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
The instant application, filed on 11 September, 2023, is a 371 of PCT/US2022/022368 filed 29 March, 2022 which claims domestic benefit to US provisional application no. 63/168,225, filed on 30, March,2021 and US provisional application no. 63/305,587, filed on 01, February 2022.
Information Disclosure Statement
The 5 information disclosure statements (IDS) submitted on 25, February, 2026 have been considered by the examiner.
The 5 information disclosure statements (IDS) submitted on 24, February, 2026 have been considered by the examiner.
Status of Application, Amendments, and/or Claims
The response filed on 29 March, 2024 has been entered in full. These are the amended claims of the original claim set received on 11 September, 2023. In the amendment, claims 1, 3, 6, 11, 22, 27-30, 32, 38, 46, 50, 53, and 55 are amended and claims 4, 7-10, 12-21, 23-26, 31, 33-37, 40-45, 48, and 52 are cancelled. Therefore, claims 1-3, 5, 6, 11, 22, 27-30, 32, 38, 39, 46, 47, 49-51, and 53-55 are pending and are the subject of this Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 5, 30, and 49 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 5 recites “the modified cell of claim 4” this is unclear because claim 4 is cancelled and thus cannot be depended upon. For the purpose of further examination, the claim will be interpreted to be dependent upon claim 2.
Claim 30 recites the limitation "generating the modified cell of claim 1 comprising expressing said CD16t, CD32t, or CD64t protein". There is insufficient antecedent basis for this limitation in the claim. Further, claim 1 from which it depends does not recite claim to a CD16t, CD32t or CD64t protein, however claim 2 does. For the purpose of further examination claim 30 will be interpreted to be dependent on claim 2.
Claim 49 recites “the modified cell of any one of claims 46-48” this is unclear because claim 48 is cancelled and thus cannot be depended upon. For the purpose of further examination, the claim will be interpreted to be dependent upon claims 46 and 47.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Qin et al. (2004) Differential Gene Expression Modulated by the Cytoplasmic Domain of FcγRIa (CD64) α-Chain Journal of Immunology 173 6211-6219 (hereafter Qin) as evidenced by Brandsma et al. (2015) Fc receptor inside-out signaling and possible impact on antibody therapy Immunological Reviews (268) 74-87 (hereafter Brandsma).
In regards to claim 1, Qin anticipates a modified cell, wherein the modified cell expresses a FcγRI protein truncated by removal of its cytoplasmic domain (pg.6211 col 2, lines 26-30). The truncated protein directly downregulates the production of M-CSF, MIC-1, LSP1, and NFκB when stimulated with anti-FcγRI mAb (pg.6215, col 1, lines 2-7/ pg.6218, col 1, lines 8-10), and further Qin demonstrated that the truncation of the cytoplasmic domain did not alter association of the γ-chain (pg.6214, col 1, lines 6-9). Though not explicitly stated Qin anticipates the cell being less susceptible to antibody dependent cellular cytotoxicity (ADCC) and having reduced intracellular signaling as evidenced by Brandsma which states the cytoplasmic domain of FcγRI contains serine residues necessary for full signaling of the γ chain, phagocytosis, and could be important for effector function (pg.77, col 1, lines 35-46/ pg.77, col 2, lines 1-3). Thus, Qin’s removal of the cytoplasmic domain anticipates interrupting intracellular signaling and ADCC effector function.
In regards to claim 2 Qin anticipates the truncated Fc receptor being a CD64 protein with a truncated cytoplasmic domain (pg.6211 col 2, lines 26-30).
In regards to claim 30 Qin anticipates the modified cell comprising a truncated CD64 in a parental non-modified mouse macrophages (pg.6211 col 2, lines 26-30).
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.
Claims 3, 6, 22, 27-29, 32, 38, 39, 50, 51, and 53 - 55 are rejected under 35 U.S.C. 103 as being unpatentable over Qin as applied to claim 1 and 30 above, and further in view of Deuse et al (2019) Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients Nature Biotechnology (37) 252-258 (of record 02/24/2026) (hereafter Deuse) and Zhu and Kaufman (2019) Engineered human pluripotent stem cell -derived natural killer cells: the next frontier for cancer immunotherapy Journal of Chinese Medical Association (1) 4-11 (of record 02/24/2026) (hereafter Zhu and Kaufman).
Qin fails to teach the modified cell being a pluripotent cell of claim 3, the modified cell being derived from a human hypo-immunogenic pluripotent (HIP) cell of claim 6, the modified cell being selected from the cells listed in claim 22, 28, and 39, and the modified cell being selected from the cells listed in claim 32. Qin also fails to teach the use of the modified cells are therapeutics to treat diseases of claims 27, 29, and 38. Further, Qin fails to teach the modified cell comprising a SIRPα engager protein of claim 50, where the SIRPα engager protein comprises an immunoglobulin superfamily domain, and antibody fab, or a single chain variable fragment of claim 51, the SIRPα engager protein being CD47 of claim 54, and the modified cell is an engineered NK cell of claim 55. Qin also fails to teach the modified cell comprising the B2M -/- and CITA -/- phenotype, a CD64t and a SIRPα-engager molecule of claim 53.
Deuse, however in regards to claims 3 and 6 teaches the use of human inducible pluripotent stem cells which have been genetically modified to be a hypo-immunogenic cell which can evade immune rejection and suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation (pg.253, col 1 line 57 – pg.255, col 2, line 38/ abstract).
In regards to claims 22, 28, 32, and 39 Deuse further teaches that the hypo-immunogenic iPSCs can be differentiated into edited endothelial cells or edited cardiomyocytes before in vivo use (pg.255, col 1, lines 4-6).
In regards to claims 27, 29, and 38 Qin suggest modified cells with altered FcRs have shown protection from some forms of autoimmunity, and altered antibody response and highlights how these changes could be important in the biological effects or side effects of Ig based therapeutic (pg.6218, col 2, lines 15-22). Deuse further teaches the use of the hypoimmunogenic cells in vivo can evade immune rejection in immunocompetent allogeneic recipients highlighting their benefit as a therapeutic to treat diseases such as heart failure (pg.258, col 1, lines 4-8) and further teaches delivering the cell in vivo using a pharmaceutical composition comprising saline (methods, pg.2, section: “teratoma assays to study miPSC survival in vivo).
In regards to claim 50, 51, and 54 Deuse teaches that the hypoimmunogenic cells were edited to overexpress CD47 (an immunoglobulin superfamily domain SIRPα-engager protein) to interact with several cell surface receptors to inhibit phagocytosis (pg.252, col 2, lines 11-13) and further as an effective method to silence all innate immune response (pg.256, col 1, lines 3-4).
In regards to claim 53, Deuse teaches that the hypoimmunogenic iPSCs were edited to have B2M-/- phenotype the structural component of MHC class I, and the phenotype CIITA-/- which is the master regulator of MHC class II molecules.
Deuse fails to teach the modified cell being a NK cell of claim 55. Zhu and Kaufman however teach that NK cells have shown benefit as an adoptive immunotherapy to treat a variety of both hematological malignancies and solid tumors (pg.5, Section 3). Further Zhu and Kaufman teach universal hypoimmunogenic iPSCs need HLA class I expression eliminated and teaches this is done by knocking out B2M to avoid T -cell mediated rejection and further employing CD47 to avoid NK cell mediated rejection (pg.8, Section 10). Zhu and Kaufman also suggest that NK cells derived from the universal hypoimmunogenic iPSCs would presumably be resistant to rejection by the recipient’s immune system and have longer in vivo persistence (pg.8, Section 10).
Thus, Qin discloses a modified cell wherein the CD64 is truncated of its cytoplasmic domain decreasing its intracellular signaling and susceptibility to ADCC, and Deuse teaches the addition of a SIRPα engager protein wherein that engager protein is CD47 to develop hypoimmunogenic iPSCs and further wherein the cells are B2M-/- and CIITA-/- and can be differentiated into endothelial cells or cardiomyocytes for universal adoptive cell therapy with reduced risk of rejection. Zhu and Kaufman further, suggest the use of hypoimmunogenic iPSCs derived universal adoptive NK cells with immune rejection resistance for the treatment of hematological malignancies or solid tumor cancers. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Qin and Deuse and motivated by Zhu and Kaufman with a reasonable expectation of success to develop a modified cell derived from an iPSC which has a truncated CD64, increased CD47 expression and is B2M-/- and CIITA-/- to develop a hypoimmunogenic which has increased resistance to immune rejection for a universal cell therapy.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Qin as applied to claim 1 and 2 above, and further in view of Fu and Kenney (WO2020/227510; of record 02/24/2026).
Qin teaches a modified cell comprised of a truncated CD64 missing its cytoplasmic domain, but fails to teach SEQ ID No 16 of claim 5. Fu and Kenney, however, teach the sequences of SEQ ID No 16 (SEQ ID No 133 of Fu and Kenney) and further teaches using this truncated CD64 allows the modified cell to bind to IgG but lacks the ability to interact with the γ chain necessary to trigger cellular activation (pg.32, lines 5-11).
Thus, Qin discloses a modified cell comprising a truncated CD64 and, Fu and Kenny teach the specific sequence of truncated CD64 of the instant claims to bind IgG without triggering cellular activation. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Qin with the teaching of Fu and Kenny with a reasonable expectation of success to develop a modified cell comprising a truncated CD64 of the sequence of SEQ ID No 16 to allow the cell to bind to IgG without triggering cellular activation.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Qin as applied to claim 1 above, and further in view of Maryamchik et al. (2020) New directions in chimeric antigen receptor T cell [CAR-T] therapy and related flow cytometry Cytometry (98) 299-327 (hereafter Maryamchik).
Qin fails to teach the modified cells comprising a suicide gene of claim 11, however, Maryamchik teaches the use of suicide genes as an OFF switch in synthetic immunology as a means for better control on in vivo control of therapeutics as a safety mechanism (pg.302 col 2, lines 2-5).
Thus, Qin discloses a modified cell wherein the CD64 is truncated of its cytoplasmic domain and decreases its intracellular signaling and is less susceptible to ADCC, and Maryamchik teaches the use of suicide genes as off switches as a means for enhanced safety and control of cellular therapeutics. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Qin and Maryamchik with a reasonable expectation of success to develop a modified cell with decreased susceptibility to ADCC and reduced or eliminated intracellular signaling and a suicide gene for in vivo control of the modified cell for enhanced safety.
Claims 46, 47, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Qin as applied to claim 1 above, and further in view of Kruskal et al. (1992) Phagocytic Chimeric Receptors Require Both Transmembrane and Cytoplasmic Domains from the Mannose Receptor J. Exp. Med (176) 1673-1680 (hereafter Kruskal) and Jing et al. (1990) Role of the Human Transferrin Receptor Cytoplasmic Domain in Endocytosis: Localization of a Specific Signal Sequence for Internalization The Journal of Cell Biology (110) 283-294 (hereafter Jing).
Qin fails to teach the modified Fc Receptor of the modified cell being a chimera comprising a cytoplasmic domain that does not mediate an Fc receptor signaling pathway and promotes endocytosis. Further Qin fails to teach the Fc receptor chimera cytoplasmic domain being from a transferrin receptor and further TfR1 or TfR2.
Kruskal, however, teaches that replacing the transmembrane and/or cytoplasmic tail regions of a FcγRI receptor with the autologous parts of the macrophage mannose receptor (pg.1674, col 1, lines 38-42) you can improve the endocytosis of the receptor (Table 1).
Kruskal fails to teach replacing the cytoplasmic tail of the Fc receptor with one of a transferrin, however, Jing teaches that the transferrin receptors cytoplasmic domain contains structural determinants that allow for the receptor to have high efficiency endocytosis (abstract).
Thus, Qin discloses a modified cell wherein the CD64 is truncated of its cytoplasmic domain and decreases its intracellular signaling and is less susceptible to ADCC, Kruskal teaches the use of chimeric Fc receptors in which their cytoplasmic domain is replaced to increase endocytosis, and Jing teaches that transferrin receptor cytoplasmic domains contain determinants which allow for high efficiency endocytosis. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Qin, Kruskal, and Jing with a reasonable expectation of success to create a modified cells containing a modified Fc Receptor wherein the cytoplasmic domain is replaced to increase endocytosis by the simple substitution of the macrophage mannose receptor domains with transferrin domains for high efficiency endocytosis.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 6, 11, 22, 27, 28, 29, 30, 32, 38, and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 9, 20, 24-27, 29, 31, 35, 36, 43, 46-50 of copending Application No. 17/768,217 (claim set 01/19/2026) (reference application) in view of Qin as evidenced by Brandsma.
Claim 1 of the reference application recites a modified cell wherein said modified cell have an elevated level of CD64 is less susceptible to ADCC or CDC and wherein the cell does not comprise sufficient intracellular motifs which encompasses claims 1 and 2 of the instant application.
Claim 4, 5, and 6 of the reference application recites the modified cell is derived from a HIP cell, a human hypo-immunogenic pluripotent ABO blood group O rhesus Factor negative (HIPO-) cell, or an iPSC respectively. These claims encompass claims 3 and 6 of the instant application.
Claim 9 of the reference application recites the modified cell comprising a suicide gene activated by a trigger to signal cell death this encompasses claim 11 of the instant application.
Claim 20 of the reference application recites the modified cell is a CAR-T cell this encompasses an embodiment of instant claim 22.
Claims 24 -26 recite a method of using the modified cell to treat a disease wherein the modified cell is selected from the group consisting of CAR-T cell, an endothelial cell, a dopaminergic neuron, a pancreatic islet cell, a cardiomyocyte, a retinal pigment endothelium cell and a thyroid cell, and the disease is selected from the group consisting of Type I Diabetes, a cardiac disease, a neurological disease, a cancer, an ocular disease, a vascular disease, and a thyroid disease. These claims encompass the instant claims 27-29
Claim 27 of the reference application recites a method of generating the modified cells comprising increasing the expression of CD64 in said parental non-modified cell, this significantly encompasses the instant claim 30.
Claim 29 of the reference application recites the modified cell generated from the method of claim 27 is derived from a HIP or HIPO- cell and Claim 31 of the reference application recites the modified cell is derived from an iPSC or ESC. These claims significantly encompass the instant claim 32.
Claims 35 and 36 of the instant application recite the modified cell in a pharmaceutically acceptable carrier and further wherein the modified cell is a CAR-T cell. These claims encompass claims 38 and 39 of the instant application.
The reference application fails to teach the truncated CD64 of instant claims 2 and 30, however Qin teaches a cell comprised of a CD64 truncated to remove its cytoplasmic domain shows reduced intracellular activity and is less susceptible ADCC as evidenced by Brandsma as outlined above in the rejection of claim 1.
Thus, the reference application significantly encompasses the invention of the instant application, and Qin teaches the use a truncated CD64 to disrupt intracellular signaling and reduce susceptibility to ADCC. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention in possession of the invention of the reference application would have found it obvious to incorporate the teachings of Qin with a reasonable expectation of success to develop the invention of the instant application.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 22, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/260,222 (reference application) in view of Brandsma.
Claim 1 of the reference application recites a hypoimmunogenic T cell comprising eliminated B2M and CIITA activity and increased CD47 expression this significantly encompasses instant claims 1, 22, and 53.
Claim 1 of the reference application fails to teach a modified Fc receptor with reduced or eliminated intracellular activity and further makes the cell less susceptible to ADCC. Brandsma, however, teaches that the cytoplasmic domain of the Fc receptor CD64 impacts intracellular signaling and ADCC susceptibility and further that modifications to this domain can inhibit these functions (pg.77, col 1 line 35- col 2 line 3) which would allow for a decreased risk of host rejection.
Thus, the reference application significantly encompasses the invention of the instant application, and Brandsma teaches the cytoplasmic domain of the Fc receptor CD64 impacts intracellular signaling and ADCC susceptibility and further that modifications to this domain can inhibit these functions for therapeutic use. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention in possession of the invention of the reference application would have found it obvious to incorporate the teachings of Brandsma with a reasonable expectation of success to develop the invention of the instant application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Thursday from 8am to 6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights