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 following objection of record has been modified to take the amendments to the drawings into consideration.
Withdrawn Objections/Rejections
The objections to the specification are withdrawn as the amendments to the specification addresses the issues of the objection.
The rejection of claims 5-6 and 8-13, 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. The amendments to the claims overcome this rejection.
The rejection of claim(s) 1 and 4 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Studer (WO 2020/069515 A1 publication date:4/2/2020 and effectively filed:9/28/2018). A translation of the priority document was provided and thus Studer no longer serves as prior art under 102(a)(1).
Drawings
The drawings filed 12/0/2025 are objected to under 37 CFR 1.83(a) because they fail to show the following:
Color discernment in figure 1. Figure 1, as amended, was has legend boxes that appear to be different colors but cannot be discerned in the actual drawing because it is in black and white. The drawing was amended to show “mesendoderm induction” as a black box, and “Proliferative survival” as an asterisks. However, it is not apparent how to discern “Primitive hematopoietic patterning”. As such, the drawing are still objected to.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1 and 4, as amended or previously presented, are is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Studer (WO 2020/069515 A1 publication date:4/2/2020 and effectively filed:9/28/2018).
Regarding claim 1, Studer discloses contacting cells with compounds such as activators, inhibitors, inducer is done by contacting the cells with a medium comprising these compounds (p. 21, lines 11-20), teaching a medium composition as claimed. Studer discloses that suitable culture medium include but are not limited to neural basal medium supplemented with N2). See page 42, lines 6-10. Studer further discloses contacting with an inhibitor of Wnt signaling which can be XAV939, and at least one of BMP (e.g. BMP4) and activin (e.g. Activin A). See page 28, lines 19-30. XAV939 comprise the chemical structure of formula 1. As such, Studer discloses a medium comprising all of the requisite structural elements of the claimed medium composition.
Regarding claim 4, Studer discloses that in a second stage of culture, VEGF and FGF can be added (p. 33, line 29 to p. 34, line 2). As such, Studer discloses all the structural elements of the medium composition of claim 4.
Response to Arguments
Applicant's arguments filed 12/30/2025 have been fully considered but they are not persuasive.
Applicant submits that Studer does not disclose the claims as amended, particularly for inducing differentiation of microglia from yolk sac-mimic organoids. In response, the amendments to claim 1 and 4 further specify the intended use for the claimed medium composition but does not change the structural limitations of the claimed medium, which Studer expressly discloses. As such, Studer is still anticipatory prior art under 35 U.S.C 102(a)(2).
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.
Claim(s) 5-6 and 8-13, as amended or previously presented, is/are rejected under 35 U.S.C. 103 as being unpatentable over Muffat (Muffat et al. Nature Medicine. 2016. 22(11):1358-1367 and online methods pp. 1-2. Of record in IDS 6/16/2022) in further view of Studer (WO 2020/069515 A1 publication date:4/2/2020 and effectively filed:9/28/2018).
Regarding claim 5, Muffat teaches culturing human ES cells or human iPSC in suspension directly in NGD containing CSF1 and IL-34 (microglial differentiation medium) which lead to the formation of yolk-sac EB (YS-EB). These YS-EB are reported to have cells at island borders in 3D ropes that are for markers of early yolk sac myelogenesis before definitive hematopoiesis. This marker expression pattern is consistent with cells representing the in vitro counterparts of early haemogenic endothelia (i.e. hematopoietic precursor cells; see page 1 of online methods; p. 1359, col 1, induction of primitive microglia from human pluripotent cells). These teaching encompass a method of differentiating of microglia comprising preparing yolk sac-mimic organoids from human pluripotent stem cells.
Muffat does not teach culturing in a NGD medium comprising BMP4 and activin A with N2 supplementation and the compound of formula I (i.e. XAV939). However, Studer teaches a method of differentiating human stem cell, starting from human ES cell or human iPSC into microglia cells by differentiating the pluripotent cells into cells express primitive hematopoietic precursor cell markers and then stepwise differentiation to cell expressing microglial markers (p. 22, line 32 to p. 23, line 20). As discussed above in the 102 rejection, Studer teaches culturing the pluripotent cell derived primitive hematopoietic precursor cell in a medium that can be supplement with N2 supplement also comprising a wnt inhibitor, which can be XAV939, BMP4 and activin A (p. 28, line 19 to p. 31, line 31). Studer further teaches adding VEGF and FGF to the medium to further differentiate the cells to one expressing erythromyeloid progenitor markers and IL-34 and M-CSF to promoter microglia formation (p. 33-39). These disclosures comprise the limitations of the replacing an NGD medium as claimed and a method of differentiating microglia as claimed.
As such, it would have been obvious to an artisan of ordinary skill to choose the medium taught by Studer from a finite number of mediums that differentiate pluripotent cell derived primitive hematopoietic progenitor cells to microglia to use with the YS-EB derived from human pluripotent cells for production of microglia taught by Maffat to predictably arrive at the limitations of claim 5. An artisan would have a reasonable expectation of using the medium taught by Studer with the YS-EB taught by Maffat because Maffat the YS-EB of Maffat comprises the same starting material cells as Studer (i.e. cell expressing early primitive hematopoietic progenitor markers and cell of erythromyeloid progenitor lineage, all of which where differentiated from human pluripotent cells and Studer’s medium successfully differentiating the starting material cells of both Maffat and Studer to microglia as claimed. Thus Maffat in view of Studer render claim 5 obvious.
Regarding claim 6, Maffat in view of Studer teach the use of the NGD medium supplemented with N2 as discussed above.
Regarding claim 8, the media of Studer adds VEGF and FGF as discussed above.
Regarding claim 9, the media of Studer adds IL-34 and M-CSF as discussed above.
Regarding claim 10, the medium of Studer comprises TGF-beta as discussed above.
Regarding claim 11, since it is not apparent how wherein clause of claim 11 is intended to relate back to the method of the base claim and because it does not impart any active steps to the base claim method because it is a wherein clause, the claim will be interpreted as an capacity of the base claim method and not further limiting to the active method of the base claim. As such, Maffat in view of Studer render the claim obvious.
Regarding claim 12, Maffat and Studer are silent as to the CO2 content for incubator in which the cells were cultures. However, the CO2 content for human cell culture has been long and well established to be between 1-10%. As such, an ordinary artisan would only need to use routine optimization of CO2 content in the incubator in the combined methods of Maffat and Studer to arrive at the limitation of claim 12.
Regarding claim 13, the claims does not specify from what the cell sorting is not separate and both Maffat (p. 3 of online methods) and Studer teach the use of cell sorting in their methods (for example page 34). As such Maffat in view of Studer render claim 13 obvious.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and E are applicable. The claimed method was known in the art at the time of filing as indicated by Maffat in view of Studer. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Response to Arguments
Applicant's arguments filed 12/30/2025 have been fully considered but they are not persuasive.
Applicant submits that Applicant submits that Muffat describes differentiation of microglia from human stem cells via embryoid bodies formed in NGD medium containing CSF-1 and IL-34, not from yolk sac mimic organoids derived from human pluripotent stem cells. Applicant submits that Muffat does not teach organoid formation because EB represents general early 3D cell aggregates of stem cells, whereas organoids are miniaturized organ-like structure capable of mimicking specific organ function.
In response, Muffat does expressly discloses the formation of yolk-sac EB which are expressly described as having cells at island bordered in 3D ropes that are markers of early yolk sac myelogenesis before definitive hematopoiesis (see rejection reiterated above). As such, yolk-sac EB of Muffat are not solely an aggregate of stem cells but rather comprise yolk-sac organ like structures and markers. Further the amendment to the claims state that the organoids are derived from pluripotent stem cells, which Muffat discloses, and that the EB differentiate into a YS-EB as they call it or an YS organoid as claimed. Thus the teachings of Muffat expressly teach the limitations of preparing yolk sac-mimic organoids derived from human pluripotent stem cells.
Applicant submits that Muffat does not teach producing the yolk sac organoid in NGD medium as claimed and neither does Studor. As such, an artisan would have no motivation to combine these prior art teachings. In response, the rejection expressly states that Muffat does not teach YS organoids prepared and cultured in NGD medium. However Studor does teach the claimed medium from differentiating pluripotent stem cell EB to microglia cells and is capable of differentiating EB down a microglia lineage pathway. An artisan thus would have a reasonable expectation of using the medium taught by Studer with the YS-EB taught by Maffat because Maffat the YS-EB of Maffat comprises the same starting material cells as Studer (i.e. cell expressing early primitive hematopoietic progenitor markers and cell of erythromyeloid progenitor lineage, all of which where differentiated from human pluripotent cells and Studer’s medium successfully differentiating the starting material cells of both Maffat and Studer to microglia as claimed.
Applicant further submits that it was unexpected that the claimed method would result in a large quantity of microglia. The present invention enables the formation of yolk sac-mimic organoids from hESCs and subsequent large scale production therefrom. In response, while the claim recites to “obtain a large quantity of microglia” in the preamble as an intended result. The claim does not further specify what would be considered a large quantity. As such, a large quantity can be any quantity because any amount is larger than zero. As such the breadth of the claims merely encompasses the intended result of producing microglia from the YS-EB of Muffat already demonstrated to produce microglia by placing it in a medium taught by Studer that is also taught to produce microglia.
Applicant submits that there method produces 4 times more microglia cells than Muffat and 30-40 times more compared to Abud. These results demonstrate superior efficiency of the present invention in generating large quantities of function microglia. In response, the claims do not require “a large quantity” to be any particular amount and the term large quantity is relative language. The claim does not specify a reference point that define “a large quantity”. As such, any amount of microglia formation can be considered a large quantity relative to zero microglia cells. As such, the breadth of the claims are encompassed by the combined teaching of Muffat and Studer.
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632