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 .
This action is in response to the papers filed June 23, 2026 and September 02, 2026.
Claims 1-12, 14-19, and 42-52 are pending in the application. Claims 1-2, 5, 7, 10, 12, 19, and 42-45 are amended, claims 13 and 20 are canceled, and claims 46-52 are newly added as set forth in the claim set filed 06/23/2026 and 09/02/2026.
Therefore, claims 1-12, 14-19, and 42-52 are examined on the merits.
The examiner acknowledges receiving an executed Declaration under 37 C.F.R. § 1.132 executed by Dr. Gary K Steinberg on September 01, 2026 (“Steinberg Declaration ”), and filed on 09/02/2026.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/054362, filed October 11, 2021.
Applicant’s claim for the benefit of a prior-filed parent provisional applications 63/090,671 filed 10/12/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is October 12, 2020.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Objections
The objections of claims 1, 2, 5, 7, 10, 13, and 42-45 are withdrawn in light of the amendments made to spell out acronyms.
Claim Rejections - 35 USC § 112
The rejection of claims 1-20 and 42-45 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second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
Applicant’s arguments and amendments filed on 06/23/2026 and 09/02/2026 have been considered and are persuasive. In particular, amendments have been made to either cancel claims, remove indefinite terms, remove Trademarks, or correct antecedent basis.
Claim Rejections - 35 USC § 102
The rejection of claims 1-7, 9-19, and 42-44 under 35 U.S.C. 102(a)(1) as being anticipated by Azevedo-Pereira (Stroke 50.Suppl_1 (2019): ATP142-ATP142) as evidenced by Andres (Brain 2011: 134; 1777–1789) is withdrawn.
Applicant’s arguments and amendments filed have been considered and are persuasive regarding the requirement of normal karyotypes, specific expression and secretion of factors.
Claim Rejections - 35 USC § 103
The rejection of claim 45 under 35 U.S.C. 103 as being unpatentable over Chen (Methods Mol Biol, 2019:1919:59-72) in view of Gonzalez (Methods Mol Biol, 2019:1919:43-58) is withdrawn.
Applicant’s arguments and amendments filed have been considered and are persuasive regarding additional components in the cell culture.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claim 1-12, 14-19, and 42-44 remain rejected and claim 47 is newly rejected under 35 U.S.C. 103 as being unpatentable over Azevedo-Pereira (Stroke 50.Suppl_1 (2019): ATP142-ATP142) as evidenced by Andres (Brain 2011: 134; 1777–1789; IDS reference) and Ito (2017, K. Houkin et al. (eds.), Cell Therapy Against Cerebral Stroke, Chapter 5) in view of Daadi (2008, PLoS ONE 3(2): e1644) and Wechsler (Stroke. 2018;49:1066-1074).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 06/23/2026 and 09/02/2026.
Regarding claim 1 and 47, Azevedo-Pereira teaches administering NR1 (hES-derived) human neural cells to pre-clinical stroke models which resulted in restoring circuit excitability (i.e. restore neurologic function) (p. 1). Azevedo-Pereira further teaches that the transplantation of the NR1 cells resulted in different gene expression in all cortical layers (i.e. augment endogenous neural repair) (p. 1). As evidenced by Ito, NR1 cells are known in the art to be obtained from H9 cells and are a non-genetically modified cell line and points to Daadi as a reference teaching on NR1 cells (p. 64-65, bridging paragraph).
However, Azevedo-Periera does not explicitly mention that the cells have a normal karyotype through passaging.
Daadi teaches SD56 NSCs derived from H9 cells which are transplanted in models of stroke (Abstract, p. 6, 2nd column). These cells were passaged at least 12 times and the isolated cells were passaged up to 20 times with a stable phenotype of normal, non transformed cell karyotypes as well as generated 75 vials containing 2 to 5 million cells each (p. 3, 1st-2nd column). Passage 13 cells specifically once the karyotypes were stabilized were prepared for transplantation (p. 7, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to passage the cells to a normal karyotype for at least 12 and up to 20 passages as taught by Daadi with a reasonable expectation of success. An artisan would be motivated to do so as the 20 passages of Daadi produced a normal karyotype, stable phenotype and 75 vials containing 2 to 5 million cells each were generated (p. 3, 2nd column).
Regarding the secreted trophic factors, as each and every limitation is met for the NSCs derived from ES cells in claim 1, and the cells of Azevedo-Pereira are NR1 cells which are the type of cell utilized in the present application, the NR1 cells would have the same trophic factors secreted with a reasonable expectation of success. Moreover, Daadi states that NSCs derived from H9 cells do not form tumors (Abstract).
Regarding claim 2, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches administering NR1 (hES-derived) human neural cells, it is interpreted that these cells are in an isolated composition for therapeutic use.
Regarding claim 3 and 4, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches administering NR1 cells to an ischemic cortex of a brain (i.e. cortical transplantation) (p. 1). Therefore, the subject has suffered an ischemic stroke. Additionally, Daadi teaches administering NSCs to MCAO rodents (Abstract).
Regarding claim 5, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches the ischemic stroke is produced by distal middle cerebral artery occlusion before administering NR1 cells to an ischemic cortex of a brain (p. 1, 1st half). Therefore, the ischemic cortex would be the cerebral cortex or near it.
Regarding claims 6 and 9, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches the peri-infarct motor cortex is part of the ischemic cortex (p. 1, 1st half).
Regarding claim 7, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches administering the cells 1 week after distal middle cerebral artery occlusion (p. 1, 1st half)
However, regarding claim 8, Azevedo-Pereira and Daadi do not teach administration to the subcortical area of the brain such as the hippocampus, amygdala, extended amygdala, claustrum, basal ganglia, or basal forebrain.
Wechsler teaches clinical studies for stroke which administer neuronal cells to the basal ganglia surrounding the infarct using a stereotactic technique and improvement in clinical scales was observed (p. 1068-1069, bridging paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the NR1 cells of Azevedo-Pereira to the basal ganglia (i.e. subcortical region) as taught by Wechsler in order to treat conditions of stroke. An artisan would have been motivated to do so as Wechsler teaches after administration to the basal ganglia, improvement in clinical scales was observed (p. 1068-1069, bridging paragraph).
Regarding claims 10-12 and 14, although Azevedo-Pereira and Daadi do not teach the specific proteins and secreted trophic factors, these are inherent to the NR1 cells which are the same cells as those in Azevedo-Pereira as no evidence has been provided to the contrary. As seen in the instant application’s Figure 22 and Table 10, these are inherent to the NR1 cells of Azevedo-Pereira’s characterization and secretome. As evidenced by Andres, factors such as VEGF are known in the art to have the property of enhancing structural plasticity (p. 1778, Figure 4). Moreover, axonal transport, which is critical for both proper axonal function and axonal sprouting, is inhibited by stroke and that this is rescued by the stem cell treatment through their secreted factors (Abstract, Figure 4).
Regarding claim 15 and 16, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches that neurological recovery was accessed by the Whisker-paw test which showed NR1 enhances post-stroke behavioral recovery post transplantation (p. 1, 1st half). As Whisker-paw tests involve upper extremity motion, it is an improvement in upper extremity function in raising or lifting.
Regarding claims 17-19, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Although Azevedo-Pereira does not teach the gait improvements and reversal of impaired mobility, these are inherent to the NR1 cells being administered to a subject in need there of as claimed. As each and every limitation is taught by Azevedo-Pereira, the same method steps would yield the same predictable results with a reasonable expectation of success.
Regarding claims 42-43, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches administering NR1 (hES-derived) human neural cells to pre-clinical stroke models which resulted in restoring circuit excitability (i.e. restore neurologic function) (p. 1). Therefore, it is interpreted that Azevedo-Pereira reads on an isolated composition of NR1 cells which secrete trophic factors.
Regarding claim 44, the combined teachings of Azevedo-Pereira and Daadi make obvious claim 1. Moreover, Azevedo-Pereira teaches administering NR1 (hES-derived) human neural cells to pre-clinical stroke models which resulted in restoring circuit excitability (i.e. restore neurologic function) (p. 1). As the control is a “vehicle” only (p. 1, line 4) it is interpreted that the vehicle (i.e. pharmaceutically acceptable carrier) is present in the NR1 cell composition. Therefore, it is interpreted that Azevedo-Pereira reads on an isolated composition of NR1 cells which secrete trophic factors with a pharmaceutically acceptable carrier.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments filed 09/02/2026 regarding the 103 rejection,
Applicant’s arguments and amendments filed 09/02/2026 regarding the 103 rejections have been considered and are persuasive in light of the amendments newly claiming limitations within claim 1 as well as the new limitations regarding passaging. The references of Ito and Daadi have been utilized to provide teachings for these new limitations in the modified rejection above.
Regarding Applicant’s arguments against the predictability of tumors forming with NSCs provided by Weschler, Weschler merely states that this is a possibility, but does not discourage the administration of NSCs. Moreover, the new reference of Daadi and the primary reference both provide teachings of administering NSCs/ derived from ES cells without tumor formation, therefore there is a reasonable expectation of success.
Applicant argues that a secretome analysis was not performed in Azevedo-Pereira and therefore inherency cannot be claimed. However, the limitations regarding passaging are met and NR1 cells are met as well. Absent of evidence to the contrary the NR1 cells of Azevedo-Pereira are the NR1 cells of the present invention, moreover, Dr. Steinberg is an author to both the present application and a contributing author to Azevedo-Pereira.
Applicant argues that Andres is improperly utilized. However, the Examiner disagrees. It does provide teachings and evidence towards VEGF’s properties. The arguments against the cell source and nomenclature are moot as the rejection and evidence is not directed towards that subject matter.
The Steinberg Declaration under 37 CFR 1.132 filed 09/02/2026 is insufficient to overcome the 103 rejection as set forth in the last Office action because:
The declaration while demonstrating a significant therapeutic result in improving stroke, is only directed towards the method of treatment. If the results are unexpected, the method should be differentiated from that of Azevedo-Pereira which uses NR1 cells to treat stroke. If this is through a dosage or particular route of administration, it should be reflected in the independent claim. The method of treatment involves the specific cell population of NR1 cells at a Methods of producing the NR1 cells and the cells themselves are known in the art and/or obvious (See Azevedo-Pereira and Ito). Moreover, as the normal karyotype is required, passaging to obtain said normal karyotype should also be included in the independent claim.
Response to arguments
New objections/ Rejections in response to Applicants’ arguments or amendments
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:
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.
Claim 45 and 47-52 are newly rejected under 35 U.S.C. 103 as being unpatentable over George (Biomaterials 178 (2018) 63-72) in view of Gonzalez (Methods Mol Biol, 2019:1919:43-58). This is a new rejection necessitated by amendment of the claims in the responses filed 06/23/2026 and 09/02/2026.
As the specification describes NR1 cells being made from H9 cells, the claim is interpreted as H9 cells cultured under the claimed conditions to produce the claimed NR1 cells derived from the ES H9 cells as NR1 ES cells which the NR1 ES derived neural stem cells are made from.
Regarding claim 45, George teaches a method of producing NSCs from ES cells by culturing the ES cells with B27, N2, LIF, EGF, FGF, and pooled serum albumin (p. 64, 2nd column). These cells are produced through 17-22 passages and no feeder cells are utilized.
However, George does not teach that Glutamax (i.e. L-alanyl-l-glutamine dipeptide alternative to L-glutamine) is utilized.
Gonzalez teaches that Glutamax is utilized with N2 and B27 supplements as neural induction media in cell culture plates (i.e. solid support) (Table 2, p. 45).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to add Glutamax as taught by Gonzalez to the neural induction medium of George in a plate with a reasonable expectation of success. An artisan would have been motivated to do so, as Gonzalez teaches it is known in the art to utilize Glutamax with N2 and B27 (which are found within George’s induction media) in neural induction media in culture plates (Table 2).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
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 applicant regards as his invention.
Claims 1-12, 14-19, and 42-52 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 applicant regards as the invention. This is a new rejection necessitated by amendment of the claims in the responses filed 06/23/2026 and 09/02/2026.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
In the present instance, claim 1 recites the broad recitation “express trophic factors”, and the claim also recites specific types of express trophic factors which is the narrower statement of the range/limitation.
Claims 2-12 and 14-19 are rejected insofar as they depend on claim 1,
Moreover, 42 recites secrete trophic factors in line 2 and the claim also recites specific types of express trophic factors, e.g., SPARC, Galectin 1. VEGF-A, SDFla, TIMP1. CSF3 and PAl1/serpine 1, which is the narrower statement of the range/limitation.
Claims 43-44, 45, 46 47-52 are rejected insofar as they depend on claim 42 or 1.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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