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 .
Applicant's arguments filed 4/27/2026 have been fully considered but they are not persuasive.
Claims 4, 13-14, and 18 have been cancelled.
The rejection of claims 1-2, 7, 12, and 17 under 35 U.S.C. 103 as being unpatentable over Robinson et al. (WO 2020/081786, of record) in view of Brinkmann et al. (U.S. Patent Application Publication 2010/0081796, of record), and Brinkmann et al. (2017, of record) is withdrawn in view of the claim amendments incorporating the sequences recited in claim 4 (now cancelled).
The rejection of claims 1-3, 7, 12, and 17 under 35 U.S.C. 103 as being unpatentable over Robinson et al. (WO 2020/081786, of record) in view of Brinkmann et al. (U.S. Patent Application Publication 2010/0081796, of record), and Brinkmann et al. (2017, of record) as applied to claims 1-2, 7, 12, and 17 above, and further in view of Chang et al. (U.S. Patent Application Publication 2021/0214436) and Sabsevari et al. (U.S. Patent Application Publication 2020/0048351) is withdrawn in view of the claim amendments incorporating the sequences recited in claim 4 (now cancelled).
The certified translation of the foreign priority document submitted 4/27/2026 is acknowledged. It is noted that the sequence listing (pages 19-35 of the CN 202010487524.3 document) was not included. Applicant claims benefit to the foreign priority document China 202010487524.3 (filed 6/2/2020). This document provides support for instant claims 2 and 3. However, there is no basis in this document for the anti-PDL1xEGFR bispecific antibody of instant claim 1, part (b), and SEQ ID NOS: 23-29 (see instant claim 6). As such, the effective filing date of claims 1, 5-7, 12, and 17 remains the filing date of PCT/CN2021/097785; namely, 6/1/2021.
Zhu et al. (WO 2021/227782, published 18 November 2021, filed 19 April 2021) and Zhu et al. (WO 2021/226984, published 18 November 2021, filed 15 May 2020) are not valid prior under 35 USC 102(a)(1). Page 11 of applicant’s 4/27/2026 response contains a conspicuous statement invoking an exception under 35 USC 102(b)(2)(C) thereby removing these two documents as valid prior art under 35 USC 102(a)(2).
The rejection of claims 1-7, 12, and 17 under 35 U.S.C. 103 as being unpatentable over Robinson et al. (WO 2020/081786, of record) Brinkmann et al. (U.S. Patent Application Publication 2010/0081796, of record), Brinkmann et al. (2017, of record), Chang et al. (U.S. Patent Application Publication 2021/0214436) and Sabsevari et al. (U.S. Patent Application Publication 2020/0048351) as applied to claims 1-3, 7, and 12 above, and further in view of Zhu et al. (WO 2021/227782, published 18 November 2021, filed 19 April 2021; inventors Z. Zhu, Zhao, Huang, and Xia) (i.e. by other than the instant inventive entity), Zhu et al. (WO 2021/226984 (published 18 November 2021, filed 15 May 2020; inventors Z. Zhu, Zhao, Huang, and Xia) (i.e. by other than the instant inventive entity), and Ng et al. (U.S. Patent No 10,273,303) is withdrawn in view of the disqualification of both Zhu et al. references. However, applicant did not disqualify WO 2021/244328 (published 9 December 2021, filed 21 May 2021) and WO 2021/244371 (published 9 December 2021, filed 26 May 2021). They remain valid prior art under 35 USC 102(a)(2). These documents were cited in the prior Office action and disclose PDL-1 antibody sequences recited in the instant claims. The art rejection has been revised as set forth below.
Specification
The substitute specification submitted 4/27/2026 has been entered.
The replacement sequence listing submitted 4/27/2026 is acknowledged.
Election/Restriction
Claims 8-11 and 15-16 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/30/2025.
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.
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, 5-7, 12, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Robinson et al. (WO 2020/081786, of record), Brinkmann et al. (U.S. Patent Application Publication 2010/0081796, of record), and Brinkmann et al. (2017, of record) in view of Chang et al. (U.S. Patent Application Publication 2021/0214436, of record), Sabsevari et al. (U.S. Patent Application Publication 2020/0048351, of record), Ng et al. (U.S. Patent No 10,273,303, of record), Zhu et al. (WO 2021/244328, published 9 December 2021, filed 21 May 2021, of record), and Huang et al. (WO 2021/244371, published 9 December 2021, filed 21 May 2021, of record)
The Zhu et al. and Huang et al. references have a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, they constitute prior art under 35 U.S.C. 102(a)(2). They do not constitute prior art under 35 USC 102(a)(1).
Robinson et al. (WO 2020/081786) discloses that PD-L1 and EGFR bispecific antibodies would be therapeutically useful. The bispecific antibody can be in multiple formats such as an IgG-scFv and scFv-IgG format. Pharmaceutical compositions are disclosed. The heavy chain isotypes can be IgG (including IgG1, IgG2, IgG3, and IgG4) and the light chains can be lambda or kappa types. (See instant claim 7.) See at least claims 1, 4, 9-11, and 14 and paragraphs [0016, 0031, 0034, 0041, and 0043].
Brinkmann et al. (U.S. Patent Application Publication 2010/0081796) discloses bispecific antibodies where an scFv for IGF-1 is fused at the N- or C- terminus of an EGFR antibody heavy chain or an scFv for EGFR is fused at the N- or C- terminus of an IGF-1 antibody heavy. See at least paragraphs [0038-0041] and Figure 2A-B. At least Figure 18 and paragraphs [0082 and 0423] disclose that antibodies can be labeled with Alexa647 (a known detectable fluorescent label). See instant claims 17. These IgG-Hc-scFv and scFv-Hc-IgG formats can also be visualized in Figure 2, Box 10, Brinkmann et al. (2017, of record). The IgG-Hc-scFv (Box 10, 1st construct on left) and scFv-Hc-IgG (Box 10, 7th construct from left) formats would have been well known and have the linkers disclosed in the instant claims. At least Figure 18 and paragraphs [0082 and 0423] disclose that antibodies can be labeled with Alexa647 (a known detectable fluorescent label). See instant claim 17.
Chang et al. discloses using flexible linkers (G4S)4 (four repeats of GGGGS) in bispecific antibodies against EGFR as well as PDL1. See at least SEQ ID NO: 427 and paragraphs [0009, 0023, 0101] and claims 4-5, 45, and 77-78.
Sabsevari et al. also discloses using flexible linkers in multispecific antibody constructs such as the linker (G4S)n where n can be 2-6. See at least paragraphs [0017-0018].
Ng et al. discloses a known antibody against EGFR. The VH of SEQ ID NO: 1 corresponds to instant SEQ ID NO: 15. The VL of SEQ ID NO: 2 corresponds to instant SEQ ID NO: 16. See at least EGFR cetuximab antibody designated 4353; sequence listing, Table 1; Table B; and columns 69-71.
Zhu et al. (WO 2021/244328, published 9 December 2021, filed 21 May 2021, of record) is by other than the instant inventive entity and discloses anti-PD-L1 antibody sequences recited in the instant claims. SEQ ID NO: 20 corresponds to instant SEQ ID NO: 13. SEQ ID NO: 19 corresponds to instant SEQ ID NO: 14. SEQ ID NO: 26 corresponds to instant SEQ ID NO: 22. See at least table starting at page 7. Zhu et al. discloses anti-PDL1/HER2 bispecific antibodies having a structure comparable to the instant claims. See at least pages 2-3. The anti-PD-L1 antibody is referenced as the M8 antibody.
Huang et al. (WO 2021/244371, published 9 December 2021, filed 21 May 2021, of record) is by other than the instant inventive entity and discloses anti-PD-L1 antibody sequences recited in the instant claims. SEQ ID NO: 18 corresponds to instant SEQ ID NO: 13. SEQ ID NO: 17 corresponds to instant SEQ ID NO: 14. SEQ ID NO: 5 corresponds to instant SEQ ID NO: 22. See at least table starting at page 6. The anti-PD-L1 antibody is referenced as the M8 antibody.
The basic structure of the anti-PDL1 x EGFR bispecific antibody structures in the claims is suggested by the combination of Robinson et al. (WO 2020/081786, of record) Brinkmann et al. (U.S. Patent Application Publication 2010/0081796, of record), and Brinkmann et al. (2017, of record). Chang et al. and Sabsevari et al. suggest the claimed linkers for linker1 and linker2.
It would have been obvious to make a bispecific anti-PD-L1xEGFR antibody in the IgG-scFv or scFv-IgG format as suggested by Robinson et al. This format would have been well known for bispecific antibodies (including all of the linkers) as evidenced by Brinkmann et al. (2017). Brinkmann et al. (U.S. Patent Application Publication 2010/0081796) demonstrates that it would have been routine to produce a bispecific antibody including EGFR in this format. It would have been obvious to make pharmaceutical compositions containing a bispecific antibody as disclosed by Robinson et al. It would have been obvious to label the bispecific antibody with a detectable label as disclosed by Brinkmann et al. (U.S. Patent Application Publication 2010/0081796). The kappa, lambda, and IgG isotypes of instant claim 7 are disclosed by Robinson et al. Anti-PDL1 X EGFR bispecific antibodies are suggested by the combination of the prior art.
Note that a polypeptide chain that comprises VL-PDL1-linker1-VH-PDL1-linker2-VH-
EGFR-CH1-CH2-CH3 paired with a VL-EGFR-CL light chain is a bispecific antibody in an scFv-Hc-IgG format. The scFv binds PDL1 and the Hc-IgG/light chain portion binds EGFR.
Note that a polypeptide chain that comprises a VH-PDL1-linker1-VL-PDL1-1inker2-VH-EGFR-CH1-CH2-CH3 paired with a VL-EGFR-CL light chain is a bispecific antibody in an scFv-Hc-IgG format. The scFv binds PDL1 and the Hc-IgG/light chain portion binds EGFR.
Note that a polypeptide chain that comprises VH-EGFR-CH1-CH2-CH3-linker2-VL-PDL1-linker1-VH-PDL1 paired with a VL-EGFR-CL light chain is a bispecific antibody in an IgG-Hc-scFv format. The scFv binds PDL1 and the Hc-IgG/light chain portion binds EGFR.
Note that a polypeptide chain that comprises VH-EGFR-CH1-CH2-CH3-linker2-VH-PDL1-linker1-VL-PDL1 paired with a VL-EGFR-CL light chain is a bispecific antibody in an IgG-Hc-scFv format. The scFv binds PDL1 and the Hc-IgG/light chain portion binds EGFR.
Note that a polypeptide chain that comprises VL-EGFR-linker1-VH-EGFR-linker2-VH-
PDL1-CH1-CH2-CH3 paired with a VL-PDL1-CL light chain is a bispecific antibody in an scFv-Hc-IgG format. The scFv binds EGFR and the Hc-IgG/light chain portion binds PDL1.
Note that a polypeptide chain that comprises VH-EGFR-linker1-VL-EGFR-linker2-VH-PDL1-CH1-CH2-CH3 paired with a VL-PDL1-CL light chain is a bispecific antibody in an scFv-Hc-IgG format. The scFv binds EGFR and the Hc-IgG/light chain portion binds PDL1.
Note that a polypeptide chain that comprises VH-PDL1-CH1-CH2-CH3-linker2-VL-EGFR-linker1-VH-EGFR paired with a VL-PDL1-CL light chain is a bispecific antibody in an IgG-Hc-scFv format. The scFv binds EGFR and the Hc-IgG/light chain portion binds PDL1.
Note that a polypeptide chain that comprises VH-PDL1-CH1-CH2-CH3-linker2-VH-EGFR-linker1-VL-EGFR paired with a VL-PDL1-CL light chain is a bispecific antibody in an IgG-Hc-scFv format. The scFv binds EGFR and the Hc-IgG/light chain portion binds PDL1.
The prior art suggests all of these combinations. One of ordinary skill in the art would have known each of these formats for bispecific antibodies.
It would have been obvious to use the flexible (G4S)4 linker as taught by Chang et al. and Sabsevari et al. in the bispecific antibody constructs suggested by the combination of Robinson et al. (WO 2020/081786, of record), Brinkmann et al. (U.S. Patent Application Publication 2010/0081796, of record), and Brinkmann et al. (2017, of record) as discussed above. One would have been motivated to do so as Chang et al. and Sabsevari et al. make clear that these would have been conventional linkers routinely used in such constructs.
It would have been obvious to use the PD-L1 antibody sequences disclosed by Huang et al. and Zhu et al. and the EGFR antibody sequences disclosed by Ng et al. in the anti-PDL1 X EGFR bispecific antibody structures suggested by the combination of Robinson et al. (WO 2020/081786, of record) Brinkmann et al. (U.S. Patent Application Publication 2010/0081796, of record), Brinkmann et al. (2017, of record), Chang et al. (U.S. Patent Application Publication 2021/0214436) and Sabsevari et al. (U.S. Patent Application Publication 2020/0048351).
At least for example, claim 6 includes an embodiment wherein the polypeptide chain is instant SEQ ID NO: 26 and the light chain is instant SEQ ID NO: 22. Instant SEQ ID NO: 26 paired with instant SEQ ID NO: 22 forms a bispecific antibody in an IgG-Hc-scFv format. The scFv binds EGFR and the Hc-IgG/light chain portion binds PDL1.
Instant SEQ ID NO: 22 is a VL-PDL1-CL light chain and a kappa chain (see instant claim 7). Zhu et al. discloses SEQ ID NO: 26 which corresponds to instant SEQ ID NO: 22. Huang et al. discloses SEQ ID NO: 5 which corresponds to instant SEQ ID NO: 22.
Instant SEQ ID NO: 26 is a polypeptide chain that comprises VH-PDL1-CH1-CH2-CH3-linker2-VL-EGFR-linker1-VH-EGFR. SEQ ID NO: 25 of Zhu et al. corresponds to amino acids 1-447 of instant SEQ ID NO: 26 (i.e. the VH-PDL1-CH1-CH2-CH3 portion of the polypeptide chain). SEQ ID NO: 2 of Huang et al. corresponds to amino acids 1-447 of instant SEQ ID NO: 26. Amino acids 448-462 of instant SEQ ID NO: 26 correspond to (G4S)3 (i.e. the linker 2 portion of the polypeptide chain). This linker is suggested by Sabsevari et al. Amino acid 463-569 of instant SEQ ID NO: 26 correspond to SEQ ID NO: 2 of Ng et al. (i.e. the VL-EGFR portion of the polypeptide chain). Amino acids 570-589 of instant SEQ ID NO: 26 correspond to (G4S)4 (i.e. the linker 1 portion of the polypeptide chain). This linker is suggested by Chang et al. and Sabsevari et al. Amino acids 590-708 of instant SEQ ID NO: 26 correspond to SEQ ID NO: 1 of Ng et al. (i.e. the VH-EGFR portion of the polypeptide chain).
Huang et al., Zhu et al., and Ng et al. provide the particular sequences required by the claims. With respect to claim 1, the light and heavy chain PDL1 CDRs recited are present in the sequences of both Huang et al. and Zhu et al. and the light and heavy chain EGFR CDRs recited are present in the sequences of Ng et al. With respect to claim 5, the PDL1 VH and VL sequences recited are present in the sequences of Huang et al. and Zhu et al. and the EGFR VH and VL sequences recited are present in the sequences of Ng et al.
Other embodiments of claims 1 and 5-6 would also have been obvious and the PD-L1 antibody sequences of Huang et al. and Zhu et al., the EGFR antibody sequences of Ng et al. and the linkers of Chang et al. and Sabsevari et al. could be mapped out for these embodiments as set forth above for the SEQ ID NO: 26/SEQ ID NO: 22 embodiment.
The claimed bispecific antibodies, pharmaceutical compositions (claim 12), and immune conjugates (claim 17) would have been obvious.
Applicant’s arguments with respect to unexpected results are not persuasive. The unexpected results argued by applicant are not commensurate with the claims. The claims are not limited to the bispecific antibody embodiment tested in Figure 10. There is no demonstration that the bispecific antibody embodiment in Figure 10 is statistically significantly better than administration of the two separate antibodies. See error bars. At least for example, Koopmans et al. (2018, of record) discloses an anti-PD-L1xEGFR bispecific antibody that would be closer prior art for comparison to establish unexpected results. See also results disclosed in Examples 6-7 and 11 and Figures 11-14 that are not statistically significantly different. No unexpected results have been shown.
Claims 2-3 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. These claims have basis in the foreign priority document. The recited anti-PD-L1 antibody sequences are not found in the art of record that is prior to this date.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/Marianne P Allen/Primary Examiner, Art Unit 1647
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