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
Applicants’ response filed on 12/12/2025 has been received and entered in the application file.
Claims 13-16, 18, 20-21, and 23 are pending and examined on the merits herein.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 13-16 and 18-23 under 35 U.S.C. 102(a)(2) over Gao, et al.:
The cancellation of claims 19 and 22 renders the rejections thereof moot.
Applicants assert Gao, et al. does not teach the inclusion of a ROCK inhibitor and nicotinamide or analogous substance thereof. Respectfully, this argument is not found persuasive. Gao, et al. teaches a method for culturing hepatocytes using a serum-free cell culture basal medium (par. 0007) comprising a ROCK inhibitor (par. 0013) and nicotinamide (par. 0084).
Therefore, the remaining rejections of record are maintained.
RE: Rejection of claims 13-16 and 18-23 under 35 U.S.C. 103 over Kondo, et al., in view of Meng, et al.:
The cancellation of claims 19 and 22 renders the rejections thereof moot.
The amendment to independent claims 13 and 15 requiring a culturing period of one week or more is sufficient to obviate the remaining rejections of record as Kondo, et al. does not explicitly teach culturing the hepatocyte-like cells of the disclosure for a period of one week or more.
Therefore, the remaining rejections of record are withdrawn.
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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13-16, 18, 20-21, and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 13, 15: A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claims 13 and 15 recite the broad recitation “…in a medium for culturing a hepatocyte, comprising: one or more of a ROCK inhibitor, nicotinamide, and an analogous substance of the nicotinamide…”; the claims also recite “…the medium contains the ROCK inhibitor and the nicotinamide or the analogous substance of the nicotinamide…” which is the narrower limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For purposes of examination, the instant claims are interpreted as requiring both a ROCK inhibitor and nicotinamide or analogous substance thereof.
Claims 14, 18, 20-21, and 23 depend from claims 13 and 15, inherit the deficiencies, and are likewise rejected for indefiniteness.
In the interest of compact prosecution, the following claim amendments would overcome the instant rejections under 35 U.S.C. 112(b):
13. A method of maintaining and culturing a hepatocyte in a medium and nicotinamide[[,]] or an analogous substance of the 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,
a content of the ROCK inhibitor is 0.001 to 1,000 µmol/L, and/or a content of nicotinamide or analogous substance of the nicotinamide is 10 µmol/L to 1 mol/L,
a culturing period is one week or more, and
an expression level of at least one of CYP3А4, СҮР1A2, CYP2C9, СYP2C19 and albumin within cells after 48 hours of culture is increased compared to an expression level within cells cultured in medium lacking the ROCK inhibitor and the nicotinamide or the analogous substance of the nicotinamide.
15. A method of producing a model for evaluating effects on a liver in drug discovery, comprising culturing a hepatocyte in a medium and nicotinamide[[,]] or an analogous substance of the 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,
a content of the ROCK inhibitor is 0.001 to 1,000 µmol/L, and/or a content of nicotinamide or analogous substance of the nicotinamide is 10 µmol/L to 1 mol/L,
a culturing period is one week or more, and
an expression level of at least one of CҮР3А4, СYP1A2, CYP2C9, CYP2C19 and albumin within cells after 48 hours of culture is increased compared to an expression level within cells cultured in medium lacking the ROCK inhibitor and the nicotinamide or the analogous substance of the nicotinamide.
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 13-16, 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).
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.
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, the wherein the medium contains the ROCK inhibitor and the nicotinamide limitation recited in claim 22, as well as the wherein the ROCK inhibitor is Y-27632 limitation recited in claim 23.
Regarding claims 14, 16: Following the above discussion, Gao, et al. further teaches the hepatocyte as any cell isolated from the liver, e.g. a primary hepatocyte (par. 0081); this reads on the wherein the hepatocyte is a tissue-derived hepatocyte limitation recited in claims 14 and 16.
EXAMINER’S COMMENT
In the interest of compact prosecution, the Examiner notes 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 of the instant disclosure further illustrates 2D long-term culturing of hepatocytes at timepoints of 1 week and 3 weeks.
Conclusion
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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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633