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 .
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Lindhofer et al (US20140369985A1), hereinafter Lindhofer.
Lindhofer discloses an ex vivo method for removal of tumor cells from intraoperatively salvaged blood comprising the steps of
collecting an intraoperatively salvaged blood which may contain immune cells and/or tumor cells in a reservoir (Para. 0019 and 0030),
contacting the intraoperatively salvaged blood with at least one trifunctional antibody and/or scaffold protein in order to obtain an intraoperatively salvaged blood containing cell associates (i.e. aggregates) in which the trifunctional antibody and/or scaffold protein is cross-linked with tumor cells and/or immune cells, wherein said antibody or scaffold protein binds to a T cell, a tumor-associated antigen on a tumor cell, and an Fc-receptor positive cell via its Fc portion (Para. 0019, Claims 1, 2, and 10),
removing said associates from the intraoperatively salvaged blood via centrifugation, filtration, or a combination thereof, wherein the centrifugation step precedes the filtration step (Claim 12 and Para. 0141). Centrifugation is performed generally by a density gradient centrifugation followed by washing with physiological saline for a time and with a rotational speed sufficient to remove said tumor cells-comprising associates and to separate erythrocytes from said tumor cell associates and optionally from leukocytes (Para. 0145). Centrifugation that pellets red blood cells and separates them from plasma results in an erythrocyte concentrate per step iii of the instantly claimed method. After centrifugation, washing the pelleted cells is equivalent to “washing the erythrocyte concentrate” per step iv of the instantly claimed method.
additional filtration steps of the erythrocyte concentrate are performed in order to remove residual associates and/or leukocytes (Para. 0148). Filtration is achieved using a leukocyte reduction/depletion filter wherein all leukocytes contaminated by tumor cells are removed while erythrocytes are collected (Para. 0142).
As such, the trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells, immune cells such as T cells, and Fc-receptor positive accessory cells, thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient (Abstract, Field of the Invention, and Summary of Invention). The filters might be selected from screen filters with pore sizes of between 20 μm to 40 μm (Para. 0142). The trifunctional antibody and/or scaffold protein used is applied in an amount of 1 μg to 5 μg per liter of intra-operatively salvaged blood (Claim 8). The incubation time of the antibody and/or the scaffold protein with said intra-operatively salvaged blood is between 10 and 180 minutes, preferably between 20 and 90 minutes, further preferably between 30 and 60 minutes, optionally wherein said incubation is performed at a temperature of between 19 to 25° C., preferably at room temperature (Claim 11). The trifunctional antibody is a bispecific, trispecific, tetraspecific or multispecific antibody (Claim 1). The trifunctional bispecific antibody is preferably selected of a group of antibodies with the following isotype combinations: (a) rat-IgG2b/mouse-IgG2a; (b) rat-IgG2b/mouse-IgG2b; (c) rat-IgG2b/human-IgG1; and (d) mouse-[VH-CH1; VL-CL]-human-IgG1/rat-[VH-CH1, VL-CL]-human-IgG1-[hinge]-human-IgG3*-[CH2-CH3] [*=Caucasian allotypes G3m(b+g)=no binding to protein A] (Claim 2). The Fc-receptor positive cells that the trifunctional antibody/scaffold proteins bind to via its Fc portion include Fc-gamma receptor I/ IIa/III-positive accessory cells, preferably monocytes, macrophages, dendritic cells, natural killer cells, neutrophiles and/or eosinophile cells (Claim 3). The tumor associated antigen is selected from the group consisting of: EpCAM, Her2neu, EGFR, CD30, CD20, CD22, MUC1, MUC1*, PSMA, CD33, MCSP, cMet, EphA2, Endosialin, Carboanhydrase IX, IGF-1R, FAP-alpha, CD19, CD52, GD2, CEA, FR, proteoglycans, G250, GC182, GT468, GT512 (Claim 4). The trifunctional bispecific antibody recognizes a surface marker of T cells selected from the group consisting of CD3, CD2, CD4, CD5, CD6, CD6, CD8 and CD28 (Claim 5). In an example, anti-EpCAM mediated removal of tumor cells through multicell complex depletion by centrifugation and/or filtration during intraoperative blood salvage was demonstrated. Specifically, 1500 ml patient blood was collected with addition of anti-coagulants during surgery. Thus, the intraoperatively salvaged blood collected has a volume of 300-400 mL or more. Further, with the addition of anti-coagulants, the intraoperatively salvaged blood is a mixture of blood and dilution. 1000 ml this blood was incubated for 1 h with 2 μg of the anti-EpCAM antibody catumaxomab. After incubation, 500 ml of the patient blood was centrifuged, purified with a leucocyte filter, and the resulting erythrocyte concentrate (EC) was collected. There were no detectable remaining tumor cells in the EC following the purification protocol (see Examples on Para. 0152-0162). The purification protocol described in the examples can be adapted for the use of other trifunctional bispecific antibodies other than anti-EpCAM, wherein the method begins with salvaged blood and may be repeated for multiple rounds to obtain a purified erythrocyte concentrate ready for reinfusion as shown by the schematic provided in Figure 3. The schematic of the method provided in Figure 3 shows a continuous cycle, indicating each step of the method for ex vivo removal of tumor cells from intraoperatively salvaged blood can be repeated sequentially starting from collection of the intraoperative blood salvage through removal of tumor cells and/or leukocytes via centrifugation and filtering to obtain a purified erythrocyte concentrate. The blood products obtained by using the method of the invention are then re-administered into the patient from whom the starting blood sample was obtained (Para. 0151). The trifunctional bispecific antibody is a required element of the ex vivo method for removal of tumor cells from intraoperatively salvaged blood. As such, the trifunctional bispecific antibody of the instantly claimed method and product is taught by Lindhofer. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the prior art. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight. Lastly, the courts have stated that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As discussed earlier, Lindhofer teaches that 1-5 ug of trifunctional antibody can be contacted with a particular volume of intraoperative blood salvage to form complexes that facilitate removal and provides a specific example wherein 2 ug of the anti-EpCAM antibody catumaxomab is contacted with 1000 mL of intraoperative blood salvage. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of trifunctional antibody to contact with a volume of intraoperative blood salvage to facilitate removal of complexes and arrive at the specific embodiments of the claims including 2.5 ug to 50 ug of antibody with 300-1000 mL of intraoperative blood salvage.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18577197 in view of Lindhofer et al (US20140369985A1), hereinafter Lindhofer.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite an intact whole IgG bispecific antibody comprising the following properties: a) binding to a T cell and b) binding to a tumor associated antigen (co-pending claim 1), wherein the antibody is a trifunctional bispecific antibody (co-pending claim 3); the tumor associated antigen is the neuroblastoma-associated antigen GD2 (co-pending claim 4); and the T cell surface antigen that the bispecific antibody binds is selected from the group consisting of CD2, CD3, CD4, CD8, CD28, CD40L, and CD44 (co-pending claim 5).
The co-pending claims do not recite an ex vivo method for removal of tumor cells from intra-operatively salvaged blood using the trifunctional bispecific antibody.
However, Lindhofer discloses an ex vivo method for removal of tumor cells from intraoperatively salvaged blood comprising the steps of
i) collecting an intraoperatively salvaged blood which may contain immune cells and/or tumor cells in a reservoir (Para. 0019 and 0030),
ii) contacting the intraoperatively salvaged blood with at least one trifunctional antibody and/or scaffold protein in order to obtain an intraoperatively salvaged blood containing cell associates (i.e. aggregates) in which the trifunctional antibody and/or scaffold protein is cross-linked with tumor cells and/or immune cells, wherein said antibody or scaffold protein binds to a T cell, a tumor-associated antigen on a tumor cell, and an Fc-receptor positive cell via its Fc portion (Para. 0019, Claims 1, 2, and 10),
iii) removing said associates from the intraoperatively salvaged blood via centrifugation, filtration, or a combination thereof, wherein the centrifugation step precedes the filtration step (Claim 12 and Para. 0141). Centrifugation is performed generally by a density gradient centrifugation followed by washing with physiological saline for a time and with a rotational speed sufficient to remove said tumor cells-comprising associates and to separate erythrocytes from said tumor cell associates and optionally from leukocytes (Para. 0145). Centrifugation that pellets red blood cells and separates them from plasma results in an erythrocyte concentrate per step iii of the instantly claimed method. After centrifugation, washing the pelleted cells is equivalent to “washing the erythrocyte concentrate” per step iv of the instantly claimed method.
iv) additional filtration steps of the erythrocyte concentrate are performed in order to remove residual associates and/or leukocytes (Para. 0148). Filtration is achieved using a leukocyte reduction/depletion filter wherein all leukocytes contaminated by tumor cells are removed while erythrocytes are collected (Para. 0142). The filters might be selected from screen filters with pore sizes of between 20 μm to 40 μm (Para. 0142).
As such, the trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells, immune cells such as T cells, and Fc-receptor positive accessory cells, thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient (Abstract, Field of the Invention, and Summary of Invention). The trifunctional antibody and/or scaffold protein used is applied in an amount of 1 μg to 5 μg per liter of intra-operatively salvaged blood (Claim 8). The incubation time of the antibody and/or the scaffold protein with said intra-operatively salvaged blood is between 10 and 180 minutes, preferably between 20 and 90 minutes, further preferably between 30 and 60 minutes, optionally wherein said incubation is performed at a temperature of between 19 to 25° C., preferably at room temperature (Claim 11). The trifunctional bispecific antibody is preferably selected of a group of antibodies with the following isotype combinations: (a) rat-IgG2b/mouse-IgG2a; (b) rat-IgG2b/mouse-IgG2b; (c) rat-IgG2b/human-IgG1; and (d) mouse-[VH-CH1; VL-CL]-human-IgG1/rat-[VH-CH1, VL-CL]-human-IgG1-[hinge]-human-IgG3*-[CH2-CH3] [*=Caucasian allotypes G3m(b+g)=no binding to protein A] (Claim 2). The Fc-receptor positive cells that the trifunctional antibody/scaffold proteins bind to via its Fc portion include Fc-gamma receptor I/ IIa/III-positive accessory cells, preferably monocytes, macrophages, dendritic cells, natural killer cells, neutrophiles and/or eosinophile cells (Claim 3). In an example, anti-EpCAM mediated removal of tumor cells through multicell complex depletion by centrifugation and/or filtration during intraoperative blood salvage was demonstrated. Specifically, 1500 ml patient blood was collected with addition of anti-coagulants during surgery. Thus, the intraoperatively salvaged blood collected has a volume of 300-400 mL or more. Further, with the addition of anti-coagulants, the intraoperatively salvaged blood is a mixture of blood and dilution. 1000 ml this blood was incubated for 1 h with 2 μg of the anti-EpCAM antibody catumaxomab. After incubation, 500 ml of the patient blood was centrifuged, purified with a leucocyte filter, and the resulting erythrocyte concentrate (EC) was collected There were no detectable remaining tumor cells in the EC following the purification protocol (see Examples on Para. 0152-0162). The purification protocol described in the examples can be adapted for the use of other trifunctional bispecific antibodies other than anti-EpCAM, wherein the method begins with intraoperatively salvaged blood and may be repeated for multiple rounds to obtain a purified erythrocyte concentrate ready for reinfusion as shown by the schematic provided in Figure 3. The schematic of the method provided in Figure 3 shows a continuous cycle, indicating each step of the method for ex vivo removal of tumor cells from intraoperatively salvaged blood can be repeated sequentially starting from collection of the intraoperative blood salvage through removal of tumor cells and/or leukocytes via centrifugation and filtering to obtain a purified erythrocyte concentrate.
It would have been obvious to one of ordinary skill in the art to use the claimed whole IgG bispecific antibody in the ex vivo method for removal of tumor cells from intraoperatively salvaged blood taught by Lindhofer. One of ordinary skill in the art would have been motivated to do so since these trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells and leukocytes thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient. Further, the courts have stated that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As discussed earlier, Lindhofer teaches that 1-5 ug of trifunctional antibody can be contacted with a particular volume of intraoperative blood salvage to form complexes that facilitate removal and provides a specific example wherein 2 ug of the anti-EpCAM antibody catumaxomab is contacted with 1000 mL of intraoperative blood salvage. As such, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of trifunctional antibody to contact with a volume of intraoperative blood salvage to facilitate removal of complexes and arrive at the specific embodiments of the claims including 2.5 ug to 50 ug of antibody with 300-1000 mL of intraoperative blood salvage. Therefore, one of ordinary skill in the art would reasonably expect that the trifunctional bispecific antibody of the co-pending claims can be used effectively for the ex vivo removal of tumor cells from intraoperatively salvaged blood.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10-24 of copending Application No. 16143889 in view of Lindhofer et al (US20140369985A1), hereinafter Lindhofer.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a kit comprising a multispecific antibody comprising having specificity against a T cell surface antigen and specificity against a tumor-associated antigen (co-pending claim 23). The multispecific antibody can comprise an Fc moiety (co-pending claim 12). The tumor associated antigen can be selected from the group consisting of EpCAM, Her2neu, EGFR, CD30, CD20, CD22, MUC1, CD33, MCSP, EphA2, carboanhydrase IX, CD19, GD2, CEA, proteoglycans, GC182, GT468, and GT512 (co-pending claim 10). In particular, the multispecific antibody can be anti-EpCAM x CD3, anti-CD20 x CD3, anti-Her2/neu x CD3, anti-GD2 x CD3, or anti-CD19 x CD3 (co-pending claim 11). Thus, the T cell surface antigen that the multispecific antibody targets can be CD3.
The co-pending claims do not recite an ex vivo method for removal of tumor cells from intra-operatively salvaged blood using the trifunctional bispecific antibody.
However, Lindhofer discloses an ex vivo method for removal of tumor cells from intraoperatively salvaged blood comprising the steps of
i) collecting an intraoperatively salvaged blood which may contain immune cells and/or tumor cells in a reservoir (Para. 0019 and 0030),
ii) contacting the intraoperatively salvaged blood with at least one trifunctional antibody and/or scaffold protein in order to obtain an intraoperatively salvaged blood containing cell associates (i.e. aggregates) in which the trifunctional antibody and/or scaffold protein is cross-linked with tumor cells and/or immune cells, wherein said antibody or scaffold protein binds to a T cell, a tumor-associated antigen on a tumor cell, and an Fc-receptor positive cell via its Fc portion (Para. 0019, Claims 1, 2, and 10),
iii) removing said associates from the intraoperatively salvaged blood via centrifugation, filtration, or a combination thereof, wherein the centrifugation step precedes the filtration step (Claim 12 and Para. 0141). Centrifugation is performed generally by a density gradient centrifugation followed by washing with physiological saline for a time and with a rotational speed sufficient to remove said tumor cells-comprising associates and to separate erythrocytes from said tumor cell associates and optionally from leukocytes (Para. 0145). Centrifugation that pellets red blood cells and separates them from plasma results in an erythrocyte concentrate per step iii of the instantly claimed method. After centrifugation, washing the pelleted cells is equivalent to “washing the erythrocyte concentrate” per step iv of the instantly claimed method.
iv) additional filtration steps of the erythrocyte concentrate are performed in order to remove residual associates and/or leukocytes (Para. 0148). Filtration is achieved using a leukocyte reduction/depletion filter wherein all leukocytes contaminated by tumor cells are removed while erythrocytes are collected (Para. 0142). The filters might be selected from screen filters with pore sizes of between 20 μm to 40 μm (Para. 0142).
As such, the trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells, immune cells such as T cells, and Fc-receptor positive accessory cells, thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient (Abstract, Field of the Invention, and Summary of Invention). The trifunctional antibody and/or scaffold protein used is applied in an amount of 1 μg to 1 to 5 μg per liter of intra-operatively salvaged blood (Claim 8). The incubation time of the antibody and/or the scaffold protein with said intra-operatively salvaged blood is between 10 and 180 minutes, preferably between 20 and 90 minutes, further preferably between 30 and 60 minutes, optionally wherein said incubation is performed at a temperature of between 19 to 25° C., preferably at room temperature (Claim 11). The trifunctional bispecific antibody is preferably selected of a group of antibodies with the following isotype combinations: (a) rat-IgG2b/mouse-IgG2a; (b) rat-IgG2b/mouse-IgG2b; (c) rat-IgG2b/human-IgG1; and (d) mouse-[VH-CH1; VL-CL]-human-IgG1/rat-[VH-CH1, VL-CL]-human-IgG1-[hinge]-human-IgG3*-[CH2-CH3] [*=Caucasian allotypes G3m(b+g)=no binding to protein A] (Claim 2). The Fc-receptor positive cells that the trifunctional antibody/scaffold proteins bind to via its Fc portion include Fc-gamma receptor I/ IIa/III-positive accessory cells, preferably monocytes, macrophages, dendritic cells, natural killer cells, neutrophiles and/or eosinophile cells (Claim 3). In an example, anti-EpCAM mediated removal of tumor cells through multicell complex depletion by centrifugation and/or filtration during intraoperative blood salvage was demonstrated. Specifically, 1500 ml patient blood was collected with addition of anti-coagulants during surgery. Thus, the intraoperatively salvaged blood collected has a volume of 300-400mL or more. Further, with the addition of anti-coagulants, the intraoperatively salvaged blood is a mixture of blood and dilution. 1000 ml this blood was incubated for 1 h with 2 μg of the anti-EpCAM antibody catumaxomab. After incubation, 500 ml of the patient blood was centrifuged, purified with a leucocyte filter, and the resulting erythrocyte concentrate (EC) was collected There were no detectable remaining tumor cells in the EC following the purification protocol (see Examples on Para. 0152-0162). The purification protocol described in the examples can be adapted for the use of other trifunctional bispecific antibodies other than anti-EpCAM, wherein the method begins intraoperatively salvaged blood and may be repeated for multiple rounds to obtain a purified erythrocyte concentrate ready for reinfusion as shown by the schematic provided in Figure 3. The schematic of the method provided in Figure 3 shows a continuous cycle, indicating each step of the method for ex vivo removal of tumor cells from intraoperatively salvaged blood can be repeated sequentially starting from collection of the intraoperative blood salvage through removal of tumor cells and/or leukocytes via centrifugation and filtering to obtain a purified erythrocyte concentrate.
It would have been obvious to one of ordinary skill in the art to use the claimed whole IgG bispecific antibody in the ex vivo method for removal of tumor cells from intraoperatively salvaged blood taught by Lindhofer. One of ordinary skill in the art would have been motivated to do so since these trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells and leukocytes thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient. Further, the courts have stated that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As discussed earlier, Lindhofer teaches that 1-5 ug of trifunctional antibody can be contacted with a particular volume of intraoperative blood salvage to form complexes that facilitate removal and provides a specific example wherein 2 ug of the anti-EpCAM antibody catumaxomab is contacted with 1000 mL of intraoperative blood salvage. As such, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of trifunctional antibody to contact with a volume of intraoperative blood salvage to facilitate removal of complexes and arrive at the specific embodiments of the claims including 2.5 ug to 50 ug of antibody with 300-1000 mL of intraoperative blood salvage. Therefore, one of ordinary skill in the art would reasonably expect that the trifunctional bispecific antibody of the co-pending claims can be used effectively for the ex vivo removal of tumor cells from intraoperatively salvaged blood.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 89-103 of copending Application No. 19262309 in view of Lindhofer et al (US20140369985A1), hereinafter Lindhofer.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a combination therapy comprising an immune checkpoint inhibitor and a T-cell redirecting multifunctional antibody, wherein the multifunctional antibody is mouse IgG2a/rat IgG2b antibody selected from the group consisting of catumaxomab (anti-CD3 x EpCAM), lymphomum/FBTA05 (anti-CD3 x CD20), ertumaxomab (anti-CD3 x Her2-neu), and ektomab/ektomun (anti-CD3 x GD2) (co-pending claim 99). Thus, the co-pending claims recite trifunctional bispecific antibodies that target tumor associated antigens and T cell antigens recited in the instant claims.
The co-pending claims do not recite an ex vivo method for removal of tumor cells from intra-operatively salvaged blood using the trifunctional bispecific antibody.
However, Lindhofer discloses an ex vivo method for removal of tumor cells from intraoperatively salvaged blood comprising the steps of
i) collecting an intraoperatively salvaged blood which may contain immune cells and/or tumor cells in a reservoir (Para. 0019 and 0030),
ii) contacting the intraoperatively salvaged blood with at least one trifunctional antibody and/or scaffold protein in order to obtain an intraoperatively salvaged blood containing cell associates (i.e. aggregates) in which the trifunctional antibody and/or scaffold protein is cross-linked with tumor cells and/or immune cells, wherein said antibody or scaffold protein binds to a T cell, a tumor-associated antigen on a tumor cell, and an Fc-receptor positive cell via its Fc portion (Para. 0019, Claims 1, 2, and 10),
iii) removing said associates from the intraoperatively salvaged blood via centrifugation, filtration, or a combination thereof, wherein the centrifugation step precedes the filtration step (Claim 12 and Para. 0141). Centrifugation is performed generally by a density gradient centrifugation followed by washing with physiological saline for a time and with a rotational speed sufficient to remove said tumor cells-comprising associates and to separate erythrocytes from said tumor cell associates and optionally from leukocytes (Para. 0145). Centrifugation that pellets red blood cells and separates them from plasma results in an erythrocyte concentrate per step iii of the instantly claimed method. After centrifugation, washing the pelleted cells is equivalent to “washing the erythrocyte concentrate” per step iv of the instantly claimed method.
iv) additional filtration steps of the erythrocyte concentrate are performed in order to remove residual associates and/or leukocytes (Para. 0148). Filtration is achieved using a leukocyte reduction/depletion filter wherein all leukocytes contaminated by tumor cells are removed while erythrocytes are collected (Para. 0142). The filters might be selected from screen filters with pore sizes of between 20 μm to 40 μm (Para. 0142).
As such, the trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells, immune cells such as T cells, and Fc-receptor positive accessory cells, thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient (Abstract, Field of the Invention, and Summary of Invention). The trifunctional antibody and/or scaffold protein used is applied in an amount of 1 μg to 1 to 5 μg per liter of intra-operatively salvaged blood (Claim 8). The incubation time of the antibody and/or the scaffold protein with said intra-operatively salvaged blood is between 10 and 180 minutes, preferably between 20 and 90 minutes, further preferably between 30 and 60 minutes, optionally wherein said incubation is performed at a temperature of between 19 to 25° C., preferably at room temperature (Claim 11). The trifunctional bispecific antibody is preferably selected of a group of antibodies with the following isotype combinations: (a) rat-IgG2b/mouse-IgG2a; (b) rat-IgG2b/mouse-IgG2b; (c) rat-IgG2b/human-IgG1; and (d) mouse-[VH-CH1; VL-CL]-human-IgG1/rat-[VH-CH1, VL-CL]-human-IgG1-[hinge]-human-IgG3*-[CH2-CH3] [*=Caucasian allotypes G3m(b+g)=no binding to protein A] (Claim 2). The Fc-receptor positive cells that the trifunctional antibody/scaffold proteins bind to via its Fc portion include Fc-gamma receptor I/ IIa/III-positive accessory cells, preferably monocytes, macrophages, dendritic cells, natural killer cells, neutrophiles and/or eosinophile cells (Claim 3). In an example, anti-EpCAM mediated removal of tumor cells through multicell complex depletion by centrifugation and/or filtration during intraoperative blood salvage was demonstrated. Specifically, 1500 ml patient blood was collected with addition of anti-coagulants during surgery. Thus, the intraoperatively salvaged blood collected has a volume of 300 mL or more. Further, with the addition of anti-coagulants, the intraoperatively salvaged blood is a mixture of blood and dilution. 1000 ml this blood was incubated for 1 h with 2 μg of the anti-EpCAM antibody catumaxomab. After incubation, 500 ml of the patient blood was centrifuged, purified with a leucocyte filter, and the resulting erythrocyte concentrate (EC) was collected There were no detectable remaining tumor cells in the EC following the purification protocol (see Examples on Para. 0152-0162). The purification protocol described in the examples can be adapted for the use of other trifunctional bispecific antibodies other than anti-EpCAM, wherein the method begins with intraoperatively salvaged blood and may be repeated for multiple rounds to obtain a purified erythrocyte concentrate ready for reinfusion as shown by the schematic provided in Figure 3. The schematic of the method provided in Figure 3 shows a continuous cycle, indicating each step of the method can be repeated sequentially starting from collection of the intraoperative blood salvage through removal of tumor cells and/or leukocytes via centrifugation and filtering to obtain a purified erythrocyte concentrate.
It would have been obvious to one of ordinary skill in the art to use the claimed whole IgG bispecific antibody in the ex vivo method for removal of tumor cells from intraoperatively salvaged blood taught by Lindhofer. One of ordinary skill in the art would have been motivated to do so since these trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells and leukocytes thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient. Further, the courts have stated that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As discussed earlier, Lindhofer teaches that 1-5 ug of trifunctional antibody can be contacted with a particular volume of intraoperative blood salvage to form complexes that facilitate removal and provides a specific example wherein 2 ug of the anti-EpCAM antibody catumaxomab is contacted with 1000 mL of intraoperative blood salvage. As such, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of trifunctional antibody to contact with a volume of intraoperative blood salvage to facilitate removal of complexes and arrive at the specific embodiments of the claims including 2.5 ug to 50 ug of antibody with 300-1000 mL of intraoperative blood salvage. Therefore, one of ordinary skill in the art would reasonably expect that the trifunctional bispecific antibody of the co-pending claims can be used effectively for the ex vivo removal of tumor cells from intraoperatively salvaged blood.
Claims 1-11 and 13-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17628176 in view of Lindhofer et al (US20140369985A1), hereinafter Lindhofer.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite an ex vivo method for removal of tumor cells from intraoperatively salvaged blood comprising the steps of:
providing intraoperatively salvaged blood which may contain tumor cells;
contacting said intraoperatively salvaged blood with at least one antibody selected from the group consisting of a bispecific, trispecific, tetraspecific, and multispecific antibody and/or with at least one scaffold protein with multispecific binding properties,
,wherein the at least one antibody and/or at least one scaffold protein comprises the following properties:
binding to a pan-leukocyte antigen. Pan leukocyte antigens would be present on all leukocytes including T cells. Thus, the antibodies recited by the co-pending claims can target T cells as well.
binding to a tumor associated antigen on a tumor cell; and
binding via the Fc portion to an Fc-receptor positive cell
, wherein the at least one antibody and/or scaffold protein is contacted with the intraoperatively salvaged blood for a time period of 10-240 minutes (preferably 10-180 minutes) to crosslink tumor cells leukocytes in order to obtain associates and/or aggregates comprising the antibody or scaffold protein; and
mechanically removing the associates and/or aggregates from the intraoperatively salvaged blood (co-pending claims 1, 17, and 18), wherein removal of the associates and/or aggregates is by centrifugation, filtration, or a combination thereof (co-pending claim 9).
In some embodiments, the at least one antibody can be a trifunctional bispecific antibody having the isotype selected from the following: (a) rat-IgG2b/mouse-IgG2a; (b) rat-IgG2b/mouse-IgG2b; (c) rat-IgG2b/human-IgG1; and (d) mouse-[VH-CH1; VL-CL]-human-IgG1/rat-[VH-CH1, VL-CL]-human-IgG1-[hinge]-human-IgG3*-[CH2-CH3] [*=Caucasian allotypes G3m(b+g)=no binding to protein A] (co-pending claims 2 and 3). The incubation time of the antibody and/or scaffold protein with the intraoperatively salvaged blood is between 10 and 90 minutes (or preferably between 20 and 60 minutes) optionally wherein the incubation is performed at a temperature of between 19 to 25℃ or at room temperature (co-pending claim 9). The one or more antibodies or scaffold proteins are applied in an amount of 1-20 ug (preferably 1-10 ug or 1-5 ug or 1 to 2 ug) per liter of intraoperatively salvaged blood (co-pending claim 7). The method further comprises at least one of the following additional steps: a) mixing the intra-operatively salvaged blood before addition of the at least one antibody and/or scaffold protein with at least one anticoagulating agent; b) separating erythrocytes from the associates and further blood components via density gradient centrifugation; c) optionally filtering the mixture to remove potentially residual associates and residual cell complexes; and/or d) collecting the erythrocyte-containing fraction and further blood components in separate containers (co-pending claim 8). Filtration to remove the leukocytes and/or tumor cells can be achieved using a leukocyte adsorption/depletion filter in a separate step (co-pending claim 11).
The co-pending claims do not recite that the ex vivo method occurs according to the specific sequence recited in the instant claims, in particular, that after centrifugation to obtain an erythrocyte concentrate (EC), the EC is then washed and filtered to remove residual aggregates or cell complexes. Further, the co-pending claims do not recite that the intraoperatively salvaged blood obtained has a volume of 300 mL or more in the reservoir prior to application of the trifunctional antibody nor that the method steps are repeated from start to finish in multiple rounds, wherein the first round of collected blood is in a volume of 400-1500 mL.
However, Lindhofer discloses an ex vivo method for removal of tumor cells from intraoperatively salvaged blood comprising the steps of
i) collecting an intraoperatively salvaged blood which may contain immune cells and/or tumor cells in a reservoir (Para. 0019 and 0030),
ii) contacting the intraoperatively salvaged blood with at least one trifunctional antibody and/or scaffold protein in order to obtain associates (i.e. aggregates) (Para. 0019, Claims 1, 2, and 10),
iii) removing said associates from the intraoperatively salvaged blood via centrifugation, filtration, or a combination thereof, wherein the centrifugation step precedes the filtration step (Claim 12 and Para. 0141). As such, the trifunctional bispecific antibodies can mediate the formation of multicellular complexes or associates comprising tumor cells, immune cells such as T cells, and Fc-receptor positive accessory cells, thus facilitating their removal from intraoperatively salvaged blood by mechanical means including density gradient centrifugation and filtration in order to obtain a purified blood salvage or erythrocyte concentrate that can be reinfused into the patient (Abstract, Field of the Invention, and Summary of Invention). Centrifugation is performed generally by a density gradient centrifugation followed by washing with physiological saline for a time and with a rotational speed sufficient to remove said tumor cells-comprising associates and to separate erythrocytes from said tumor cell associates and optionally from leukocytes (Para. 0145). Centrifugation that pellets red blood cells and separates them from plasma results in an erythrocyte concentrate per step iii of the instantly claimed method. After centrifugation, washing the pelleted cells is equivalent to “washing the erythrocyte concentrate” per step iv of the instantly claimed method.
iv) additional filtration steps of the erythrocyte concentrate are performed in order to remove residual associates and/or leukocytes (Para. 0148). The filters might be selected from screen filters with pore sizes of between 20 μm to 40 μm (Para. 0142). In an example, anti-EpCAM mediated removal of tumor cells through multicell complex depletion by centrifugation and/or filtration during intraoperative blood salvage was demonstrated. Specifically, 1500 ml patient blood was collected with addition of anti-coagulants during surgery. Thus, the intraoperatively salvaged blood collected has a volume of 300 mL or more. Further, with the addition of anti-coagulants, the intraoperatively salvaged blood is a mixture of blood and dilution. 1000 ml this blood was incubated for 1 h with 2 μg of the anti-EpCAM antibody catumaxomab. After incubation, 500 ml of the patient blood was centrifuged, purified with a leucocyte filter, and the resulting erythrocyte concentrate (EC) was collected There were no detectable remaining tumor cells in the EC following the purification protocol (see Examples on Para. 0152-0162). The purification protocol described in the examples can be adapted for the use of other trifunctional bispecific antibodies other than anti-EpCAM, wherein the method begins with intraoperatively salvaged blood and may be repeated for multiple rounds to obtain a purified erythrocyte concentrate ready for reinfusion as shown by the schematic provided in Figure 3. The schematic of the method provided in Figure 3 shows a continuous cycle, indicating each step of the method can be repeated sequentially starting from collection of the intraoperative blood salvage through removal of tumor cells and/or leukocytes via centrifugation and filtering to obtain a purified erythrocyte concentrate.
It would have been obvious to one of ordinary skill in the art to modify the ex vivo method for removal of tumor cells from intraoperatively salvaged blood recited by the co-pending claims such that the method steps have the following sequence: centrifugation to obtain erythrocyte concentrate[Wingdings font/0xE0]washing of erythrocyte concentrate[Wingdings font/0xE0]filtering erythrocyte concentrate to remove residual tumor cells or antibody complexes. Further, artisans would have been motivated to collect 300 mL or more (e.g. 1000 mL or 1500 mL) of intraoperatively salvaged blood in a reservoir and repeat the method from blood collection through centrifugation and filtering to obtain purified erythrocyte concentrate. One of ordinary skill in the art would have been motivated to do so in order to effectively remove tumor cells and/or leukocytes from intraoperatively salvaged blood to yield a purified erythrocyte concentrate as demonstrated in the examples of Lindhofer. Further, the courts have stated that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As discussed earlier, Lindhofer teaches that 1-5 ug of trifunctional antibody can be contacted with a particular volume of intraoperative blood salvage to form complexes that facilitate removal and provides a specific example wherein 2 ug of the anti-EpCAM antibody catumaxomab is contacted with 1000 mL of intraoperative blood salvage. As such, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of trifunctional antibody to contact with a volume of intraoperative blood salvage to facilitate removal of complexes and arrive at the specific embodiments of the claims including 2.5 ug to 50 ug of antibody with 300-1000 mL of intraoperative blood salvage. Therefore, one of ordinary skill in the art would expect that modifying the method of the co-pending claims such that it proceeds according to the sequence using the initial volume of collected blood set forth by Lindhofer, wherein the method steps are repeated one or more times.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 9605242B2 in view of Lindhofer et al (US20140369985A1), hereinafter Lindhofer.
The issued claims recite an ex vivo method for removal of tumor cells from blood of a tumor patient comprising the steps of:
providing blood suspected of containing tumor cells intra-operatively salvaged from a tumor patient;
contacting the intra-operatively salvaged blood for a time period of between 10 and 180 minutes with a crosslinking agent capable of forming a three-dimensional network comprising the tumor cells,
wherein the crosslinking agent comprises at least one antibody selected from the group consisting of a bispecific antibody, a trispecific antibody, a tetraspecific antibody, a multispecific antibody, a bivalent antibody, a trivalent antibody, a tetravalent antibody, and a multivalent antibody, or at least one scaffold protein with multispecific or multivalent binding properties similar to antibodies, or a combination thereof,
wherein the at least one antibody, scaffold protein, or combination thereof specifically binds to at least one epitope of the tumor cells to crosslink the tumor cells,
and wherein the time period of between 10 and 180 minutes is sufficient to form associates by cross-linking tumor cells present in the intra-operatively salvaged blood with the at least one antibody, scaffold protein, or combination thereof of a size sufficient to be retained by filtration or to be separated by centrifugation, optionally wherein the associates further comprise cross-linked immune cells and/or other tumor cells. Thus, the associates can comprise antibodies, tumor cells, and immune cells;
mechanically removing the associates from the intra-operatively salvaged blood by centrifugation, filtration, or a combination thereof;
readministering the intra-operatively salvaged blood to the patient after mechanically removing the associates (issued claims 1, 9, and 14).
The method further comprises removing leukocytes and/or tumor cell-containing cell complexes using a leukocyte adsorption filter (issued claim 15). In step (ii) the at least one antibody and/or scaffold protein is contacted with the intraoperatively salvaged blood in an amount of 1 μg to 5 μg per liter of said blood and for a time period of 20-90 minutes or 30-60 minutes at a temperature of between 19 to 25° C, or optionally at room temperature (issued claims 10 and 13). The amount of antibody/scaffold protein contacted with the intraoperatively salvaged blood encompasses the claimed range of 2.5 ug or more and 5.0 ug or less. The method further comprises at least one of the following additional steps: a) mixing the intra-operatively salvaged blood before addition of the at least one antibody and/or the at least one scaffold protein with at least one anticoagulating agent to obtain a mixture, and optionally filtering the mixture to remove potentially residual associates and residual cell complexes; and/or b) separating erythrocytes from the associates and further blood components via separate containers (issued claim 12). The antibody comprises a trifunctional bispecific antibody having the following properties: (a) binding to a T cell;( b) binding to a tumor-associated antigen on a tumor cell; and (c) binding via its Fc-portion to an Fc-receptor positive cell, wherein the trifunctional bispecific antibody is selected from among the following isotype combinations: (a) rat-IgG2b/mouse-IgG2a; (b) rat-IgG2b/mouse-IgG2b; (c) rat-IgG2b/human-IgG1; and (d) mouse-[VH-CH1; VL-CL]-human-IgG1/rat-[VH-CH1, VL-CL]-human-IgG1-[hinge]-human-IgG3*-[CH2-CH3] [*=Caucasian allotypes G3m(b+g)=no binding to protein A] (issued claim 2). The tumor associated antigen is selected from the group consisting of EpCAM, Her2/neu, EGFR, CD30, CD20, CD22, MUC1, MUC1*, PSMA, CD33, MCSP, cMet, EphA2, endosialin, carboanhydrase IX, IGF-1R, FAP-alpha, CD19, CD52, GD2, CEA, FR, a proteoglycan, G250, GC182, GT468, and GT512 (issued claim 6). The trifunctional bispecific antibody recognizes a surface marker of T cells selected from the group consisting of CD3, CD2, CD4, CD5, CD6, CD6, CD8 and CD28 (issued claim 7). The Fc-receptor positive cell is selected is an Fcy receptor type I, II, or III cell or selected from the group consisting of monocyte, a macrophage, a dendritic cell, a natural killer cell, a neutrophil, and an eosinophil (issued claims 5 and 6).
The issued claims do not recite that the ex vivo method occurs according to the specific sequence recited in the instant claims, in particular, that after centrifugation to obtain an erythrocyte concentrate (EC), the EC is then washed and filtered to remove residual aggregates or cell complexes. Further, the issued claims do not recite that the intraoperatively salvaged blood obtained has a volume of 300 mL or more in the reservoir prior to application of the trifunctional antibody nor that the method steps are repeated from start to finish in multiple rounds, wherein the first round of collected blood is in a volume of 400-1500 mL.
However, Lindhofer discloses an ex vivo method for removal of tumor cells from intraoperatively salvaged blood comprising the steps of
i) collecting an intraoperatively salvaged blood which may contain immune cells and/or tumor cells in a reservoir (Para. 0019 and 0030),
ii) contacting the intraoperatively salvaged blood with at least one trifunctional antibody and/or scaffold protein in order to obtain associates (i.e. aggregates) (Para. 0019, Claims 1, 2, and 10),
iii) removing said associates from the intraoperatively salvaged blood via centrifugation, filtration, or a combination thereof, wherein the centrifugation step precedes the filtration step (Claim 12 and Para. 0141). Centrifugation is performed generally by a density gradient centrifugation followed by washing with physiological saline for a time and with a rotational speed sufficient to remove said tumor cells-comprising associates and to separate erythrocytes from said tumor cell associates and optionally from leukocytes (Para. 0145). Centrifugation that pellets red blood cells and separates them from plasma results in an erythrocyte concentrate per step iii of the instantly claimed method. After centrifugation, washing the pelleted cells is equivalent to “washing the erythrocyte concentrate” per step iv of the instantly claimed method.
iv) additional filtration steps of the erythrocyte concentrate are performed in order to remove residual associates and/or leukocytes (Para. 0148). The filters might be selected from screen filters with pore sizes of between 20 μm to 40 μm (Para. 0142). In an example, anti-EpCAM mediated removal of tumor cells through multicell complex depletion by centrifugation and/or filtration during intraoperative blood salvage was demonstrated. Specifically, 1500 ml patient blood was collected with addition of anti-coagulants during surgery. Thus, the intraoperatively salvaged blood collected has a volume of 300 mL or more. Further, with the addition of anti-coagulants, the intraoperatively salvaged blood is a mixture of blood and dilution. 1000 ml this blood was incubated for 1 h with 2 μg of the anti-EpCAM antibody catumaxomab. After incubation, 500 ml of the patient blood was centrifuged, purified with a leucocyte filter, and the resulting erythrocyte concentrate (EC) was collected. There were no detectable remaining tumor cells in the EC following the purification protocol (see Examples on Para. 0152-0162). The purification protocol described in the examples can be adapted for the use of other trifunctional bispecific antibodies other than anti-EpCAM, wherein the method begins intraoperatively salvaged blood and may be repeated for multiple rounds to obtain a purified erythrocyte concentrate ready for reinfusion as shown by the schematic provided in Figure 3. The schematic of the method provided in Figure 3 shows a continuous cycle, indicating each step of the method can be repeated sequentially starting from collection of the intraoperative blood salvage through removal of tumor cells and/or leukocytes via centrifugation and filtering to obtain a purified erythrocyte concentrate.
It would have been obvious to one of ordinary skill in the art to modify the ex vivo method for removal of tumor cells from intraoperatively salvaged blood recited by the issued claims such that the method steps have the following sequence: centrifugation to obtain erythrocyte concentrate[Wingdings font/0xE0]washing of erythrocyte concentrate[Wingdings font/0xE0]filtering erythrocyte concentrate to remove residual tumor cells or antibody complexes. Further, artisans would have been motivated to collect 300 mL or more (e.g. 1000 mL or 1500 mL) of intraoperatively salvaged blood in a reservoir and repeat the method from blood collection through centrifugation and filtering to obtain purified erythrocyte concentrate. One of ordinary skill in the art would have been motivated to do so in order to effectively remove tumor cells and/or leukocytes from intraoperatively salvaged blood to yield a purified erythrocyte concentrate as demonstrated in the examples of Lindhofer. Further, the courts have stated that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As discussed earlier, Lindhofer teaches that 1-5 ug of trifunctional antibody can be contacted with a particular volume of intraoperative blood salvage to form complexes that facilitate removal and provides a specific example wherein 2 ug of the anti-EpCAM antibody catumaxomab is contacted with 1000 mL of intraoperative blood salvage. As such, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of trifunctional antibody to contact with a volume of intraoperative blood salvage to facilitate removal of complexes and arrive at the specific embodiments of the claims including 2.5 ug to 50 ug of antibody with 300-1000 mL of intraoperative blood salvage. Therefore, one of ordinary skill in the art would expect that modifying the method of the issued claims such that it proceeds according to the sequence using the initial volume of collected blood set forth by Lindhofer, wherein the method steps are repeated one or more times.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 8277806B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for reducing or inhibiting the formation of ascites fluid in a subject comprising administering intraperitoneally a pharmaceutical composition comprising trifunctional bispecific antibodies, wherein the trifunctional bispecific antibodies have (1) a first binding arm that binds to a T cell via CD3, (2) a second biding arm that binds to EpCAM on a tumor cell, (3) an Fc portion that binds to an Fc receptor-positive cell that has an FcyRI, II, III or combination thereof, and (4) isotype combination rat IgG2b/mouse IgG2a (issued claim 1). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claims 15-20.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 7018632B2 in view of Seimetz et al (Seimetz, Diane, Horst Lindhofer, and Carsten Bokemeyer. "Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM× anti-CD3) as a targeted cancer immunotherapy." Cancer treatment reviews 36.6 (2010): 458-467).
The issued claims recite a method for preparing an antibody-tumor cell preparation for immunization of humans and animals against tumor cells comprising isolating tumor cells and incubating them with intact heterologous bispecific antibodies having the following properties: (i) binding to a T cell via CD2, CD3, CD4, CD5, CD6, CD8, CD28 or CD44.; (ii) binding to a least one tumor associated antigen on a tumor cell; and (iii) binding by their Fc portion to Fc receptor positive cells, (issued claims 1 and 5), wherein said antibodies bind Fc receptor-positive cells having a Fcγ receptor I, II, or III (issued claim 2). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
The issued claims do not teach that the tumor associated antigen targeted by the trifunctional antibody is EpCAM.
However, Seimetz teaches that EpCAM is expressed by tumors in the vast majority (87–100%) of patients with epithelial cancers, such as ovarian, gastric, colorectal, pancreatic, breast, lung, and endometrial tumors. It has also been shown to drive tumor growth and to be expressed on cancer stem cells. EpCAM-positive carcinomas maintain EpCAM expression in metastatic conditions, including dissemination into the peritoneal cavity, and they are present in 71–100% of malignant effusions. In some carcinomas, high EpCAM expression is associated with a poor prognosis. In normal tissues, EpCAM is only expressed basolaterally and is shielded by tight junctions. In contrast, in tumor cells, EpCAM is expressed on the whole cell surface and therefore becomes easily available for binding. Thus, a trifunctional antibody such as Catumaxomab which targets EpCAM, CD3 on T cells, and type I, IIa, and III FcyRs on accessory cells, is thus expected to be effective in treating a number of different carcinomas, as EpCAM is overexpressed in the majority of epithelial tumors.
It would have been obvious to one of ordinary skill in the art to modify the trifunctional antibody of the co-pending claims such that the tumor associated antigen targeted is EpCAM. One of ordinary skill in the art would have been motivated to do so because EpCAM is expressed by tumors in the vast majority (87–100%) of patients with epithelial cancers, such as ovarian, gastric, colorectal, pancreatic, breast, lung, and endometrial tumors as taught by Seimetz. Further, in view of Seimetz, a trifunctional antibody such as Catumaxomab which targets EpCAM, CD3 on T cells, and type I, IIa, and III FcyRs on accessory cells, is expected to be effective in treating a number of different carcinomas, as EpCAM is overexpressed on the surface of most epithelial tumors. Therefore, one of ordinary skill in the art would reasonably expect that the trifunctional antibody of the co-pending claims modified to target EpCAM can effectively treat most epithelial cancers.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 9772327B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for administering to an individual with a tumor load an immune therapy comprising a trifunctional bispecific antibody capable of binding to a T cell via CD3; binding to a tumor associated antigen; and binding via their Fc portion to Fcy receptor type I, IIa, and/or III positive cells (issued claims 1-3). The tumor associated target antigen is selected from EpCAM, MUC-1, or Her2/neu (issued claim 6).The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claims meet the limitations of instant claims 15-20.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 8663638B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for destroying tumor cell comprising administering to a subject a trifunctional bispecific antibody, wherein the trifunctional bispecific antibody (i) binds to a T cell via CD3, (ii) binds to at least one tumor associated antigen on tumor cells; and (iii) binds by its Fc part to Fc receptor positive cells (issued claim 1), wherein the antibody binds to type I and/or type III Fc-γ receptor-positive cells via its Fc content (issued claim 6). The tumor associated antigen is selected from EpCAM or HER2/neu (issued claim 5). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claims 15-20.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9017676B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for the treatment of tumor diseases in a patient comprising administering to the patient a trifunctional bispecific antibody having the following properties: (1) a first binding arm that binds to a T cell; (2) a second binding arm that binds to tumor associated antigens on tumor cells; and (3) an Fc portion that binds to Fcy receptor type I and/or III positive cells (issued claim 1), wherein said trifunctional antibody is selected from the group consisting of an anti-CD3×anti-tumor-associated antigen antibody, anti-CD4×anti-tumor-associated antigen antibody, anti-CD5×anti-tumor-associated antigen antibody, anti-CD6×anti-tumor-associated antigen antibody, anti-CD8 anti-tumor-associated antigen antibody, anti-CD2×anti-tumor-associated antigen antibody, anti-CD28×anti-tumor-associated antigen antibody, anti-CD44×anti-tumor-associated antigen antibody or a combination thereof (issued claim 4). The tumor associated antigen is Her2/neu or EpCAM (issued claim 1). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claims 15-20.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9017676B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for reducing the non-specific release of a cytokine in a subject associated with treatment of cancer or tumor comprising administering to the subject a glucocorticoid before or after administration of a trifunctional bispecific antibody, wherein the trifunctional bispecific antibody is directed against a tumor associated antigen such as Her2/neu or EpCAM and the T cell antigen marker CD3 (issued claim 1). Per the issued specification, the trifunctional antibody has not only target tumor cells and T lymphocytes with its two binding arms but also Fc-receptor positive accessory cells via their Fc region (Column 3, Ln. 23-33). Thus, the trifunctional bispecific antibody of the issued claims comprises an intact immunoglobulin Fc region in addition to two binding arms that target tumor associated antigens and T cells. The Fc portion binds to FcyR type I or III positive cells or a combination thereof (issued claim 1). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claims 15-20.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 8066989B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for reducing graft versus host disease during treatment of tumor growth and metastasis in a mammal, comprising administering allogenic effector cells in combination with trifunctional bispecific antibodies having the following properties: a) binding to CD3 on a T cell; b) binding to at least one tumor associated antigen; and 3) binding via their Fc portion to Fc receptor positive cells (issued claim 1), wherein the tumor associated antigen is EpCAM or Her2/neu (issued claim 11) and wherein said binding to Fc receptor positive cells comprises binding to Fcγ receptor type I or Fcγ receptor type III (issued claim 15). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claims 15-20.
Claims 15 and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 6210668B1. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method of treatment of a patient suffering from cancer comprising the steps of 1) preparing a stem cell transplant; 2) contacting the stem cell transplant with intact bispecific antibodies capable of binding to the T cell receptor complex of a T cell, to tumor-associated antigens on a tumor cell, and to Fc receptors of accessory cells via the Fc part of the antibody; and 3) reinfusing the stem cell transplant into the patient (issued claim 1). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claims 15 and 18-20.
Claims 15-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 6551592B2 in view of Seimetz et al (Seimetz, Diane, Horst Lindhofer, and Carsten Bokemeyer. "Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM× anti-CD3) as a targeted cancer immunotherapy." Cancer treatment reviews 36.6 (2010): 458-467).
The issued claims recite a method of treatment of a human or animal subject suffering from a tumor disease consisting of administering to the subject consisting of administering to the subject an intact heterologous bispecific antibody, wherein the antibody has the following properties: (a) binding to a T cell and activating said T cell; (b) binding to a tumor associated antigen on a tumor cell; and (c) binding through its Fc portion to the Fc receptor of Fc receptor positive cells (issued claim 1), wherein said antibody binds to the T cell via a member selected from the group consisting of CD3, CD2, CD5, CD28, and CD44 (issued claim 5) and wherein Fc receptor positive cells include FcyR I, II, or III (issued claim 6).The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. Of note, the phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
The issued claims do not teach that the tumor associated antigen targeted by the trifunctional antibody is EpCAM.
However, Seimetz teaches that EpCAM is expressed by tumors in the vast majority (87–100%) of patients with epithelial cancers, such as ovarian, gastric, colorectal, pancreatic, breast, lung, and endometrial tumors. It has also been shown to drive tumor growth and to be expressed on cancer stem cells. EpCAM-positive carcinomas maintain EpCAM expression in metastatic conditions, including dissemination into the peritoneal cavity, and they are present in 71–100% of malignant effusions. In some carcinomas, high EpCAM expression is associated with a poor prognosis. In normal tissues, EpCAM is only expressed basolaterally and is shielded by tight junctions. In contrast, in tumor cells, EpCAM is expressed on the whole cell surface and therefore becomes easily available for binding. Thus, a trifunctional antibody such as Catumaxomab which targets EpCAM, CD3 on T cells, and type I, IIa, and III FcyRs on accessory cells, is thus expected to be effective in treating a number of different carcinomas, as EpCAM is overexpressed in the majority of epithelial tumors.
It would have been obvious to one of ordinary skill in the art to modify the trifunctional antibody of the co-pending claims such that the tumor associated antigen targeted is EpCAM. One of ordinary skill in the art would have been motivated to do so because EpCAM is expressed by tumors in the vast majority (87–100%) of patients with epithelial cancers, such as ovarian, gastric, colorectal, pancreatic, breast, lung, and endometrial tumors as taught by Seimetz. Further, in view of Seimetz, a trifunctional antibody such as Catumaxomab which targets EpCAM, CD3 on T cells, and type I, IIa, and III FcyRs on accessory cells, is expected to be effective in treating a number of different carcinomas, as EpCAM is overexpressed on the surface of most epithelial tumors. Therefore, one of ordinary skill in the art would reasonably expect that the trifunctional antibody of the co-pending claims modified to target EpCAM can effectively treat most epithelial cancers.
Claims 15, 16, and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 5985276A. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for the reduction of the number of tumor cells in stem cell transplants ex vivo comprising contacting the stem cell transplants with intact bispecific antibodies capable of binding to the T cell receptor complex of a T cell, to the Fc receptor of an Fc receptor positive cell, and to tumor associated antigens on a tumor cell (issued claim 1), in which said bispecific antibodies are members selected from the group consisting of anti-CD3 X anti-c-erbB-2antibodies, anti-CD3 X anti-Ep-CAM antibodies, and anti-CD3 X anti-Lewis Y antibodies (issued claim 3). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claims 15, 16, and 18-20.
Claim 15 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 6551592B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims either anticipate or are obvious variants over the instant claims.
The issued claims recite a method for the reduction of the number of tumor cells in stem cell transplants ex vivo comprising contacting the stem cell transplants with intact bispecific antibodies capable of binding to the T cell receptor complex of a T cell, to the Fc receptor of an Fc receptor positive cell, and to tumor associated antigens on a tumor cell (issued claim 1), wherein said antibody binds to the T cell via a member selected from the group consisting of CD3, CD2, CD5, CD28, and CD44 (issued claim 5) and , wherein said antibody is able to bind to Fc receptor-positive cells having a Fcγ receptor I, II, or III (issued claim 6). The trifunctional bispecific antibody is a required element of the method of the issued claims. As such, the trifunctional bispecific antibody is taught by the issued claims. The phrase “for use in a method for treating tumor or cancer” (including the methods steps for ex vivo removal of tumor cells) recited in instant claim 15 is a statement of intended use that does not result in a structural difference between the instantly claimed invention and that of the issued claims. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Thus, the issued claim meets the limitations of instant claim 15.
Claims 15 and 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10576149B2 in view of Eissler et al (Eissler, Nina, et al. "Trifunctional bispecific antibodies induce tumor-specific T cells and elicit a vaccination effect." Cancer research 72.16 (2012): 3958-3966), hereinafter Eissler.
The issued claims recite a method of using a bispecific antibody for treating lymphoma in a subject comprising administering the bispecific antibody to the subject, wherein the bispecific antibody is directed against tumor antigen CD19 and T cell marker CD3 (issued claim 1). The bispecific antibody is a required element of the method of the issued claims. As such, the bispecific antibody is taught by the issued claims.
The issued claims do not specifically recite that the bispecific antibody that targets MHCII antigen on tumor cells and CD3 on T cells is an intact whole IgG antibody.
However, Eissler teaches that trifunctional bispecific antibodies comprise an appropriate Fc region and, thus, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR) such as FcγRI, IIa, or III, providing additional T–cell-activating signals and securing presentation of tumor-derived antigens to T cells. Thus, while bispecific antibodies that lack an immunoglobulin Fc region redirects only 1 type of effector cells, for example, T lymphocytes, to malignant cells, trifunctional bispecific antibodies additionally recruit APCs and natural killer cells via their intact immunoglobulin Fc domain. Through simultaneous activation of different effector mechanisms in a “tri-cell complex”, disseminated tumor cells can effectively be killed (Introduction and Discussion, First Paragraph).
It would have been obvious to one of to modify the bispecific antibody of the issued claims such that is has an intact immunoglobulin Fc region to yield a trifunctional antibody. One of ordinary skill in the art would have been motivated to do so since, unlike bispecific antibody Fab fragments that recruit only 1 type of effector cells, trifunctional antibodies additionally recruit antigen presenting cells and natural killer cells via their intact immunoglobulin Fc domain to more effectively kill disseminated tumor cells. Therefore, it would have been obvious to one of ordinary skill in the art to modify the bispecific antibody of the issued claims such that it comprises an intact Fc region in order to more effectively treat cancer in a subject. The combined teachings of the issued claims and Eissler render obvious the trifunctional bispecific antibody of instant claim 15. It should be noted that the intended use recitation does not impart additional structural limitations and thus is not given patentable weight, including the methods steps for ex vivo removal of tumor cells recited in instant claim 15. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Claim 15 and 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10071158B2 in view of Eissler et al (Eissler, Nina, et al. "Trifunctional bispecific antibodies induce tumor-specific T cells and elicit a vaccination effect." Cancer research 72.16 (2012): 3958-3966), hereinafter Eissler.
The issued claims recite a method for reducing the non-specific release of at least one cytokine in a subject which is associated with treatment of a cancer comprising administering an effective amount of a glucocorticoid on the same day and prior to administration of a bispecific antibody directed against a tumor antigen CD19 and the T cell marker CD3 (issued claim 1).
The issued claims do not specifically recite that the bispecific antibody that targets MHCII antigen on tumor cells and CD3 on T cells is an intact whole IgG antibody.
However, Eissler teaches that trifunctional bispecific antibodies comprise an appropriate Fc region and, thus, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR) such as FcγRI, IIa, or III, providing additional T–cell-activating signals and securing presentation of tumor-derived antigens to T cells. Thus, while bispecific antibodies that lack an immunoglobulin Fc region redirects only 1 type of effector cells, for example, T lymphocytes, to malignant cells, trifunctional bispecific antibodies additionally recruit APCs and natural killer cells via their intact immunoglobulin Fc domain. Through simultaneous activation of different effector mechanisms in a “tri-cell complex”, disseminated tumor cells can effectively be killed (Introduction and Discussion, First Paragraph).It would have been obvious to one of to modify the bispecific antibody of the issued claims such that is has an intact immunoglobulin Fc region to yield a trifunctional antibody. One of ordinary skill in the art would have been motivated to do so since, unlike bispecific antibody Fab fragments that recruit only 1 type of effector cells, trifunctional antibodies additionally recruit antigen presenting cells and natural killer cells via their intact immunoglobulin Fc domain to more effectively kill disseminated tumor cells. Therefore, it would have been obvious to one of ordinary skill in the art to modify the bispecific antibody of the issued claims such that it comprises an intact Fc region and can be used as a more effective cancer treatment in the recited method. The combined teachings of the issued claims and Eissler render obvious the trifunctional bispecific antibody of instant claim 15. It should be noted that the intended use recitation does not impart additional structural limitations and thus is not given patentable weight, including the methods steps for ex vivo removal of tumor cells recited in instant claim 15. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Claim 15 and 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 6294167B1 in view of Eissler et al (Eissler, Nina, et al. "Trifunctional bispecific antibodies induce tumor-specific T cells and elicit a vaccination effect." Cancer research 72.16 (2012): 3958-3966), hereinafter Eissler.
The issued claims recite a method of treatment for treating residual tumor cells in a mammalian subject comprising transplanting bone marrow cells from a donor to the subject and administering to the subject an antibody which selectively binds to MHCII antigen expressed by the tumor cells (issued claim 1), wherein the antibody has additional specificity which recognizes CD3 on T effector cells (issued claims 3-6).
The issued claims do not specifically recite that the bispecific antibody that targets MHCII antigen on tumor cells and CD3 on T cells is an intact whole IgG antibody.
However, Eissler teaches that trifunctional bispecific antibodies comprise an appropriate Fc region and, thus, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR) such as FcγRI, IIa, or III, providing additional T–cell-activating signals and securing presentation of tumor-derived antigens to T cells. Thus, while bispecific antibodies that lack an immunoglobulin Fc region redirects only 1 type of effector cells, for example, T lymphocytes, to malignant cells, trifunctional bispecific antibodies additionally recruit APCs and natural killer cells via their intact immunoglobulin Fc domain. Through simultaneous activation of different effector mechanisms in a “tri-cell complex”, disseminated tumor cells can effectively be killed (Introduction and Discussion, First Paragraph).
It would have been obvious to one of to modify the bispecific antibody of the issued claims such that is has an intact immunoglobulin Fc region to yield a trifunctional antibody. One of ordinary skill in the art would have been motivated to do so since, unlike bispecific antibody Fab fragments that recruit only 1 type of effector cells, trifunctional antibodies additionally recruit antigen presenting cells and natural killer cells via their intact immunoglobulin Fc domain to more effectively kill disseminated tumor cells. Therefore, it would have been obvious to one of ordinary skill in the art to modify the bispecific antibody of the issued claims such that it comprises an intact Fc region in order to more effectively treat cancer in a subject. The combined teachings of the issued claims and Eissler render obvious the trifunctional bispecific antibody of instant claim 15. It should be noted that the intended use recitation does not impart additional structural limitations and thus is not given patentable weight, including the methods steps for ex vivo removal of tumor cells recited in instant claim 15. Claims 18-20 provide further limitations of the intended use but still do not impart additional structural limitations to the trifunctional antibody; thus claims 18-20 are also not given patentable weight.
Response to Arguments
Applicant’s arguments filed 06/10/2026 with respect to the rejection(s) of claim(s) under 35 USC 102 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the claim amendments.
With respect to the 35 U.S.C. 102 rejection and double patenting rejections, Applicant argues that Lindhofer does not appear to disclose, "wherein the amount of said at least one trifunctional bispecific antibody is 2.5 ug or more," as recited by amended independent claim 1 or "the amount of said at least one trifunctional bispecific antibody is 2.5 ug or more, and wherein said cell aggregates comprise said trifunctional bispecific antibody," as recited by amended independent claim 15. Lindhofer discloses "a method performed ex vivo for removal of tumor cells from intraoperatively collected blood salvage." Lindhofer, Abstract. Lindhofer at most disclose the amount of catumaxomab used for incubation with patient blood is 2 ug. Accordingly, the Applicant respectfully submits that Lindhofer does not appear to disclose each and every feature recited by amended independent claims 1 and 15. Because Lindhofer does not appear to disclose each and every feature of amended independent claims 1 and 15, the Applicant respectfully submits that Lindhofer cannot anticipate amended independent claims 1 and 15, or the claims depending therefrom. For at least these reasons, among others, the Applicant respectfully requests withdrawal of the rejections under 35 U.S.C. § 102.
However, the courts have stated that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As discussed earlier, Lindhofer teaches that 1-5 ug of trifunctional antibody can be contacted with a particular volume of intraoperative blood salvage to form complexes that facilitate removal and provides a specific example wherein 2 ug of the anti-EpCAM antibody catumaxomab is contacted with 1000 mL of intraoperative blood salvage. Because applicant has not established that using 2.5 ug (or more) of trifunctional antibody with 300 mL (or more) of intraoperative blood salvage produces a critical or unexpected result, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum amount of trifunctional antibody to contact with a volume of intraoperative blood salvage to facilitate removal of complexes and arrive at the specific embodiments of the claims including 2.5 ug to 50 ug of antibody with 300-1000 mL of intraoperative blood salvage. Hence, the claims are rejected in the present Office Action under 35 USC 103 and the double patenting rejections are also maintained.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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