CTNF 18/266,093 CTNF 100615 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Priority Acknowledgement is made that the instant application is a National Stage of International application No. PCT/US2021/062872 (filed 12/10/2021), which claims the benefits of US Provisional Application No. 63/123616 (filed 12/10/2020). Election/Restrictions 08-25-01 AIA Applicant’s election without traverse of Group I (Claims 1-6, 10, 15, 21, 24, 25, and 31), drawn to a viable cell comprising at least one exogenous nucleic acid sequence selected from the group consisting of the woolly mammoth genes in TABLE 1 in the reply filed on 05/08/2026 is acknowledged. Applicants further elected BMP2 as the species of gene selected from TABLE 1. However, upon reconsideration, the requirement for election of species is withdrawn. While the genes listed in TABLE 1 encode different proteins which have different cellular functions, the functions all relate to cold adaption. A person of ordinary skill in the art would be motivated to insert any one or more genes related to cold adaption into an elephant cell in order to make elephant cells which are better adapted to cold conditions (See Miller (National Geographic, 2014) Sec. Hairy Elephant). Claims 1-6, 10, 15, 21, 24, 25, 31, 44, 45, 48-52, and 55 remain pending. Claims 44, 45, 48-52, and 55 are withdrawn from consideration, as being directed to a non-elected invention. Claims 1-6, 10, 15, 21, 24, 25, and 31 have been examined on the merits. Claim Objections Claim 1 is objected to for improper format. Claim 1 references TABLE 1 in the specification. MPEP 2173.05(s) states “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola , 27 USPQ2d 1608 (bd. Pat. App. & Inter. 1993) (citation omitted).” The information from TABLE 1 pertinent to the claims does not qualify as an exception to circumstance. Therefore, the list of genes in TABLE 1 must be incorporated into the claims. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15 AIA Claim s 1, 2, and 21 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Lynch et al (Cell Reports, 2015) (cited in IDS filed 05/05/2025) . Lynch et al study genetic differences between wooly mammoths and Asian elephants that allow wooly mammoth adaptions to extreme cold (See abstract). Lynch et al identify a mammoth specific amino acid change in a highly conserved region of TRPV3, a gene encoding a temperature-sensitive transient receptor potential channel involved in thermal sensation and hair growth (See abstract). Lynch et al functionally characterize the effects of the mammoth specific N647D substitution in TRPV3 by transfecting HEK293 cells with either the ancestral mammoth (AncMammoth) or Ancestral Asian elephant (AncGajah) version of TRPV3 and find the N647D mutation affects temperature-dependent gating (See pg. 223, last paragraph and pg. 225 Sec. TRPV3 Function Assays). Lynch et al test changes in temperature dependent gating using a Fluo-4 calcium flux assay and find the AncMammoth TRPV3 channel is approximately 20% less active than the AncGajah channel (See pg. 223, last paragraph and Fig. 6F). Additionally, Lynch et al disclose quantifying the level of AncMammoth TRPV3 expression (See pg. 223 last paragraph and Fig. S5I). Regarding claim 1: Lynch et al disclose HEK293 cells transfected with an ancestral mammoth version of TRPV3 which reads on a viable cell comprising at least one exogenous nucleic acid sequence selected from the group consisting of the woolly mammoth genes in TABLE 1. Regarding claim 2: Following the discussion of claim 1 above, Lynch et al disclose the HEK293 cells produce AncMammoth TRPV3 protein which reads on the cell expresses a polypeptide encoded by the at least one nucleic acid sequence. Regarding claim 21: Following the discussion of claim 1 above, Lynch et al disclose quantifying a 20% decrease in calcium flux of HEK293 cells expressing AncMammoth TRPV3 which reads on the cells exhibit modulation of calcium signals . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1, 10, 24, 25, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over George Church at TEDxDeExtinction (TEDx Talks, 2013) herein referred to as Church . Church teaches arctic carbon released by melting of the arctic is an environmental threat (See Transcript at 8:16-8:43). One solution to this problem is reintroducing mammoths into the arctic to get rid of dead grass, stump down trees, and stump down insulating snow so the arctic freeze can get into the permafrost (See Transcript at 8:49-9:17). Church proposes making a hybrid elephant - mammoths by introducing physiological features of mammoths into elephants that would help them survive in Arctic regions (See Transcript at 9:26-9:47). Church teaches targeted DNA changes can be made using Zn finger nucleases and CRISPR technology (See transcript at 4:03-4:44). Church further states five gene variants, including hemoglobin and genes involved in hair color, have been tested either molecularly or in cells (See Transcript at 9:55-10:01). The presentation shows five DNA variants tested so far for a hybrid Elephant – Mammoth as Hemoglobin a(K5N), Hemoglobin b(T12A, A86S, E101Q), and MC1R (R67C) (See Church, video at 9:28-9:50). Regarding claim 1: Church discloses making elephant – mammoth hybrid cells having mammoth DNA variants including variants of Hemoglobin a and Hemoglobin b which reads on a viable cell comprising at least one exogenous nucleic acid sequence selected from the group consisting of the woolly mammoth genes in TABLE 1. Regarding claim 10: Following the discussion of claim 1 above, Church discloses making elephant-mammoth hybrid cells comprising mammoth gene variants. While Church does not explicitly state the hybrid cell is an elephant cell, however, given that the hybrid cell is made by introducing mammoth variants, the cell would necessarily need to be an elephant cell in order to be an elephant-mammoth hybrid cell. Regarding claims 24 and 25: Following the discussion of claim 1 above, Church discloses making elephant-mammoth hybrid cells comprising mammoth gene variants. While Church does not explicitly state the hybrid cell is an elephant cell, however, given that the hybrid cell is made by introducing mammoth variants, the cell would necessarily need to be an elephant cell in order to be an elephant-mammoth hybrid cell. Additionally, Church discloses the mammoth variants are single nucleotide variants. Church teaches targeted DNA changes can be made using Zn finger nucleases and CRISPR technology. Church does not state the elephant cell is edited to alter an elephant homologue of the gene. However, given that Church teaches the mammoth variants are single nucleotide variants and Zn finger nucleases and CRISPR technology can be used to make targeted DNA changes, a person of ordinary skill in the art would have found it prima facie obvious to use a Zn finger nuclease or CRISPR technology to edit the DNA of the elephant cell in order to introduce the nucleotide variant. One would have been motivated to edit the DNA of the elephant to introduce the mammoth variant because editing the DNA would introduce the mammoth version of the gene while eliminating the function of the elephant version of the gene and given that the goal of Church is to make an elephant-mammoth hybrid with traits that allow the animal to survive in the arctic, one would want to replace the elephant versions of genes with the mammoth versions of genes in order to improve tolerance to the weather. There is a reasonable expectation of success because Church gives various examples of how Zn finger nucleases and CRISPR technology can be used to edit DNA. Regarding claim 31: Following the discussion of claim 1 above, Church discloses making elephant-mammoth hybrid cells comprising mammoth DNA variants. Church further proposes making an elephant-mammoth hybrid which would be introduced to the arctic in order to improve the permafrost and prevent release of carbon from the arctic. The elephant-mammoth hybrid animal of Church et al would be produced by introducing mammoth versions of genes that would improve survival in cold conditions of the arctic. Hemoglobin a and b are taught as exemplary genes of these cold survival genes. Given that Church proposes making an elephant-mammoth hybrid animal comprising mammoth variants such as hemoglobin a and b (reads on cells of claim 1), it would have been prima facie obvious to a person of ordinary skill in the art to produce an elephant-mammoth hybrid animal by introducing mammoth variants, of the genes discloses by Church, into the cells of an elephant embryo in order to produce an elephant-mammoth hybrid. One would have been motivated to make an elephant-mammoth hybrid in order to reintroduce a mammoth like animal to the arctic to prevent release of arctic carbon. There is a reasonable expectation of success because Church teaches the mammoth genome is known and cells can be edited to introduce mammoth variants . 07-21-aia AIA Claim s 1-4, 6, 10, 15, 21, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Lynch et al (Cell Reports, 2015) in view of Callaway (Scientific American, 2015) . The teachings of Lynch et al are set forth above. Lynch et al anticipates claims 1, 2, and 21. Regarding claims 3, 4, 6, and 10: Following the discussion of claim 1, Lynch et al discloses transfecting cells with a mammoth version of TRPV3. Lynch et al does not disclose a stem cell, reprogrammed cell, fibroblast cell, mesenchymal cell, nerve cell, cartilage cell, bone cell, muscle cell, bone cell, fat cell or epidermal cell transfected with mammoth TRPV3. Callaway discusses research on creating arctic elephants. Callaway discusses Lynch et al’s research on mammoth TRPV3 and further states Lynch’s next step is to insert the mammoth TRPV3 gene into elephant cells that have been programmed to behave like embryonic cells such as induced pluripotent stem (iPS) cells in order to examine expression of mammoth proteins in different tissues (See Sec. Resurrected gene). Given that Lynch et al teaches a method of expressing mammoth TRPV3 in a viable cell and Callaway teaches Lynch et al’s next step is to express mammoth TRPV3 in an elephant iPS cell (reads on an induced stem cell and an elephant cell), it would have been prima facie obvious to express the mammoth TRPV3 of Lynch et al in an elephant iPS cell. An iPS cell would inherently express at least one stem cell marker. One would have been motivated to express mammoth TRPV3 in an elephant iPS cell because iPS cells can be differentiated to different cell types allowing one to examine expression of mammoth proteins in different cell types/tissues. There is a reasonable expectation of success because Lynch et al teaches a method of expressing mammoth TRPV3 in a non-mammoth cell and further states expressing mammoth TRPV3 in an elephant iPS cell is their next step. Regarding claim 15: Following the discussion of claims 1 and 10 above, Lynch et al and Callaway render obvious expressing mammoth TRPV3 in an elephant iPS cell. Lynch et al and Callaway further teach woolly mammoths and Asian elephants evolved from the same ancestral species and Asian elephants are the woolly mammoths’ closest relative (See Lynch et al Fig. 1 and Callaway, first and second paragraphs). Given that Lynch et al and Callaway suggest expressing a mammoth TRPV3 in an elephant iPS cell and Lynch et al and Callaway teach Asian elephants evolved from the same ancestor as woolly mammoths, it would have been prima facie obvious to a person of ordinary skill in the art to use an iPS cell derived from an Asian elephant. One would have been motivated to use an iPS cell from an Asian elephant because Asian elephants are the woolly mammoth’s closes living relative. There is a reasonable expectation for success because Asian elephants are one of three living species of elephants. Regarding claims 24 and 25: Following the discussion of claim 1 above, Lynch et al teach a method of making a HEK293 cell which expresses woolly mammoth TRPV3. Lynch et al further teaches the woolly mammoth version of TRPV3 comprises a single nucleotide variant (N647D) compared to TRPV3 of Asian elephants. Callaway discusses Lynch et al’s research on mammoth TRPV3 and further states Lynch’s next step is to insert the mammoth TRPV3 gene into elephant cells that have been programmed to behave like embryonic cells such as induced pluripotent stem (iPS) cells in order to examine expression of mammoth proteins in different tissues. Callaway further discusses similar work being performed in the lab of George Church. Callaway teaches Church’s lab is using CRISPR/Cas9 mediated gene editing to engineer elephant cells containing mammoth versions of genes with the goal of making an Asian elephant with enough mammoth genes to survive in the Arctic (See Sec. Mammoth task). Given that Lynch et al and Callaway propose making elephant iPS cell expressing mammoth TRPV3 which comprises a single nucleotide variant compared to TRPV3 from Asian elephants and Callaway further teaches CRISPR/Cas9 can be used to edit the genome of elephant cells in order to engineer elephant cells containing mammoth versions of genes, it would have been prima facie obvious to modify the method of Lynch et al by using CRISPR/Cas9 to edit the genome of an Asian elephant iPS cell in order to express mammoth TRPV3. One would have been motivated to use CRISPR/Cas9 to edit the elephant version of TRPV3 in an Asian elephant cell because editing the Asian elephant version of TRPV3 would involve making an N647D substituting which would thereby eliminate the endogenous elephant version of TRPV3 by replacing it with the mammoth version of TRPV3 which would improve cold tolerance. There is a reasonable expectation of success because using CRISPR/Cas9 to make single nucleotide edits is a known technique in the field and Callaway teaches the method can be used to engineer elephant cells to express versions of mammoth genes . 07-21-aia AIA Claim s 1-6, 10, 15, 21, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Lynch et al (Cell Reports, 2015) in view of Callaway (Scientific American, 2015) and ThermoFisher (An Overview of Pluripotent and Multipotent Stem Cell Targets, Nov. 2020) . The teachings of Lynch et al and Callaway are set forth above. Lynch et al anticipates claims 1, 2, and 21. Lynch et al and Callaway render claims 1-4, 6, 10, 15, 21, 24, and 25 obvious. Regarding claim 5: Following the discussion of claims 1 and 4 above Lynch et al and Callaway propose making elephant iPS cells that express elephant TRPV3. Lynch et al and Callaway do not teach the iPS cells express a stem cell marker selected from NANOG, SSEA1, SSEA4, or TRA-1-60. ThermoFisher teaches iPS cells require expression of Oct4 and Nanog to maintain undifferentiated state. ThermoFisher further teaches detection of the presence of these markers is one of the first steps in characterizing newly derived iPS cells (See Pg. 1 Sec. Pluripotent stem cell markers). Given that Lynch et al and Callaway propose using iPS cells and ThermoFisher teaches iPS cells require expression of Oct4 and Nanog in order to maintain pluripotency, it would have been prima facie obvious to a person of ordinary skill in the art to select iPS cell expressing Oct4 and Nanog in order to produce the iPS cells expressing mammoth TRPV3 as taught by Lynch et al and Callaway. One would have been motivated to select for iPS cells expressing Oct4 and Nanog because ThermoFisher teaches iPS cells require expression of Oct4 and Nanog in order to maintain pluripotency. There is a reasonable expectation for success because ThermoFisher teaches detecting the presence of Oct4 and Nanog is one of the first steps in characterizing newly derived iPS cells. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARISOL A O'NEILL whose telephone number is (571)272-2490. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /MARISOL ANN O'NEILL/Examiner, Art Unit 1633 /ALLISON M FOX/Primary Examiner, Art Unit 1633 Application/Control Number: 18/266,093 Page 2 Art Unit: 1633 Application/Control Number: 18/266,093 Page 3 Art Unit: 1633 Application/Control Number: 18/266,093 Page 4 Art Unit: 1633 Application/Control Number: 18/266,093 Page 5 Art Unit: 1633 Application/Control Number: 18/266,093 Page 6 Art Unit: 1633 Application/Control Number: 18/266,093 Page 7 Art Unit: 1633 Application/Control Number: 18/266,093 Page 8 Art Unit: 1633 Application/Control Number: 18/266,093 Page 9 Art Unit: 1633 Application/Control Number: 18/266,093 Page 10 Art Unit: 1633 Application/Control Number: 18/266,093 Page 11 Art Unit: 1633 Application/Control Number: 18/266,093 Page 12 Art Unit: 1633
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