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 .
Claim Status
Applicant’s submission filed 01/12/2026 has been received and entered. Claim 5 has been cancelled. Claims 1, 4 and 10 have been amended. Claim 15 has been newly added. Claims 10-14 remain withdrawn as being directed to non-elected inventions. Accordingly, claims 1-4, 6-9 and 15 are pending and under current examination.
Status of Prior Rejection/Response to Arguments
The objection to Abstract is withdrawn:
The objection to the abstract of the disclosure have been withdrawn due to applicant’s submission of Abstract as a single paragraph on a separate sheet as required.
The objection to Drawing is withdrawn:
Applicant’s argument is persuasive. Applicant’s replacement drawing sheet includes all of the figures appearing on the immediate prior version of the sheet. The objection is withdrawn.
The objection to claim 4 is withdrawn:
Applicant’s amendment to claim 4 obviates the current objection on record. The objection is withdrawn.
The rejection of claims 1 and 2 under 35 USC §102(a)(1) and 102(a)(2) over Von Maltzahn et al. is withdrawn:
Applicant’s amendment to claim 1 adds the limitation “wherein cells of said cell line undergo sufficient cell division to allow insertion and selection of cells which exhibit Class I or Class II epitope elimination and/or an increase in expression of IL-10 factor or MIF factor”, since Von Maltzahn et al. teach enucleated cells or cells having an inactivated nucleus, these cells are not able to divide. Therefore Von Maltzahn et al. do not teach the amended limitation, the rejection is withdrawn.
The rejection of claims 1-2 and 5-9 under 35 USC §103 over Han et al. in view of Zhang et al. is maintained:
The rejection of claims 1-3 and 5-9 under 35 USC §103 over Han et al. in view of Zhang et al., and further in view of Calandra et al. is maintained:
The rejection of claims 1-2 and 4-6 under 35 USC §103 over Deuse et al. in view of Zhang et al. is maintained:
Applicant’s arguments are fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting that none of the cited references expressly teach the cell lines are modified to be hypoimmunogenic thereby not activating innate or adaptive immune responses (Remarks, p4), as well as the ability of these types of cells to adequately reduce immune activity and prevent chronic rejection is unpredictable (Remarks, p5). In response, the Examiner respectfully submits that the asserted functionality (i.e., not activating innate or adaptive immune responses, adequately reduce immune activity and prevent chronic rejection) is not required by, nor recited within, the pending composition 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).
Applicant has further traversed the rejection, asserting that it is unpredictable from the cited references how IL-10 expression will affect the immune system when presented by Class I and II null cells as compared to presentation by immune cells or non-immune support cells since IL-10 is a multifunctional cytokine (Remarks, p5). Similarly, MIF has not usually been considered in cell transplant therapy because of its proinflammatory as well as anti-inflammatory activity (Remarks, p6). The skilled artisan could not reasonably predict based upon teachings of the cited combinations of references, that these cells would indeed be hypoimmunogenic and exhibit prolonged survival in vivo, including survival of neural cells derived from hypoimmunogenic HLA-KO iPSC expressing IL-10 in immunocompetent mice without any immunosuppression (Remarks, p6). In response, the Examiner submits that, first of all, as stated above, the asserted functionality is not required by, nor recited within, the pending composition 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). Moreover, Zhang et al. acknowledge that IL-10 is secreted by both innate immune cells and adaptive immune cells, and has multiple function in immune regulation (see p1, right column, and p2, Table 1). Zhang et al. further disclose that IL-10 contributes to immune homeostasis and immune tolerance (p2, left column) and has critical effects after allogenic stem cell transplantation (SCT, see p4-5) in case of Graft-versus-host disease (GVHD), asserts that IL-10 is a central mediator of the immune tolerance after allogenic SCT (P6, right column). Therefore PHOSITA would have been motivated to express IL-10 in Han et al.’s universal donor stem cell products, the human pluripotent stem cells (hPSCs) which lack of HLA-A/-B/-C proteins and CIITA gene (p10442, left column, and figure 1) or Deuse et al.’s mouse or human iPSCs which lose their immunogenicity (see Abstract) in order to further prevent the or reduce stem cell transplantation caused GVHD. Lastly, Applicant is reminded that a rejection based on obviousness only requires a reasonable expectation of success. See MPEP 2143.02.
Similarly, regarding MIF, Calandra et al. teach MIF has a central role as a regulator of innate immune and inflammatory responses (p792, left column), has the role as a regulator of host responses to infection and stress (p798, right column), therefore PHOSITA would have been motivated to express MIF in Han et al.’s human pluripotent stem cells (hPSCs) which lack of HLA-A/-B/-C proteins and CIITA gene (p10442, left column, and figure 1) in order to further prevent the or reduce stem cell transplantation caused GVHD. Moreover, as stated above, a rejection based on obviousness only requires a reasonable expectation of success. See MPEP 2143.02.
The rejection is maintained and modified necessitated by Applicant’s amendment.
Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-2 and 6-9 stand rejected and claim 15 is newly rejected under 35 U.S.C. 103 as being unpatentable over Han et al. (PNAS, 2019, 116(21):10441-10446, as cited in IDS) in view of Zhang et al. (Semin Immunol., 2019, 44:101322). The rejection is modified necessitated by Applicant’s amendment.
Han et al. employed the CRISPR/Cas9 system to selectively excise the genes encoding the polymorphic HLA class Ia members, HLA-A/-B/-C, and ablated HLA class II expression by targeting CIITA in human pluripotent stem cells (hPSCs). The resulting HLA-deficient, “immune-opaque” cells were further modified to express the immunomodulatory factors PD-L1, HLA-G, and CD47, which target immune surveillance by T cells, NK cells, and macrophages, respectively (p10441, right column).
Regarding claim 1, Han et al. teach employing multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells. It is known that Class I epitopes or Class II epitopes are referring to major histocompatibility complex (MHC, also known as human leukocyte antigen [HLA] in humans) class I and class II molecules. Han et al. teach HLA-A/-B/-C are human MHC class I genes (see p10442, left column). Han et al. also teach selective ablation of polymorphic HLA-A/-B/-C and HLA Class II expression: employing gene editing in hPSC line (HUES8), to remove HLA-A/-B/-C proteins and CIITA gene (see p10442, left column, and figure 1). This multiplex CRISPR/Cas9 genome editing to render hPSC hypoimmunogenic to both adaptive and innate immune responses (p10444, right column). This teaching reads on “a hypoimmunogenic cell line which does not express Class I epitopes or Class II epitopes” in instant claim. Han et al. also teach genome editing in hPSC line (HUES8) ablates polymorphic HLA-A/-B/-C and HLA class II expression and enables expression of immunomodulatory factors from AAVS1 safe harbor locus (p10442, right column, figure 1). This teaching indicates that the hPSC cell line has an inherent property that undergoes sufficient cell divisions to allow insertion and selection of cells which exhibit Class I or Class II epitope elimination or increase expression of immunomodulatory factors, as recited in instant claim.
Han et al. teach expressing the immunomodulatory factors PD-L1, HLA-G, and the macrophage “don’t-eat me” signal CD47 from the AAVS1 safe harbor locus (Abstract), but do not teach overexpression of interleukin-10 (IL-10) factor or migration inhibitory factor (MIF) factor. However, such is prima facie obvious in view of Zhang et al..
Zhang et al. provide an overview of the control of IL-10 secretion and signaling after stem cell transplantation (SCT) and the therapeutic interventions, with a focus on Type-1 regulatory T cells (Tr1 cells) (Abstract).
Regarding claim 1, Zhang et al. teach immune tolerance after allogenic SCT requires the dynamic regulation of immune cells, cytokines, host tissues and microbiota, and IL-10 is a central mediator of this process (p6, right column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Han et al.’s hypoimmunogenic cells which have selective ablation of polymorphic HLA-A/-B/-C and HLA Class II expression, and have these cells overexpressing IL-10 as taught by Zhang et al.. The skilled artisan would have been motivated to overexpress IL-10 in the hypoimmunogenic cells since Han et al. teach the hypoimmunogenic cells are developed to be universal donor stem cell products (see p10441, right column), and Zhang et al. teach the importance of IL-10 in stem cell transplantation: IL-10 is a central mediator of dynamic regulation of immune cells, cytokines, host tissues and microbiota after stem cell transplantation (see p6, right column), deficiency of IL-10 or its receptor results in aberrant immune responses that lead to immunopathology (Abstract). There would be a reasonable expectation of success of overexpressing IL-10, since Han et al. teach the method of knock-in/overexpressing a gene (e.g., PD-L1, see p10442, left column).
Regarding claim 2, Han et al. teach multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells (Abstract). This teaching reads on the cell line “does not express Class I epitopes and does not express Class II epitopes”.
Regarding claim 6, Han et al. teach the power of the CRISPR/Cas9 genome-editing system provided us and others with a tool to interfere with HLA class I expression in human pluripotent stem cells (hPSCs) or hematopoietic cells by knocking out the accessory chain beta-2-microglobulin (B2M) and to eliminate HLA class II expression by targeting its transcriptional master regulator, CIITA (p10441, left column). This teaching indicates that the gene editing for eliminating the expression of Class I epitopes or Class II epitopes can be used in human pluripotent stem cells (hPSCs, which including human iPSCs and ESCs) and hematopoietic cells.
Regarding claim 7, as discussed above, Han et al. teach genome editing in hPSC cell line (HUES8) ablates polymorphic HLA-A/-B/-C and HLA class II expression and enables expression of immunomodulatory factors from AAVS1 safe harbor locus (p10442, right column, figure 1), e.g., knock the immunomodulatory factors into the AAVS1 safe harbor locus (p10442, left column). This teaching reads on the knock-in / overexpressing genes can be achieved from AAVS1 safe harbor locus, as recited in instant claim.
Regarding claim 8, Han et al. employed multiplex genome editing to selectively ablate the highly polymorphic HLA class Ia and class II molecules and introduced the immunoregulatory factors PD-L1, HLA-G, and CD47 to control T cell- and NK cell mediated immune responses and macrophage engulfment in vitro and in vivo (p10441, right column, Significance). To counteract any residual T cell activity, they decided to knock in PD-L1, directly suppressing T cell responses (p10442, left column). Since Han et al. teach ablating the highly polymorphic HLA class Ia and class II molecules is necessary to prevent the activation of cytotoxic CD8+ T and CD4+ T helper cells (p10441, left column), herein the immunoregulatory factor PD-L1 which can directly suppress T cell responses is considered as an additional factor which mimics the loss of Class I and/or Class II activity, as recited in instant claim.
Regarding claim 9, following the discussion above, the immunoregulatory factor PD-L1 directly suppresses T cell responses (see p10442, left column), therefore is considered as a factor that blocks T and B cell function or alters an inflammatory response as recited in instant claim.
Regarding claim 15, it is noted that instant claim is directed to a product (the hypoimmunogenic cell line) as recited in instant claim 1. Given that teaching of Han et al. in view of Zhang et al. renders obviousness to the product, “[w]here 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)”. See MPEP 2112.01.
Claims 1-3 and 6-9 stand rejected and claim 15 is newly rejected under 35 U.S.C. 103 as being unpatentable over Han et al. (PNAS, 2019, 116(21):10441-10446, as cited in IDS) in view of Zhang et al. (Semin Immunol., 2019, 44:101322), further in view of Calandra et al. (Nat Rev Immunol., 2003 Oct;3(10):791-800). The rejection is modified necessitated by Applicant’s amendment.
The teaching of Han et al. and Zhang et al. is set forth above.
Regarding claim 3, Han et al. in view of Zhang et al. teach the hypoimmunogenic cell line overexpressing IL-10, but do not teach the hypoimmunogenic cell line which overexpresses IL-10 also overexpresses MIF factor. However, such is prima facie obvious in view of Calandra et al..
Calandra et al. review the main features and biological activities of MIF. Special emphasis is placed on the emerging concept that MIF has a central role as a regulator of innate immune and inflammatory responses, and the implications it might have for the development of new therapies for
human sepsis and other inflammatory diseases (p792, left column).
Regarding claim 3, Calandra et al. teach MIF has emerged as an important effector molecule of the innate immune system, has the role as a regulator of host responses to infection and stress. Distinctive features of MIF include its capacity to counter-regulate the immunosuppressive effects of
glucocorticoids on immune cells and to sustain proinflammatory functions by inhibiting p53-dependent
apoptosis of macrophages (see p798, right column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Han et al. and Zhang et al.’s hypoimmunogenic cells which have selective ablation of HLA Class I and Class II expression and overexpression of IL-10, and have the hypoimmunogenic cells also overexpressing MIF, as taught by Calandra et al.. The skilled artisan would have been motivated to also overexpress IL-10 in the hypoimmunogenic cells since Calandra et al. teach MIF is an important effector molecule of the innate immune system, which has the role as a regulator of host responses to infection and stress (see p798, right column). This effect of MIF is beneficial for the immune system regulation after the hypoimmunogenic cells transplantation. There would be a reasonable expectation of success of overexpressing MIF, since Han et al. teach the method of knock-in/overexpressing a gene (e.g., PD-L1, see p10442, left column).
Claims 1, 2, 4 and 6 stand rejected and claim 15 is newly rejected under 35 U.S.C. 103 as being unpatentable over Deuse et al. (Nat Biotechnol., 2019 Mar;37(3):252-258, as cited in IDS) in view of Zhang et al. (Semin Immunol., 2019, 44:101322). The rejection is modified necessitated by Applicant’s amendment.
Deuse et al. teach both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed (Abstract).
Regarding claim 1, Deuse et al. teach to achieve hypoimmunogenicity, these iPSCs from mice (miPSCs) underwent a three-step gene-editing process. First, CRISPR guide RNAs targeting the coding sequence of the mouse β2-microglobulin (B2m) gene were ligated into vectors containing the Cas9 expression cassette and subsequently transfected into miPSCs. B2m is a structural component of MHC class I. Second, B2m−/− miPSCs were transfected with a CRISPR-Cas9 vector targeting Ciita, the master regulator of MHC class II molecules. Third, the Cd47 gene sequence was synthesized and cloned into a lentivirus with blasticidin resistance, which was used to transduce B2m−/−Ciita−/− miPSC clones followed by antibiotic selection and expansion of B2m−/−Ciita−/− Cd47 transgene (tg)-expressing miPSCs. This teaching reads on “hypoimmunogenic cell line which does not express Class I epitopes or Class II epitopes” in instant claim. Deuse et al. further teach using CRISPR/Cas9- mediated disruption of major histocompatibility complex (MHC) class I and II genes in mouse iPSCs and human iPSCs (see e.g., p252-253). This teaching indicates that the iPSC cell lines have an inherent property that undergoes sufficient cell divisions to allow insertion and selection of cells which exhibit Class I or Class II epitope elimination, as recited in instant claim.
Deuse et al. teach mouse and human iPSCs cell lines which lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated, but do not teach overexpressing interleukin-10 (IL-10) factor or migration inhibitory factor (MIF) factor in said hypoimmunogenic cell lines. However, such is prima facie obvious in view of Zhang et al..
Zhang et al. provide an overview of the control of IL-10 secretion and signaling after stem cell transplantation (SCT) and the therapeutic interventions, with a focus on Type-1 regulatory T cells (Tr1 cells) (Abstract).
Regarding claim 1, Zhang et al. teach immune tolerance after allogenic SCT requires the dynamic regulation of immune cells, cytokines, host tissues and microbiota, and IL-10 is a central mediator of this process (p6, right column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Deuse et al.’s miPSCs which lacked MHC class I and II expression, and overexpress IL-10 in the miPSCs as taught by Zhang et al.. The skilled artisan would have been motivated to overexpress IL-10 since Deuse et al. teach the hypoimmunogenic cell grafts can be engineered for universal transplantation, and Zhang et al. teach the importance of IL-10 in stem cell transplantation: IL-10 is a central mediator of dynamic regulation of immune cells, cytokines, host tissues and microbiota after stem cell transplantation (see p6, right column), deficiency of IL-10 or its receptor results in aberrant immune responses that lead to immunopathology (Abstract). There would be a reasonable expectation of success of overexpressing IL-10, since Deuse et al. teach the method of gene-editing for knock-in/overexpressing a gene (see p252, right column).
Regarding claim 2, Deuse et al. teach both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed (Abstract).
Regarding claims 4 and 6, Deuse et al. teach C57BL/6 wild type (WT) miPSCs (p252, right column) and human iPSCs (hiPSCs) using a human episomal iPSC line derived from CD34+ cord blood (p253, right column) for CRISPR/Cas9- mediated disruption of major histocompatibility complex (MHC) class I and II genes.
Regarding claim 15, it is noted that instant claim is directed to a product (the hypoimmunogenic cell line) as recited in instant claim 1. Given that teaching of Deuse et al. in view of Zhang et al. renders obviousness to the product in instant claim 1, “[w]here 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)”. See MPEP 2112.01.
Conclusion
No claims are 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.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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