DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/19/2025 has been entered.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 20, 21 and dependent claims are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 4, 20 and 21 recite a “microenvironment”. It is unclear what the scope of that term includes. For example, it is unclear if there is a maximum size-limit to be considered “micro” or what constitutes an “environment”. The instant specification refers only to a “tumor microenviroment”, however, the experiments associated with the limitation referring to a “microenvironment” in the claims were all in vitro conditions. As a result, the metes and bounds of the claims is not clear.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 7-9, 19-21 and 23-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for wherein the Fc region of the antigen-binding protein construct of the method of treating cancer is a human IgG1 Fc region comprising LALA mutations or N297A mutation or a human IgG4 Fc region, does not reasonably provide enablement for wherein the Fc region is an IgG2 Fc region. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claims require “the antigen-binding construct does not activate the CD40 pathway in a microenvironment without cells expressing PD-1”. Dahan et al. (Canc. Cell, 29(6):820-831, 2016, cited in the PTO-892 filed 5/21/25) tested constructs made with the antigen-binding domain of anti-CD40 agonist antibody CP-807,893 and an Fc domain which is IgG1, IgG2 or IgG1 N297A. In a mouse model expressing human Fc receptors, both IgG1 and IgG2 isotypes activated T cells, although the activation by IgG1 was significantly greater. The IgG1 N297A Fc completely abolished CD40 activity. Further when the IgG2 isotype was deglycosylated leading to reduced binding affinity to FcγRIIB, there was a significant loss of activity compared to wildtype IgG2 (p. 822, end of col. 1 through col. 2, middle). This supports the reasonable expectation that an antigen-binding protein construct of the instant claims comprising a human IgG2 Fc region would activate the CD40 pathway in a microenvironment without cells expressing PD-1. Note that i) there is no limitation on what constitutes a microenvironment (see the rejection under 35 USC 112(b) above) and ii) no limitation about lack of activation in terms of dose, that is, if there is dose over which activation will occur. Regardless, the results of Dahan et al. agree with those shown in instant Fig. 5 as described in Example 5 of the instant specification, wherein CD40 antibody 6A70H4K2-IgG2 exhibited FcγRIIB receptor-mediated reporter cell activation through FcγRIIB receptor-mediated clustering. Dahan in Fig. 2A shows FcγR binding profiles of the anti-CD40 Fc variants, which corresponds to the information in Vidarsson et al. (Front. Immunol. 5:520, 17 pages, 2014, cited in the IDS filed 1/12/23, Table 1). As a result, it does not reasonably appear that an antigen-binding protein according to the instant claims having a human IgG2 Fc region would “not activate the CD40 pathway in a microenvironment” as required by the claims.
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.
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.
Claim(s) 1, 2, 4, 7-9, 19-21 and 23-24 remain and new claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0372155 A1 (Wang, cited in thePTO-892 mailed 8/22/23), US 20190241659 A1 (Mumm, cited in the PTO-892 mailed 07/08/2024) and 20220259330 A1 (Zhao, cited in the PTO-892 mailed 8/22/23) in view of Kluger et al. (Cancer Res 2019;79(13 Suppl):Abstract CT089, 2019, cited in the PTO-892 mailed 12/21/23) as recast here to address the claim amendments and Applicant’s arguments.
US 2022/0372155 A1 (Wang) teaches anti-PD-1/anti-CD40 and anti-PD-L1/anti- CD40 bispecific antibodies (bsAbs,e.g., [0037]). It is explained that CD40 is an antigen-presenting cell (APC) costimulatory protein required for APC activation and is found on the surface of tumor cells, such as of B lymphomas, and about 70% of all solid tumors; however, its activation leads to antigen-specific antitumor immune response ([0002]). Antibodies which have a first antigen-binding moiety that binds human CD40 and a second antigen-binding moiety which binds PD-L1 are exemplified by Ly301, Ly303, Ly338, Ly339, Ly340, Ly341, Ly342, Ly343, Ly344, Ly345, Ly349, and Ly350 ([0039]). Antibodies binding a first antigen which is PD-1 and a second antigen which is CD40 are exemplified by Ly517, Ly518, Ly519, Ly520, Ly606, Ly607, Ly608, Ly609, Ly817, Ly818, Ly819, and Ly820, all comprising the light chain of anti-PD-1 antibody Ly516 and full heavy chain thereof. ([0045]) and Table at [0340]). More specifically, described ([0191]), for example, [T]he anti-CD40/PD-1 bi-specific antibody may comprise a first chain comprising the scFv fragment fused with the heavy chain of the anti-PD-1 antibody such as that of Ly516, and a second chain that is the light chain of the anti-PD-1 antibody…. In some instances, the heavy chain of the anti-PD-1 antibody may comprise a mutated Fc region having altered binding affinity and/or binding specificity to an Fc receptor such as those described herein.” Ly517 has the HC of Ly516 (SEQ ID NO:228) with an IgG1 mutated Fc region (anti-PD-1 HC) and scFv of anti-CD40 Ly253 antibody in VL->VH orientation (SEQ ID NO:229) and light chain of Ly516 (SEQ ID NO:228). Ly518 is the same as Ly517, except with the scFv in the VH->VL orientation (SEQ ID NO:230). (See also claims 56-60, 78-81, 87-90, 97 and 98, and Table 27.) Figs. 11A-11D show stimulation of human CD40 activation indicated by IL-8 secretion in a reporter assay by various anti-PD-L1/anti-CD40 bispecific antibodies in solution or when co-cultured with PD-L1 overexpressing CHO cells. “The [CD40] agonist activity was greatly enhanced in the co-culture assay, as indicated by the saturation of does response where lowest concentration of 0.01 ug/mL bispecific antibodies exhibited maximal activity. Binding to both CD40 and PD-L1 by the tested bispecific antibodies simultaneously in a microenvironment would affect individual binding due to the avidity effect, which refers to the accumulated strength of multiple affinities of individual non-covalent binding interactions. The bi-specific antibodies showed increased activity when co-cultured with PD-L1-expressing CHO cells.” ([0349]) In a related assay, Figs. 15A-15D show activity of various anti-PD-L1/anti-CD40 in activation of human dendritic cells (DCs) from two healthy donors either in solution or co-cultured with human PD-L1-expressing CHO cells. The bispecific antibodies showed much higher DC activation than anti-CD40 antibody alone, especially in the presence of PD-L1 expressing CHO cells ([0363]; especially for the bispecific antibody Ly338 and Ly342-Ly345, all with a mutated IgG1 Fc region for Donor 1 and all of Ly301, Ly303, Ly338, Ly339, Ly340, Ly341, Ly342, Ly343, Ly344, Ly345, Ly349, and Ly350 for Donor 2, with all antibodies having the structure of a heavy chain comprising a binding domain, a light chain, and an scFv binding the other antigen; Table [0340]). These experiments illustrate the bsAb was capable of activating a CD40 pathway, and the level of activation depended on the binding of the bsAb to a cell expressing PD-L1 as evidenced by the higher activity when the bsAb was co-cultured with PD-L1-expressing CHO cells (compare Fig. 15A to 15B and 15C to 15D, and see [0435]). A number of the anti-PD-L1/anti-CD40 antibodies (including Ly338 and Ly340-Ly343) showed antitumor activity in a human CD40 extracellular domain knock-in mouse model with human PD-L1 overexpressing murine colon cancer MC38 tumor cells ([0368]-[0369]). A modified Fc region of the antibody is taught ([0208]) which is “immunologically inert, e.g., does not trigger complement mediated lysis, or does not stimulate antibody-dependent cell mediated cytotoxicity (ADCC).” This is done by having one or more mutations in the Fc region to reduce binding affinity to an Fc receptor ([0124] and [0159]).“ Further, anti-CD40 antibodies of the lgG2 or IgG4 isotypes are taught (e.g., end of [0317]-[0318]). Wang does not teach wherein the Fc region of the bispecific construct is a human IgG1 with a LALA or N297 mutation. Nor is it taught wherein the activation of CD40 pathway is dependent on the binding of the antigen-binding protein construct to a cell expressing PD-1; although, it is taught that bispecific antibodies binding CD40 and PD-L1 showed increased CD40 activity when co-cultured with PD-L1 expressing cells. No specific tumor growth inhibition (TGI%) is taught.
US 20190241659 A1 (Mumm) teaches bispecific fusion polypeptides (BFPs) for controlling T cell-mediated cytotoxicity comprising a first binding region specific for a first cell surface target, an Fc monomer and a second binding region specific for a second cell surface target wherein the first or second binding region is an antibody Fab fragment or a receptor ligand ([0013]-[0015]). The Fab fragment is an anti-PD-1 or anti-PD-L1 Fab fragment and the ligand is GITRL, OX40L, TNF-α, CD137L or CD40L ([0016]-[0017]). These TNF ligands are biologically active as homotrimers ([0139]). Both OX40 and GITR are expressed on CD4+ and CD8+ T cells, regulatory T (Treg) cells and natural killer (NK) cells, and binding by their respective ligand leads to clustering of their loosely trimeric form, resulting in potent signaling in T cells ([0008],[0009]). PD-L1 is expressed on T, B, and dendritic cells, including antigen presenting cells (ACPs, Fig. 17A), as well as macrophages, mesenchymal stem cells, and a broad range of cancers ([0007]). PD-1 is expressed on activated T cells [0093]). Figures 5-12 and 14-27 show the in vitro activity of a BFP2 and BFP3 comprising an anti-PD-L1 antibody Fab fused to an Fc fused to a OX40L trimer, which also caused OX40 clustering on MDA MB-231-PD-L1-expressing cells (Fig. 43). More specifically, MEDI5615, in which each Fc polypeptide of the bispecific molecule comprises at its N-terminus an OX40L trimer, followed by an IgG4 Fc region, attached to a C-terminal anti-PD-L1 Fab (Fig. 2: BFP2), penetrated and was retained in tumors ([0248]). Further, when Jurak NF-κB-luciferase T cell reporter cells were engineered to express human OX40 and cultured with PD-L1-surface-expressing MDA-MB231 cells or Fcγ receptor- (FcγR-) expressing HEK293 cells, MDI5615 activated OX40 signaling as measured by NF-κB signaling in the OX40-Jurkat T reporter cells in the presence of the FcγR HEK293 cells or in the presence of PD-L1 MDA-MB231 cells (e.g., Fig. 42), but there was only minimal Jurkat reporter cell activity in the absence of the PD-L1- or FcγR-expressing cells ([0252]). Fig. 67B shows that anit-PD-L1-IgG4 Fc-CD40L (BFP3, MEDI7526, Table 1) significantly inhibited tumor growth ([0086]). The murine surrogate of MEDI7526 (mMEDI7526) administered as a single dose in mice bearing B16F10 tumors led to no loss in body weight, while treatment with mouse CD40L led to more severe body weight loss ([0029]). mMEDI7526 also led to significant antitumor activity in a low responsive tumor model (([0231]). Administration to the mice further showed “robust activation of CD4+ and CD8+ cells in tumor bearing mice” ([0233]) and induction of antitumor cytokines but not those contributing to systemic toxicity. In mice with CT26 tumor cells, MEDI7526 treatment completely removed liver tumors ([0237]). Fig. 67B shows that anit-PD-L1-IgG4 Fc-CD40L (BFP3, MEDI7526, Table 1) significantly inhibited tumor growth ([0086]). FIG. 65 shows combined treatment of 5FU and MEDI7526 also effectively inhibits tumor growth ([0084] and [0237]). Anti-PD-1 BFPs were also made, with Fig. 3E showing the bispecific binding construct anti-PD-1-IgG1 Fc-CD40L and Fig. 3O shows the anti-PD-1-IgG4 Fc-CD40L antigen-binding protein construct (having two sets of CD40L trimer repeats, one on each Fc). An anti-PD1/GITRL/IgG4P BFP bound both PD-1 and GITR (Fig. 55A), activated the NFAT pathway in Jurkat cells transfected with PD-1 (Fig. 51 and [0283]), and showed a synergistic effect on T cell reactivation as measured by IFN-γ production ([0293] and Fig. 55B-C). In a BPF with an anti-PD-L1 antibody fragment, similar results were obtained. “FIG. 11B shows that anti-PD-L1-CD40L BFP has dual functions: it activated NF-κB on THP-1 cells through CD40 engagement and enhanced NFAT activity in Jurkat cells by removing PD-L1-mediated inhibition.” ([0030]) Fig. 47 and 48 show that constructs of anti-PD-1 IgG4 Fc-Ox40L or -GITRL (BFP3) both reduced the amount of PD-1 protein expression in human PBMC, but did not change the amount of OX40 or GITR protein ([0066]-[0067] and Examples 21 and 30). The anti-PD-1 portion of the bispecific construct is the Fab part of an IgG, e.g., PD1-GITRL are MEDI3387 and MEDI5771, and Fig. 13 show they had cytokine-producing activity equivalent to the combination of parent molecules but greater than either alone (Example 8 and [0032]). In some preferred embodiments ([0134]), the BFP3 format bispecific fusion proteins includes one or more N-terminus antigen binding subunits, a central Fc polypeptide core, and one or more C-terminus ligand proteins. The one or more N-terminus antigen binding subunits (BD2) can be anti-PD-1 and/or anti-PD-L1 antigen binding subunits, the Fc polypeptide core can be an IgG1 or IgG4 Fc region polypeptide (CH2 and CH3), and the one or more C-terminus TNF superfamily ligand proteins (BD1) can be, for example, CD40L. “Antigen binding regions, such as Fab fragments, that selectively bind PD-1 and PD-L1, and inhibit the binding or activation of PD-1 and PD-L1 are useful in the BFPs of the disclosure. Fab (Fragment antigen-binding) fragments consist of the VH-CH1 and VL-CL domains covalently linked by a disulfide bond between the constant regions. To overcome the tendency of non-covalently linked VH and VL domains in the Fv to dissociate when co-expressed in a host cell, a single chain (sc) Fv fragment (scFv) can be constructed consisting of a flexible and adequately long polypeptide linking either the C-terminus of the VH to the N-terminus of the VL or the C-terminus of the VL to the N-terminus of the VH.” ([0141])
US 20220259330 (Zhao) teaches a bispecific hybrid antibody comprising anti-PD-1 antibody 609 linked to an anti-CD40-Hu antibody, 609-Fab-40-lgG4 and 40-Fab-609-IgG4, for which ELISA results are shown in Figs. 25A-B and 26A-B. Antibody 609 is a humanized anti- PD-1 monoclonal antibody, also known as Mab1-25-Hu. Anti-CD40 antibody (Mab2.220), a murine monoclonal antibody against human CD40, served as the parent antibody for a humanized version named Anti-CD40-Hu having IgG4 heavy chain constant regions with mutation S228P ([0262]-[00267]). Anti-CD40-Hu-LC was selected for the common light chain of the bispecific antibody (bsAb, [0271]). The structure of the bsAb is shown in Fig. 1. It is a tetravalent bsAb. Both constructs bound both PD-1 and CD40 ([0274]). The invention, however, may have heavy chain constant regions from any of IgG1, IgG2, IgG3 or IgG4 ([0046]). It is taught that bispecific antibodies maybe in the form of IgG-scFv ([0006]). A method of treating cancer comprising administering the tetravalent bispecific antibody to a subject in need is taught (claims 1, 20 and 23-35). Figures 18 and 42 show colorectal MC38 cancer cell tumor regression in transgenic mice by two bispecific anti-PD-1 IgG4 constructs, the first with an anti-LAG-3 Fab and the second an anti-TGF-Beta Fab ([0210], [0216], [0217], [0314], [0322], [0323]). Both bispecific antibodies had a tumor inhibition rate well over 50% ([0217] and [0323]). It was concluded the bispecific antibody inhibited tumor growth more effectively than the parent monoclonal antibody(ies) ([0323]). Other PD-1 bispecific antibody constructs were also made (e.g., anti-PD- 1/anti-CD137 and anti-PD-1/anti-VEGF, Examples 5 and 1, respectively, see also Example 7). It is taught for the bispecific anti-HER2/anti-CD137 antibodies, the IgG1 domain comprised a LALA mutation to reduce interaction between the Fc region and Fcgamma receptors ([0247]). “Herein, the purpose of LALA mutation is mainly to reduce potential toxicity in vivo....” ([0245]) Also ([0003]), “Bispecific tandem scFv format has been widely used in cancer immunotherapy to retarget T cells to tumor cells or tumor-associated cells in the tumor microenvironment.”
Kluger et al. teach (Background), “Preclinical data suggest that activation of CD40 can be combined with PD-1 blockade to trigger effective T cell immunity.” A multi- center, open label Phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the anti-PD-1 antibody nivolumab (nivo) with the anti-CD40 antibody APX005M in patients with metastatic melanoma (M) and disease progression (PD) while being treated with anti-PD-1 therapy or with immunotherapy-naive non-small cell lung cancer (NSCLC) (Methods). Of the melanoma patients, 1 had partial remission (PR), 2 had stable disease (SD) and 2 had PD. For the NSCLC patients, 1 had PR, 2 had SD and 1 had PD. In the Phase II portion, 10 additional enrolled subjects with metastatic melanoma were treated with both antibodies. It ended with 2 having PR, 2 SD and 6 PD (Results). It was concluded (Conclusion), “APX005M + nivo demonstrated a good safety profile and promising antitumor activity in M subjects with PD while receiving anti- PD-1 therapy and potential activity in NSCLC.” Enrollment for the second stage of the melanoma Phase II trial and first stage of the NSCLC Phase II trial is open (Conclusion).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the invention to have treated cancer in a subject, including killing tumor cells and decreasing the rate of tumor growth, with a CD40- and PD-1-binding bispecific construct comprising a first antigen-binding site that specifically binds PD-1 and a second antigen-binding site that specifically binds CD40 and an Fc region that is an IgG2 or IgG4 Fc region and wherein the first antigen-binding site is N-terminal to the Fc region and second antigen-binding site is C-terminal to the Fc region, which format is taught by Mumm except wherein a CD40 antigen-binding site is substituted for the CD40L trimer-comprising CD40-binding site as in BFP2 or BPF3 (e.g., Fig. 3O of Mumm). Mumm also teaches wherein the Fc region-linked C-terminal binding site is in the form of a scFv [BFP2 of Mumm Fig. 2)] and as suggested by Wang and Zhao, which would have been an obvious format. The bispecific constructs of Wang and Mumm blocked the binding of PD-1 to PD-L1. It would have been obvious wherein the IgG Fc domain was an IgG4 isotype as taught by Mumm and Zhao or was mutated such that it did not bind Fc receptors, e.g., was an IgG1 with a LALA mutation, and did not induce effector activity as discussed by Zhao to reduce toxicity and as was shown for a different bispecific construct comprising an IgG1 Fc with a LALA mutation (anti-HER2/anti-CD137). Alternatively, it would have been obvious wherein the IgG Fc region was from IgG4 as exemplified for the anti-PD-1/anti-CD40 bsAb of Zhao in which the anti-CD40 portion was an IgG4 isotype antibody or the anti-PD-1 portion was as exemplified by Mumm. Both bispecific anti-PD1/anti-TGF-β Fc and anti-PD1/anti-LAG3 of Zhao had tumor inhibition rates well over 50%, supporting a reasonable expectation that an anti-PD-1-IgG4-anti-CD40 bispecific construct would also, as would similar constructs in which, for example, the Fc region is from IgG1 with a LALA mutation (see, e.g., in vivo results of Zhao and of MEDI7526 of Mumm). It reasonably appears that a “tumor inhibition rate” percentage is comparable to a “tumor growth inhibition” (TGI) percentage in that a superior effect shown by one means would reasonably be expected to be shown using the other means, absent evidence to the contrary. It is noted that in the instant claims there is no limit on dosage or time required to achieve a TGI% of at least 50%. IgG2, IgG4 and IgG1 LALA Fc regions of antibodies were known in the prior art and had been shown to be successfully used. When Fc receptor binding is eliminated, then necessarily the bispecific construct would be incapable of activating CD40 pathway through Fc receptor-mediated activity. Zhao et al. taught that an advantage or removing Fc receptor binding is that it can reduce potential toxicity in vivo. Similarly, Wang taught modifying a Fc region of an antibody to have one or more mutations in the Fc region to reduce binding affinity to an Fc receptor so it is “immunologically inert, e.g., does not trigger complement mediated lysis, or does not stimulate antibody-dependent cell mediated cytotoxicity (ADCC).” Wang also taught IgG2 and IgG4 heavy chains. It further would have been obvious wherein the bsAb anti-PD-1/anti-CD40 antigen-binding protein construct had as the C-terminal binding site of the anti-PD-1-Fc region the CD40-binding portion that was an scFv as taught for bispecific embodiments, e.g., LY517, by Wang. The IgG-scFv format was discussed also by Zhao and Mumm. There would have been a reasonable expectation that a bispecific antigen-binding protein construct as discussed above with reduced or eliminated Fc receptor binding would activate the CD40 pathway in the presence of PD-1-expressing cells but would not or would only minimally activate it (depending on circumstances) in the absence of PD-1-expressing cells in view of the teachings of Wang and Mumm. Mumm taught that MDI5615 (binding PD-L1 and OX40) activated OX40 signaling in OX40-Jurkat T reporter cells in the presence of the FcγR HEK293 cells and in the presence of PD-L1 MDA-MB231 cells (e.g., Fig. 42), but there was only minimal Jurkat reporter cell activity in the absence of the PD-L1- or FcγR-expressing cells ([0252]). Wang similarly showed using a bispecific anti-PD-L1/anti-CD40 antibody that CD40 pathway activity as measured through IL-8 assay was increased when co-cultured with PD-L1-expressing CHO cells. Further, based on the results of the Phase Ib/II clinical trials for treatment of cancer with a combination of both an anti-CD40 and anti-PD-1 antibody (Kluger et al.) and the showing by Wang that tumor volume decreased in a syngeneic mouse tumor model treated with a bispecific anti-PD-L1/anti-CD40 antibody (Fig. 47) and significant antitumor effects of several bispecific anti-PD-1 IgG4 constructs of Zhao, one skilled in the art would have expected significant antitumor activity of an anti-PD-1/anti-CD40 IgG4 or similar bispecific antigen-binding protein. This is also supported by the showings of Mumm that anti-PD-1 IgG4 Fc-Ox40L or -GITRL (BFP3) both reduced the amount of PD-1 protein expression in human PBMC, but did not change the amount of OX40 or GITR protein, and MEDI7526 (anti-PD-L1 IgG4 CD40L) also led to significant antitumor activity in a low responsive tumor model, showed “robust activation of CD4+ and CD8+ cells in tumor bearing mice” and induced antitumor cytokines but not those contributing to systemic toxicity (which supports the safety of that and similar constructs). Also, in mice with CT26 tumor cells, MEDI7526 treatment completely removed liver tumors (Mumm). Note that Mumm discusses that CD40, OX40 and GITR ligands are biologically active as homotrimers, which is facilitated by binding by their receptor. In view of the prior art, the artisan of ordinary skill would have had a reasonable expectation of successfully using a bsAb binding PD-1 and CD40, including wherein the Fc region that was part of the anti-PD-1 antibody was human IgG1 comprising LALA mutations or a human IgG4 Fc and a CD40-binding site which was an scFv as supported by the prior art of record with a TGI% of at least 50% for the reasons set forth above. It further would have been obvious wherein the cells expressing PD-1 that permitted CD40 activation by the bispecific anti-PD-1/anti-CD40 construct were T or primary B cells because Mumm taught PD-L1 is expressed on T, B, and dendritic cells, including antigen presenting cells (ACPs) and PD-1 is expressed on activated T cells.
Applicant argues (pp. 9-11/17 of REMARKS) that “a) “Wang should not be considered as prior art under 35 USC 102(d) under AIA . As a result, the Office has not established a prima facie case for obviousness.” This is based on the fact that in order to be considered prior art, Wang must receive benefit to PCT/CN2019/112809, which it does not because the subject matter relied on in the rejection under 35 USC 103 was not present in that priority application. There are no experimental results showing the effect of anti-PD-1/CD40 bispecific antibodies. The argument has been fully considered but is not persuasive. The rejection has been recast to remove subject matter from the teachings of Wang (US 2022/0372166) that do not also directly appear in its priority application PCT/CN2019/112809.
Applicant argues (pp. 11(end) through 15(middle)/17) in b) that the Wang priority document (PCT/CN2019/112809) does not describe the concept of conditional CD40 activation disclosed in the present application, saying only that the bispecific antibodies binding CD40 and PD-1 will be evaluated. Therefore, Wang should not receive priority to that document and should have the priority date of Oct. 23, 2020. Applicant notes that 35 USC 102(d)(2) requires that “as of the filing date of the earliest such application that describes the subject matter.” (top of p. 13/17, emphasis by Applicant, citing MPEP 2154.01(b)) Further (p. 14/17), bispecific binding proteins binding PD-1 and CD40 as opposed to PD-L1 and CD40 would not behave similarly because PD-L1 is expressed on cancer cells (p. 32, line 11, of the specification), while PD-1 is an immune checkpoint molecule mainly expressed on the surface of T cells and primary B cells (p. 32, line 5, of the specification). Therefore, in view of the lack of teachings of the priority document of Wang, “[A] skilled person in the art would have known that replacing the PD-L1-binding moiety in the anti-PD-L1/CD40 bispecific antibody (as described in Example 3 of PCT/CN2019/112809), may not generate a protein construct that is effective for treating cancer, because the mechanism of action may change when different cell groups are targeted for binding.” (emphasis by Applicant) Instant Example 19 showed that in vivo tumor inhibition efficacy of Atezolizumab-6A7-FVHC-IgG1-LALA and Avelumab-6A7-FVHC-IgG1-LALA (both PD-L1/CD40-binding constructs), which shared the same structure with ScFV-HC-IgG1-LALA, except that the VH and VL sequences of the anti-PD-1 arm (1A7) were replaced with the VH and VL sequences of anti-PD-L1 antibodies Atezolizumab and Avelumab, respectively. As shown in FIG. 47 and Table 33 of the present application, neither Atezolizumab-6A7-FVHC-IgG1-LALA (G3 and G6) nor Avelumab-6A7-FVHC-IgG1-LALA (G4 and G7) exhibited comparable tumor inhibition effect as compared to ScFV-HC-IgG1- LALA (G2 and G5). The present application explained that:
More specifically, the results showed that ScFV-HC-IgG1(G2, G5) inhibited tumor growth with a higher TGITV% (69.6%, 92.5%) than that of the antibodies Atezolizumab-6A7- FVHC-IgG1-LALA (G3, G6) or Avclumab-6A7-FVHC-IgG1-LALA (G4, G7) at different dose levels, and higher doses led to better therapeutic effects. Therefore, it demonstrated that different molecules having the ScFV-HC-IgG1 format can have different therapeutic effects inside B-hPD-1/hPD-L1/hCD40 mice. (Last paragraph in Example 19 of the as-filed specification; emphasis added)
“Thus, Applicant submits that a skilled person in the art, after reviewing PCT/CN2019/112809 alone, would not have concluded that the protein constructs in the claimed methods can be effective for treating cancer, without first testing the anti-tumor efficacy.” The argument has been fully considered but is not persuasive. It is noted that while AIA 35 U.S.C. 102(d) requires that a prior-filed application to which a priority or benefit claim is made must describe the subject matter from the U.S. patent document relied upon in a rejection, it does not require that this description meet the enablement requirements of 35 U.S.C. 112(a).(MPEP 2154.01(b)) The rejection under 35 USC 103 has been recast to remove subject matter from the teachings of Wang (US 2022/0372166) that does not also directly appear in its priority application PCT/CN2019/112809. All subject matter relied on in the current rejection and attributed to Wang finds direct basis in the earliest priority application thereof. For the reasons set forth in the rejection above and as discussed here, it is maintained that the artisan of ordinary skill would have found the use of an antigen-binding protein binding PD-1 and CD40 as set forth in the claims for the treatment of cancer to have a reasonable expectation of success. While there are no experimental results in the prior art for a construct used in the instant claimed method, Wang teaches anti-PD-1/anti-CD40 and anti-PD-L1/anti-CD40 bispecific antibodies, as does Zhao. Mumm teaches bispecific constructs comprising a PD-1 or PD-L1 antigen-binding domain and CD40-binding CD40L trimer. The bispecific antibodies of Wang comprise those having a heavy and light chain of a PD-1-binding antibody having at its C-terminus a scFv binding CD40. What the specifically disclosed bispecific antibodies (e.g., Ly517, Ly518) of Wang do not have is an Fc region that is human IgG1 comprising LALA mutations or N297 mutation or a human IgG4 Fc region. However, Wang suggests ([0208]) a modified Fc region of the antibody which is “immunologically inert, e.g., does not trigger complement mediated lysis, or does not stimulate antibody-dependent cell mediated cytotoxicity (ADCC).” This is done by having one or more mutations in the Fc region to reduce binding affinity to an Fc receptor ([0124] and [0159]). Mumm showed that that anit-PD-L1-IgG4 Fc-CD40L (BFP3, MEDI7526, Table 1) significantly inhibited tumor growth. Further, Mumm found using a bispecific construct which comprised OX40L instead of CD40L that when Jurak NF-κB-luciferase T cell reporter cells were engineered to express human OX40 and cultured with PD-L1-surface-expressing MDA-MB231 cells or Fcγ receptor- (FcγR-) expressing HEK293 cells, the anti-PD-L1-IgG4 Fc-OX40L activated OX40 signaling as measured by NF-κB signaling in the presence of the FcγR HEK293 cells and in the presence of PD-L1 MDA-MB231 cells (e.g., Fig. 42), but there was only minimal Jurkat reporter cell activity in the absence of the PD-L1- or FcγR-expressing cells ([0252]). Similar results were shown by Wang in Figs. 11A-11D where stimulation of human CD40 activation was increased as indicated by IL-8 secretion in a reporter assay by various anti-PD-L1/anti-CD40 bispecific antibodies in solution or when co-cultured with PD-L1 overexpressing CHO cells. Note that the bispecific constructs of Wang did not have an immunologically inert Fc region, i.e., they were able to bind Fc receptors and therefore would have been expected to have some activity in the absence of PD-L1 expressing cells. The point is that the activity was increased when the PD-L1 cells were present. While only Zhao evaluated tumor inhibition rates, multiple anti-PD-1 bispecific antigen-binding constructs had very high tumor inhibition rates. Mumm teaches PD-L1 is expressed on T, B, and dendritic cells, including antigen presenting cells (ACPs, Fig. 17A), as well as macrophages, mesenchymal stem cells, and a broad range of cancers ([0007]). PD-1 is expressed on activated T cells [0093]). It is not agreed that results from bispecific constructs comprising PD-L1 are not applicable to those comprising PD-1. While these proteins are ligand and receptor, respectively, they are both capable of facilitating the clustering of naturally trimer molecules, e.g., CD40, OX40, GITR, that bind to a second binding site in a bispecific binding protein comprising an anti-PD-L1- or anti-PD-1-binding site based on the showings of the prior art. In the absence of crosslinking by Fc receptor binding, e.g., with a human IgG1 Fc having a LALA or N297A mutation or a human IgG4 Fc region, one of ordinary skill in the art based on the prior art of record would have reasonably expected that an antigen-binding protein construct comprising a first antigen-binding site specifically binding PD-1 or PD-L1, a second antigen-binding site specifically binding CD40 and an Fc region of a human IgG1 Fc having a LALA or N297A mutation or a human IgG4 Fc region, wherein the first antigen-binding site is N-terminal to the Fc region and the second antigen-binding site is linked to the C-terminal of the Fc region, would not generally activate the CD40 pathway in the absence of cells expressing PD-1 or PD-L1, respectively, but would in their presence in a microenvironment. It additionally would have been reasonably expected that at some dosage and duration, the antigen-binding protein construct would achieve a tumor growth inhibition of at least 50% (see, e.g., in vivo results of Zhao and of MEDI7526 of Mumm). While the results of the instant application related to PD-L1 bispecific binding constructs are acknowledged, the claims recite no specific microenvironment, no specific dosage or specific duration of treatment or time at which TGI% is measured. It is maintained that there would have been a reasonable expectation based on the prior art (see above) that not only could a PD-L1/CD40-binding construct have a TGI% at least 50% , but a PD-1/CD40-binding construct could also.
Applicant argues (p. 15(middle)/17) in c) that the present application is entitled to have an earliest effective filing date of Oct. 14, 2020. This is agreed with as indicated previously. The constructs and conditional effects are disclosed in the earliest instant priority application.
Applicant argues (p. 15(end) through p. 16/17), in d) “CN116057070A is not the publication of PCT/CN2019/112809 (acknowledged in the Advisory Action date November 6, 2025).” This is agreed with as indicated previously.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
January 7, 2026