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 .
DETAILED ACTION
The amendment filed July 9, 2026 in response to the Office Action of April 9, 2026 is acknowledged and has been entered.
Claims 1, 3, and 8 have been amended.
Claims 1, and 3-11 are pending.
Claims 9 and 10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 3-8, and 11 are currently under consideration as drawn to the elected invention.
In view of amendments on claim 8, the claim objections set forth in the previous Office Action of April 9, 2026 are hereby withdrawn.
In view of amendments on claim 1 and applicant’s argument, the 112(b) rejection set forth in the previous Office Action of April 9, 2026 is hereby withdrawn.
In view of amendments on claim 1 and applicant’s argument, the 112(a) rejection set forth in the previous Office Action of April 9, 2026 is hereby withdrawn.
In view of amendments on claim 1 and applicant’s argument, the 102 rejection set forth in the previous Office Action of April 9, 2026 is hereby withdrawn.
MAINTAINED/MODIFIED REJECTIONS
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-6, 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Loew (Loew et al., WO 2019/178364 A2, Publication Date: 09/19/2019, cited in IDS of 02/20/2025, of record) in view of Zhu (Zhu et al., Scientific Reports (2019) 9:8420, Publication Date: 06/10/2019) and Kipriyanov (Kipriyanov et al., Int. J. Cancer: 77, 763-772, Publication Year: 1998).
Examiner’s Note: Claim 1 recites “the TGF-β inhibitory molecule refers to human TGF-βRII extracellular region and a derivative thereof”. Examiner interprets the limitation “a derivative thereof” as an alternative limitation.
Loew teaches multispecific molecule targeting a first and a second tumor antigen, and one of more of an immune cell engager (such as T cell engager), a cytokine modulator, wherein the first and second tumor antigens are each independently chosen from CD34, CD41, G6P, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1 (page 1, Summary of the invention, and claims 1, 42, 47).
Loew teaches that the tumor antigen moiety comprising CD34 antibody (claim 19), CD41 antibody (claim 20), P-selectin antibody (claim 22), cKIT antibody (claim 24), FLT3 antibody (claim 25); MPL antibody (claim 26); DSC2 antibody (claim 33), FCGR2A antibody (claim 34); TNFRSF10A or 10B antibody (claim 35); or TM4SF1 antibody (claim 36).
Loew teaches that the T cell engager binds to CD3, e.g., the T cell engager is an anti-CD3 antibody molecule (claim 48).
Loew teaches that the multifunctional molecule comprises a modulator of a cytokine molecule, e.g. a TGF-β inhibitor (such as an extracellular domain of TGF-βRII or TGF-βRI (claim 67, and the bottom paragraph on page 96). In some embodiments, the TGF-β inhibitor comprises two TGF-β receptor extracellular domains, linked together (page 98, para. 3).
Loew teaches in some embodiments the multispecific molecule comprises a configuration shown in Fig. 2A-2D (page 98, para. 4).
In these configurations, the molecule would have one CD3 binding moiety (x=1), one TAA binding moiety (n=1), and two TGF-β inhibitor molecules (m=2).
Loew teaches that the multispecific or multifunctional molecules are expected to target an immune cell (such as T cell) at a target cell, e.g., a cancer cell expressing the tumor antigens. Increasing the proximity and/or activity of the immune cell using the multispecific molecules is expected to enhance an immune response against the target cell, thereby providing a more effective therapy and reducing the effects of systemic toxicity (page 2, para. 2).
Taken together Loew teaches a multispecific or multifunctional molecule comprising TAA antibody, an anti-CD3 antibody and two TGF-β inhibitor molecules. However, Loew does not teach the TAA is CLDN18.2 (the elected species), and the CD3 antibody is OKT3 (the elected species).
Loew teaches that CD3 antibody can be combined with other TAAs such as EpCAM and HER2 antibody to make bispecific antibodies such as catumaxomab (CD3 x EpCAM), and ertumaxomab (CD3 x HER2) (page 67, lines 3-29).
Loew teaches the method of making multispecific antibodies and antibody fusion proteins are well known in the art (pages 66-68, 70-79).
Zhu teaches that identifying a specific TAA for an oncology target that has limited normal tissue expression is critical. CLDN18.2 represents a potentially attractive TAA because it fulfills this criterion. CLDN18.2 is expressed in a significant proportion of primary gastric cancers and their metastases, as well as in pancreatic and esophageal adenocarcinoma (page 2, para. 4). Anti-CLDN18.2 antibody, Claudiximab, has been studied in numerous clinical trials for the treatment of patients with advanced gastroesophageal cancer (page 2, para. 4).
Zhu teaches that bispecific anti-CLDN18.2/CD3 antibody shows good anti-tumor activity in vivo xenograft models (Fig. 5C), in two different antibody formats (Fig. 3a).
Kipriyanov teaches antibody OKT3 specific for human CD3 and scFv derived from OKT3 (page 764, § Vector construction).
Kipriyanov teaches that Mab OKT3, scFv derived from OKT3, and diabody comprising scFv derived from OKT3 all have good binding property (Table 1).
Kipriyanov teaches the bispecific antibody comprising OKT3 or scFv derived from OKT3 has enhanced anti-tumor activity (Fig. 6).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of Loew, Zhu and Kipriyanov, and to substitute the TAA binding moiety in the multispecific functional molecule of Loew with an antibody specific for CLDN18.2 as taught by Zhu, and to use OKT3 or scFv derived from OKT3 as the anti-CD3 antibody as taught by Kipriyanov. One of ordinary skill in the art would have had a reasonable expectation of success because Zhu teaches that CLDN18.2 is a good TAA which can be targeted by an antibody targeting both CLDN18.2 and CD3, Kipriyanov teaches that OKT3 or scFv derived OKT3 has good affinity to CD3 and has good anti-tumor activity when combined with an anti-TAA antibody in bispecific antibody settings, Loew teaches the methods of connect different functional modules into a multifunctional fusion protein are well known in the art. The motivation would have been to expand the options to other TAA and to develop a molecule for treating CLDN18.2 expressing cancers.
Regarding claim 4, Loew teaches that the antibody molecule has a heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4 from human (page 65, para. 4). In some embodiments, the one or more immunoglobulin chain constant regions (e.g., Fc regions) comprise an amino acid substitution at a position chosen from one or more of 347, 349, 350, 351, 366, 368, 370, 392, 394,395,397,398,399,405,407, or 409, e.g., of the Fc region of human IgG1, optionally wherein the one or more immunoglobulin chain constant regions (e.g., Fc regions) comprise an amino acid substitution chosen from: T366S, L368A, or Y407V (e.g., corresponding to a cavity or hole), or T366W (e.g., corresponding to a protuberance or knob), or a combination thereof (page 34, para. 4; claim 102). This combination reads on the combination number 2 of instant claim 4.
Regarding claim 5, although Loew does not explicitly teach the configuration as instantly claimed. However, Loew teaching various configurations with two TGF-β inhibitors fused to the C-terminal of A chain and B chain of Fc segment respectively (Figs. 2A and 2B). Both Loew and Zhu teach various antibodies (including Fab and scFv) to different TAAs. Loew teaches methods of making multispecific antibodies and antibody fusion proteins with different antibody fragments and polypeptide are well known in the art. Kipriyanov teaches scFv derived OKT3 which binds CD3 and shows good therapeutic activity. One of ordinary skill in the art would make different configurations to modify the locations of each functional module and valence of binding to each target, with the well-known components to reach the claimed configuration through routine practice in the art. The motivation would be to find the molecule with optimal therapeutic properties for specific conditions.
Regarding claim 8, Loew teaches that the multispecific molecule includes one, two, three or four linkers, e.g., a peptide linker. In one embodiment, the peptide linker can be G4S (SEQ ID NO: 69); (G4S)2 (SEQ ID NO:70); (G4S)3 (SEQ ID NO: 71) (page 140, para. 2; and claims 105-107).
Regarding claim 11, Loew teaches a nucleic acid molecule encoding the multifunctional molecule, a vector comprising the nucleic acid molecules thereof, and a host cell comprising the nucleic acid molecule thereof (claims 124-126).
Response to Arguments
For the 103 rejection, Applicant argues:
The present application proposed a technical scheme for constructing a trifunctional fusion protein comprising a tumor-associated antigen (TAA) antibody targeting CLDN18.2, a TGF-β inhibitor and a CD3 antibody, and constructed 7 exemplary trifunctional fusion protein molecules, QP32133212, QP34133414, QP34153416, QP34173418, QP34193420, QP34213422 and QP146134233424 (Protein 1-7, Table 1). Experiments proved that the 7 trifunctional fusion protein molecules having the claimed general structure have good properties, especially QP146134233424.
It is submitted that the claimed trifunctional fusion protein of the present application would not have been readily derived from the teaching of the prior art. Further, the superior properties of the claimed bispecific antibody makes it NOT anticipated or rendered obvious by the prior art.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Loew teaches that the multispecific or multifunctional molecules are expected to target an immune cell (such as T cell) at a target cell, e.g., a cancer cell expressing the tumor antigens. Increasing the proximity and/or activity of the immune cell using the multispecific molecules is expected to enhance an immune response against the target cell, thereby providing a more effective therapy and reducing the effects of systemic toxicity (page 2, para. 2). One of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention because Zhu teaches that CLDN18.2 is a good TAA which can be targeted by an antibody targeting both CLDN18.2 and CD3, Kipriyanov teaches that OKT3 or scFv derived OKT3 has good affinity to CD3 and has good anti-tumor activity when combined with an anti-TAA antibody in bispecific antibody settings, Loew teaches the methods of connect different functional modules into a multifunctional fusion protein are well known in the art.
Applicant further argues the superior properties of the claimed constructs, i.e., QP146134233424. This statement appears based on Figure 11 which seemingly shows better inhibitory effects than vehicle (no other controls, such as single antibodies were used in the experiment). The effect of tumor inhibition, which is only slightly better than that of vehicle, is not considered as unexpected and superior effect.
In addition, the claims are not limited to the configurations of QP146134233424. The claims encompass different antibodies to CLDN18.2, different antibodies to CD3 and different TGF-β inhibitory molecules, different configurations and different formats Thus, the example is not commensurate in scope with the claimed invention.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Conclusion
Claims 1, 3-6, 8 and 11 are rejected.
Claim 7 is objected because they are dependent on the rejected claims directly or indirectly. However, claim 7 would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646
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