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 response filed 06/17/2026 has been received and entered. Claims 1-24 remain pending. Claims 1-8 and 23-24 are withdrawn from consideration, as being directed to a non-elected inventions. Claims 11-22 have been examined on the merits.
Claim Objections
Claims 19-21 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 17 and 18 are rejected under 35 U.S.C. 112(d)
Claims 17 and 18 have been amended to require an active step of inducing nephron progenitor cells from pluripotent stem cells. The amendments to the claims overcome the rejection of record.
The rejection over claims 17 and 18 is withdrawn.
RE: Rejection of claims 11, 12, 16-18, and 22 under 35 U.S.C. 102 over Nishinakamura
Claim 11 has been amended to require a medium that does not comprise growth factors other than FGF9 and/or FGF20.
The culture medium of Nishinakamura comprises BMP and LIF which reads on growth factors other than FGF9 and/or FGF20. Thus, the amendments to the claims overcome the rejection of record.
The rejection over claims 11, 12, 16-18, and 22 is withdrawn.
RE: Rejection of claims 11, 12, and 16-22 under 35 U.S.C. 103 over Nishinakamura in view of Sueta
Claim 11 has been amended to require a medium that does not comprise growth factors other than FGF9 and/or FGF20.
The culture medium of Nishinakamura comprises BMP and LIF which reads on growth factors other than FGF9 and/or FGF20. Additionally, Sueta does not disclose a method of culturing and expanding nephron progenitors in a medium comprising a GSK-3ß inhibitor, a ROCK inhibitor, and at least one FGF selected from FGF9 and FGF20 but not comprising any growth factors other than FGF9 and/or FGF20. Thus, the amendments to the claims overcome the rejection of record.
The rejection over claims 11, 12, and 16- 22 is withdrawn.
RE: Rejection of claims 11-18 and 22 under 35 U.S.C. 103 over Nishinakamura in view of Morizane and Oxburgh
Claim 11 has been amended to require a medium that does not comprise growth factors other than FGF9 and/or FGF20.
The culture medium of Nishinakamura comprises BMP and LIF which reads on growth factors other than FGF9 and/or FGF20. Additionally, Morizane and Oxburgh do not disclose a method of culturing and expanding nephron progenitors in a medium comprising a GSK-3ß inhibitor, a ROCK inhibitor, and at least one FGF selected from FGF9 and FGF20 but not comprising any growth factors other than FGF9 and/or FGF20. Thus, the amendments to the claims overcome the rejection of record.
The rejection over claims 11-18, and 22 is withdrawn.
Arguments are addressed insofar as they pertain to new rejections.
Applicants argue Morizane is directed to a differentiation protocol, not a long-term culture and expansion of NPCs.
In response, the argument has been fully considered but is not found persuasive. The claims recite “culturing cells obtained in [previous step]”. The cells being further cultured are not required to be undifferentiated.
Applicants further argue Oxburgh describes general nephron progenitor biology and signaling pathways but does not disclose the claimed method.
In response, the argument has been fully considered but is not found persuasive. A person of ordinary skill in the art would be able to use the teachings of Oxburgh as a motivation to modify a culture medium for culturing nephron progenitor cells.
New Rejections
Claim Rejections - 35 USC § 102
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 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.
Claims 11, 12, 16-18, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Taguchi et al (Cell Stem Cell, 2017).
Taguchi et al discloses a method for differentiating mouse embryonic stem cells (mESCs) to nephron progenitors. The method of Taguchi et al comprises steps of culturing mESCs on feeder cells to form embryoid bodies (EB). One day 2, the EBs were dissociated and reaggregated in serum-free differentiation medium comprising Activin A. On Day 3, the medium was switched to medium containing CHIR-99021. On day 4.5 the medium was replaced with medium containing Y27632 and CHIR-99021. On day 5.5, the medium was changed to medium containing Activin A, Bmp4, CHIR-99021, RA, and Y27632. On day 6.5, the medium was changed to medium containing CHIR-99021, Fgf9, and Y27632 (See Sec. NP lineage induction from mESCs and Fig. S4A). The resulting nephron progenitor cells were maintained in medium containing CHIR-99021, FGF9, and Y27632 until day 9.5 (See Fig. S4A). Taguchi et al further discloses forming kidney organoids from the mESC-derived nephron progenitors (See Sec. Kidney reconstitution by the differentially sorted progenitor fraction).
Taguchi et al further discloses a method for differentiating human induced pluripotent cells (hiPSCs) to nephron progenitors. The method comprises aggregating cells to form EBs in the presence of Y27632 and Activin A. On day 1, the spheres were transferred to U-bottom 96-well low cell-binding plates containing mesoderm-inducing medium with CHIR-99021 and Y27632. Subsequently, half of the culture medium was refreshed with new medium every other day (on days 3 and 5). On day 7, the medium was changed to ABC3R medium containing Activin A, Bmp4, CHIR-99021, Retinoic acid (RA), and Y27632. On day 9, the medium was changed to C1F medium containing CHIR-99021, Fgf9, and Y27632 (See Sec. NP lineage induction from hiPSCs).
For kidney organoid reconstruction experiments, the ABC3R medium culture was continued for 3 days, and on day 10 the culture condition was switched to modified C1F medium containing CHIR-99021, Fgf9, LDN193189, BMS493, and Y27632 for 3 days (See Sec. NP lineage induction from hiPSCs). On day 13, the nephron progenitor embryoid bodies were dissociated, centrifuged, washed, and further dissociated into single cell suspensions. The single cells were then resuspended in medium containing Y27632 and FGF9 (See Sec. Kidney reconstitution from the differentially induced human iNPs and iUB).
Regarding claims 11, 17, and 18: Taguchi et al discloses a method of producing nephron progenitor cells from mESCs comprising a final step of culturing the nephron progenitor cells in a medium containing CHIR-99021 (reads on a GSK-3ß inhibitor), FGF9, and Y27632 (Reads on a ROCK inhibitor) for three days. The step of culturing for three days reads on a method for culturing and expanding nephron progenitor cells in a medium comprising a GSK-3ß inhibitor, a ROCK inhibitor, and FGF9, and not comprising any other growth factors).
Taguchi et al additionally discloses a method of producing nephron progenitor cells from hiPSCs (reads on inducing the nephron progenitors from iPS cells) comprising a final step of culturing the nephron progenitor cells in a medium containing CHIR-99021 (reads on a GSK-3ß inhibitor), FGF9, and Y27632 (Reads on a ROCK inhibitor) for three days or CHIR-99021, Fgf9, LDN193189, BMS493, and Y27632 for 3 days. The step of culturing for three days reads on a method for culturing and expanding nephron progenitor cells in a medium comprising a GSK-3ß inhibitor, a ROCK inhibitor, and FGF9, and not comprising any other growth factors).
Regarding claim 12: Following the discussion of claim 11 above, Taguchi et al discloses collecting nephron progenitor EBs on day 13; dissociating the EBs into single cells, and resuspending the cells in medium which reads on subculturing the nephron progenitor cells.
Regarding claims 16: Following the discussion of claim 11 above, Taguchi et al discloses producing nephron progenitor cells from hiPSCs. Given that the nephron progenitors are differentiated from human iPSCs, the resulting nephron progenitors will be human nephron progenitors.
Regarding claim 22: Following the discussion of claim 11 above, Taguchi et al discloses forming kidney organoids from both mESC and hiPSC derived nephron progenitors which reads on a method for producing renal organoids comprising culturing and expanding the nephron progenitors according to claim 11 and differentiating the cultured and expanded nephron progenitors into renal organoids.
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.
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 11-13, 16-18, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Taguchi et al (Cell Stem Cell, 2017) in view of Morizane (Nature Protocols, 2017) and Oxburgh (US9752115B2).
The teachings of Taguchi et al are set forth above.
Taguchi et al anticipates claims 11, 12, 16-18, and 22.
Regarding claim 13: Taguchi et al discloses a method of culturing nephron progenitors in medium comprising CHIR-99021, Y27632, and FGF9 for 3 days.
Ta does not disclose the cells are cultured for 30 to 60 hours.
Morizane teaches a method of producing kidney organoids from IPS cells with an intermediate step of differentiating the cells to nephron progenitor cells (See pg. 15, Steps 21 – 23 A). The intermediate step comprises culturing nephron progenitor cells for 2 days. Morizane further teaches the cells should be fed every 2-3 days (reads on culturing 30 to 60 hours) or sooner if the medium becomes yellow.
Given that Taguchi et al teaches a method of culturing nephron progenitors and Morizane teaches culture medium used for culturing nephron progenitors should be changed every 2-3 days or when medium becomes yellow, it would have been prima facie obvious to optimize the length of time for which the cells or Taguchi et al are cultured and arrive at the claimed time of 30-60 hours through routine experimentation in order to prevent the medium from becoming yellow. Where the general conditions of a claim are disclosed in the prior art it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP2144.05(II).
Additionally, Taguchi et a does not teach further culturing the nephron progenitors in medium comprising FGF9 and a GSK-3ß inhibitor but not comprising a ROCK inhibitor.
Oxburgh teaches that without ROCK inhibition, cells form clumps and begin to differentiate See Col. 3, lns 5-12).
Morizane teaches culturing nephron progenitor cells in medium comprising CHIR99021 and FGF9 results in differentiation of the nephron progenitors to kidney organoids and renal vesicle structures (See steps 23A i-iv).
Given that Taguchi et al discloses a method of culturing nephron progenitor cells, Oxburgh teaches ROCK inhibition prevents nephron progenitors from differentiating, and Morizane teaches nephron progenitors can be differentiated to kidney organoids and renal vesicle structures in medium comprising CHIR99021 and FGF9, it would have been prima facie obvious to further culture the cells of Taguchi et al in a medium comprising CHIR99021 and FGF9, but not comprising a ROCK inhibitor, in order to further differentiate the nephron progenitors to renal vesicle structures. One would have been motivated to add a step of culturing in medium comprising CHIR99021 and FGF9 but not comprising ROCK inhibitor to the culture method of Taguchi et al in order to further differentiate the nephron progenitors. There is a reasonable expectation of success because Morizane teaches a method of differentiating nephron progenitor cells in a medium comprising CHIR99021 and FGF9 but not comprising ROCK inhibitor.
Claims 11-18 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Morizane (Nature Protocols, 2017), Oxburgh (US9752115B2), and Nishinakamura (WO2017010448A1).
The teachings of Taguchi et al, Morizane, and Oxburgh are set forth above.
Taguchi et al anticipates claims 11, 12, 16-18, and 22.
Taguchi et al, Morizane, and Oxburgh render claims 11-13, 16-18, and 22 obvious.
Regarding claim 14: Following the discussion of claims 1 and 13 above, Taguchi et al, Oxburgh, and Morizane teach a method of culturing nephron progenitors according to claim 13 to produce kidney organoids.
Oxburgh further teaches including a ROCK inhibitor in culture medium increases survival during plating (See Table 1).
Nishinakamura teaches a method of producing three-dimensional nephron structures (reads on kidney organoids) from nephron progenitors comprising steps of passaging the cells every 3-4 days (See English translation, pg. 10, Example 4).
Given that Taguchi et al, Oxburgh, and Morizane teach a method of producing kidney organoids in medium comprising CHIR99021 (reads on a GSK-3ß inhibitor) and FGF9, Nishinakamura teaches cells should be passaged every 3-4 days (reads on subculturing) during differentiation to kidney organoids, and Oxburgh teaches ROCK inhibitors increase survival during plating, it would have been prima facie obvious to passage the cells in medium comprising CHIR99021, FGF9, and a ROCK inhibitor in order to increase cell survival during passaging of the cells. One would have been motivated to use medium comprising CHIR99021, FGF9, and a ROCK inhibitor while replating the cells after passaging because Oxburgh teaches ROCK inhibitors increase survival during plating and CHIR99021 and FGF9 are used in medium for culturing kidney organoids. There is a reasonable expectation of success because Taguchi et al, Morizane and Nishinakamura disclose culturing nephron progenitors and differentiating the nephron progenitors in medium comprising CHIR99021 and FGF9 and Oxburgh teaches including ROCK inhibitors in culture medium increases survival.
Regarding claim 15: Following the discussion of claims 1, 13, and 14 above, Taguchi et al, Oxburgh, Morizane, and Nishinakamura teach a method of culturing nephron progenitors according to claim 14 to produce kidney organoids.
Taguchi et al does not disclose culturing the cells from step (C) for 30 to 60 hours.
Morizane teaches a method of producing kidney organoids from IPS cells with an intermediate step of differentiating the cells to nephron progenitor cells (See pg. 15, Steps 21 – 23 A). The intermediate step comprises culturing nephron progenitor cells for 2 days. Morizane further teaches the cells should be fed every 2-3 days (reads on culturing 30 to 60 hours) or sooner if the medium becomes yellow.
Given that Taguchi et al teaches a method of culturing nephron progenitors and Morizane teaches culture medium used for culturing nephron progenitors should be changed every 2-3 days or when medium becomes yellow, it would have been prima facie obvious to optimize the length of time for which the cells or Taguchi et al are cultured in and arrive at the claimed time of 30-60 hours through routine experimentation in order to prevent the medium from becoming yellow. Where the general conditions of a claim are disclosed in the prior art it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP2144.05(II).
Additionally, Taguchi et al does not teach further culturing the cells obtained in step (D) in medium comprising FGF9 and a GSK-3ß inhibitor but not comprising a ROCK inhibitor.
Oxburgh teaches that without ROCK inhibition, cells form clumps and begin to differentiate See Col. 3, lns 5-12).
Morizane teaches culturing nephron progenitor cells in medium comprising CHIR99021 and FGF9 results in differentiation of the nephron progenitors to kidney organoids and renal vesicle structures (See steps 23A i-iv).
Given that Taguchi et al discloses a method of culturing nephron progenitor cells, Oxburgh teaches ROCK inhibition prevents nephron progenitors from differentiating, and Morizane teaches nephron progenitors can be differentiated to kidney organoids and renal vesicle structures in medium comprising CHIR99021 and FGF9, it would have been prima facie obvious to further culture the cells of Taguchi et al in a medium comprising CHIR99021 and FGF9, but not comprising a ROCK inhibitor, in order to further differentiate the cells. One would have been motivated to add a step of culturing in medium comprising CHIR99021 and FGF9 but not comprising ROCK inhibitor to the culture method of Taguchi et al in order to further differentiate the nephron progenitors. There is a reasonable expectation of success because Morizane teaches a method of differentiating nephron progenitor cells in a medium comprising CHIR99021 and FGF9 but not comprising ROCK inhibitor.
Allowable Subject Matter
Claims 19-21 contain allowable subject matter but depend from rejected base claims. The claims would thus be allowable if written in independent form.
The following is a statement of reasons for the indication of allowable subject matter:
Claim 19 is drawn to a method of culturing and expanding nephron progenitor cells comprising steps of differentiating pluripotent stem cells to nephron progenitors.
Sueta et al (US20200248148A1) discloses a method of differentiating pluripotent stem cells to nephron progenitors comprising the following steps (See claims 13 and 18):
(i) a step of culturing pluripotent stem cells in a medium containing FGF2, BMP4, a GSK-3β inhibitor, and retinoic acid or a derivative thereof;
(ii) a step of culturing cells obtained in Step (i) in a medium containing FGF2, a GSK-3β inhibitor, and BMP7;
(iii) a step of culturing cells obtained in Step (ii) in a medium containing FGF2, a GSK-3β inhibitor, BMP7, and a TGFβ inhibitor;
(iv) a step of culturing cells obtained in Step (iii) in a medium containing FGF2, a GSK-3β inhibitor, BMP7, activin, and a ROCK (Rho-kinase) inhibitor;
(v) a step of culturing cells obtained in Step (iv) in a medium containing retinoic acid or a derivative thereof, and FGF9; and
(vi) a step of culturing cells obtained in Step (v) in a medium containing a GSK-3β inhibitor, a ROCK inhibitor, and FGF9, to induce renal progenitor cells from intermediate mesodermal cells.
The method of Sueta et al differs from the method for differentiating pluripotent stem cells to nephron progenitors recited in claim 19 in that step (iii) of Sueta et al requires FGF2 whereas claim 19 step (iii) of the instant application states the medium does not comprise FGF2.
There is no motivation to exclude FGF2 from step (iii) of Sueta et al because there is not a reasonable expectation that omitting a specific growth factor would result in production of the same nephron progenitor cells.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARISOL A O'NEILL whose telephone number is (571)272-2490. The examiner can normally be reached Monday - Friday 7:30 - 5:00 EST.
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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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