DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10 July 2025 has been entered.
Claim 66 is newly presented. Claims 1-24, 29, 30, 35, 37, and 63 remain withdrawn. Claims 25-28, 31-34, 65, and 66 are currently pending and under examination.
This Application is a national phase application under 35 U.S.C. §371 of International Application No. PCT/US2017/052022, filed September 18, 2017, which claims priority to U.S. Provisional Application No. 62/395503, filed September 16, 2016.
Maintained/Modified Rejections:
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.
Claims 25-28, 31-34, 65, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Ogimura et al. (IDS; Bile salt export pump inhibitors are associated with bile acid-dependent drug-induced toxicity in sandwich-cultured hepatocytes, Biochemical and Biophysical Research Communications, Vol. 426, (2011), pp. 313-317), and further in view of Demetriou et al. (US 2003/0049840; Published 2003 – Previously Presented).
With regard to claims 25, 27, 28, and 65, Ogimura et al. teach in vitro sandwich cultured, which is 2D cultured, hepatocytes, which is a hepatic cell system (HCS), comprising a capacity for bile acid synthesis, bile acid transport, and/or bile acid regulation; one or more bile acids with an established toxicity potency within the HCS; and an assay for determining the hepatotoxicity of a compound when exposed to the HCS in the presence of the one or more bile acids (Abs.; Fig. 1, 3).
Ogimura et al. do not specifically teach that the HCS includes a media comprising one or more free fatty acids and/or a predetermined glucose concentration.
Demetriou et al. teach a hepatocyte conditioning and cryopreservation medium, the medium including d-Glucose at 20 mM, which is a defined amount of glucose, and linoleic acid, which is a free fatty acid (Para. 22, 30; Ex. 1; Table 1).
It would have been obvious to one of ordinary skill in the art to combine the teachings of Ogimura et al. and Demetriou et al., because both teach hepatocyte culture. The use of hepatocyte culture components including glucose and linoleic acid is known in the art as taught by Demetriou et al. The use of the hepatocyte conditioning and cryopreservation medium of Demetriou et al., which includes a defined amount of glucose and/or linoleic acid in the culture system of Ogimura et al. would have predictably improved the system by allowing for the further advantageous use of conditioning and/or cryopreserving the hepatocytes.
Taken together, Ogimura et al. and Demetriou et al. render obvious the in vitro system as claimed, including the components as claimed. As such, the taught system is necessarily usable for predicting in vivo hepatotoxic potential of a compound, including for candidate pharmaceuticals to predict the potential for drug-induced liver injury (Abs.). Further, as Ogimura et al. and Demetriou et al. render obvious the in vitro system including an assay as claimed, including all structural components as claimed, the taught assay is necessarily configured to determine a potential of a compound to cause systemic and/or hepatic toxicity by (1) characterizing a compound as having a potential to cause cholestatic hepatic toxicity if the compound causes an increase in bile acid toxicity potency upon exposure of the compound to the HCS in the presence of the one or more bile acids; and (2) determining whether the compound is a bile acid efflux inhibitor, a farnesoid X receptor (FXR) antagonist, or combination thereof.
Additionally, as Ogimura et al. and Demetriou et al. render obvious the in vitro system including an assay as claimed, including all structural components as claimed, the taught assay is necessarily capable of being used to provide the result that an increase in a toxicity potency in the assay indicates a potential to cause cholestatic hepatoxicity, where a decrease in the toxicity potency in the assay indicates a potential to cause cholestasis resulting in systemic toxicity.
With regard to claim 26, Ogimura et al. teach that the in vitro HSC includes an integrated hepatic cell system with bile acid synthesis, transport, and bile acid homeostasis feedback mechanisms (Abs.; Fig. 1-4).
With regard to claim 31, Ogimura et al. teach that the in vitro HSC includes the bile acids: cholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid, ursodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurochenpodeoxycholic acid, taurolithocholic acid, and tauroursodeoxycholic acid (Abs.; Table 1).
With regard to claims 32-34, Ogimura et al. teach that the established toxicity potency of the bile acids comprises a toxicity profile of the bile acids based on a hepatotoxic response using a cytotoxicity assay, including an enzyme leakage assay, including LDH (p. 314, Right Col., 2.6, Para. 1; Table 1).
With regard to claim 66, Ogimura et al. do not specifically teach that the HCS includes a media comprising the one or more free fatty acids in an amount ranging from about 100 µm to about 2 mM.
Demetriou et al. teach that the medium includes 34 mM linoleic acid (Table 1). With regard to the term “about” Applicant indicates:
As used herein, the term "about," when referring to a value or to an amount of a composition, dose, sequence identity (e.g., when comparing two or more nucleotide or amino acid sequences), mass, weight, temperature, time, volume, concentration, percentage, etc., is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments +5%, in some embodiments +1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions (Specification, p. 6, line 34 to p. 7, line 5).
It is noted that the above passage does not narrowly define the term “about,” but instead provides for possible embodiments. As such, the range of “about” 100µM to “about” 2 mM is deemed to encompass 34 mM linoleic acid.
The rationale for the combination of Ogimura et al. and Demetriou et al. has been set forth previously.
Response to Arguments
With regard to the obviousness rejection over Ogimura in view of Demetriou, Applicant urges that these references fail to teach or suggest with a reasonable expectation of success the functions of the system as claimed. The system of Ogimura is not configured for measuring the disruption of bile acid regulation, and is different as shown by the data that different toxicity levels are found for the same compounds in each system. Demetriou discloses glucose and linoleic acid in aqueous cell preconditioning and cryopreservation medium, and there is no cell viability testing done without this media, so there is no way to tell if their presence in Ogimura’s system would have improved results. With regard to new claim 66, Applicant urges that linoleic acid is much more toxic than other fatty acids, and the high mM amounts of linoleic acid in the media in Demetriou would not be expected to benefit cell health, and would just be a confounding variable in hepatoxicity evaluation.
Applicant’s arguments have been fully considered, but have not been found persuasive.
With regard to Applicant’s argument that Ogimura is not configured for measuring the disruption of bile acid regulation, and is different as shown by the data that different toxicity levels are found for the same compounds in each system, it is noted 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’s argument that the system of Ogimura does not provide the noted function is not based on the combined system of Ogimura and Demetriou.
With regard to Applicant’s argument that Demetriou discloses glucose and linoleic acid in aqueous cell preconditioning and cryopreservation medium, and there is no cell viability testing done without this media, so there is no way to tell if their presence in Ogimura’s system would have improved results; Demetriou et al. teach a hepatocyte medium that clearly works for the intended purpose of being a conditioning and cryopreservation medium. The use of the hepatocyte conditioning and cryopreservation medium of Demetriou et al., which includes a defined amount of glucose and/or linoleic acid in the culture system of Ogimura et al. would have predictably improved the system by allowing for the further advantageous use of conditioning and/or cryopreserving the hepatocytes.
Taken together, Ogimura et al. and Demetriou et al. render obvious the in vitro system as claimed, including the components as claimed. As such, the taught system is necessarily usable for predicting in vivo hepatotoxic potential of a compound, including for candidate pharmaceuticals to predict the potential for drug-induced liver injury (Abs.). Further, as Ogimura et al. and Demetriou et al. render obvious the in vitro system including an assay as claimed, including all structural components as claimed, the taught assay is necessarily configured to determine a potential of a compound to cause systemic and/or hepatic toxicity by (1) characterizing a compound as having a potential to cause cholestatic hepatic toxicity if the compound causes an increase in bile acid toxicity potency upon exposure of the compound to the HCS in the presence of the one or more bile acids; and (2) determining whether the compound is a bile acid efflux inhibitor, a farnesoid X receptor (FXR) antagonist, or combination thereof. Additionally, as Ogimura et al. and Demetriou et al. render obvious the in vitro system including an assay as claimed, including all structural components as claimed, the taught assay is necessarily capable of being used to provide the result that an increase in a toxicity potency in the assay indicates a potential to cause cholestatic hepatoxicity, where a decrease in the toxicity potency in the assay indicates a potential to cause cholestasis resulting in systemic toxicity.
With regard to Applicant’s arguments about linoleic acid toxicity, it is noted that independent claim 25 does not require any specific free fatty acid in any specific amount, and also does not exclude any free fatty acid(s). As such, it appears that Applicant is indicating that the system as claimed is potentially not enabled with regard to the inclusion of any free fatty acid and concentration as currently claimed. Demetriou et al. teach a hepatocyte medium including 34 mM linoleic acid that clearly works for the intended purpose of being a hepatocyte conditioning and cryopreservation medium. Thus, an ordinary artisan would not expect linoleic acid, including 34 mM linoleic acid, to be toxic to hepatocytes.
Conclusion
No claims are allowable.
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/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653