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 .
Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 1/13/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of “the claims of Group I, including claims 1-4, 7-9, 13, and 15, drawn to a method for determining risk of a subject developing insulin resistance…[and] the following species: (a) CDH13 for the biomarker and measuring levels of mRNA, which reads on claims 1-4, 7-9, 13, and 15; (b) modifying diet of the subject to reduce carbohydrate intake for the pre-diabetic treatment, which reads on claims 2-4; (c) a thiazolidinedione for the treatment, which reads on claims 2-4; (d) obesity for the risk factor, which reads on claims 1-4, 7-9, 13, and 15; and (e) peripheral blood mononuclear cells (PBMCs) for the somatic cell, which reads on claims 1-4, 7-9, 13, and 15” in the reply filed on 4/15/2025 is acknowledged. The species election of: A particular pre-diabetic treatment or particular combination of pre-diabetic treatments remains withdrawn, as noted in the Office Action of 5/16/2025.
The species election of measuring levels of mRNA or protein as set forth in the Requirement for Restriction/Election of 2/21/2025 (relevant to claim 9) is withdrawn.
In the reply of 04/15/2025 Applicants elected the particular biomarker that is CDH13. The instant claims (the amended claims of 12/19/2025) require “two or more” of the recited biomarkers (i.e.: the claims require measurement of two or more biomarkers rather than one or more biomarkers in the amended claims entered on 1/13/2026). In the interests of customer service and compact prosecution, the claims are examined in so far as they are directed to combinations of two or more biomarkers that include the particular biomarker that is CDH13(i.e.: the two or more biomarkers required by the claims will include CDH13 and one or more of the other biomarkers listed) to remain consonant with the elected species.
Claims 1, 3-4, 7-9, 13, and 35-36 are pending and being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. Examples at least include the listing of references on pages 15 and 52-54. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The Remarks of 1/13/2026 do not acknowledge the lack of an IDS to cover references cited in the specification and no further IDS has been submitted, therefore all references not present on an IDS remain unconsidered unless cited by the examiner on form PTO-892.
Withdrawn Claim Rejections - 35 USC § 112b – Indefiniteness
The rejection of claims 1, 3, 4, 7-9, 13, 35 and 36 under 35 U.S.C. 112(b) as detailed in the Office Action of 9/19/2025 is withdrawn in light of Applicant’s amendments to the claims.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Amendments
Claims 1, 3-4, 7, 9, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Philippova et al. (European Heart Journal, 2012) in view of Gu et al. (European Heart Journal, 2015; cited on IDS of 4/29/2022), Belair et al. (Stem Cell Reviews and Reports, 2015), McKenna et al. (US 9217747 B2), and Kroder et al. (JCI, 1996).
Claim 1: Philippova et al. teach an in vitro method in which insulin resistance is studied in human endothelial cells (ECs), particularly in relation to the expression of T-cadherin (claim 1e, reads on CDH13; T-cadherin is another name for the CDH13 protein). More specifically, Philippova et al. teach that overexpression of CDH13 promotes insulin resistance in endothelial cells (claim 1f; Discussion, paragraph 1 and Figure S1). Additionally, Philippova et al. teach that the overexpression of CDH13 not only promotes insulin resistance, but results in a decrease in phosphorylated Akt (Figure 1) and a decrease in IRS1 expression (Figure 2B).
Claim 9: Philippova et al. generated a human EC line in which CDH13 was over-expressed, and measured CDH13 transcript levels via RT-PCR (reads on measuring a level of a mRNA; Abstract – Methods and results). Philippova et al. additionally measured levels of IRS1 expression via immunoblotting (reads on measuring a level of a protein; Figure 2).
While Philippova et al. teach measuring expression of CDH13, levels of phosphorylated Akt, and expression of IRS1 in ECs as discussed above, they do not teach measuring these biomarkers in IPSC-ECs (claim 1a-c and e). And while Philippova et al. do acknowledge that insulin resistance is closely associated with obesity and type 2 diabetes, they do not teach determining risk of developing insulin resistance in a subject with the risk factor of obesity (claim 7). However, generation of ISPC-ECs from somatic cells derived from subjects with obesity in the study of metabolic syndromes is known in the art, as taught by Gu et al.
Gu et al. teach a method in which culturing of IPSC-ECs is used to study the effects of obesity on endothelial cell function of a high-fat diet-induced obesity mouse model (DIO; Abstract). Gu et al.’s method involves harvesting of somatic cells (claim 1a; tail tip fibroblasts) from control and DIO mice, reprogramming (i.e., inducing) of these somatic cells into iPSCs (claim 1b), and then differentiation of the iPSCs into ECs (claim 1c; Results - Reprogramming of fibroblasts from control (i.e., reference) and diet-induced obesity mice into induced pluripotent stem cells; Control (i.e., reference) and diet-induced obesity induced pluripotent stem cells can be successfully differentiated into induced pluripotent stem cell-derived endothelial cells). Following generation of these iPSC-ECs, Gu et al. teach observation of endothelial cell dysfunction in the DIO-derived IPSC-ECs and measuring of the levels of expression of proteins involved in this metabolic syndrome and compare these to control IPSC-ECs (eNOS and iNOS; Results - Activation of Akt-endothelial nitric oxide synthase signaling pathway is suppressed in diet-induced obesity induced pluripotent stem cell-derived endothelial cells).
Gu et al. do not explicitly teach determining risk of developing insulin resistance using IPSC-ECs, but do acknowledge that the DIO mice had decreased insulin tolerance (Results - Reprogramming of fibroblasts from control and diet-induced obesity mice into induced pluripotent stem cells). Gu et al. also acknowledge the close association of insulin resistance, dysglycaemia, and obesity (Introduction - paragraph 1). Additionally, Gu et al. point out that obesity is “strongly linked to the progression of heart disease and type 2 diabetes” (claim 7; Introduction – paragraph 1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Philippova et al. (which teaches measuring levels of expression of CDH13 and IRS1 and levels of phosphorylated Akt in human ECs in the development of insulin resistance) to perform these measurements in cells derived from a subject at risk of developing insulin resistance such as IPSC-ECs derived from an obese mouse (as taught by Gu et al.). One would be motivated to measure these biomarker levels in IPSC-ECs due to the findings of Philippova et al. demonstrating how increased levels of expression of CDH13 lead to insulin insensitivity in human EC lines and were additionally associated with decreased levels of phosphorylated Akt and decreased IRS1 expression (claim 1f; Discussion, paragraph 1). One would be motivated to use IPSC-ECs from a subject rather than an EC cell line due to the advantages that IPSC-EC models offer. For example, Belair et al. teach that IPSC-ECs are a robust model with well-established methods of differentiation (Discussion, paragraph 1). Belair et al. teach that one would be motivated to use IPSC-ECs rather than primary ECs given that primary ECs often exhibit “tissue-specific heterogeneity” which complicates in vitro studies. Gu et al. indicate that IPSC-derived ECs navigate around the ethical and political concerns associated with using traditional sources of ECs from patients (Introduction, paragraph 2) and that the IPSC-ECs derived from obese individuals exhibited similar endothelial dysfunction as those seen in primary ECs (Results - Diet-induced obesity induced pluripotent stem cell-derived endothelial cells exhibit endothelial dysfunction phenotype in vitro). One would have a reasonable expectation of success given that Gu et al. successfully generated IPSC-ECs from somatic cells derived from mice and were able to measure expression levels of target proteins.
Philippova et al. in view of Gu et al. and Belair et al. do not teach administering a pre-diabetic treatment of diet modification or thiazolidinedione upon determining that the subject is at risk of developing insulin resistance (claims 1 and 3-4) or determining the risk of developing insulin resistance in a subject which is not exhibiting clinical symptoms of pre-diabetes or type 2 diabetes (claim 13).
However, administering pre-diabetic treatments (such as exercise and thiazolidinedione) to subjects at risk of developing insulin resistance and determining risk of developing insulin resistance in subjects that have not developed clinical symptoms is known in the art, as taught by McKenna et al.
McKenna et al. teach a method of measuring biomarkers in asymptomatic individuals to determine their risk for developing diabetes, pre-diabetes, or a pre-diabetic condition (claim 13, reads on subject has not yet developed clinical symptoms of pre-diabetes or type 2 diabetes; col 15, lines 5-10). McKenna et al. teach that insulin resistance refers to either a diabetic or pre-diabetic condition (col 20, ln 37). McKenna et al. teach that this method provides for prophylaxis (or pre-diabetic) treatment of someone at risk of developing a diabetic condition in which the subject is treated in order to “delay or prevent the onset of diabetes” (claim 1; col 10, ln 1-3). McKenna et al. teach that this treatment can comprise implementation of an exercise regimen and use of therapeutics such as metformin, troglitazone, and rosiglitazone (claims 3 and 4, exercise regimen reads on increasing amount of exercise of the subject and troglitazone and rosiglitazone read on a thiazolidinedione; col 26, ln 52-55 and col 3, ln 55-57, respectively).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Philippova et al. in view of Gu et al. and Belair et al. to administer pre-diabetic treatments such as exercise regimens and therapeutics (as taught by McKenna et al.). While McKenna et al. does not explicitly state that the exercise regimen would involve an increase in exercise, it is obvious to those of ordinary skill in the art that an exercise regimen being implemented as a pre-diabetic treatment would be an increase in the amount of exercise. One would be motivated to employ an exercise regimen and treat with a thiazolidinedione or metformin to prevent the onset of overt diabetes in those individuals determined to be at increased risk of developing insulin resistance. As taught by McKenna et al., modification of lifestyle such as an increase in exercise and treatment with therapeutics such as thiazolidinediones and metformin are known to improve or prevent/delay the onset of diabetes (McKenna et al., col 3, ln 55-57).
Philippova et al. in view of Gu et al., Belair et al., and McKenna et al. do not teach stimulating the IPSC-ECs with glucose and tumor necrosis factor-alpha (TNFα; claim 1d). However, stimulation of cells with glucose and TNFα is known in the art, as taught by Kroder et al.
Kroder et al. teaches examining the downstream signaling effects of treating cells with either TNFα or high glucose to study the mechanisms of each treatment in inhibition of insulin receptor signaling (Abstract). Kroder et al. teaches that TNFα and glucose modulate and promote insulin resistance by different mechanisms (Abstract). Kroder et al. also teaches treating cells with both TNFα and glucose together and that this combination “appears to cause a more pronounced inhibition of insulin and IRS-1 phosphorylation”, however the difference was not statistically significant and the data is not shown (pg 1474, col 2).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Philippova et al. in view of Gu et al., Belair et al., and McKenna et al. with the treatment of TNFα and glucose as taught by Kroder et al. One would be motivated to do so given the assertion by Kroder et al. that TNFα and glucose stimulate different downstream targets and lead to development of insulin resistance via fundamentally different mechanisms. Therefore, one skilled in the art would recognize that treating cells with both TNFα and glucose would provide more data on activation/inactivation of downstream targets. One would have a reasonable expectation of success given that Kroder et al. successfully treats cells with TNFα and glucose together (“A combination of TNF-a and glucose appears to cause a more pronounced inhibition of insulin and IRS-1 phosphorylation”; pg 1474, col 2), however this data is not presented.
Claim 3 is further rejected under 35 U.S.C. 103 as being unpatentable over Philippova et al. (European Heart Journal, 2012) in view of Gu et al. (European Heart Journal, 2015; cited on IDS of 4/29/2022), Belair et al. (Stem Cell Reviews and Reports, 2015), McKenna et al. (US 9217747 B2), and Kroder et al. (JCI, 1996) as applied to claims 1, 3-4, 7, 9, and 13 above, and further in view of Eikenberg and Davy (J Acad Nutr Diet, 2013).
The teachings of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. are detailed above. Relevant to the instantly rejected claims, Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. teach determining risk of developing insulin resistance in a patient and administering a pre-diabetic treatment such as dietary modification, exercise regimen, or therapeutics (McKenna, col 26, lns 52-57).
McKenna et al. does not explicitly teach that the dietary modification for treatment of pre-diabetes involves reducing carbohydrate intake (claim 3). However, it was known in the art that reducing carbohydrate intake was an effective treatment strategy of pre-diabetes, as taught by Eikenberg and Davy.
Eikenberg and Davy teach that low carb diets improve insulin sensitivity (Pathophysiology of Prediabetes, paragraph 3).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. to administer a pre-diabetic treatment such as reducing carbohydrate intake (as taught by Eikenberg and Davy). One would be motivated to employ a dietary modification such as reducing the intake of carbohydrates to prevent the onset of overt diabetes in those individuals determined to be at increased risk of developing insulin resistance. As taught by Eikenberg and Davy modification of diet to reduce carbohydrate intake improves insulin sensitivity and prevents/delays the onset of diabetes (Pathophysiology of Prediabetes, paragraph 3).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Philippova et al. (European Heart Journal, 2012) in view of Gu et al. (European Heart Journal, 2015; cited on IDS of 4/29/2022), Belair et al. (Stem Cell Reviews and Reports, 2015), McKenna et al. (US 9217747 B2), and Kroder et al. (JCI, 1996) as applied to claims 1, 3-4, 7, 9, and 13 above, and further in view of Churko et al. (Methods Mol Biol, 2013).
The teachings of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. are detailed above. Relevant to the instantly rejected claims, Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. teach using somatic fibroblasts to generate IPSCs. They do not teach using peripheral blood mononuclear cells (PBMCs) for generating IPSCs.
However, using PBMCs as the source for reprogramming into IPSCs was known in the art, as taught by Churko et al.
Churko et al. teach a method of obtaining PBMCs from a subject and reprogramming the cells into IPSCs (Abstract).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. to use PBMCs rather than fibroblasts (as taught by Churko et al.). One would be motivated to use PBMCs instead of fibroblasts due to the fact that obtaining blood rather than tissue from a subject is much more non-invasive and would increase patient willingness (in the case of humans) to donate a sample for testing, as taught by Churko et al. (Introduction – paragraph 3). One would have a reasonable expectation of success given that Churko et al. successfully isolate PBMCs from patient blood samples and reprogram them into IPSCs which can then be differentiated into a desired cell type for study.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Philippova et al. (European Heart Journal, 2012) in view of Gu et al. (European Heart Journal, 2015; cited on IDS of 4/29/2022), Belair et al. (Stem Cell Reviews and Reports, 2015), McKenna et al. (US 9217747 B2), and Kroder et al. (JCI, 1996) as applied to claims 1, 3-4, 7, 9, and 13 above, and further in view of Mathew et al. (Placenta, 2017) and Jonk et al. (Physiology, 2007).
The teachings of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. are detailed above. Relevant to the instantly rejected claims, Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. teach treating IPSC-ECs with glucose and TNFa and measuring expression levels of biomarker CDH13 and ISR1 and levels of phosphorylated Akt, wherein increased levels of expression of CDH13, decreased levels of phosphorylated Akt, and decreased levels of expression of ISR1 compared to a control indicates risk of developing insulin resistance.
Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. do not teach performing a tube formation assay following glucose and TNFa treatment. However, performance of tube formation assays to determine extent of endothelial dysfunction in cells is known in the art, as taught by Mathew et al.
Mathew et al. teach assessing endothelial dysfunction (in this case dysregulated angiogenesis) in cells which are also exhibiting insulin resistance by performing a tube formation assay (Materials and Methods, 2.11 In-vitro tube formation assay). Mathew et al. teaches that cells that exhibit an insulin resistant state present with a decreased capacity to form tubes in vitro, with decreased tube branch points and decreased tube lengths (“lesser percentage of the total master junction (Av: 53.1%; p value: 0.001), master segments length (Av: 61.3%; p value: 0.009), length (Av: 74.3%; p value < 0.01) and branching length (Av: 68.83%; p value: 0.02)”; Results – 3.9 Hampered in-vitro tube forming ability and Figure 4).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. to additionally perform a tube formation assay as taught by Mathew et al. One would be motivated to do so given the teaching of Mathew et al. that cells exhibiting decreased tube length and decreased branch points were also exhibiting an insulin resistant state. Additionally, Jonk et al. teach that “there is support for the suggestion that microvascular dysfunction precedes and even predicts the development of insulin resistance and Type 2 diabetes” (Microvascular Dysfunction and Insulin Resistance, paragraph 7). One would have a reasonable expectation of successfully applying this methodology to the IPSC-ECs taught by Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. given that Belair et al. successfully perform a tube formation assay using IPSC-ECs (Fig. 3).
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Philippova et al. (European Heart Journal, 2012) in view of Gu et al. (European Heart Journal, 2015; cited on IDS of 4/29/2022), Belair et al. (Stem Cell Reviews and Reports, 2015), McKenna et al. (US 9217747 B2), and Kroder et al. (JCI, 1996) as applied to claims 1, 3-4, 7, 9, and 13 above, and further in view of Mikkelsen et al. (Nature, 2008).
The teachings of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. are detailed above. Relevant to the instantly rejected claims, Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. teach using somatic fibroblasts to generate IPSCs. They do not teach that this results in a loss of epigenetic modifications that are present in the somatic cells
However, loss of epigenetic modification of somatic cells upon generation of IPSCs is known in the art, as taught by Mikkelsen et al.
Mikkelsen et al. teaches a method reprogramming somatic cells into IPSCs in which the somatic cells are treated with DNA methyltransferase inhibitors in the process of reprogramming into pluripotency (Abstract and Results-Inhibition of Dnmt1 accelerate reprogramming). Mikkelsen et al. teaches that this is necessary given findings that generation of IPSCs from somatic cells retains a residual epigenetic memory from the donor (Results-Inhibition of Dnmt1 accelerate reprogramming).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Philippova et al. in view of Gu et al., Belair et al., McKenna et al., and Kroder et al. to lose epigenetic modifications present in the somatic cells, as taught by Mikkelsen et al. One would be motivated to use Mikkelsen’s methodology given the assertion by Mikkelsen et al. that treatment with an inhibitor of Dnmt1 induces a “rapid and stable transition to a fully reprogrammed iPS state” (Results-Inhibition of Dnmt1 accelerate reprogramming). One would have a reasonable expectation of success given that Mikkelsen et al. applies this treatment to somatic cells that are being induced into pluripotency using the same induction method as Gu et al.
Response to Remarks
Applicant traverses the rejections of claims 1, 3-4, 7-9, 13, and 35-36 under 35 U.S.C. 103 on pages 7-14 of Remarks submitted on 1/13/2026 (hereinafter “Remarks”). Applicant’s arguments have been carefully considered but are not deemed persuasive for the following reasons.
In response to applicant's argument that the references fail to show certain features of the invention on page 9 of Remarks, it is noted that the features upon which applicant relies (i.e., testing potential to develop insulin resistance before clinical onset) are not recited in the rejected claim(s) until claim 13. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, as noted above, McKenna et al. does teach the benefits of testing individuals prior to clinical onset of symptoms and administering treatments.
Regarding Applicant’s arguments concerning “conventional diagnostics” and “prior work” (page 9 of Remarks), Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, Applicant should not merely rely upon counsel’s arguments in place of evidence in the record.
Applicant argues on page 9 of Remarks that none of the cited references teach a predictive approach. However, as noted above, McKenna et al. teach a method of measuring biomarkers in asymptomatic individuals to determine their risk for developing diabetes, pre-diabetes, or a pre-diabetic condition (including insulin resistance, col 15, lines 5-10). McKenna et al. teach that this method provides for prophylaxis (or pre-diabetic) treatment of someone at risk of developing a diabetic condition in which the subject is treated in order to “delay or prevent the onset of diabetes” (col 10, ln 1-3).
Applicant argues on page 9-10 of Remarks that Philippova does not teach or suggest measuring two or more biomarkers in IPSC-ECs derived from a subject nor does it indicate a risk of developing insulin resistance. This argument is in regards to a new limitation added after Final Rejection. As has been noted above in the modified 103 rejection, Philippova does in fact teach measuring two or more biomarkers from the group of biomarkers defined in claim 1 and demonstrates the association with insulin resistance. Philippova does not teach measuring these biomarkers in IPSC-ECs specifically, which is why claim 1 has been rejected as obvious in light of the teachings of all references presented and does not solely rely on the teachings of Philippova.
Applicant argues on page 10 of Remarks that “Philippova also fails to describe or suggest stimulating cells with glucose and TNF-alpha before measuring biomarkers”. 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). This limitation is addressed by Kroder et al., as described above.
Applicant argues on page 10 of Remarks that “Gu cannot make up for the deficiencies of Philippova because Gu also does not describe or suggest…measuring two or more biomarker levels in IPSC-ECs”. 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).
Applicant underscores “the fact that Gu is describing expression changes linked to obesity rather than susceptibility to insulin resistance” (page 10 of Remarks). This is noted in the 103 rejections above (Gu et al. do not explicitly teach determining risk of developing insulin resistance using IPSC-ECs, but do acknowledge that the DIO mice had decreased insulin tolerance). Additionally, Gu et al. is used as a reference for teaching generation of ISPC-ECs from somatic cells derived from subjects (for claim 1b-c) and specifically in doing so from subjects with one or more risk factors for developing insulin resistance, specifically obesity (claim 7).
Applicant argues on page 10 of Remarks that Gu “does not describe or suggest” stimulating the cells with glucose or TNF-alpha before measuring biomarkers. 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).
Applicant argues that the IPSC-ECs of Gu were significantly different than those of the claimed invention given that Gu detected significantly lower eNOS expression compared with control iPSC-ECs, whereas Applicants detected increased expression of eNOS in insulin-resistant IPSC-ECs. Again, it is reiterated that Gu was studying obesity-derived endothelial dysfunction, not specifically insulin resistance. Gu provides evidence that it was known in the prior art that somatic cells could be differentiated into IPSC-ECs, expression levels of proteins could be measured in them, and they were a valid choice for studying endothelial dysfunction related to diseases such as obesity, diabetes, and insulin resistance.
Applicant argues on page 11 of Remarks that McKenna et al. does not teach or suggest measuring two or more biomarkers from the listed biomarkers in claim 1 and does not describe or suggest stimulating cells with glucose and TNF-alpha before measuring said biomarkers. 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).
Applicant argues on page 11 of Remarks that Belair is silent in regards to the two or more biomarkers from the listed biomarkers in claim 1 and that Belair focuses on using IPSC-ECs for modeling blood vessel formation and does not mention insulin resistance or diabetes. 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). Additionally, Belair et al. teaches that it was known in the prior art that there were advantages for using IPSC-ECs as a model system given that they do not exhibit tissue specific heterogeneity and are well-defined.
Applicant argues on page 11 of Remarks that Kroder is silent in regards to the two or more biomarkers from the listed biomarkers in claim 1. 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).
Applicant argues on pages 12-14 that Eikenberg and Davy, Churko, Mathew and Jonk, and Mikkelsen “cannot fill the gaps” of Philippova in view of Gu, Belair, McKenna, and Kroder. However, as has been argued in the response to remarks and the rejection under 103 above, Philippova in view of Gu, Belair, McKenna, and Kroder teach all limitations of claim 1, therefore there are no gaps for these references to fill.
For these reasons, and the reasons presented in the 103 rejections above, all claims remain rejected.
Conclusion
No claims are allowed.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683