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 .
Priority
This application was filed on Sept. 10, 2021, and is a 371 application of PCT/US20/27327 filed on April 8, 2020, which claims benefit to the provisional application 62/832,622 filed on April 11, 2019. Applicants claim for priority to a provisional application is acknowledged. The effective filing date for the claims is 4/11/2019.
Claim status
In the response filed March 4, 2026, Applicants have amended claim 1, 11, 25, and 27, and have canceled claim 36. Currently, claims 29-35, 37-39, and 42-50 are withdrawn.
Claims 1-28 and 40-41 are currently under examination.
Information Disclosure Statement
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 1-28 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle et al., (WO2019/173693 A1; published 3/8/2019, prior art of record), in view of Valamehr et al., (WO2017/079673 A1, cited IDS 5/6/2022; published 2017, prior art of record), Sadelain et al., (WO 2017/180989 A2, cited IDS 11/15/2023), and Themeli et al., (Cell stem cell 16.4: 357-366; published 2015, prior art of record).
This is a new rejection necessitated by amendment to the claims. However, since it is substantially similar to a rejection set forth in the Official action mailed on Dec. 4, 2025, any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claims 1-2, 4, 6, 10-11, and 27-28, Baeuerle et al., discloses a cell or a population thereof, wherein (i) the cell is a pluripotent stem cell (see e.g. abstract, para. 7-13 and 23-31, claims 1, 9, and 80); (ii) an endogenous TCR of the cell is knocked out (TCRneg)(i.e. KO or disrupted)(see e.g. para. 10, 13, 15, 20-27, 132, 239, 266, 304-307, 342, 348, claims 88-91, fig. 2); (iii) the cell comprises one or more polynucleotide encoding one or more exogenous protein (i.e. T cell receptor (TCR) fusion protein or TFP)(see e.g. para. 48, 348, fig. 6 below and Example 4) to provide a cell surface CD3 complex (cs-CD3)(i.e. CD3s-TFP) when expressed (see e.g. para. 48, 132-133,228, 341-342, 350, 357-359, 362-369 and 371, fig. 6-10, Example 4 and 6); (iv) expression of the one or more exogenous protein (i.e. fusion protein or TFP)(see e.g. para. 132-133, Example 5) in the cell therefrom induces formation of the cs-CD3 comprising (a) a CD3ζ endodomain, and (b) one or more the CD3ε ectodomain and (c) the CD3δ ectodomain or the CD3γ ectodomain (i.e. extracellular domain)(see e.g. claims 1, 15, 38-42), and (v) the one or more exogenous protein comprises: (a) a non-binding recombinant TCR (nb-rTCR) characterized by one or both of (1) a transgenic TCRα constant region (tgTRAC) with no antigen-binding variable region, or (2) a transgenic TCRβ constant region (tgTRBC) with no antigen-binding variable region (see e.g. pages 10-11, 57, fig. 2-6, Example 5); and (d) a CD3 chimeric chain (ccCD3) comprising a fusion between (1) and the CD3ε ectodomain, (2) the CD3δ ectodomain or the CD3γ ectodomain, and (3) a CD3ζ endodomain (see e.g. para. 154, 211, 221 and claims 1, 15, 38-42, 79-80, Example 5).
Baeuerle does not explicitly disclose an induced pluripotent cell (iPSC), and a derivative cell obtained from differentiating the said iPSC or the derivative is a T cell.
However, the prior art of Valamehr discloses methods and compositions for obtaining genome-engineered iPSCs modified to express a T cell receptor (TCR) or a chimeric antigen receptor (CAR), and the genome-engineered iPSCs derivative cells (e.g. T cells or NK cells) with stable and functional genome editing (see e.g. abstract, Example 22, claim 1, 27, 48-50, and 54-55, fig. 18-20 and 32-34).
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify pluripotent stem cell methods as taught by Baeuerle with the iPSCs and derivative cells as taught by Valamehr because Valamehr discloses that the cells can then avoid the need for HLA matching in adoptive cell therapy and thus provide a source of universal and off-the-shelf therapeutic regimen (see page 81). A person of ordinary skill in the art would have reasonable expectation of success because both Baeuerle and Valamehr discloses methods where the cells may be a hematopoietic stem cell or pluripotent stem cell (see e.g. claim 80 and page 34, respectively). Moreover, both Baeuerle and Valamehr disclose methods adoptive cell therapy (i.e. immunotherapy or cellular therapy) (see e.g. para. 322 and para. 136, respectively). Additionally, Valamehr discloses that chimeric antigen receptors (CARs) are engineered transmembrane receptor that serve to apply specificity onto an immune cell such as T or NK cells (para. 317). Further, Valamehr suggests that that CAR-immune effector cells have potent universal cancer immunotherapy (see e.g. page 120). Therefore, an artisan of ordinary skill in the art of genomic engineered cells for cell therapy has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 1-2, 4, 6, 10-11, and 27-28, as stated supra, Baeuerle et al., discloses a cell or a population thereof, wherein (i) the cell is a pluripotent stem cell (see e.g. abstract, para. 7-13 and 23-31, claims 1, 9, and 80); (ii) an endogenous TCR of the cell is knocked out (TCRneg)(i.e. KO or disrupted)(see e.g. para. 10, 13, 15, 20-27, 132, 239, 266, 304-307, 342, 348, claims 88-91, fig. 2).
Although Baeuerle does not explicitly state that the cs-CD3 complex is lacking antigen recognition activity.
Nevertheless, the prior art of Sadelain et al. teaches that the TCRneg feature can be easily derived by a person skilled in the art considering that CAR+TCRneg T cells are known for universal T-cell based immunotherapy (see abstract), and the polynucleotide for CD3 can be easily derived by a person skilled in the art from the teaching of Baeuerle et al., where an endogenous TCR of the cell is knocked out (TCRneg)(i.e. KO or disrupted)(see e.g. para. 10, 13, 15, 20-27, 132, 239, 266, 304-307, 342, 348, claims 88-91, fig. 2).
Accordingly, a person of ordinary skilled in the art would easily arrive at the claimed invention by a combination of the teachings of Baeuerle et al. and Sadelain et al. because Baeuerle discloses that the “activation of the TCR complex on the surface of donor T cells by receiver antigens (i.e., recognition of antigens presented by the major histocompatibility complex (MHC) on antigen presenting cells) can trigger unwanted effects such as graft-versus-host disease (GvHD) and cytokine release syndrome (CRS) and that following examples describe methods of introducing a transgene in TCR knock-out cells encoding for a truncated version of TCRα or TCRβ (see e.g. para. 342, page 89). Further, the prior art of Themeli et al., teaches that “the combination of iPSC technology and immune engineering may thus provide an opportunity to generate T cells that uniquely combine favorable attributes including antigen specificity, lack of alloreactivity, enhanced functional properties and histocompatibility” (see Perspective for “Synthetic T cells”; and adapted Fig. 4). Thus, a person of ordinary skill art would have had predictable results with a reasonable expectation of success. Therefore, an artisan of ordinary skill in the art of genomic engineered cells for cell therapy has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
[AltContent: textbox ([img-media_image1.png])]
Regarding claim 3, as stated supra, Baeuerle discloses wherein one or more polynucleotides encodes exogenous protein comprising one or more of: (i) a transgenic fusion protein comprising full or partial length of ectodomains of CD3ε and CD3δ, and a full or partial TCRα constant region (tgCD3(ε-δ)-TRAC)(see e.g. para. 194-220, pages 10-14, 51-67, 89, claims 1-2, 15, 38-44 and 49, fig. 1-2); (ii) a transgenic fusion protein comprising full or partial length of ectodomains of CD3ε and CD3γ, and a full or partial TCRβ constant region (tgCD3(ε-γ)-TRBC) )(see e.g. para. 194-220, pages 10-14, 51-67, 89, claims 1-2, 15, 38-44 and 49, fig. 1-2); (iii) a transgenic fusion protein comprising full or partial length of ectodomains of CD3ε and CD3γ, and a full or partial TCRα constant region (tgCD3(ε-γ)-TRAC)(see e.g. para. 194-220, pages 10-14, 51-67, 89, claims 1-2, 15, 38-44 and 49, fig. 1-2); (iv) a transgenic fusion protein comprising full or partial length of ectodomains of CD3ε and CD3δ, and a full or partial TCRβ constant region (tgCD3(ε-δ)-TRBC) (see e.g. para. 194-220, pages 10-14, 51-67, 89, claims 1-2, 15, 38-44 and 49, fig. 1-2); (vii) a transgenic fusion protein comprising a full or partial length of ectodomain of CD3ε, a transgenic fusion protein comprising a full or partial length of ectodomain of CD3γ or CD3δ, a full or partial length of endodomain of CD3ζ, and a signaling domain of CD28 (tgCD3(ε-γ/δ)-28ζ)(see e.g. para. 194-220, pages 31, 42-43, 45-46, 51-67, 88-89, claims 1-2, 15, 38-44 and 49, fig. 1); (viii) a transgenic fusion protein comprising a full or partial length of ectodomain of CD3ε, a transgenic fusion protein comprising a full or partial length of ectodomain of CD3γ or CD3δ, a full or partial length of endodomain of CD3ζ, and a signaling domain of 41BB (tgCD3(ε-γ/δ)-BBζ)(see e.g. para. 194-220, pages 31, 42-43, 45-46, 51-67, 88-89, claims 1-2, 15, 38-44 and 49, fig. 1); (ix) a transgenic fusion protein comprising a full or partial length of ectodomain of CD3γ or CD3δ, a full or partial length of endodomain of CD3ζ, a signaling domain of CD28, and a signaling domain of 41BB (tgCD3(ε-γ/δ)-(28-BB)ζ))(see e.g. para. 194-220, pages 31, 42-43, 45-46, 51-67, 88-89, claims 1-2, 15, 38-44 and 49, fig. 1); and/or (x) a transgenic TCRα (tgTCRα) or a transgenic TCRβ (tgTCRβ) (see e.g. para. 194-220 and 357, pages 95-99 Examples 3-5).
Regarding claim 5, Baeuerle et al., discloses wherein the polynucleotide encoding tgTRAC comprises a sequence encoding a full length of the constant region of TCRα and a poly A tail at C-terminal, and optionally an N-terminal signal peptide (see e.g. page 7, 11, 28, 89, 97-98 claim 60, fig. 5); or wherein the polynucleotide encoding tgTRBC comprises a sequence encoding a full length of the constant region of TCRβ and a poly A tail at C-terminal, and optionally an N-terminal signal peptide (see e.g. page 7, 11, 28, 89, 97-98, claim 60, fig. 5).
Regarding claim 7-8, Baeuerle discloses wherein the one or more polynucleotide inserted in TRAC and/or TRBC locus (see e.g. page 64, 101) is driven by (i) constitutive, inducible, tissue specific promoter (see e.g. page 26-27) or (ii) a heterologous promoter EIF1α (i.e. EIF1a) or CMV (see e.g. para. 254, page 64, claims 59,70).
Regarding claim 9, Baeuerle discloses the cell or population wherein (i) the nb-rTCR comprises both of a tgTRAC and a tgTRBC (see e.g. page 11-12, 51-53, para. 194, 205, Example 5, fig. 10).
Regarding claims 12, 14, 20, and 23, Baeuerle et al., discloses wherein the genetically engineered cell (i.e. when used in combinations with an anti-CD19 TFP (i.e. transgenic T cell)), improves the persistence of the T cell (see e.g. page 46).
Baeuerle, as stated supra, is silent regarding wherein the cell is a derivative NK or T cell, and where the derivative is a hematopoietic cell and comprises longer telomeres in comparison to its native counterpart cell.
However, Valamehr et al. discloses the cell is a derivative NK or T cell (see e.g. pages 37-38, Example 18, claim 9, 14) and wherein the derivative cell is a hematopoietic cell (see e.g. page 3, 13, fig. 22-23) and comprises longer telomeres in comparison to its native counterpart cell (para. 77, Fig. 31; Example 21, page 123) obtained from peripheral blood (para. 113, 116, 302; Example 21). Further, Valamehr et al. discloses that the iPSCs are capable of differentiating into hematopoietic lineage cells, wherein the partially differentiated cells comprise mesodermal cells, CD34 cells, hemogenic endothelium cells, hematopoietic stem and progenitor cells, hematopoietic multipotent progenitor cells, T cell progenitors, or NK cell progenitors (see e.g. page 28); and wherein the fully-differentiated cells comprise T cells, NKT cells, NK cells, or B cells (see claims 40, 41), and (i) wherein the genome-engineered iPSCs have improved persistency improved persistency) (see e.g. claim 44, page 134).
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify pluripotent stem cell methods as taught by Baeuerle with the derivative T or NK cells as taught by Valamehr because Valamehr discloses that the cells can then avoid the need for HLA matching in adoptive cell therapy and thus provide a source of universal and off-the-shelf therapeutic regimen (see page 81). A person of ordinary skill in the art would have reasonable expectation of success because both Baeuerle and Valamehr discloses methods where the cells may be a hematopoietic stem cell or pluripotent stem cell (see e.g. claim 80 and page 34, respectively). Further, Valamehr discloses that chimeric antigen receptors (CARs) are engineered transmembrane receptor that serve to apply specificity onto an immune cell such as T or NK cells (para. 317). Moreover, both Baeuerle and Valamehr disclose methods adoptive cell therapy (i.e. immunotherapy or cellular therapy) (see e.g. para. 322 and para. 136, respectively). Thus, providing a reasonable expectation of success. Further, Baeuerle teaches that traditional treatment options often have serious side effects (para. 2), whereas successful patient therapy with engineered T cells may require the T cells to be capable of strong activation, expansion, persistence over time, and, in case of relapsing disease, to enable a ‘memory’ response in disease, such as cancer (abstract, para. 4). Further, Valamehr suggests that that CAR-immune effector cells (i.e. T cells or NK cells) have potent universal cancer immunotherapy (see e.g. page 120). Therefore, an artisan of ordinary skill in the art of genomic engineered cells for cell therapy has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 13, and 15-17, Baeuerle discloses wherein the cell further comprises (iv) an exogenous CD16 or a variant thereof (see e.g. page 3-5, 20, 42 claims 9-11 and 40) and (v) a chimeric antigen receptor (CAR)(i.e. intracellular signaling domain)(see e.g. pages 1, 2, 31-32, 43-45, 51) and wherein the exogenous CD16 or a variant thereof further comprises (b) a full or partial ectodomain originated from CD64 (see e.g. page 42-43, 52); (c) a non-native (or non-CD16) transmembrane domain (see e.g. pages 42-43, 52, claims 40-42).; (d) a non-native (or non-CD16) intracellular domain (see e.g. claims 40-42); (e) a non-native (or non-CD16) signaling domain (see e.g. claims 40-42) (g) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide (see e.g. pages 42-43, 52, claims 40-44). Further, Baeuerle discloses (a) a non-native (or non-CD16) transmembrane domain is derived from CD3δ, CD3ε, CD3γ, CD3ζ, CD4, CD8, CD16, CD28, (see e.g. page 56-57, claim 40); (b), a non-native stimulatory domain derived from CD27, CD28, 4-IBB (CD137), OX40, ICOS (CD278) (see e.g. page 56-57, claim 41-42); (c) the non-native signaling domain is derived from CD3ζ, CD137 (41BB), DAP12 or NKG2D polypeptide (see e.g. para. 219-220, 237, page 56, 60, claim 41-42, 45); (d) the non-native transmembrane domain is derived from NKG2D (page 20, para. 73), the non-native stimulatory domain is derived from 2B4 (para. 337), and the non-native signaling domain is derived from CD3ζ (see e.g. page 5 and 31, claims 40-45).
Regarding claims 18, as stated supra, Baeuerle discloses wherein the cell further comprises a chimeric antigen receptor (CAR)(i.e. intracellular signaling domain)(see e.g. pages 1, 2, 31-32, 43-45, 51). Further, Baeuerle discloses wherein the CAR is (xi) co-expressed with a checkpoint inhibitor (i.e. PD1)(see e.g. page 46), and specific to (xii) CD19 or BCMA (see e.g. para. 124, 133, 138, 147, 173; page 37-38; Example 6) and/or (xiii) CD5, CD7, CD22, CD30, Mucin 16 (Muc-16 and NKG2D ligands (see e.g. para. 60, page 17, 20).
Regarding claim 19, Baeuerle disclose wherein the cell comprising a partial or full length peptide of a cell surface expressed exogenous cytokine or a receptor thereof (a) comprises at least one of IL2 (see e.g. para 331, page 86) IL10 (see e.g. para. 270, page 70) and its respective receptor (see e.g. para. 134, page 16-17, 42, claim 102).
Regarding claim 21, Baeuerle discloses wherein the checkpoint inhibitors are antagonists to one or more checkpoint molecules comprising PD-1, PDL-1, TIM-3, TIGIT, LAG-3, CTLA-4, 2B4, 4-1BB, BTLA, CD160, LAIR-1, and VISTA (see e.g. para. 174).
Regarding claim 22, Baeuerle discloses wherein the checkpoint inhibitors comprise (a) ipilimumab (also referred to as MDX-010 and MDX-101 and marketed as Yervoy®; Bristol-Myers Squibb)(see e.g. para. 337).
Regarding claim 24-26, as stated supra, Baeuerle discloses (i) one or more exogenous polynucleotides integrated in one safe harbor locus; wherein the safe harbor locus comprises the TCR and is a constant region of TCR alpha or TCR beta (see e.g. pages 97-98, Example 5).
Regarding claim 27-28, as stated supra, Baeuerle discloses that the engineered T cells may be isolated and frozen for later use in T cell therapy for any number of diseases or conditions that would benefit from T cell therapy (see e.g. para. 274, page 72), and Valamehr discloses methods and compositions for obtaining genome-engineered induced pluripotent stem cells (iPSCs)(i.e. CAR-T derived iPSC (see whole document), as discussed above. Further, Valamehr discloses method like monolayer differentiation strategy that combines enhanced differentiation efficiency with large-scale expansion, which enables the delivery of therapeutically relevant number of pluripotent stem cell derived hematopoietic cells for various therapeutic applications (see e.g. page 68).
Baeuerle and Valamehr et al., do not explicitly state a clonal master cell bank comprising the iPSC cell line.
However, the prior art of Themeli et al. suggests that the combination of iPSC technology and immune engineering may provide T cells that uniquely combine favorable attributes like antigen specificity, lack of alloreactivity, enhanced functional properties and histocompatibility for cell therapy (see e.g. abstract, page 357, fig. 3, 4, and adapted Fig. 4 below). Further, Themeli suggests a bank of cells (i.e. clonal master cell bank) such as iPSCs would be critical for enabling off-the-shelf adoptive T cell therapy (see e.g. page 363, fig. 3).
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify the methods of Baeuerle and Valamehr with a clonal master cell bank as suggested by Themeli because Themeli et al. discloses that iPSCs further opens up new perspectives for the generation of histocompatibility, off-the-shelf T cells that could eventually be administered to multiple recipients (page 363, col. 1). A person of ordinary skill in the art would have a reasonable expectation of success because Baeuerle, Valamehr, and Themeli disclose methods for adoptive T cell therapy, as discussed above. Further, Themeli et al. discloses autologous T cell manufacturing (see fig. 3). Thus, providing a person of ordinary skill in the art a reasonable expectation of success. Moreover, an artisan of ordinary skill in the art of genomic engineered cells for cell therapy has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal
Applicant argues that the cited references fail to disclose or reasonably suggest a cell characterized by all of 1) an endogenous TCR knockout, 2) a polynucleotide encoding an exogenous nb-TCR or CD3 fusion protein, and 3) that expression of the recited exogenous protein(s) induces formation of a cell surface CD3 complex lacking antigen recognition activity and comprising the specified domains (Remarks, page 18-19). Applicant asserts that FIG. 6 of Baeuerle appear to indicate a structure includes antigen binding domains. Applicant argues that FIG. 6 in Baeuerle includes a "TFP-TCR fusion molecule" (Baeuerle; para. [0365]), which is "generally capable of i) binding to a surface antigen on target cells" (Baeuerle, para. [0048]). Applicant argues that the cited complex of Baeuerle does not lack antigen recognition activity, as required by the present claims (Remarks, page 19).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
As discussed above, Baeuerle discloses (a) a non-binding recombinant TCR (nb-rTCR) characterized by one or both of (1) a transgenic TCRα constant region (tgTRAC) with no antigen-binding variable region, or (2) a transgenic TCRβ constant region (tgTRBC) with no antigen-binding variable region (see e.g. pages 10-11, 57, fig. 2-6, Example 5), shown in figure 6 at the antigen binding domain having no antigen variable region. Further, Baeuerle discloses that “the cytoplasmic domain of the TFP can include an intracellular signaling domain, if the TFP contains CD3 gamma, delta or epsilon polypeptides; TCR alpha and TCR beta subunits are generally lacking in a signaling domain (page 43). Accordingly, a person of ordinary skilled in the art would easily arrive at the claimed invention by a combination of the teachings of Baeuerle et al. and Sadelain et al. because Baeuerle discloses that the “activation of the TCR complex on the surface of donor T cells by receiver antigens (i.e., recognition of antigens presented by the major histocompatibility complex (MHC) on antigen presenting cells) can trigger unwanted effects such as graft-versus-host disease (GvHD) and cytokine release syndrome (CRS) and that following examples describe methods of introducing a transgene in TCR knock-out cells encoding for a truncated version of TCRα or TCRβ (see e.g. para. 342, page 89). Further, the prior art of Themeli et al., teaches that “the combination of iPSC technology and immune engineering may thus provide an opportunity to generate T cells that uniquely combine favorable attributes including antigen specificity, lack of alloreactivity, enhanced functional properties and histocompatibility” (see Perspective for “Synthetic T cells”; and adapted Fig. 4). Thus, a person of ordinary skill art would have had predictable results with a reasonable expectation of success. Therefore, an artisan of ordinary skill in the art of genomic engineered cells for cell therapy has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Applicant argues that the present application explains that while TCRneg T cells (e.g., iPSC-derived T cells) have reduced alloreactivity, "it has been found that TCR disruption also results in the elimination of the CD3 signaling complex from the T-cell surface despite the CD3 subunit gene expression in the cell" and that "lack of cell surface CD3 may alter the cells' capacity for expansion and/or survival and reduce the cells' functional potential" (US20220184142Al, para. [000130]; emphasis added). (Remarks, page 21).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicant’s arguments are acknowledged, have been fully considered and deemed unpersuasive. In response to Applicants argument, Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). In the instant case, Baeuerle discloses modified T cells comprising T-cell receptor (TCR) fusion protein (TFP) and a TCR constant domain, methods of producing the modified T cells, and methods of use thereof for the treatment of diseases (see e.g. page 2).
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.
Claims 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle et al., (WO2019/173693 A1; published 3/8/2019, prior art of record), in view of Valamehr et al., (WO2017/079673 A1, cited IDS 5/6/2022; published 2017, prior art of record), Sadelain et al., (WO 2017/180989 A2, cited IDS 11/15/2023), and Themeli et al., (Cell stem cell 16.4: 357-366; published 2015, prior art of record), as applied to claims 1-28 above, and in further view of Minagawa, et al. (Cell Stem Cell 23.6: 850-858; published 2018, prior art of record).
This is a new rejection necessitated by amendment to the claims. However, since it is substantially similar to a rejection set forth in the Official action mailed on Dec. 4, 2025, any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Baeuerle et. al. applies here as indicated above.
Regarding claims 40-41, as stated supra, Baeuerle et al., discloses a cell or a population thereof, wherein (i) the cell is a pluripotent stem cell (see e.g. abstract, para. 7-13 and 23-31, claims 1, 9, and 80); (ii) an endogenous TCR of the cell is knocked out (TCRneg)(i.e. KO or disrupted)(see e.g. para. 10, 13, 15, 20-27, 132, 239, 266, 304-307, 342, 348, claims 88-91, fig. 2); (iii) the cell comprises one or more polynucleotide encoding one or more exogenous protein (i.e. T cell receptor (TCR) fusion protein or TFP)(see e.g. para. 48, 348, fig. 6 below and Example 4) to provide a cell surface CD3 complex (cs-CD3)(i.e. CD3s-TFP) when expressed (see e.g. para. 48, 132-133,228, 341-342, 350, 357-359, 362-369 and 371, fig. 6-10, Example 4 and 6); Further, Baeuerle teaches CRISPR mediated editing (see e.g. para. 308, page 81) and wherein the editing further comprises an insertion of a CAR at a TRAC or a TRBC locus (para. 20-21. 23, 341, 345; Example 2-3, Fig. 2-3).
Baeuerle does not explicitly disclose CRISPR mediated editing of clonal iPSCs.
However, Valamehr discloses the human iPSC genome editing with CRISPR (see e.g. para. 260, Example 9). Additionally, the prior art of Sadelain discloses CRISPR/Cas9-targeted integration of a CAR-GFP fusion gene into TRAC locus (see e.g. page 43, para. 171, and fig. 5-7, 9 and 14).
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify pluripotent stem cell methods as taught by Baeuerle with the iPSCs as taught by Valamehr and Sadelain because Valamehr discloses that the cells can then avoid the need for HLA matching in adoptive cell therapy and thus provide a source of universal and off-the-shelf therapeutic regimen (see page 81). Further, Valamehr et al. discloses that iPSC-derived cellular have longer telomere length which is representative of greater proliferative potential (see e.g. para. 325). A person of ordinary skill in the art would have reasonable expectation of success because both Baeuerle and Valamehr discloses methods where the cells may be a hematopoietic stem cell or pluripotent stem cell (see e.g. claim 80 and page 34, respectively). Moreover, both Baeuerle and Valamehr disclose methods adoptive cell therapy (i.e. immunotherapy or cellular therapy) (see e.g. para. 322 and para. 136, respectively). Additionally, Valamehr discloses that chimeric antigen receptors (CARs) are engineered transmembrane receptor that serve to apply specificity onto an immune cell such as T or NK cells (para. 317). Further, Valamehr suggests that that CAR-immune effector cells have potent universal cancer immunotherapy (see e.g. page 120). Therefore, an artisan of ordinary skill in the art of genomic engineered cells for cell therapy has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 40-41, Baeuerle discloses that the engineered T cells may be isolated and frozen for later use in T cell therapy for any number of diseases or conditions that would benefit from T cell therapy (see e.g. para. 274, page 72), and Valamehr discloses methods and compositions for obtaining genome-engineered induced pluripotent stem cells (iPSCs)(i.e. CAR-T derived iPSC (see whole document), as discussed above. Further, Valamehr discloses method like monolayer differentiation strategy that combines enhanced differentiation efficiency with large-scale expansion, which enables the delivery of therapeutically relevant number of pluripotent stem cell derived hematopoietic cells for various therapeutic applications (see e.g. page 68).
Baeuerle and Valamehr et al., do not explicitly state a clonal master cell bank comprising the iPSC cell line.
However, the prior art of Themeli et al. suggests a bank of cells (i.e. clonal master cell bank) such as iPSCs would be critical for enabling off-the-shelf adoptive T cell therapy (see e.g. page 363, fig. 3). Additionally, the prior art of Minagawa discloses induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs)iPSCs using CRISPR and suggests that “a single product of TCR iPSC-derived HLA-matched, quality controlled, antigen-specific allogeneic T cells can be unlimitedly provided to multiple patients for multiple injections at a relatively lower cost and shorter time than personalized TCR gene therapy (see e.g. page 856).
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify the methods of Baeuerle and Valamehr with a clonal master cell bank as suggested by Themeli and Minagawa because Themeli et al. suggests that the combination of iPSC technology and immune engineering may provide T cells that uniquely combine favorable attributes like antigen specificity, lack of alloreactivity, enhanced functional properties and histocompatibility for cell therapy (see e.g. abstract, page 357, fig. 3, 4). Themeli et al. discloses that iPSCs further opens up new perspectives for the generation of histocompatibility, off-the-shelf T cells that could eventually be administered to multiple recipients (page 363, col. 1). A person of ordinary skill in the art would have a reasonable expectation of success because Baeuerle, Valamehr, Themeli and Minagawa disclose methods for adoptive T cell therapy, as discussed above. Further, Themeli et al. discloses autologous T cell manufacturing (see fig. 3). Thus, providing a person of ordinary skill in the art a reasonable expectation of success. Moreover, an artisan of ordinary skill in the art of genomic engineered cells for cell therapy has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal
Applicant argues that the cited references of Sadelain and Minagawa both fail to provide the missing teaching of a cell surface CD3 complex that lacks antigen recognition activity (Remarks, page 22-23). Further, Applicant asserts that “it further remains that modification of Baeuerle to remove antigen recognition activity from the complexes thereof would impermissibly change their principle of operation, and render them unsatisfactory for their intended purpose” (Remarks, page 23).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicants are reminded that the test for obviousness is not whether the features of a secondary reference maybe 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). The MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. In instant case, the prior art of Sadelain et al. teaches that the TCRneg feature can be easily derived by a person skilled in the art considering that CAR+TCRneg T cells are known for universal T-cell based immunotherapy (see abstract), and the polynucleotide for CD3 can be easily derived by a person skilled in the art from the teaching of Baeuerle et al., where an endogenous TCR of the cell is knocked out (TCRneg)(i.e. KO or disrupted)(see e.g. para. 10, 13, 15, 20-27, 132, 239, 266, 304-307, 342, 348, claims 88-91, fig. 2). Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). In the instant case, the prior art of Minagawa discloses induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs)iPSCs using CRISPR and is not cited for disclosing a cell surface CD3 complex that lacks antigen recognition activity. In the instant case, Minagawa suggests that “a single product of TCR iPSC-derived HLA-matched, quality controlled, antigen-specific allogeneic T cells can be unlimitedly provided to multiple patients for multiple injections at a relatively lower cost and shorter time than personalized TCR gene therapy (see e.g. page 856).
Further, it is unclear what Applicant is asserting when stating that “modification of Baeuerle to remove antigen recognition activity from the complexes thereof would impermissibly change their principle of operation, and render them unsatisfactory for their intended purpose” (Remarks, page 23). As discussed above, Baeuerle discloses that the “activation of the TCR complex on the surface of donor T cells by receiver antigens (i.e., recognition of antigens presented by the major histocompatibility complex (MHC) on antigen presenting cells) can trigger unwanted effects such as graft-versus-host disease (GvHD) and cytokine release syndrome (CRS) and that following examples describe methods of introducing a transgene in TCR knock-out cells encoding for a truncated version of TCRα or TCRβ (see e.g. para. 342, page 89). Thus, Baeuerle suggests for a person of ordinary skill in the art to form a cell surface CD3 complex that lacks antigen recognition activity as to provide a way to not have unwanted effects of GvHD.
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.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 9AM - 5:00PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631