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 .
Status of the Claims
Claims 1, 11-17, and 19-21 are currently pending.
Claims 1 and 11-13 are amended.
Claims 2-10 and 18 are cancelled.
New claims 19-21 have been added.
Claims 1, 11-17, and 19-21 have been considered on the merits.
Withdrawn Objections/Rejections
The objections made onto the specification are withdrawn in light of the amendments made onto the specification submitted on 05/11/2026.
The 112(b) rejections made onto claims 1-4 and 11-18 are withdrawn in light of the amendments submitted on 05/11/2026.
The 102 rejection made into claims 1-4 and 11-18 is withdrawn in light of the amendments submitted on 05/11/2026.
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.
Claims 1, 11, 13-17, 19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Journal of Hepatology, 2019), as evidenced by ThermoFisher (Technical document for DMEM/F12), in view of Zhang et al (Stem Cell Reports, 2018).
Regarding claim 1, Kim teaches a method for de-differentiating a terminally differentiated human cell into an induced multipotent endoderm stem cell (smEnSC) comprising the steps of culturing the differentiated cell in a culture system under a first culture condition including EGF, A83-01, and CHIR99021 (pg. 98, col. 1, last para; and pg. 98, col. 2, para 1). Kim teaches that the differentiated cell is an adult cell (pg. 98, col. 2, para 1). Kim teaches that the adult cell is a primary parenchymal hepatic cell (also known as a hepatocyte) taken from human patient’s liver (pg. 98, col. 2, para 1).
Regarding claim 1, Kim teaches that their culture system further comprises L-glutamine as evidenced by ThermoFisher. ThermoFisher teaches that the DMEM/F12 base media employed in Kim contains L-glutamine (see amino acid components list on pg. 1).
Regarding claim 11, Kim teaches that the smEnSCs show a homogenous epithelial-like cell morphology (see Fig. 1D), and that the cells are able to be expanded indefinitely in vitro (pg. 101, col. 2, para 1).
Regarding claims 13-15, Kim teaches that their method further comprises differentiating the smEnSC into an endoderm-derived cell, and wherein the endoderm-derived cell is a parenchymal hepatic cell (pg. 98, col. 2, last para spanning col. 1, para 1 of pg. 99).
Regarding claim 16, Kim teaches wherein the first culture condition comprises a first culture medium (pg. 98, col. 2, para 1).
Regarding claim 17, Kim teaches that the first medium is DMEM/F12 (pg. 98, col. 2, para 1).
Regarding claim 21, Kin teaches wherein the smEnSC co-express EpCAM and SOX9 (pg. 99, col. 2, para 3).
Kim does not teach that the culture system comprises Ascorbic acid phosphate magnesium, MTG and bFGF as required by claim 1. Kim does not teach that the smEnSC expresses CDX2 as required by claim 11.
However, Zhang also teaches the method of claim 1 employing a different starting material, in which an iPSC is cultured in a culture system under a first culture condition, wherein the culture system comprises EGF, A83-01, CHIR99021, Ascorbic acid, bFGF (FGF2), and monothiolglycerol (MTG) to form an smEnSC (Summary/abstract and pg. 791, col. 2, para 2).
Regarding claim 1, Zhang teaches that the cell culture system comprises the components EGF, A83-01, and CHIR99021 just as Kim above, and further includes Ascorbic acid, bFGF (FGF2), and monothiolglycerol (MTG) (pg. 791, col. 2, para 2).
Regarding claim 11, Zhang teaches that the smEnSC produced expresses CDX2 (Summary/abstract, pg. 781, col. 2, last para).
Regarding claim 19, Zhang teaches the full cell culture system as not comprising HGF by the omission of the inclusion of HGF (pg. 791, col. 2, para 2).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of producing smEnSCs as taught by Kim with the similar CDX2+ smEnSCs taught by Zhang to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Zhang also teaches the method of claim 1 employing a different starting material, in which an iPSC is cultured in a culture system under a first culture condition, wherein the culture system comprises EGF, A83-01 and CHIR99021 to form an smEnSC (Summary/abstract). One of ordinary skill in the art would have a reasonable expectation of success when combining Kim with Zhang because both produce the smEnSC using nearly identical methods.
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 12 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (Journal of Hepatology, 2019), as evidenced by ThermoFisher (Technical document for DMEM/F12), in view of Zhang et al (Stem Cell Reports, 2018), as applied to claims 1, 11, 13-17, 19, and 21, and in further view of Mizuguchi et al (US20120231490A1).
With regards to claims 12 and 20, the limitations of the independent claim 1 are taught above.
Regarding claim 12, Kim teaches that the smEnSCs demonstrate an upregulated SOX9 transcription factor (pg. 99, col. 2, para 3).
Regarding claim 20, Kim teaches wherein the SmEnSCs express SOX 17 (pg. 99, col. 2, para 3).
Kim does not teach that the smEnSC comprises upregulated transcription factors of FOXA1, TBX3, CEBPA, and PROX1 as required by claim 12. Kim does not teach that the smEnSCs also express FOXA1 as required by claim 20.
However, Mizuguchi teaches about genes/transcription factors which are involved in the differentiation of hepatocyte lineage cells.
Regarding claim 12, Mizuguchi teaches that FOXA1, TBX3, CEBPA, and PROX1 are involved in the differentiation of hepatocyte lineage cells ([0083]).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of producing smEnSCs as taught by Kim with the genes/transcription factors involved in hepatocyte lineage differentiation taught by Mizuguchi to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Mizuguchi teaches about genes/transcription factors which are involved in the differentiation of hepatocyte lineage cells ([0083]). One of ordinary skill in the art would have a reasonable expectation of success when combining Kim with Zhang because both concern the differentiation of hepatocyte lineage 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.
Response to Arguments
Applicant’s arguments, see Remarks, filed 05/11/2026, with respect to the rejections made under 35 U.S.C. 102 have been fully considered and are persuasive. The rejection of claims 1-4 and 11-18 has been withdrawn.
Applicant's arguments filed 05/11/2026 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 12) that Zhang fails to remedy the deficiencies of Kim regarding the newly added limitations of claim 1, that there would be no motivation to combine Kim with Zhang, and that Zhang does not teach limitations which Kim is relied upon to teach.
In response, the argument is not found persuasive. The combination of Kim and Zhang teach the limitations of independent claim 1.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of producing smEnSCs as taught by Kim with the similar CDX2+ smEnSCs taught by Zhang to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Zhang also teaches the method of claim 1 employing a different starting material, in which an iPSC is cultured in a culture system under a first culture condition, wherein the culture system comprises EGF, A83-01 and CHIR99021 to form an smEnSC (Summary/abstract). One of ordinary skill in the art would have a reasonable expectation of success when combining Kim with Zhang because both produce the smEnSC using nearly identical methods.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 13) that Mizuguchi does not teach the newly added limitations of claim 1 and that they do not suggest specific combinations of the transcription factors for which the expression profiles of the cells should contain.
In response, the argument is not found persuasive. The combination of Kim and Zhang teach the limitations of independent claim 1.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of producing smEnSCs as taught by Kim with the genes/transcription factors involved in hepatocyte lineage differentiation taught by Mizuguchi to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Mizuguchi teaches about genes/transcription factors which are involved in the differentiation of hepatocyte lineage cells ([0083]). One of ordinary skill in the art would have a reasonable expectation of success when combining Kim with Zhang because both concern the differentiation of hepatocyte lineage cells. Further, it would be obvious for a person of ordinary skill in the art to select smEnSCs based on the expression of any of the factors which Mizuguchi teaches because Mizuguchi teaches that they are known factors involved in the differentiation of hepatocyte lineage cells. Therefore, the argument is not found persuasive.
Conclusion
No claims are allowed.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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