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 with traverse of Invention group 2, method of treating lysosomal storage disease, claims 20-22, in the reply filed on 10/22/2025 is acknowledged. New claims, 25-34, are considered under the invention group 2.
Applicants elected the species, donor hematopoietic stem cells with genetically corrected GBA1 locus .
Based on the results of the search, the species election requirement between the species of claim 22 has been withdrawn.
Claim 1, 15, 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species/invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on10/22/2025.
The traversal is on the grounds that there is not a serious burden on the examiner to search all of the claims together, and that there is a special technical feature shared between the groups. This is not found persuasive because as evidenced by the rejection below, the special technical feature was known in the art. Thus the groups do not contain a special technical feature which contributes over the prior art. In addition, while the groups may overlap in search, an overlapping search is not a coextensive search. As such a reference that anticipates one group may not anticipate or even make obvious the invention of another group.
The requirement for the restriction of Inventions group 1 and group 2 is still deemed proper and is therefore made FINAL.
Claims 20-22 and 25-34 are presented for examination on the merits.
Claim Status
Claims 20-22 and 25-34 are currently pending.
Claims 20-22 are amended.
Claims 1, 15 and 16 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/Invention, there being no allowable generic or linking claim.
Claims 2-14, 17-19 and 23-24 are cancelled.
New claims 25-34 have been added.
Claims 20-22 and 25-34 have been considered on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The disclosure is objected to because of the following informalities:
There is description of color in the Specification of fig.3 (page 4), fig 4 (page 5), fig6 (page7), fig 11 (page 8) and fig 12( pages 8, 9) 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 interpretation
Also, steps (i) and (iii) of the body of the claim 20 recites ablation steps and the claim language does not specify any order in which the steps 1-3 must be performed, see eMPEP section 2111.01 Plain meaning [ R-01.2024]“It is improper to import claim limitations from the specification”. eMPEP states in the same section that “Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order”. Therefore the claim was given the broadest possible interpretation of performing one ablation prior to transplantation, in view of prior art
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 20-22 and 25-34 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.
Regarding claim 20, the preamble recites a method of replacement of endogenous microglial cells with donor circulation-derived myeloid cells CDMC. However, the body of the claim recites the transplantation/infusion of hematopoietic stem or progenitor cells (HSPC), and not the transplantation of CDMC. Thus making the claim language unclear and failing to point and distinctly claim the subject matter recited in the independent claim 20.
Also, the claim language recites “efficient replacement of endogenous microglial cells”. The term “efficient” is a relative term in claim 20 which renders the claim indefinite. The term "efficient" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Also, there are two different step #1s recited in the body of the claim 20 indicated by the roman numeral (i). Where step (i) recites ‘performing hematopoietic stem or progenitor cell transplantation(HSPCT) by (i) ablation of endogenous HSPC’. The claim language fails to clearly and meaningfully recite the subject matter and one of ordinary skill in the art may not be able to understand the claimed subject matter, because transplantation and ablation serves two different purposes and one cannot transplant by ablation of endogenous cells alone.
Regarding claim 22, this claim recites that gene GBA1 encodes the enzyme galacto-cerebrosidase. It is known in the art, and also taught in Jayakumar et al. that GBA1 encodes the enzyme glucocerebrosidase and the defective enzyme causes the lysosomal storage disease, Gaucher. Reciting GBA1 encodes galacto-cerebrosidase makes the claim unclear and ambiguous, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claim 27, the claim language of the independent claim 20 points to two different steps of transplant. Step (i) and (ii) both refer to transplant 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.
Since claims 21, 25-26, and 28-34 depend from indefinite claim 20 and do not clarify the above points of confusion, claims) 21, 25-26, and 28-34 must also be rejected under 35 U.S.C. § 112, second paragraph.
Appropriate correction is required.
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 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Xu, Zhen, et al. "Efficient strategies for microglia replacement in the central nervous system." Cell reports 32.6 (2020) in view of Jeyakumar, Mylvaganam, et al. "Storage solutions: treating lysosomal disorders of the brain." 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 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 two weeks as recited in claim 20. Similarly, Xu does not teach the lysosomal storage disease is Gaucher disease as recited in claim 21. Additionally, Xu does not teach that the donor hematopoietic stem cells express functional glucocerebrosidase, encoded by the GBA1 gene as recited in claim 22
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).
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, this claim recites that gene GBA1 encodes the enzyme galacto-cerebrosidase. This was interpreted as a mistake (see the 112b rejection above), as it is known in the art, and also taught in Jayakumar et al. that GBA1 encodes the enzyme glucocerebrosidase and defective enzyme causes the lysosomal storage disease, Gaucher. 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 will 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, by ablating the endogenous microglia with CSF1R inhibitor (the microglial cell conditioning factor recited in the instant application) and infusing the mice with donor -derived BMCs, and modify it with the teachings of Jayakumar that teaches the microglial replacement with BMT to correct lysosomal storage disease, Gaucher, by correcting the associated enzymatic defect. One of ordinary skill in the art would have been motivated to combine the teachings of Xu and Jayakumar to successfully correct the lysosomal disease, Gaucher via microglial replacement therapy. There’s reasonable expectation of success to combine the teachings of Xu and Jayakumar, because Xu teaches a method to replace 92.66% of endogenous microglia and Jayakumar teaches that such effective replacement of endogenous microglia 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 two weeks”, Xu et al teaches that 30 days after recovery, an average 92.66% of endogenous microglia was replaced by the allotransplanted microglia-like cells expressing the microglia specific marker, Ionized calcium-binding adaptor molecule1 (IBA1) (pages 3-4, figs 2B-2D), the same marker recited in the specification to establish microglia-like morphology in the instant application. The replacement ratio of endogenous microglia by the BMT derived microglia was maintained 60 days (8.5 weeks) after the treatment ( description in page 3, figures S4A-S4E), and the study does not mention monitoring mice beyond 8.5 weeks post-transplant. Xu et al. also teaches that in 4 out of 11 investigated mouse brains had more than 99% of endogenous microglia replaced by allotransplanted cells (Fig 2D, page 4). Therefore it is reasonable for someone in the 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.
Claims 29-33 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. in view of Jayakumar et al., as applied to claims 20-22 and 25-26 above, and further in view of Capotondo, Alessia, et al. "Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation." Proceedings of the National Academy of Sciences 109.37 (2012): 15018-15023.
The teachings of Xu and Jayakumar are relied on above.
Xu and Jayakumar do not teach the administration of purified HSPC as recited in claim 29, 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.
Regarding claim 29, Capotondo teaches the administration of purified HSPC in order to restore the enzymatic defects associated with lysosomal storage diseases. Capotondo transplanted purified and transduced 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 30, Capotondo teaches the ablation of endogenous HSPC with myeloablative conditioning. Capotondo administered myeloablative agents in a two- step transplant protocol in which busulfan and treosulfan ( myeloablative agents) were 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) to ablate endogenous HSPC before transplant, in order to study the microglia turnover in the brain with the donor-derived 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 et al. 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.
Therefore, it will 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 is comprised of HSPC, by ablating the endogenous microglia with CSF1R inhibitor (the microglial cell conditioning factor recited in the instant application) and infusing the mice with donor -derived BMCs, and modify it with the teachings of Jayakumar that teaches the microglial replacement with BMT to correct lysosomal storage diseases by correcting enzymatic defects, and further modify their teachings with Capotondo that teaches the use of purified HSPC as donor cells in transplant, and the use of myeloablative conditioning to ablate endogenous cells such as busulfan and chemotherapeutic agents. One of ordinary skill in the art would have been motivated to combine the teachings of Xu, Jayakumar and Capotondo in order to increase the efficiency, safety and to minimize rejection of transplant with donor derived purified HSPCs, and to use myeloablative conditioning to completely ablate endogenous myeloid to minimize the chance of disease cells from repopulation. There would be a reasonable expectation of success in administering the myeloablative/chemotherapeutic agent busulfan to ablate endogenous microglia and purified donor HSPC to treat the lysosomal storage disease, because Capotondo illustrated the capability of busulfan to ablate endogenous microglia facilitating the reconstitution of microglia from donor -derived cells.
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. ., as applied to claims 20-22 and 25-26 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 and Jayakumar are relied on above.
Xu and Jayakumar do not teach the use of guided ultrasound to ablate endogenous cells as recited in claim 34.
Fomenko teaches the use of focused ultrasound that has high target specificity to ablate brain tissue ( paragraph 1, page 1509)
Therefore, it will 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 is comprised of HSPC, by non-myeloablation of the endogenous microglia with CSF1R inhibitor (the microglial cell conditioning factor recited in the instant application), in the absence of busulfan and infusing the mice with donor -derived BMCs, and modify it with the teachings of Jayakumar that teaches the microglial replacement with BMT to correct lysosomal storage diseases by correcting enzymatic defects, and further modify their teachings with Fomenko that teaches the use of focused ultrasound with high target specificity. One of ordinary skill in the art would have been motivated to combine the teachings of Xu, 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.
Conclusion
No claim is allowed
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/HASHANTHI KOMITIGE ABEYRATNE-PERERA/ Examiner, Art Unit 1632
/EMILY A CORDAS/ Primary Examiner, Art Unit 1632