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 canceled claims 1-62, and added new claims 63-82, in the remarks of 8/21/2025; applicants amended claims 63 and 78 in the remarks of 12/23/2025.
Applicant’s remarks, filed 3/27/2026, are acknowledged and entered into the record. Applicants amended claims 63, 65, 69, 72 and 79 in the remarks of 3/27/2026.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/20/2026 has been entered.
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. The present application is drawn from PCT/US2019/041739, filed 7/12/2019.
Election of Species
Applicant's election with traverse of the various species of the single embodiment of the invention in the reply filed on 12/23/2025 is acknowledged. The examiner replied to the traversal and made the election of species Final in the Office Action of 2/20/2026. The requirement is still deemed proper and is FINAL.
Specifically, applicant’s election of the species of extracellular binding domain of TGFβ-RII, the intracellular activation domain of KIR2DS2, a second nucleic acid encoding cytokine IL-2, wherein the NK cells are allogenic, whereby the third domain encodes truncated CD19, is acknowledged. As none of RBDNR, NKA or NKCT (re. claim 78) comprise an intracellular domain of KIR2DS2 (see specs., pg. 70, line 5-15), claim 78 does not read on the elected species, and is withdrawn. Further, claims 65-66, 71-72, and 75 are withdrawn as they do not read on the elected species; see response to election filed 12/23/2025.
Status of Claims
Claims 63-82 are pending; claims 65-66, 71-72, 75 and 78 are withdrawn; claims 63-64, 67-70, 73-74, 76-77 and 79-82 are being examined on the merits.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claims 63-64, 67-70, 73-74, 76-77 and 79-82 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, is withdrawn. Applicants moved the “optional” language to the end of the claim, thereby clarifying the optional parts.
Claim Rejections - 35 USC § 103
The rejection of claims 63-64, 67-70, 73, 76 and 79-82 under 35 U.S.C. 103 as being unpatentable over Bollard et al., (from IDS, Cite No. 45; Blood, 2002, 99(9)); and Mohammed et al., (Molecular Therapy, 2017, 25(1)); and Milone et al., (US Patent 9,745,368; issued 8/29/2017), is withdrawn. The examiner has amended the obviousness rejections to include more appropriate references.
Claim Objections
Claim 63 objected to because of the following informalities: Claims 63 recites “wherein in (a) the second intracellular NK activation domain is not that of TGF-β receptor I and a TGF-β receptor II”. The claim does not recite “selected from a group consisting of”; therefore the conjugation should be “the NK activation domain is not that of TGF-βRI or TGF-βRII.” Appropriate correction is required.
Claim Rejections – New
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.
Claims 63-64, 67-70, 73, 76 and 79-82 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., (from IDS of 1/10/2022; Cancer Immunol Immunother; 2017) in view of Milone et al., (US Patent 9,745,368; issued 8/29/2017) and Bollard et al., (from IDS, Cite No. 45; Blood, 2002, 99(9)).
The applied reference has a common inventor, Catherine Bollard, with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1).
Wang et al. teaches genetically modifying a NK-92 cell to express a chimeric receptor with a TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (abstract). Wang teaches the goal was to convert the suppressive signal induced by TGF-β to an activating signal. In doing so, Wang teaches the modified NK-92 cells were resistant to TGF-β-induced suppressive signaling and had higher killing capacity and IFN-γ production against tumor cells compared with control cells; further, that their cytotoxicity could be further enhanced by TGF-β. Still further, Wang teaches the genetically engineered NK-92 cells were better chemo-attracted to the tumor cells expressing TGF-β, and that inverted chimeric receptors comprising TGF-βR extracellular domains coupled to NKG2D NK cell activating intracellular domains (i.e., TN) can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy (abstract). Specifically, Wang utilized the TGF-βR II extracellular domain (pg. 541, Fig. 2).
Wang teaches NK cells expressing chimeric receptors which invert the immunosuppressive TGF-β extracellular signal into an NK cell activating NKG2D-mediated signal. However, Wang does not teach wherein the NK cell activating intracellular domain is derived from the KIR2DS2 receptor.
Milone et al. teaches CARs wherein the CAR is termed a “KIR-CAR” which is a CAR design comprising a component of a receptor naturally found on natural killer (NK) cells, including wherein the NK receptor includes activating receptors of NK cells (abstract); and that one such activating receptor is KIR2DS2 (col. 277, claim 13). Milone teaches the CAR comprises an extracellular antigen binding domain, and a transmembrane (TM) and cytoplasmic domain, wherein the TM and cytoplasmic domain are from an NK cell receptor (col. 2, lines 1-7). Milone teaches in one embodiment the KIR-CAR is an activating CAR (i.e., actKIR-CAR), whereby the TM domain comprises a positively charged moiety which can interact with and promote signaling from an ITAM-containing polypeptide or adapter molecule, and which can act with and promote signaling from a DAP12 polypeptide (col. 3, lines 33-43). Milone teaches the extracellular domain comprises a target-specific binding element, or antigen-binding domain fused to a KIR or fragment thereof (col. 37, lines 11-13); and wherein the antigen-binding domain has affinity for a target antigen, such as tumor antigens on a cancer cell (col. 55, lines 10-14). Milone teaches that one such embodiment is an actCAR-KIR comprising a KIR2DS2 TM domain and/or a KIR2DS2 cytoplasmic domain (col. 3, lines 48-51). Milone reduces to practice one such embodiment, which is a mesothelin-specific SS1 KIR CAR with a KIR2DS2 TM and intracellular domain (col. 16, lines 53-63; see Fig. 5), which delivers its activating signal through an interaction with DAP12, which is mediated by residues within the transmembrane domains of these proteins (col. 22, lines 58-65). In another embodiment, Milone teaches a KIR-based CAR with CD19 specificity, whereby the anti-CD19 scFv FMC63 is fused to the TM and cytoplasmic domain of KIR2DS2 (col. 19, lines 50-60). Milone provides the amino acid sequence of the KIR2DS2, specifically delineating the TM domain and cytoplasmic domain (Fig. 29). The TM domain sequence of VLIGTSVVKIPFTILLFFLL, of Milone Fig. 29, is 100% identical to the selected TM domain of the instant invention, as described in Table Z (KIR2D; specs., pg. 25), corresponding to instant SEQ ID NO: 17 (pg. 26, lines 2-5). Thus, Milone teaches CARs comprising the TM and/or cytoplasmic domain of activating KIR2DS2 receptors, whereby the KIR2D TM domain interacts with DAP12 to activate the NK cells in response to antigen binding the KIR-CAR. Milone also teaches that NK cell stimulatory signals can be mediated by KIRs, as well as NKG2C and NKG2D receptors (col. 33, lines 38-41); and that truncated forms of intact receptors, such as NKG2 type receptors, may be constructed to form a functional signaling complex (col. 49, lines 1-10).
However, Milone does not teach whereby the extracellular domain of the chimeric receptor is directed to TGF-β, or that it is a truncated TGF-β receptor which may be functionally coupled to the intracellular domains of Milone.
Bollard et al. teaches adapting a transforming growth factor β (TGF-β)-related tumor protection strategy to enhance antitumor immunity (title). Bollard teaches that TGF-β plays a role in T-cell homeostasis by limiting the immune responses to antigen and by inducing tolerance, thereby diminishing the effectiveness of anti-tumor T-cell immune responses (pg. 3179, col. 1, para. 2). Bollard teaches that tumor cells express TGF-β as one of the most widely used evasion strategies; and that tumor cells also express a mutated TGF-β receptor (TGF-βR) that allows evasion of the adverse effects on the tumor cells themselves (pg. 3179, col. 2, para. 2). Bollard teaches that forced expression of a dominant-negative TGF-βRII in ex vivo-expanded EBV tumor-specific cytotoxic T lymphocytes (CTLs) for patients with relapsed Hodgkin disease renders them resistant to the inhibitory effects of TGF-β, while enabling them to retain their dependence on other growth regulatory signals (pg. 3180, col. 1, para. 2); and that the transduced CTLs were resistant to the antiproliferative and anticytotoxic effects of TGF-β and would have selective function and survival advantages in the presence of TGF-β secreting tumors, as a treatment (abstract). Specifically, Bollard teaches the TGF-βRII cDNA was truncated at nt597, thereby deleting most of its cytoplasmic tail and all of its cytoplasmic kinase domain, leaving only 7 amino acids remaining in the intracellular domain (pg. 3180, col. 1, para. 4). Further, Bollard teaches that the function and biochemistry of the truncated TGF-βRII has been extensively characterized in previous literature. Thus, Bollard teaches the modified, truncated TGF-β receptor extracellular domain, exogenously expressed in immune cells, for the purpose of imparting reduced sensitivity to the inhibitory functions of TGF-β, which is highly released by tumor cells, in order to enhance the anti-tumor activity of the immune cells in the tumor microenvironment. However, Bollard does not teach a chimeric fusion protein comprising the modified TGF-βRII extracellular domain linked to a heterologous intracellular domain which activates NK cells.
It would have been obvious to one of skill in the art to generate NK cells expressing a chimeric inverse receptor fusion protein, of Wang et al., wherein the fusion protein is modified to comprise the truncated TGF-βRII exodomain, of Bollard, linked to a KIR2DS2 NK cell activating endodomain, of Milone. One would have been motivated to do so given the knowledge that inversing immunosuppressive TGF-β signaling by expressing an inverted TGF-βR chimeric receptor coupled to an NK cell activating intracellular signaling domain promotes the therapeutic efficacy of engineered NK cells in the immunosuppressive tumor microenvironment, as taught by Wang et al. There would have been a reasonable expectation for success given that NKG2D and KIR2DS2 are alternate NK cell activating intracellular domains for use in the same way, as taught by Milone; the TGF-βRII domain will bind and sequester excessive immunosuppressive TGFβ around the tumor, as taught by Bollard et al., and will instead activate the cells via the KIR2DS2 endodomain, as taught by Milone; and that the KIR2DS2 endodomain may be linked to various exodomains via a linker, as taught by Milone et al. Thus the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 63-64, 67, 70 and 73; the combination of Wang, Milone and Bollard make obvious a TGF-βRII/KIR2DS2 inverted chimeric receptor fusion protein as described above, including wherein the construct comprises a portion of (i.e. truncated) extracellular binding domain of TGF-βRII (re. claim 73) and a TM of KIR2DS2 (re. claim 67). Milone teaches the chimeric proteins may be expressed in NK cells (col. 10, lines 5-6), which are allogenic (re. claim 70; col. 10, lines 6-7), or NK92 cell lines (col. 10, lines 7-8), which are a known human NK cell line. Thus, the combination construct of Wang, Milone and Bollard, expressed in human NK cells, make obvious instant claims 63-64, comprising a TM of KIR2DS2, of claim 67, and a truncated TGF-βRII extracellular domain, of claim 73, and whereby the cells are allogenic, of claim 70.
Regarding claim 68, Milone teaches a method of treating a subject comprising administering an effective amount of a cytotoxic cell comprising the KIR-CAR, whereby the cell is an autologous NK cell (col. 9, lines 52-57, lines 65-67, and col. 10, lines 4-6). Autologous NK cells are primary NK cells derived from the blood of the human patient; therefore the combination of Wang, Milone and Bollard make obvious instant claim 68.
Regarding claim 69, Wang teaches that TGF-β is a tumor-produced immunosuppressive cytokine (pg. 538, col. 1, para. 2), and thus makes obvious wherein the TGF-β is expressed by a cancer cell. Bollard teaches tumor cells may express TGF-βR type I or II receptors (pg. 3179, col. 2, para. 2). Thus the combination of Wang, Milone and Bollard make obvious instant claim 69.
Regarding claims 76 and 79, Milone teaches vectors comprising the nucleic acid encoding the constructs for expressing the constructs in cells (col. 69, lines 18-55). Milone teaches pharmaceutical compositions comprising the engineered cytotoxic cells expressing the KIR-CAR constructs (col. 84, lines 54-58). Thus, the combination of Wang, Milone and Bollard make obvious the vectors and pharmaceutical compositions of instant claim 76. Further, Milone teaches the engineered cells may be used in combination with chemotherapy (col. 85, lines 66-67), where the cells may be administered in conjunction with chemotherapy agents (col. 86, lines 13-17). Thus, the teachings of Milone make obvious pharmaceutical compositions comprising the engineered cells and a chemotherapeutic agent, and make obvious instant claim 79.
Regarding claims 80-82; Milone teaches methods of treating a subject having cancer comprising administering an effective amount of the engineered cells (col. 9, line 65 – col. 10, line 1; see also Therapeutic Application, col. 82, line 25). Milone teaches solid tumors for which the methods are applicable include neuroblastoma (col. 83, lines 49-54). Bollard teaches neuroblastoma includes malignant cells that secrete TGF-β which are a target of the truncated TGF-βRII extracellular domains, and that expressing TGF-β is among the most widely used evasion strategies (pg. 3179, col. 1, para. 2). Thus the combination of Wang, Milone and Bollard make obvious a method of administering the engineered NK cells to kill target cells that express TGF-β, wherein the target cell is a cancer cell, and wherein the cancer cell is neuroblastoma, of instant claims 80-82.
Claim Rejections - 35 USC § 103
Claim 74 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., (from IDS of 1/10/2022; Cancer Immunol Immunother; 2017) in view of Milone et al., (US Patent 9,745,368; issued 8/29/2017) and Bollard et al., (from IDS, Cite No. 45; Blood, 2002, 99(9)) as applied to claims 63-64, 67-70, 73, 76 and 79-82 above, and further in view of Nagashima et al., (Blood, 1998, 91(10)).
The combination of Wang, Milone and Bollard make obvious modified human NK cells comprising a TGF-βRII/KIR2DS2 construct, as described above. However, they do not teach wherein the cells further comprise an exogenous nucleic acid encoding one or more cytokines, or wherein said cytokine is IL-2.
Nagashima et al. teaches the stable transduction of the IL-2 gene into human NK cell lines (title). Nagashima teaches that subsets of NK cells, designated A-NK cells, which are activated by IL-2 were found to be able to kill a variety of tumor cell targets (pg. 3850, col. 1, para. 1). Nagashima teaches that in many cases the anti-tumor activity of the NK cells was dependent on the presence of exogenous IL-2. However, in this report they demonstrate successful retroviral transduction of the human IL-2 gene into two NK cell lines; whereby the cells produced and secreted bioactive IL-2 in quantities sufficient to support various functions, including the growth of the NK-92 line, and significantly prolonged the survival of the mice with established liver metastases (pg. 3850, col. 2, para. 4). Nagashima teaches the NK-92 cell line is a human NK cell line established from a patient with non-Hodgkin’s lymphoma (pg. 3850, col. 2, para. 5). Nagashima teaches the IL-2 expression vector comprises a 490-bp DNA fragment encoding human IL-2 cDNA, which is the full-length human IL-2 cDNA (pg. 3851, col. 1, para. 2). Thus, Nagashima teaches transducing human NK cells with an exogenous nucleic acid sequence encoding the cytokine IL-2, for inducing growth and anti-tumor activity of the NK cells.
It would have been obvious to one of skill in the art to modify the combination NK cells of Wang, Milone and Bollard to further comprise an exogenous nucleic acid encoding an IL-2 cytokine. One would have been motivated to do so given the knowledge that exogenous IL-2 can promote the growth and anti-tumor activity of human NK cells, and that endogenous expression and secretion of IL-2 by the NK cells can support the same actions of exogenous IL-2 on the NK cells, as taught by Nagashima et al. There would have been a reasonable expectation for success given that a retroviral vector can be used to introduce IL-2 cDNA into human NK cells which results in successful expression of IL-2 by the NK cells, as taught by Nagashima et al. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 74, the combination of Wang, Milone, Bollard and Nagashima make obvious human NK cells comprising an exogenous nucleic acids which encodes a TGF-βRII/ KIR2DS2 construct, and a second exogenous nucleic acid encoding an IL-2 cytokine; and thus make obvious the human cell of instant claim 74.
Claim 77 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., (from IDS of 1/10/2022; Cancer Immunol Immunother; 2017) in view of Milone et al., (US Patent 9,745,368; issued 8/29/2017) and Bollard et al., (from IDS, Cite No. 45; Blood, 2002, 99(9)) as applied to claims 63-64, 67-70, 73, 76 and 79-82 above, and further in view of Budde et al., (Blood; 2013, 122(21)).
The combination of Wang, Milone and Bollard make obvious modified human NK cells comprising a TGF-βRII/KIR2DS2 construct, as described above. However, they do not teach wherein the first exogenous nucleic acid encoding the chimeric protein further encodes a third domain encoding a truncated form of CD19.
Budde et al. teach a truncated cell-surface CD19 as a conditional suicide switch for adoptive T cell immunotherapy (title). Budde taches that CAR-T cell therapy is a promising treatment for human malignancies, however, that there is a lack of effective commercially available agents which allow for monitoring of CAR expression, tracking, isolating, and eliminating CAR-transduced cells. Therefore, adoptive T cell immunotherapy would benefit from a molecule which is stably expressed on the cell surface, of human origin, easily detected on transduced cells, lacking active biological function at baseline and capable of effectively ablating transduced cells on demand. Truncated CD19 (CD19t) harbors excellent features to be such a molecule (abstract). Budde teaches that lentiviral constructs containing a CD20 CAR and CD19t were used to transduce primary human T cells to generate cells that express both molecules on the cell surface; and that CD19-mediated selection was carried out using PE conjugated anti-CD19 antibody (pg. 2, para. 1). Budde teaches that truncated CD19 was able to enrich transduced cells to more than 90% purity when used as a selectable marker (pg. 2, para. 2). Budde concludes that CD19t will be an excellent molecule to mark, select, track and eliminate modified T cells in vivo (pg. 2, para. 3).
It would have been obvious to one of ordinary skill in the art to modify the nucleic acid encoding the TGF-βRII/KIR2DS2 chimeric protein of Wang, Milone and Bollard to further comprise a nucleic acid encoding a truncated CD19. One would have been motivated to do so given that co-expressing the CD19t on the surface of the engineered cell allows for marking, selecting and tracking immune cells engineered with a chimeric construct, and that such a selection protocol allows for obtaining more than 90% purity of transduced cells in production. There would have been a reasonable expectation for success given that CD19t was encoded on the same nucleic acid, and comprised in the same vector, which a CD20 CAR, for successfully transducing CAR-T cells, as taught by Budde et al. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 77; Budde teaches the art of using a CD19t nucleic acid to co-express CD19t with a chimeric protein (i.e. a CD20 CAR), in T cells. As including a CD19t construct in the expression of a chimeric protein in immune cells was common knowledge in the art, it would have been obvious to include a nucleic acid encoding CD19t in human NK cells expressing the TGF-βRII/KIR2DS2 chimeric protein of Wang, Milone and Bollard. Thus, the combination of Wang, Milone, Bollard and Budde make obvious instant claim 77.
Response to Arguments
Applicant's arguments filed 3/27/2026 have been fully considered but they are not persuasive. Applicants contend that Milone does not suggest an inverted NK cell receptor comprising the particular configuration of extracellular and intracellular domains required by the claims (remarks, pg. 6, para. 4). Applicants contend that despite references to the TGF-β extracellular domain and the KIR2DS2 intracellular domains, obviousness requires a reason for the ordinary artisan to combine the elements in the same way the claimed inventions does; and that there is no suggestion to combine the particular domains instead of numerous other extracellular and intracellular domains. Rather, the examiner’s positions is based on impermissible hindsight (pg. 7, para. 1). Applicants contend there is not a reasonable expectation for success given the unpredictability of T cell and NK cell immunology. Applicants contend that given the unpredictability, there is not a reasonable expectation that the constructs would properly assemble or function, and such considerations would affect the functional properties of engineered NK cells, including the degree of toxicity, cytokine secretion and persistence (pg. 8, para. 1).
The examiner highlights that the rejections to which applicant’s remarks were directed have been withdrawn and replace by reference to Wang, Milone and Bollard. Nonetheless, the examiner will respond to the remarks to the degree that they apply to the new rejections of record. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Milone, by itself, does not teach inverted TGF-β receptors. However, Wang teaches inverted TGF-β receptors, which are heterologous, comprising an NK cell stimulatory domain. Thus, Wang provides the motivation for generating such receptors and their expression in NK cells. Milone teaches a viable alternative stimulatory NK cell intracellular signaling domain, and its reduction to practice in making functional fusion proteins (or CARs) for expression in immune cells. The KIR2DS2 intracellular domains of Milone are identical in structure to those of the instant invention, specifically instant SEQ ID NO: 17. In response to applicant's argument that Milone doesn’t teach the inverted TGF-β constructs of the instant claims, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As Milone teaches fusion proteins comprising an extracellular domain and a KIR2DS2 intracellular domain, and Wang teaches TGF-βR II extracellular domains in inverted TGF-β fusion proteins comprising an alternate NK cell stimulatory domain, it is obvious to substitute the KIR2DS2 intracellular domain of Milone into the constructs of Wang. Similarly, it is obvious to substitute the truncated TGF-βRII construct of Bollard in place of the TGF-βRII construct of Wang, in the constructs of Wang. Each substituted component is being used in the same way as they were taught in the art. Wang provides clear motivation for generating inverted TGF-β receptors, and their expression in NK cells, which is to enhance anti-tumor therapeutics and cancer treatments by inverting an immunosuppressive TGF-β signal into an NK cell stimulatory signal. The alternate components of the receptor, of Bollard and Milone, are obvious to substitute into the construct of Wang, as they are art-recognized equivalents being used for the same purpose. See MPEP Section 2143(I). Further, as Milone teaches the specific domains of KIR2DS2, functionally linked to various alternative extracellular domain, in various embodiments, the artisan has a reasonable expectation for success that the heterologous extracellular domains and intracellular domains of the fusion construct will be “operably” linked and function accordingly. Wang further supports the expectation for functionality with their example of an alternative species of the same genus of inverted TGF-β receptors expressed in NK cells.
In response to applicant's argument that the construct of the references may fail to show certain functional properties of engineered NK cells, including the degree of toxicity, cytokine secretion and persistence, it is noted that the features upon which applicant relies are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The artisan needs only a reasonable expectation of success that the fusion proteins will work, and will enhance NK cell cytotoxicity against tumor cells; this is provided by Wang. Thus, regarding applicants suggestion that the combination of Wang, Milone and Bollard is not enabled to properly integrate into the membranes of NK cells, examiner points to MPEP section 2121(I) and section 2123 (I) and (II). The prior art is presumed fully enabled for all that it discloses. The combined teachings of Wang and Milone make obvious the construct of Wang with the intracellular domain of Milone. There is no teachings that such a specific construct will not work, thus it is presumed to be enabled even if the specific construct was not reduced to practice. Similarly, instant claim 63 may be presumed to be enabled across its numerous iterations of alternative intracellular domains, even though these iterations are not embodied or reduced to practice in the specifications. The general knowledge in the art of generating trans-membrane spanning fusion proteins and their genetic engineering into alternative immune effector cell types supports that the various claimed embodiments, as well as the obvious construct of Wang, Milone and Bollard, are similarly enabled and will function with a reasonable expectation for success, as was demonstrated in Wang et al.
Applicants arguments are not found persuasive and the rejections are maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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