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 6/11/2026, are acknowledged and entered into the record. Applicants amended claims 66, 86-87 and 91, and canceled claims 68-69, 72-73 and 90, in the remarks of 6/11/2026.
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, on 11/6/2025.
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, 74, 76-87 and 91-93 are pending and are being examined on the merits.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 102
The rejection of claims 66, 74, 77, 79-80, 82-85 and 92-93 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by Loew et al., (US 20200377571; priority to 12/7/2018), as evidenced by Inamura et al., (Cancers, 2018, 10, 252), is withdrawn. Applicants amended instant claim 66 to recite specific structural sequences of the Trop2 and CD33 binding domains; the specific species of anti-Trop2 and anti-CD33 binding domains of amended claim 66 are not taught in Loew, and therefore, Loew does not anticipate.
Claim Rejections - 35 USC § 103
The rejection of claims 66, 68-69, 72, 74-80, 82-85 and 92-93 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et al., (from IDS; Blood, 2014, 123(19)) as evidenced by Sakakura et al., (Laboratory Investigation, 2016, 96), is withdrawn. Applicants amended instant claim 66 to recite specific structural sequences of the Trop2 and CD33 binding domains; the specific species of anti-CD33 binding domains of amended claim 66 are not taught in Chang or Gleason.
Affidavits or Declarations under 37 CFR 1.132
The applicant’s remarks, filed 6/11/2026, contains evidence submitted to traverse the rejection or objection on a basis not otherwise provided for without an oath or declaration under section 37 C.F.R. 1.132. Specifically, Applicant’s remarks contain Appendix A, supplementary figures 1-10, which contain evidence regarding the obviousness or predictability of the invention that was not disclosed previously in the application. Such evidence requires an affidavit or declaration, and are considered to the extent that they are probative and properly submitted.
Claim Rejections – Maintained, Amended
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, 74, 76-80, 82-87 and 91-93 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)) and Klein et al., (US 20170114146; published 4/27/2017), 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, a CD33 x TROP2 bispecific antibody conjugated to a cytotoxic agent was prima facie obvious to one of skill in the art at the time the invention was made.
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 66.
However, the CD33 x TROP2 bispecific antibody of Chang and Gleason does not teach wherein the CD33 binding domain comprises the HCDRs 1-3 of SEQ ID NOs: 45-47, respectively, and the LCDRs 1-3 of SEQ ID NOs: 60-62, respectively.
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 66.
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, which is to target a bispecific construct to the CD33 antigen presented on cells in the tumor microenvironment.
Regarding claims 66, 86-87 and 91; the modified CD33 x TROP2 bispecific antibody, conjugated to a cytotoxic agent (e.g. dasatinib), of Chang, Gleason and Klein would comprise 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. 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 66. Further, 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. Klein teaches the CD33 binding domain 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. 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), with 100% sequence identity, and comprises the identical CDR domains therein. Thus, the modified CD33 x TROP2 bispecific antibody of Chang, Gleason and Klein would make obvious the multi-specific antibody of claims 66, 86-87 and 91.
Regarding claims 74 and 76-78; 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 claim 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; 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, Gleason and Klein 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, Gleason and Klein would target both CD33+ MDSC and TROP2+ tumor cells. The modified bispecific of Chang, Gleason and Klein 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, Gleason and Klein, and the methods of Chang, makes obvious claims 82-85.
Regarding 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, Gleason and Klein would inherently target TAM immunosuppressive cells, including M2-TAMs, as well as MDSCs, and thus makes obvious instant claims 92-93.
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)) and Klein et al., (US 20170114146; published 4/27/2017), as evidenced by Sakakura et al., (Laboratory Investigation, 2016, 96)as applied to claims 66, 74, 76-80, 82-87 and 91-93 above, and further in view of Schnepp et al., (Microbiology Spectrum, 2014).
The modified bispecific antibody of Chang, Gleason and Klein and the methods for treating using the antibody are described above. However, Chang, Gleason and Klein 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, Klein 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 6/11/2026 have been fully considered but they are not persuasive. Applicants contend that neither Chang nor Gleason teaches or suggests a bispecific ADC (remarks, pg. 9). Applicants contend that Chang teaches its bispecific antibody is not itself an ADC, but that it may be used in combination therapy with an ADC (pg. 10, para. 1). Thus applicants contend that to arrive at the claimed ADC, the skilled artisan would have to abandon Chang’s T cell engagement entirely (pg. 10, para. 3).
In response the examiner cites Chang pg. 87; whereby Chang claims a bispecific antibody comprising at least one binding site for Trop-2 and at least one binding site for CD3 (claim 24). Chang further recites the bispecific antibody of claim 24, wherein the bispecific antibody is conjugated to a therapeutic protein, which is a cytotoxic agent (claim 31). Chang further recites the bispecific antibody of claim 31, wherein the drug is dasatinib (claim 32). Thus, Chang claims a bispecific ADC as the invention. It is understood that embodiments comprising a conjugated cytotoxic agent are not required of the invention of Chang, but they are encompassed. In this case, where the TROP2 x CD3 bispecific antibody of Chang is modified to a TROP2 x CD33 bispecific antibody of the combination of Chang, Gleason and Klein, the CD3-mediated recruitment of T cells is not a property of the TROP2 x CD33 bispecific antibody. Chang is relied upon for teaching the art a specific TROP2 binding domain, which is identical to that of the instant claims, which may be used in a bispecific antibody format, and whereby the bispecific antibody format may be conjugated to a cytotoxic drug. The concept of conjugating a drug to an antibody, including bispecific antibodies, was known in the art, and Chang evidences this concept in their claims. Applicants can see Andreev et al., (Mol. Cancer Ther., 2017) for an example of a HER2 x PRLR bispecific ADC, as further evidence to support Chang in that a “bispecific ADC” is not a novel format. Contrary to applicant’s assertion, Chang teaches that the bispecific antibody, itself, may be an ADC. Regarding applicant’s contention that the skilled artisan would have to abandon Chang’s T cell engagement entirely, the obviousness is based on the combined teachings of Chang, Gleason and Klein. The CD3 binding domain, and subsequent recruitment of T cells, is a means of inducing cytotoxicity against the Trop2-expressing cells. Alternative means of inducing cell lysis include using full length antibody constructs to induce ADCC, or conjugating a cytotoxic agent; in either case, the format of the antibody of Chang will be altered accordingly, based on known techniques in the art. In the combination of Chang, Gleason and Klein, a cytotoxic agent would complement the Trop2 and CD33 cell targeting of the bispecific binding domain, rather than relying on the CD3 binding domain. The motivation to combine is discussed in more detail below. Here, in response to applicant’s contention that Chang, nor Gleason, teach conjugating a drug to a bispecific antibody, the examiner is highlighting that Chang claims such conjugates are encompassed, and the techniques for doing so are known in the art; and that modifying a bispecific antibody to shift from a CD3/T-cell-mediated means for target cell lysis to a ADC means for target cell lysis are art-recognized alternative strategies, which do not present a point of novelty. If applicants believe the conjugation of a drug to the bispecific antibody is a particular point of novelty of the instant invention, the claims should be drawn to the specific structural aspects of the instant ADC which are novel over art-recognized techniques for conjugation. For example, if the conjugation occurs at specific amino acid residues, or use particular linkers, in combination with particular drug compounds, such that they provide a technical advantage to the instant ADC, then those limitations should be claimed so they may be considered for patentability. Otherwise, conceptually, Chang teaches that conjugating a cytotoxic drug to a bispecific antibody is known in the art and is encompassed in the claims to Trop2 bispecific antibodies.
Applicants contend that there is no motivation to combine the teachings of Chang and Gleason (remarks, pg. 11). Applicants contend Changs entire paradigm is built on recruiting effector T cells (via CD3) to kill tumor cells; thus replacing the CD3 arm would destroy the core functionality that Chang teaches. Similarly, applicants contend replacing the CD16 binding in Gleason’s BiKE would destroy Gleason’s NK cell engagement mechanism. Thus, neither reference provides any teaching or suggestion to combine their respective binding domains into a single bispecific ADC (pg. 11, para. 1). Applicants also cite knowledge in the art, as well as discussion in Klein, which suggest that prior CD33 ADC approaches failed due to off-target toxicity associated with CD33-directed therapy (pg. 11, para. 2). Thus, applicants contend that the failure of CD33 ADCs in clinical trials would discourage the skilled artisan from using CD33 in any ADC context.
Regarding the motivation to combine the paradigms of Chang and Gleason (and Klein). Chang teaches Trop2-targeting bispecific antibodies, which may be conjugated to a cytotoxic agent, 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 maintains 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, the examiner is highlighting that Chang reduces to practice a mono-specific Trop2-cytotoxin ADC (IMMU-132; pg. 40, Example 9, para. 0378) for the purposes of killing tumor cells, and Chang claims the Trop2 bispecific antibodies of the invention may also be ADCs with a cytotoxic agent and/or CD3 x Trop2 bispecifics to recruit T-cell-mediated cell lysis. Thus, the conjugated cytotoxic agent provides the cell lysis mechanism of the antibodies of Chang, and obviates recruiting any CD3+ immune cells for cell-mediated cytotoxicity. Thus the principle concept of Chang is targeting Trop2 antigens for tumor cell lysis, and Chang provides the identical Trop2 binding domain of the instant claims.
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, the principle concept of Gleason is targeting CD33 antigens to promote tumor cell lysis, which is particularly beneficial as CD33 is expressed on both immunosuppressive cells and on tumor cells, in the tumor microenvironment. Klein provides an alternative CD33 binding domain to Gleason, whereby Klein’s anti-CD33 binding domain is identical to that of the instant claims. Both Chang and Gleason use an effector cell recruitment strategy to provide a mechanism for target cell lysis, but the mechanism for cell lysis is not the principle concept of either Chang nor Gleason, and alternative strategies for target cell lysis are available for the artisan to consider. The obviousness of combining Chang and Gleason is based on a bispecific construct co-targeting Trop2 and CD33+ immunosuppressive cells to promote tumor cell lysis, whereby each of the anti-Trop2 and anti-CD33 binding domains are being used for the same purpose as they were taught in the art. The artisan may select to include a CD3-binding domain, for example in a tri-specific antibody, to recruit T cell-mediated lysis, or a CD16-binding domain to recruit NK cell-mediated lysis, or an Fc domain to induce ADCC, or conjugating a cytotoxic drug; each are alternative strategies for providing a mechanism of cell lysis, which were known in the art.
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, the anti-Trop2 binding domains of Chang, as well as the anti-CD33 binding domains of Gleason and Klein were in the public domain at the time of the invention. Thus, a skilled artisan, with motivation to promote therapeutic effectiveness of an anti-Trop2 ADC would include an anti-CD33 binding domain to inhibit/ablate immunosuppressive MDSCs, based on the guidance of Gleason. 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, and are not the result effective variable of the invention. Rather, the targeting domains of the bispecific antibody, the Trop2 antigen binding domain and the CD33 antigen binding domain, are the result effective variables of the invention, whereby each binding domain’s specificity and affinity provide the principle means for therapeutic activity. Here both binding domains were known in the art, and both are being used in the same way, for the same purposes as they were taught in the art, thus their combination into a single bispecific construct is obvious. 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 removing the CD3 cell-mediated lysis mechanism of Chang and/or Gleason also removes the motivation to combine the Trop2/CD33 targeting domains of Chang and Gleason, is unpersuasive. The mechanism for cell lysis is provided when the antibody is made into an ADC comprising a cytotoxic agent, as is well known in the art and encompassed by Chang.
Regarding the applicant’s contention that previous art-recognized anti-CD33 ADCs had some failures at the level of clinical trials, MPEP 2143 supports that the combination of prior art elements are obvious if there is a reasonable expectation for success. The Chang reference recites a CD16/CD33 BiKE, which is the same as that of Gleason (pg. 45, para. 0423). Chang also teaches the addition of an anti-CD33-SN-38 ADC further enhances the cytotoxic effect of the BiKE. Thus, Chang provides suggestion and motivation for a CD33 ADC. Further, the bispecific Trop2/CD33 bispecific of the combination of Chang, Gleason and Klein would comprise a Trop2 targeting domain which would restrict the construct more than a monospecific CD33 ADC, which is not an embodiment relied upon in the combination construct of Chang, Gleason and Klein.
Applicants contend that post-filing data demonstrates unexpected results (remarks, pg. 12). Applicants contend that “the present invention is not merely directed to co-targeting a tumor cell and an immunosuppressive cell, it is about a specific dual-action ADC that independently kills both cell types,” and that “this mechanism is fundamentally different from either Chang’s T cell engagement or Gleason’s NK cell engagement,” (pg. 12, para. 2).
The data presented in Appendix A show a comparison of the Trop2 x CD33 bispecific antibody with Trodelvy, a Trop2-SN-38 ADC, and Mylotarg, a CD33-calicheamicin ADC. Thus, each of the compounds are mono-specific ADCs. As discussed above, the motivation for the combination of Chang, Gleason and Klein is the co-targeting of Trop2 and CD33. It is not the drug compound, or T-cell engagement or NK-cell engagement cell lysis mechanism. The species of cytotoxic agent is not a limitation of independent claim 66, rather the claim is amended to include specific species of Trop2 and CD33 binding domains. It would be expected, based on the teachings of Chang and Gleason, that combining an anti-Trop2 and anti-CD33 binding domain into a single construct would augment Trop2 directed tumor cell lysis by also inhibiting CD33+ immunosuppressive cells, as taught by Gleason. Thus a proper comparison would be the instant invention versus an alternative Trop2 x CD33 construct, which has alternative binding domains for Trop2 and/or CD33, or which has different drug moieties, or has an alternative format, such that the construct produces “unexpected” benefits over its counterpart. Here it is expected that a bispecific construct would be more therapeutically beneficial that a monospecific construct. Perhaps even a comparison to a combination treatment, such as Trodelvy and Mylotarg being co-administered in combination, would serve as a better comparison to illustrate potential unexpected benefits of Trop2/CD33 bispecific antibody. Instead the results of Appendix A are expected to be more therapeutic than mono-specific ADCs. Applicants contend that “the present invention is not merely directed to co-targeting a tumor cell and an immunosuppressive cell, it is about a specific dual-action ADC that independently kills both cell types,” and that “this mechanism is fundamentally different from either Chang’s T cell engagement or Gleason’s NK cell engagement.” The examiner response is that the combination bispecific antibody of Chang and Gleason is a dual action ADC, using the specific Trop2 binding domain of Chang and the specific CD33 binding domain of Klein, and the combination of Chang, Gleason and Klein, does not rely on any T-cell or NK-cell engagement mechanism. It is obvious to substitute the mechanism for cell lysis from a cell-mediated lysis mechanism to a cytotoxic drug lysis mechanism in antibody engineering. If applicants believe the specific construct(s) of Appendix A are technologically advantageous, then the specific structural limitations should be claimed. For example, a Trop-2 Fab at the N terminal, a CD33 scFv at the C-terminal, 2-4 cytotoxic moieties, which are MMAE and/or Exatecan, which are conjugated to the Fc domains at specific amino acid residues, etc. Instead the claims are drawn to a Trop-2 binding domain taught by Chang with 100% sequence identity, a CD33 binding domain taught by Klein with 100% identity, in any general ADC bispecific format, which is broadly made obvious over the combination of Chang, Gleason and Klein, and lacks a patentably distinct point of novelty.
Applicant’s contend that the addition of Klein or Schnepp does not cure the deficiencies of Chang and Gleason (remarks, pg. 15). Applicants contend that Klein teaches CD33 ADCs were withdrawn from clinical studies, and that Klein’s approach of targeting T cells via CD3 would lead the artisan to conclude that CD33-targeted ADCs are ineffective. Applicant’s further contend that Klein teaches reduced Fc effector function to minimize off-target effects, which is incompatible with the ADC format of the instant invention, and a skilled artisan would not look to Klein’s CD33 binder as a starting point for constructing a bispecific ADC. Applicants also contend that Schnepp provides no motivation to select a Trop2 x CD33 bispecific for nucleic acid delivery.
The rejection is over the combination of Chang, Gleason and Klein. Klein’s reference to monospecific CD33 ADCs is not comparable to the bispecific Trop2 x CD33 ADC of the combination. As discuss above, Chang also recites a CD16/CD33 BiKE construct, similar to that of Gleason, and Chang recites that addition of an anti-CD33-SN-38 ADC further enhances the cytotoxic effect of the BiKE. Thus, Chang teaches the artisan a potential benefit of a monospecific CD33 ADC. As applicant’s noted, the Klein reference was used to teach that the identical anti-CD33 binding domain of the instant claims was known in the art, and substitutable for the anti-CD33 binding domain of Gleason, in the combination Trop2/CD33 ADC of Chang and Gleason. One cannot show nonobviousness by attacking references individually, when the rejection is based on the combination of references, and what their combined teachings suggest to the skilled artisan. 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). Klein was not a starting point for constructing a bispecific ADC. Chang’s monospecific Trop2 ADC is the starting point, which Chang teaches may be constructed in a bispecific format, and may be a bispecific ADC; to which adding Gleason’s CD33 binding domain is obvious based on the teachings and motivation for using a CD33 binding construct in a cancer immunotherapy as taught by Gleason; Klein’s specific CD33 binding domain is substitutable for Gleason’s alternate CD33 binding domain, for the same purpose. Similarly, Schnepp teaches that art of administering nucleic acids encoding an antibody, in a viral vector, instead of administering the antibodies directly. Claim 81 is rejected over the combination of Chang, Gleason, Klein and Schnepp. Schnepp does not need to consider the specific constructs of the instant claims to incorporate Schnepp’s teachings in the art of the methods and benefits of administering nucleic acid constructs instead of an antibody constructs as therapeutics. Applicants arguments are not found persuasive and the rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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