DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Status of Claims
The Amendments and Remarks filed 12/29/2025 in response to the Office Action of 06/30/2025 are acknowledged and have been entered.
Claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 41, 61, 67 and 68 are currently pending.
Claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35 and 38 have been amended by Applicant.
Claim 61 remains withdrawn.
Claims 67 and 68 have been newly added by Applicant.
Claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 41, 67 and 68 are under examination on the merits in the instant Office Action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Office Action contains New Rejections based on New Considerations.
Specification Objections - Withdrawn
Applicant has amended the specification as suggested and so the objections have been withdrawn.
Claim Objections – Withdrawn
Applicant has amended claims 2 and 6 and as such the objections have been withdrawn.
Claim Rejections – 35 USC § 112 – Withdrawn
Given that Applicant has now amended claims 2-6 26, 28, 35, 38, and 41, the 112(b) rejection of these claims is hereby withdrawn.
Given that Applicant has now amended claims 2, 6 26, 35, 38, and 41 and canceled claims 3-5 and 28, the rejection of these claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn.
Given that Applicant has now amended claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38 and 41 and canceled claims 3-5, 7, 12, and 28, the enablement rejection of these under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
Given that Applicant has now amended claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38 and 41 and canceled claims 3-5, 7, 12, and 28, the written description rejection of these under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
The rejection of claims 13, 14, 26, 28, 35, 38 and 41 based on the judicially-created basis that they contain an improper Markush grouping of alternatives has been withdrawn.
The rejection of claims 1, 7-9, 12, 17, 26, 28, 35 and 38 under 35 U.S.C. 103 as being unpatentable over Keyt (US 20170183409 A1 Date Published 2017-06-29) in view of Zhang (CN 108409840 A Date Published 2018-08-17) and Bernett (US 20170081424 A1 Date Published 2017-03-23) has been withdrawn.
The rejection of claims 1, 7-9, 12-14, 17, 26, 28, 35 and 38 under 35 U.S.C. 103 as being unpatentable over Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), and Bernett (US 20170081424 A1 Date Published 2017-03-23) as applied to claims 1, 7-9, 12, 17, 26, 28, 35 and 38, and further in view of Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn.
Double Patenting - Withdrawn
The nonstatutory double patenting rejection of claims 1, 7-9, 12-14, 17, 26, 28, 35 and 38 over claims 1-5 of U.S. Patent No. 9951134B2 (Date of Patent 2018-04-24) in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the referenced patent is drawn to a J-chain that is patentably distinct from the instant application that recites a variant J-chain.
The nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35 and 38 over claims 1-4, 12-13, 15-16 and 18-22 of U.S. Patent No. 10899835B2 (Date of Patent 2021-01-26) in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the combination of the cited patent with cited references does not render the instant claims obvious.
The provisional nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35 and 38 as being unpatentable over claims 38, 64, 67, 69-72 and 82-87 of copending Application No. 17110550 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application was abandoned.
The provisional nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35 and 38 over claims 63, 66-68 of copending Application No. 17287828 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application was abandoned.
The provisional nonstatutory double patenting rejection of claims 1, 3-9, 12-14, 17, 26, 28, 35 and 38 over claims 32 and 36 of copending Application No. 17998307 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application is drawn to IgM that binds to DR5 which is patentably distinct from the instant application that recites IgM that binds to CD123.
The provisional nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35 and 38 over claims 1, 5, 9, 10 and 48 of copending Application No. 17635078 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application was abandoned.
The provisional nonstatutory double patenting rejection of claims 1, 3-9, 12-14, 17, 26, 28, 35 and 38 over claims 1, 10-17 and 20 of copending Application No. 17758207 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application is drawn to highly sialylated IgM that specifically binds a target which is patentably distinct from the instant application that recites IgM that binds to CD123.
The provisional nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35, 38 and 41 over claims 1, 7 and 8-14 of copending Application No. 17996760 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application was abandoned.
The provisional nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35 and 38 over claims 3, 8, 9, 13-16 and 18 of copending Application No. 18261145 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the combination of the cited copending application with cited references does not render the instant claims obvious.
The provisional nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35 and 38 over claims 1, 2, 6, 7, 15 and 19 of copending Application No. 18400974 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application is drawn to IgM that binds to CD20 which is patentably distinct from the instant application that recites IgM that binds to CD123.
The provisional nonstatutory double patenting rejection of claims 1-9, 12-14, 17, 26, 28, 35 and 38 over claims 12, 21, 23, 24, 33-35 and 37-44 of copending Application No. 18719191 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application is drawn to IgM that binds to CD38 which is patentably distinct from the instant application that recites IgM that binds to CD123.
The provisional nonstatutory double patenting rejection of claims 1, 3-9, 12-14, 17, 26, 28, 35 and 38 over claims 1, 12, 14, 15, 18, 28 and 36 of copending Application No. 17637349 in view of Keyt (US 20170183409 A1 Date Published 2017-06-29), Zhang (CN 108409840 A Date Published 2018-08-17), Bernett (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO 2018208864 A1 Date Published 2018-11-15) has been withdrawn because the reference application was abandoned.
Claim Objections
Claim 35 objected to because of the following informalities:
Claim 35 appears to be missing the phrase “heavy chain” in line 3 between the phrase “the VH situated amino terminal to an IgM” and “constant region”.
Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 103 (first)
Claim(s) 1, 2, 6, 8, 9, 26, 35, 38 and 67 are rejected under 35 U.S.C. 103 as being unpatentable over Baliga et al. (WO2019169314A1 Date Published 2019-09-06; Priority Date 2019-03-01) in view of Zhang et al. (CN 108409840 A Date Published 2018-08-17) and Bernett et al. (US 20170081424 A1 Date Published 2017-03-23).
Please note that the citations from Zhang et al. below reference positions in the translation attached as an office action appendix.
Baliga et al. teaches an IgM antibody comprising a variant J-chain and/or variant IgM heavy chain constant regions that can confer increased serum half-life upon the antibody (Abstract). Baliga et al. also teaches that the variant J-chain includes one or more single amino acid substitutions, deletions, or insertions relative to a reference J-chain identical to the variant J-chain except for the one or more single amino acid substitutions, deletions, or insertions that can affect serum half-life of the IgM antibody in such a manner that exhibits an increased serum half-life upon administration to a subject animal relative to a reference IgM antibody that is identical except for the one or more single amino acid substitutions, deletions, or insertions in the variant J-chain, and is administered in the same way to the same animal species (paragraph [0008]).
Baliga et al. teaches a modified J-chain comprising a wild-type human J-chain fused at its N-terminus to an scFv that binds to CD3 (paragraphs [0026]] and [0117]). They teach the J-chain of the IgM antibody can comprise an amino acid substitution at the amino acid position corresponding to amino acid Y102 of the mature wild-type human J-chain (SEQ ID NO: 2) wherein Y102 of SEQ ID NO: 2 can be substituted with alanine (paragraph [0111]). They further teach the variant human J-chain can comprise the amino acid sequence of SEQ ID NO: 3 which corresponds to the amino acid sequences having a Y102A substitution on SEQ ID NO: 2 (paragraphs [0111] and [0118]). It is noted that SEQ ID NOs: 2 and 3 as taught by Baliga et al. match 100% to instant SEQ ID NOs: 2 and 3 (alignment not shown).
Baliga et al. teaches an IgM antibody that includes five bivalent antibody binding units and a variant J-chain (paragraph [0008]). Baliga et al. also teaches that each binding unit of the antibody includes two IgM heavy chain constant regions or multimerizing fragments or variants thereof, each associated with an antigen-binding domain (paragraph [0008]). Baliga et al. further teaches that the antigen-binding domain the IgM antibody can be a single-chain Fv (scFv) fragment or the antigen-binding domain subunit of the IgM antibody can be a heavy chain variable region (VH); and the IgM antibody can further include two light chain constant regions each associated with an antigen-binding domain that can be a scFv fragment or the antigen-binding domain subunit can be a light chain variable region (VL) (paragraphs [0015] and [0016]). They also teach that binding unit can further comprise two light chain constant regions (claim 46). Moreover, Baliga et al. teaches that a “full length IgM antibody heavy chain” is a polypeptide that comprises a VH domain situated at the N-terminal to the IgM heavy chain constant domains 1 to 4 (paragraph [0061]). Moreover, Baliga et al. also teaches that a VL chain can be fused to and located at the N-terminal of the antibody light chain constant region (paragraph [0143]).
Baliga et al. teach that pentameric IgM antibodies that bind to CD20 and that comprises a modified human J-chain wherein the modified human J-chain comprises a mature human J-chain mutated at N49A and comprises a heterologous antigen-binding domain that binds to CD3 fused to its N-terminus via a 15-amino acid linker, are able to activate T-cells through the CD3 binding domain to facilitate T-cell-mediated cytotoxicity (paragraphs [0195], [0196] and [0188]). They teach that human IgM heavy chain constant region comprises the amino acid sequence as set forth in SEQ ID NO: 12 (paragraph [0025] and Figure 1A-1B). This amino acid sequence is an exact match to the human IgM constant region comprising instant SEQ ID NO: 22 (see alignment below; top sequence Qy is instant SEQ ID NO: 22, bottom sequence Db is SEQ ID NO: 47 as taught by Keyt et al.).
Alignment of instant SEQ ID NO: 22 (top) with SEQ ID NO: 47 as taught by Baliga et al. (bottom)
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Baliga et al. specifically teaches in Figure 5 the effect of the J-chain Y102A mutation either alone, or in combination with either the IgM heavy chain S401A or E401A mutations, on overall serum half-life of an anti-CD20/anti-CD3 IgM bispecific antibody as compared to an IgG antibody comprising the same anti-CD20 VH and VL binding regions (153 IgG) (paragraph [0029]).
Baliga et al. does not specifically teach the binding molecule comprising a binding unit-associated antigen-binding domain which specifically binds to CD123 and wherein the binding molecule can induce T cell-dependent killing of cells expressing CD123. They also do not specifically teach that the said binding unit-associated antigen-binding domain comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of an antibody having a VH and VL amino acid sequences of instant SEQ ID NO(s): 113 and 114 respectively as recited in instant application claim 26.
However, these deficiencies are made up in the teachings of Zhang et al.
Zhang et al. teaches an anti-CD123 single-chain (scFv) antibody (Abstract). The CD123-scFV-2 of their invention consists of the amino acid sequence shown in SEQ ID NO: 2 (Pg. 4 lines 19-20). Both elected VH and VL amino acid sequences of instant SEQ ID NO(s): 113 and 114 are comprised within SEQ ID NO 2 (length of 247 amino acid residues) taught by Zhang. Instant SEQ ID NO: 113 matches exactly to amino acid residues 1-118 of SEQ ID NO: 2 of Zhang, while instant SEQ ID NO: 114 aligns exactly with amino acid residues 137-247 of SEQ ID NO: 2 of Zhang. Thus, Zhang teaches an anti-CD123 antibody fragment wherein the specific VH and VL amino acid sequences are the amino acid sequence of instant SEQ ID NOs: 113 and 114 respectively.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating a multimeric bispecific binding molecule comprising five bivalent binding units and a modified J-chain wherein the modified J-chain comprises a variant J chain fused to a J chain-associated antigen-binding domain comprising a single-chain Fv (scFv) that specifically binds to CD3,wherein the variant J chain comprises the mature wild-type human J chain having the amino acid sequence set forth in SEQ ID NO: 2 except for an alanine (A) amino acid substitution at amino acid Y102 of SEQ ID NO: 2, wherein this Y102A substitution is SEQ ID NO: 3, wherein each binding unit comprises two antibody heavy chains, each comprising an IgM heavy chain constant region or multimerizing fragment or variant thereof and at least a heavy chain variable region (VH) of a binding unit-associated antigen-binding domain, wherein each binding unit-associated antigen-binding domain is identical and specifically binds to CD20, and wherein the binding molecule can induce T cell-dependent killing of cells as taught by Baliga et al. and wherein the CD20 binding unit as taught by Baliga is substituted with the CD123-binding scFv unit comprising SEQ ID NO: 2 as taught by Zhang et al., because Baliga et al. teaches that said IgM binding molecule comprising a modified J-chain that comprises (i) the amino acid sequence of SEQ ID NO:3, i.e. a Y102A substitution in SEQ ID NO:2; and (ii) an scFv that binds to CD3 that is attached to SEQ ID NO: 3, exhibit an increased serum half-life upon administration to a subject animal relative to a reference IgM that is identical, except for the single amino acid substitutions J-chain when both antibody and reference antibody are administered in the same way to the same animal species, Zhang et al. teaches that CD123 is overexpressed in leukemia stem cells or leukaemia naive cells, and have no or low expression in normal hematopoietic stem cells making CD123 a leukemia-associated antigen that can be used as a specific target for treating acute myeloid leukaemia (AML) (Pg. 3 paragraph third), and further Bernett teaches that anti-CD123×anti-CD3 bispecific antibodies have the ability to co-engage and redirect CD3-expressing cytotoxic T cells to specifically kill target cells that are CD123+, such as human AML cell lines (paragraphs [0005], [0152], [0155], [0166] and [0167]) thereby providing positive therapeutic responses and improvements in hematopoietic malignancies which have unregulated CD123 expression (paragraphs [0384] and [0393])
This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and of (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second)
Claim(s) 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 67 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Baliga et al. (WO2019169314A1 Date Published 2019-09-06; Priority Date 2019-03-01), Zhang et al. (CN 108409840 A Date Published 2018-08-17) and Bernett et al. (US 20170081424 A1 Date Published 2017-03-23) as applied to claims 1, 2, 6, 8, 9, 26, 35, 38 and 67, and further in view of Walker et al. (WO2018208864A1 Date Published 2018-11-15).
The combined teachings of Baliga et al., Zhang et al. and Bernett et al. render obvious instant claims 1, 2, 6, 8, 9, 26, 35, 38 and 67 as discussed above in the first 103 which is incorporated here in its entirety.
Baliga et al., Zhang et al. and Bernett et al. do not specifically teach the binding molecule wherein the J-chain-associated antigen-binding domain comprises an antibody single chain Fv (scFv) fragment that specifically binds to CD 3 comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH complementarity-determining regions VHCDR1, VHCDR2, and VHCDR3 and the VL comprises VL complementarity-determining regions VLCDR1, VLCDR2, and VLCDR3, wherein the VHCDR1, VHCDR2, and VHCDR3 comprise the elected amino acid sequences of instant SEQ ID NOs: 130, 132, and 135 respectively, and the VLCDRI, VLCDR2, and VLCDR3 comprise the elected amino acid sequences of instant SEQ ID NOs: 138, 140, and 142 respectively, and wherein the scFv fragment comprises the elected VH and VL amino acid sequences of instant SEQ ID NO: 119 and 120 respectively.
However, these deficiencies are made up in the teachings of Walker et al.
Walker et al. teaches anti-CD3 binding domains and antibodies comprising said binding domains with desirable T-cell activation and (re)directed target cell killing potency and developability (Abstract). Walker et al. also teaches that antigen-binding domains include antibody fragments that can be single-chain Fv (scFv) antibodies (paragraphs [0122] and [0141]). Walker et al. further teaches SEQ ID NO: 1090 which matches exactly with the elected VH of instant SEQ ID NO: 119. Walker et al. also teaches SEQ ID NO: 346 which matches exactly with the elected VL of instant SEQ ID NO: 120. The elected VHCDR1, VHCDR2, and VHCDR3 amino acid sequences of instant SEQ ID NOs: 130, 132 and 135 respectively, are comprised within SEQ ID NO: 1090 as taught by Walker et al. Correspondingly, the elected VLCDR1, VLCDR2, and VLCDR3 amino acid sequences of instant SEQ ID NOs: 138, 140 and 142 respectively are comprised within SEQ ID NO: 346 as taught by Walker et al.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating a multimeric bispecific binding molecule comprising five bivalent binding units and a modified J-chain wherein the modified J-chain comprises a variant J chain fused to a J chain-associated antigen-binding domain comprising a single-chain Fv (scFv) that specifically binds to CD3, wherein the variant J chain comprises the mature wild-type human J chain having the amino acid sequence set forth in SEQ ID NO: 2 except for an alanine (A) amino acid substitution at amino acid Y102 of SEQ ID NO: 2, wherein this Y102A substitution is SEQ ID NO: 3, wherein each binding unit comprises two antibody heavy chains, each comprising an IgM heavy chain constant region or multimerizing fragment or variant thereof and at least a heavy chain variable region (VH) of a binding unit-associated antigen-binding domain, wherein each binding unit-associated antigen-binding domain is identical, and wherein the binding molecule can induce T cell-dependent killing of cells as taught by Baliga et al., wherein binding unit comprises the CD123-binding scFv unit comprising SEQ ID NO: 2 as taught by Zhang et al., and further the scFv that binds to CD3 as taught by Baliga is substituted with the scFv that binds to CD3 comprising the VH and VL amino acid sequences of SEQ ID NO: 1090 and 346 respectively as taught by Walker et al., because a CD123-binding and CD3-binding bispecific binding molecule with a substituted variant J-chain that comprises SEQ ID NO:3 as taught by Baliga, a CD123-binding unit as taught by Zhang et al. and a CD3-binding scFv as taught by Walker et al. possess advantages that include having: (1) an increased serum half-life via the substituted variant J-chain that comprises SEQ ID NO:3 as taught by Baliga et al., (2) the ability to specifically target AML cells that overexpress CD123 via the CD123-binding unit as taught by Zhang et al. and Bernett et al., and (3) the ability to recruit, activate and redirect T cells via the J chain associated scFv that binds to CD3 for targeted T cell killing of CD123+ cells as taught by Walker et al. and Bernett et al.
This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and of (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third)
Claim(s) 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 41, 67 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Baliga et al. (WO2019169314A1 Date Published 2019-09-06; Priority Date 2019-03-01), Zhang et al. (CN 108409840 A Date Published 2018-08-17), Bernett et al. (US 20170081424 A1 Date Published 2017-03-23) and Walker et al. (WO2018208864A1 Date Published 2018-11-15) as applied to claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 67 and 68, and further in view of Baliga and Ng (WO2018187702A2 Date Published 2018-10-11; Priority Date 2017-07-04).
The combined teachings of Baliga et al., Zhang et al., Bernett et al. and Walker et al. render obvious instant claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 67 and 68 as discussed above in the second 103 which is incorporated here in its entirety.
Baliga et al., Zhang et al., Bernett et al. and Walker et al. do not specifically teach the binding molecule wherein each IgM heavy chain constant region comprises a variant of the amino acid sequence set forth in SEQ ID NO: 22, wherein the variant comprises an amino acid substitution at position P311 and/or at position P313 of SEQ ID NO: 22.
However, these deficiencies are made up in the teachings of Baliga and Ng.
Baliga and Ng teach modified human IgM heavy chain constant regions that include one or more amino acid substitutions, e.g., in the Cμ3 domain, where a modified human IgM antibody comprising the modified IgM constant region and a heavy chain variable region specific for a target antigen exhibits reduced complement-dependent cytotoxicity (CDC) of cells expressing the target antigen relative to a corresponding wild-type human IgM antibody (Abstract). They teach that wild-type human IgM comprises the amino acid sequence as set forth in SEQ ID NO: 1 (paragraph [0005]). They also teach that at least one amino acid substitution can be at position P311 of SEQ ID NO: 1, such that P311 of SEQ ID NO: 1 can be substituted with alanine (P311A), serine (P311S), or glycine (P311G) or (paragraph [0008]). They also teach that at least one amino acid substitution can be at position P313 of SEQ ID NO: 1, e.g., P313 of SEQ ID NO: 1 can be substituted with alanine (P313A), serine (P313S), or glycine (P313G) (paragraph [0009]). They further teach that the P311A substitution of SEQ ID NO: 1 is the modified IgM constant region as set forth in SEQ ID NO: 2; the P313S substitution of SEQ ID NO: 1 is the modified IgM constant region as set forth in SEQ ID NO: 3; and the P311A and P313S substitution of SEQ ID NO: 1 is the modified IgM constant region as set forth in SEQ ID NO: 4. The SEQ ID NO: 1 of Baliga and Ng is an exact match to instant SEQ ID NO: 22 (see alignment below). Therefore, Baliga and Ng teaches substitutions at P311 and/or P313 of instant SEQ ID NO: 22.
Alignment of instant SEQ ID NO: 22 (top sequence) with SEQ ID NO: 1 of Baliga and Ng (bottom sequence)
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating a multimeric bispecific binding molecule as taught by Baliga et al., Zhang et al., Bernett et al. and Walker et al. as described above, wherein the IgM heavy chain constant region comprises a variant of the human IgM amino acid sequence, wherein the variant comprises an amino acid substitution at position P311 and/or at position P313 of SEQ ID NO: 1 as taught by Baliga and Ng, because Baliga and Ng teach that mutations at P311 and P313 of wild type human IgM constant region had reduced complement-dependent cytotoxicity (CDC) activity with an increased EC50 but without having significantly affecting T cell activation, thus making IgM a more desirable immunotherapeutic agent which does not trigger excessive downstream complement components (paragraphs [0002], [0003] and [0145], FIG. 8 and Table 2)
This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and of (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Double Patenting
First NSDP: U.S. Patent No. 10899835B2
Claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 41, 67 and 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 12-13, 15-17 and 18-22 of U.S. Patent No. 10899835B2 (Date of Patent 2021-01-26) in view of Zhang et al. (CN 108409840 A Date Published 2018-08-17), Bernett et al. (US 20170081424 A1 Date Published 2017-03-23), Walker et al. (WO2018208864A1 Date Published 2018-11-15) and Baliga and Ng (WO2018187702A2 Date Published 2018-10-11; Priority Date 2017-07-04).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims are drawn to an IgM antibody with enhanced serum half-life comprising five bivalent antibody binding units and a variant J-chain, wherein each binding unit comprises two IgM heavy chain constant regions, each associated with a heavy chain variable region (VH), wherein the variant J-chain comprises an alanine (A) substitution at a position corresponding to amino acid Y102 of SEQ ID NO: 2, wherein the IgM antibody exhibits an increased serum half-life upon administration to a subject animal relative to a reference IgM antibody that is identical except for the amino acid substitution in the variant J-chain, and is administered in the same way to the same animal species, wherein the IgM heavy chain constant regions are each associated with a heavy chain variable region (VH), wherein each binding unit further comprises two light chain constant regions each associated with a light chain variable region (VL), wherein the variant J-chain further comprises one or more heterologous polypeptides directly or indirectly fused to the variant J-chain via a peptide linker, wherein at least one heterologous polypeptide comprises a binding domain comprising an antibody or antigen-binding fragment thereof that is an scFv that specifically binds to CD3.
Patent specification discloses that each binding unit of an IgM antibody can further include two light chain constant regions each associated with a VL and wherein the VH domain is situated at the N-terminal to the IgM heavy chain constant region and the VL chain is located at the N-terminal of the antibody light chain constant region.
Patent claims differ from the instant claims in that the patent claims do not specifically teach the binding unit-associated antigen binding domain specifically binds to CD123 or comprises specific amino acid sequence for VH and VL domains as recited in instant claims. Patent claims also do not specifically teach the CD3-binding scFv linked to the variant J-chain comprises specific amino acid sequence for the VH and VL domains as recited in instant claims. Patent claims also do not specifically teach the IgM heavy chain constant region is a human IgM constant region comprising amino acid sequence as recited in instant claims, or that the IgM heavy chain constant region comprises a variant amino acid sequence as recited in the instant claims.
However, these deficiencies are made up in the teachings of Zhang et al., Bernett et al., Walker et al. and Baliga and Ng.
The teachings of Zhang et al., Bernett et al., Walker et al. and Baliga and Ng have been discussed above in the 103 rejections above.
It would be obvious to generate the patent IgM antibody construct wherein the patent construct is a multimeric, bispecific binding molecule comprising five bivalent binding units and a modified J-chain wherein the modified J-chain comprises a variant J chain fused to a J chain-associated antigen-binding domain comprising a single-chain Fv (scFv) that specifically binds to CD3, wherein the variant J chain comprises the mature wild-type human J chain having the amino acid sequence set forth in SEQ ID NO: 2 except for an alanine (A) amino acid substitution at amino acid Y102 of instant SEQ ID NO: 2, wherein each binding unit comprises two antibody heavy chains, each comprising an IgM heavy chain constant region or multimerizing fragment or variant thereof and at least a heavy chain variable region (VH) of a binding unit-associated antigen-binding domain as recited by the patent, wherein the binding unit comprises CD123-binding scFv unit comprising SEQ ID NO: 2 as taught by Zhang et al., wherein the scFv that binds to CD3 as recited by the patent is substituted with the CD3-binding scFv comprising the VH and VL amino acid sequences of SEQ ID NO: 1090 and 346 respectively as taught by Walker et al., and wherein further the IgM heavy chain constant region recited by the patent is substituted with the variant IgM amino acid sequence wherein position P311 and/or at position P313 of SEQ ID NO: 1 are substituted with alanine (P311A), serine (P311S), or glycine (P311G) as taught by Baliga and Ng, because the generated binding molecule would have the advantages of: (1) an increased serum half-life via the substituted variant J-chain that comprises a Y102A substitution in the J-chains of SEQ ID NO: 2 as recited by the patent, (2) having the ability to specifically target AML cells that overexpress CD123 via the CD123-binding unit as taught by Zhang et al. and Bernett et al., (3) having the ability to recruit, activate and redirect T cells via the J chain associated scFv that binds to CD3 for targeted T cell killing of CD123+ cells as taught by Walker et al. and Bernett et al., and (4) a reduced complement-dependent cytotoxicity (CDC) activity with an increased EC50 but without significantly affecting T cell activation when either P311 and/or P313 of wild type human IgM constant region are substituted with alanine (P313A), serine (P313S), or glycine (P313G), thus making IgM a more desirable immunotherapeutic agent which does not trigger excessive downstream complement components as taught by Baliga and Ng.
Second NSDP: Copending Application No. 18/261145
Claims 1, 2, 6, 8, 9, 13, 14, 17, 26, 35, 38, 67 and 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over allowed claims 3, 6-9, 11-16, 18 and 28 of copending Application No. 18261145 in view of Baliga et al. (WO2019169314A1 Date Published 2019-09-06; Priority Date 2019-03-01), Zhang et al. (CN 108409840 A Date Published 2018-08-17), Bernett et al. (US 20170081424 A1 Date Published 2017-03-23), Walker et al. (WO2018208864A1 Date Published 2018-11-15) and Baliga and Ng (WO2018187702A2 Date Published 2018-10-11; Priority Date 2017-07-04).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to polynucleotides encoding and methods of producing a multimeric pentameric antibody comprising ten antigen-binding domains that specifically bind to CD123, wherein each binding unit comprises two heavy chains each comprising an IgM heavy chain constant region and a copy of the VH, and further comprises two light chains each comprising a light chain constant region and a copy of the VL, wherein each IgM heavy chain constant region is a human IgM constant region, wherein the pentameric antibody further comprises a J chain, or fragment thereof, or variant thereof, wherein the J-chain is a mature human J-chain comprising the amino acid sequence SEQ ID NO: 7 comprising an amino acid substation at Y102A (SEQ ID NO: 8 which is identical to instant SEQ ID NO: 3), wherein an IgM antibody comprising the variant J-chain J chain exhibits an increased serum half-life upon administration to an animal relative to a reference IgM antibody that is identical except for the amino acid substitution in the J chain, and is administered in the same way to the same animal species, wherein the J-chain is fused to an scFv fragment that binds to CD3.
Copending claims are also drawn to polynucleotides encoding and methods of producing bispecific IgM antibody constructs that bind to human CD123 and human CD3 comprising five bivalent binding units and a modified J chain, wherein each binding unit comprises: two heavy chains and two light chains, each heavy chain comprising a heavy chain variable region (VH) with the amino acid sequence SEQ ID NO: 76 and a human IgM heavy chain constant region, and each light chain comprising a light chain variable region (VL) with the amino acid sequence SEQ ID NO: 79 and a human kappa light chain constant region, and wherein the modified J chain comprises the amino acid sequence SEQ ID NO: 84 (identical to instant SEQ ID NO: 3 variant J-chain).
Copending claims differ from the instant claims in that the copending claims do not specifically teach the binding unit-associated antigen binding domain that specifically binds to CD123 comprises specific amino acid sequence for the VH and VL domains as recited in instant claims. Copending claims also do not specifically teach the CD3-binding scFv linked to the variant J-chain comprises specific amino acid sequence for the VH and VL domains as recited in instant claims. Copending claims also do not specifically teach the IgM heavy chain constant region is a human IgM constant region comprising amino acid sequence as recited in instant claims, or that the IgM heavy chain constant region comprises a variant amino acid sequence as recited in the instant claims.
However, these deficiencies are made up in the teachings of Zhang et al., Bernett et al., Walker et al. and Baliga and Ng.
The teachings of Zhang et al., Bernett et al., Walker et al. and Baliga and Ng have been discussed above in the 103 rejections above.
It would be obvious to generate polynucleotides encompassed by the copending claims to produce an IgM construct that is a multimeric, bispecific binding molecule comprising five bivalent binding units and a modified J-chain wherein the modified J-chain comprises a variant J chain fused to a J chain-associated antigen-binding domain comprising a single-chain Fv (scFv) that specifically binds to CD3,wherein the variant J chain comprises the mature wild-type human J chain having the amino acid sequence set forth in SEQ ID NO: 8 except for an alanine (A) amino acid substitution at amino acid Y102 of SEQ ID NO: 8, wherein each binding unit comprises two antibody heavy chains, each comprising an IgM heavy chain constant region or multimerizing fragment or variant thereof and at least a heavy chain variable region (VH) of a binding unit-associated antigen-binding domain, wherein each binding unit-associated antigen-binding domain specifically binds to CD123 as recited by copending claims, and wherein the CD123-binding unit as recited by copending claims is substituted with the CD123-binding scFv unit comprising SEQ ID NO: 2 as taught by Zhang et al., further wherein the scFv that binds to CD3 as recited by the copending claims is substituted with the CD3-binding scFv comprising the VH and VL amino acid sequences of SEQ ID NO: 1090 and 346 respectively as taught by Walker et al., and even further wherein the IgM heavy chain constant region as recited by the copending claims is substituted with variant IgM amino acid sequence wherein position P311 and/or position P313 of SEQ ID NO: 1 are substituted with alanine (P311A), serine (P311S), or glycine (P311G) as taught by Baliga and Ng, because the generated binding molecule would have the advantages of: (1) an increased serum half-life via the substituted variant J-chain that comprises a Y102A substitution in the J-chains of SEQ ID NO: 8 as recited by the copending claims, (2) having the ability to specifically target AML cells that overexpress CD123 via the CD123-binding unit as taught by Zhang et al. and Bernett et al., (3) having the ability to recruit, activate and redirect T cells via the J chain associated scFv that binds to CD3 for targeted T cell killing of CD123+ cells as taught by Walker et al. and Bernett et al., and (4) a reduced complement-dependent cytotoxicity (CDC) activity with an increased EC50 but without significantly affecting T cell activation when either P311 and/or P313 of wild type human IgM constant region are substituted with alanine (P313A), serine (P313S), or glycine (P313G), thus making IgM a more desirable immunotherapeutic agent which does not trigger excessive downstream complement components as taught by Baliga and Ng.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/YIE CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642