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 .
Claims 1-11, 13-14, and 16-17, of record 11/25/2025, are pending and subject to prosecution. Claims 1-2, 8-9, and 16 are amended.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-3, 6-10, and 16 under 35 U.S.C. 103 over Yanagita et al. (WO 2011155641 A1), evidenced by Duffield (Journal of Clinical Investigation, 2014) and Kobayashi et al. (Journal of Clinical Investigation, 2016):
RE: Rejection of claims 1-10 and 16-17 under 35 U.S.C. 103 over Yanagita et al. (WO 2011155641 A1), evidenced by Duffield (Journal of Clinical Investigation, 2014) and Kobayashi et al. (Journal of Clinical Investigation, 2016), in view of Chambers et al. (Human Embryonic Stem Cell Protocols, 2013) and Levinson et al. (Seminars in Cell & Developmental Biology, 2003):
RE: Rejection of claims 1-3, 6-11, and 16 under 35 U.S.C. 103 over Yanagita et al. (WO 2011155641 A1), evidenced by Duffield (Journal of Clinical Investigation, 2014) and Kobayashi et al. (Journal of Clinical Investigation, 2016), in view of Kumar et al. (eLife, 2015):
RE: Rejection of claims 1-3, 6-10, 13, and 16 under 35 U.S.C. 103 over Yanagita et al. (WO 2011155641 A1), evidenced by Duffield (Journal of Clinical Investigation, 2014) and Kobayashi et al. (Journal of Clinical Investigation, 2016), further in view of Zhou et al. (American Journal of Physiology – Renal Physiology, 2010):
RE: Rejection of claims 1-3, 6-10, 13-14, and 16 under 35 U.S.C. 103 over Yanagita et al. (WO 2011155641 A1), evidenced by Duffield (Journal of Clinical Investigation, 2014) and Kobayashi et al. (Journal of Clinical Investigation, 2016), further in view of Zhou et al. (American Journal of Physiology – Renal Physiology, 2010), further in view of Murakami et al. (Pediatric Nephrology, 1997):
The applicant asserts that Duffield does not disclose any in vitro culture methods for obtaining or maintaining FOXD1+ stromal precursors or demonstrate that the precursors can be generated in vitro from neural crest cells under the conditions described by Yanagita et al. (Applicant Remarks, page 6). The applicant asserts that no evidence is provided to show that cultured neural cells inevitably pass through a FOXD1+, EPO- precursor state under the culture conditions of Yanagita et al. (Applicant Remarks, page 6). The applicant also asserts that the prior art do not teach a medium comprising FGF9 as required by the amended claims (Applicant Remarks, page 6-7).
In light of the applicant’s arguments and amendment to independent claims 1, 8, and 16 to require FGF9, the rejections are withdrawn. It is noted that amendment of the independent claims to require FGF9 is considered a new limitation, as previous versions of dependent claims listed FGF9 as an alternate option, reciting “further comprising a basic fibroblast growth factor and/or fibroblast growth factor 9’” in claims 2 and 9,
New Rejections
Claim Interpretation
The limitation “renal stromal cell” is interpreted as requiring cells that are express CD73, PDGFRβ, and EPO, consistent with ¶0071 of the instant application’s PGPub.
The limitation “renal stromal precursor” is interpreted as requiring cells that express FOXD1, CD73, and PDGFRβ but do not express EPO, consistent with ¶0073.
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.
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 1-3, 6-10, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagita et al. (WO 2011155641 A1), of record, in view of Duffield (Journal of Clinical Investigation, 2014), of record, Kobayashi et al. (Journal of Clinical Investigation, 2016), of record, and Barak et al. (Developmental Cell, 2012).
Regarding claims 1-3, 7-10, and 16: Yanagita et al. teach culturing neural crest cells in vitro to generate neural crest-derived EPO-producing cells, which can be fibroblasts (which read on “renal stroma cells”) (See ¶0007-0011). Yanagita et al. teach the neural crest-derived cells can be cultured in a medium comprising PDGF (which reads on “a platelet derived growth factor receptor agonist”) and bFGF to promote EPO production (See ¶0013). Yanagita et al. teach that neural crest-derived EPO-producing renal interstitial fibroblasts are positive for CD73 and PDGFRβ (See ¶0007-0011, and 0027). Yanagita et al. teach that neural crest-derived EPO-producing renal interstitial fibroblast cells generated can be encapsulated and transplanted into subjects with renal diseases such as renal failure or anemia (which reads on “a medicament” and “a medicament for the prevention or treatment of kidney damage”) (See ¶0020 and 0034).
Yanagita et al. do not expressly teach cultured “renal stromal precursors” in the method of culturing the “neural crest-derived EPO-producing renal interstitial fibroblasts” from neural crest cells or that the cultured cells are positive for CD73 and PDGFRβ. However, one of ordinary skill in the art would reasonably expect the EPO-producing cells resulting from the culture of neural crest cells to be positive for CD73 and PDGFRβ like the naturally occurring EPO-producing cells of the kidney taught by Yanagita et al. (See ¶0027).
Yanagita et al. also do not teach the status of FOXD1 expression in the cells or the addition of FGF9 to the culture medium.
Duffield teaches that neural crest lineage cells to give rise to FOXD1-positive stromal progenitor cells in vivo during differentiation to renal stromal cells, as revealed by fate-mapping studies (See page 2300, col. 1, full ¶3 and col. 2, ¶1-3 and fig. 2).
Kobayashi et al. teach that all EPO-producing cells share a common FOXD1-positive stromal progenitor (See page 1927, col. 2, ¶1).
Barak et al. examine the roles of FGF9 and FGF20 in embryonic nephron development and teach that the growth factors act redundantly to promote the proliferation, survival, and “stemness” of renal mesenteric progenitors (See Abstract and; page 1192, col. 1, full ¶2). Barak et al. suggest that stemness signals could be used to maintain and expand populations of multipotent renal stem cells in an artificial niche (See page 1191, col. 2, full ¶2 and page 1192, col. 1, ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Yanagita et al. to comprise the addition of FGF9 to the culture medium. One would have been motivated to do so because Barak et al. suggest that it could promote the growth and survival of renal progenitor cells in culture (See page 1191, col. 2, full ¶2 and page 1192, col. 1, ¶1-2), and such a modification could be readily made.
Because the teachings of Duffield and Kobayashi et al. indicate that EPO-producing renal stromal cells are derived from FOXD1-positive progenitors in vivo, one of ordinary skill in the art could reasonably infer that EPO-producing renal stromal cells generated in vitro also arise from a FOXD1-positive precursor.
Regarding claim 6: Following the discussion of claims 1-3, 7-10, 15-16, and 18-20, Yanagita et al. teach the generation of EPO-producing renal stromal cells but do not expressly teach the cells as producing EPO under hypoxic conditions.
Kobayashi et al. teach that renal stromal cells derived from FOXD1-positive stromal precursors produce EPO in response to hypoxic conditions (See fig. 2B). Kobayashi et al. are cited as evidence to show that production of EPO from renal stromal cells is an inherent response to hypoxia, and therefore, the neural crest-derived EPO-producing renal interstitial fibroblast cells of Yanagita et al. would also produce EPO in hypoxic conditions.
Claims 1-10 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagita et al. (WO 2011155641 A1), of record, in view of Duffield (Journal of Clinical Investigation, 2014), of record, Kobayashi et al. (Journal of Clinical Investigation, 2016), of record, and Barak et al. (Developmental Cell, 2012), further in view of Chambers et al. (Human Embryonic Stem Cell Protocols, 2013), of record, and Levinson et al. (Seminars in Cell & Developmental Biology, 2003), of record.
The teachings of Yanagita et al., Duffield, Kobayashi et al., and Barak et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 4-5 and 17: Following the discussion of claims 1-3, 6-10, and 16, Yanagita et al., modified by Duffield, Kobayashi et al., and Barak et al., render obvious a method for producing renal stromal cells. Yanagita et al. teach that neural crest cells can be induced from iPSCs (See ¶0007, 0018-0019, and 0034) but do not teach the use of a GSK3β inhibitor, a TGFβ inhibitor, and retinoic acid.
Chambers et al. teach the induction of neural crest cells and derivatives from human embryonic stem cells or iPSCs in medium comprising SB-431542 (which reads on “a TGFβ inhibitor”) and CHIR99021 (which reads on “a GSK3β inhibitor”) (See page 331-332 and 336-337, section 2.1-2.2 and 3.2). Chambers et al. also teach that the neural crest cells can be posteriorized (which reads on “hindbrain neural crest cells”) by addition of retinoic acid to the culture medium (See page 341, section 4).
Levinson et al. teach that retinoic acid is required in the embryonic kidney for branching morphogenesis and stromal cell differentiation (See page 227, col. 2, ¶1; page 228, col. 2, full ¶1; and fig. 5 and 7).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Yanagita et al., modified by Duffield, Kobayashi et al., and Barak et al., to comprise the induction method taught by Chambers et al. for generating neural crest cells from PSC. One would be motivated to make this modification because Chambers et al. teach it as a simple and efficient protocol for yielding neural crest cells from stem cells (See Abstract and page 330, full ¶3). One would also be motivated to add retinoic acid because Levinson et al. teach retinoic acid as necessary for proper kidney development during embryonic stages as well as for renal stromal cell differentiation (See page 227, col. 2, ¶1; page 228, col. 2, full ¶1; and fig. 5 and 7), which suggests that the presence of retinoic acid may confer a benefit for progenitor cells destined toward renal lineages. There would be a reasonable expectation of success in making this modification because Yanagita et al. teach that iPSCs can be used for producing neural crest cells (See ¶0007, 0018-0019, and 0034).
Claims 1-3, 6-11, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagita et al. (WO 2011155641 A1), of record, in view of Duffield (Journal of Clinical Investigation, 2014), of record, Kobayashi et al. (Journal of Clinical Investigation, 2016), of record, and Barak et al. (Developmental Cell, 2012), further in view of Kumar et al. (eLife, 2015), of record.
The teachings of Yanagita et al., Duffield, Kobayashi et al., and Barak et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 11: Following the discussion of claims 1-3, 6-10, and 16, Yanagita et al., modified by Duffield, Kobayashi et al., and Barak et al., render obvious renal stromal cells produced from culturing renal stromal progenitors with PDGF but do not teach the production of kidney organoids.
Kumar et al. teach the generation of kidney organoids from the culture of intermediate mesoderm-derived metanephric mesoderm cells, but not ESCs, with dissociated rat embryonic kidney cells (See fig. 9). Kumar et al. suggest that the cells must be more lineage-restricted than ESCs in order for organoids to form (See fig. 9). The majority of organoid-incorporated rat cells were stromal cells, as shown by expression of FOXD1 (See page 14, ¶1 and fig. 9).
It would have been obvious to modify the method of Yanagita et al., modified by Duffield, Kobayashi et al., and Barak et al., to comprise kidney organoid formation, such as is taught by Kumar et al., by combining mesenchymal cells with the stromal cells. One would be motivated to make this modification because Kumar et al. teach that the organoids can be used therapeutically or for research (See page 1, ¶1). There would be a reasonable expectation of success in making this modification because Kumar et al. demonstrate that intermediate mesoderm-derived cells and renal stromal cells can be co-cultured to form kidney organoids (See fig. 9). While Kuman et al. do not expressly teach the use of intermediate mesoderm itself in experiments, their results suggest that intermediate mesoderm could be sufficiently differentiated to enable organoid formation (See fig. 7 and 9).
Claim 1-3, 6-10, 13, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagita et al. (WO 2011155641 A1), of record, in view of Duffield (Journal of Clinical Investigation, 2014), of record, Kobayashi et al. (Journal of Clinical Investigation, 2016), of record, and Barak et al. (Developmental Cell, 2012), further in view of Zhou et al. (American Journal of Physiology – Renal Physiology, 2010), of record.
The teachings of Yanagita et al., Duffield, Kobayashi et al., and Barak et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 13: Following the discussion of claims 1-3, 6-10, and 16, Yanagita et al., modified by Duffield, Kobayashi et al., and Barak et al., render obvious renal stromal cells produced from culturing renal stromal progenitors with PDGF but do not teach use of the cells for assessing fibrosis.
Zhou et al. teach an in vitro assay to examine the effects of Smad pathway inhibition on aristolochic acid (which reads on “a substance that induces the fibrosis of the cells”)-mediated renal dysfunction (See Abstract). Tubular epithelial cells were treated with siRNA targeting Smad3 or the JNK inhibitor SP600125 (which read on “a test substance” and “a test substance that has reduced the degree of fibrosis of the cells”), and the cells were exposed to aristolochic acid (See page F1006, col. 2, full ¶4 and page F1007, col. 1, ¶1-2). The expression of α-SMA and collagen I mRNA was measured in aristolochic acid-treated and untreated cells (which reads on “measuring a degree of fibrosis of the cells… and selecting a test substance that has reduced the degree of fibrosis of the cells… cultured in the presence of the test substance as compared with the cell population cultured in the absence of the test substance”) (See fig. 7-9). Zhou et al. do not teach the use of renal stromal cells.
Duffield teaches that FOXD1-lineage stromal cells give rise to interstitial fibrogenic cells in kidney injury and chronic kidney disease (See page 2300, col. 1, full ¶3 and col. 2, ¶1-3 and fig. 2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Yanagita et al., modified by Duffield, Kobayashi et al., and Barak et al., to comprise using the renal stromal cells for assessing fibrosis-reducing agents. One would be motivated to make this modification because Duffield teaches stromal cells as relevant to interstitial renal fibrosis (See page 2300, col. 1, full ¶3 and col. 2, ¶1-3). There would be a reasonable expectation of success in doing so because the assays of Zhou et al. could be readily performed with the renal stromal cells of Yanagita et al., modified by Duffield, Kobayashi et al., and Barak et al.
Claims 1-3, 6-10, 13-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yanagita et al. (WO 2011155641 A1), of record, in view of Duffield (Journal of Clinical Investigation, 2014), of record, Kobayashi et al. (Journal of Clinical Investigation, 2016), of record, and Barak et al. (Developmental Cell, 2012), further in view of Zhou et al. (American Journal of Physiology – Renal Physiology, 2010), of record, further in view of Murakami et al. (Pediatric Nephrology, 1997), of record.
The teachings of Zhou et al., Duffield, Kobayashi et al., Barak et al., and Zhou et al. are set forth in the rejection above.
Regarding claim 14: Following the discussion of claims 1-3, 6-10, 13, and 16, Yanagita et al., modified by Duffield, Kobayashi et al., Barak et al., and Zhou et al., render obvious the generation of renal stromal cells and culturing in the presence of a substance that induces fibrosis but do not expressly teach the comparison of a substance in the culture medium to a substance in the body fluid of a mammal with renal fibrosis.
However, Zhou et al. teach the in vitro and in vivo use of aristolochic acid (which reads on “a substance that induces fibrosis of the cells”) to study the role of Smad3 in chronic nephropathy (See Abstract). Serum and urine from treated mice were analyzed for creatine and protein levels, respectively, and the expression of markers such as TGF-β in cultured cells was measured and found elevated (See fig. 1 and 5).
Murakami et al. teach that TGF-β (which reads on (a biomarker” and “a substance”) is secreted by various cells and suggest that renal interstitial cells (which read on “renal stromal cells”) secrete it in fibrotic disease (See page 334, col. 2, ¶1 and page 336, col. 1, full ¶1). TGF-β can be detected in urine (which reads on “a body fluid”) and that its levels are positively correlated with degree of renal interstitial fibrosis (See Abstract and page 334, col. 2, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the methods of Yanagita et al., modified by Duffield, Kobayashi et al., Barak et al., and Zhou et al., to comprise measuring and comparing urinary TGF-β with supernatant TGF- β following aristolochic acid treatment. One would be motivated to make this modification because Murakami et al. teach that TGF- β in urine correlates with renal fibrosis and suggest that TGF- β is secreted by interstitial cells (See Abstract; page 334, col. 2, ¶1-2; and page 336, col. 1, full ¶1). There would be a reasonable expectation of making this modification because TGF-β levels in urine and cell culture supernatants could be readily tested.
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.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633