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 .
Withdrawn Objections/Rejections
112b rejection on claim 20 based on the use of the relative term ‘efficient’ is withdrawn. The amendment to the claim remove the word ‘efficient’.
112b rejection on claim 20 based on having two different step #1s indicated by two different (i) is withdrawn. The applicant remarks indicate they removed one (i).
112b rejection on claim 22 is withdrawn, the amendment to the claim recites glucocerebrosidase.Claims 20-22, 25 and 26 rejection under 35 U.S.C. 103 as being unpatentable over Xu, Zhen, et al., in view of Jeyakumar, et al., is withdrawn.
Drawings
The disclosure is objected to because of the following informalities:
There is description of color in the specification fig. 4 (page 5), paragraph 15, regarding volcano plot, and the various colors cannot be distinguished from each other since the figures are in black and white.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claim 27 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.
Regarding claim 27, the claim language of the independent claim 20 points to two different steps of transplant. Transplantation of HSPCT and infusion of donor HSPCs. Therefore it is not clear how the claim 27 is applicable to method recited in claim 20 or when the administration of microglial cell conditioning agent is done over the course of transplant, in other words after which of these transplantation or infusion steps, the administration step of claim 27 is meant to occur.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 20-22, 25, 26, 30-33 are rejected under 35 U.S.C. 103 as being unpatentable over Xu, Zhen, et al., Cell reports 32.6 (2020) in view of Capotondo, Alessia, et al., Proceedings of the National Academy of Sciences 109.37 (2012): 15018-15023, and Jeyakumar, Mylvaganam, et al., Nature Reviews Neuroscience 6.9 (2005): 713-725.
Regarding claim 20, Xu teaches methods for central nervous system (CNS) wide microglia replacement in mice, using bone marrow transplantation (BMT) which is comprised of hematopoietic stem cells (HSPC) and peripheral blood cells (PBCs) (page 2, introduction), as a way of treating microglia associated CNS disorders. Regarding steps (i) and (iii), Xu, ablated the endogenous microglia by feeding C57BL/6J mice with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) which is the same ‘cell conditioning factor’ used to ablate endogenous microglia according to the specification section of the instant application. Regarding steps (i) and (ii), then the mice were injected with donor bone marrow cells.
Regarding claim 25, Xu teaches that colony stimulating factor receptor (CSF1R) is essential for microglia survival and PLX5622, the same drug used in the instant application recited in the specification section, to inhibit the CSF1R is used in the Xu study to ablate microglia (page 3, under the heading, ‘ BMC-derived microglia-like cells can replace endogenous microglia at the CNS-wide scale by mrBMT’) . It’s obvious to an ordinary artisan in the field that PLX5622 is an inhibitor of the CSF-1 signaling pathway.
Regarding claim 26, Xu teaches that CSF1R inhibitor PLX5622 was used to fully ablate the CNS-resident microglia CSF1R (page 3, under the heading ‘ BMC-derived microglia-like cells can replace endogenous microglia at the CNS-wide scale by mrBMT), indicating it is a brain-penetrant inhibitor of the CSF1R.
Xu does not teach the infusion of purified donor HSPC in step (II), and the correction of the enzymatic defect of the lysosomal storage disease by microglial replacement or that after step (iii) at least 50% of brain-resident microglial cells in the individual are derived from the donor HSC that correct the enzymatic defect of the lysosomal storage disease, for a period of at least 12 weeks as recited in claim 20. Similarly, Xu does not teach performing myeloablative conditioning as recited in claim 30, administration of busulfan as recited in claim 31, administration of chemotherapeutic agent or a combination of agents as recited in claim 32 or a brain penetrant chemotherapeutic agent as recited in claim 33. Additionally, Xu does not teach the lysosomal storage disease is Gaucher disease as recited in claim 21, and that the donor hematopoietic stem cells express functional glucocerebrosidase, encoded by the GBA1 gene as recited in claim 22.
Regarding claim 20, Capotondo teaches transplantation of purified HSPC to either naive or mice pre-treated with myeloablative agent (materials and methods section, HSPC transplantation, page 15023), to study the microglia reconstitution in CNS by the donor cells.
Regarding claim 31, Capotondo teaches the myeloablative conditioning comprising busulfan. Capotondo transplanted GFP+ HSPC after busulfan treatment, and illustrated successful ablation of endogenous microglia after busulfan treatment (Figs S6, page 7 of 13 in supporting information, section heading depletion of endogenous proliferation microglia and proliferation of donor cells in the brain are critical for microglia reconstitution, page 15020-15021, discussion, page 15022),
Regarding claim 32, Capotondo administered myeloablative/chemotherapeutic agents in a two- step transplant protocol in which the chemotherapeutic agents busulfan and treosulfan was used sequentially (Fig 3, page 15020, section heading depletion of endogenous proliferation microglia and proliferation of donor cells in the brain are critical for microglia reconstitution, page 15020-15021) in order to ablate endogenous HSPC before transplant.
Regarding claim 33, Capotondo teaches that the chemotherapeutic/ myeloablative agent busulfan is a brain penetrating (section heading macrophage/microglia replacement in the brain of preconditioned mice, paragraph 1, page1509), by stating that “treosulfan is the only regimen , among the tested ones , unable to cross blood brain barrier” , and busulfan is the other chemotherapeutic agent they used.
Regarding claim 20, Jayakumar teaches the correction of the enzymatic defect of the lysosomal storage disease, Gaucher with bone marrow derived donor cells taking up residency in CNS as microglial cells. The BMT-derived donor cells then secrete the required enzyme correcting the lysosomal storage disease (page 7, under the heading opportunities for therapeutic intervention) in claim 20.
Regarding claim 21, Jayakumar teaches the correction of the enzymatic defect of the lysosomal storage disease, Gaucher with bone marrow derived donor cells taking up residency in CNS as microglial cells.
Regarding claim 22, Jayakumar teaches that lack of glucocerebrosidase activity leads to accumulation of glucosylceramide, causing Gaucher disease (pages 3-4, cellular pathology). Jayakumar also teaches donor derived BMT which include HSPC takes up residency as microglia in the CNS and secrete the required enzyme which corrects the lack of glucocerebrosidase activity leading to the correction of the Gaucher disease (page 7, opportunities for therapeutic intervention).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the above-mentioned teachings of Xu that teaches the microglial replacement in mice with BMT which includes HSPC, and modify it with the teachings of Capotondo and Jayakumar that respectively teach the microglial replacement with purified HSPC, and the correction of enzymatic defect that corrects the lysosomal storage disease, Gaucher. One of ordinary skill in the art would have been motivated to combine the teachings of Xu, Capotondo and Jayakumar to successfully correct the lysosomal disease, Gaucher via microglial replacement therapy with purified HSPC . There’s reasonable expectation of success to combine the teachings of Xu, Capotondo and Jayakumar, because Xu teaches a method to replace 92.66% of endogenous microglia, while Capotondo and Jayakumar teaches that such effective replacement of endogenous microglia with purified HSPC will lead to correction of lysosomal storage diseases, including Gaucher.
Regarding the limitation of “wherein after step (iii) at least 50% of brain-resident microglial cells in the individual are derived from the donor HSC that correct the enzymatic defect of the lysosomal storage disease, for a period of at least ordinary art to expect that at least 50% of brain resident microglial cells will be of BMT origin for a period of 12 weeks post-transplant. Also, the combined teachings of Xu and Jayakumar teach the step of the independent claim 20, once administered the combined methods will successfully correct the lysosomal storage disease associated with microglia. Thus, the replacement of 92.66% of endogenous microglia over 8.5 weeks must be inherent to the method as taught by the Xu et al. and a necessary effect of practicing the method.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. and in view of Capotondo, et al., and Jayakumar et al., as applied to claims 20-22, 25, 26, 30-33 above, and further in view of Fomenko, Anton, and Andres M. Lozano. "Neuromodulation and ablation with focused ultrasound–toward the future of noninvasive brain therapy." Neural Regeneration Research 14.9 (2019): 1509-1510.
The teachings of Xu, Capotondo and Jayakumar are relied on above.
Xu, Capotondo and Jayakumar do not teach the use of guided ultrasound to ablate endogenous cells.
Regarding claim 34, Fomenko teaches the use of focused ultrasound that has high target specificity to ablate brain tissue ( paragraph 1, page 1509).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the above-mentioned teachings of Xu that teaches the microglial replacement in mice with BMT which includes HSPC, and modify it with the teachings of Capotondo and Jayakumar that respectively teach the microglial replacement with purified HSPC, and correction of enzymatic defect that corrects the lysosomal storage disease, and further modify their teachings with Fomenko that teaches the use of focused ultrasound with high target specificity to ablate the required endogenous brain tissue. One of ordinary skill in the art would have been motivated to combine the teachings of Xu, Capotondo, Jayakumar and Fomenko in order to optimize the specificity of the ablation process to facilitate the donor cell colony formation. There would be a reasonable expectation of success in administering non-myeloablative conditioning taught by Xu in combination with focused ultrasound treatment taught by Fomenko as both studies teaches the specific ablation of brain tissue which may minimize damage to surrounding tissues.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments filed 04/21/2026 have been fully considered but they are not persuasive.
Regarding the objection to drawings, applicant removed the reference to color made on some figures, but not all of it (see the objection to drawings). Therefore the objection to drawings is maintained.
Regarding 112b rejection on claim 20, preamble recites “A method for the replacement of endogenous microglial cells with CDMCs”, and the body of the claim recites the use of HSPCs to achieve the said replacement. Applicant argues that CDMCs are derived from HSPCs and they experimentally determined that HSCs derived CDMCs showed microglia-like morphology post transplantation.
Applicant’s argument is relied on experimental data/information that are not real limitations and therefore not a requirement in the claim 20, and is not persuasive. As such, the relationship from of CDMCs in the preamble and the body of the method is still not apparent. Therefore, the rejection is maintained.
Applicant argues that Xu doesn’t teach administration of purified HSCs to achieve repopulation of microglia. However, Capotondo teaches the use of purified HSCs to repopulate microglia after ablation. Therefore, the combined teachings of Xu, Captondo and Jayakumar teach all the limitations of the relevant claims as recited in the new 103 rejection in the final action.
Applicant further argues that claims 20-22, 25, and 26 are not obvious over Xu in view of Jeyakumar and further in view of Capotondo at least because the claimed invention achieves unexpected results. However, the unexpected results are drawn to limitations that are not recited in the claimed invention. Therefore, the obviousness rejection is maintained.
Regarding the 103 rejection on claim 34, applicant argues that Fomenko is directed to the use of focused ultrasound to ablate brain tissue and is silent on microglia. It is noted that the 103 obviousness rejection was made relying upon the combined teachings of Xu, Capotondo, Jayakumar and Fomenko. Applicant further argues that claim 34 is not obvious over Xu in view of Jayakumar and further in view of Fomenko at least because the claimed invention achieves unexpected results. However, the unexpected results are drawn to limitations that are not recited in the claimed invention. Therefore, the obviousness rejection is maintained.
Conclusion
No claim is allowed
THIS ACTION IS MADE FINAL. 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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/HASHANTHI KOMITIGE ABEYRATNE-PERERA/ Examiner, Art Unit 1632
/MARCIA S NOBLE/ Primary Examiner, Art Unit 1632
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