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
Claims 2-3, 9, 11-20, 24, 26-27, 34, 36-39, and 42-44 are cancelled. Claims 1, 4-8, 10, 21-23, 25, 28-33, 35, and 40-41 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/US2022/046790 (filed on 10/14/2022) which claims benefit of Provisional U.S. Application No. 63/255,830 (filed on 10/14/2021). 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.
Claims 1, 4-8, 10, 21-23, 25, 28-33, 35, and 40-41 have an effective filing date of 10/14/2021 corresponding to Provisional U.S. Application No. 63/255,830.
Information Disclosure Statement
The information disclosure statement(s) filed on 03/12/2025 has/have been considered. Signed copies are enclosed.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Claim Objections
Claims 6-8, 10, and 41 are objected to because of the following informalities:
Claims 6-8: “The mammalian cell of claim 5” should be replaced with “The modified cell of claim 5” for consistency.
Claim 6: “comprises” should be replaced with “comprise”.
Claim 10: “of HLA-E” should be replaced with “HLA-E”.
Claim 41: the colon after “comprising” should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-8, 10, 22-23, 25, 28-33, 35, and 40-41 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “overexpressed” in claims 1 and 4 and “overexpression” in claims 5 and 10 are relative terms which render the claims indefinite. The terms “overexpressed” and “overexpression” are not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The use of “overexpressed” renders the expression levels of SIGLEC14, MUC15, GPC4, and TEX10 indefinite (claims 1 and 4). The use of “overexpression” renders the expression levels of the following indefinite:
one or more genes associated with inhibition of macrophage phagocytosis, one or more genes associated with inhibition of complement activation and deposition, and one or more genes associated with inhibition of natural killer (NK) cell activation (claim 5); and
CD47, CD55, CD59, CD46, HLA-G, and HLA-E (claim 10).
The instant specification states “the term ‘overexpression’ is used to refer to gene expression that is increased relative to a reference level. In many embodiments, the reference level is the level of gene expression that is typical from an endogenous locus for the gene, for a similar cell (e.g., of a parental cell line) that has not been artificially modified (e.g., genetically or otherwise manipulated to modulate gene expression). In some embodiments, a gene that is not present in a host cell is overexpressed; thus, in these situations, there is no corresponding endogenous locus for the gene, and the reference level is zero” (¶ 0058, emphasis added). Therefore, an adequate reference level is not established for overexpression despite the definition given as a person having ordinary skill in the art would not understand the metes and bounds of the claims (i.e. the reference level can be relative to another cell or zero) and the rejection still applies.
Claims 6-8, 22-23, 25, 28-33, 35, and 40-41 are included in this rejection as they incorporate and/or depend on claim 1 and/or 5. It is noted that claim 21 recites “each overexpressed gene is overexpressed by at least 1.5-fold relative to expression in a control cell” in lines 2-3, establishing a reference level for overexpression that removes indefiniteness. Therefore, claim 21 will not be included in this rejection.
For the purposes of claim interpretation, the terms “overexpressed” or “overexpression” in claims 1, 4-5, and 10 will be treated as increased expression relative to any reference level.
Claim 7 recites the limitation "the one or more genes associated with complement activation and deposition" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
For the purposes of claim interpretation, "the one or more genes associated with complement activation and deposition" will be treated as "the one or more genes associated with inhibition of complement activation and deposition".
Claim 23 recites the limitation "The method of claim 22" in line 1. There is insufficient antecedent basis for this limitation in the claim.
For the purposes of claim interpretation, "The method of claim 22" will be treated as "The modified mammalian cell of claim 22".
Regarding claim 31, the phrase "the one or more genes associated with NK cell activation comprise one or more NKG2D ligands" renders the claim indefinite because it is unclear whether the limitation is directed to genes that encode NKG2D ligands or the NKG2D ligands themselves. Claim 32 is included in this rejection as it incorporates and/or depends on claim 31.
For the purposes of claim interpretation, "the one or more genes associated with NK cell activation comprise one or more NKG2D ligands" will be treated as "the one or more genes associated with NK cell activation encode one or more NKG2D ligands".
Regarding claim 32, the phrase "the one or more NKG2D ligands are selected from the group consisting of MICA, MICB, and a combination thereof" renders the claim indefinite because it is unclear whether the limitation is directed to genes that encode NKG2D ligands or the NKG2D ligands themselves. MICA and MICB are genes that encode NKG2D ligands.
For the purposes of claim interpretation, "the one or more NKG2D ligands are selected from the group consisting of MICA, MICB, and a combination thereof " will be treated as "the one or more NKG2D ligands are selected from the group consisting of MICA, MICB, and a combination thereof " to refer to the protein products.
Claim Rejections - 35 USC § 102
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 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, 25, and 35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al. (Genome-Scale CRISPRa Screen Identifies Novel Factors for Cellular Reprogramming, Stem Cell Reports, 2019 Apr 9;12(4):757-771).
Regarding instant claims 1 and 35, Yang et al. teach “CRISPRa to induce expression of Klf5, Fam189a2, Tex10, and Tet3 in Oct4-GFP EpiSCs [epiblast stem cells]” (Pg. 766, column 1, ¶ 3, lines 1-2, emphasis added) (instant claim 1) wherein the stem cells are derived from mice (Pg. 757, Abstract, line 4, “mouse EpiSCs”) i.e. it is a mammalian stem cell (instant claim 35). The reference level for gene expression is an EpiSC that has not undergone CRISPR. Induced expression of Tex10 via CRISPRa increased expression of Tex10 relative to the reference level. Therefore, this teaching reads on a modified mammalian stem cell (i.e. mouse EpiSCs modified with CRISPRa) (instant claim 35) in which the gene TEX10 is overexpressed (instant claim 1).
Regarding instant claim 25, Yang et al. further teach CRISPR/Cas9 editing employs “RNA-programmable (single guide RNA [sgRNA])… directed toward promoter regions to increase gene expression” (Pg. 757, column 2, ¶ 2, lines 4-9). This teaching reads on an exogenous gene activation system (i.e. CRISPR/Cas9 editing utilizing exogenous ssRNA) that is capable of driving expression of an endogenous gene (i.e. CRISPR/Cas9 is directed to endogenous promotors regions to increase gene expression).
Claims 1 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Eid et al. (Genome-wide identification of CBX2 targets: insights in the human sex development network, Mol Endocrinol, 2015 Feb;29(2):247-57).
Regarding instant claims 1 and 21, Eid et al. teach “the influence of CBX2 [Chromobox homolog 2] on the expression of the selected genes… under overexpression of [CBX2]” (Pg. 251, column 1, ¶ 3, lines 17-19) in “human Sertoli-like cells” (Pg. 248, column 2, ¶ 2, line 2) i.e. a mammalian cell (instant claim 1). Eid et al. further teach “CBX2 significantly enhanced the expression of endogenous EXO1, SOX3, MAMLD1, TBX2, TEX10 (instant claim 1), FGF2, WTAP, TSPYL4, and MTM1 (by 2.9-, 2.6-, 2.6-, 2.3-, 2.2-, 2.4-, 1.6-, 2.2- (instant claim 21), and 1.6-fold, respectively)” (Pg. 251, column 2, ¶ 3, lines 2-6, emphasis added). This teaching reads on a modified mammalian cell (i.e. human Sertoli-like cells modified to overexpress CBX2) in which the gene TEX10 is also overexpressed (instant claim 1) by at least 1.5-fold (i.e. 2.2-fold) relative to a control cell (i.e. human Sertoli-like cells that do not overexpress CBX2) (instant claim 21).
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.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Leung (In vitro modeling of pancreatic duct cell carcinogenesis, 2013, University of Toronto, Pg. 1-133) in view of Wang et al. (RNAi Screening Identifies that TEX10 Promotes the Proliferation of Colorectal Cancer Cells by Increasing NF-κB Activation, Adv Sci, 2020 Jul 7;7(17):2000593) , Fong et al. (Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14, EMBO J, 2015 Nov 12;34(22):2775-88), Ling et al. (KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma, Cancer Cell, 2012 Jan 17;21(1):105-20) and Deshmukh et al. (Gemcitabine treatment promotes immunosuppressive microenvironment in pancreatic tumors by supporting the infiltration, growth, and polarization of macrophages, Sci Rep, 2018 Aug 10;8(1):12000).
Leung teaches a TGF-β resistant mammalian cell line, also referred to as a TβR cell line, generated by “culture of the H6c7 cells in increasing concentrations of TGF-β until a cell line emerged that was completely insensitive to the growth inhibitory properties of TGF-β” (Pg. 79, last ¶, lines 1-3) in a model for pancreatic cancer. Leung further teaches the TβR cell line underwent “Smad4 silencing through the loss of Smad4 gene copies, methylation of the promoter, and mutation of the Smad4 gene” (Pg. 81, ¶ 1, last 2 lines). This teaching indicates a mammalian cell line that was deliberately manipulated in a laboratory to alter its genetic content i.e. a modified cell as defined by the instant specification (see ¶ 0055 of the instant specification).
Leung further teaches the genes MUC15 and GPC4 are upregulated i.e. overexpressed in the TβR cell line (Pg. 117, Table 5, shows both MUC15 and GPC4 are upregulated in TβR cells) due to acquiring resistance to TGF-β signaling and introduction of an oncogenic KRAS mutation. This teaching reads on overexpression of MUC15 and GPC4.
Leung does not teach (i) overexpression of TEX10 and SIGLEC14 nor (ii) motivation for overexpressing TEX10 and SIGLEC14 in the TβR-KRAS cell line as taught by Leung. These deficiencies are remedied by Wang et al., Fong et al., Deshmukh et al., and Ling et al.
Wang et al. teach the genes TEX10 and GPC4 are upregulated i.e. overexpressed in a mammalian cell line used as a model for colorectal cancer (Pg. 2, column 1, ¶ 1, lines 21-27, discusses 9 genes that are upregulated in colorectal cancer progression including TEX10 and GPC4 in HT-29 cells). This teaching reads on overexpression of TEX10 and GPC4.
Wang et al. further teach “TEX10 overexpression significantly promoted NF-𝜅B activity” (Pg. 2, column 2, ¶ 3, fourth to last line to third to last line), wherein NF-𝜅B activity “accelerated tumor progression and poor prognosis in CRC [colorectal cancer]” (Pg 1., column 2, ¶ 2, third to last line to second to last line). This teaching indicates NF-𝜅B activation can be increased by TEX10 overexpression.
Ling et al. teach “constitutive NF-κB activation is required for PDAC [pancreatic ductal adenocarcinoma] development and proposed the mechanism for NF-κB activation by KrasG12D” (Pg. 117, column 1, ¶ 2, lines 1-3) in a mouse model. This teaching indicates NF-κB activation promotes carcinogenesis in a pancreatic cancer model with a KRAS mutation, applicable to the TβR-KRAS cell line as taught by Leung (i.e. the cell line is also a pancreatic cancer model with a KRAS mutation).
Therefore, a person having ordinary skill in the art wishing to increase the carcinogenic or metastatic potential of the TβR-KRAS cell line (i.e. a pancreatic cancer model) as taught by Leung can further drive NF-𝜅B activation by overexpression of TEX10. This modification would create a model for studying a highly malignant form of pancreatic cancer driven by increased NF-κB activation in a KRAS mutation background.
Leung, Wang et al., and Ling et al. do not teach (i) overexpression SIGLEC14 nor (ii) motivation for overexpressing SIGLEC14 in the TβR-KRAS cell line as taught by Leung. These deficiencies are remedied by Fong et al. and Deshmukh et al.
Fong et al. teach “THP1 monocytic cells overexpressing… Siglec-14” (Pg. 2778, column 1, ¶ 2, lines 5-6) wherein THP1 cells are mammalian cells. This teaching reads on overexpression of SIGLEC14.
Fong et al. further teach “Siglec-14 is pro-inflammatory” (Pg. 2775, column 1, Abstract, line 15), wherein Siglec-14-expressing cells secrete “higher levels of pro-inflammatory cytokine IL-8” (Pg. 2782, column 1, ¶ 2, lines 3-4). This teaching demonstrates overexpression of SIGLEC14 increases IL-18 secretion.
Deshmukh et al. teach IL-8 “promotes [tumor-associated] macrophage [TAMs]… migration, invasion, and growth” (Pg. 7, ¶ 3, line 2) in a pancreatic cancer mouse model. This teaching indicates IL-8 contributes to creating the immunosuppressive tumor microenvironment in pancreatic cancer via its effect on TAMs, relevant for hiding tumor cells from the immune system and allowing pancreatic cancer to grow, applicable to the pancreatic cancer TβR-KRAS cell line as taught by Leung and thus obvious to add Siglec-14 to promote immunosuppression and metastasis.
Therefore, a person having ordinary skill in the art wishing to prevent the immune system from attacking cancer cells can overexpress SIGLEC14 in the TβR-KRAS cell line as taught by Leung to drive IL-8 secretion up and thus also allow TAMs to create a tumor immunosuppressive microenvironment, effectively hiding a pancreatic tumor and promoting its growth. This modification would serve to further increase the carcinogenic and metastatic potential of the model for studying a highly malignant form of pancreatic cancer driven by (i) increased NF-κB activation in a KRAS mutation background and (ii) alternation of TAM activity to contribute to the tumor immunosuppressive microenvironment.
Overexpression of the genes TEX10 and SIGLEC14 was a known modification of mammalian cells used prior to the effective filing date of the application. Leung, Wang et al., and Fong et al. are considered analogous to the present invention as they are all in the same field of overexpression of genes in mammalian cells. Ling et al. and Deshmukh et al. provide motivation for modifying the TβR-KRAS cell line as taught by Leung, giving context to the mechanisms of TEX10 and SIGLEC14 that are relevant to pancreatic cancer.
Leung teaches a mammalian TβR-KRAS cell line used as a model for pancreatic cancer wherein MUC15 and GPC4 are upregulated. Wang et al. teach NF-𝜅B activation can be increased by TEX10 overexpression. Ling et al. teach NF-κB activation promotes carcinogenesis in a pancreatic cancer model with a KRAS mutation, applicable to the TβR-KRAS cell line as taught by Leung. Therefore, a person having ordinary skill in the art wishing to increase the carcinogenic or metastatic potential of the TβR-KRAS cell line as taught by Leung can further drive NF-𝜅B activation by overexpression of TEX10. Furthermore, Fong et al. teach overexpression of SIGLEC14 increases IL-18 secretion. Deshmukh et al. teach IL-8 contributes to creating the immunosuppressive tumor microenvironment in pancreatic cancer via its effect on TAMs, relevant for hiding tumor cells from the immune system and allowing pancreatic cancer to grow, applicable to the pancreatic cancer TβR-KRAS cell line as taught by Leung. Therefore, a person having ordinary skill in the art wishing to prevent the immune system from attacking cancer cells can overexpress SIGLEC14 in the TβR-KRAS cell line as taught by Leung to drive IL-8 secretion up and thus also allow TAMs to create a tumor immunosuppressive microenvironment, effectively hiding a pancreatic tumor and promoting its growth. These modifications would increase the carcinogenic and metastatic potential of the model for studying a highly malignant form of pancreatic cancer driven by (i) increased NF-κB activation in a KRAS mutation background and (ii) alternation of TAM activity to contribute to the tumor immunosuppressive microenvironment.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. overexpression of TEX10 as taught by Wang et al. and SIGLEC4 as taught by Fong et al. are linked to pancreatic carcinogenesis and/or metastasis via NF-κB activation as taught by Ling et al. and the immunosuppressive effects on tumor-associated macrophages in pancreatic cancer via IL-8 secretion as taught by Deshmukh et al.) would have led one of ordinary skill to modify the prior art reference (i.e. the TβR-KRAS cell line as taught by Leung) to arrive at the claimed invention.
Overexpression of the genes TEX10 and SIGLEC14 was a known modification of mammalian cells used prior to the effective filing date of the application. Leung, Wang et al., and Fong et al. are considered analogous to the present invention as they are all in the same field of overexpression of genes in mammalian cells. Ling et al. and Deshmukh et al. provide motivation for modifying the TβR-KRAS cell line as taught by Leung, giving context to the mechanisms of TEX10 and SIGLEC14 that are relevant to pancreatic cancer. A person having ordinary skill in the art would recognize the results of the combination were predictable and have a reasonable expectation of success because 1) TEX10 and SIGLEC14 were successfully overexpressed in mammalian cells by Wang et al. and Fong et al. respectively and 2) TEX10 and SIGLEC14 were known to increase NF-𝜅b activity and Il-8 secretion respectively and would be expected to retain these functions when co-expressed.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to modify the TβR-KRAS cell line as taught by Leung to overexpress TEX10 as taught by Wang et al. and SIGLEC4 as taught by Fong et al. to (i) increase NF-κB activation in a KRAS mutation background as taught by Ling et al. and (ii) alter TAM activity to contribute to the tumor immunosuppressive microenvironment as taught by Deshmukh et al., thereby creating a model for studying a highly malignant form of pancreatic cancer.
Claims 5-8, 10, 22-23, 28-33, and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (Genome-Scale CRISPRa Screen Identifies Novel Factors for Cellular Reprogramming, Stem Cell Reports, 2019 Apr 9;12(4):757-771) in view of US20200095543A1 (published 2020-03-26, filed 2018-03-30, hereinafter referred to as US ‘543) as evidenced by Szeto et al. (TCR Recognition of Peptide-MHC-I: Rule Makers and Breakers, Int J Mol Sci, 2020 Dec 23;22(1):68) and Xie et al. (CAR-NK cells: A promising cellular immunotherapy for cancer, EBioMedicine, 2020 Sep;59:102975).
Yang et al. is as discussed above and incorporated by reference herein. Yang et al. teach a modified mammalian cell in which the gene TEX10 is overexpressed (instant claim 1) as fully described in the 102 rejection section.
Yang et al. do not teach:
overexpression of CD47 (instant claims 6 and 10), associated with inhibition of macrophage phagocytosis (instant claim 5);
overexpression of CD55, CD59, and CD46 (instant claims 7 and 10), associated with inhibition of complement activation and deposition (instant claim 5);
overexpression of HLA-E and HLA-G (instant claims 8 and 10), associated with inhibition of NK cell activation (instant claim 5);
the exogenous nucleic acid construct of instant claims 22-23;
abrogated expression of genes associated with T-cell activation (instant claims 28), specifically B2M and TAP1 (instant claims 29 and 33);
abrogated expression of genes associated with NK cell activation (instant claim 30), specifically the genes that encode the NKG2D ligands (instant claim 31) MICA and MICB (instant claim 32);
a cell differentiated from the modified mammalian cell (instant claim 40); and
a method of administering the modified mammalian cell to a mammalian subject (instant claim 41).
These deficiencies are remedied by US ‘543.
Regarding instant claims 5-8 and 10, US ‘543 teaches “a method for making a genetically engineered stem cells… to express the following genes: (i) CD46/Crry, CD55, and CD59 (instant claims 7 and 10)… ; (ii) HLA-E and HLA-G (instant claims 8 and 10)… ; (iii) CD47 (instant claim 6 and 10)” (¶ 0109). US ‘543 further teaches (i) overexpression of CD46, CD55, and CD59 “prevent[s] classical and alternative complement deposition” (¶ 0121; prevention of complement deposition reads on inhibition of complement deposition) and inhibits activation of the complement pathway (Table 1, ¶ 0232, shows CD46, CD55, and CD59 inhibit complement pathway activation individually); (ii) overexpression of HLA-E and HLA-G “substantially reduces NK cell activation” (¶ 0119); and (iii) overexpression of CD47 inhibits macrophage phagocytosis (Table 1, ¶ 0232, shows CD47 inhibits phagocytosis; ¶ 0119, specifies CD47 affects “phagocytotic macrophages”) (instant claim 5). Therefore, this teaching reads on a cell that is immune-evasive and characterized by overexpression of the following:
CD47 (instant claims 6 and 10), associated with inhibition of macrophage phagocytosis (instant claim 5);
CD55, CD59, and CD46 (instant claims 7 and 10), associated with inhibition of complement activation and deposition (instant claim 5); and
HLA-E and HLA-G (instant claims 8 and 10), associated with inhibition of NK cell activation (instant claim 5).
Regarding instant claims 22-23, US ‘543 further teaches “lentiviral vectors” (¶ 0192) (instant claim 23) wherein said vectors “contain a promoter operably linked to a transcribable nucleic acid molecule” (¶ 0131) (instant claim 22). This teaching reads on (i) an exogenous nucleic acid expression construct (i.e. lentiviral vectors) wherein each exogenous nucleic acid expression construct encodes a gene (i.e. contains a transcribable nucleic acid molecule for gene expression) and comprises a promoter operably linked to the gene (instant claim 22) and (ii) the exogenous nucleic acid expression construct is a lentiviral construct (instant claim 23).
Regarding abrogated expression of target genes as recited in instant claims 29 and 31-33, US ‘543 further teaches a cell line comprising “inactivating mutations in both alleles of β2m and TAP1 and one allele of CD74… [and] using CRISPR to ablate the remaining allele of CD74 and both alleles of CIITA” (¶ 0229), resulting in cells that are deficient in B2M, TAP1, CD74, and CIITA i.e. abrogated expression (instant claims 29). US ‘543 further teaches the HLA-deficient cell line “evades direct recognition by CD4+ T cells” (¶ 0113). US ‘543 further teaches the HLA-deficient cell line was “retargeted with CRISPR/Cas9, to generate a clone with frameshift mutations in all 4 alleles of MICA and MICB” (¶ 0234) wherein MICA and MICB are “NKG2D ligands” (¶ 0234), resulting in no gene expression of the NKG2D ligands (instant claim 31) MICA and MICB i.e. abrogated expression (instant claim 32 and 33). These teachings read on abrogated expression of (i) B2M, TAP1, CD74, and CIITA (instant claim 29), (ii) the NKG2D ligands (instant claim 31) MICA and MICB (instant claim 32), and (iii) B2M, TAP1, CD74, CIITA, MICA, and MICB (instant claim 33). As discussed above, abrogated expression of B2M, TAP1, CD74, and CIITA in the HLA-deficient cell line allows the cells to evade direct recognition by CD4+ T cells (¶ 0113). However, the HLA-deficient cell line in “the absence of HLA-I may render target cells susceptible to NK cell-mediated cytolysis” (¶ 0234). When abrogate expression of MICA and MICB is additionally incorporated into the HLA-deficient cell line, the cells show reduced “NK cell reactivity” (¶ 0231). In summary, US ‘543 teaches a cell line with abrogated expression of B2M, TAP1, CD74, CIITA, MICA, and MICB produces cells that can reduce immunogenicity by simultaneously targeting the mechanisms of T cells and NK cells in order “ to avoid immune rejection” in cell-based therapeutics (¶ 0073).
Regarding instant claim 40, US ‘543 further teaches the stem cells “can be used to generate any other cell type currently being developed for use in patient therapy. Such differentiated cells are administered to a patient in need of such cells” (¶ 0153). This teaching reads on a cell differentiated from the modified mammalian cell of instant claim 40 as US ‘543 suggests generating cells that are differentiated from modified stem cells.
Regarding instant claim 41, US ‘543 further teaches “the stem cell is transplanted into a subject” (¶ 0057) wherein “[t]he subject can be… a mammal” (¶ 0154). This teaching reads on the modified mammalian cell is administered to a mammalian subject.
US ‘543 further teaches that the genetically engineered stem cells can be used “to avoid immune rejection within a host” (¶ 0008) as they are “minimally immunogenic and considered a ‘universal’ donor” (¶ 0087). This teaching gives motivation for using the stem cells of US ‘543 as they are less likely to be rejected by the host.
US ‘543 further teaches a “stem cell line that evades recognition by the following immune cells: (i) CD8+ T cells (i.e., due to lack of MHC Class I expression with genetic modifications in the β2 microglobulin [B2M] and TAP1-encoding genes); (ii) CD4+ T cells (i.e., due to lack of MHC Class II expression with genetic modifications in genes encoding CD74 and CITTA)” (¶ 0108). Therefore, US ‘543 teaches B2M, TAP1, CD74, and CIITA are associated with T-cell recognition.
US ‘543 does not teach overexpression of TEX10 (instant claim 1). This deficiency is remedied by Yang et al. In addition, US ‘543 does not explicitly teach (ii) B2M, TAP1, CD74, and CIITA are associated with T-cell activation (instant claim 28) nor (ii) the NKG2D ligands MICA and MICB are associated with NK cell activation (instant claim 30). These deficiencies are remedied as evidenced by Szeto et al. and Xie et al.
Szeto et al. teach a T-cell “recognition event is the first step that leads to T cell activation” (Pg. 1, Abstract, lines 5-6). As US ‘543 teaches B2M, TAP1, CD74, and CIITA are associated with T-cell recognition, B2M, TAP1, CD74, and CIITA are also associated with T-cell activation as evidenced by Szeto et al. (instant claim 28).
Xie et al. teach “[u]pon engaging with its ligand, NKG2D signals through adapter molecule DAP10 to trigger NK activation” (Pg. 2, Fig. 1 legend, lines 2-3), applicable to the NKG2D ligands MICA and MICB. This teaching indicates the NKG2D ligands MICA and MICB are associated with NK cell activation as evidenced by Xie et al. (instant claim 30).
Genetic modifications of stems cells to reduce immunogenicity were known and used prior to the effective filing date of the application. In addition, both US 543 and Yang et al. are in analogous arts (i.e. genetically modified stem cells). Since US ‘543 teaches their modifications can be used to prevent stem cell rejection in a host, there is motivation for using the genetic modifications of stems cells as taught by US ‘543 in the mammalian stem cell that overexpresses TEX10 as taught by Yang et al. to create a cell line that evades immune detection and promotes transplantation into a patient.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. US ‘543 teaches their modifications can be used to prevent rejection in a host) would have led one of ordinary skill to modify the prior art reference (i.e. using the genetic modifications of stems cells as taught by US ‘543 in the mammalian stem cell that overexpresses TEX10 as taught by Yang et al.) to arrive at the claimed invention. There is a reasonable expectation of success as genetic modifications of stems cells to reduce immunogenicity were known and used prior to the effective filing date of the application. These modifications can be applied to the stem cell of Yang et al. while retaining overexpression of TEX10 and would be routine in the art. In addition, both US ‘543 and Yang et al. are in analogous arts (i.e. genetically modified stem cells).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the genetic modifications of stems cells as taught by US ‘543 in the mammalian stem cell that overexpresses TEX10 as taught by Yang et al. to create a cell line that evades immune detection as taught by US ‘543 in order to promote transplantation into a patient.
Conclusion
Claims 1, 4-8, 10, 21-23, 25, 28-33, 35, and 40-41 are pending. Claims 6-8, 10, and 41 are objected to. Claims 1, 4-8, 10, 21-23, 25, 28-33, 35, and 40-41 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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