CTNF 18/035,470 CTNF 73509 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Election/Restrictions 08-25 AIA Applicant's election with traverse of Group I and species which is NEG258 (sections (a)-(d) of claim 169) as ABM1 (antigen binding module), CD3-21 (VH/VL SEQ ID NO:172-173) as ABM2 and CD58-6 (SEQ ID NO:327) as ABM3 in the reply filed on 04/20/2026 is acknowledged. The traversal is on the ground(s) that all of Groups I-V require the technical feature of a CD19 binding molecule with the heavy and light chain CDRs of claim 169. While the Examiner stated this does not make a contribution over the prior art in view of US Patent 12,221,481, each claim also requires a two variant IgG1 Fc comprising substitutions L234A, L235A, S267K and P329A. These substitutions are not found in the patent and, therefore, represent a special technical feature over the ’481 patent. As a result, the restriction should be withdrawn . This is not found persuasive because US Patent 12,221,481 does teach these substitutions. For example, it teaches an Fc region ablation mutation can be S267K and/or P329A (col. 515, lines 54-57, and col. 516, lines 5-6 and 32-33). It further teaches that IgG Fc silence mutations, which reduce or eliminate the ability of a CD19 binding molecule to mediate antibody dependent cellular cytotoxicity (ADCC) and/or antibody dependent cellular phagocytosis (ADCP) can be achieved with Fc mutations of LALA: L234A and L235A, and P329A (col. 41, lines 43-56). It is reported that decreasing binding to Fc receptor FcγRIIb (an inhibitory receptor) can be beneficial in some circumstances (col. 44, lines 4-5). It would have been obvious to have any or all of these four mutations in the Fc of the CD19 binding antibody in order to reduce or eliminate Fc effector function, such as ADCC or ADCP for the reasons discussed in the patent. Therefore, neither the technical feature of CD19 binding or the Fc receptor mutations are special technical features because they do not make a contribution over the prior art. Claims 169, species (e)-(h), 171, 178(ii), 184(a)-(e) and (g)-(k), 185, 192(ii), 200-202 and 204-207 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/02/2026 . The requirement is still deemed proper and is therefore made FINAL. Information Disclosure Statement It is noted that US Patent 5,951,893 (Bikko) is entitled: Integrated Circuit Pad Structure with High Temperature Heating Element and Method Therefor. Claim Rejections - 35 USC § 112(b) 07-30-02 AIA The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. 07-34-01 Claims 195, 196 and 198 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 195 is indefinite because it recites “FCV-4”, which is merely a name not well known in the art. If one does not know the metes and bounds of a “FCV-4”, then one cannot know what sequences are 95% identical thereto. The specification lists FCV-4 in Table A as a human IgG1 Fc variant comprising a LALASKPA substitution and having the sequence of SEQ ID NO:1150. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns , 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). See also In re Prater , 415 F.2d 1393, 162 USPQ 541 (CCPA 1969) and In re Winkhaus , 527 F.2d 637, 188 USPQ 129 (CCPA 1975), which discuss the premise that one cannot rely on the specification to impart limitations to the claim that are not recited in the claim. This rejection could be obviated by referring to SEQ ID NO:1150. Claim 196 is indefinite because it is unclear if these substitutions are in addition to the substitutions already required in section (ii) of claim 169. If they are additional, the claim should make that clear. Claim 198 is indefinite because it depends from a canceled claim. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claims 169, 172-184, 186, 188-193, 195, 196,199 and 203 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Independent claim 169, 186 and 192 are drawn to a CD19 binding molecule that comprises CDR-H1 to -H3 and CDR-L1 to -L3 of particular sequences. What the claims do not have is the structural context in which the CDRs are found. This is also true of dependent claims 172-185, 188-191, 193, 195, 196, 199 and 203. For example, there is no requirement that the CDRs be respectively within a variable heavy chain region (VH) and variable light chain region (VL). Further, because the molecule comprises both light and heavy chain CDRs, it cannot be a single domain antibody (SDAB) or a VH only or VL only or VHH domain (see claim 179). There are no working examples of single domain antibodies meeting the limitations of the claims. Additionally, the specification discloses only a CD19 binding site comprising CDRs and CD3 binding site comprising a VH and VL that are binding sites comprising both a VH and VL (see Table 1A, 1B and 12A-C). The CDRs of the CD19 antibody are from antibody “NEG258” ([0046] and Table 1A), which comprises both a VH and VL. The original CD3 antibodies had both VH and VL (see instant [0511] attributing CD3 antibodies to US 2016/0355600, and see paragraphs [0052]-[0058] therein). Even single chain antibodies (scFv), such as CD3 scFv of SEQ ID NO:174, comprise both a VH and VL linked by a peptide. While the T-cell receptor (TCR) complex may be CD3 (claims 172 and 175), and a variety of antibody formats binding CD3 are known, including SDABs, the CD3 binding module in a multispecific binding molecule with the CD19 binding molecule is only supported by written description for a CD3 binding site comprising a VH and VL. For claim 181 that means comprising the recited CDRs. The CD3 binding module is not a monospecific binding molecule, but part of a multispecific binding molecule and the structural context of the different binding domains matters. With the exception of the CD19 and CD3 binding sites comprising both a VH and VL comprising the CDR1-3 sequences referred to in the claims, the skilled artisan cannot immediately envision the detailed chemical structure of the encompassed binding sites and, therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The binding site itself is required. See Fiers v. Revel , 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd ., 18 USPQ2d 1016 (Fed. Cir. 1991). Further, there are non-immunoglobulin scaffolds that are not considered immunoglobulin variable heavy and light chain regions into which CDRs may under some circumstances with further experimentation be placed and are able to bind their target antigen. For example, adnectins, aptamers, avimers and DARPins use non-immunoglobulin scaffolds to present antigen-binding regions. Making these types of antibodies is accomplished generally through screening of libraries with protein variants made by targeted or random mutagenesis of the parent protein or through binding specificity selection using screening display libraries (phage, yeast or RNA; Simeon et al., Protein Cell, 9(1):3–14, 2018, p. 4, col. 2, second paragraph, through p. 6, col. 1, first paragraph). However, as can be seen in Figure 1 of Simeon et al., antigen-binding site presentation in these alternative scaffolds is more complex than merely dropping existing heavy and light chain CDRs into set positions. For an antibody it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework (FR) sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions may dramatically affect antigen-binding function. MacCallum et al. (J. Mol. Biol 262:732, 1996) analyzed a variety of antibodies for their interaction with their antigen and found that although CDR3 of the variable heavy chain dominated the interaction, a number of residues outside the CDRs make antigen contact and residues in the CDR which do not contact antigen are important for backbone conformations (e.g., p. 733, section beginning at the end of col. 1, and p. 735, paragraph bridging cols. 1-2). Similarly, Kunik et al. (PLoS Computational Biology, 8(2): e1002388, 2012, Abstract) found, “Analyzing the predicted contribution of antigen binding residues to the stability of the antibody-antigen complex, we show that residues that fall outside of the traditionally defined CDRs are at least as important to antigen binding as residues within the CDRs, and in some cases, they are even more important energetically.” It is noted that were the claims limited to wherein the CD19 and CD3 binding sites comprised a VH and VL and where appropriate also comprising the recited CDRs, then the binding molecule would reasonably be expected to inherently bind CD18 and CD3 in the context of the claimed binding molecules as supported by the instant disclosure. It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd ., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., In c., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…” However, there is a very limited disclosure of antibodies meeting at least some of the functional limitations of the claims. All the disclosed CD19 binding molecules either have the CDRs of parent antibody NEG258 or NEG218 (Tables 1A and 1B). There is no disclosed structure-function correlation responsible for the specific functional limitation of the claim such that the skilled artisan could readily envision the encompassed species of binding molecules. It does not appear the inventors were in possession of the genus of CD19 binding molecules that specifically bind human CD19, particularly in the context of a multispecific binding molecule as claimed. The only disclosed CD19 binding molecules comprise a VH and VL comprising CDR1-3 of the NEG258 or NEG218 antibody. One skilled in the art could not readily envision a representative diversity of species encompassed nor does the specification support the breadth of the genus of competing antibodies or antigen-binding fragments thereof of the claim. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116) Therefore, only CD19 binding molecules comprising a VH and VL of CDRs1-3 set forth in independent claims 169, 186 and 192, and the CD3 binding site (antigen-binding module) in the context of a multispecific binding molecule comprises a VH and VL, but not the full breadth of the claim, meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115). 07-06 AIA 15-10-15 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. Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-20-02-aia AIA 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 . 07-21-02-aia AIA Claim (s) 169, 170, 172-184, 186-199 and 203 is/are rejected under 35 U.S.C. 103 as being obvious over US Patent 12,221,481 B2 (Granda) in view of Stohl (2009, Curr. Opin. Biotechnol. 20(6):685-691) . The applied reference has a common Applicant and inventors with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). US Patent 12,221,481 B2 (Granda) teaches a CD19 binding molecule specifically binding human CD19 and which comprises the heavy and light chain variable region (VH and VL) CDR1-3 of SEQ ID NO:1-3 and 14-16, respectively, or 4-6 and 17-19, respectively. It discloses trispecific binding molecules (TBMs, e.g., Fig.1G-1J), which bind human CD19 and were able to induce T cell-mediated cytokine release and redirected T cell cytotoxicity by human donor cells (Figs. 12A-C, 9A-P, 10A-10P and 11A-11L and Table). The TBMs contained a CD3 binding domain of CD3-21 (Tables 12A-C, col. 457, lines 52-53) and variant CD58 domain which binds CD2 (col. 346, lines 63-66 and Table 15). For example (Section 8.13.1, beginning col. 418, line 1), the structure of the TBM is in the N-terminal to C-terminal direction, an anti-CD19 heavy chain comprising (i) an anti-CD19 VH domain fused to a constant hIgG1 CH1 domain, (ii) a linker, (iii) an anti-CD3 scFv, (iv) a second linker and (v) a hIgG1 Fc domain containing mutations for a hole to facilitate heterodimerization as well as silencing mutations and a light chain in the N-terminal to C-terminal direction, comprising an anti-CD19 VL domain and a constant human kappa sequence, and also a second half antibody comprising in the N-terminal to C-terminal direction a CD58 disulfide stabilized variant fused to a constant hIgG1 domain containing mutations for a knob to facilitate heterodimerization as well as silencing mutations, including wherein the CD3 binding domain is an scFv. The CD19 binding molecule is claimed as in a pharmaceutical composition with an excipient (Claim 7). It is useful for treatment of diseases and disorders associated with expression of CD19, such as B-cell lymphomas and leukemias (col. 1, lines 31-56). The CD19 binding molecule may be conjugated to PEG in order to prolong serum half-life (col. 281, lines 20-36). It can also or alternatively be conjugated to a therapeutic moiety forming an “antibody-drug conjugate” (ADC) (col. 3, lines 49-55), wherein the drug is cytotoxic or cytostatic and is conjugated by a cleavable or noncleavable linker (col. 286, line 45, through col. 327, line 22). Granda teaches specific TBM “CD3Hi TSP1 H variant” (Table 19C), which comprised the sequence of the CD19 and CD3 binding regions and IgG Fc region of SEQ ID NO:1077 (first half antibody heavy chain Fc; H variant; anti-CD19 Fab is amino acids 1-223 and anti-CD3scFv is amino acids 234-487 of SEQ ID NO:1077) and sequence of CD58 variant (CD2 binding region) and IgG Fc region of SEQ ID NO: 1086 (second half antibody comprising the CD58 variant is amino acids 1-94 of SEQ ID NO:1086) and light chain of SEQ ID NO:759 (comprising the CD19 light chain, identical to instant SEQ ID NO:1110) as shown in Table 19C (see also claim 12). This TBM has the trispecific binding regions that are identical to the instant TBM with the first heavy chain of SEQ ID NO:1127 and second heavy chain of SEQ ID NO:1129 and the light chain of SEQ ID NO:1110 (see Sequence Comparison below), with the exception of the substitutions L234A, L234A, D265A (LALADA) and S267K and N297A in SEQ ID NO:1077 and 1086. The overall structure is that of Fig. 2I. This TBM comprises instant SEQ ID NO:13 (CD19 VH), 26 (CD19 VL), 172-174 (CD3 VH, VL and scFv), 327 (CD58 variant) and 1110 (CD19 LC) and the CDRs thereof. All SEQ ID NOs for sequences are the same between US 12,221,481 and the instant application through SEQ ID NO:327. This includes SEQ ID NO:172, 173, 174, the CD3-21 VH, VL and scFv, respectively, SEQ ID NO:13 and 26, the respective VH and VL of the CD19-binding site (which comprise CDR1-3 of SEQ ID NO:1-3 and 14-16 [combined format numbering] and CDR1-3 of SEQ ID NO:4-6 and 17-19 [Kabat numbering]), and SEQ ID NO:327, the CD58 moiety that binds human CD2. Granda discusses that effector function, which includes Fc receptor-mediated effector function may be involved in autoimmune hypersensitivity teaches (col. 41, lines 43-36), “Fc regions can also be modified to “silence” the effector function, for example, to reduce or eliminate the ability of a CD19 binding molecule to mediate antibody dependent cellular cytotoxicity (ADCC) and/or antibody dependent cellular phagocytosis (ADCP). This can be achieved, for example, by introducing a mutation in an Fc region. Such mutations have been described in the art: LALA and N297A (Strohl, 2009, Curr. Opin. Biotechnol. 20(6):685-691); and D265A (Baudino et al., 2008, J. Immunol. 181: 6664-69; Strohl, supra). Examples of silent Fc IgG1 antibodies comprise the so-called LALA mutant comprising L234A and L235A mutation in the IgG1 Fc amino acid sequence. Another example of a silent IgG1 antibody comprises the D265A mutation.” Fc region variants with decreased FcR binding can be referred to as “FcγR ablation variants” or “FcγR silencing variants” (col. 47, lines 45-47) and include Fc region ablation mutations S267K and/or P329A (col. 515, lines 54-57, and col. 516, lines 5-6 and 32-33). The mutation grouping of D265A/N297A/P329A is taught to reduce Fc receptor binding (col. 46, line 65, through col. 47, line 2). Additionally, Granda teaches the advantage of heterodimerization of Fc regions for stability of heterodimerized molecules, which is particularly useful when the two arms of a multispecific antibody are not the same (col. 50, lines 44-50). It is stated (col. 50, lines 28-32), “Many multispecific molecule formats entail dimerization between two Fc regions that, unlike a native immunoglobulin, are operably linked to non-identical antigen-binding domains (or portions thereof, e.g., a VH or VH-CH1 of a Fab).” This can be accomplished by creating a “hole” in a first and a “knob” in a second CH3 domain. This involves amino acids T366 in one CH3 and T366, L368 and Y407 in the other CH3 (col. 62, lines 19-51). The heterodimerization can be accomplished by introducing a pair of cysteine residues with paired CH3 domains. This can be accomplished with a first CH3 domain comprising a C at 354 (S354C) and also having T366W, and a second CH3 domain comprising Y349C, T366S, L368A and Y407V (col. 63, lines 21-30). Stohl (cited by Granda, supra ) discusses optimization of Fc-mediated effector function of antibodies. It is taught that silencing Fc-mediated effector function can be desirable for therapeutic antibodies in order to reduce the risk of injection site reaction (p. 687, col. 2, third paragraph), reducing inflammatory response to the antibody (p. 688, col. 2, second paragraph), and reduce the risk of cytokine storm (Table 2 and p. 687, col. 2, second paragraph). It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have the TBM “CD3Hi TSP1 H variant”, which comprised the sequence of the binding regions and IgG Fc region of SEQ ID NO:1077 (first half antibody heavy chain Fc (N variant) and second half antibody including binding regions and Fc region of SEQ ID NO:1086 and first half light chain of SEQ ID NO:759 as shown in Table 19C of Granda, with the exception that the first and second Fc regions comprised FcγR silencing variants L234A and L235A and D265A, as well as N297A and S267K as taught by Granda. With these mutations, the first Fc region is identical to instant SEQ ID NO:1127, the second to SEQ ID NO:1129, and the light chain of SEQ ID NO:759 (unmutated) is identical to instant SEQ ID NO:1110. These Fc region mutations were known in the art and had desirable properties for therapeutic antibodies and would have reasonably been expected to successfully silence FcγR binding. It further would have been obvious wherein the CD19 Fab binding site was switched with the CD3 scFv binding site with a reasonable expectation that either binding domain could successfully function in either location with the structure of that location. Because the two arms of the TBM are not the same, in order to increase the likelihood of forming the desired asymmetrical multispecific binding structure, it would have been obvious to introduce heterodimerization-inducing mutations in the Fc CH3, for example, the “knob-into-hole” described by Granda wherein the Fc regions comprised T366W: T366S/L368A/Y407V and/or stabilizing mutations S354C: Y349C to ensure proper heterodimeric pairing of the different arms of the TBM . This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Sequence Comparison Instant SEQ ID NO:1127(Qy) to SEQ ID NO:1077 (Db) of Granda Sequence 1077, US/16877878, Patent No. 12221481 Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWIQWVRQAPGQRLEWMGAVYPGDADTRY 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWIQWVRQAPGQRLEWMGAVYPGDADTRY 60 Qy 61 TQKFQGRVTLTADRSASTAYMELSSLRSEDTAVYYCGRDAGLEYYALDYWGQGTLVTVSS 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 TQKFQGRVTLTADRSASTAYMELSSLRSEDTAVYYCGRDAGLEYYALDYWGQGTLVTVSS 120 Qy 121 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 121 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180 Qy 181 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLVES 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 181 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCGGGGSGGGGSEVQLVES 240 Qy 241 GGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGLEWVGRIRSKYNNYATYYADSVK 300 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 241 GGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGLEWVGRIRSKYNNYATYYADSVK 300 Qy 301 DRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGG 360 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 301 DRFTISRDDSKSTLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSGG 360 Qy 361 GGSGGGGSGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKP 420 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 361 GGSGGGGSGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKP 420 Qy 421 GQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGG 480 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 421 GQAPRGLIGGTNKRAPWTPARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGG 480 Qy 481 GTKLTVLGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKH 540 ||||||||||||||||||||||||| ||||||||||||||||||||||||||||| | | Db 481 GTKLTVLGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSH 540 Qy 541 EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 600 |||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||| Db 541 EDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 600 Qy 601 AAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPE 660 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 601 AAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPE 660 Qy 661 NNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 719 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 661 NNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 719 Instant SEQ ID NO:1129(Qy) to SEQ ID NO:1086 (Db) of Granda Sequence 1086, US/16877878, Patent No. 12221481 Qy 1 SQQIYGVVYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGS 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 SQQIYGVVYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGS 60 Qy 61 LTIYNLTSSDEDEYEMESPNITDTMKFFLYVLESGGGGSDKTHTCPPCPAPEAAGGPSVF 120 |||||||||||||||||||||||||||||||||||||||||||||||||||| |||||| Db 61 LTIYNLTSSDEDEYEMESPNITDTMKFFLYVLESGGGGSDKTHTCPPCPAPELLGGPSVF 120 Qy 121 LFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 180 ||||||||||||||||||||||| | ||||||||||||||||||||||||||||| |||| Db 121 LFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYR 180 Qy 181 VVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCREEMTKN 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 181 VVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCREEMTKN 240 Qy 241 QVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 300 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 241 QVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 300 Qy 301 VFSCSVMHEALHNHYTQKSLSLSPGK 326 |||||||||||||||||||||||||| Db 301 VFSCSVMHEALHNHYTQKSLSLSPGK 326 Double Patenting 08-33 AIA 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 169, 170, 172-184, 186-199 and 203 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 12 of U.S. Patent No. 12/221,481 (‘481) in view US 2019/0367628 A1 (Abujoub). The instant application claims a CD19 binding molecule, including a trispecific binding molecule with antigen-binding module 1 (ABM1) binding CD19 with the same VH and VL comprising the same CDRs (SEQ ID NO: 13 and 26, respectively, corresponding to claims 1-2 of ‘481), ABM2 binding CD3 and comprising the scFv of SEQ ID NO:174, and ABM3 binding CD2 and comprising SEQ ID NO:327 (corresponding to claim 8 of ‘481). The heavy chains and light chain have the sequences of SEQ ID NO:1127, 1129 and 1110 (claim 197), which correspond to SEQ ID NO:1077, 1086 and 759 of ‘481 (claim 12 of ‘481), with the exception of substitutions LALASK and D265A and N297A of the instant Fcs. Both claim a pharmaceutical composition comprising the trispecific CD19 binding molecule and an excipient, as well as the trispecific molecule conjugated to an agent (instant claims 198-199, 203 and claims 6-7). ‘481 does not claim wherein the CD19 binding site is an scFv or wherein the Fc region is modified by LALASKPA substitutions, D265A, N297A or one or more heterodimerizing substitutions of instant claim 196. Abujoub teaches ([0358]) Fc modifications that reduce or silence FcγR, which for some therapeutic applications, “is desirable to reduce or remove the normal binding of an Fc domain to one or more or all of the Fcγ receptors (e.g., FcγR1, FcγRIIa, FcγRIIb, FcγRIIIa) to avoid additional mechanisms of action. That is, for example, in many embodiments, particularly in the use of BBMs that bind CD3 monovalently, it is generally desirable to ablate FcγRIIIa binding to eliminate or significantly reduce ADCC activity…. In some embodiments, both of the Fc regions comprise one or more Fcγ receptor ablation variants. These ablation variants are depicted in Table 5, and each can be independently and optionally included or excluded….” Fc modifications listed in Table 5 include S267K and P329A (end of [0358]). Also in [0288]), Fc silencing mutation LALA (L234A and L123A in the IgG1 Fc region) is described, as well as mutation DAPA (D265A and P329A). Also taught ([0358]) is, “Many multispecific molecule formats entail dimerization between two Fc regions that, unlike a native immunoglobulin, are operably linked to non-identical antigen-binding domains (or portions thereof, e.g., a VH or VH-CH1 of a Fab). Inadequate heterodimerization of two Fc regions to form an Fc domain has always been an obstacle for increasing the yield of desired multispecific molecules and represents challenges for purification.“ “Heterodimerization strategies are used to enhance dimerization of Fc regions operably linked to different ABDs (or portions thereof, e.g., a VH or VH-CH1 of a Fab) and reduce dimerization of Fc regions operably linked to the same ABD or portion thereof. Typically, each Fc region in the Fc heterodimer comprises a CH3 domain of an antibody “ (([0386]) Heterodimerization strategies such as “knobs-into-holes” are set forth in Table 6, including Fc 1 substitutions T366W and S354C and Fc 2 substitutions T366S, L368A,Y407V and Y349C (see No. Fc 2 of Table 6). It would have been obvious to use any combination of these mutations in the Fc region for silencing, i.e. , to decrease or remove FcγR binding activity that could lead to undesirable effects in vivo, such as combining the LALA and DAPA and other beneficial mutations, such as S267K as taught by Abujoub. It further would have been obvious to switch the CD19 Fab and CD3 scFv such that the CD3 binding site was ABM1 and a Fab and the CD19 binding site was ABM2 and a scFv with a reasonable expectation of success. In order to favor proper pairing of the heterodimeric trispecific molecule it would have been obvious to use a heterodimerizing strategy involving Fc CH3 mutation such as the No. Fc 2 strategy taught by Aujoub with a reasonable expectation of success. Claims 169, 170, 172-184, 186-199 and 203 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 121, 122, 124, 126-142, 145, 148-157 of copending Application No.18/035,472 (‘472) Both applications claim a trispecific with antigen-binding module 1 (ABM1) binding CD19 with the same VH and VL comprising the same CDRs (SEQ ID NO: 13 and 26, respectively), ABM2 binding CD3 and comprising the scFv of SEQ ID NO:1281 (CD3hi from Table 9a of ‘472) identical to instant SEQ ID NO:174, and ABM3 binding CD2 and comprising SEQ ID NO:1315 of ‘472 which is identical to instant SEQ ID NO:327. The CD19 binding molecule comprises variant Fc regions forming an Fc heterodimer and comprising substitutions LALAPA or DAPASK (‘472) or LALAPASK (instant). Further the Fc can comprise mutations T366W: T366Y, L368A and Y407V and or S345C: Y349C (claims 140-141 of ‘472 and instant claim 196). It would have been obvious wherein the heterodimeric Fc regions comprised both the LALAPA and DAPASK for increased silencing of the Fc effector function.’472 also claims (136) wherein the CD19 binding molecule is in combination with a BAFF receptor binding molecule, which would have been obvious as an additional therapeutic agent for treatment of a B-cell lymphoma or leukemia (see claims 151 and 156 of ‘472). Therefore, a pharmaceutical composition comprising the CD19 binding molecule and an excipient is obvious. This is a provisional nonstatutory double patenting rejection. 08-37 AIA Claim s 169, 170, 172-184, 186-199 and 203 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-26 of copending Application No. 18/856,230 (‘230) in view of US 2019/0367628 A1 (Abujoub). Both applications claim a trispecific with antigen-binding module 1 (ABM1) binding CD19 with the same VH and VL comprising the same CDRs (instant SEQ ID NO: 13 and 26, respectively), ABM2 binding CD3 and comprising the scFv of instant SEQ ID NO:174, and ABM3 binding CD2 and comprising instant SEQ ID NO:327, which are within the molecule of claim 3 of ‘230 (see also claims 17 and 18 of ‘230), wherein the first polypeptide (anti-CD19 x anti-CD3-Fc) comprises SEQ ID NO:37, the second (light chain) comprises SEQ ID NO:38 and the third (CD58 variant-Fc) comprises SEQ ID NO:39, with the exception that the Fcs of ‘230 do not comprise LALASKPA substitutions (see instant claims). Nor do the claims of ‘230 comprise heterodimerization mutations. Even though the claims of ‘230 are drawn to a method of treating a condition which is non-Hodgkin lymphoma or acute lymphoblastic leukemia by administering the trispecific binding molecule, these claims render obvious the trispecific molecule itself. Further, it may be administered in combination with a CRS therapy (claim 13 of ‘230 and instant claim 203). Abujoub teaches ([0358]) Fc modifications that reduce or silence FcγR, which for some therapeutic applications, “is desirable to reduce or remove the normal binding of an Fc domain to one or more or all of the Fcγ receptors (e.g., FcγR1, FcγRIIa, FcγRIIb, FcγRIIIa) to avoid additional mechanisms of action. That is, for example, in many embodiments, particularly in the use of BBMs that bind CD3 monovalently, it is generally desirable to ablate FcγRIIIa binding to eliminate or significantly reduce ADCC activity…. In some embodiments, both of the Fc regions comprise one or more Fcγ receptor ablation variants. These ablation variants are depicted in Table 5, and each can be independently and optionally included or excluded….” Fc modifications listed in Table 5 include S267K and P329A (end of [0358]). Also in [0288]), Fc silencing mutation LALA (L234A and L123A in the IgG1 Fc region) is described, as well as mutation DAPA (D265A and P329A). Also taught ([0358]) is, “Many multispecific molecule formats entail dimerization between two Fc regions that, unlike a native immunoglobulin, are operably linked to non-identical antigen-binding domains (or portions thereof, e.g., a VH or VH-CH1 of a Fab). Inadequate heterodimerization of two Fc regions to form an Fc domain has always been an obstacle for increasing the yield of desired multispecific molecules and represents challenges for purification.“ “Heterodimerization strategies are used to enhance dimerization of Fc regions operably linked to different ABDs (or portions thereof, e.g., a VH or VH-CH1 of a Fab) and reduce dimerization of Fc regions operably linked to the same ABD or portion thereof. Typically, each Fc region in the Fc heterodimer comprises a CH3 domain of an antibody “ (([0386]) Heterodimerization strategies such as “knobs-into-holes” are set forth in Table 6, including Fc 1 substitutions T366W and S354C and Fc 2 substitutions T366S, L368A,Y407V and Y349C (see No. Fc 2 of Table 6). It would have been obvious to use any combination of these mutations in the Fc region for silencing, i.e. , to decrease or remove FcγR binding activity that could lead to undesirable effects in vivo , such as combining the LALA and DAPA and other beneficial mutations, such as S267K as taught by Abujoub. It further would have been obvious to switch the CD19 Fab and CD3 scFv such that the CD3 binding site was ABM1 and a Fab and the CD19 binding site was ABM2 and a scFv with a reasonable expectation of success. In order to favor proper pairing of the heterodimeric trispecific molecule it would have been obvious to use a heterodimerizing strategy involving Fc CH3 mutation such as the No. Fc 2 strategy taught by Aujoub with a reasonable expectation of success. Since '230 claims a method of treatment, it would have been obvious wherein the trispecific binding molecule was combined with another therapeutic agent or was conjugated to a cytotoxic agent to enhance therapeutic efficacy . This is a provisional nonstatutory double patenting rejection. 08-37 AIA Claim s 169, 170, 172-184, 186-199 and 203 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1, 5, 13, 40, 41, 95, 135, 136, 151, 165, 187-190, 192 and 197 of copending Application No. 18/944,885 (‘885) in view of US 2019/0367628 A1 (Abujoub). Both applications claim a trispecific with antigen-binding module 1 (ABM1) binding CD19 with the same VH and VL comprising the same CDRs (instant SEQ ID NO: 13 and 26, respectively), ABM2 binding CD3 and comprising the scFv of instant SEQ ID NO:174, and ABM3 binding CD2 and comprising instant SEQ ID NO:327, which are within the molecule of claim 187,188 and 190 of ‘885 (see also claims 1, 5 and 13), wherein the first polypeptide (anti-CD19 x anti-CD3-Fc) comprises SEQ ID NO:758 and 1077, the second (light chain) comprises SEQ ID NO:759 and the third (CD58 variant-Fc) comprises SEQ ID NO:760 and 1086 (these correspond to all instant claims, with the exception of substitutions LALASK and D265A and N297A of the instant Fcs. Claim 192 of ‘885 is drawn to a combination comprising the trispecific molecule and a least one additional therapeutic agent (instant claim 198 and 203). Claim 135 of ‘885 is drawn to a pharmaceutical composition comprising the CD19 binding molecule of claim 1 and an excipient, while claim 95 is drawn to a conjugate comprising the binding molecule and an agent, corresponding to instant claims 198, 199 and 203. Claim 197 of ‘885 is drawn to a method of treating a CD19-associated disease or condition by administering the trispecific binding molecule render obvious the trispecific molecule itself. Abujoub teaches ([0358]) Fc modifications that reduce or silence FcγR, which for some therapeutic applications, “is desirable to reduce or remove the normal binding of an Fc domain to one or more or all of the Fcγ receptors (e.g., FcγR1, FcγRIIa, FcγRIIb, FcγRIIIa) to avoid additional mechanisms of action. That is, for example, in many embodiments, particularly in the use of BBMs that bind CD3 monovalently, it is generally desirable to ablate FcγRIIIa binding to eliminate or significantly reduce ADCC activity…. In some embodiments, both of the Fc regions comprise one or more Fcγ receptor ablation variants. These ablation variants are depicted in Table 5, and each can be independently and optionally included or excluded….” Fc modifications listed in Table 5 include S267K and P329A (end of [0358]). Also in [0288]), Fc silencing mutation LALA (L234A and L123A in the IgG1 Fc region) is described, as well as mutation DAPA (D265A and P329A). Also taught ([0358]) is, “Many multispecific molecule formats entail dimerization between two Fc regions that, unlike a native immunoglobulin, are operably linked to non-identical antigen-binding domains (or portions thereof, e.g., a VH or VH-CH1 of a Fab). Inadequate heterodimerization of two Fc regions to form an Fc domain has always been an obstacle for increasing the yield of desired multispecific molecules and represents challenges for purification.“ “Heterodimerization strategies are used to enhance dimerization of Fc regions operably linked to different ABDs (or portions thereof, e.g., a VH or VH-CH1 of a Fab) and reduce dimerization of Fc regions operably linked to the same ABD or portion thereof. Typically, each Fc region in the Fc heterodimer comprises a CH3 domain of an antibody “ ([0386]) Heterodimerization strategies such as “knobs-into-holes” are set forth in Table 6, including Fc 1 substitutions T366W and S354C and Fc 2 substitutions T366S, L368A,Y407V and Y349C (see No. Fc 2 of Table 6). It would have been obvious to use any combination of these mutations in the Fc region for silencing, i.e. , to decrease or remove FcγR binding activity that could lead to undesirable effects in vivo , such as combining the LALA and DAPA and other beneficial mutations, such as S267K as taught by Abujoub. It further would have been obvious to switch the CD19 Fab and CD3 scFv such that the CD3 binding site was ABM1 and a Fab and the CD19 binding site was ABM2 and a scFv with a reasonable expectation of success. In order to favor proper pairing of the heterodimeric trispecific molecule it would have been obvious to use a heterodimerizing strategy involving Fc CH3 mutation such as the Fc 2 strategy taught by Aujoub with a reasonable expectation of success . This is a provisional nonstatutory double patenting rejection. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600. Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice . Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. Claire Kaufman /Claire Kaufman/ Primary Examiner, Art Unit 1674 June 12, 2026 Application/Control Number: 18/035,470 Page 2 Art Unit: 1674 Application/Control Number: 18/035,470 Page 3 Art Unit: 1674
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