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. Election/Restrictions Applicant’s election of group I and species of SEQ ID NO: 1 in the reply filed on 1/21/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1 and 4-13 read on the elected of SEQ D NO: 1 are considered. Claims 2-3 and 15- 21 are withdrawn from consideration. Remark Claims 1 and 4-14 are pending and considered with the elected species of SEQ ID NO: 1 . Claims Objection Claim 1 is objected to because of the following informalities: please spell out the complete names for AAV9Retro VP1 and AAV10Retro VP1 . Appropriate correction is required. Claim 1 is also confusing to cite that the claimed method is for “ targeted retrograde infection of injured neuron ” , Please clarify if the claimed method is for a targeted retrograde infection of an injured neuron or for targeting an retrograde infection of an injured neuron . Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 1 and 4-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention using AAV9Retro VP1 and AAV10Retro VP1, and wherein the polypeptide VP1 comprises the following amino acid sequence: LADQDYTKTA (SEQ ID NO: 3) to be introduced into neuronal tissue/organ, however, it does not have a possession read on a method for targeted retrograde infection of an injured neuron comprising administering a viral particle or virus-like particle to a subject with the injured neuron, wherein the viral particle or virus-like particle comprises a virion protein 1 (VP1) polypeptide selected from the group consisting of AAV9Retro VP1 and AAV10Retro VP1, and wherein the polypeptide comprises the following amino acid sequence: LAxxDxTKxA (SEQ ID NO: 1) or LAxDxTKxxA (SEQ ID NO: 2), wherein X is any amino acid or is absent . wherein the numbers of the variants of LAxxDxTKxA (SEQ ID NO: 1) alone will be read in astronomic numbers of peptides, roughly speaking 1 60,000 possible peptides in all. However, Applicants only teaches peptide of LADQDYTKTA (SEQ ID NO: 3) that is able to more specifically neurogenic tropism. Therefore, the applicants do not have possession of the claimed method using such astronomic numbers of roughly millions of peptides in the claimed method. Applicants can calculate such numbers by using a geometric progression with ration 24 (24 1 , 24 2 , 24 3 , 24 4 ), and then picking the 4 terms in sum. . Generally speaking by the US patent rule under US 112 (a) written description , if a claim that reads a generic sequence or molecule as product of method for using the same that read d on many species or even a countless species of molecules as a choices for instant case, a quit a few species needs to be presented by the Application to indicate that Applicants do have a possession for a generic claimed of invention. However, in the instant case, the specification does not describe with any degree of particularity all of the members of peptide formulated as LAxxDxTKxA ( SEQ ID NO: 1 ), wherein X can be any 24 amino acids or deletion in any combinations . In fact, Applicants only present seems as one species of peptide LADQDYTKTA (SEQ ID NO: 3). MPEP § 2163.02 states, "[a] n objective standard for determining compliance with the written description requirement is “does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed’ ". The courts have decided: The purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the "written description" inquiry, whatever is now claimed. See Vas-Cathy, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991). Furthermore, the written description provision of 35 USC § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, paragraph 1, "'Written Description” Requirement (66 FR 1099-1111, January 5, 2001) states, "possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention" (Id. at 1104). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was F Therefore, absent a detailed and particular description of a representative number, or at least a substantial number of the members of the genus of nucleic acid molecules, the skilled artisan could not immediately recognize or distinguish members of the claimed genus of nucleic acid sequences. Moreover, since the specification has not identified which amino acid molecules of many peptide molecules of the genus of sequences, one skilled in the art would not recognize that Applicant had possession of the claimed invention at the time the application was filed. There is insufficient support the generic claims as provided by the Interim Written Description Guidelines published in the June 15, 1998 Federal Register at Volume 63, Number 114, pages 32639-32645. The full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph. Claim s 1 and 4-13 are rejected under 35 U.S.C. 112 (a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for using adeno-associated virus serotype 2 (rAAV2)as a backbone to make retrograde infecting recombinant AAV comprising the heterologous cap protein VP1 from AAV9 or AAV9 VP1, wherein the VP1 protein comprising a peptide sequence of LADQDYTKTA (SEQ ID NO: 3, hereby to establish a retrograde rAAV to infect neuron cells, wherein the retrograde infection of neuron cells is in the gigantocellular reticular nucleus (Gi), the sublaterodorsal tegmental nucleus (SLD), the locus coeruleus (LC), the caudal pontine reticular nucleus (PnC), the pontine reticular formation (PnO), the cortex, the hypothalamic nuclei, or the red nucleus , does not reasonably provide enablement for using any or all virus particle r virus like particle for just comprising AAV9 or AAV10 VP1 polypeptide of the cap protein even with the core peptide sequence of LAxxDxTKxA (SEQ ID NO: 1) or LAxDxTKxxA (SEQ ID NO: 2), wherein X is any amino acid or is absent to be able to retrograde infection of neuron cells is in the gigantocellular reticular nucleus (Gi), the sublaterodorsal tegmental nucleus (SLD), the locus coeruleus (LC), the caudal pontine reticular nucleus (PnC), the pontine reticular formation (PnO), the cortex, the hypothalamic nuclei, or the red nucleus. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. The test of an enablement or scope of enablement is whether one skilled in the art could make and use the claimed invention from the disclosure in the application coupled with information known in the art would render undue experimentation (See United States v. Theketronic Inc., 8USPQ2d 1217 (fed Cir. 1988). Whether undue experimentation is required is not based upon a single factor but rather a conclusion reached by weighting many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in re Wands, 8USPQ2d 1400 (Fed. Cir. 1988), which are set forth below: 1). Nature of invention; 2). Scope of claims; 3). State of art; 4). Unpredictability; 5). Level of skill; 6). Number of working examples and 7). Amount of guidance presented in the specification. The nature of invention is directed to a method for making and using a retrograde rAAV including serotypes 1-10, which are capable of infecting neuron cells in different efficiency, wherein Applicants select using serotype 2 AAV as a backbone , wherein the VP1 capsid protein comprises LADQDYTKTA (SEQ ID NO: 3 insertion to increase the efficacy of the receptor binding to neuron cells as well as marker as it is linked with GFP, More preferably the rAAV2 comprises endogenous rep with a chimeric cap protein (VP1-3) selected from AAV9 or AAV10, wherein the VP1 polypeptide is also inserted with LADQDYTKTA (SEQ ID NO: 3 that increase the efficacy of the heparin receptor binding to the human neuro cells. The specification also teaches using said recombinant AAV viruses to be injected into mice model with artificially brain injury, wherein the injection of rAAV can retrograde to the central nervous system , such as spinal cord as well as brain vial a retrograde infection via gigantocellular reticular nucleus (Gi), the sublaterodorsal tegmental nucleus (SLD), the locus coeruleus (LC), the caudal pontine reticular nucleus (PnC), the pontine reticular formation (PnO), the cortex, the hypothalamic nuclei, or the red nucleus . Retrograde viruses are viral vectors used to trace and manipulate neurons by traveling from axon terminals back to the neuron cell body. However, not all viruses are retrograde viruses. Therefore, the scope of claims read on any or all virus particles or virus like particles are unpredictable. The specification has not taught other viruses except adeno-associated viruses (AAV) is constructed as a retrograde virus. The state of art also teach that regrade AAV ( AAVrg ) can be used to deliver a wide array of genetic tools for neural interrogation like optogenetic tools , HYPERLINK "https://www.addgene.org/chemogenetics/" chemogenetic tools , and biosensors . By using AAVrg in Cre transgenic mouse lines, AAVrg can be used for access ing and manipulat ing an in certain defined population of neurons. These specific neurons hence could then be manipulated (e.g., activated or inhibited) by any genetic tool delivered by the AAV . Because Applicants do not teach how to use any or all viruses comprise the AAV9 orAAV10 VP1 can become a retrograde viruses. More sufficient examples and adequate guidance need to be provided for enable the broad scope of the claims read on provide sufficient evidence to support the . broad scope of the claims read on a method using any viruses or virus like particle comp[rising only VVA9 Retro VP1 or VVA10 Retro VP1 to be able retrograde infecting any or all neurons. Therefore, given the above analysis of the factors which the courts have determined are critical in asserting whether a claimed invention is enabled, it must be considered that the skilled artisan would have to conduct undue and excessive experimentation in order to practice the claimed invention . 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. 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 appl icant regards as his invention. Claim 8 recites the limitation "the disease or disorder" in claim 1. There is insufficient antecedent basis for this limitation in the claim. 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: 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. Claims1, 4, 7- 8, 1 1 -1 3 and 14 are rejected under 35 U.S.C. 103 as obvious over by Jan et al. (Neuroscience Insights , 2019, Vol. 14, pages 1-12 ) and further in view of Dudman et al. in WO 2017/218842 (D842) or Patent No. 10,961,282B2 (D282) a or US Patent No. 11,939,355 (D355) or Tervo et al. ( Neuron. 2016 Oct 6;92(2):372–382) . The rejected claim 14 is drawn to a product of an expression vector comprising a replication open reading frame from adeno- associated virus serotype 2 (AAV2 Rep), and a capsid open reading frame, wherein the capsid open reading frame is selected from the group consisting of AAV9Retro Cap and AAV10Retro Cap, and wherein the capsid open reading frame encodes a virion protein 1 (VP1) comprising the following amino acid sequence: LAxxDxTKxA (SEQ ID NO: 1) or LAxDxTKxxA (SEQ ID NO: 2), wherein X is any amino acid or is absent. The rejected claims 1 and 4 However, are drawn to a method using a non-specific AAV , a retrograde viral like particle or retrograde virus like particle (VLP) to infect any injured neuron, wherein the virus particle or VLP compris es AAV9Rretro VP1 or AAV10Retro VP1 polypeptide, wherein the polypeptide further comprises LAxxDxTKxA (SEQ ID NO: 1) or LAxDxTKxxA (SEQ ID NO: 2) insertion and the X is any amino acid or is absent. Jan et al. teach chimeric retrograde recombinant adeno-associated virus vectors including AAV2/6, AAV2/8 and AAV2/9 , wherein the AAV2 is constructed as the backbone and the capsid protein is derived from AAV9 . For example, rAAV2/9 is the one that recombinant genome containing the AAV2-inverted terminal repeats is packaged in capsid derived from AAV9 )1 st paragraph of introduction. Jan et al. is silent regarding how the AAV2/9 is constructed for comprising the rep gene of AAV and Cap gene encoding the VP1-3). While Jan et al. do not explicitly teach that AAV2/9 construct being constructed inherently comprise the AAV2 Rep gene and AAV9 cap gene, which is evidenced by Low et al. (Human Gege Therapy 2013, Vol. 24, issue 6, pages 613-629). Low et al. disclosed that for production of recombinant AAV 2/9, which is made by supplement of Cap for the AAV9 and Rep for AAV2 (See Material and Methods, paragraph of Purification and titration of recombinant AAV2/6,AA2/8 and AAv2/9 vectors. Mover, Low et al. also disclose that recombinant AAV9 single strain viral genome persisted in nigral dopaminergic neurons within cell bodies and axon terminals in the striatum, and intact assembled AAV capsid was enriched in nuclei of nigral neurons, 4 weeks after virus injections to the substantia nigra. 6-Hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra reduced the number of viral genomes in the striatum, in line with viral genome persistence in axon terminals. This disclosure inherently teaches the limitation of the infected neuron by the retrograde AAV comprises an axon or cell body proximal injury if an injury did exist. So the disclosure AAV2/9 anticipates claim 7. Jan et al. further teach that the term retrograde transduction reported by them refers to the uptake of injected rAAV particles at nerve terminals, retrograde transport, and subsequent transduction of nerve cell soma . Among the commonly used rAAV serotypes, rAAV2/6, 2/8, and 2/9 have been shown to transduce neurons in dorsal root ganglia (DRG) and spinal cord following peripheral routes of delivery, purportedly via retrograde transduction. The rAAV capsid protein Vp1-3) is attribute to the retrograde capacity of the infection in different potential. Some modifications can enhance their neuronal tropism and promote retrograde transduction. However, Jan et al. do not teach how to modified the cap protein by inserting a peptide, wherein the peptide comprises LAxxDxTKxA (SEQ ID NO: 1) or LAxDxTKxxA (SEQ ID NO: 2) insertion and the X is any amino acid or is absent. Dudman et al. teach a method for producing rAAV comprising either endogenous or heterologous cap proteins VP1-3 chimeric with rep protein of the AAV2, In particular, the method for generating such chimeric rep/Cap rAAV is taught in example 2 that Four previously generated viral libraries were used at the start of the directed evolution procedure: 1) a random mutagenesis library generated by subjecting the AAV2 cap gene encoding viral proteins VP 1-3 and assembly-activating protein (AAP) to error prone PCR library of AAV2 cap gene variants containing 7-mer peptide inserts between N587 and R588, 3) library of AAV2 cap gene variants containing randomized loop regions and 4) a DNA shuffling library generated from wild-type AAV1, AAV2, AAV4, AAV5, AAV6, AAV8 and AAV9 cap gene sequences. Each pool of mutant DNA had been originally sub-cloned into the replication-competent AAV packaging plasmid to create a viral plasmid library that, when packaged into AAV virions, can be selected for any new property or function. The replication-competent AAV system incorporates the mutant cap gene into the viral payload, and thus, the genotype of each variant is linked to its phenotype. Capsid sequences of the desired property can then be recovered by DNA sequence analysis of the encapsulated AAV genome. Therefore, the other heterologous gene carried or linked to the capsid protein in the rAAV vector, will be encapsulated . This meets the limitaiton of claim 11 too. In particular, the four replication-competent AAV libraries were packaged by calcium phosphate transient transfection of HEK293-T cells followed by viral harvest, iodixanol gradient centrifugation, wherein the cap gene encoding proteins VP1-3 a of delivering a payload to one or more neurons is provided. Such a method typically includes contacting one or more neurons with a variant adeno-associated virus (AAV) that includes a payload packaged therein, wherein the variant AAV includes a capsid protein comprising a sequence selected from the group consisting of xxDxTKx (SEQ ID NO:1) and xDxTKxx (SEQ ID NO:2). More preferably the peptide LADQDYTKTA (SEQ ID NO: 85) as a variant of the VP1 cap protein of the rAAV is selected and used. Dudman et al. concluded that the peptide LADQDYTKTA (SEQ ID NO:85)+V708I+N382D) that displayed the strongest retrograde transport in two independent circuits in this secondary screen (cortex to globus pallidus and inferior olive/basal pontine nucleus to cerebellum) was chosen for further analysis and dubbed rAAV2-retro. When two additional promoters more commonly used in rodent in vivo studies were assessed (CAG—FIG. 1 B, or human Synapsin-1, data not shown), Dudman et al. also teach that the viral particle as described herein further includes a nucleic acid encoding a payload. In some embodiments, the nucleic acid encoding a payload includes a promoter sequence operably linked to a coding sequence that encodes the payload. Representative promoter sequences include, without limitation, synapsin-1, CMV, GFAP, CAG, CaMKII, MBP, EF1alpha, TRE and mDlx. In some embodiments, the coding sequence encoding the payload is selected from the group consisting of a protein-coding gene and an inhibitory RNA nucleic acid. In some embodiments, the inhibitory RNA nucleic acid is an antisense oligonucleotide, an siRNA, or an RNAi.(para7). Dudman et al. also teach es that in certain instances, a payload can be one or more protein- coding genes. Without limitation, protein-coding genes include an optical reporter construct, a therapeutic gene, or an effector protein. Many types of optical reporter constructs are known in the art, and the following list is meant to be representative and not exhaustive. For example, optical reporter constructs include, without limitation, GCaMP6 (GCaMP6s, GCaMP6m, or GCaMP6f; see WO 2014/059154), a fluorophore (e.g., green fluorescent protein (GFP), enhanced GFP (EGFP), red fluorescent protein (RFP), yellow fluorescent protein (YFP), tdTomato), a color-flipping construct (e.g., a payload that expresses one reporter in one cell population and a different reporter in another population), Glucose Sensors (See paragraph of Methods of Making Virus Particles that Exhibit a Preference for Retrograde Movement in Neurons. These disclosures meet the limitation of claims 12 and 13 also because the glucose sensor is so closely related to insulin-like growth factor 1 (IGF1) or the IGF-1 is one of the sensor for glucose disorder related disease as evidenced by Clemmons (Curr Opinion Pharmacology 2006, Vol. 6, pp. 620-625). In addition, Dudman et al. teach that In some embodiments, the therapeutic gene is survival motor neuron 1 for treatment of Spinal muscular atrophy, amyotrophic lateral sclerosis (ALS), autism, dementia, peripheral neuropathy, schizophrenia, or retinal degeneration.(Para 11). These disclosures indicate that the claimed retrograde rAAV vector can be used for treating a disease or disorder associated with a neurodegenerative disease or disorder. Therefore, it would have bene obvious for any person with an ordinarily skilled in the art to be motivated by the teachings from Jan et al. and Dudman et al. and combining the methods for making a rAAV2 with chimeric Cap selected form a group consisting of AAV1, AAV2, AAV4, AAV5, AAV6, AAV8 and AAV9 cap gene, wherein the VP1 also comprising the short peptide selected from the group consisting of xxDxTKx (SEQ ID NO:1) and xDxTKxx (SEQ ID NO:2), and more preferably the peptide LADQDYTKTA (SEQ ID NO: 85) as a variant of the VP1 cap protein of the rAAV , which has been approved by Dudman et al that had displayed the strongest retrograde transport for the transducing rAAV retrograde vector infection, herein to achieve more efficient and widespread retrograde transduction following intramuscular and possibly other peripheral routes of delivery with a reasonable expectation of success. As there are no unexpected results have been provided, hence the claimed invention as a whole is prima facie obvious absence unexpected results. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT BAO Q LI whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0904 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M-F 8 am to 8 pm EST . 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 Michael Allen can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-270-3497 . 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