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 .
Status of the Claims/Application
Claims 2 and 15-20 are canceled. Claims 21-27 are new. Claims 1, 3, 5-9, 13-14 are amended. Claims 1, 2-14 and 21-27 are pending and are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/01/2026 is acknowledged and is in compliance with the provisions of CFR 1.97. It has been considered by the examiner.
Withdrawn Rejections
112(b)
Claims 1, 7-9, 17, 19 were rejected for reciting a broad range or limitation together with a narrow range or limitation. Applicant has canceled claims 17 and 19 and the rejection as it applies to these claims have been withdrawn. Regarding the rejection of claims 1, 7-9, applicant has amended the claims. The rejection as it applies to these claims is withdrawn.
Claim 1 was rejected for lacking clarity as to the use of the phrase, “other tumor cells.” Applicant has deleted the phrase. The rejection as it applies to this rejection is withdrawn.
Claims 15 and 16 recite “use claims.” Applicant has canceled claims 15 and 16 and the rejection as it applies to these claims is withdrawn.
101
Claims 15 and 16 were rejection as being drawn to an abstract idea. Claims 15 and 16 have been canceled and the rejection as it applies to these claims is withdrawn.
102
The rejection as it applies to claims 1-20 as being anticipated by US Patent 9605242 (‘242) is withdrawn. Claims 15-20 are canceled. The rejection as they apply to these claims is withdrawn. Applicant has amended the claims and the rejection as it applies to 1-14 is withdrawn.
NSDP
Regarding the NSDP rejection of claims 1-13, 15, 16 as being unpatentable over claims 1-3, 6, 8-15 of US Patent 9605242, the rejection has been updated in view of applicant’s amendments. It is noted the rejection of claims 15, 16 is withdrawn as the claims are canceled.
Regarding the rejection of claims 1-3 as being unpatentable over claim 5 of 8066989, the rejection has been withdrawn in view of applicant’s amendments.
Regarding the rejection of claims 17-20 as being unpatentable over claims 1, 3, 6, 11 of US Patent 9605242 in view of Sebastian, the rejection is withdrawn in view of applicant’s amendments.
Regarding the provisional rejection of claims 1-3, 7, 9-11 as being provisionally rejected over claims 1-3, 7, 9, 10 of copending application 18033942, the rejection is withdrawn in view of applicant’s amendments.
New Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-14 and 21-27 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 9605242 (‘242) in view of Ross SL, Sherman M, McElroy PL, Lofgren JA, Moody G, Baeuerle PA, et al., 2017, Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing. PLoS ONE 12(8): e0183390, Szabo et al., 2010, “Direct conversion of human fibroblasts to multilineage blood progenitors,” Nature, 468: 521-526, Oehler et al., 2010, “CD52 Expression In Leukemic Stem/Progenitor Cells,”, 116:2743, Friedman M, Lindström S, Ekerljung L, Andersson-Svahn H, Carlsson J, Brismar H, et al. Engineering and characterization of a bispecific HER2 x EGFR-binding affibody molecule. Biotechnol Appl Biochem. 2009;54:121–131. doi: 10.1042/BA20090096.
Regarding claim 1, ‘242 teaches and ex vivo method for the removal of tumor cells from blood of a tumor patient, the method comprising, providing blood suspected of containing tumor cells intra-operatively salvaged from a tumor patient, contacting the intra-operative salvaged blood for a time period between 10 and 180 minutes with a cross-linking agent capable of forming a three-dimensional network comprising the tumor cells, wherein the cross-linking agent comprises: at least one antibody selected from a bispecific antibody, wherein at least one of the antibodies binds to a tumor cell (and optional immune cells), wherein the cross-linked tumor cells is a size sufficient to be retained by filtration or be separated by centrifugation, and after mechanically removing the cross-linked tumor cells from the intra-operatively salvaged blood, readministering the intra-operatively salvaged blood to the patient (‘242, claim 1).
In addition to the cross-linking agent binding to a cancer cell, the trifunctional bispecific antibody can bind to an immune cell, wherein the cell is a T cell (‘242, claim 1). Regarding the bispecific antibody is trifunctional, ‘242, claim 3, indicates that the antibody exhibits binding via its Fc-portion to an Fc-receptor positive cell.
While ‘242 provides guidance on forming a complex that binds tumor cells (and optional immune cells) for removal from a patient, ‘242 does not teach that the immune cell is a pan-leukocyte.
Regarding instant claim 1being drawn to the use of an antibody binding region that binds to a pan-leukocyte, at the time of filing, Ross et al. teach that an EGFR/CD3 BiTE bispecific antibody construct can be used to recruit CD3+ pan-T cells and lyse EGFR-positive cancer cells (Ross et al., abstract). While Ross et al. teach recruitment of pan-T cells, it is noted that one would have also made a BiTE construct comprising a CD45 binding arm, wherein CD45 is an epitope expressed by hematopoietic progenitor cells. According to Szabo et al., CD45+ fibroblasts give rise to macrophages, granulocytic cell types, neutrophils, eosinophils, and basophils (Szabo et al., page 522, 2nd col., 1st parag.). CD45+ cells also can give rise to erythroid and megakaryocytic cells (Szabo et al., page 523, 2nd col.).
It would have been obvious for an artisan to substitute the antibody arm or binding region in the scaffold protein that binds T cells in ‘242 with an antibody that binds to CD45 on a pan-leukocyte cell. One would have done so in order to arrive at a system that recruits a progenitor cell that can differentiate into a number of different types of immune cells that can be used to attack cancer. There would have been reasonable expectation of success as ‘242 teach that T cells (immune cells) can be recruited to attack cancer cells.
Regarding claim 3, ‘242 teaches that the trifunctional bispecific antibody has the isotypes:
rat-IgG2b/mouse-IgG2a,
rat-IgG2b/mouse-IgG2b,
rat-IgG2b/human-IgG1,
mouse-[VH-CH1; VL-CL]-human-IgG 1/rat-[VH-CH1, VL-CL]-human-IgG1-[hinge]human-IgG3*-[CH2-CH3]
[*=Caucasian allotypes G3m(b+g)=no binding to protein A] (‘242, claim 3).
Regarding claims 4-6, 13, wherein the pan-leukocyte marker is CD52, Oehler et al. teach that CD52 is a cell surface glycoprotein that is expressed in B and T lymphocytes, macrophages, and monocytes, but is not expressed in normal hematopoietic stem/progenitor cells (Oehler et al., abstract). It would have been obvious for an artisan to have used an antibody to CD52 in order to arrive at ‘242’s complex that binds to tumor and to immune cells. Specifically for claim 5, one would have taken ‘242’s bispecific antibody/scaffold and made two versions of it. One bispecific antibody would bind to a tumor antigen and to CD45 and another bispecific antibody would bind to a tumor antigen and to CD52. One would have made 2 different bispecific antibody/scaffolds in order to arrive at a system that recruits hematopoietic cells (CD45) and defined immune cells (CD52) that would attack cancer cells. Specifically for claim 13, the bispecific antibody made with ‘242 and targeting CD52 would address the bispecific antibody binding to T cells.
Regarding claims 7, 22-24, wherein at least one trifunctional antibody is applied in an amount of 1-20 ug per liter of intraoperatively salvaged blood, ‘242 claim 10 indicates the various dosages of antibody used in a liter of blood.
Regarding claim 8, wherein the method comprises at least a) mixing the intraoperatively salvaged blood before addition of the trifunctional bispecfic antibody with at least one anticoagulation agent, b) separating erythrocytes from associates/aggregates via centrifugation, c) optionally filtering the mixture to remove residual associates/aggregates, and d) collecting the erythrocyte-containing fraction and further blood components in separate containers, the steps are recited in claim 12 of ‘242.
Regarding claims 9, 26, 27 being drawn to an incubation time of trifunctional bispecific antibody with blood and wherein the incubation is optionally performed between 19-25oC, claim 13 of ‘242 teach similar incubation time and temperature.
Regarding claims 10-11, 25 being drawn to removing associates/aggregates by centrifugation, filtration, or a combination thereof and to removing cell complexes using leukocyte adsorption/depletion filter, claims 14-15 of ‘242 are drawn to these steps.
Regarding claim 12, wherein the tumor cells are epithelial, hematological, or neuroectodermal, while Ross et al. teach an EGFR/CD3 bispecific construct, they also teach a bispecfic antibody, CD19/CD3, that has been successful in treating CD19 hematological malignancies (Ross et al., abstract).
Regarding claim 14, wherein the trifunctional bispecific antibody binds two different tumor-associated antigens, Friedman et al. teach a bispecfic antibody that targets EGFR and HER2, two proteins highly expressed in breast, bladder, colorectal, and prostate cancer (Friedman et al., page 122, 2nd col., 2nd parag.). Given the teaching of Friedman et al., one would have taken the trifunctional bispecific antibody taught by ‘242 and used used antibodies that bind to EGRF and HER2 to bind to cancer cells. There would have been reasonable expectation of success as Friedman et al. teach that bispecific EGFR/HER2 bispecific antibodies were known to treat cancer (and EGFR/HER2 is in claim 6 of ‘242) and as ‘242 teach in claim 1 that the bispecific antibody (or the scaffold that binds to tumor cells) is used to bind to tumor cells. The Fc region in the bispecific antibody/scaffold is used to induce ADCC to kill cancer cells.
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, 3-14, 21-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US 9605242 (‘242), Ross SL, Sherman M, McElroy PL, Lofgren JA, Moody G, Baeuerle PA, et al., 2017, Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing. PLoS ONE 12(8): e0183390, Szabo et al., 2010, “Direct conversion of human fibroblasts to multilineage blood progenitors,” Nature, 468: 521-526, Oehler et al., 2010, “CD52 Expression In Leukemic Stem/Progenitor Cells,”, 116:2743.
The instant claims and those of ‘242 overlap in teaching an ex vivo method for introducing a trifunctional bispecific antibody that is introduced to intra-operatively salvaged blood in a tumor patient. The bispecific arms of the antibody can bind to one tumor antigen and one immune cell (wherein in ‘242, the immune cell is a T cell) or two tumor antigens. The antibody comprises an Fc domain which interacts with a FcReceptor expressed on an immune cell. The difference between the instant claims and ‘242 is that in ‘242, the immune cell is a T cell, while in the instant case, the immune cell is a pan-leukocyte. The use of an antibody that binds to a pan-leukocyte cell in the instant claims is obvious because Ross et al. teach that BiTE bispecfic antibodies are commonly used to bind to a cancer cell and to a T cell such that the T cell, in close proximity destroys the cancer cell. Szabo et al. and Oehler et al. teach that CD45 is expressed on hematopoietic cells and CD52 is expressed on B and T lymphocytes, macrophages, and monocytes and are other cell types that can be used to mount an immune response against a cancer cell. There would have been reasonable expectation of success in substituting Ross et al.’s antibody that binds to a T cell with an antibody that binds to a number of other immune cells that can be used to kill a cancer cell.
Claims 1, 3-14, 21-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending US Application No. 18/033942 (‘942) in view of Ross SL, Sherman M, McElroy PL, Lofgren JA, Moody G, Baeuerle PA, et al. (2017) Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing. PLoS ONE 12(8): e0183390. https://doi.org/10.1371/journal.pone.0183390, as evidenced by Szabo et al., 2010, “Direct conversion of human fibroblasts to multilineage blood progenitors,” Nature, 468: 521-526 Direct conversion of human fibroblasts to multilineage blood progenitors | Nature
Oehler et al., 2010, “CD52 Expression In Leukemic Stem/Progenitor Cells,”, 116:2743CD52 Expression In Leukemic Stem/Progenitor Cells | Blood | American Society of Hematology.
The instant claims and those of ‘942 overlap in teaching an ex vivo method for introducing a trifunctional bispecific antibody that is introduced to intra-operatively salvaged blood in a tumor patient. The bispecific arms of the antibody can bind to one tumor antigen and a T cell. The antibody comprises an Fc domain which interacts with a FcReceptor expressed on an immune cell. The difference between the instant claims and ‘942 is that in ‘942, the immune cell is a T cell, while in the instant case, the immune cell is a pan-leukocyte. The use of an antibody that binds to a pan-leukocyte cell in the instant claims is obvious because Ross et al. teach that BiTE bispecfic antibodies are commonly used to bind to a cancer cell and to a T cell such that the T cell, in close proximity destroys the cancer cell. Szabo et al. and Oehler et al. teach that CD45 is expressed on hematopoietic cells and CD52 is expressed on B and T lymphocytes, macrophages, and monocytes and are other cell types that can be used to mount an immune response against a cancer cell. There would have been reasonable expectation of success in substituting Ross et al.’s antibody that binds to a T cell with an antibody that binds to a number of other immune cells that can be used to kill a cancer cell.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
Applicants’ 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanna Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMMANUEL LED YOUTCHOM PENDIE/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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