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 .
Claim Status
Applicant’s submission file 12/15/2025 has been received and entered. No claim is cancelled, amended or new added. Claims 1-13 and 16-20 remain withdrawn as being directed to un-elected inventions. Accordingly, claims 25 and 30-31 are pending and under current examination.
Status of Prior Rejection/Response to Arguments
The objection to Abstract is withdrawn:
The objection to the abstract of the disclosure have been withdrawn due to applicant’s amendment the abstract and submitted as a single paragraph on a separate sheet as required.
The rejection to claims 25 and 30 under 35 U.S.C. 103 over Nakauchi et al. in view of Accili et al. is maintained:
The rejection to claims 25, 30 and 31 under 35 U.S.C. 103 over Nakauchi et al. in view of Accili et al., further in view of Teng et al. and Lu et al. is maintained:
Applicant traverses the rejection, asserting that the Office Action would have taught away from knocking out IGF1R gene or INR gene in a host embryo in a blastocyst complementation method (see Remarks, p7). The traversal is on the grounds that: 1) The Office Action does not provide any support that the INR gene was known to have the same function as the FGFR gene in blastocyst development. In addition, Accili taught that INR knockout animals died a few days after birth (Remarks, p7); 2) the teaching that IGFR knockout causes intrauterine growth retardation would have led the person of ordinary skill in the art to expect that an embryo would not develop sufficiently at all, rather than to expect that the blastocyst would develop except for a specific target organ or organs. This would have taught away from IGFR knockout. Therefore it could not have been predicted from the cited documents that such INR knockouts and IGFR knockouts could be successfully complemented in host embryos used in a blastocyst complementation method (Remarks, p7). Moreover, Applicant alleges that instant application has an unpredictable property (Remarks, p8).
Applicant’s argument is fully considered but not found persuasive. Regarding Applicant’s argument that there is no support that the INR gene was known to have the same function as the FGFR gene in blastocyst development, the Examiner submits that it is not required that the genes used in Nakauchi et al.’s blastocyst complementation method have to be the same function as FGFR gene. Instead, Nakauchi et al. teach the criteria of selecting a recipient which has a gene caused deficiency of organ(s): it is desirable to use an embryo derived from an animal which has an abnormality associated with a lack of development of the organ to be produced in a development stage, and whose offspring has a deficiency of the organ. As long as the animal develops such an organ deficiency, knock out animal having an organ deficiency as a result of the deficiency of a specific gene or a transgenic animal having an organ deficiency as a result of incorporating a specific gene may be used (see parag 0069). For instance, Nakauchi et al. also teach PdX1 gene, which has different function compared to FGFR gene. In addition, Applicant alleges the prior art teach away since Accili taught that INR knockout animals died a few days after birth. It is not persuasive since Nakauchi et al. teach Pdx1 knockout can’t survive homozygosity (die in approximately one week after birth) (see parag 0212), and Pdx1 can be used for the blastocyst complementation method. As long as the gene meets the criteria stated above is possible for use in the blastocyst complementation method.
Applicant further asserts that IGFR knockout causes intrauterine growth retardation would have led the person of ordinary skill in the art to expect that an embryo would not develop sufficiently at all, rather than to expect that the blastocyst would develop except for a specific target organ or organs. This would have taught away from IGFR knockout (Remarks, p7). However, this is not persuasive since intrauterine growth retardation is delayed growth but not stopped development. It's Applicant’s burden to explain how the IGF1R affects and/or stops the stage of embryo developing to blastocyst.
As stated in the Office Action mailed 08/14/2025, the Examiner submits that regarding instant claims, Nakauchi et al. teach when a pancreas is produced as the organ, embryos of a knockout animal having an abnormality associated with a lack of development of a pancreas in the development stage (such as Pdx1) can be used as the recipient non-human embryo (see parag 0070). Accili et al. teach INR may act as a growth factor, IGF1R may mediate the growth-promoting effects of insulin (p108, left column), homozygous INR knockout mice die shortly after born as a result of diabetic ketoacidosis (see p106, left column). The teachings above indicate that IGF1R or INR is affecting the development of a pancreas in the development stage, which has similar function with Nakauchi et al.’s genes for blastocyst complementation (e.g., lack of development of a single organ or multiple organs). Therefore one of ordinary skill in the art would have substituted Nakauchi et al.’s blastocyst complementation with knockout of genes such as Pdx1 or FGFR, and use the candidate genes such as IGF1R gene or INR gene with a reasonable expectation of success, since IGF1R gene or INR gene also be a good candidate for blastocyst complementation based on the reason above.
Moreover, Applicant alleges examples of the instant application provide evidence that the claimed non-human animal embryos with a IFGR gene knockout have an unpredictable property (Remarks, 8). It is not persuasive since Applicant fails to explain how the claimed invention has a superior result comparing to the closest prior art, which is Nakauchi et al.. Therefore the rejection is maintained.
Maintained Rejections
Maintained 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 25 and 30 stand rejected under 35 U.S.C. 103 as being unpatentable over Nakauchi et al. (US 2014/0338008 A1, published in 2014) in view of Accili et al. (Nat Genet., 1996; 12(1):106-9).
Nakauchi et al. teach a method for producing a target organ, using an induced pluripotent stem cell (iPS cell), in a living body of a non-human mammal having an abnormality associated with a lack of development of the target organ in a development stage, the target organ produced being derived from a different individual mammal that is an individual different from the non-human mammal (see Abstract).
Regarding claim 25, Nakauchi et al. teach in a blastocyst complementation method, a next generation is born when a deficiency of an organ, such as pancreas, is complemented by injection of induced pluripotent stem cells (iPS cells) into a developed blastocyst, and further discovered that a transgenic animal having the pancreas thus complemented can transmit its phenotype to the next generation as a founder (parag 0016). Nakauchi et al. teach Example 1, a mouse was selected to be a founder animal, and pancreas was selected as an organ to be defected. Further, for preparation of a knockout mouse that was characterized by pancreas deficiency, a Pdx1 gene was used (parag 0194). As a knockout mouse that was characterized by pancreas deficiency, Pdx1wt/LacZ and Pdx1LacZ/LacZ (founders) were used (parag 0196). An iPS cell or the like is injected into the thus obtained blastocyst under a microscope using a micromanipulator so as to complement a deficiency of pancreas (parag 0210). The embryo after the injection is transplanted into the womb of a surrogate parent, and thus a litter can be obtained. When double embryo manipulations are applied in which a transgene is introduced into an embryo and then an iPS cell is injected into the embryo, it is possible to complement a pancreas in the first generation transgenics (parag 0210). Nakauchi et al. teach in one embodiment, the iPS cell is derived from any one of a human, a rat, and a mouse (parag 0028). Herein the embryo after the iPS cell injection reads on “a non-human animal host embryo” in instant claim. It comprises: a) a genetically modified genome comprising a knockout of (Pdx1 gene herein); b) transplanted mammalian stem cells (iPS cells herein), wherein said non-human animal host embryo produces chimeric organs and tissue (complement a pancreas herein) comprising mammalian cells from the mammalian stem cells during development. Given that Nakauchi et al. teach using iPS cells for injection into an embryo to obtain a litter with chimeric pancreas, the iPS cells are considered as healthy and fully functional iPS cells with the inherent property that having a wild-type growth factor receptor gene which support the stem cells’ development and differentiation for obtaining a litter. This teaching reads on “transplanted mammalian stem cells having a wild-type growth factor receptor gene” in step (b) in instant claim.
Instant claim differs from Nakauchi et al. that instant claim teaches a knockout of an insulin-like growth factor 1 receptor (IGF1R) gene or an insulin receptor (INR) gene in the host non-human animal. In addition to Pdx1 gene, Nakauchi et al. also list some genes responsible for single organ or multiple organs development which have already been used or can be used for blastocyst complementation method. For example, embryos of a dominant negative-type transgenic mutant animal model which overexpresses the deficiency of an intracellular domain of fibroblast growth factor (FGF) receptor (FGFR), and which causes deficiencies of multiple organs such as kidney and lung, can be used (see parag 0070). Nakauchi et al. do not teach knocking out of an IGF1R gene or an INR gene in the non-human animal. However, this deficiency is cured by the teachings of Accili et al..
Accili et al. generated mice lacking insulin receptors by targeted mutagenesis in embryo-derived stem (ES) cells. Homozygous null mice develop severe hyperglycaemia and hyperketonaemia, and die as the result of diabetic ketoacidosis in 48-72 hours after birth (see Abstract).
Regarding claim 25, Accili et al. teach homozygous null mice of lacking insulin receptors can be generated, which develop severe hyperglycaemia and hyperketonaemia, and die as the result of diabetic ketoacidosis in 48-72 hours after birth (see Abstract). This teaching indicates the availability of insulin receptor knockout mice, and that insulin receptors as well as IGF1 receptors are critical to the embryo development.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Nakauchi et al.’s blastocyst complementation for Pdx1 gene knockout induced pancreas deficiency or a dominant negative-type FGFR induced deficiencies of multiple organs, and use IGF1R or INR as the candidate genes for the blastocyst complementation, as suggested by Nakauchi et al. and Accili et al.. The only difference between instant claim and Nakauchi et al.’s blastocyst complementation is instant claim uses a genetically modified genome comprising a knockout of an IGF1R gene or an INR gene. Given that Nakauchi et al teach reasoning of choosing a candidate gene such as Pdx1 or FGFR for blastocyst complementation (see parag 0070), Accili et al. teach the function of IGF1 receptor or insulin receptor (e.g., cause intrauterine growth retardation, see p108) and early neonatal death of insulin receptor knockout mice, which have similar function with Nakauchi et al.’s genes for blastocyst complementation (e.g., lack of development of a single organ or multiple organs), one of ordinary skill in the art would have substituted Nakauchi et al.’s blastocyst complementation with knockout of genes such as FGFR, and use the candidate gene such as IGF1R gene or INR gene, since IGF1R gene or INR gene also be a good candidate for blastocyst complementation based on the reason above. This simple substitution of one known element (blastocyst complementation combined with knockout of IGF1R gene or INR gene) for another known element (Nakauchi et al.’s blastocyst complementation combined with gene knockout with a gene such as FGFR gene) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 30, following the discussion above, for the iPSC used in the blastocyst complementation, Nakauchi et al. teach in one embodiment, the iPS cell is derived from any one of a human, a rat, and a mouse (parag 0028). The iPS cells derived from human are human stem cells.
Claims 25, 30 and 31 stand rejected under 35 U.S.C. 103 as being unpatentable over Nakauchi et al. (US 2014/0338008 A1, published in 2014) in view of Accili et al. (Nat Genet., 1996; 12(1):106-9), further in view of Teng et al. (Cell Transplantation, 2018, Vol. 27(9) 1313–1319) and Lu et al. (Ann Transl Med, 2019; 7(20):576, as cited in IDS).
The teaching of Nakauchi et al. and Accili et al. is set forth above.
Regarding claim 31, Nakauchi et al. in view of Accili et al. do not teach the mammalian stem cells are genetically modified to overexpress the IGF1R gene or the INR gene. However, the deficiency is cured by Teng et al. and Lu et al..
Teng et al. summarize the essential roles of insulin-like growth factor 1 receptor (IGF1R) signaling in self-renewal, pluripotency (or multipotency), and therapeutic efficacy of stem cells, including human embryonic stem cells, neural stem cells, cardiac stem cells, bone marrow mesenchymal stem cells, placental mesenchymal stem cells, and dental pulp mesenchymal stem cells (Abstract).
Lu et al. teach human-animal chimeras provide the ability to produce human organs in other species using autologous stem cells [e.g., induced pluripotent stem cells (iPSCs) or adult stem cells], which would be patient-specific and immune-matched for transplantation. Lu et al. review technological advances, including options of donor stem cell types and gene editing in donor cells and host animals, in addition to perspectives on human-animal chimeras in clinical and basic research (see Abstract).
Regarding claim 31, Teng et al. teach IGF1R is a cell surface receptor tyrosine kinase that can bind its cognate ligands IGF1 and IGF2 to activate two principle downstream signaling pathways – the phosphoinositide 3-kinase (PI3 K)/ AKT and the RAS/mitogen activated protein kinase (MAPK) pathways – to promote cell proliferation, differentiation, migration, and survival, and inhibit apoptosis (p1313, right column). Lu et al. teach the advantage of gene editing of stem/progenitor cells for chimera production (see p4): several recent studies demonstrated that the survival of injected stem cells is also crucial for chimerism. Both rat and human EpiSCs overexpressing anti-apoptotic genes (e.g., BCL2, BCL-XL, CRMA, BMI1, etc.) can form interspecies chimeras in mouse embryos (p4, right column). In addition, gene editing in injected stem cells may trigger directed differentiation and guide contribution to specific tissues or organs. For example, Mixl1-overexpressed ESCs or iPSCs tended to contribute to endodermal organs after blastocyst injection (p4, right column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Nakauchi et al. in view of Accili et al.’s blastocyst complementation by transplanting iPS cells in the blastocyst of IGF1R or INR gene knockout non-human animal host, and overexpress the IGF1R, due to the function of IGF1R in stem cells as taught by Teng et al. and the advantage of gene editing of stem cells for blastocyst complementation as taught by Lu et al.. The skilled artisan would have been motivated to overexpress IGF1R in mammalian stem cells since Lu et al. teach stem/progenitor cells overexpressing genes which are anti-apoptotic, inducing proliferation, or promoting differentiation is beneficial for chimera production in blastocyst complementation (p4, right column), and Teng et al. teach IGF1R gene can promote cell proliferation, differentiation, migration, and survival, and inhibit apoptosis (see p1313, right column), therefore overexpressing IGF1R gene in transplanted stem cells is helpful for improving stem cell survival and chimera production. There would be a reasonable expectation of success of overexpressing the IGF1R in stem cells since overexpressing a gene in the stem cells is known in the art and considered as a routine operation (e.g., by transfection or viral transduction).
Conclusion
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 QINHUA GU whose telephone number is (703)756-1176. The examiner can normally be reached M-F: 9:00 - 5:00.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699