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 .
Response to Amendment
The amendment filed on 04/06/2026 has been received and entered into the application file.
Claims 14 and 16 have been cancelled; new claim 24 has been entered. Claims 13, 15, 18, 20-21, and 23-24 are pending and examined on the merits herein.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 13-16, 18, 20-21, and 23 under 35 U.S.C. 112(b):
The cancellation of claims 14 and 16 renders the rejections thereof moot.
The amendment to independent claims 13 and 15 in accordance with the suggestion set forth by the Examiner in the non-final Office action dated 01/05/2026 is sufficient to overcome the remaining rejections of record.
Accordingly, the rejections are withdrawn.
RE: Rejection of claims 13-16, 18, 20-21, and 23 under 35 U.S.C. 102(a)(2) over Gao:
The cancellation of claims 14 and 16 renders the rejections thereof moot.
Independent claims 13 and 15 have been amended to recite, “…wherein the hepatocyte is a pluripotent stem cell-derived hepatocyte…”.
Applicants assert Gao, et al. teaches away from employing hepatocytes differentiated from pluripotent stem cells such as iPS cells and ES cells and therefore, the presently claimed invention is non-obvious to a person having ordinary skill in the art in view of the Gao, et al. disclosure.
Respectfully, this argument is not found persuasive. The amended claims as currently written recite a pluripotent stem cell-derived hepatocyte. However, as evidenced by Biehl, et al., in natural mammalian development, pluripotent stem cells are present for a brief period in the embryo prior to differentiation into multipotent stem cells, with subsequent differentiation into even more restricted specialized cells (pg. 2; par. 1). That is to say, all primary hepatocytes, indeed all mammalian cells, are derived from pluripotent stem cells. Under broadest reasonable interpretation, the pluripotent stem cell-derived hepatocyte limitation is not restricted to induced pluripotent stem cells.
Accordingly, the remaining rejections of record are maintained. New grounds of rejection necessitated by amendment are additionally set forth below.
Claim Interpretation
The following comments are made to establish broadest reasonable interpretation for the record.
Regarding claims 13, 15: These claims contain the term “analogous substance”; specifically, “…analogous substance of the nicotinamide.” This term is interpreted as meaning functional analog; i.e., a molecule or compound that shares biochemical or pharmacological properties but is not necessarily similar in chemical structure.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 13, 15, 18, 20-21, and 23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Gao, et al. (WO 2019/185017), as evidenced by Biehl, et al. (J Cardiovasc Nurs. 2009).
Gao, et al. is in the Korean language. A translation is provided. Citations are made to the translated document. Gao, et al. teaches a culture medium for liver cell culture and liver organoid preparation (Abstract).
Regarding claims 13, 18, 20: Gao, et al. teaches a method for culturing hepatocytes (par. 0080), wherein the method uses a serum-free cell culture basal medium (par. 0007), wherein the culture medium further comprises a ROCK inhibitor, e.g., Y-27632, in the range of 0.5-50 µM (par. 0013) and nicotinamide in the amount of 1-50 mM (par. 0084); Gao, et al. further discloses an embodiment wherein the culture medium comprises 1-1000 ng/mL keratinocyte growth factor (par. 0012).
This reads on the method of maintaining and culturing a hepatocyte in a medium for culturing a hepatocyte, comprising a ROCK inhibitor and nicotinamide, wherein the medium does not contain a serum component, a content of an EGF receptor activating factor is less than 1 ng/mL, a content of an ALK inhibitor is less than 0.1 µmol/L, and a content of the ROCK inhibitor is 0.001 to 1000 µmol/L and a content of nicotinamide is 10 µmol/L to 1 mol/L limitation recited in claim 13; additionally, this reads on the wherein the medium does not contain the EGF receptor activating factor and does not contain the ALK inhibitor limitation recited in claim 18, as well as the wherein the ROCK inhibitor is Y-27632 limitation recited in claim 20.
Gao, et al. further teaches culturing primary hepatocytes in the medium for 14 days (par. 0157), further disclosing the organoids can be passaged and can be continuously cultured for at least 6 months without losing important characteristics (par. 0120); this reads on the a culturing period is one week or more limitation recited in claim 13. As evidenced by Biehl, et al., in natural mammalian development, pluripotent stem cells are present for a brief period in the embryo prior to differentiation into multipotent stem cells, with subsequent differentiation into even more restricted specialized cells (pg. 2; par. 1); i.e., primary hepatocytes are derived from pluripotent stem cells. Under broadest reasonable interpretation, the pluripotent stem cell-derived hepatocyte limitation is not unduly restricted to hepatocytes differentiated from induced pluripotent stem cells; thus, the primary hepatocytes of Gao, et al. reads on the wherein the hepatocyte is a pluripotent stem cell-derived hepatocyte limitation recited in claim 13.
Gao, et al. further discloses expression of CYP3A4 in the organoids (par. 0167), as well as albumin (par. 0006). Gao, et al. does not explicitly teach an increase in expression of CYP3A4 and albumin in the hepatocyte organoids compared to organoids cultured in a medium that does not contain a ROCK inhibitor or nicotinamide. However, where the claimed and prior art products are produced by identical or substantially identical processes, a prima facie case of anticipation has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. Thus, as Gao, et al. discloses a method comprising the same steps of the claimed method, an increased expression level of the recited metabolic markers is considered inherent, especially in the absence of evidence to the contrary.
Regarding claims 15, 21, 23: Following the above discussion, Gao, et al. additionally teaches the cell cultures of the disclosure may replace commercial primary liver cell lines for toxicity assays for drug development and drug screening (par. 0121); this reads on the method of producing a model for evaluating effects on a liver in drug discovery limitation recited in claim 15. Thus, this necessarily reads on the wherein the medium does not contain the EGF receptor activating factor and does not contain the ALK inhibitor limitation recited in claim 21, as well as the wherein the ROCK inhibitor is Y-27632 limitation recited in claim 23.
New Grounds of Rejection
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.
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.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Gao, et al. (WO 2019/185017), as evidenced by Biehl, et al. (J Cardiovasc Nurs. 2009).
The teachings of Gao, et al. are set forth above.
Regarding claim 24: Following the above discussion, Gao, et al. teaches an embodiment wherein the hepatocytes are seeded with extracellular matrix (ECM; “matrix glue”, see e.g. par. 0083) onto cell culture plates, such as 6-well plates and 24-well plates (pars. 0128, 0152); further disclosed is an embodiment wherein the ECM is a synthetic hydrogel matrix comprising collagen (par. 0083). This renders obvious the seeding hepatocytes on a plate coated with collagen limitation recited in claim 24.
EXAMINER’S COMMENT
In the interest of compact prosecution, the Examiner reiterates the invention of the instant application appears to differ from the teachings of Gao, et al. in that Gao, et al. teaches culturing hepatocytes for one week or more as organoids; i.e., 3D structures. As described by Applicants in pars. 0057, 0061, and 0066 of the instant specification, the hepatocytes were seeded on collagen-coated 96-well plates; Fig. 2 further illustrates 2D culturing of hepatocytes.
Claim 24 is directed to a method of culturing hepatocytes which comprises seeding hepatocytes on a plate coated with collagen. However, under broadest reasonable interpretation, this does not preclude seeding the hepatocytes then culturing under conditions in which they form organoids (e.g., the method of Gao, et al.). Again, it appears Applicants’ invention differs from that of Gao, et al. in that Applicants have demonstrated long-term 2D culturing of hepatocytes wherein the hepatocytes have remained in 2D culture (also known in the art as a monolayer) for 3 weeks (Fig. 2); i.e., a method of culturing hepatocytes according to the limitations of claims 13 or 15 wherein the method comprises long-term 2D culturing for 3 weeks, and wherein the hepatocytes remain in a 2D culture, or monolayer, is non-obvious over the Gao, et al. disclosure.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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