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 1-2, 7, 29 are cancelled. Claims 3- 6, 8-12, 14-28, 30-32 are pending. Claims 3-6, 8-10 are examined on the merits. Election/Restrictions Applicant’s election without traverse of Group I corresponding to claims 3-6, 8-10, in the reply filed on 11/11 /2025 is acknowledged. Claims 11-12, 14-28, 30-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/11/2025. Priority The applicant’s application is a U.S. National Stage application of PCT International Patent Application Serial No. PCT/EP2021/069854, filed July 1 5 , 202 1 , which itself claims the benefit of Great Britain Patent Application Serial No. GB2010981.5, filed July 16 , 20 20 is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. 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. Claims 3 -6, 8- 10 are rejected under 35 U.S.C. 103 as being unpatentable over Hou et al. (“Hou”, WO 2019 /222444 A2, cited as reference 1 on IDS filed 01/13/2023) in view of Jang et al. (“Jang”, Molecular Therapy, 2011, cited as reference 2 on IDS filed 01/13/2023 ) , Tehranirokh et al. (“ Tehranirokh ”, Biomicrofluidics , 2013) and Moore et al. (“Moore”, Scientific Reports, 2019). Regarding claims 3 , 6, Hou teaches compositions and methods for the preparation, manufacture, formulation and therapeutic use of adeno-associated vims (AAV ) particles for the prevention and/or treatment of diseases (e.g., abstract). Hou teaches capsid proteins (e.g., chimeric AAV capsid proteins ). The capsid proteins provided herein have been selected for their ability to infect tissues (e.g., central nervous system tissues) as well as specific cell types (e.g., neurons and/or astrocytes) (e.g., paragraph 0008). Hou teaches Directed evolution involves the generation of AA V capsid libraries ("~ 104- 108) by any of a variety of mutagenesis techniques and selection of lead candidates based on response to selective pressure by properties of interest (e.g., tropism) . Directed evolution of AAV capsids allows for positive selection from a pool of diverse mutants without necessitating extensive prior characterization of the mutant library . AAV capsid libraries may be subjected to more than one round of selection using directed evolution for further optimization . Directed evolution methods are most commonly used to identify AAV capsid proteins with enhanced transduction of a target tissue. Capsids with enhanced transduction of a target tissue have been identified for the targeting of human airway epithelium, neural stem cells, human pluripotent stem cells, retinal cells, and other in vitro and in vivo cells (e.g., paragraph 0162). Hou teaches directed evolution methods are used to identi f y AAV capsids having enhanced transduction of a target tissue (e.g., CNS or PNS ). Multiple strategies of directed evolution , including random-point mutagenesis , inse r tional mutagenesis , and capsid shuffling are available for the selection of AAV capsids w ith the desired properties (e.g., paragraph 0163). Hou teaches that the first round of directed evolution, a subject may be injected with the hybrid viruses, which may be prepared in any buffer (e.g. PBS). Subjects may be a mammal, including but not limited to mice, rats, rabbits, non-human primates, and humans (e.g., paragraph 0503) . Hou teaches that the production, purification and quality control of hybrid viruses may be performed as for the first-round preparation. Directed evolution may be perfo rmed for at least two rounds , at least three rounds, at least four rounds, at least five rounds, or at least six rounds. In some embodiments, the dose of hybrid viruses may decrease with each round of directed evolution (e.g., paragraph 0506) . Hou teaches that d irected evolution may also be performed in cells . Those cells may include, but are not limited to, astrocytes, glia, microglia, neurons , and oligodendrocytes. T he cells may be infected w ith MOI at between from about 100 to about 10,000 hybrid viruses. The cells may be infected at about 1000 hybrid viruses. The hybrid viruses may be preincubated with human intravenous i mmunoglobu li n prior to infection. The cells may be infected for up to 1 0 hours, up to 24 hours, up to 36 hours, up to 72 hours, or up to one week. The chimeric capsid library may then be recovered from genomic DNA of cells for next round of directed evolution (e.g., paragraphs [0507]-[0746-0747]). Hou teaches that after the desired round of directed evolution , CNS tissues and / or cells may be harvested , and the chimeric capsid library may be recovered (e.g. by PCR), and then subcloned and transformed. A chimeric capsid library may be transformed into bacterial cells (e.g. Escherichia co li with standard transformation techniques. Random colonies may then be sequenced via next-generation sequencing , and any other sequencing method (e.g., paragraphs [0508], [0747-0748]; Example 2, page 183). Hou teaches that AAV capsid libraries may be subjected to more than one round of selection using directed evolution for further optimization . Directed evolution methods are most commonly used to identify AAV capsid proteins with enhanced transduction of a target tissue. Capsids with enhanced transduction of a target tissue have been identified for the targeting of human airway epithelium, neural stem cells , human pluripotent stem cells , retinal cells, and other in vitro and in vivo cells (e.g., paragraph 0162). Hou teaches that capsid protein : As used herein, the phrase '·capsid protein" refers to a structural protein that can be incorporated into the AAV capsid of an AAV particle, and can include a VP1, VP2 or VP3 protein (e.g., paragraph 0638; Tables 1-3). Regarding claim 10, Hou teaches AAV particle comprising one or more capsid proteins described herein may be administered to a subject (e.g., to the CNS of a subject) in a therapeutically effective amount to reduce the symptoms of neurological disease of a subject (e.g., paragraph 0413). Hou teaches that the AA V particles described herein may be administered by any delivery route that results in a therapeutically effective outcome. These include, but are not limited to, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), sub-pial (between pia and CNS parenchyma), intramuscular (into a muscle) (e.g., paragraph 0414). Hou does not teach neuron derived from iPSC or embryonic stem cells, as required by instant claims 3, 8, 9. However, this is cured by Jang. Hou does not teach the microfluidic chamber as required by instant claim s 3- 4. However, this is cured by Tehranirokh and Moore. Regarding claims 3, 8, 9, Jang teaches several diverse AAV capsid libraries—including randomly mutagenized , DNA shuffled , and random peptide insertion variants —we applied directed evolution to create a “designer” AAV vector with enhanced delivery efficiency for neural stem cells ( NSC s) . A novel AAV variant , carrying an insertion of a selected peptide sequence on the surface of the threefold spike within the heparin-binding site, emerged from this evolution. Importantly, this evolved AAV variant mediated efficient gene delivery to rat, mouse, and human NSCs , (e.g . , abstract). Jang teaches that l ibraries were packaged to generate a large pool of AAV mutant capsids containing the genome encoding those mutants. NSCs , isolated from the hippocampus of adult Fisher 344 rats,27 were infected by each AAV library , adenovirus serotype 5 was added to induce the replication and rescue of the “successful” AAV variants, the surviving AAV cap genes were recovered by PCR and cloned into the AAV genome plasmid, and the next generation library was packaged (e.g., paragraph 3 rd , left column, page 668; Fig. 1). Jang teaches that d uring the three rounds of evolution and 10 selection steps, the variant pool became progressively more infectious than wild-type AAV2 (e.g., paragraph 1 st , right column, page 668). Jang teaches NSC culture. A dult rat NSCs, isolated from the hippocampal region of 6-week-old female Fisher 344 rats were cultured on tissue culture . Human neural progenitor cells were derived from a variant of the human embryonic stem cell line BG01 , BG01V2, using the stromal derived inducing activity involving a co-culture system of during the three rounds of evolution and 10 selection steps, the variant pool became progressively more infectious than wild-type AAV2 and mouse stromal cell line PA6 (e.g., paragraph 2 nd , right column, page 672-673). Fig. 1: Jang teaches that DNA sequencing analysis revealed that the final pools contained seven AAV variants: two shuffled, three peptide-inserted, and two error prone clones (e.g., paragraph 2 nd , page 668; Fig. 2). Regarding claim 4, Tehranirokh teaches microfluidic technology allows dynamic cell culture in microperfusion systems to deliver continuous nutrient supplies for long term cell culture. It offers many opportunities to mimic the cell-cell and cell-extracellular matrix interactions of tissues by creating gradient concentrations of biochemical signals such as growth factors, chemokines, and hormones. Other applications of cell cultivation in microfluidic systems include high resolution cell patterning on a modified substrate with adhesive patterns and the reconstruction of complicated tissue architectures (e.g., abstract). Tehranirokh teaches d ynamic cell co-cultures in multicompartmental bioreactors allow the study of several cell lines that share the same environment (e.g., paragraph 2 nd , page 4). Moore teaches microfluidic transduction device (MTD) that combines microfluidic spatial confinement with advective flow through a membrane to efficiently colocalize target cells and virus particles. We demonstrate that the MTD can improve the efficiency of lentiviral transduction for both T-cell and hematopoietic stem-cell (HSC) targets by greater than two fold relative to static controls (e.g., abstract) . Moore teaches fluidic flow can be used to improve the colocalization of target cells with viral vector and increase transduction efficiency. Moore devised a scalable microfluidic transduction device (MTD) designed to transduce 2 million (2M) target cells under continuous perfusion in order to colocalize cells and vector. The 2M-MTD is comprised of a semi-permeable membrane sandwiched between two machined acrylic plates and sealed with nested O-rings, creating a membrane-partitioned microfluidic flow chamber . Moore teaches t arget cells and virus are introduced into the MTD either in tandem or sequentially by flowing suspension medium into the transduction chamber, down through the membrane, and out the bottom chamber . Computational fluid dynamics (CFD) simulations of fluid flow through the transduction device at operational flow rates predict a uniform distribution of cells and vector across the surface of the membrane with minimal shear stresses (e.g., paragraph 4 th , page 2; Fig. 1). Moore teaches the advantages of microfluidic transduction devise to enhance viral transduction in lentivirus and AAV (e.g., paragraph 2 nd , page 8, FIG. 1). Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Hou - methods for the preparation, manufacture, formulation of adeno-associated vi rus particles by directed evolution (random-point mutagenesis, insertional mutagenesis, and capsid shuffling ) of AAV capsids (VP1, VP2, VP3) through more than one round of selection for further optimization allowing positive selection for their ability to infect tissues (e.g., central nervous system tissues) as well as specific cell types (e.g., neurons and/or astrocytes) with the teachings of Jang -AAV capsid libraries including randomly mutagenized, DNA shuffled, and random peptide insertion variants applying directed evolution to create a designer AAV vector with enhanced delivery efficiency for neural stem cells (NSCs) or human neural progenitor cells and use of microfluidic devise for cell culture or cell-cell interactions taught by Tehranirokh and using the microfluidic transduction devise can improve the efficiency of lentiviral and AAV transduction for both T-cell and hematopoietic stem-cell (HSC) taught by Moore; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing a method to obtain AAV particles with high affinity to infect neurons, neural stem cells or human embryonic stem cell by performing rounds of selection on microfluidic devises using directed evolution (rand om-point mutagenesis, insertional mutagenesis, and capsid shuffling ) . One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method for the preparation, manufacture, formulation and therapeutic use of adeno-associated vims (AAV) particles targeting specific cells from the central nervous system, neural stem cells or human embryonic stem cell for the prevention and/or treatment of diseases . Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT JULIO GOMEZ RODRIGUEZ whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)270-0991 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Friday 8:00 am - 5:00 pm . 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, FILLIN "SPE Name?" \* MERGEFORMAT Jennifer Dunston can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 5712722916 . 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. /JULIO WASHINGTON GOMEZ RODRIGUEZ/ Examiner, Art Unit 1637 /J. E. ANGELL, Ph.D./ Primary Examiner, Art Unit 1637