Methods and Compositions for Cells Expressing a Chimeric Intracellular Signaling Molecule

§102 §103 §112

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 . Applicant’s amendments to the claims dated 7/2/26 are acknowledged. Claims 1, 3-7, 9 and 31-40 are pending and subject to prosecution. Claims 1, 4, 32-33 and 35 are amended. Claim 2 is cancelled. Replacement drawings dated 7/2/26 are acknowledged. STATUS OF OBJECTIONS/REJECTIONS WITH RESPONSE TO ARGUMENTS Objection to the Drawings The objection to the DRAWINGS is WITHDRAWN in light of Replacement drawings dated 7/2/26. Objections to the Claims The objections to claims 1, 4, and 32-33 are WITHDRAWN in light of Applicant’s amendments to the claims. 112(b) Rejections The 112(b) rejections over claims 1-7, 9 and 31-40 are WITHDRAWN in light of Applicant’s amendments to the claims. 102(a)(1) and (a)(2) Rejection The 102(a)(1) and (a)(2) rejection over claims 1, 3, 9, 31-32, 34-35 as anticipated over WO2004/127261 to Wu is MAINTAINED. The rejection over canceled claim 2 is WITHDRAWN. Applicant’s arguments regarding the 102 rejection of the claims as anticipated by Wu have been fully considered but are not persuasive (Reply at pages 10-13). Applicant argues the amendments to claims 1 and 32 are sufficient to overcome the rejection. Applicant argues claims 1 and 32, directed to a metabolically enhanced T-cell(s), newly require, at least, the limitation of cancelled claim 2, wherein upon activation, the expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell(s). Applicant further argues Wu does not teach or suggest T-cells with the claimed function because A) Wu’s disclosure does not articulate any metabolic enhancement of a T-cell, and B) there is no inherent disclosure of metabolic enhancement. The Examiner has considered these arguments, in view of both amended claims and the prior rejection, but is not convinced of error. Initially, the Examiner disagrees with Applicant’s assertion that “claims 1 and 32 are amended to incorporate now cancelled claim 2.” While the Examiner agrees that limitations from cancelled claim 2 have been introduced into claims 1 and 32, the amendment is comprises more than asserted. Cancelled claim 2 recited, “The metabolically enhanced T cell of claim 1, wherein expression of the chimeric intracellular signaling molecule metabolically enhances the T cell.” However, amended claims 1 and 32 newly recite, “wherein upon activation of the T cell(s), expression of the chimeric intracellular signaling molecule metabolically enhances the T cell(s)” (emphasis added). There was no previous requirement that “metabolic enhancement” was tied to activation of the T-cell – only that the T-cells expressed the chimeric intracellular signaling molecule. Regardless, the new requirement wherein “upon activation of the T-cell(s), expression of the chimeric signaling receptor results in metabolically enhanced T-cell(s)” does not appear to significantly alter the scope of the pending claims. Metabolic enhancement of the cell is still the result of expression of the chimeric intracellular signaling molecule in the cell. “Expression” of the chimeric intracellular signaling molecule is the presence of the translated protein, absent evidence to the contrary. In addition, there is no limiting definition of “activation” of T-cells in the specification. Paragraph [0050] of the published specification teaches: “’Activation,’ as used herein, refers to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production, and detectable effector functions. The term ‘activated T cells’ refers to, among other things, T cells that are undergoing cell division.” There is no requirement of what “detectable cellular proliferation” encompasses: is the upregulation of proliferation signal(s) within the cell, that are detectable via assay (mRNA? protein?), but prior to actual cell division encompassed? Or have the cells necessarily divided? There is no mechanism articulating how activation is “associated” with induced cytokine production and/or detectable effector functions. Cytokine production can be the result of T-cell activation as well as a cause of T-cell activation (See, Curtsinger et al. Inflammatory Cytokines as a Third Signal for T Cell Activation. Current Opinion in Immunology, 2010. 22(3):333-340). Thus the “activation” of T-cells appears to encompass from initiation of the activation process through to an “activated” T-cell. As such, “upon activation” does not require a step-wise order of events. There is no requirement that metabolic enhancement occurs after (some undefined point after initiation) “activation” of T-cells, and the claims can be reasonably interpreted as wherein “expression of the intracellular signaling molecule in the cell metabolically enhances the T cell(s)” can be concurrent with the initiation of activation, encompassed by “upon activation.” In addition, as noted in the “Claims” section at page 6 of the Non-Final Office action dated 04/02/2026, the instant specification does not define “metabolically enhanced” T-cells: PNG media_image1.png 246 566 media_image1.png Greyscale As such, the claimed requirement of “metabolically enhanced” was interpreted based on the structural requirements recited in the previously pending claims: expression of the chimeric signaling receptor in the T-cells. The claimed requirement of “metabolically enhanced” is similarly interpreted. Taken together, the broadest reasonable interpretation of the amended claims, directed to T-cells comprising a chimeric intracellular signaling molecule reciting “wherein upon activation of the T cell(s), expression of the chimeric intracellular signaling molecule metabolically enhances the T cell(s)” is interpreted as encompassing: a T-cell(s) expressing a chimeric intracellular signaling molecule with recited structures and lacking an extracellular ligand binding domain, wherein expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell(s), wherein expression of the chimeric intracellular signaling molecule metabolically enhancing the T-cell(s) occurs concurrently or later than the initiation of activation of the T-cell(s). Thus, Applicant’s arguments regarding Wu are considered both in light of the interpretation of the previously pending claims as well as the interpretation of the amended claims as iterated above. Applicant argues Wu does not teach or suggest T-cells with the claimed function because A) Wu’s disclosure does not articulate any metabolic enhancement of a T-cell, and B) there is no inherent disclosure of metabolic enhancement. The Examiner cannot agree. With regard to Applicant’s arguments that Wu does not articulate the exact phrase “metabolic enhancement” of the cells, the Examiner agrees. Applicant’s arguments that Wu does not disclose “metabolically enhanced” T-cells because Wu does not recite “a metabolically enhanced T cell” or any “metabolic activity” or any “metabolic enhancement properties” in the T-cells is not persuasive to show that Wu does not disclose the T-cells are “metabolically enhanced.” Applicant’s argument is circular: Wu does not disclose “metabolically enhanced” because Wu does not state “metabolically enhanced.” The argument gives no new information and does not explain what “metabolically enhanced” encompasses and how Wu does not teach it. Applicant has not provided any definition or interpretation of “metabolically enhanced” disclosed in the specification, thereby rebutting the Examiner’s need to define “metabolically enhanced” structurally during prosecution as iterated above. Nor has Applicant argued that Wu does not disclose all of the claimed structural features of the claimed chimeric intracellular signaling molecule. Nor has Applicant provided an art-recognized definition of a “metabolically enhanced” T-cell. With regard to Applicant’s argument that Wu does not inherently disclose the T-cells are metabolically enhanced, the Examiner is not persuaded. Applicant does not argue Wu’s disclosure is missing any structural element (previously or newly) claimed – rather Applicant’s only arguments are that Wu does not expressly or inherently disclose that the T-cells are “metabolically enhanced.” However, MPEP 2112 reads, “The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.” Something that is old does not become patentable upon the discovery of a new property, use, or application. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). The requirements relating to a prima facie case of anticipation or obviousness of a composition based on inherency are clear – if the prior art products are identical in structure or composition a prima facie case of anticipation is made; and if a composition is physically the same, it must have the same properties (MPEP 2112.01 (I) and (II)): Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. In the Non-final rejection dated 4/02/2026, Wu 1) discloses T-cells comprising chimeric intracellular signaling molecules comprising every structural limitation of claim 1; and 2) because Wu discloses the chimeric signaling molecules were expressed on the T-cells, Wu also anticipated claim 2. Thus, with regard to the previously pending claims, such a rejection was proper to establish a prime facie case of anticipation. With regard to Applicant’s argument that Wu does not inherently disclose the claims as amended, the Examiner does not agree. Applicant does not argue that the T-cells of Wu do not disclose the claimed structures, only that Wu does not disclose explicitly or inherently any “metabolic enhancement.” Applicant provides no information regarding what “metabolically enhanced” encompasses and how Wu does not teach it. In addition, Applicant has provided no argument explaining why the new requirement of “wherein upon activation” of the T-cells expressing the chimeric intracellular signaling molecule further aids in overcoming the 102 rejection in light of Wu, within pages 10-12 of the Reply. Any argument directed towards Wu presented in rebuttal of 103 rejections of record will be addressed in those sections. Considering Wu in light of the pending claims as interpreted above, Wu discloses activation of the T-cells expressing the chimeric intracellular signaling molecules, wherein activation results in intracellular signaling responses and cytokine production (paragraphs [00161], [00191], and [00209]-[00214]). As shown, both in the rejection of record, and/or herein, Wu discloses 1) T-cells that anticipate the structural requirements of the claimed chimeric intracellular molecule; 2) the T-cells express the chimeric intracellular molecule; and as newly required, 3) activation of the T-cells expressing the chimeric intracellular molecule. As such, Wu necessarily inherently discloses “upon activation of the T cell(s), expression of the chimeric intracellular signaling molecule metabolically enhances the T cell(s) ” according to the broadest reasonable interpretation of the claims in light of the specification (MPEP 2111) and the requirements of inherency (MPEP 2112.01 (I) and (II)). Applicant cites to Ex parte Levy and Hughs Aircraft arguing any alleged inherency of “metabolic enhancement” in Wu need be affirmatively demonstrated by the Office. However, Applicant has not articulated how the fact pattern of Ex parte Levy and Hughs Aircraft is similar to the fact pattern herein. Regardless, any allegation that an inherent teaching relevant to a claim under examination was not properly articulated is not persuasive. The Examiner has detailed above how 1) the previous rejection of record properly articulated how Wu inherently anticipated the previously pending claims and their scope; and 2) how Wu inherently anticipates the currently pending amended claims and their scope. The Examiner notes that once an inherency rejection of a function made over a disclosed structure is made, Applicant has the burden of showing the structures are not the same, and/or how the differences would not necessarily result in the claimed function (MPEP 2112.01). Applicant has not articulated any rationale as to why T-cells comprising all of the claimed structural limitations, such as taught by Wu, would not necessarily be “metabolically enhanced” “upon activation” as claimed, or how a skilled artisan would be able to identify differences between the T-cells of Wu (allegedly not “metabolically enhanced”) vs. the T-cells of the present claims (that are “metabolically enhanced”) “upon activation” as claimed. 103 Rejections The 103 rejection over claims 4-6, 33 and 37 as obvious over WO2004/127261 to Wu in view of US2013/0315884 to Galletto is MAINTAINED. With regard to the 103 rejection of record over Wu in view of Galletto, Applicant reiterates that Wu does not anticipate (expressly or inherently) the amended independent claims relating to “metabolically enhanced” T-cells as argued over the 102 rejection, and that the combination of Galletto with Wu does not cure the deficiencies of Wu and thus does not render obvious “metabolically enhanced” T-cells (pages 13-16). Initially, the Examiner disagrees with Applicant’s arguments regarding Wu’s teachings and interpretations thereof made in rebuttal of the anticipation of Wu, and maintains Wu anticipates the independent claims, for the reasons stated above. At page 14 of the Reply, Applicant argues that Wu’s disclosure requires heterodimeric CARs comprising a first polypeptide comprising an extracellular ligand-binding domain/Transmembrane domain and second polypeptide comprising a hinge/transmembrane domain and intracellular signaling domain, wherein activation only occurs in the presence of antigen and dimerizing agent in order for heterodimerization of the two chimeric first and second polypeptides. Applicant further argues, “one of ordinary skill in the art would understand that Wu does not disclose, teach, or suggest that its second polypeptide comprising a hinge/transmembrane domain and an intracellular co-stimulatory domain would be activated or exhibit functional effects without the Wu's specific dimerizing event” (page 14). Applicant’s arguments are not persuasive. The statement “Wu does not disclose, teach, or suggest that its second polypeptide comprising a hinge/transmembrane domain and an intracellular co-stimulatory domain would be activated or exhibit functional effects without the Wu's specific dimerizing event” is confusing in light of the claims and specification for at least the following reasons: Claims 1 and 32 recite, “upon activation of the T cell, expression of the chimeric intracellular signaling molecule metabolically enhances the T cell.” Initially, Applicant statement appears to take the position that “expression of the chimeric intracellular signaling molecule metabolically enhances the T cell” is interpreted as “signal transduction through the expressed chimeric signaling molecule metabolically enhances the T cell.” There is no requirement that “expression of the chimeric intracellular signaling molecule” equates to “signal transduction through the expressed chimeric intracellular signaling molecule.” “Expression” of the chimeric intracellular signaling molecule is the presence of the translated protein, absent evidence to the contrary. In addition, the claims recite “upon activation of the T cell” but Applicant’s arguments over Wu refer to a lack of activation of the receptor that results in a functional result. Applicant’s argument suggests “activation” of a T-cell (as claimed) is necessarily separate from the “activation” of (i.e. signal transduction through) the intracellular chimeric signaling receptor. However, no such definition is supported by the specification (paragraph [0050]) or claims, as iterated above. Applicant’s arguments raise the question of how “upon activation of the T cell” is interpreted within the claim: stimulated and proliferating cells? as signal transduction through the chimeric intracellular signaling molecule? And how would the skilled artisan know the difference between activation of the claimed T-cells and those of the prior art? With regard to Applicant’s concern that “Wu does not disclose, teach, or suggest that its second polypeptide comprising a hinge/transmembrane domain and an intracellular co-stimulatory domain would be activated or exhibit functional effects without the Wu's specific dimerizing event” does not undermine Wu’s relevancy to the pending claims. The claims do not require that the metabolic enhancement is the result of signal transduction through the chimeric receptor (expression of the chimeric intracellular signaling molecule metabolically enhances the cell). In addition, even if the claims were interpreted as encompassing wherein the metabolic enhancement was the result of signal transduction through the chimeric receptor, neither the claims nor specification exclude the presence of an additional non-covalent interacting domain providing signals resulting in “activation.” There is no limiting definition of how/when/what signal transduction through the claimed chimeric intracellular signaling molecule is initiated. Based on the teachings of the instant disclosure, the “activation” of T-cells appears to encompass from initiation of the activation process through to an “activated” T-cell, and “upon activation” does not require a step-wise order of events and can be concurrent with “signal transduction through the expressed intracellular signaling molecule in the cell metabolically enhances the T cell(s).” With regard to Applicant’s argument that Wu’s recombinant T-cells are only “activated” via CAR heterodimerization of the extracellular domain and the intracellular domain with both an antigen and a dimerization agent, the Examiner cannot agree. There is no disclosure in Wu that “activation” of immune cells expressing the heterodimeric CAR can only be activated by antigen binding and dimerization. Wu discloses transduced immune cells expressing the CAR peptides include cytotoxic cells obtained from an individual, including CD8+ T-cells, primary CD8+ T-cells, and NK cells (paragraphs [0049], [00208]-[00209], [00273], [00282], [00306]). CD8+ T-cells and NK cells are antigen-specific before being transduced with the CAR peptides. See, Sun et al. NK Cell Development, Homeostasis and Function: Parallels with CD8+ T Cells. Nature Reviews Immunology, 2011. 11:645-657. In addition, Wu discloses the cytotoxic activity of cytotoxic immune cells expressing the CAR peptides heterodimerize in the presence of antigen and dimerization agent is increased over cytotoxic cells expressing the CAR peptides in the presence of antigen but absence of dimerization agent (paragraphs [0070], [00205], [00212]-[00213], [00229]-[00230]). Wu teaches activation of the heterodimeric CAR may result in activation of the immune cell via one or more ITAMs, or activation of the heterodimeric CAR may result in intracellular signal transduction from any desired signaling domain that provides a distinct and detectable signal, including increased cytokine, alteration of target gene expression, cell death, cell differentiation, etc. (paragraphs [00161], [00209], claims 34-35). At page 15 of the Reply, Applicant argues because activation of Wu requires heterodimerization in the presence of antigen and dimerizing agent, and does not disclose metabolic enhancement, Wu cannot be used to sustain an obviousness rejection. The Examiner is not persuaded. Initially, as noted above, the claims do not require that signaling through the chimeric intracellular results in metabolic enhancement of the T-cell. The claims, as amended, require “upon activation of the T cell(s), expression of the chimeric intracellular signaling molecule metabolically enhances the T cell(s).” And, as articulated above, the Examiner has articulated how Wu necessarily anticipates the pending claims – based on the interpretation of the claims in light of the specification. At page 15, Applicant states, “The Examiner's allegation that Wu's second polypeptide might exhibit some basal level of signaling activity in the absence of a dimerizing agent is speculative, and in any event Wu is entirely silent on whether any such activity would constitute or produce metabolic enhancement as claimed.” (emphasis added). The Examiner is unable to find any evidence in the Non-Final office action dated 4/02/26 wherein the Examiner argued that Wu’s second polypeptide might exhibit some basal level of signaling activity in the absence of dimerization agent, nor has Applicant cited where within the document such an allegation was made. However, contrary to Applicant’s assertion, Wu indeed suggests the cells expression the heterodimeric CAR peptides exhibit some activity in the presence of antigen but lack of dimerization agent. Wu discloses the cytotoxic activity of cytotoxic immune cells expressing the CAR peptides heterodimerize in the presence of antigen and dimerization agent is increased over cytotoxic cells expressing the CAR peptides in the presence of antigen but absence of dimerization agent (paragraphs [0070], [00205], [00212]-[00213], [00229]-[00230]). For example, at [00212] Wu states: Contacting a genetically modified cytotoxic cell (e.g., cytotoxic T lymphocyte) with a dimerizing agent and a second member of a specific binding pair (e.g., an antigen, a ligand, a receptor) can increase cytotoxic activity of the cytotoxic cell by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, at least about 2-fold, at least about 2.5-fold, at least about 5-fold, at least about 10-fold, or more than 10-fold, compared to the cytotoxic activity of the cytotoxic cell in the absence of the dimerizing agent. Thus, Wu teaches the inclusion of the CAR peptides, antigen and dimerization agent has at least 10% increased cytotoxic activity compared to the cytotoxic activity of “the cytotoxic cell” in the absence of dimerizing agent. Here the cells without the dimerizing are 1) necessarily cytotoxic (i.e. have some activity), and 2) the only articulated difference is that these cells do not have the dimerizing agent. In addition, Wu exemplifies activation of T-cells expressing the heterodimeric CARs peptides in the presence of antigen but absence of dimerizing agent. Wu shows increased NFAT expression (indicative of T-cell activation) in T-cells transduced with the heterodimeric CAR in the presence of antigen but in the absence of dimerizing agent compared to T-cells transduced with the heterodimeric CAR peptides in the absence of antigen and in the absence of dimerizing agent in FIG. 16. The relevant portions of FIG 16 are reproduced below, comprising arrows indicating the specific data relating to T-cell activation in the presence of antigen (+) but absence of dimerizing agent (0) vs. absence of antigen (-) and absence of dimerizing agent (0)): PNG media_image2.png 714 652 media_image2.png Greyscale Thus, while no such argument was made in the previous office action, such an assertion would not have been speculative, as Wu both discloses and exemplifies basal activity from cells expressing both CAR heterodimer peptides in the presence of antigen but absence of dimerizing agent. With regard to Applicant’s argument that even if any basal activity was demonstrated from Wu’s second peptide, the basal activity would not constitute metabolic enhancement, because Wu allegedly does not disclose metabolic enhancement. This argument is not persuasive for the same reasons as stated above. At page 16, Applicant argues the combination of Galetto with Wu does not cure the deficiencies of Wu, as neither prior art reference discloses metabolic enhancement of T-cells. The examiner disagrees for the reasons stated above articulating how Wu necessarily discloses metabolically enhanced T-cells. The 103 rejection over claims 7 and 37-38 as obvious over WO2004/127261 to Wu in view of US2013/0315884 to Galletto and Muller and Kontermann, 2010; The 103 rejection over claim 36 as obvious over WO2004/127261 to Wu in view of US2013/0315884 to Galletto, Sharon 2005 and WO2011/057124 to Lum; and The 103 rejection over claims 7 and 37-38 as obvious over WO2004/127261 to Wu in view of US2013/0315884 to Galletto and US Patent No. 6,004,554 to Thorpe: Each of the above 103 rejections are MAINTAINED. Applicant’s arguments with regard to each of the 103 rejections of record reiterate Applicant’s previous arguments: that Wu does not teach or suggest metabolically enhanced T-cells, and no combination of Galletto, Muller and Kontermann, Sharon, Lum and/or Thorpe cure the deficiencies of Wu and teach or suggest metabolically enhanced T-cells. This argument is not persuasive for the same reasons as stated above. PRIORITY The instant application, filed 4/18/2023, is a DIVISIONAL of US Patent No. 11,649,435, filed 02/28/2018 which is a 371 of PCT/US2016/048638, filed 08/25/2016, which claims priority to US Provisional Application No 62/211,295, filed 08/28/2015. Thus, the earliest possible priority for the instant application is 08/28/2015. CLAIMS Independent claims 1 and 32 are directed to a metabolically enhanced T-cell (claim 1) or population thereof (claim 32) comprising a chimeric intracellular signaling molecule, wherein (a) the chimeric intracellular signaling molecule comprises, at least, (i) an intracellular domain of a co-stimulatory molecule, and (ii) a myristoylation signal; or a hinge and a transmembrane domain; and (b) the chimeric intracellular signaling molecule substantially lacks an extracellular ligand binding domain; (c) the metabolically enhanced T-cell expresses the chimeric intracellular signaling molecule; and (d) upon activation of the T-cell, expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell. The term "chimeric intracellular signaling molecule" refers to recombinant receptor comprising one or more intracellular domains of one or more co-stimulatory molecules. The chimeric intracellular signaling molecule substantially lacks an extracellular ligand-binding domain, such as an non-antigen binding domain, or substantially lacks an extracellular domain. In some embodiments, the chimeric intracellular signaling molecule comprises additional domains, such as a transmembrane domain, a detectable tag, and a spacer domain. Paragraph [0068] of the published specification. The specification does not define “hinge.” A "co-stimulatory molecule" refers to the cognate binding partner on a T-cell that specifically binds with a co-stimulatory ligand, thereby mediating a co-stimulatory response by the T-cell, such as, but not limited to, proliferation. Paragraph [0071] of the published specification. As used herein, the term "substantially lacks an extracellular ligand-binding domain" refers to a molecule that is essentially free of a binding domain that specifically binds to a molecule. In one embodiment, the chimeric intracellular signaling molecule lacks any functional ligand binding domain in the extracellular domain, such as lacking an antigen binding domain. In another embodiment, the chimeric intracellular signaling molecule includes an extracellular domain but lacks the capacity to specifically bind to a ligand, such as an antigen. Paragraph [0118] of the published specification. Thus, a “chimeric intracellular signaling molecule” that “lacks an extracellular ligand-binding domain” is a chimeric receptor that comprises a transmembrane domain or a myristolation signal, which anchors the chimeric receptor within the cell membrane; wherein the chimeric receptor is able to signal within the cell, but is unable to bind an extracellular ligand, either because the ligand binding domain is mutated or deleted. See also FIGs. 10-12 of the published specification. A non-limiting diagram comparing a “a chimeric intracellular signaling molecule” to a “chimeric intracellular signaling molecule” that “substantially lacks an extracellular ligand-binding domain” is provided below: PNG media_image3.png 640 1004 media_image3.png Greyscale The instant specification does not define "metabolically enhanced" T-cells. Paragraph [0138] of the published specification discloses expression of the chimeric intracellular molecule metabolically enhances the T-cell. Paragraph [0160] of the published specification discloses expression of a Chimeric Antigen receptor metabolically enhances the T-cell. Paragraph [0227] of the published specification discloses stimulation of a T-cell expressing a chimeric intracellular signaling molecule metabolically enhances the T-cell. Thus, for the purposes of prosecution, based on the teachings of the specification, a T-cell expressing a chimeric intracellular molecule lacking an extracellular ligand binding domain reads on a metabolically enhanced T-cell. The independent claims have been amended to recite, upon activation of the T-cell, expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell. The new requirement wherein “upon activation of the T-cell(s), expression of the chimeric signaling receptor results in metabolically enhanced T-cell(s)” does not appear to significantly alter the scope of the pending claims. Metabolic enhancement of the cell is still the result of expression of the chimeric intracellular signaling molecule in the cell. “Expression” of the chimeric intracellular signaling molecule is the presence of the translated protein, absent evidence to the contrary. In addition, there is no limiting definition of “activation” of T-cells in the specification. Paragraph [0050] of the published specification teaches: “’Activation,’ as used herein, refers to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production, and detectable effector functions. The term ‘activated T cells’ refers to, among other things, T cells that are undergoing cell division.” There is no requirement of what “detectable cellular proliferation” encompasses: is the upregulation of proliferation signal(s) within the cell, that are detectable via assay (mRNA? protein?), but prior to actual cell division encompassed? Or have the cells necessarily divided? There is no mechanism articulating how activation is “associated” with induced cytokine production and/or detectable effector functions. Cytokine production can be the result of T-cell activation as well as a cause of T-cell activation (See, Curtsinger et al. Inflammatory Cytokines as a Third Signal for T Cell Activation. Current Opinion in Immunology, 2010. 22(3):333-340). Thus the “activation” of T-cells appears to encompass from initiation of the activation process through to an “activated” T-cell. As such, “upon activation” does not require a step-wise order of events. There is no requirement that metabolic enhancement occurs after (some undefined point after initiation) “activation” of T-cells, and the claims can be reasonably interpreted as wherein “expression of the intracellular signaling molecule in the cell metabolically enhances the T cell(s)” can be concurrent with the initiation of activation, encompassed by “upon activation.” The claimed requirement of “metabolically enhanced” is interpreted based on the structural requirements recited in the pending claims: expression of the chimeric signaling receptor in the T-cells. Taken together, the broadest reasonable interpretation of the amended claims, directed to T-cells comprising a chimeric intracellular signaling molecule reciting “wherein upon activation of the T cell(s), expression of the chimeric intracellular signaling molecule metabolically enhances the T cell(s)” encompasses: a T-cell(s) expressing a chimeric intracellular signaling molecule with the recited structures and lacking an extracellular ligand binding domain, wherein expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell(s), wherein expression of the chimeric intracellular signaling molecule metabolically enhancing the T-cell(s) occurs concurrently or later than the initiation of activation of the T-cell(s). NEW OR MODIFIED REJECTIONS Claim Rejections - 35 USC § 112 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. Claims 1, 3-7, 9 and 31-40 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. This rejection is necessitated by Applicant’s amendments to the claims. Claims 1 and 32 directed to “a metabolically enhanced T-cell”, or population thereof, comprising (at least) a chimeric intracellular signaling molecule; wherein the metabolically enhanced T-cell expresses the chimeric intracellular signaling molecule; and wherein “upon activation of the T-cell, expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell.” The new limitation renders the claims indefinite because it is not clear whether the limitation is an active step required to practice the invention (and if so, what step? Activation? Expression?), or a product-by-process limitation that generates the metabolically active cell. If the claims require an active step, the presence of an active step within a composition claim creates indefiniteness. A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011). The presence of a method step within a composition claim creates confusion as to whether infringement occurs when one creates the composition or whether infringement occurs when the one actually uses the composition. See MPEP 2173.05 (p). Use of the term “upon activation” is indefinite. There is no limiting definition of “activation” of T-cells in the specification. Paragraph [0050] of the published specification teaches: “’Activation,’ as used herein, refers to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production, and detectable effector functions. The term ‘activated T cells’ refers to, among other things, T cells that are undergoing cell division.” There is no requirement of what “detectable cellular proliferation” encompasses: is the upregulation of proliferation signal(s) within the cell, that are detectable via assay (mRNA? protein?), but prior to actual cell division encompassed? Or have the cells necessarily divided? There is no mechanism articulating how activation is “associated” with induced cytokine production and/or detectable effector functions. Cytokine production can be the result of T-cell activation as well as a cause of T-cell activation (See, Curtsinger et al. Inflammatory Cytokines as a Third Signal for T Cell Activation. Current Opinion in Immunology, 2010. 22(3):333-340). Thus the “activation” of T-cells appears to encompass from initiation of the activation process through to an “activated” T-cell. As such, “upon activation” does not require a step-wise order of events. There is no requirement that metabolic enhancement occurs after (some undefined point after initiation) “activation” of T-cells, and the claims can be reasonably interpreted as wherein “expression of the intracellular signaling molecule in the cell metabolically enhances the T cell(s)” can be concurrent with the initiation of activation, encompassed by “upon activation.” Taken together, a skilled artisan would not know the metes and bounds of the claimed phrase, “upon activation of the T-cell, expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell.” Claims 3-7, 9, 31 and 33-40 are included in the rejection because they depend from a rejected claim. Claim Rejections - 35 USC § 102 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claims 1, 3, 9, 31-32 and 34-35 remain rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by WO2004/127261 to Wu, of record. This rejection is modified in response to Applicant’s amendments to the claims. With regard to claims 1 and 32, Wu discloses T-cells comprising heterodimeric chimeric antigen receptors (CARs), wherein a CAR comprises, at least, a first polypeptide comprising an extracellular ligand-binding domain and a transmembrane domain, and a second polypeptide comprising a hinge/transmembrane domain and an intracellular co-stimulatory domain, and the two polypeptides form a heterodimer via an intracellular heterodimerization domain (paragraphs [0060]-[0062], [0066], [0082], [00206]-[00208], [00216]). See, FIG. 17 of Wu: PNG media_image4.png 509 567 media_image4.png Greyscale Wu discloses transmembrane/hinge domains can be present on both the first and second polypeptides, and are selected from CD8 (paragraphs [0045], [0074], [0083]-[0084], [0087]-[0093]. The intracellular signaling domains the second peptide are selected from 4-1BB, CD28, ICOS, OX-40, CD27, CD30, GITR, DAP10, CD3 delta, CD3 epsilon, CD3 gamma, CD3 zeta, CD79 (paragraphs [0098]-[0101], [00104]-[00112], [00162]-[0163]). Wu discloses the chimeric receptor transmits signal from the ligand-binding domain of the first polypeptide to the second polypeptide when the chimeric receptor heterodimerizes (paragraph [0060], [0066]-[0075]). Thus, the second polypeptide of the chimeric receptor domain of Wu necessarily comprises all of the structural elements recited in the claims of 1) the intracellular signaling domains of the co-stimulatory proteins to be selected from the group consisting of 4-1BB, CD28, ICOS, OX-40, CD27, CD30, GITR, DAP10, CD3 delta, CD3 epsilon, CD3 gamma, CD3 zeta, CD79, and 2) substantially lacks an extracellular ligand-binding domain. In addition, Wu necessarily discloses the new requirement wherein “upon activation of the T-cell, expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell” for at least the following reasons: The requirements relating to a prima facie case of anticipation or obviousness of a composition based on inherency are clear – if the prior art products are identical in structure or composition a prima facie case of anticipation is made; and if a composition is physically the same, it must have the same properties (MPEP 2112.01 (I) and (II): Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. Initially, the phrase “upon activation of the T-cell, expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell” renders the claims indefinite, for the reasons stated above in the 112b rejection. For the purposes of prosecution, the broadest reasonable interpretation of the amended claims encompasses: a T-cell(s) expressing a chimeric intracellular signaling molecule with recited structures and lacking an extracellular ligand binding domain, wherein expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell(s), and wherein expression of the chimeric intracellular signaling molecule metabolically enhancing the T-cell(s) occurs concurrently or later than the initiation of activation of the T-cell(s). However, Wu does not explicitly describe the T-cells therein exhibit “metabolic enhancement.” As mentioned above, “metabolic enhancement” is not defined in the specification or claims. A prior art reference that discloses a T-cell with the same claimed structures necessarily reads on “metabolically enhanced” T-cells (MPEP 2112.01 (I) and (II)). Because Wu discloses T-cells comprising chimeric intracellular signaling molecules comprising every structural limitation of claims 1 and 32, and Wu discloses the chimeric intracellular signaling molecules are expressed in the T-cells, the T-cells of Wu are necessarily “metabolically enhanced.” In addition, Wu discloses activation of the T-cells expressing the chimeric intracellular signaling molecules, wherein activation results in intracellular signaling responses and cytokine production (paragraphs [00161], [00191], and [00209]-[00214]). As such, Wu necessarily inherently discloses “upon activation of the T-cell(s), expression of the chimeric intracellular signaling molecule metabolically enhances the T-cell(s)” according to the broadest reasonable interpretation of the claims in light of the specification (MPEP 2111) and the requirements of inherency (MPEP 2112.01 (I) and (II)). Thus, Wu anticipates claims 1 and 32. With regard to claim 3, because Wu anticipates the T- cells of claim1, Wu necessarily anticipates function recited in the claim. With regard to claim 9, Wu discloses the T-cells comprising the CARs are generated ex vivo and administered to a subject in need as a treatment, as an intravenous injection (paragraph [00215]-[00220], [00226]-[00227],[00267]-[00268], and [00306]) which reads on a pharmaceutical composition comprising the cells and a pharmaceutically acceptable carrier, absent evidence to the contrary. With regard to claim 31, Wu discloses the T-cells comprising the CARs are generated ex vivo and administered to a subject in need as a treatment, as an intravenous injection (paragraph [00215]-[00220], [00226]-[00227],[00267]-[00268], and [00306]) which reads on a composition comprising the cells, absent evidence to the contrary. With regard to claim 34, Wu discloses the CARs comprise detectable tags (paragraphs [00184]-00190]). With regard to claim 35, Wu discloses the hinge and transmembrane domain are from CD8 alpha (SEQ ID NO: 29, 30, 56, 143, 144] (paragraphs [0090], [0093]). 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. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 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 4-6, 33 and 37 remain rejected under 35 U.S.C. 103 as being unpatentable over WO2004/127261 to Wu, as applied to claims 1, 3, 9, 31-32 and 34-35 above, further in view of US2013/0315884 to Galetto, of record. Claims 4-6, 33 and 37 are directed to embodiments wherein the cells further comprise a bispecific antibody. Wu is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Wu discloses T-cells comprising heterodimeric chimeric antigen receptors (CARs), wherein a CAR comprises, at least, a first polypeptide comprising an extracellular ligand-binding domain and a transmembrane domain, and a second polypeptide comprising a hinge/transmembrane domain and an intracellular co-stimulatory domain, and the two polypeptides form a heterodimer via an intracellular heterodimerization domain (paragraphs [0060]-[0062], [0066], [0082], [00206]-[00208], [00216]). Wu discloses the ligand—binding domain can be an antigen-binding domain from an antibody, and the antigen binding domain can have a variety of antigen-binding specificities, including cancer cell antigens/epitopes (paragraphs [0077]-[0079]). However, Wu does not disclose that the antigen-binding domain comprises a bispecific antibody as required by claims 4 and 33. Galetto discloses T-cells expressing multi-chain chimeric antigen receptors which form dimeric, trimeric and tetrameric CARS, wherein at least one chain does not have an extracellular ligand binding domain, and upon ligand binding, the dimers transmit signal through the chain that does not have an extracellular ligand binding domain (paragraphs [0127]-[0128], [0136]-[0146]; FIGs 3-4). Galetto further discloses a chain of the multi-chain CAR comprises a bispecific antibody, or the cell encodes and expresses a bispecific antibody (paragraphs [0133], [0151], [0162], [0214]) and wherein the bispecific antibodies comprise two distinct antigen binging domains, which function to direct the T-cells to target antigens as well as activate the T-cells (paragraphs [0162], [0246]). It would have been obvious to combine the T-cells expressing multi-chain CARs of Wu, wherein at least one chain comprises an antigen-biding domain from an antibody, further with the disclosure of Galetto. A skilled artisan would have been motivated to include a bispecific antibody in the T-cells of Wu because Wu discloses the multi-chain CARs can have a variety of antigen-binding specificities, and Galetto teaches bispecific antibodies in T-cells expressing multi-chain antibodies allow for targeting two different antigen binding domains, allowing to redirect and activate the T-cells. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as including bispecific antibodies in T-cells expressing multi-chain CARs was known at the time of the invention. With regard to claims 5-7 and 37, Wu does not disclose the use of bispecific antibodies. However, Galetto discloses the bispecific antibodies comprise two distinct antigen binging domains, and they function to direct the T-cells to target antigens as well as activate the T-cells (paragraphs [0162], [0246]). Claims 7 and 37-38 remain rejected under 35 U.S.C. 103 as being unpatentable over WO2004/127261 to Wu and US2013/0315884 to Galetto, of record, as applied to claims 1, 3-6, 9, 31-33, 34-35 and 37 above, and further in view of Müller and Kontermann. Bispecific Antibodies for Cancer Immunotherapy. Biodrugs, 2010. 24(2): 89-98, of record. The disclosures of Wu and Galetto are applied as in the 102 and 103 rejections above, the content of which is incorporated herein in its entirety. Wu and Galetto combine to render obvious T-cells comprising a chimeric receptor and a bispecific antibody, as required by claims 1, 4-5, and 32-33. Galetto discloses the bispecific antibodies can be produced in any variety of ways (paragraph [0246]). However, neither Wu nor Galetto disclose wherein the bispecific antibody is a first and second single-chain antibody as required by claim 28; or wherein the bispecific antibody comprises a first whole immunoglobulin and a second whole immunoglobulin comprising IgG, IgA or IgD, as required by claims 37 and 38. Müller and Kontermann disclose bispecific antibodies utilize multiple formats, having evolved over time with technology and clinical requirements (Abstract, page 91, first column). Müller and Kontermann discloses known formats include wherein the bispecific antibodies comprise a first and second single chain variable fragment molecule, or wherein the bispecific antibody comprises an antigen binding domain comprising a first whole immunoglobulins and a second whole IgG molecule (FIG 1; page 90, 95). Müller and Kontermann disclose the use of two ScFV in an antigen binding domain allows two binding sites for a single antigen or a binding site for two distinct antigens, which can result in bivalent, trivalent or more formats in small and compact molecules (page 90, second column last paragraph bridging page 91, first column). Müller and Kontermann disclose use of whole immunoglobulins such as IgG increases the half-life of the bispecific antibodies (page 95, Half-Life Extension Strategies section). It would have been obvious to combination the disclosures of Wu and Galetto on T-cells expressing multi-chain CARs comprising a bispecific antibody, further with the disclosure of Müller and Kontermann. A skilled artisan would have been motivated to use known bispecific antibody structures known in the art which are known for use in cancer therapies (MPEP2143(I)(A); MPEP2144.07). A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as multiple formats of bispecific antibodies used in cancer therapies comprising T-cells were known in the art at the time of the invention. Claim 36 remains rejected under 35 U.S.C. 103 as being unpatentable over WO2004/127261 to Wu and US2013/0315884 to Galetto, of record, as applied to claims 1, 3-6, 9, 31-33, 34-35 and 37 above, and further in view of Sharon et al. Recombinant Polyclonal Antibodies for Cancer Therapy. Journal Cellular Biochemistry, 2005. 96:305-313, of record, and WO2011/057124 to Lum (publication dated May 12, 2011), of record. The disclosures of Wu and Galetto are applied as in the 102 and 103 rejections above, the content of which is incorporated herein in its entirety. Wu and Galetto combine to render obvious T- cells comprising a chimeric receptor lacking an extracellular ligand-binding domain and a bispecific antibody, as required by claims 1, 4-5, and 32-33. Galetto discloses the bispecific antibodies can be produced in any variety of ways (paragraph [0246]). However, neither Wu nor Galetto disclose wherein the bispecific antibody is chemically heteroconjugated to a polyclonal antibody specific for a tumor-associated antigen (TAA), and the metabolically enhanced T-cell specifically binds the TAA polyclonal antibody, as required by claim 36. Sharon discloses anticancer treatments using monoclonal antibodies (directed to a single target antigen) eventually result in escape variants which render the therapy ineffective (Abstract). Sharon discloses the use of polyclonal antibodies, which target multiple epitopes/antigens on a cancer cell could minimize the generation of escape variants and be more efficient than monoclonal antibodies (Abstract). Sharon discloses the generation of a polyclonal library of a cancer would provide multiple antibodies against different tumor-associated epitopes/antigens which would allow for the polyclonal library to be effective on cancers using lower density tumor-associated antigens, as more polyclonal antibodies are used - compared to a single monoclonal antibody directed to a single tumor antigen (page 308-309; Fig 2). Sharon generates a library of polyclonal antibodies directed to a colorectal cancer cell line, and shows the polyclonal antibody library bound with higher density than a known corresponding anti-colorectal cancer antibody CO17-1A, and was more effective at inhibiting a human colorectal cell line in culture (page 310, second column). Lum discloses generating polyclonal bispecific antibodies, wherein the bispecific antibody is generated from the fusion of a T cell antibody binding portion (first antigen binding portion) to a polyclonal antibody directed to a second target antigen (paragraph [0007], [0042]-[0043], [0061]). Lum discloses the polyclonal antibody directed to the second target antigen is directed to different epitopes on an antigen or to two different antigens (paragraph [0011]). Lum discloses the polyclonal bispecific antibodies are produced by heteroconjugating a polyclonal antibody directed to the second antigen to the T cell antibody binding portion (paragraphs [0031], [0095]-[0100]). Lum discloses the polyclonal antibodies are armed on T-cells (paragraph [0014]). Lum discloses the concentration of polyclonal bispecific antibodies needed to arm cells is reduced compared to traditional bispecific antibodies, thus reducing the amount of antibody necessary to achieve a therapeutic effect, and reduce the possibility of an immune response generated against the bispecific antibodies by a patient (paragraph [0023]). It would have been obvious to combine the disclosures of Wu and Galetto on T-cells expressing multi-chain CARs comprising a bispecific that binds a T-cell and a tumor cell, further with the disclosures of Sharon and Lum. A skilled artisan would have been motivated to use polyclonal bispecific antibodies, as Sharon identifies the benefits of using polyclonal antibodies as therapeutics for cancer treatments by providing multiple antibodies which bind lower concentrations of individual tumor associated antigens, but result in more overall binding to cancer cells compared to monoclonal antibodies directed a single tumor antigen, and suggests use of polyclonal antibodies would reduce escape variants. Lum further shows that generating polyclonal bispecific antibodies can localize the bispecific polyclonal antibodies to a target site using a significantly reduced amount of antibody necessary to result in a therapeutic effect. The skilled artisan would have been motivated to generate the polyclonal antibodies by chemically conjugating the polyclonal antibodies targeted to a tumor antigen to a T-cell binding segment, as Lum discloses polyclonal bispecific antibodies are made using such methods. MPEP 2143 (I)(A). A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as the benefits of using polyclonal antibodies in cancer therapies, and the generation of polyclonal bispecific antibodies were known in the art at the time of the invention. Claims 39-40 remain rejected under 35 U.S.C. 103 as being unpatentable over WO2004/127261 to Wu and US2013/0315884 to Galetto, of record, as applied to claims 1, 3-6, 9, 31-33, 34-35 and 37 above, and further in view of US Patent No. 6,004,554 to Thorpe, of record. The disclosures of Wu and Galetto are applied as in the 102 and 103 rejections above, the content of which is incorporated herein in its entirety. Wu and Galetto combine to render obvious T- cells comprising a chimeric receptor lacking an extracellular ligand-binding domain and a bispecific antibody, as required by claims 1, 4-5, and 32-33. Galetto discloses the bispecific antibodies can be produced in any variety of ways (paragraph [0246]). However, neither Wu nor Galetto disclose wherein the T-cell expresses and displays two or more bispecific antibodies, as required by instant claim 39. Thorpe discloses T-cells displaying two distinct bispecific antibodies, wherein a first bispecific antibody binds to a first T-cell cell-surface marker and a first tumor-associated antigen and a second bispecific antibody that binds to a second cell cell-surface marker and a second tumor-associated antigen, to activate or localize the T-cells (column 8, line 1- column 9, line 21; Column 9, lines 50-62, column 10, lines 20-40, column 11 lines 18-65; column 16, lines 7-24; Claims 1-5; claims 20-21). Thorpe discloses that using two different bi-specific antibody increases T-cell activation (column 51, lines 24-44). It would have been obvious to combine the disclosures of Wu and Galetto on T-cells expressing multi-chain CARs and expressing bispecific antibodies, further with the disclosure of Thorpe on T-cells expressing and displaying two different bispecific antibodies. A skilled artisan would have been motivated to use two different bispecific antibodies in order to increase T-cell activation of the cells, as taught by Thorpe. A skilled artisan would have had a reasonable expectation of practicing the claimed invention as use of two bispecific antibodies to target and activate T-cells were known in the art at the time of the invention. With regard to claim 40, Galetto discloses the bispecific antibody binds CD3 (paragraph [0162]). Thorpe discloses the two bispecific antibodies bind CD3 (column 51, lines 24-44). This claim is obvious for the same reasons as stated above for claim 39. Conclusion No claims are allowed. No claims are free of the prior art. FINAL REJECTION THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY A ARON whose telephone number is (571)272-2789. 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