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 .
The preliminary amendment filed 5/24/2023 has been received and entered into the application file.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/10/2026 has been entered.
Status of Claims
Claims 1-2,4-6, 10 and 13-20 are under examination.
Claims 3, 7-9, and 11-12 are cancelled
Priority
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional application 63/275,237(filed 11/3/2022).
Information Disclosure Statement
The IDS submitted 07/05/2023 is in compliance with 37 CFR 1.97 and thus
references have been considered. Applicants did cite and provide a copy of (reference);
however, the online publication contains a supplemental document which is relied upon for one or more rejections. To make the supplemental material of record, a copy of Heinrich et al(Stem Cell Reports 2014, C6 on IDS) supplemental document is additionally made of record on the included PTO-892. IDS submitted 03/14/2025 has been considered by the examiner.
Objections Withdrawn
Specification
The objections to the specification are withdrawn in view of the applicants amendments.
Claim Rejections - 35 USC § 112
Rejection to claims 8 and 17 under 112(a) are withdrawn because the applicant has canceled claim 8.
The rejection to claim 6 under 112(d) is withdrawn in view of the applicant’s amendments.
The rejection to claim 13 has been withdrawn in view of the applicant’s amendments.
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, 4-6, and 10-20 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.
Claim 1 recites the limitation "said SOX2 agonist" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 1 has been amended to no longer cite a SOX2 agonist and now cites a SOX2 expression vector. It is unclear what “said SOX2 agonist” is referring to.
Claim Rejections - 35 USC § 102
Rejection of claims 1, 3-7, and 9-12 under 102(a) over Kang are withdrawn in view of the applicant’s amendments filed 3/14/2025.
Rejection of claims 1-7, 9-10, and 13-16 under 102(a) over Heinrich are withdrawn in view of the applicant’s amendment amendments filed 3/14/2025.
Claim Rejections - 35 USC § 103
Rejections of Claims 1-8, 9-10, and 13-18 over 103(a) over Heinrich et al in view of Kang et al, and as evidenced by Dr. Alexander at Georgia Hand, shoulder, and Elbow are withdrawn in view of applicant’s amendments.
Rejection to claims 1-6, 10, 13-16 and 20 under 35 U.S.C. 103 as being unpatentable over Heinrich et al (Stem Cell Reports 2014, C6 on IDS) have been withdrawn in view of the applicant’s amendments filed 09/25/2025.
Rejections necessitated by amendment:
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-2,4-6, 10, 13-18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Heinrich et al (Stem Cell Reports 2014) in view of Kang et al (WO2014/163425Al), and as evidenced by Dr. Alexander at Georgia Hand, Shoulder, and Elbow (Can Physical Therapy Help Nerve Damage?).
Regarding claims 1 and 2, Heinrich teaches that genetic fate mapping demonstrates the reprogramming of NG2 glia into induced neurons upon expression of Sox2 (page 1006, figure 3 legend). Heinrich teaches that Sox2 alone is capable of inducing neurogenesis in the adult mouse cerebral cortex following a traumatic injury(page 1007, Discussion). Neurogenesis reads on inducing regeneration, repair and/or growth of nerve tissue. Heinrich teaches the induction of neuronal cells in the injured adult cerebral cortex upon forced expression of Sox2 alone (Page 1005, Figure 2 title), which reads on contacting with Sox2 agonist. Heinrich teaches mice in study received an injection of a retroviral or lentiviral vector encoding Sox2 (page 1011, experimental procedures). Heinrich teaches the viral vectors driven under the control of an internal chicken B-actin promoter with a cytomegalovirus enhancer(CAG), which is optimized for strong and long-term expression over months in the adult mouse brain(page 13, Supplemental Information).
Heinrich does not teach Sox2 under the control of an NG2 specific promoter. However, Heinrich teaches NG2 glia can be readily targeted by retroviruses at the injury site in vivo. Heinrich teaches that the majority of the cells transduced were NG2 glia (page 1003, right column). Heinrich further teaches retrovirus-mediated expression of NeuroD1 under control of a human NG2 promoter construct to promote neurogenesis in vivo, which also teaches NG2 glia can be reprogrammed into induced neurons (page 1007, discussion).
Therefore, one of ordinary skill in the art would be motivated to combine the teachings of an NG2 glial specific promoter with the teachings of reprogramming NG2 glia into induced neurons upon expression of Sox2 to further define and target expression to the NG2 cell. There would be a reasonable expectation of success because most studies aim at reprogramming brain-resident glia into neurons focused on NG2 glia because of their abundance and capacity for proliferation (page 1007, left column). Heinrich teaches human NG2 promoter construct was also found to elicit neurogenesis in the cerebral cortex in vivo (page 1007, discussion). Heinrich further teaches that Sox2 alone is capable of inducing neurogenesis in the adult mouse cerebral cortex following a traumatic injury(page 1007, Discussion). Heinrich teaches the potential of NG2 glia as cellular candidates for de novo generation of new neurons and further that their retroviral injection the majority of cells transduced were NG2 glia. The above combination would be an attempt at improving maturation of the newly generated neuronal cells to fully reveal the potential of such fate conversion for brain repair as taught is a goal of Heinrich (page 1007, discussion).
Henrich et al. do not teach a neuronal growth factor selected from brain-derived neurotrophic factor (BDNF), noggin (NOG), p75-2 orNT3.
Kang et al teaches differentiation of non-neuronal cells into neurons using an induction medium including the neuronal growth factor brain derived neurotrophic factor (BDNF)(page 33, Example 6-1). Kang’s differentiation lasts for 10-25 days, where the cells would be contacted with the growth factor more than once(page 34, Example 6-1).
One of ordinary skill in the art would have been motivated prior to the filing of this application to combine the teachings of Heinrich’s Sox2 reprogrammed cells for treating mammalian spinal cord injury with teachings of Kang to improve the differentiation and self- renewal potential of non-neuronal cells. There is a reasonable expectation of success because Kang teaches that BDNF along with Sox2 aids in the reprogramming of non-neuronal cells (page 34, Example 6-1). Therefore, the induction of neural stem cells would improve treatment of spinal cord injury by adding a source of neurons to replace lost or damaged neurons in the area affected.
Regarding Claim 3, Heinrich teaches converting glial cells into induced neurons in the adult cerebral cortex(page 1000, Results).
Regarding Claim 4, Heinrich teaches that expression of Sox2 in non-neuronal cells pushes the conversion of those cells to DCX+ neurons in the adult murine cortex(page 1001, right column). DCX+ neuron reads on neural cell is a neuron. Heinrich teaches that the majority of the cells transduced were NG2 glia (page 1003, right column).
Regarding Claim 5, Heinrich teaches NG2 glial cells induction to neurons in the injured cerebral cortex, an area of the brain devoid of neurogenesis(page 1009, right column). Neurons in the cerebral cortex reads on brain neuron.
Regarding claim 6, Heinrich teaches the neuronal cell is an NG2 glial cell capable of receiving synaptic input from GABAergic neurons, describing its inhibitory role thereby stating the NG2 glial can be an inhibitory cell (page 1009, right column).
Regarding to Claim 10, Heinrich teaches the mice in study received an injection of a retroviral or lentiviral vector encoding Sox2(page 1011, experimental procedures). A retroviral or lentiviral vector reads on viral expression vector.
Regarding to claim 13, Heinrich teaches the conversion of non-neuronal cells into neurons in the adult mouse cortex (page 1003, left paragraph). Heinrich teaches that the majority of the transduced cells were NG2 glia (page 1003, right column). Further the combination of teachings in Heinrich of claim one teaches targeting of NG2 glia. In the adult mouse cortex reads on in mammalian subject.
Regarding to claim 14, Heinrich teaches replacement of degenerated neurons in the adult cerebral cortex following traumatic injury(page 1000, Abstract). Traumatic injury in the adult cerebral cortex reads on suffered a nerve injury.
Regarding claim 15, Heinrich teaches a mouse model of traumatic injury induced by a local stab wound to the upper layers of the cerebral cortex(page 1000, Results). Traumatic injury to the cerebral cortex reads on traumatic brain injury.
Regarding claim 16, As previously stated Heinrich teaches the viral vector optimized for strong and long-term expression of Sox2 over months post injection in the adult mouse brain(page 13, Supplemental Information). Strong, long-term expression of Sox2 over months reads on Sox2 agonist is contacted with the NG2 cell taught in claim 1 more than once.
Regarding claim 17, Kang teaches differentiation lasts for 10-25 days, where the cells would be contacted with the growth factor more than once(page 34, Example 6-1).
Regarding claim 18, Heinrich teaches induction of neurons in the context of an adult mouse cortex (page 1003, left column). Heinrich does not teach treating the subject with physical therapy or other nerve deficit therapy prior to or at the time of, or post-contacting Sox2 agonist. It is known in the art that physical therapy has proven an effective strategy in addressing nerve damage without surgery, as evidenced by Dr. Alexander(page 3, final paragraph of webpage). It would be prima facie obvious to one of ordinary skill in the art to determine the additional treatment strategy of the of subject based on their condition and the type and severity of nerve deficit. There is a reasonable expectation of success because a PHOSITA would examine the condition of the subject and could determine physical therapy and other common treatment strategies to accompany the proposed treatment method.
Regarding claim 20, Heinrich teaches NG2 glia were shown to receive synaptic inputs from glutamatergic neurons, which teaches the excitatory nature of the NG2 glial cells, thereby stating the NG2 glial can be an excitatory cell (page 1009, right column).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Heinrich et al (Stem Cell Reports 2014) in view of Kang et al. (WO2014/163425Al), as applied to claims 1-2, 4-6, 10, 13-18 and 20 above, and further in view of Vasan et al. (Front. Cell Dev. Biol., 2021).
Regarding claim 19, Heinrich and Kang teach the living subject is a mammal but do not teach the subject is a human. Vasan teaches that in neurodegenerative diseases the dying neurons are not replaced, so new therapeutic options are required. Vasan further teaches that new strategies that drive neuronal replacement in the infarct region post-stroke are required. Vasan teaches neuronal replacement strategies for brain injury or neurodegenerative diseases can comprise endogenous repair (page 21, Comparing the Potential of Exogenous vs. Endogenous Neuronal Repair). Vasan further teaches the advantage of neuronal reprogramming in situ allows resident glial cells in the brain to be targeted, so that brain rejection is not an issue (page 22, Potential of Endogenous repair). Vasan teaches intracranial injections for endogenous repair in humans (page 22, Delivery challenges).
One of ordinary skill in the art would have been motivated to combine the reprogramming of glial cells into neurons in a mammal of Heinrich and Kang with the human neuronal reprogramming in situ of Vasan. One would have been motivated to make this combination as Vasan teaches new therapeutics are required to treat humans with neurodegeneration. There would have been a reasonable expectation of success because both teach endogenous treatment of a subject in need of neurogenesis facilitated by a viral vector.
Response to Arguments
Applicant's arguments filed 3/10/2026 have been fully considered but they are not persuasive.
Applicant argues: Applicants argue it has been demonstrated in the literature that constitutive SOX2 expression is actually inhibitory for converting glial cells into neurons (Niu et al., 2013; previously submitted). This may well explain why only a very few neurons could be obtained using Heinrich's methods'. This was only two NeuN+ neurons were shown in Figure 2H. The inventors have shown (FIG. 4) that SOX2 alone is not sufficient to produce the required mature neurons for neural repair. This would certainly not have led those of skill the art to the presently claimed methods.
Examiner’s response: Regardless of number of cells induced Heinrich teaches the reprogramming of NG2 glia into induced neurons upon expression of Sox2 (page 1006, figure 3 legend). Regardless of the efficiency the teachings of Heinrich et al. and Kang make obvious the invention of the present application. The prior art make obvious the elements of claim .
Applicant’s argument: Heinrich did not use the NG2 promoter, and the portion of Heinrich that mentions an NG2 specific promoter is the previous work of Guo et al. (2014) stating that "Retrovirus-mediated expression of NeuroD1 under control of a human NG2 promoter construct was also found to elicit neurogenesis in the cerebral cortex in vivo (Guo et al., 2014), providing independent evidence that NG2 glia can be reprogrammed into induced neurons." So, while NG2 specific promoters are mentioned, no one had any reason to believe that they would address the clear problems with SOX2 expression, set out above, namely, that SOX2 expression can be inhibitory.
Examiner’s response: Heinrich makes obvious the use of NG2 promoters for expression in NG2 cells, the “problem” they are setting out to solve is not a matter of consequence. The method of the present application is made obvious by the elements in Heinrich.
Applicant’s argument: Moreover, durable SOX2-mediated reprogramming of a significant percentage of glial cells is also required, which Heinrich readily admitted they did not achieve such (see footnote 1).
Examiner’s response: Reprogramming of a significant percent of glial cells is not a requirement of the present application. Furthermore, the combination of elements in Heinrich and Kang make obvious limitations of the present claim 1.
Applicant’s argument: Kang was working with hiNSCs, not glial cells like Heinrich. SOX2 is downregulated during the differentiation process in hiNSCs, whereas glial cells are terminally differentiated cells and do not have the intrinsic ability to produce neurons.
Examiner’s response: Kang relates to producing a reprogrammed derivative neuronal stem cell from a differentiated cell (cover page, abstract). Glial cells are as applicant stated differentiated cells.
Applicant’s arguments: Applicant argues in vivo conversion of glial cells to neurons were not expected to require growth factors, as shown in many publications (PMID: 24360883, 31551137, 31552908, 32107381, 31488328, 26166567, 28844658). Thus, applicant's findings that both SOX2 and growth factors can convert glial cells into neurons is a surprising result that cannot possibly have been predicted by Heinrich and/or Kang.
Examiner’s response: Growth factors are well-known factors of cell differentiation. Heinrich et al. cite the importance of growth factors in differentiation. Heinrich et al. teach growth-factor-induced conversion of cultured OPCs into multipotent neural-stem-cell-like cells was accompanied by the reactivation of the Sox2 gene (page 1009, first paragraph). Heinrich et al. further teach cytokines, growth factors, and morphogens released upon injury may directly impinge on reprogramming mechanisms, as activation or interference with these signaling pathways can dramatically enhance fate conversion into neurons (page 1009, second paragraph). Therefore, the combination of growth factors and SOX2 to convert glial cells into neurons is not a surprising result.
Applicant's arguments filed 3/14/2025 have been fully considered but they are not persuasive.
Applicant argues: The applicant amended claim 1 to recite that the non-nerve cell is an NG2 glial cell, and the provision of the SOX2 is delivered in a glial cell specific fashion which is distinct from the teachings of Heinrich. Applicant further argues that Heinrich uses a CAG promoter which would express globally in the brain as opposed to their glial specific promotor.
Examiner’s response In response, the newly argued limitations are addressed by the new 103(a) rejection over Henrich. Henrich et al. does describe a CAG promoter which would express globally, however Henrich also describes work using an NG2 specific promoter therefore combining the teachings would render the amended claim obvious.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights