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 .
DETAILED ACTION
Claim status
Claims 1-12, 14-16 are pending
Claims 14 is withdrawn
Claims 1-12, 15-16 are under examination
Election/Restrictions
Applicant’s election of the following invention without traverse in the reply filed on 1/28/2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Group I, claims 1-12, 15-16, drawn to methods of culturing human hepatic cells in media.
Claim 14 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 7/11/2023, 12/27/2024, and 1/14/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
However, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 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.
Objection to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code ([0030]). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “www” can be replaced with “world wide web” as the URL code. See MPEP § 608.01.
Claim Objections
Claim 16 is objected to because of the following informalities: instant claim uses the preamble phrase to produce “a medium”, which is dependent on Claim 15 directed to culturing cells in “a medium”. Although it is clear that the medium of Claim 16 is different from the medium of Claim 15, it is recommended to term the media of Claim 16 as a “mixed medium”.
Claim Rejections - 35 USC § 112(b)
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.
Claim 16 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
At issue for the instant case is that claim 16 recites mixing “a” culture supernatant produced by 15, and should recited “the” culture supernatant for proper antecedence.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(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 15-16 rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Vallier et al. (WO2020/030822, filed 8/12/2019, published 2/13/2020).
With respect to claim 15, Vallier teaches methods of producing a cell culture supernatant of human hepatoblasts, the methods comprising:
culturing the human hepatoblasts in culture media comprising a WNT signaling promoter, the mitogenic growth factor EGF, a ROCK inhibitor, and a TGF-beta inhibitor (Abstract, p. 6, line 21 to p. 10, 7th para., see also Claims 1 and 6 of Vallier), and
separating a supernatant from the medium after the culturing. Specifically, Vallier teaches media is change every two days and cells are allowed to settle by gravity (p. 10, 7th para.).
Not that the term “nonparenchymal” is being interpreted as excluding hepatocytes. Furthermore, “nonparenchymal” cells may include not only cholangiocytes, but also their progenitors (i.e., hepatoblasts), and mixtures thereof.
With respect to claim 16, as stated supra, Vallier teaches media is change every two days, which would involve a step of mixing any remaining culture supernatant of the human hepatoblasts with fresh hepatoblast media comprising the WNT signaling promoter and mitogenic growth factor.
Accordingly, Vallier anticipates instant claims.
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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Ortega (US2018/0066233, filed 7/31/2017, published 3/08/2018 see IDS 7/11/2023), in view of Gupta et al., (US2015/0166953, filed 6/27/2013, published 6/18/2015).
Ortega teaches methods of expanding and differentiating human hepatocytes in one or more culture media, wherein at least one of the culture media comprises the conditioned media of other cells, a Wnt signaling promoter and a mitogenic factor ([0013, 0075, 0084, 0097-0098, 0243, 0330, 0334, 0348], Examples 3 & 9, Fig. 11).
However, Ortega is silent with respect to culturing the human hepatocytes in a medium comprising the culture supernatant of a human hepatic nonparenchymal cell.
Gupta teaches methods of culturing human hepatocytes and media for hepatocyte differentiation comprising the culture supernatant from fetal human hepatoblasts (Summary of the Invention, [0020-0025], see Claims 1, 2, and 6 of Gupta).
Not that the term “nonparenchymal” is being interpreted as excluding hepatocytes. Furthermore, “nonparenchymal” cells may include not only cholangiocytes, but also their progenitors (i.e., hepatoblasts), and mixtures thereof.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice the method of culturing human hepatocytes in a medium for human hepatocyte development in liver organoids as taught by Ortega, and combine the culture supernatant of a human fetal hepatoblast as taught by Gupta with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Gupta because the conditioned media from human fetal hepatoblast can induce the differentiation of hepatocytes in the mixed liver organoid cultures of Ortega.
In regard to claim 2, Ortega teaches the Wnt singling promoter is Wnt family protein ([0075, 0084, 0097-0098, 0243, 0334], Example 3).
In regard to claim 3, Ortega teaches the Wnt singling promoter further comprises Rspondin1 ([0097-0098, 0243, 0334], Example 3).
In regard to claim 4, Ortega teaches the mitogenic factors are one or more selected from the group of EGF, FGF, and HGF ([0097-0098, 0243, 0334], Example 3).
In regard to claims 5 and 6, Ortega teaches the media can further contain the ROCK inhibitor Y-27632 ([0050]).
In regard to claims 5 and 7, Ortega teaches the media can further contain the TGF-beta inhibitor such as A83-01 ([0330], Example 3, see also Table 1, p.10).
In regard to claims 5 and 8, Ortega teaches the media can further contain the IL-6 family member oncostatin M (see Table 2).
In regard to claim 9, Ortega teaches the media further comprises nicotinamide ([0097-0098, 0243, 0334], Example 3)
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 10-12, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ortega (US2018/0066233, filed 7/31/2017, published 3/08/2018 see IDS 7/11/2023), in view of Gupta et al., (US2015/0166953, filed 6/27/2013, published 6/18/2015), as applied to claim 1, in further view of Vallier et al. (WO2020/030822, filed 8/12/2019, published 2/13/2020)
Ortega in view of Gupta suggests methods of expanding and differentiating human hepatocytes in one or more culture media, wherein at least one of the culture media comprises the conditioned media of human fetal hepatoblasts, a Wnt signaling promoter and a mitogenic factor.
However, although Gupta contemplates culture conditions for expanding the subculture of human fetal hepatoblasts [0054], they are silent to including a WNT signaling promoter, the mitogenic growth factor EGF, a ROCK inhibitor, and a TGF-beta inhibitor in the human fetal hepatoblast culture media.
With respect to claims 10-12, and 15, Vallier teaches methods of culturing human hepatoblasts in culture media comprising a WNT signaling promoter, the mitogenic growth factor EGF, a ROCK inhibitor, and a TGF-beta inhibitor (Abstract, p. 6, line 21 to p. 10, 7th para., see also Claims 1 and 6 of Vallier).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice the method of culturing human hepatocytes in a liver organoid in a media comprising the supernatant of subcultured human fetal hepatoblasts as suggested by Ortega in view of Gupta, and combine a WNT signaling promoter, the mitogenic growth factor EGF, a ROCK inhibitor, and a TGF-beta inhibitor in the subculture media of the human hepatoblasts as taught by Vallier with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Vallier so as to promote expansion of the human hepatoblasts (Abstract).
Furthermore, in regard to claim 15, Gupta teaches isolating the conditioned medium obtained from the subculture of hepatoblasts [0028], thus it would have been obvious to include a sedimentation or settling by gravity step so as to separate the supernatant from any debris or hepatoblast cells in the conditioned medium.
In regard to claim 16, Ortega teaches the liver organoid media are changed every few days (Example 3, [0334-0335]), thus there would have been a step of mixing of the condition media from the human fetal hepatoblasts with any remaining liver organoid media comprising the Wnt signaling promoter and mitogenic factor.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631