DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
The objections to the Title, Abstract, Specification ([0011]) and Claims 1, 2, 11 and 18 are withdrawn in view of the amendment to each.
The rejections of claims 2 and 3 are moot in view of the cancellation of the claims.
The rejection of claims 1, 4 and 19 and dependent claims under 35 U.S.C. 112(b), second paragraph, is withdrawn in view of the amendment removing the term “domain” from the claims.
The rejection of claims 1-20 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of the cancellation of claims 2-3 and amendment to claims 1 and 19 to include a full-length NKG2D, i.e., comprising an ECD, TMD and ICD, and DAP10 or DAP12 fused or linked to a cytoplasmic effector domain comprising a cytoplasmic domain of CD3zeta.
Declaration under 37 CFR 1.132
The declaration by Dr. Liu under 37 CFR 1.132 filed 07/21/2026 is insufficient to overcome the rejection of claims 1 and 4-20 based upon 35 USC 103 as obvious over US Patent 7,994,298 B2 (‘298) in view of VanSeggelen et al. (Mol. Ther. 23(10):1600-1610, Oct. 2015), Karimi et al. (J. Immunol. 175(12):7819-7828, 2005), US Patent 9,511,092 B2 (‘092) and US 11,845,804 B2 (‘804) as set forth in the last Office action because: There is no comparison of the evidence provided in the declaration to support unexpected results with the closest prior art. Further, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) MPEP § 716.2.
The structure formed by a NKG2D homodimer and two DAP10 or DAP12 proteins is described as forming a hexametric complex in paragraphs 3, 4 and the first part of 5. The encoding polynucleotide of the claims encodes a chimeric natural killer receptor (CNK) comprising a NKG2D protein linked via a self-cleavage peptide to an adaptor protein, a DAP10 or -12 fused directly or linked to a cytoplasmic effector domain comprising a cytoplasmic domain of CD3zeta, that when expressed forms the hexamer. It is stated in paragraph 5 that the CNK “confers to an engineered immune cell enhanced cell expansion and cytotoxicity when compared to the expression of NKG2D-basd CAR or the adaptor protein.” This is supported by a description in paragraphs 6, describing the various constructs tested, and experiments summarized in paragraphs 7 and 8. In paragraph 7 it is concluded that because CD4+ and CD8+ T cells express NKG2D ligands, expression of the NKG2D-CD3zeta and the DAP10-CD3zeta construct on CD8+ T cells depleted all CD4+ T cells, while expression of NKG2D on CD8+ cells also downregulated NKG2D ligands through endocytosis. Figure S1 is provided for support. It is noted, however, that the words on the X- and Y-axes of S1 are illegible. Regardless, this is not a surprising result. The prior art supports endocytosis of NKG2D and downregulation of NKG2D surface expression on CD8+ T cells upon direct contact with NKG2D ligand MIC-expressing target cells (Molfetta et al., Trends Immunol. 37(11):790-802, 2016, paragraph bridging pp. 792-793). If the ligand is still attached to the receptor when it is endocytosed, then it would reasonably be expected that the ligand is also endocytosed. Also, because as discussed in paragraph 7, both CD4+ and CD8+ T cells express NKG2D ligands, but only CD8+ T cells express NKG2D receptor, then expression of either NKG2D or DAP10 on CD8+ T cells, which endogenously express NKG2D and DAP10 (e.g., Prajapati et al., Cell Mol. Immunol. 15(5):470-479, 2018, p. 470, col. 1, first paragraph, and col. 2, second paragraph), would have been reasonably expected to target and deplete cells expressing a NKG2D ligand, such as CD4+ T cells and tumor cells. These are inherent properties of the cells expressing NKG2D, a DNAX-activating protein and a NKG2D ligand or binding to a NKG2D ligand on a cell.
In paragraph 8, it is stated that expression of NKG2D-T2A-DPA10-CD3Z led to higher expansion of T cells than either part alone, although T cells expressing NKG2D also expanded well but were not cytotoxic. As illustrated by Molfetta et al. (supra, Fig. 1), NKG2D requires DAP10 or DAP12 to produce a signal and, therefore, cytotoxic activity. Further, VanSeggelen et al. (Mol. Ther., 2015) showed not only that cells transfected with a polynucleotide encoding DAP10 and a chimeric NKG2D-CD3zeta led to T cell expansion (Fig. 1b and c, NKz10), but that cells from different mouse strains responded differently (compare Fig. 1b to 1c, and sentence bridging pp. 1601-6102; see also Fig. 2b and c). Further, US 9,511,092 B2 showed that a NKG2D-DAP10-CD3zeta expressed construct-increased cytotoxicity of activated NK cells against a wide variety of tumor cell targets (col. 58, lines 25-27) and markedly reduced tumor burden (col. 37, lines 52-57). The amount of cytokine/chemokine secretion was significantly higher in NKG2D-DAP10-CD3zeta-expressing cells than DAP10-CD3zeta-expressing cells (Table 1 and Fig. 1A, note the transcription initiation signal between the CD3zeta-NKG2D and DAP10 encoding portions of the vector). For the reasons discussed above, it is not agreed that compared to the prior art the CNK polypeptide of the claims showed exceptional or unexpected cell properties (see paragraph 10). Note that the only data provided with the declaration are in the figures and percents in paragraph 8, none of which have numbers of samples/replicates and for Figs. 2A-B and percentages, no means to determine significance, e.g., no standard deviation or error reported.
Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) MPEP § 716.2(c) There is an insufficient showing to support evidence of unexpected properties.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
This application repeats a substantial portion of prior Application No. 16/827,697, filed 03/23//2020, and adds disclosure not presented in the prior application. Because this application names the inventor or at least one joint inventor named in the prior application, it may constitute a continuation-in-part of the prior application. Should applicant desire to claim the benefit of the filing date of the prior application, attention is directed to 35 U.S.C. 120, 37 CFR 1.78, and MPEP § 211 et seq. The presentation of a benefit claim may result in an additional fee under 37 CFR 1.17(w)(1) or (2) being required, if the earliest filing date for which benefit is claimed under 35 U.S.C. 120, 121, 365(c), or 386(c) and 1.78(d) in the application is more than six years before the actual filing date of the application. There is no support in the parent application as filed for a human NKG2D intracellular domain that is amino acids 1-52 of SEQ ID NO:1, which is the same as current SEQ ID NO:12. The disclosure added after the filing date of application 16/827,697 is SEQ ID NO:12, designated “Human NKG2D intracellular domain”.
The prior-filed applications did not originally disclose SEQ ID NO:12 per se, “Human NKG2D intracellular domain" as defined at the end of the instant specification and in the sequence listing. It did not disclose the amino acid ranges for each NKG2D domain, even though it disclosed the full-length “Human NKG2D” as SEQ ID NO:1. Nevertheless, there is no basis in parent application 16/827,697 as originally filed for the intracellular domain of SEQ ID NO:1 being amino acids 1-52 thereof, i.e., being SEQ ID NO:12, nor is there support in the prior art for this as an inherent feature. What is now SEQ ID NO:12 was added after the filing date of that application. The prior art only supports the intracellular domain as amino acids 1-51. For example, Uni-ProtKB/Swiss-Prot Database Accession No. P26718, version 174 (see “TOPO_DOM”; Feb. 2019; attached and cited on the accompanying PTO-892), sets forth the intracellular domain as amino acids 1-51 not 1-52. Similarly, NCBI GenBank Database Accession No. NP_031386.2 (Feb.2019) also sets forth the intracellular domain as 1-51 (see “FEATURES”, attached and cited on the accompanying PTO-892). As a result, it appears the instant application may constitute a continuation-in-part of the prior application.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later- filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AJA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc.,38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994) The disclosure of the prior-filed application, provisional Application No. US 62/919,750, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
There is disclosure in provisional application 62/919,750 of the chimeric NK receptor polypeptide that recognizes an NKG2D ligand and triggering subsequent down signaling. The provisional application describes a NK chimeric antigen receptor (NK CAR2) comprising a full-length NKG2D and adaptor protein DAP10 and/or DAP12, optionally fused to a T cell activation signal (e.g., CD3Z as illustrated in Fig. 1). “[P]olynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor” is set forth. It reasonably appears “the receptor” refers to the chimeric NK receptor. It does not describe a self-cleave peptide as part of the CNK polypeptide. Also, no sequences are disclosed.
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
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.
Claim(s) 1 and 4-20 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent 7,994,298 B2 (‘298) in view of VanSeggelen et al. (Mol. Ther. 23(10):1600-1610, Oct. 2015), Karimi et al. (J. Immunol. 175(12):7819-7828, 2005), US Patent 9,511,092 B2 (‘092) and US 11,845,804 B2 (‘804) for the reasons set forth in the previous Office action and for the following reasons addressing the amendment to claims 1 and 19: The limitations from now cancelled claims 2-3 have been added to the independent claims; however, for the reasons of record and as discussed below in the recast rejection, the invention remains obvious.
US 7,994,298 teaches two proteins that can make a complex: wildtype NKG2D and chDAP10, which comprises wildtype DAP10 fused to the cytoplasmic domain of CD3ζ (Fig. 1, referred to hereafter as either chDAP10 or chDAP10-CD3ζ). In col. 11, lines 16-18, and col. 17, lines 10-14, a particular embodiment of a chimeric construct which is a fusion between full-length DAP10 and the cytoplasmic domain of CD3ζ, e.g., chDAP10 is described. ‘298 teaches a human chimeric NKG2D receptor comprising human NKG2D and human CD3zeta, as well as human DAP10 and human CD3zeta (e.g., col. 8, lines 20-28, and col. 17, lines 24-25). Additionally, it was taught that only when both NKG2D and DAP10 were transfected in the same cell (Bosc23) did NKG2D cell surface expression result (col. 8, lines 28-34). When human chimeric NKG2D (having a human NKG2D ECD)-bearing CD8+T cells were contacted with a variety of human cancer cell lines, the T cells secreted IFNγ (Table 2 and col. 5, lines 40-50). The amount of IFNγ produced when chimeric NKG2D-expressing human CD8+ T cells are brought into contact with human tumor cells is about 5-times higher than for wildtype NKG2D-expressing T cells (Table 2 and col. 5, lines 40-51). Figure 2 shows that the highest amount of target cell lysis occurs when the target cells are co-cultured with effector T cells that have been transfected with murine chDAP10>> chNKG2D> wtDAP12> wtNKG2D≈wtDAP10 (col. 3, lines 47-57, and col. 6, lines 9-44). Both chNKG2D- and chDAP10-transduced T cells recognized NKG2D ligands as shown by production of higher amounts of IFNγ after co-culture with cells expressing NKG2D ligands but not with cells that did not express ligand (col. 5, lines 10-20). Human chimeric NKG2D also produced a high amount of IFNᵞ in response to NKG2D ligands (col. 9, lines 21-32). Blocking human chNKG2D with an anti-NKG2D antibody prevented killing of tumor cells by chNKG2D-transduced human T cells (Table 7, sentence bridging cols. 8-9). It is disclosed (col. 2, lines 8-10) that the prior art has established that “NKG2D is associated with the transmembrane adaptor protein DAP10”. The invention is designed for the production of tumor-specific T cells by increasing the cytotoxic activity of activated NKG2D receptors (e.g., col. 3, lines 61-64). It is taught that the CD3ζ may be that of GENBANK accession number human NM_198053; SEQ ID NO:6 (col. 11, lines 10-12). The DAP protein may be human DAP10 with the sequence of GENBANK accession number AJ001383; SEQ ID NO:4 (encoding a protein identical to instant SEQ ID NO:3), or human DAP12 with the sequence of GENBANK accession number AF019562; SEQ ID NO:5 (which encodes a protein identical to instant SEQ ID NO:4; col. 10, lines 55-60). GENBANK accession number BC039836 encodes human NKG2D protein (SEQ ID NO:2, differing by one amino acid from instant SEQ ID NO:1; col. 10, lines 36-43). Also, ‘298 teaches introduction of exogenous chDAP10 (DAP10-CD3zeta) and chNKG2D (NKG2D-CD3zeta) into primary murine immune T cells led to cytotoxicity when NKG2D ligand-expressing tumor cells were present, with in most cases the chDAP10-transfected cells having the highest specific lysis activity (Fig. 2B-D, and col. 2, lines 47-57). Further, murine spleen T cells genetically engineered to express wildtype or chimeric NKG2D or DAP10 showed that none of the wildtype constructs induced significant surface expression of NKG2D, while chNKG2D showed 42% increased expression and chDAP10 induced 64% increased expression, noting that the NKG2D surface expression by chDAP10 was of endogenous NKG2D and by chNKG2D was a combination of endogenous and exogenous NKG2D (col. 4, line 59, through col. 5, line 9). Also, looking at Table 1 of ‘298, which shows the amount of the cytokine IFNγ produced by chNKG2D-expressing murine T cells co-transfected with a variety of constructs, use of chDAP10 induced the largest amount of IFNγ production, nearly twice as much as chNKG2D. A similar study was done (col. 9 lines 21-45) using chNKG2D-transduced human T cells, showing that high amounts of IFNγ were produced when the T cells were co-cultured with NKG2D ligand-expressing tumor cells (chDAP10 co-transfection was not tested), supporting the reasonable expectation that human and murine immune cells expressing NKG2D function similarly in response to a target cell expressing NKG2D ligand. ‘298 does not teach wherein all or part of the NKG2D was human in a complex with a chimeric DAP10- CD3ζ adaptor protein, or wherein the DAP10 and/or CD3ζ in the NKG2D complex were human. Nor is a chimeric DAP12-effector explicitly taught. ‘298 does not teach a protein comprising a NKG2D domain linked by a self-cleavage peptide to a DAP10 adaptor protein comprising a CD3ζ effector domain and optionally a 4-1BB costimulatory domain.
VanSeggelen et al. teach a chimeric NKG2D comprising NKG2D fused to CD3Z (NKz), a NKG2D CAR comprising the extracellular domain of NKG2D fused to a CD8 hinge, and CD28 and CD38 intracellular signaling domains, as well as a construct comprising DAP10 linked to the NKz by a self-cleaving p2A peptide (NKz10) (Fig. 1a). This NKz10 polypeptide showed protein expression of 7-10 fold higher than a construct without the DAP10 domain (Fig. 1a, and p. 1602, col. 1, first paragraph). Its expression in T cells led to significant killing of tumor target cells in vitro (e.g., p. 602, col. 2, third paragraph).
Karimi et al. used interfering RNA (RNAi) to silence human NKG2D, DAP10 or DAP12 in activated CD8+ T cells and NK cells in vitro to disrupt the NKG2D/DAP complex to investigate the role of each component in cytokine release and cytotoxicity (e.g., p. 7821, col. 2, end of second paragraph). Further, in vivo it was shown that NKG2D silencing in expanded activated human CD8+ T cells administered to a mouse tumor model significantly increased tumor progress (p. 7825, col. 2 middle). Human NKG2D forms a hexameric complex with DAP10, with a NKG2D homodimer interacting with four DAP10 proteins in the transmembrane domains (p. 7824, col. 2, middle). Activated human CD8+ T cells transduced with DAP10 RNAi lost 75% of cytolytic activity compared to ineffective DAP10 shRNA or empty vector (p. 7823, col. 1, first paragraph), but was less effective than silencing NKG2D (p. 7823, col. 1, start of second paragraph). Silencing DAP12 in activated human CD 8+ T cells showed a significant though reduced reduction in cytotoxicity compared to silenced DAP10 or NKG2D (p. 7823, col. 2, first paragraph). When both DAP10 and DAP12 were knocked down in activated human CD8+ T cells, suppression of in vitro cytolysis was greater than 80% compared to negative controls, “reflecting more potent suppression than silencing DAP10 or DAP12 alone.” (p. 7824, paragraph bridging cols. 1-2). The ability to coprecipitate DAP12 and NKG2D from activated CD8+ T cells whether or not DAP10 is silenced indicates that human NKG2D can pair with DAP12 when DAP10 is absent (p. 7825, col. 1, first paragraph).
US 9,511,092 B2 teaches a chimeric NKG2D receptor made of NKG2D linked to CD3zeta and expressed with DAP10, all encoded by a single polynucleotide (Fig. 1A). It is discussed that the prior art has shown that NKG2D associates with DAP10, which promotes and stabilizes its surface expression, and that NKG2D signal transduction occurs only through its association with DAP10 (col. 2, lines 18-34). In the same section it references US ‘298 (supra) as teaching use of chimeric receptors comprising NKG2D or DAP10 fused to CD3zeta for expression in T cells. Transduction of the encoded chimeric receptor of ‘092 led to increased NKG2D surface expression in NK cells, which were more cytotoxic than mock-transduced cells against leukemia and sold tumor cell lines (col. 56, line 36, through line 63). It also led to increased cytokine secretion (Table 1, e.g., of IFNγ). These chimeric receptor-expressing NK cells had antitumor activity in a mouse osteosarcoma xenograft model (col. 56, line 64, through col. 57, line 17). A vector comprising the polynucleotide can be used for expression in the host cell (e.g., col. 3, lines 15-16). As shown in Fig. 1A, the NKG2D and DAP10 encoding portions of the polynucleotide are separated by a ribosome entry site (IRES) that functions to allow translation initiation in the middle of a mRNA sequence so that the NKG2D and DAP10 proteins are expressed as independent proteins (col. 11, lines 40-44). The NKG2D may be human, having the sequence of SEQ ID NO:22 (col. 7, lines 39-40; which is identical to instant SEQ ID NO:1).
US 11,845,804 teaches a chimeric antigen receptor comprising an antigen-binding domain (AD) which comprises a tumor-associated antigen (TAA) and is an scFv in the form of anti-CD30 scFv AC10, a hinge domain (HD) comprising an IgG4 hinge having the sequence of SEQ ID NO:10 (identical to instant SEQ ID NO:7), a transmembrane domain (TMD) and an intracellular domain (ICD) comprising costimulatory domains which are CD28 and 4-1BB and a cytoplasmic domain of CD3zeta of SEQ ID NO:23 (identical to instant SEQ ID NO:5; col. 7, line 32, through col. 8, line 57, and claim 1). Claim 1 is drawn to the same CAR except wherein the costimulatory domain comprises CD3zeta, CD28 and OX40 ICDs. Claim 10 is drawn to a nucleic acid encoding the CD30 CAR of claim 1. Claim 12 is drawn to a vector comprising the nucleic acid and claim 13 is drawn to a cell comprising the vector. Treatment of a CD30+ expressing cancer, such as CD30-expressing tumors, including lymphoid malignancies, leukemia and solid tumors, by administration of the encoding nucleic acid to a subject is taught (claim 17 and col. 1, lines 19-23). CAR-T cells comprising the CAR are taught (col. 27, line 44, through col. 28, 65).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to combine for expression in a single polynucleotide an encoded NKG2D protein and the chDAP10-CD3ζ of ’298 for transduction into a T cell for expression of the NKG2D/chDAP10-CD3ζ complex taught by ‘298, wherein NKG2D is separated from the chDAP10-effector molecule by a self-cleavage peptide as taught for a similar construct by VanSeggelen et al. Based on the success of VanSeggelen, there would have been a reasonable expectation of successful expression and NKG2D receptor DAP10-CD3ζ complex formation in human T cells that could function cytotoxically. Both ‘298 and VanSeggelen et al. showed it was advantageous to express DAP10 when NKG2D was expressed because it led to increased surface expression of NKG2D. This is also supported by ‘092, which showed that expression of a similar construct in NK cells also lead to cytotoxicity of cancer cells. It would have been obvious wherein all the components of the single polypeptide were human in order to reduce the chance of immunogenicity for anti-cancer human T cell therapy. Therefore, it would have been obvious to have an immune cell expressing a chimeric receptor NKG2D/chDAP10-CD3ζ in order to produce a cytotoxic effect on tumor cells expressing of NKG2D ligand(s).
It further would have been obvious wherein DAP10 was substituted with DAP12 because Karimi et al. discussed that both DAP10 and DAP12 complex with NKG2D to induce cell lysis, but through different signaling pathways. The findings of Karimi et al. showed that even in the absence of DAP10, DAP12 still exercised some tumor cell cytotoxicity. Because the transmembrane domain of NKG2D regulates complex formation with DAP10 or DAP12, and both DAP proteins signal through different pathways, it would have been desirable wherein either or both signaling pathways were enabled by NKD2D ligand activation in order to induce T or NK cell cytotoxicity toward tumor cells. One of ordinary skill in the art would have expected an increase in activity of either pathway, e.g., by increased cell surface expression of NKG2D on T or NK cells, would have led to increased target cell lysis and IFNγ release (e.g., Karimi et al., ‘092 and ‘298). Karimi et al. provides the reasonable expectation that the NKG2D/DAP10-CD3Z complex would have been in a hexameric configuration. As shown by the prior art, genetic engineering of immune cells to comprise a polynucleotide encoding protein capable of forming a NKG2D/DAP10-CD3z complex would have been obvious and desirable wherein components of the chimeric receptor protein, NKG2D and either DAP10-CD3zeta or DAP12--CD3ζ, were of human origin for the same purpose, i.e., to cytotoxically target tumor cells by the NKG2D/chDAP12-CD3ζ complex expressed in T or NK cells. One would have desired this to analyze the therapeutic potential of the immune cells with the complex and with a therapeutic goal. There would have been a reasonable expectation of success because ‘298 showed that chDAP-CD3ζ with wildtype NKG2D in T cells caused an increased amount of IFNγ release after co-culture with cells expressing NKG2D ligand, and the chDAP10-CD3ζ led to significantly higher NKG2D surface expression on the transduced T cells. Further, when murine T cells were co-cultured with murine NKG2D ligand-expressing target cells, chDAP10-CD3ζ induced the greatest amount of target cell lysis, closely followed by chNKG2D-CD3ζ (‘293 Fig. 2). Similarly, when human cancer target cells were contacted with human chimeric NKG2D-expressing T cells, IFNγ was released, which did not occur in the absence of the tumor cells (Table 2 of ‘298). As referenced in ‘904, the ICD human CD3ζ sequence (SEQ ID NO:23) is identical to instant SEQ ID NO:5. The amino acid translations of the ‘298 GENBANK human DAP10 and DAP12 are identical to instant SEQ ID NO:3 and 4, respectively. The human NKG2D of ‘092 is identical to instant SEQ ID NO:1. The sequence of human NKG2D of ‘092 is identical to instant SEQ ID NO:1 and it would have been obvious to use this NKG2D protein in the DAP10-associated chimeric receptor. However, it would have been obvious to use any wildtype human CD3ζ intracellular domain NKG2D, DAP10 or DAP12 protein (unless expressing the CNK in a mouse, in which case use of wildtype murine sequences necessary for function would have been obvious to use). It further would have been obvious to have the genetically engineered immune cell also express a CAR, such as taught by ‘804, for the treatment of CD30+ tumors, such as lymphoid malignancies, leukemia and sold tumors, or substituting any other TAA-binding site for CD30 for the same expected TAA-directed cytotoxic function.
The Supreme court has acknowledged that (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 at 1390, U.S. 2007, emphasis added):
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person' s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions… (at 1390)
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (at 1395).
Applicant’s arguments (pp. 8-9 or REMARKS) are directed to the showing in the Inventor Declaration under 37 CFR 1.132. The arguments have been fully considered but are not persuasive for the reasons addressed in the “Declaration under 37 CFR 1.132” section above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Claire Kaufman
/CLAIRE KAUFMAN/Primary Examiner, Art Unit 1674
