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 remarks, filed 11/6/2025, are acknowledged and entered into the record. Applicants amended claims 66, 68 and 91, canceled claims 67 and 88-89, and added new claims 92-93 in the remarks of 11/6/2025.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/6/2025 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2020/012139, filed 1/30/2020; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 62/788495, filed 1/4/2019.
Election/Restrictions
Applicant’s election without traverse of TROP2 as the species of the first biding moiety and CD33 as the species of the second binding moiety of the bispecific antibody of claim 68, in the reply filed on 10/9/2024, is acknowledged. Election was made without traverse in the reply filed on 10/9/2024.
Status of Claims
Claims 66, 68-69, 72-74, 76-87 and 90-93 are pending and are being examined on the merits.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112
The rejection of claim 78 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. Applicants amended claim 66 to obviate the indefiniteness of dependent claim 78.
The rejection of claims 88-89 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn. Applicants canceled claims 88-89, thus obviating the rejection.
Claim Rejections - 35 USC § 102- Withdrawn
The rejection of claims 66, 74, 76-77 and 79-80 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Chang et al., (US 20150132217; published 5/14/2015), is withdrawn. Applicants amended independent claim 66 to recite that the multispecific antibody conjugated to a cytotoxic moiety induces killing of an immunosuppressive cell, wherein the immunosuppressive cell is a MDSC or TAM. Chang does not teach targeting cell killing to an MDSC or TAM immunosuppressive cell specifically, and therefore Chang does not present an embodiment that encompasses all the limitations of amended claim 66.
Claim Rejections – Maintained, Amended
Claim Rejections - 35 USC § 102
The rejection is maintained and updated to reflect amendments to the claims, including removal of canceled claims, and the addition of new claims 92-93, as filed on 11/6/2025.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 66, 74, 77, 79-80, 82-85 and 92-93 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Loew et al., (US 20200377571; priority to 12/7/2018), as evidenced by Inamura et al., (Cancers, 2018, 10, 252).
Loew et al. teaches multispecific molecules targeting CSF1R or CCR2 and methods of use (abstract). Specifically, Loew teaches novel multispecific molecules comprising (i) a first immunosuppressive myeloid cell binding moiety, e.g. a tumor associated macrophage (TAM) binding moiety or a myeloid derived suppressor cell (MDSC) binding moiety (pg. 1, para. 0003-0004). Loew teaches that TAMs are recruited to tumors in high numbers, and can promote tumor cell proliferation and metastasis by causing such responses as inhibition of B and T cell activation; consequently therapies that deplete TAMs or inhibit their activity would be useful (pg. 23, para. 0222). Thus, Loew claims a multispecific molecule comprising (i) a TGF-beta inhibitor; (ii) and anti-CSF1R binding moiety and (iii) a tumor targeting moiety (pg. 281, claim 1; pg. 18, para. 0180). In some embodiments the first TAM binding moiety binds to CSF1R (pg. 1, para. 0007), which is expressed on TAMs (pg. 21, para. 0205; pg. 26, para. 0259). In some embodiments the multispecific molecule is a full antibody, wherein the antibody includes complete heavy chains (para. 0008), wherein the heavy chain constant regions is chosen from IgG1, IgG2, IgG3 or IgG4 (para. 0009); in some embodiments the CSF1R binding moiety comprises the heavy chain constant region (pg. 10, para. 0086). In some embodiments the heavy chain constant region (e.g. Fc region) induces antibody dependent cellular toxicity (ADCC; pg. 2, para. 0014). Loew teaches embodiments wherein the tumor targeting moiety is PD-1 (Figure 1), or that the tumor targeting moiety may be selected from a group including a tumor targeting antibody molecule that binds to mesothelin, CD47 or PMSA (pg. 7, para. 0036; pg. 282-283, claim 17). Loew teaches an embodiment of the invention comprising SEQ ID NOs: 176, 138, 185 and 147 (pg. 78, table 14) which results in a CSF1R x PDL1 bispecific antibody (Fig. 1A); wherein the PD-L1 binding domain targets the tumor associated antigen PD-L1 (pg. 19, para. 0189). Loew teaches nucleic acid molecules encoding the multispecific molecule (pg. 20, para. 0193; pg. 289, claim 58), pharmaceutical compositions comprising the multispecific molecule (pg. 20, para. 0198; pg. 289, claim 62) and methods of treating cancer in a subject comprising administering the subject in need thereof the multispecific molecule wherein the multispecific molecule is effective to reduce the number of TAMs in or near a tumor in a subject, inhibit the proliferation of TAMs or reduce or inhibit macrophage infiltration into a tumor in the subject (pgs. 20-21, para. 0199-0200; pg. 289, claim 63). Loew also teaches wherein the antibody molecule can be linked to another functional molecule, i.e. a toxin, or a cytotoxic agent (pg. 31, para. 0296).
Thus the invention of Loew et al., for example an embodiment of a multispecific antibody with (i) a CSF1R binding domain, (ii) a PD-L1 tumor antigen binding domain and (iii) a Fc domain capable of inducing ADCC, or (iii) a cytotoxic agent; whereby the multispecific antibody targets TAMs or MDSCs for killing in the tumor microenvironment anticipates the multispecific antibody of instant claim 66. Further, Loew teaches the Fc region may be IgG1 or IgG4, thus anticipating instant claim 74. Loew teaches pharmaceutic compositions comprising the multispecific antibody, thus anticipating claim 77. Further Loew teaches administering the multispecific antibody or the pharmaceutical composition in a method for treating cancer, or for the purposes of reducing TAMs in a tumor environment and promoting immune cell activity against the tumor cells, thus anticipating instant claims 79-80 and 82. Loew teaches wherein the multispecific antibody may be conjugated to a cytotoxic agent; thus by administering, for example, a CSF1R-CD47 bispecific antibody conjugated to a cytotoxin, Loew’s method for treating anticipates instant claims 83-85.
Regarding claims 92-93; as Loew teaches the CSF1R is the first TAM binding moiety, and thus targets TAM immune suppressive cells, the multispecific antibody of Loew anticipates instant claim 92. Loew is silent as to M2 TAMs. However, Inamura et al. (Cancers, 2018, 10, 252) teaches that CSF1R-expressing TAMs induce a tumor-promoting microenvironment by regulating immunity (abstract), and demonstrate that TAMs express CSF1R, whereby it may be upregulated to high(er) expression in some lung cancer patients (pg. 5, Table 1; pg. 7, Figure 2). Inamura teaches TAMs exhibit both anti-tumor and tumor-promoting functions depending on their acquired immunophenotype, M1 or M2, and that M2 TAMs are characterized by high expression of CD163, which may correlate with increased CSF1 (ligand) expression, and its binding to CSF1R on M2 TAMs (pg. 11, para. 3). Thus, Inamura provides evidence that CSF1R is expressed on M2 TAMs, and thus the CSF1R domain of the multispecific antibody of Loew would target M2 TAMs. Thus, Loew, as evidenced by Inamura, anticipates instant claim 93.
Response to Arguments
Applicant's arguments filed 11/6/2025 have been fully considered but they are not persuasive. Applicants amended independent claim 66 to include wherein the antibody comprises at least one cytotoxic moiety, and wherein the antibody induces killing in the tumor cell and in the immunosuppressive cell, and wherein the immunosuppressive cell is a MDSC, a TAM or an M2-TAM. Applicants contend that the antibodies of Loew do not act by killing the immunosuppressive cells and tumor cells, but by inhibiting the activity of the immunosuppressive cells by blocking the TGF-beta pathway; specifically, applicants contend that Loew uses a TGFβ trap to prevent recruitment of TAMs to the tumor microenvironment, thereby depleting the number of TAMs (remarks, pg. 11, paras. 2-3). Applicants also contend that although Loew mentions ADCC and mentions functional linkage to a cytotoxic agent, nowhere does it specific that the antibody that targets TAMs is linked to a cytotoxic agent, and that the cytotoxic agent targets and kills TAMs (remarks, pg. 11, para. 1). Thus, applicants contend that Loew fails to teach each and every limitation of the claimed invention (remarks, pg. 10, para. 5).
Examiner highlights paragraph 0222 of Loew, final sentence, wherein Loew teaches that “therapies that deplete TAMs or inhibit their activity would be useful.” Loew teaches, as used herein, the term “reducing TAMs” generally refers to decreasing the number of TAMs, including decreasing the number of TAMs in a tumor or near a tumor (pg. 26, para. 0254). Loew also states at the initial summary of the invention, “the multispecific molecules disclosed herein are expected to deplete TAMs and/or MDSCs,” (pg. 1, para. 0004). Thus, examiner contends that while inhibiting the activity of TAMs via TGFβ is within the scope of the invention, so too is depleting TAMs of MDSCs via cell death. As described above, Loew teaches in some embodiments the heavy chain constant region induces antibody dependent cellular cytotoxicity (ADCC; pg. 2, para. 0014); which highlights that cell killing is within the scope of the method for depleting TAMs. Regarding amended claim 66, the instant specifications describe “inducing cell killing” to include direct cell death of both cancer cells and immunosuppressive cells by activating apoptotic pathways; and in other instances, the method comprises utilizing ADCC to induce cell kill effect (Specs., pg. 9, para. 0049). Thus, the cell killing encompasses ADCC mediated cell killing. It is understood in the art that as the antibody of Loew is bound to a TAM, the ADCC mechanism would target the TAM for cell death via recruitment of effector immune cells. Further, as Loew teaches the antibody may be bispecific, further comprising an antigen-binding domain for a tumor associated antigen (e.g. the CSF1R/PD-L1 bispecific antibody embodiment described above), wherein the antibody is simultaneously bound to a CSF1R-expressing TAM and a PD-L1-expressing tumor cell, the ADCC cell killing effect would target both the TAM and the tumor cell for cell death. Thus, the cell killing of instant claim 66 need not be via the cytotoxic agent. Nonetheless, and as described above, Loew also teaches the antibody may be linked to a cytotoxic agent (pg. 31, para. 0296). It is clear that when teaching the antibody may be conjugated to a cytotoxic agent, it is understood that the cytotoxic agent is intended to induce death in the cells the antibody is targeting; in this case, those cells are TAMs and MDSCs. Thus, the examiner disagrees with the applicant’s interpretation that the methods and antibodies of Loew are limited to inhibiting TAM or MDSC activity via TGFβ inhibition; rather that the method and antibodies of Loew are explicitly designed to deplete, or reduce the number, of TAM or MDSCs in the tumor microenvironment (see pg. 1, para. 0004, summary of invention). Thus, the invention of Loew is a method for treating cancer via targeting the depletion of TAMs, such that a reduction in cell numbers encompasses ADCC mediated cell killing or cell death via conjugation with a cytotoxic agent. Thus, the examiner maintains that the scope of the invention of Loew anticipates that of the instant invention, and the rejection of claims 66, 74, 77, 79-80, 82-85 and 92-93 is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 66, 68-69, 72, 74-80, 82-85 and 92-93 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., (US 20150132217; published 5/14/2015) and Gleason et al., (from IDS; Blood, 2014, 123(19)) as evidenced by Sakakura et al., (Laboratory Investigation, 2016, 96) .
Chang teaches bispecific antibodies comprising a binding site for TROP2 and a binding site for CD3, wherein the bispecific is capable of targeting T cells; and methods of administering said bispecific antibodies for treating TROP2 expressing tumors (abstract; pg. 85, claim 1). Chang teaches TROP2 is expressed on cancer cells (pg. 1, para. 0003; pg. 3, para. 0015), CD3 is expressed on T cells (including CD4+ immunosuppressive T cells), and the bispecific antibody brings CD3+ T cells into direct contact with targeted disease cells (pg. 1, para. 0004). Chang teaches an embodiment of a TROP2 x CD3 bispecific antibody named E1-3s (pg. 38, para. 0356). Chang teaches that E1-3s binds to Jurkat T cells, which are known as a CD4+ T cell leukemia line (pg. 36, para. 0337), and that E1-3 binds and increases the expression of CD69-positive CD4+ T cells (pg. 7, para. 0090; Fig. 29A). Chang teaches the bispecific antibody may be conjugated to a cytotoxic agent (pg. 2, para. 0012; pg. 28, para. 0264; pg. 87, claim 31)
Thus, Chang teaches a bispecific antibody comprising a first binding moiety that binds to a tumor-associated antigen and a second binding moiety that binds to an antigen expressed on an immunosuppressive cell (pg. 85, claims 1 and 19), whereby the bispecific antibody is conjugated to a cytotoxic agent (pg. 85, claim 31). Chang teaches the antibodies can be of various isotypes including IgG1 or IgG4 (pg. 4, para. 0023). Chang teaches the cytotoxic agent may be dasatinib (pg. 28, para. 0265; pg. 87, claims 19 and 31-32). Chang teaches a composition comprising the antibody and a pharmaceutically suitable excipient (pg. 30, para. 0278). Chang teaches administering the bispecific antibody in a method for inducing an immune response to a TROP2 expression cancer, thus Chang teaches a method of treating comprising administering the antibody, or the antibody in a pharmaceutical composition (pg. 85, claim 1). However, Chang does not teach wherein the immunosuppressive cell is a MDSC or a TAM, or wherein the antigen expressed on an immunosuppressive cell is CD33.
Gleason et al. teaches a CD16 x CD33 bispecific killer cell engager (BiKE), which activates NK cells against primary MDS (tumor) targets and MDSC CD33+ (immunosuppressive cell) targets (title, abstract; pg. 3017, col. 1, top). Gleason teaches CD16 is the FcγRIII, which mediates antibody-dependent cell-mediated cytotoxicity (ADCC; pg. 3016, col. 2). Gleason teaches suppressive MDSCs are phenotypically defined as CD33+ (pg. 3020, col. 1, para. 2). Gleason teaches MDSCs have been shown to suppress NK cell activity (pg. 3020, col. 2, last paragraph); however, when treated with the CD16 x CD33 BiKE, there was a significant increase in MDSC killing (pg. 3021, col. 2; pg. 3022, Fig. 5B). Gleason teaches, “overall, these data demonstrate the ability of the CD16 x CD33 BiKE to induce blood and marrow MDS-NK cell activation to overcome MDSC immunosuppression,” (pg. 3022, col. 1, top paragraph); and that the CD33+ cell population contains both the premalignant clone and immunosuppressive MDSCs (pg. 3022, col. 2, last paragraph). Thus, Gleason teaches that a CD33 antigen binding domain will target CD33+ immunosuppressive MDSC cells, and that an Fc domain will bind CD16 FcγRIII receptors on NK cells and induce ADCC.
It would have been obvious to one of skill in the art to modify the CD3 x TROP2 bispecific antibody of Chang to comprise a CD33 antigen binding domain. One would have been motivated to do so given the suggestion by Gleason et al. that CD33 is expressed on tumor cells and immunosuppressive MDSC cells and thus a CD33 binding domain would target both cell populations, and that targeting killing of immunosuppressive MDSCs would promote an immune response against tumor cells by overcoming MDSC immunosuppression. There would have been a reasonable expectation for success given that a CD16 x CD33 BiKE successfully targeted CD33+ MDSC cells for elimination via NK cell-mediated ADCC, as taught by Gleason et al. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 66 and 68-69, the modified CD33 x TROP2 bispecific antibody, conjugated to a cytotoxic agent (e.g. dasatinib), of Chang and Gleason would comprises a tumor associated antigen binding domain (TROP2) and a binding moiety that binds to an antigen expressed on an immunosuppressive cell (CD33). As Gleason teaches that CD33 is expressed on MDSCs, the modified bispecific antibody of Chang and Gleason would target MDSCs for killing via the cytotoxic agent. The modified CD33 x TROP2 bispecific antibody of Chang and Gleason would make obvious the multi-specific antibody of claims 66, 68 and 69.
Regarding claim 72, the modified CD33 x TROP2 bispecific antibody of Chang and Gleason is described above. Chang teaches the TROP2 binding domain may be from a humanized TROP2 antibody, RS7 (pg. 87, claim 19). Chang teaches RS7 comprises the light chain CDRs 1-3 of SEQ ID NOs: 115-117, respectively, and the heavy chain CDRs 1-3 of SEQ ID NOs: 118-120, respectively, (pg. 9, para. 0114). The 6 CDRs of RS7 of Chang SEQ ID NOs: 115-120 are 100% identical to instant SEQ ID NOs: 1-6 of the TROP2 binding domain of instant claim 72. Thus, the modified bispecific antibody of Chang and Gleason makes obvious the multi-specific antibody of claim 72.
Regarding claims 74-78; Chang teaches the antibodies can be of various isotypes including IgG1 or IgG4 (pg. 4, para. 0023), and thus makes obvious instant claim 74. Chang teaches the cytotoxic agent may be dasatinib (pg. 28, para. 0265; pg. 87, claims 19 and 31-32), and thus makes obvious instant claims 75-76. Chang teaches a composition comprising the antibody and a pharmaceutically suitable excipient (pg. 30, para. 0278), and thus makes obvious instant claim 77. Change teaches nucleic acids encoding the antibody and expression vectors comprising the nucleic acids (pg. 32, para. 0294-0295), and thus makes obvious instant claim 78.
Regarding claims 79-80 and 82-85; Chang teaches administering the bispecific antibody in a method for inducing an immune response to a TROP2 expression cancer (pg. 85, claim 1), whereby the method of treating comprises administering the antibody, or the antibody in a pharmaceutical composition (pg. 30, paras. 0278-0279). Thus, the combination of Chang and Gleason make obvious instant claims 79-80.
Regarding claims 82-85, the methods of Chang for treating a cancer, and the modified bispecific antibody of Chang and Gleason are described above. Gleason teaches the CD33 binding domain directed a CD16 x CD33 BiKE to kill both MDS tumor cells and MDSC immunosuppressive cells, via NK cell mediated cytotoxicity. The modified CD33 x TROP2 bispecific of Chang and Gleason would target both CD33+ MDSC and TROP2+ tumor cells. The modified bispecific of Chang and Gleason may comprise an IgG Fc domain which would recruit NK cells, via FcγRIII expressed on NK cells, to kill bound MDSCs and TROP2+ cells via ADCC. Alternatively, the antibody is conjugated to a cytotoxic agent whereby the ADC would target MDSCs and TROP2 tumor cells for lysis (pg. 28, paras. 0264-0265; pg. 87, claims 19 and 31-32). Thus, the bispecific antibody of Chang and Gleason, and the methods of Chang, makes obvious claims 82-85.
Regarding new claims 92-93; Sakakura et al teaches that tumor associated macrophages (TAMs) have been classified into an immunostimulatory M1 subset and an immunoregulatory M2 subset (abstract). In doing a phenotype analysis of the M1 and M2 TAM subsets, Sakakura teaches that each subset had similar expression levels of CD33 (pg. 997, Fig. 1). Thus, Sakakura provides evidence that M2 TAMs express CD33. Therefore, the CD33/TROP2 ADC of Chang and Gleason would inherently target TAM immunosuppressive cells, including M2-TAMs, as well as MDSCs, and thus makes obvious instant claims 92-93.
Response to Arguments
Applicant's arguments filed 11/6/2025 have been fully considered but they are not persuasive. Applicants contend that the Chang reference fails to teach a multispecific antibody that binds and induces killing in both tumor and immunosuppressive cells (remarks, pg. 13, para. 4). Further, applicants contend that the antibodies of Gleason are for treating myelodysplastic syndromes (MDS), which are stem cell disorders that may develop into leukemia, and that Gleason teaches killing of CD33+ immunosuppressive MDSC cells by recruitment of CD16+ NK cells (remarks, pg. 14, para. 1). Applicants contend that there is no motivation to modify the CD3/Trop2 bispecific antibody of Chang to include a CD33 antigen binding domain because that would recruit immunosuppressive cells and thus replace the cell killing mechanism of Chang’s recruitment of CD3 effector cells; that Chang does not contemplate killing immune cells at all (pg. 14, para. 2). Thus, applicants contend that there is no motivation for a skilled artisan to make the combinations or modifications of the prior art to arrive at the claimed invention (remarks, pg. 13, para. 2; pg. 14, para. 3).
In response to the argument that the Chang reference does not teach killing immunosuppressive cells, the examiner reiterates that claim 66 has been amended to include wherein the immunosuppressive cells are MDSCs or TAMs, and that the amended rejection therefore relies on the combination Chang and Gleason; and not on Chang alone. Chang teaches bispecific antibodies, which may be conjugated to a cytotoxic agent, comprising a Trop2 binding domain to target tumor cells for lysis. Gleason teaches a bispecific construct that is useful for targeting immunosuppressive cells, for lysis, as a cancer therapeutic. Therefore a skilled artisan, looking to optimize an anti-cancer bispecific construct, would be motivated to combine the tumor cell targeting component of Chang with the immunosuppressive cell targeting component of Gleason, whereby both cell types are targeted for lysis, with a bispecific antibody construct conjugated to a cytotoxic moiety. The examiner contends that the mechanism of inducing cytotoxic activity against a target cell is not the inventive feature of either Chang or Gleason; and that inducing cytotoxic activity by way of recruiting an immune cell to generate cytotoxicity or by inclusion of a cytotoxic agent, via an antibody drug conjugate (ADC), are not distinct, but rather are analogous alternative means to reach the same result. Chang claims the bispecific antibodies of the invention may comprise a cytotoxic agent, wherein the cytotoxic agent is conjugated to the antibody to form an ADC, as described above. Thus, examiner is highlighting that Chang reduces to practice a Trop2-cytotoxin ADC for the purposes of killing tumor cells, and Chang claims the bispecific antibodies of the invention as ADCs with a cytotoxic agent. Thus, the conjugated cytotoxic agent provides the killing effect of the antibodies of Chang, and obviates the mechanisms of recruiting any CD3+ immune cells for cell-mediated cytotoxicity.
Similarly, the reference of Gleason is an analogous field of study (see MPEP section 2141.01(a)); namely using antibodies to target cytotoxic activity to a specific subset of cells in a therapeutic for cancer; myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are both considered types of cancer. Gleason teaches that a CD33 antigen binding domain allows targeting cytotoxicity to CD33+ immunosuppressive MDSC targets, which may be efficacious in patients with myelodysplastic syndromes (pg. 3017, col. 1, para. 1). Specifically, Gleason teaches, “MDS patients had a significantly increased proportion of immunosuppressive CD33+ myeloid-derived suppressor cells (MDSCs) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells; treatment with the CD16/CD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis,” (abstract). Gleason teaches “targeting of the CD33+ cell population that contains both the premalignant clone and immunosuppressive MDSCs,” (pg. 3022, col. 2, Discussion, para. 1). Thus, while Gleason presents a bispecific embodiment, CD33/CD16, for co-activating and recruiting NK cells to perform the cytotoxic function of killing the MDSCs, Gleason also teaches anti-CD33 antibodies for targeted killing of CD33+ immunosuppressive MDSCs as a therapeutic strategy. The claims are rejected as being obvious over a skilled artisan combining the anti-CD33 binding domain, for the purposes as taught by Gleason, to the anti-Trop2 bispecific antibody of Chang, for the purposes as taught by Chang, wherein the bispecific antibody is conjugated to a cytotoxic agent to provide the killing effect, as taught by Chang.
In response to applicant's arguments against the references 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). Further, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). 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).
In this case, Chang teaches anti-Trop2 antibodies which may be conjugated to a cytotoxic agent for targeting the cytotoxic agent to Trop2-expressing tumors, and wherein the Trop2 antibodies may be bispecific. Gleason teaches anti-CD33 antibodies for targeting cytotoxicity to CD33+ immunosuppressive MDSCs for targeted cell lysis of CD33+ MDSCs in a cancer therapeutic; wherein the anti-CD33 antibodies may also be in a bispecific format. Both references were in the public domain at the time of the invention. Thus, a skilled artisan, with motivation to inhibit/ablate MDSCs, based on the guidance of Gleason, and kill Trop2 expressing cancer cells, based on the guidance of Chang, would make a bispecific Trop2/CD33 antibody conjugated to a cytotoxic agent as an ADC. Using a cytotoxic agent for inducing cytotoxicity in the antibody-mediated cellular targets versus recruiting effector immune cells to impart cytotoxicity to said target cells, are analogous alternative approaches to achieve the same goal. The introduction of a Trop2 antigen binding domain for targeting an antibody to a tumor associated antigen, of Chang, and a CD33 antigen binding domain for targeting MDSCs for cell lysis, of Gleason, both for use as a cancer therapeutic, are the result effective variables of the invention; and both are being used in the same way, for the same purposes as they were taught in the art. Section 2143 of the MPEP provides examples of rationales that support a prima facie case of obviousness; including 2143(I) A- combining prior art elements according to known methods to yield predictable results; B-simple substitution of one known element for another to yield predictable results; C-use of known technique to improve similar methods in the same way; and D-applying a known technique to a known device, method or product ready for improvement to yield predictable results. As a Trop2 targeting bispecific antibody and a CD33 targeting bispecific antibody were each known in the art at the time of the invention, and each component is being used in the same way it was taught in the art, it is obvious to combine the anti-Trop2 binding domain and the anti-CD33 binding domain into a single bispecific antibody. Further, as recruiting immune cell-mediated cytotoxicity and cytotoxic agent-mediated cytotoxicity are analogous mechanisms of inducing antibody-mediated cytotoxicity to target cells, it is obvious to substitute one known element for another (i.e. to conjugate the antibody to a cytotoxic agent) to obtain predictable results. Thus, the applicant’s arguments that the modified Trop2/CD33 bispecific antibody of Chang and Gleason would have no killing mechanism, and therefore there is no motivation to combine is unpersuasive; the killing mechanism is provided when the antibody is made into an ADC comprising a cytotoxic agent, as is well known in the art and as described in the Chang disclosure. Further, the killing mechanism is not the result-effective variable of the invention, as numerous means of inducing cytotoxicity are known in the art. The result effective variable of the present invention is the co-targeting of an antigen on an immunosuppressive cell and a tumor associated antigen by a bispecific antibody; the combination Trop2/CD33-dasatinib bispecific antibody-drug conjugate of Chang and Gleason arrives at the invention. Thus, the rejection is maintained.
Claim Rejections - 35 USC § 103
Claims 73 and 86-91 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., (US 20150132217; published 5/14/2015) and Gleason et al., (from IDS; Blood, 2014, 123(19)) as evidenced by Sakakura et al., (Laboratory Investigation, 2016, 96) as applied to claims 66, 68-69, 72, 74-80, 82-85 and 92-93 above, and further in view of Klein et al., (US 20170114146; published 4/27/2017).
The modified CD33/TROP2 bispecific antibody conjugated to a cytotoxic agent of Chang and Gleason, and methods of administering said antibody for treatment of cancer, is described above. Chang teaches the humanized Trop2 binding domain, RS7, as described above. Chang teaches RS7 comprises the light chain CDRs 1-3 of SEQ ID NOs: 115-117, respectively, and the heavy chain CDRs 1-3 of SEQ ID NOs: 118-120, respectively, (pg. 9, para. 0114), which are 100% identical to instant SEQ ID NOs: 1-6 of the TROP2 binding domain of instant claim 72. Chang teaches RS7 comprises the VH of SEQ ID NO: 110 and a VL of SEQ ID NO: 108 (pg. 46, col. 1, hRS7); which are 100% identical to the VH and VL of instant SEQ ID NOs: 9 and 10, respectively. However, Chang and Gleason do not teach wherein the binding moiety that binds CD33 comprises the HCDRs of SEQ ID NOs: 45-47 and the LCDRs of SEQ ID NOs: 60-62.
Klein et al. teaches novel bispecific antibodies for T cell redirection towards target cells (abstract). Specifically, Klein has developed a novel T cell activating bispecific antigen binding molecule with unexpected, improved properties, targeting CD33 (pg. 2, para. 0016). Klein teaches CD33 is overexpressed on bone marrow cells with AML, and thus an antibody targeting CD33, with low toxicity and favorable pharmacokinetic properties, would solve the need for better therapeutics for AML (pg. 2, para. 0015). Klein teaches the bispecific comprises a first antigen binding moiety and a second antigen biding moiety, wherein the first antigen binding moiety is CD33 and the second antigen binding moiety is a T cell antigen (pg. 2, para. 0017). Klein teaches that CD33 binding moiety comprises heavy chain CDRs 1-3 of SEQ ID NOs: 22-24, and light chain CDRs 1-3 of SEQ ID NOs: 25-27 (pg. 2, para. 0018; pg. 65, claim 1); or wherein the heavy chain variable region comprises the amino acids of SEQ ID NO: 28 and the light chain variable region comprises the amino acids of SEQ ID NO: 29 (pg. 2, para. 0020; pg. 65, claim 2). The HCDRs 1-3 of Klein SEQ ID NOs: 22-24 are 100% identical in sequence identity to instant SEQ ID NOs: 45-47, respectively; and the LCDRs 1-3 of Klein SEQ ID NOs: 25-27 are 100% identical to instant SEQ ID NOs: 60-62. Klein teaches the antigen binding moieties include antibody fragments (pg. 11, para. 0089), which include ScFvs (pg. 13, para. 0105). Thus Klein teaches antigen binding moieties that target CD33 and comprise the amino acids sequences of the CD33 binding moiety of instant claim 73.
It would have been obvious to one of skill in the art to substitute the CD33 binding moiety of Klein in the modified CD33 x TROP2 bispecific antibody of Chang and Gleason with a reasonable expectation for success. Section 2143(I)(B) of the MPEP highlights examples of rationales that support a conclusion of obviousness, including simple substitution of one known element for another to obtain predictable results. In this case, the substitution is one species of CD33 binding domain for an alternate species of CD33 binding domain, for the same use. The CD33 binding domain of Klein comprises the VH of SEQ ID NO: 28, which is 100% identical to instant the VH of instant SEQ ID NO: 48; and the VL of SEQ ID NO: 29, which is 100% identical to instant SEQ ID NO: 63. The anti-Trop2 binding domain (RS7) of Chang comprises the VH of SEQ ID NO: 110, which is 100% identical to instant SEQ ID NO: 9; and the VL of SEQ ID NO: 108, which is 100% identical to instant SEQ ID NO: 10. Thus, the modified CD33 x TROP2 bispecific antibody of Chang, Gleason and Klein comprises identical VH and VL domains of instant SEQ ID NOs: 9, 10 (anti-Trop2) and 48, 63 (anti-CD33), including comprising the identical CDR domains therein, and thus makes obvious the multispecific antibody of instant claims 73, 86(a), 87(a), 88(a, f), 89(a, f) and 90-91.
Response to Arguments
Applicant's arguments filed 11/6/2025 have been fully considered but they are not persuasive. Applicants contend that the combination of Chang, Gleason and Klein fail to teach the claimed invention because the combination of Chang and Gleason fails to teach or suggest a multi-specific antibody that targets both a tumor cell and immunosuppressive cell and induces killing in an immunosuppressive cell, and Klein does not remedy the deficiencies of Chang and Gleason (Remarks, pg. 14, para. 5). Applicants acknowledge that Klein simply teaches a species of CD33 binding domain which comprises the amino acid sequences of the CD33 binding domain of instant claim 73 (pg. 15, para. 1); and that the traversal is on the grounds of the Chang and Gleason references to a modified Trop2/CD33 bispecific antibody conjugated to a cytotoxic agent, as described above. Applicants contend that there is no motivation to substitute the CD33 binding domain of Klein in place of the CD33 binding domain of Gleason because the CD33 binding domain of Gleason already successfully targets MDSCs (remarks, pg. 15, para. 2). Applicants further contend that the CD33 binding domains of Klein and Gleason are not for the same use, as they were each conjugated to separate second binding domains, which bind completely different antigens; and that the art of bispecific antibodies is inherently unpredictable, therefore one of skill in the art could not simply substitute one binding domain for another and expect predictable results (remarks, pg. 15, para. 3).
In response, the examiner has maintained that the combination of Chang and Gleason make obvious a Trop2/CD33 bispecific antibody which, when conjugated to a cytotoxic agent, induces killing of both a Trop2-expressing tumor cell and a CD33-expressing immunosuppressive cell, as described above. Further, the anti-Trop2 binding domain of Chang and the anti-CD33 binding domain of Klein comprise identical CDRs, VH and VL domain amino acid sequences, respectively, to the anti-Trop2 and anti-CD33 embodiments of claim 73 and new claims 86-91. The fact that the anti-CD33 biding domain of Gleason is already successful for targeting CD33+ MDSCs does not obviate motivation for substitution. MPEP section 2143 teaches that obviousness is inherent when substituting one known element for another to yield predictable results. In this case, it is obvious to substitute an alternative species of anti-CD33 binding domain for the same purpose, and doing so would have a high expectation for success.
Regarding applicant’s contention that the anti-CD33 binding domains are not for the same use as they were each conjugated to a second binding domain, wherein the second binding domains target separate antigens/cells, the examiner states that the various alternative embodiments comprising the anti-CD33 binding domains do not change the properties of the anti-CD33 binding domains themselves. In each case, the anti-CD33 binding domain is intended to bind CD33, and CD33 is inherently expressed on MDSCs and TAMs, as taught by Gleason and Sakakura. Therefore both of the anti-CD33 binding domains, of Gleason or Klein, were available in the art at the time of the invention, and a skilled artisan may use either one for the purpose of binding immunosuppressive cells. Chang teaches the art of multispecific binding constructs; Chang teaches that the constructs may comprise binding domains to various other immune cell antigens (pg. 3, para. 0016), and various alternative tumor-associated antigens (pg. 3, para. 0017), and may even be a tri-specific antibody (pg. 45, para. 0424, example 18). Chang teaches Dock-and-Lock technology may be used to generate various embodiments of the bi-specific constructs (pg. 22, para. 0227) to result in stable and functional constructs. Therefore, Chang provides guidance for producing, and a reasonable expectation for success, for the skilled artisan to make and use anti-CD33/anti-Trop2 bispecific construct conjugated to a cytotoxic agent. Applicant’s arguments are not found persuasive, and the rejection over the combination of Chang, Gleason and Klein is maintained.
Claim Rejections - 35 USC § 103
Claim 81 is rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., (US 20150132217; published 5/14/2015) and Gleason et al., (from IDS; Blood, 2014, 123(19)) as evidenced by Sakakura et al., (Laboratory Investigation, 2016, 96) as applied to claims 66, 68-69, 72, 74-80, 82-85 and 92-93 above, and further in view of Schnepp et al., (Microbiology Spectrum, 2014).
The modified bispecific antibody of Chang and Gleason and the methods for treating using the antibody is described above. However, Chang and Gleason do not teach administering to the subject a therapeutically effective amount of the nucleic acid encoding the antibody.
Schnepp et al. teaches that genes encoding antibodies may be administered via vector-mediated gene transfer strategies (abstract). Schnepp teaches that injecting antibody proteins repeatedly is not cost effective (pg. 2, col. 1, first para.) Schnepp teaches a strategy for immunoprophylaxis by gene transfer which reduces the number of repeated injections needed (pg. 3, Fig. 1). Schnepp teaches that recombinant adeno-associated virus (AAV) vectors can be used, wherein a dual promotor system allows insertion of an expression cassette comprising the genes (nucleic acid sequences) encoding a full length native antibody (pg. 4, Fig. 2C). Schnepp teaches the use of antibody gene transfer for cancer, highlighting an example wherein an antiangiogenic VEGFR2 antibody was delivered via an rAAV8 vector, and resulted in shrinkage of tumors and prolonged survival time compared to untreated animals (pg. 8, section: Antibody Gene Transfer for Cancer). Schnepp teaches these encouraging results set the stage for combining antibody gene transfer technology with an increasing number of antibody-based therapies for cancers. Thus, Schnepp teaches administering nucleic acids encoding antibodies as a method for treating cancers.
It would have been obvious to one of skill in the art to utilize the methods of administration of the bispecific antibody of Chang and Gleason for treating cancer with the modification of administering the nucleic acids encoding the antibody. One would have been motivated to do so given the suggestion by Schnepp et al. that vector-mediated gene transfer is a more cost-effective approach and reduces the need for repeated administrations of the antibody protein. There would have been a reasonable expectation for success given the knowledge that vector-mediated gene delivery encoding full length antibodies have been used successfully in a method for treating cancer, resulting in shrinkage of tumors and prolonged survival rates, as taught by Schnepp et al. Thus the invention as a whole was prima facie obvious at the time the invention was made. As such, the combined teachings of Chang, Gleason and Schnepp make obvious the method of treating of claim 81, by administering the nucleic acid encoding the antibody.
Response to Arguments
Applicant's arguments filed 11/6/2025 have been fully considered but they are not persuasive. Applicants contend that the combination of Chang, Gleason and Schnepp fail to teach the claimed invention because the combination of Chang and Gleason fails to teach or suggest a multi-specific antibody that targets both a tumor cell and immunosuppressive cell and induces killing in an immunosuppressive cell (remarks, pg. 16, para. 2). Applicants contend that Schnepp fails to cure the deficiencies of Chang and Gleason; and that the traversal is on the grounds of that the Chang and Gleason references to a modified Trop2/CD33 bispecific antibody conjugated to a cytotoxic agent, as described above, is not obvious.
In response, the examiner has maintained that the combination of Chang and Gleason make obvious a Trop2/CD33 bispecific antibody which, when conjugated to a cytotoxic agent, induces killing of both a Trop2-expressing tumor cell and a CD33-expressing immunosuppressive cell, as described above. As the examiner has maintained that rejection, and the applicants do not traverse administering a nucleic acid encoding the bispecific antibody in a method of treating cancer, of Schnepp, the rejection is maintained.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644