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 .
Terminal Disclaimer
The terminal disclaimer filed on 6/10/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Patents 12,275,791, 12,264,200, 11,834,506, 11,884,732, 11,884,733, 11,939,384, 12,129,300, 12,157,771 and 12,215,157 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Response to Amendment
Claim 40 has been canceled and, therefore, rejections of it are moot.
The rejection of claims 21, 42 and dependent claims 29-33, 39, 41 and 43 are rejected under 35 U.S.C. 112(b) are withdraw in view of the amendment to claim 21 specifying the claimed cell is “cultured in vitro”, and to claim 42 specifying the amino acid sequence “additionally” differs.
The rejection of claims 21, 29-33 and 39, 41-43 under 35 U.S.C. 112(a) as lacking enablement is withdrawn in view of the amendment to claim 21 specifying the claimed cell is “cultured in vitro”.
The rejection of claims 21, 29-33 and 39 under 35 U.S.C. 112(a) as lacking written description is withdrawn in view of the amendment to claim 21 specifying the first and second Fc domains are each of human IgG1 isotype.
The provisional rejections on the ground of nonstatutory double patenting over claims of, separately, applications 16/615,261 and 17/265,879 are withdrawn in view of their abandonment.
The rejections on the ground of nonstatutory double patenting over claims of US Patents 12,275,791 (issuing from application 17/265,876), 12,264,200 (issuing from application 18/501,427), 11,834,506, 11,884,732, 11,884,733, 11,939,384, 12,129,300, 12,157,771 and 12,215,157 are withdrawn in view of the accepted terminal disclaimer.
Declaration
The Declarations under 37 CFR 1.132 filed 6/10/2025 are insufficient to overcome the rejection of claims 21, 29-33, 39 and 41-43 based upon 35 U.S.C. 103 as being unpatentable over US 20170368169 A1 (Loew) in view of WO 2016/207273 (Gauthier), US Patent 9,963,513 B2 (Vu) and US Patent 9,951,145 B2 (Kim) as set forth in the last Office action and below because:
The Declarations of Drs. Lanier and Joshi are directed to Application 16/483,330 and the issues therein. Of particular note is the requirement in the allowed claims of that application, now US Patent 11,834,566 (see claim 1), that the first antigen-binding site binds and activates human NKG2D, and the orientation of the multi-specific binding protein is further defined as having the first antigen-binding site linked to the N-terminus of the first antibody Fc domain, and the second antigen-binding site linked to the N-terminus of the second antibody Fc domain. These limitations are not found in the instant claims. Additionally, the Declaration of Dr. Lanier is directed to a 35 USC 103 rejection based on obviousness of claims over WO 2016/207273 (Gauthier), US 2004/038339 (Kufer) and Cho (Canc. Res., 2010). Instead, the instant rejection relies on US 2017/0368169 (Loew) in view of Gauthier, US Patent 9,963,513 B2 and US Patent 9,951,145 B2 (Kim).
In the Declaration of Dr. Lanier, expert opinions are shared. It is stated in ⁋ 5 the multi-specific binding protein of the invention brings together three elements that optimize “engagement of NK cells or T cells and direct them against tumors to achieve a therapeutic purpose. The construct provides synergist signaling between NKG2D and CD16 receptors expressed on NK cells or T cells and bridges the effector cells to tumor cells for elimination.” In ⁋6 Gauthier is discussed as focusing on a CD19-/NKp46-binding construct, which resulted in NK cell-mediated killing of B cells expressing CD19. In ⁋7, the difference in NKp46 and NKG2D pathways are discussed. Even though both are receptors expressed on NK cells, “NKp46 receptor transmits its signal by its noncovalent association with either the CD3ζ or FcεR1γ adaptor protein…. By contrast, NKG2D associates with a DAP10 adaptor protein to transmit signals.” Simultaneously activating multiple signaling pathways in the same cell leads to unpredictable effects (⁋6). One skilled in the art would not have expected the same results replacing NKG2D in Gauthier (⁋9). Gauthier provides an apparent laundry list of immune cell receptors with diverse actions, e.g., CD137, CD3, NKp30, as well as NKG2D and NKp46, some of which have different expression patterns after activation (NK vs. T cells, ⁋10). The Declaration as it relates to Gauthier has been considered and is not persuasive. It is acknowledged that NKp46 and NKG2D use different signaling pathways when the receptor is activated. Instant claim 1 does not require the NKG2D receptor to be activated but only bound. Loew teaches immune and tumor cell engaging proteins that have an Fc domain. It is taught (top of p. 33 of previous Office action), “It is further noted in [0669] that, “NKG2D is a receptor that provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity.... CD16 is a receptor for the Fc region of IgG, which binds complexed or aggregated IgG and also monomeric IgG and thereby mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis.” Multispecific antibodies in a number of configurations are taught….” One of ordinary skill in the art would have reasonably expected the Fc domain to bind CD16. Loew further describes (middle of p. 33 of previous Office action) the expectation of increased immune response against cancer cells expressing a tumor associated antigen (TAA) as, “([0004]): “Increasing the proximity and/or activity of the immune cell using the multispecific molecules described herein is expected to enhance an immune response against the cancer cell, thereby providing a more effective cancer therapy. Without being bound by theory, a targeted, localized immune response against the cancer cell is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein.”” On the basis of binding both NKG2D and a TAA, there would have been a reasonable expectation of enhanced NK cell killing of the TAA-expressing cell. As stated in [0669], “NKG2D is a receptor that provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity.” The instant claims do not require any level of activity. The prior art provides motivation to combine NKG2D and a TAA in a trispecific format wherein an IgG Fc region binds CD16. This is further supported by Gauthier teaching (end pf p. 15 of previous Office action), “…(p. 3, lines 6-13) “a multispecific protein comprising (i) a first antigen binding domain that binds to an activating receptor on an immune cell (e.g. effector cell), optionally an activating NK receptor... selected from a NKp46, NKp30, NKp44, CD137, CD3, CD8 and NKG2D polypeptide, (ii) a second antigen binding domain that binds to an antigen of interest expressed by a target cell, and a dimeric Fc domain that ... binds human CD16A.” Binding to human NKG2D is also disclosed to activate immune effector cell receptors (e.g., p. 7, lines 14-15).” The second antigen may be a TAA, including BCMA (p. 35, end of first paragraph, of previous Office action). The remaining two references relied upon support the use of multi-specific BCMA-binding proteins and Fc mutations to facilitate heterodimerization. The references are not relied upon alone but in combination. Further, as discussed in MPEP 716.02(d) (see In re Clements, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”” As noted above, the instant claims do not require activation of NKG2D on an NK or T cell or structure beyond comprising two antigen binding sites and heterodimerized human IgG1 Fc domains that bind CD16. The only activity required is antigen binding. No degree or specificity of binding is required. It is maintained the prior art provides both motivation to make the claimed multi-specific binding protein and provides a reasonable expectation of at the minimum trispecific binding (NKG2D, BCMA and CD16), as well as bringing NK cells into proximity with TAA-expressing cancer cells to facilitate their killing.
The discussion of Kufer and Cho (paragraphs 11-13) is not pertinent to the rejection in the instant application.
In the Declaration of Dr.Joshi, expert opinions are shared. It is stated in ⁋7 that instant Fig. 66 of the 16/483,330 application, reproduced in ⁋8 of the instant Declaration shows in the assay used but not described, that neither the HER2-TRINKET-D265, which has no CD16 binding, nor trastuzumab, which binds HER2 and CD16 but not NKG2D, alone or together, had significant cell lysis compared to the HER2-TRINKET. “This is significant because it shows the synergistic effect requires that all three functions (NKG2D-binding, CD16-binding, and binding to a tumor-associated antigen) be in the same molecule…. The synergy is presumably specific to the NKG2D and CD16 molecules and requires bringing those receptors into close proximity.” (See also ⁋10.) This discussion has been fully considered, but is not persuasive because not only do the claims not require synergy, but the NKG2D binding site is not required to produce NKG2D-mediated signaling. That is, unlike the TriNKET, the first binding site is required only to bind human NKG2D but not to activate it. The scope of the multi-specific binding protein for which the results are shown in the Declaration is much narrower than that of the instant claims. Additionally, the TriNKET data relied upon [ADI-29404 (F04) and a HER2 binding domain, Example 17 of US 11,834,506 and instant application] reasonably appears to have the form of an IgG1 Fc domain at the N-terminal of which is at least one NKG2D binding and HER2 binding domain (see Figures). No such structure is required for the instant multi-specific binding protein.
In ⁋⁋8-9 it is discussed that the lysis assays of Gauthier used Daubi cells (Fig. 8) which when activated with NKp46 and CD16, both of which signal through FcεR1γ, would not surprisingly show enhanced signaling compared with either alone and would increase CD137 expression. This CD137 upregulation on NK cells may be mediated by the dual NKp46 and CD16 targeting as discussed by Gauthier. Daubi cells are known to express the ligand of CD137 and “upregulation of CD137 alone would not increase NK cell function unless its ligand was present on the target cell (Figs. 1B and 1C at the end of ⁋8 of the Declaration). Joshi states that replacement of the NKp46-binding site with a different NK receptor binding site would not have been expected to have the same effect because CD137 expression would not have been the same. This discussion has been fully considered, but is not persuasive because not only do the claims require only a multi-specific binding protein that binds NKG2D, BCMA and CD16, the prior art supports enhancement of target cell killing when a NK cell is brought into proximity with a target cell, i.e., by a multi-specific protein that binds both the NK and target cell. Further, Gauthier was not relied upon in isolation. Loew as discussed in the rejection provided motivation to make a multi-specific NKG2D-TAA-CD16-binding protein and a reasonable expectation of cell lysis upon introduction of said protein in the presence of NK and TAA-expressing cells, particularly in view of Gauthier.
In ⁋11 Gauthier is discussed as providing a list of diverse immune cell receptors with diverse actions, e.g., CD137, CD3, NKp30, as well as NKG2D and NKp46. There would have been no reason to believe that one receptor could be substituted for another. This opinion has been considered and is not persuasive. It is acknowledged that NKp46 and NKG2D use different signaling pathways when the receptor is activated. Instant claim 1 does not require the NKG2D receptor to be activated but only bound. Loew teaches immune and tumor cell engaging proteins that have an Fc domain. It is taught (top of p. 33 of previous Office action), “It is further noted in [0669] that, “NKG2D is a receptor that provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity.... CD16 is a receptor for the Fc region of IgG, which binds complexed or aggregated IgG and also monomeric IgG and thereby mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody- dependent responses, such as phagocytosis.” As discussed in the middle of p. 33 of the previous Office action quoting Loew, “The theory of function of a multispecific molecule that binds a NK cell and a tumor cell is described as being that the molecule will target the immune cell (NK) to the cancer cell ([0004]): “Increasing the proximity and/or activity of the immune cell using the multispecific molecules described herein is expected to enhance an immune response against the cancer cell, thereby providing a more effective cancer therapy. Without being bound by theory, a targeted, localized immune response against the cancer cell is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein.”” It is maintained that the artisan of ordinary skill would have been motivated to have an NKG2D-binding/TAA-binding/CD16-binding protein for the reasons explained in Loew, and there would have been a reasonable expectation of them functioning also as explained by Loew in view of the prior art relied upon.
The discussion of Kufer and Cho (paragraphs 12-16) is not pertinent to the rejection in the instant application.
Joshi sets forth in ⁋17 “that TriNKETs are more effective than antibody fusion proteins with natural ligands of NKG2D, referring to the Chang Declaration and addressing the Cho reference. In response, the Cho reference was not relied upon in the rejection under 35 USC 103. No declaration by Chang has been submitted.
NEW:
Claim Rejections - 35 USC § 112(b)
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.
Claim 41 and dependent claim 42 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 41 is dependent on cancelled claim 40. As a result there is insufficient antecedent for the limitations in claim 41. Because the limitation from claim 40 was added to claim 21, it appears claim 41 may have been intended to now depend from claim 21.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 21, 29-33, 39 and 41-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending applications as follows:
Application # Title
^16/484,936 PROTEINS BINDING BCMA, NKG2D AND CD16
16/486,921 PROTEINS BINDING CD33, NKG2D AND CD16
16/615,261 PROTEINS BINDING NKG2D, CD16 AND A TUMOR-ASSOCIATED ANTIGEN (CD19 is the target of the second antigen-binding site)
*16/967,218 COMBINATION THERAPY OF CANCER INVOLVING MULTI-SPECIFIC BINDING PROTEINS THAT ACTIVATE NATURAL KILLER CELLS
17/055,792 PROTEIN BINDING NKG2D, CD16 AND A FIBROBLAST ACTIVATION PROTEIN
*17/058,335 MULTI-SPECIFIC BINDING PROTEINS AND IMPROVEMENTS THEREON
17/095,238 MULTISPECIFIC BINDING PROTEINS TARGETING CAIX, ANO1, MESOTHELIN, TROP2, OR CLAUDIN-18.2 (TROP2 is the target of the second antigen-binding site)
^17/266,349 MULTI-SPECIFIC BINDING PROTEINS THAT BIND BCMA, NKG2D AND CD16, AND METHODS OF USE (this application has been allowed)
@17/266,966 PROTEINS BINDING NKG2D, CD16 AND A TUMOR-ASSOCIATED ANTIGEN ) (cMET is the target of the second antigen-binding site)
17/682,367 PHARMACEUTICAL FORMULATIONS AND DOSAGE REGIMENS FOR MULTI-SPECIFIC BINDING PROTEINS THAT BIND HER2, NKG2D, AND CD16 FOR CANCER TREATMENT
@17/686,238 METHODS OF TREATING CANCER USING MULTI-SPECIFIC BINDING PROTEINS THAT BIND NKG2D, CD16 AND A TUMOR-ASSOCIATED ANTIGEN (HER2 is the target of the second antigen-binding site)
17/769,160 PROTEINS BINDING NKG2D, CD16 AND FLT3
18/003,308 PROTEINS BINDING NKG2D, CD16 AND EGFR
18/107,292 MULTISPECIFIC BINDING PROTEINS TARGETING CEA
18/108,961 PROTEINS BINDING NKG2D, CD16 AND NECTIN4
18/177,847 METHODS OF TREATING CANCER USING MULTI-SPECIFIC BINDING PROTEINS THAT BIND NKG2D, CD16, AND HER2
18/304,652 PROTEINS BINDING CD123, NKG2D AND CD16
18/366,876 PROTEINS BINDING NKG2D, CD16, AND CEACAM5
*Generic claims to protein comprising (a), (b) and (c) and/or method of treating cancer therewith.
^ Claims wherein the second antigen-binding site includes wherein the antigen may be BCMA.
@ The application has been allowed, but not yet issued. When it issues, the rejection will no longer be provisional.
Provisional Rejections:
Claims 21, 29-33, 39 and 41-43 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Applications listed above in view of US 2017/0368169 (Loew) and US 9,951,145 B2 (Kim) for the reasons set forth in the previous Office action.
[N.b., Kim is only necessary for those copending application or patents cited above which do not claim wherein the Fc domains differ by having one domain of the Fc pair comprise K360E and K409W substitutions and the other comprise Q347R, D399V and F405T substitutions.]
The instant claims are drawn to a cell comprising one or more nucleic acids encoding a multi-specific binding protein comprising (a) a first antigen-0binding site that binds human NKG2D; (b) a second antigen-binding site that binds a tumor-associated antigen (TAA); and (c) a first antibody Fc domain and second antibody Fc domain that together are sufficient to bind human CD16, wherein the first and second antibody Fc domains comprise different amino acid mutations to promote heterodimerization (independent claim 21). Claim 29 specifies first antigen-binding site binds human or non-human primate NKG2D. Claims 30-34 recite that first (a) and/or second (b) antigen-binding site comprises a variably heavy chain domain (VH) and variable light chain domain (VL), with claim 31 further specifying the (a) VH and VL of the first binding site are on the same polypeptide. Claim 39 limits (a) to being linked to the N-terminus of the first antibody Fc domain and (b) to being linked to the N-terminus of the second antibody Fc domain. Claims 40-42 limit the Fc domain to human IgG1, and further to comprising one Fc domain with K360/K409W and the other with W347R/D299V/F405T (claim 41) and/or with S354C and with Y349C (claim 42, see rejection under 35 USC 112(b) below) numbered according to EU index as in Kabat. Claim 43 specifies the multi-specific binding protein is capable of binding the TAA on a cancer cell and NKG2D and human CD16 on a natural killer (NK) cell to activate the NK cell.
All applications recite a protein and/or methods of treating cancer by administration of the protein, wherein the protein comprises (a) a first antigen-binding site that binds NKG2D, (b) a second antigen-binding site that binds generically a tumor-associated antigen (*) or a specific tumor associated antigen, and (c) an antibody Fc domain or a portion thereof sufficient to bind CD16, or a third antigen-binding site that binds CD16. For those copending applications which recite specific NKG2D-binding site sequences species for (a) and/or specific TAA-binding site species for (b) in one or more claims, then those claimed species anticipate the respective instant generic (a) and/or (b) binding sites. Those applications in the list designated with a “*” have at least one claim in which (b) recites binding generically to a TAA, and the application with “^” recites at least one claim in which (b) may be BCMA. The copending applications do not claim a cell comprising one or more nucleic acids encoding the multi-specific binding protein.
Loew teaches multispecific antibodies that engage immune cells and tumor cells, wherein the immune cell is a NK cell, including wherein the antibody comprises antigen-binding domains that bind to NKG2D and CD16 ([0102]), and wherein the construct has a Fc domain ([002] and [0033]-[0035]). Further, it is taught that the multispecific antibody binds a cancer/tumor cell, including one expressing a hematological antigen. There are 12 cancer antigens designated as hematological antigens, of which BCMA is one (end of [0099]). The multispecific antibody can treat cancer, including hematological cancer (claim 182). Cancers that can be targeted with the multispecific protein include multiple myeloma ([0098] and [0645]). Multiple myeloma is a hematological cancer ([1172]). Methods of using the multispecific antibody to treat cancer are disclosed ([0266]-[0268]). It is taught that NKG2D is a receptor that acts both in a stimulatory and costimulatory manner in innate immune responses on activated NK cells, leading to cytotoxic activity ([0669]). Paragraph [0102] lists 27 targets for NK cell engagers which can be a ligand or antigen-binding domain, including NKG2D and CD16 as targets. It is further noted in [0669] that, “NKG2D is a receptor that provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity.... CD16 is a receptor for the Fc region of IgG, which binds complexed or aggregated IgG and also monomeric IgG and thereby mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody- dependent responses, such as phagocytosis.” Multispecific antibodies in a number of configurations are taught, including wherein the first (NKG2D) or second (BCMA) antigen-binding site heavy chain variable domain (VH) and light chain variable domain (VL) are present on the same polypeptide (e.g., Fig. 7). Additionally, first and second Fc domains are taught comprising different amino acid mutations that promote heterodimerization, e.g., “knob- in-hole” as shown in Figs. 5A and 7, including wherein the first antigen-binding site has the light and heavy variable domain on the same polypeptide (e.g., an ScFv as shown in Fig. 12). The “knob” has an Fc CH3 domain mutation at one or more amino acids and the “hole” has an Fc CH3 domain mutation at one or more different amino acids specifically of human IgG1 ([0481]-[0482], see also [0485]-[0489]), for example, wherein the “knob” mutation is S354C and the “hole” is Y349C ([0489]). All experiments were performed by transfecting cells with nucleic acids encoding the proteins making up the multi-specific binding protein (e.g., [1210]). Recombinant production of the multispecific antibody comprises culturing a host cell comprising one or more nucleic acids encoding the multispecific antibody (e.g., claims 178-180 and [1166]-[1167]). An example of an NK-binding, TAA-binding multispecific molecule is set forth in Example 3, describing the NK cell engager as an NKp30-binding site, and a tumor-associated antigen-binding site as a mesothelin targeting arm. This construct had cell-killing activity and induced release of IFNγ ([1210]). The theory of function of a multispecific molecule that binds a NK cell and a tumor cell is described as being that the molecule will target the immune cell (NK) to the cancer cell ([0004]): “Increasing the proximity and/or activity of the immune cell using the multispecific molecules described herein is expected to enhance an immune response against the cancer cell, thereby providing a more effective cancer therapy. Without being bound by theory, a targeted, localized immune response against the cancer cell is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein.” Pharmaceutical compositions comprising a multispecific antibody and a pharmaceutically acceptable carrier are set forth ([(0264]). Antibodies of the invention may be primate, e.g., monkey ([00445]).
Kim makes obvious those copending applications claim wherein the Fc domains differ by having one domain of the Fc pair comprise K360E and K409W substitutions and the other comprise Q347R, D399V and F405T substitutions. Fc pairs comprising these mutations would have been obvious in view of the desirability of favoring heterodimeric Fc pairing in view of Kim, which teaches Fc CH3 domain variant pairs that induce formation of heterodimeric heavy chain constant regions (Fc regions) to favor desired antigen-binding arm combinations in a single molecule. Specifically, claims 1-3 of Kim recite wherein a first CH3 domain comprises K360E and K409W and the second CH3 domain comprises Q347R, D399V and F405T according to the EU index (see also Fig. 11 “EW-RVT variant pair”). The substitutions may be in human IgG1, the wildtype sequence of which is shown in Fig. 10. Fig. 9 shows different multi-specific constructs comprising the heterodimeric Fc domains, including wherein the VH and VL are on the same polypeptide (scFab or scFv). All experiments were conducted with human antibody IgG1 (col. 20, lines 5-7). As stated in col. 27, lines 61-67, “As a result, it can be understood that the Fc dimer including the CH3 domain into which the EW-RVT mutation pair is introduced has the same mean residue ellipticity as the Fc dimer including the wild type CH3 domain. This indicates that there is no change in the secondary structure of the protein even when the mutation pair is introduced (FIG. 20).” Kim states (col. 6, lines 25-34), “In a CH3 domain heterodimer of a heavy chain constant region of an antibody according to the present invention, a mutation is induced using a method different from the conventional method, formation of the homodimer is minimized, and the heterodimer can be formed at a high yield of 90 to 95% or more. When a heterodimeric Fc pair protein prepared using the CH3 domain heterodimer is expressed in animal cells, the protein has an expression level, a production yield and a thermodynamic stability that are similar to or more improved than an original wild type antibody.” Claim 16 of Kim is drawn to a method of preparing a heterodimeric Fc pair protein comprising transforming a host cell with an expression vector encoding the heterodimeric Fc pair protein, culturing the host cell, and purifying and recovering the heterodimeric Fc pair protein.
It would have been obvious wherein the multi-specific binding protein of the copending applications was recombinantly produced by a cell comprising one or more nucleic acids encoding the multi-specific binding protein because both Loew and Kim successfully used that method to produce multi-specific proteins, including having heterodimeric Fc regions such as the knob-into-hole substitutions taught by Loew and/or EW-RVT substitutions taught by Kim. Kim supports thermodynamic stability of heterodimeric Fc substituted domains and heterodimerization can increase the prevalence of desired antigen-binding arm pairing. It would have reasonably been expected that the multi-specific binding protein would inherently have been capable of binding a cancer cell expressing the TAA and an NK cell via the NKG2D antigen-binding site and CD16-binding Fc domains as supported by Loew. It further would have been obvious wherein the TAA was BCMA because as taught by Loew, antibodies binding it were known and the antigen was expressed on cancer cells.
These are provisional nonstatutory double patenting rejections.
Even though the instant application’s elected species of (b) is the second antigen-binding site wherein the TAA is BCMA, instant claim 21 is currently generic with respect to (b). Were (b) to be limited to BCMA as the TAA, the double patenting rejections would be removed for all copending applications except i) 17/266,349 and 16/484,936, which designate (b) as binding BCMA, and ii) copending applications designated with “ * “ above.
Applicant argues (section spanning pp. 8-9 of Remarks) that the provisional non-statutory rejections over the copending applications should be withdrawn in accordance with MPEP 804.I.B.1(b) wherein those rejections are the only remaining, because the instant application has an earlier patent term filing date. The argument has been fully considered, but is not persuasive. These provisional rejections are not the only remaining. Were they, then the provisional non-statutory double patenting rejections would be withdrawn for the reasons Applicant discusses.
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 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
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21, 29-33, 39 and 41-43 remain rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0368169 A1 (Loew) in view of WO 2016/207273, US Patent 9,963,513 B2 (Vu,) and US Patent US 9,951,145 B2 (Kim), all of which references are cited in the IDS filed 2/13/2024 for the reasons set forth in the previous Office action.
Loew teaches multispecific antibodies that engage immune cells and tumor cells, wherein the immune cell is a NK cell, including wherein the antibody comprises antigen-binding domains that bind to NKG2D and CD16 ([0102]), and wherein the construct has a Fc domain ([002] and [0033]-[0035]). Further, it is taught that the multispecific antibody binds a cancer/tumor cell, including one expressing a hematological antigen. There are 12 cancer antigens designated as hematological antigens, of which BCMA is one (end of [0099]). The multispecific antibody can treat cancer, including hematological cancer (claim 182). Cancers that can be targeted with the multispecific protein include multiple myeloma ([0098] and [0645]). Multiple myeloma is a hematological cancer ([1172]). Methods of using the multispecific antibody to treat cancer are disclosed ([0266]-[0268]). It is taught that NKG2D is a receptor that acts both in a stimulatory and costimulatory manner in innate immune responses on activated NK cells, leading to cytotoxic activity ([0669]). Paragraph [0102] lists 27 targets for NK cell engagers which can be a ligand or antigen-binding domain, including NKG2D and CD16 as targets. It is further noted in [0669] that, “NKG2D is a receptor that provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity…. CD16 is a receptor for the Fc region of IgG, which binds complexed or aggregated IgG and also monomeric IgG and thereby mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis.” Multispecific antibodies in a number of configurations are taught, including wherein the first (NKG2D) antigen-binding site heavy chain variable domain (VH) and light chain variable domain (VL) are present on the same polypeptide, including wherein each binding site is linked to the N-terminal of the Fc regions (e.g., Fig. 7). Additionally, first and second IgG Fc domains are taught as comprising different amino acid mutations that promote heterodimerization, e.g., “knob-in-hole” as shown in Fig. 5A and 7. The “knob” has an Fc CH3 domain mutation at one or more amino acids and the “hole” has an Fc CH3 domain mutation at one or more different amino acids specifically of human IgG1 ([0481]-[0482], see also [0485]-[0489]), for example, wherein the “knob” mutation is S354C and the “hole” is Y349C ([0489]). An example of an NK-binding, TAA-binding multispecific molecule is set forth in Example 3, describing the NK cell engager as an NKp30-binding site and the tumor-associated antigen-binding site as a mesothelin-targeting arm. This construct had cell-killing activity and induced release of IFNγ ([1210]). The theory of function of a multispecific molecule that binds a NK cell and a tumor cell is described as being that the molecule will target the immune cell (NK) to the cancer cell ([0004]): “Increasing the proximity and/or activity of the immune cell using the multispecific molecules described herein is expected to enhance an immune response against the cancer cell, thereby providing a more effective cancer therapy. Without being bound by theory, a targeted, localized immune response against the cancer cell is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein.” Recombinant production of the multispecific antibody wherein a host cell comprises one or more nucleic acids encoding the multispecific antibody is taught (e.g., claims 178-180 and [1166]-[1167]). Loew does not teach wherein the Fc domain comprises one or more positions substituted as set forth in instant claim 41 or wherein the antibody binds human and non-human primate NKG2D.
WO 2016/207273 teaches (p. 3, lines 6-13) “a multispecific protein comprising (i) a first antigen binding domain that binds to an activating receptor on an immune cell (e.g. effector cell), optionally an activating NK receptor... selected from a NKp46, NKp30, NKp44 CD137, CD3, CD8 and NKG2D polypeptide, (ii) a second antigen binding domain that binds to an antigen of interest expressed by a target cell, and a dimeric Fc domain that ... binds human CD16A.” Binding to human NKG2D is also disclosed to activate immune effector cell receptors (e.g., p. 7, lines 14-15). The second antigen-binding domain may be an antigen expressed on a cancer cell, for example, a cancer antigen (p. 3, lines 24-25). Examples of target cancer antigens include BCMA (p. 31, line 34). Specific embodiments of the encompassed bispecific antigen-binding protein comprising human lgG1 Fc domains were made and tested. Formula 5 (F5) comprises a CD19- and NKp46-binding site (CD19-F5-NKp46) as shown in Fig. 2D. Fig. 2D also shows Formula 13, in which an anti-NKp46 scFv is linked to an Fc domain. The IgG1 is described as having hinge and CH2 domains (p. 49, lines 14-17). The Fc may comprise a mutation, e.g., at K409, T366, L351 or Y407 by EU numbering as in Kabat, to prevent homodimer formation (p. 45, line 32, through p. 46, line 10). This multispecific binding protein bound human and cynomolgus primate Fcγ receptors, while a multispecific binding protein (F6) that was identical with the exception of a mutation in the Fc domain (N297, p. 105, line 7, to eliminate binding to CD16) did not (p. 108, lines 22-end, and p. 106, lines 18-21). Example 12 looked at the role of NKp46 and the Fc domain in the bispecific protein by comparing CD19-F5-NKp46, CD19-F6-NKp46 and the corresponding anti-CD19 IgG1 antibody in inducing NK-mediated cell lysis of Daudi target cells, which express CD19. Both CD19-F6-NKp46 and full-length IgG1 anti-CD19 antibody were potent mediators of NK cell lysis; however, CD19-F5-NKp46 “was far more potent in mediating Daudi target cell lysis” than either the F6 bispecific or lgG1 antibody. “This would suggest that NKp46 can enhance target cell lysis even when CD16 is triggered. In fact, at comparable levels of target cell lysis, the CD19-F5-NKp46 was at least 1000 times more potent than the full-length anti-CD19 IgG1. These potency results suggest that the inventive multispecific NKp46 antibodies should be well suited for use in human therapy, e.g., in treating cancer or infectious diseases.” (see p. 105, lines 6-21) Neither the F5 or F6 construct lysed HUT78 cells, which do not express CD19 (p. 105, lines 29-34). Similarly, a CD20-binding CD20-F5-NKp46-1 and CD20-F6- NKp46-1 bispecific protein were tested for the ability to lyse Daubi cells, with the F5 construct significantly more effective than the F6 (Fig. 10 and Ex. 14 on p. 106). It is further stated (p. 109, lines 20-end) that those proteins comprising Fc domains “have the advantage of being suitable for usage in affinity chromatography without the need for the incorporation of peptide tags. This is beneficial as such tags are undesirable in a therapeutic product as they may potentially elicit undesired immunogenicity. By contrast, BiTe and DART antibodies cannot be purified using protein A, whereas F1 to F17 are all bound by protein A.” Further, the invention allows for a wide range of antibody variable regions to be used, and the bispecific protein to be manufactured by standard recombinant production without the need for product-specific folding or purification techniques (p. 2, lines 14-17). The bispecific proteins can be produced by expression of a first and second nucleic acid in a host cell, followed by recovery of the protein comprising a dimeric Fc domain that binds CD16. The bispecific Fc-containing proteins disclosed have the “ability to be produced in standard cell lines and standardized methods with high yields, unlike BiTE™, DART™ and other bispecific formats,...” (p. 54, lines 1-4) More generally, it is taught that a variety of bispecific antibodies have been reported, including one by Baeuerle et al. (2009) which binds receptors on both immune effector cells and tumor cells to bring the two different cell types into proximity (p. 1, lines 20-30). A pharmaceutical composition comprising the multispecific protein and a pharmaceutically acceptable carrier, as well as a method of treating cancer therewith are disclosed (e.g., p. 19, lines 13-14, and p. 62, lines 15-36). Examples of cancer antigens include BCMA (p.31, lines 25 and 34).
Vu teaches a BCMA antibody having the variable heavy and light chain regions (VH and VL) of SEQ ID NO:29 and 19 (col. 8, line 41, TABLE 1, antibody 83A10). Recombinant production of the antibody or a bispecific antibody in which one or more expression vectors comprising a nucleic acid encoding the antibody is expressed in vitro in a host cell is taught (col. 9, line 55, through col. 10, line 12, col. 26, lines 21-41). Bispecific antibodies using scFvs with knobs-into-holes Fc regions was taught in the prior art (col. 2, lines 28-30). The antibody binds BCMA expressed by a human multiple myeloma cell line (TABLE 7, Fig. 4A). The antibody cross-reacts with cynomolgus monkey BCMA (Example 1H6 and TABLE 4). A preferred embodiment is wherein the anti-BCMA antibody binds to both cynomolgus and human BCMA (e.g., col. 5, lines 27-29). Example 3B discloses IgG1 anti-BCMA antibody comprising a Fc region (see TABLE 6). It is taught (col. 13, lines 39-43) that, “Another advantage of the antibody according to the invention is based on the inclusion of an Fc portion, which is associated with an elimination half-life of about ~12 days and allows at least once or twice/week administration.” Also taught are bispecific BCMA-CD3-binding antibodies with an Fc region which bind multiple myeloma cells as well as CD3-expressing T cells, and were designed to redirect T cell cytotoxicity to multiple myeloma cells (Example 5C, Examples 7-8 and 11). A 2007 reference is cited which found that anti-BCMA antibodies that blocked BCMA ligand activity promoted cytotoxicity of multiple myeloma cell lines (col. 1, lines 48-51). Separately two WO documents are cited as disclosing antibodies against BCMA and their use in treatment of lymphomas and multiple myeloma (col. 1, lines 43-45). The claims are drawn to a method of treating multiple myeloma comprising administering to a subject in need thereof a bispecific antibody that binds BCMA and CD3 and comprises an Fc portion (claims 1 and 4).
Kim teaches Fc CH3 domain variant pairs that induce formation of heterodimeric heavy chain constant regions (Fc regions). Specifically, claims 1-3 of Kim recite wherein a first CH3 domain comprises K360E and K409W and the second CH3 domain comprises Q347R, D399V and F405T according to the EU index (see also Fig. 11 “EW-RVT variant pair”). The substitutions may be in human IgG1, the wildtype sequence of which is shown in Fig. 10. Fig. 9 shows different multi-specific constructs comprising the heterodimeric Fc domains, including wherein the VH and VL are on the same polypeptide (scFab or scFv). All experiments were conducted with human antibody IgG1 (col. 20, lines 5-7). As stated in col. 27, lines 61-67, “As a result, it can be understood that the Fc dimer including the CH3 domain into which the EW-RVT mutation pair is introduced has the same mean residue ellipticity as the Fc dimer including the wild type CH3 domain. This indicates that there is no change in the secondary structure of the protein even when the mutation pair is introduced (FIG. 20).” Kim states (col. 6, lines 25-34), “In a CH3 domain heterodimer of a heavy chain constant region of an antibody according to the present invention, a mutation is induced using a method different from the conventional method, formation of the homodimer is minimized, and the heterodimer can be formed at a high yield of 90 to 95% or more. When a heterodimeric Fc pair protein prepared using the CH3 domain heterodimer is expressed in animal cells, the protein has an expression level, a production yield and a thermodynamic stability that are similar to or more improved than an original wild type antibody.” Claim 16 is drawn to a method of preparing a heterodimeric Fc pair protein comprising transforming a host cell with a nucleic acid expression vector encoding the heterodimeric Fc pair protein, culturing the host cell , purifying and recovering the heterodimeric Fc pair protein (see also col. 19, lines 49-59, col. 11, lines 40-42 and 65-67).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have a cell comprising one or more nucleic acids encoding a trispecific construct as disclosed by Loew which bound both NKG2D and CD16, as well as a tumor-associated antigen, and specifically a hematological cancer-associated antigen which is BCMA, for production of the multispecific binding protein for the treatment of multiple myeloma or other BCMA-expressing cancer. The cited prior art taught such cell-based recombinant methods were used and well-known in the prior art. WO 2016/207273 and Vu also support an IgG1 Fc-comprising construct binding an effector cell, e.g., by binding NKG2D, and a tumor cell, e.g.¸ by binding BCMA. Several BCMA antibodies had been shown to be useful in the treatment of multiple myeloma (Vu), a hematological cancer, including 83A10, which bound both human and non-human primate BCMA. Binding human antigen had the well-known advantage of being less immunogenic when used as a therapeutic in humans and providing more accurate in vitro experimental results when using human cells. Binding non-human primate antigens had the well-known advantage of being useful in preclinical therapeutic trials with non-human primates, with results being more applicable to potential human application than if the antigen was from and tested in a rodent, for example. It would have been obvious and desirable wherein the NKG2D antigen-binding portion bound human NKG2D for therapy and also bound non-human primate NKG2D, such as cynomolgus, for in vitro and in vivo preclinical testing, like the cross-species binding of anti-BCMA antibody 83A10 (see Vu, Example 1H6, and WO 2016/207273). The inclusion in the trispecific antibody of a NKG2D and a CD16-binding region, especially a CD16-binding Fc domain, would have been desirable because as stated by Loew ([0669]), in reference to NKG2D, “[I]t is a receptor that provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity…. CD16 is a receptor for the Fc region of IgG, which binds complexed or aggregated IgG and also monomeric IgG and thereby mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses,…” The inclusion of an Fc domain also extends the serum half-life of the molecule to which it is attached (Vu). It is also discussed (Vu [0004]) that by bringing NK cells in proximity to tumor cells, a more effective immune response with enhanced cytotoxicity can occur, also reducing systemic toxicity by producing a localized immune response. This is supported by the teachings of WO 2016/207273 discussed above. Further, Vu taught a trispecific immune cell-engaging construct comprising a tumor-targeting moiety that is a BCMA-binding antibody with a CD3 T cell-binding site and having an Fc, i.e., CD16-binding, region. It would have been obvious to have an immune cell-targeting domain with a BCMA-binding domain, wherein an NKG2D-binding site was combined with a BCMA-binding site so that instead of redirecting T cell cytotoxicity to multiple myeloma cells as taught for the BCMA-CD3-binding bispecific antibody of Vu, NK cytotoxicity was directed toward multiple myeloma cells in light of the disclosure of Loew. It also would have been obvious to have the NKG2D antigen-binding site formed by a VH and VL on the same polypeptide, e.g., a single chain scFv binding site, as taught by Loew, WO 2016/207273 and Kim. It would have been obvious to have had as the BCMA-binding site of the trispecific protein comprise a VH and VL, such as that of the 83A10 antibody as taught by Vu. Based on the teachings of the prior art showing the effectiveness of killing cancer cells with a multispecific binding protein comprising an immune cell-binding site, a tumor antigen-binding sit