CTNF 18/278,719 CTNF 89129 DETAILED ACTION 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. Applicant's election without traverse of Group I, claims 1, 2, 4-17, 20, and 22-25, and the species of mature IPSC-derived neurons as the cell type associated with the genetic mutations, which reads on claims 1, 2, 4, 7-17, 20, and 22- 25; neurodegenerative disease, which reads on claims 7-15; using CRISPR as the further method, which reads on claims 10-12 and 15; Substantia nigra as the brain region of interest, which reads on claims 17, 20, 22, and 23; and neurons as the cell type requiring at least two types of mature IPSC-derived cells, which reads on claim 24, in the reply filed on 29 January 2026 is acknowledged. Claims 13-15, 25-31, and 33-35 have been withdrawn. Claims 1, 2, 4-12, 16, 17, 20, and 22-24 are currently pending and under examination. This Application is a national phase application under 35 U.S.C. §371 of International Application No. PCT/US2022/017942, filed 25 February 2022, which claims priority to U.S. Provisional Application Nos. 63/215179, filed 25 June 2021, and 63/154305, filed 26 February 2021. Claim Rejections - 35 USC § 112 07-30-02 AIA 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. 07-34-01 Claim 8 is 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. Claim 8 recites the condition “lipofusis.” This term is indefinite, because it is unclear what “lipofusis” is intended to be. While Applicant recites “neuronal ceroid lipofusis” in para. 4 of the Specification, this condition is not defined. It appears that this condition should instead be neuronal ceroid lipofuscinosis, also known as Batten disease. 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. 07-21-aia AIA Claim s 1-7, 16, 17, 20, and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Moore et al. (IDS; US 2020/0386742, Published Dec. 10, 2020) . With regard to claim 1 , Moore et al. teach a method of producing an assembled three-dimensional organoid comprising mature neurons and mature glia (Abs.; Para. 39, 136; Fig. 8; claim 1, 3). The neurons and glia may be derived from induced pluripotent stem cells (IPSCs) (Para. 191). A population of IPSCs are cultured to produce mature neurons and another population of IPSCs are cultured to produce mature glia (Para. 49). A plurality of isolated glial cells and a plurality of neuronal cells are combined at a ratio and aggregated on a hydrogel, producing a mixed culture, and cultured to generate an assembled three-dimensional organoid (Para. 96; claim 1, 3, 8). As Moore et al. expressly teach the noted steps, it would have been obvious to one of ordinary skill in the art to utilize the taught steps together to produce an assembled three-dimensional organoid comprising the mature neurons and mature glia as desired. With regard to claim 2 , Moore et al. teach that the neurons include interneurons, motor neurons, sensory neurons, glutamatergic neurons, cholinergic neurons, GABAergic neurons, dopaminergic neurons, and serotonergic neurons (Para. 121). C laim 4 , is directed to the mature IPSC-derived neurons, which are produced by the claimed process. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Here, the neurons of Moore et al. are similarly derived from IPSCs, and are used for the same purpose as claimed: for combining with glia to form a three-dimensional organoid. Functionally, the neurons of Moore et al. are the same as the claimed neurons. Therefore, the neurons of Moore et al. are the same as, or would have rendered obvious, the neurons produced by the claimed process. PNG media_image1.png 18 19 media_image1.png Greyscale "The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an unobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 798, 802, 218 USPQ 289, 292 (Fed. Cir. 1983). With regard to claim 5 , Moore et al. teach that the glia include astrocytes, oligodendrocytes, ependymal cells, and microglia (Para. 121). C laim 6 , is directed to the mature IPSC-derived glia, including astrocytes, which are produced by the claimed process. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Here, the astrocytes of Moore et al. are similarly derived from IPSCs, and are used for the same purpose as claimed: for combining with neurons to form a three-dimensional organoid. Functionally, the astrocytes of Moore et al. are the same as the claimed astrocytes. Therefore, the astrocytes of Moore et al. are the same as, or would have rendered obvious, the astrocytes produced by the claimed process. PNG media_image2.png 18 19 media_image2.png Greyscale "The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. In re Fessmann, 489 F.2d 742, 744, 180 USPQ 324, 326 (CCPA 1974). Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an unobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 798, 802, 218 USPQ 289, 292 (Fed. Cir. 1983). With regard to claim 7 , Moore et al. teach that the cells used in the method, which include neurons and glia, comprise a genetic mutation that is relevant to a particular model of human disease, including a neurodegenerative disease (Para. 119, 193). With regard to claim 16 , Moore et al. teach that the neurons and glia are derived from human stem cells, including induced pluripotent stem cells (Para. 191). Which is generating the neurons and glia from IPSCs derived from the same source. With regard to claims 17, 20, 22, and 23 , Moore et al. teach that the organoid is created to mimic structural and functional characteristics of in vivo brain structures (Para. 3), where the neurons and the glia may be present in the organoid at a ratio including about 1 neuron to 1 astrocyte (Para. 9; claim 8). Applicant indicates that a ratio of 1:1 is within the range of a brain region of interest, including within the substantia nigra ( see Specification, para. 198). Additionally, the neurons include dopaminergic neurons (Para. 121), which are a type of neuron found in a brain region of interest, including in the substantia nigra; and the glia include astrocytes, oligodendrocytes, and microglia (Para. 121), which are a type of glia found in a brain region of interest, including in the substantia nigra. With regard to claim 24 , as Moore et al. teach that one or more different types of neurons may be present in the organoid (Para. 121), it would have been obvious to one of ordinary skill in the art that the organoid may comprise at least two types of mature IPSC-derived glia . 07-22-aia AIA Claim s 1 and 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Moore et al ., as applied to claim s 1 and 7 above, and further in view of Sances et al. (WO 2019/195798; Published 10 Oct. 2019) . The teachings of Moore as applied to claims 1 and 7 have been set forth above. With regard to claims 8-12 , Moore et al. teach that the cells used in the method, which include neurons and glia, comprise a genetic mutation that is relevant to a particular model of human disease, including a neurodegenerative disease (Para. 119, 193). However, it is not specifically taught that the mutation is a GRN mutation associated with frontotemporal dementia or lipofusis, the mutation results in knockdown or knockout of a GRN gene, CRISPR is used to make genetic changes to a gene of interest, including the GRN gene, or the CRISPR system comprises a GRN guide RNA (gRNA) comprising SEQ ID NO: 1 including with up to three nucleotide changes, the gRNA capable of hybridizing to a target GRN gene sequence. Sances et al. teach that common genetic mutations underling frontotemporal dementia (FTD) include loss of function mutations in the GRN genes, and that FTD is ideally suited for multicellular 3D forebrain-on-chip modeling (Ex. 21, p. 40 to p. 41, para. 2). The use of CRISPR to make genetic changes to a gene of interest, including GRN, in mature iPSC-derived neurons is also taught (Ex. 21, p. 42, last para.; Ex. 27). As Sances et al. teach using CRISPR to make genetic changes to GRN, gRNA providing the coding sequence for GRN is necessary to provide this, where SEQ ID NO: 1 has 100% identity to human GRN mRNA ( see BLASTn search results). As such, it would have been routine for an ordinary artisan to utilize a known gRNA sequence with the CRISPR system to make genetic changes to the GRN gene in mature iPSC-derived neurons, as taught by Sances et al. As SEQ ID NO: 1 has 100% identity to human GRN mRNA, the gRNA is necessarily capable of hybridizing to a target GRN sequence. It would have been obvious to one of ordinary skill in the art to combine the teachings of Moore et al. and Sances et al., because both teach 3D models that include a genetic mutation relevant to a particular model of human disease, including a neurodegenerative disease. GRN mutations associated with frontotemporal dementia that result in knockdown or knockout of a GRN gene, the use of CRISPR to make genetic changes to a gene of interest, including the GRN gene, and the use of gRNA comprising SEQ ID NO: 1, which capable of hybridizing to a target GRN gene sequence, is taught or rendered obvious by Sances et al. The use of the system of Sances et al. to provide a model for study of GRN mutations in frontotemporal dementia would have been expected to predictably improve the method of Moore et al., by allowing for the study of an additional neurodegenerative disease. Conclusion No claims are allowable. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER M.H. TICHY whose telephone number is (571)272-3274. The examiner can normally be reached Monday-Thursday, 9:00am-7:00pm ET. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila G. Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653 Application/Control Number: 18/278,719 Page 2 Art Unit: 1653 Application/Control Number: 18/278,719 Page 3 Art Unit: 1653 Application/Control Number: 18/278,719 Page 4 Art Unit: 1653 Application/Control Number: 18/278,719 Page 5 Art Unit: 1653 Application/Control Number: 18/278,719 Page 6 Art Unit: 1653 Application/Control Number: 18/278,719 Page 7 Art Unit: 1653
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