGN5093 or other current therapies are not safe and effective anti-cancer drugs that block both ligand dependent and ligand independent MET signaling. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., blocking both ligand dependent and ligand independent MET signaling are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, Applicants is reminded that Babb et al., teach the instantly claimed bispecific antibody. Here Babb et al., teach the instantly recited antibody, and the inherently properties of the antibody are retained by the antibody, regardless of whether Babb recognized those properties. The discovery of a new property or function in an old, known material does not make that material novel or patentable. See MPEP 2112.
Finally, Applicants argue that the inventors found that treatment with a 250 -2000mg does of a MET x MET bispecific antibody was safe and effective to treat NSCLC. Thus, Applicants attention is directed to MPEP 2144.05 which states, Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Here, Jarkowski et al., already taught treating locally advanced unresectable non-small- cell lung cancer (NSCLC) with an antibody at 1500mg. Therefore administering antibodies at a dosage of between 250mg- 2000mg is not new or unexpected for the treatment of NSCLC. Likewise, as previously stated, administering a bispecific antibody comprising: a first antigen-binding domain (D1) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 9; and a second antigen-binding domain (D2) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 5 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 9; wherein D1 specifically binds a first epitope of human MET; and wherein D2 specifically binds a second epitope of human MET; just as taught by Babb et al., to reduce or regress NSCLC tumors has been previously described by Babb et al., and is not surprising or unexpected. Therefore, the argument is not found persuasive.
Claim Objections
6. Claims 19-24 are objected to because of the following informalities: Claims 19-24 are dependent on rejected claims. Appropriate correction is required.
Pertinent Art
7. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. Bean et al., “MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to getfitnib or erlotinib,” Proc. Natl. Acad. Sci. 2007 Dec. 26, 104(52): 20932-20937).
Harrison et al., (Semin Cancer Biol. 2020 Apr;61:167–179). Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Two mutations, deletions in exon 19 and the single amino acid substitution L858R in exon 21, often referred to as “classical” EGFR mutations, together account for ˜85% of observed EGFR mutations in NSCLC (Fig. 1) and confer sensitivity to EGFR tyrosine kinase inhibitors (EGFRi). Rare mutations account for the remaining ˜15% of EGFR mutations in NSCLC and include point mutations, deletions and insertions within exons 18–25 of the EGFR gene (Fig. 1, Fig. 2). For example, in 2018 the FDA approved the second-generation EGFRi afatinib for treatment of S768I, L861Q and G719X rare EGFR point mutations based on evidence from pooled analysis of three clinical trials, LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 .
Kobayashi et al., (J Thorac Oncol. 2013 Jan;8(1):45–51). Non-small-cell lung cancers (NSCLCs) containing epidermal growth factor receptor (EGFR) mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). This is the case of the most common EGFR mutations affecting exon 18 (G719X), 19 (inframe deletions) and 21 (L858R and L861Q). However, the frequency of compound (i.e., double or complex) EGFR mutations - where an EGFR TKI sensitizing or other mutation is identified together with a mutation of unknown clinical significance – and their pattern of response/resistance to EGFR TKIs are less well described.
Lio et al., (Oncol Lett. 2024 Dec 20;29(3):109) The most common oncogenic driver in non-small cell lung cancer (NSCLC) is epidermal growth factor receptor (EGFR) gene mutations, which are more common in Asian (30–50%) than in Caucasian (10–15%) populations. Exon 19 deletion (ex19del) and exon 21 L858R (ex21 L858R) mutations account for ~45 and 40% of all EGFR mutations, respectively. Moreover, EGFR-tyrosine kinase inhibitors (TKIs) may be more effective and improve the quality of life of patients with NSCLC more than chemotherapy regimens.
Conclusion
8. No claims allowed.
9. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JANA A HINES/Primary Examiner, Art Unit 1645
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