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 .
Claim Status
To expedite the compact prosecution, the Examiner is pursuing the amended claims dated 28 March 2024, in which applicants amended claims 7, 10, 15, 17, 20, 23-31, 34-45, 48-50, 55-57 and 59. Therefore, claims 1-59 are pending in the application.
Election/Restrictions
Applicant elects with traverse of Group 1: claims 1-14, 16-19, 21, and 22 are drawn to a method for preparing a conditioned medium from cultured human hepatocytes (CMHH), cultured human hepatocytes thereof in the reply filed on 30 July 2026 is acknowledged. Claim 15 is within the scope of the elected invention, however, typographically was not listed in the restriction requirement mailed on 05/13/2026.
Applicant argues that all the Groups of claims have common technical features associated with Group I. Therefore, it would not constitute an undue burden to examine all of the Groups of the claims. However, this is not found persuasive because examiner was able to provide art which satisfied the limitations of the product claims without being able to satisfy the limitations of all the method claims thereby demonstrating that a search burden exists between the restricted groups.
Claims 20 and 23-59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-19, 21, and 22 are under current examination.
Priority
This application was filed 03/28/2024 and is a 371 application of PCT/US2022/077330 filed on 09/30/2022, which claims benefit to the Provisional Application 63250529 and 63250541 filed on 09/30/2021. It is noted that 63250541 application does not have support for claimed scope such as chimeric, humanized and replaced the medium with a fresh volume every 24 to 120 hours. However, examiner found that the provisional application 63250529 has support for claimed scope. Thus, the earliest possible priority for the instant application is 09/30/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/28/2024, 12/19/2024, 08/07/2025, 10/28/2025, 11/26/2025, 02/27/2026, 07/06/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, and the signed and initialed PTO Forms 1449 are mailed with this action.
Title Objection
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims scope are directed. See MPEP 606.01
The following title is suggested:
“Conditioned Medium Derived from Cultured Human Hepatocytes.”
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.
Claim 15 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.
Claim 15 is recited “medium is replaced with a fresh volume every 24 to 120 hours,” however, it is not clear from the claim language which medium is replaced. Independent claim 1 recited two different type of medium, therefore, it is insufficient antecedent basis for the limitation “medium” in the claim 15. Therefore, clarification of the recited medium is required.
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.
Claims 1-2, 17, 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tasnim et al., (US20190352610A1; cited in IDS filed 05/28/2024; hereinafter “Tasnim”).
With respect to claim 1, Tasnim discloses a method for preparing a conditioned medium from cultured human hepatocytes (HH) in a serum-free cell culture medium in the presence of an extracellular matrix for 1 to 7 days [0019]; primary human hepatocyte conditioned medium, [0012], and harvesting the culture medium having been incubated with the HH for at least 1 hour, as the conditioned medium (conditioned medium is obtained by the method ([0019], [0012]).
With respect to claim 2, Tasnim discloses that the HH comprise primary human hepatocytes (PHH) [0012].
With respect to claim 17, Tasnim discloses that the HH do not comprise HepG2 cells, Huh7 cells or murine hepatocytes ([0015] of Tasnim).
With respect to claim 22, Tasnim discloses that the CMHH comprises one or more humoral factors secreted by human hepatocytes and a hepatocyte clonal growth medium or a hepatocyte maintenance medium (Table 1, chemokines (e.g. MCP-1 and CXCL1, [0048]).
Accordingly, Tasnim anticipates the instant claims 1-2, 17, 22.
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 1-2, 3-4 and 17, 18-19, 21, 22 are rejected under 35 U.S.C. 103 as being unpatentable over Tasnim et al., (US20190352610A1; cited in IDS filed 05/28/2024; hereinafter “Tasnim”), in view of Oshimura et al. (US 2014/0241991; cited in IDS filed 05/28/2024; hereinafter, "Oshimura").
As discussed previously, Tasnim discloses a method for preparing a conditioned medium from cultured human hepatocytes (HH) in a serum-free cell culture medium in the presence of an extracellular matrix for 1 to 7 days [0019]; primary human hepatocyte (PHH) conditioned medium, [0012], and harvesting the culture medium having been incubated with the HH for at least 1 hour, as the conditioned medium (conditioned medium is obtained by the method ([0019], [0012]).
Regarding Claim 3, Tasnim fails to explicitly disclose wherein the hepatocytes derived from a chimeric animal with humanized liver are humanized liver chimeric mice derived-human hepatocytes (HLCM-HH), which are obtained from a liver derived from a mouse injected with PHH or with previously isolated HLCM-HH into the spleen. However, such was known in the prior art.
With respect to claims 3-4, Oshimura teaches hepatocytes derived from the chimeric animal with humanized liver are humanized liver chimeric mice derived-human hepatocytes (HLCM-HH) (abstract, [0016], [0018], [0067]), which are obtained from a liver derived from a mouse injected with PHH or with previously isolated HLCM-HH into the spleen ([0054], [0067]). Oshimura further teaches mouse has a replacement index of at least 10% before the HLCM-HH are obtained with human hepatocytes to be determined ([0097], [0033], [0067]; See Figures 8-1 and 8-2).
MPEP 2143 (B) states that simple substitution of one known element for another to obtain predictable results. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Accordingly, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Tasnim with the teaching of Oshimura for the purpose of generating animal models for the precise evaluation of the capacity of human hepatocytes to metabolize chemical substances and drugs ([0007] of Oshimura).
Regarding Claims 18-19, and 21, Oshimura teaches HH comprise hepatocytes derived from a chimeric animal with humanized liver and a method further comprises obtaining hepatocytes derived from the chimeric animal with humanized liver before a culturing step ([0016]; [0018]; [0067], wherein the obtaining of the hepatocytes derived from the chimeric animal with humanized liver comprises isolating hepatocytes derived from a liver of an animal injected with PHH or with previously isolated hepatocytes derived from a humanized liver chimeric animal into a spleen of the animal, thereby obtaining the hepatocytes derived from the chimeric animal with humanized liver a chimeric non-human animal having a human hepatocyte population in vivo, [0016]; human hepatocytes, which comprises transplanting human hepatocytes into a non-human animal, wherein the non-human animal is a mouse, [0018]; a portion (hepatocyte population) of the liver of a chimeric non-human animal is collected [0067]; Human hepatocytes are injected into the spleen or a portal vein of the above non-human animal to allow the cells to be transplanted into the liver of the non-human animal via the spleen or a portal vein [0054]. Oshimura further teaches hepatocytes derived from a chimeric animal are isolated via collagenase perfusion of the liver of the chimeric animal [0047], and the chimeric animal has a replacement index of at least 10% before the HH are isolated [0033]; [0067); See Figures 8-1 and 8-2).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Tasnim with the teaching of Oshimura for the purpose of generating animal models for the precise evaluation of the capacity of human hepatocytes to metabolize chemical substances and drugs ([0007] of Oshimura).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 1-4, 5-10 and 17-19, 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Tasnim et al., (US20190352610A1; cited in IDS filed 05/28/2024; hereinafter “Tasnim”), in view of Oshimura et al. (US 2014/0241991; cited in IDS filed 05/28/2024; hereinafter, "Oshimura") as applied to claims 1-4, and 17-19, 21-22 above, and further in view of Win et al. (Int. J. Med. Sci. 2018, Vol. 15; cited in IDS filed 05/28/2024; hereinafter, "Win") and Vacanti et al. (US8173361B2; cited in IDS filed 05/28/2024; hereinafter "Vacanti").
As discussed previously, Tasnim discloses a method for preparing a conditioned medium from cultured human hepatocytes (HH) in a serum-free cell culture medium.
Regarding claim 5, Tasnim fails to explicitly disclose wherein the medium is a dimethyl sulfoxide (DMSO), dimethyl sulfone (DMSO2), or tetramethylene sulfoxide (TMSO)-supplemented hepatocyte clonal growth medium (dHCGM, d2HCGM, or tHCGM), and the HCGM comprises, or consists essentially of, a standard cell culture base medium, L-proline, insulin, dexamethasone, EGF, and L-ascorbic acid 2-phosphate (Asc-2P). However, such was known in the prior art.
With respect to claims 5 and 7-10, Win is in the field of chimeric mice-derived human hepatocyte PXB cells (Pg. 1154, left-hand column, second paragraph), and teaches a medium is a dimethyl sulfoxide (DMSO) supplemented hepatocyte clonal growth medium (dHCGM, d2HCGM, or tHCGM), and the HCGM comprises, or consists essentially of, a standard cell culture base medium, L-proline, insulin, dexamethasone, EGF, and L-ascorbic acid 2-phosphate (Asc-2P) (p. 1154, left-hand column, second paragraph). Win further teaches standard cell culture base medium is Dulbecco's Modified Eagle's Medium (DMEM) (p. 1154, left-hand column, second paragraph) and cell culture base medium is DMEM, and the DMEM is DMEM-10, and the DMEM-10 comprises, or consists essentially of, DMEM, HEPES, penicillin-streptomycin, and serum (e.g., fetal bovine serum (FBS)) (p. 1154, left-hand column, 1st, 2nd and 4th ¶).
MPEP 2143 (B) states that simple substitution of one known element for another to obtain predictable results. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Accordingly, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Tasnim with the teaching of Win for the purpose of culturing hepatocyte-humanized liver cells in an environment which enables drug screening (Win, Pg. 1154, left-hand column, second paragraph of Win).
Regarding claim 6, Tasnim and Win silent to the medium is a DMSO, DMSO2, or TMSO supplemented hepatocyte maintenance medium. However, such was known in the prior art.
Vacanti teaches a hepatocyte maintenance medium (Col. 61, Ln. 44 of Vacanti) and detecting metabolites of test agents (Abstract).
MPEP 2143 (B) states that simple substitution of one known element for another to obtain predictable results. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Accordingly, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Tasnim with the teaching of Vacanti for the purpose of measuring metabolic function of hepatocyte cell cultures (Col. 61, Lns. 49-50 of Vacanti).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 1-10, 11-14 and 17-19, 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Tasnim et al., (US20190352610A1; cited in IDS filed 05/28/2024; hereinafter “Tasnim”), in view of Oshimura et al. (US 2014/0241991; cited in IDS filed 05/28/2024; hereinafter, "Oshimura") as applied to claims 1-4, and 17-19, 21-22 above, and further in view of Win et al. (Int. J. Med. Sci. 2018, Vol. 15; cited in IDS filed 05/28/2024; hereinafter, "Win") and Rogiers et al. (US20090130064A1; cited in IDS filed 05/28/2024; hereinafter "Rogiers").
As discussed previously, Tasnim discloses a method for preparing a conditioned medium from cultured human hepatocytes (HH) in a serum-free cell culture medium.
Regarding claims 11-14, Tasnim discloses DMSO ([0017]), still Tasnim is silent to dHCGM, d2HCGM, or tHCGM comprises L-proline at 15 μg/mL…and penicillin at 100 IU/ml, streptomycin at 100 μg/ml, and the serum at 10% in the standard cell culture base medium. However, such was known in the prior art.
Win teaches wherein dHCGM comprises or consists essentially of L-proline at 15 μg/mL, insulin at 0.25 μg/mL, dexamethasone at 50 nM, EGF at 5 ng/mL, Asc-2P at 0.1 mM, HEPES at 20 mM and the serum at 10% in the standard cell culture base medium (DMEM 10% fetal bovine serum) (p. 1154, left-hand column, 1st and 2nd ¶). Separately Rogiers teaches primary hepatocytes culturing method for stabilization of the phenotype of isolated primary cells in vitro for use in assays of biotransformation.
Rogiers further use penicillin at 100 IU/mL, streptomycin at 100 μg/mL (supplemented with 1 mg/ml LA-BSA, 100 IU/ml penicillin, 100 μg/ml streptomycin, inducing differentiation of stem cells into hepatocyte(Abstract, [0151], [0155]-[0156]¶).
MPEP 2143 (B) states that simple substitution of one known element for another to obtain predictable results. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Accordingly, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Tasnim with the teaching of Win and Rogiers for the purpose of culturing hepatocyte-humanized liver cells in an environment which enables drug screening (Win, Pg. 1154, left-hand column, 2nd ¶ of Win) and cultivating hepatocytes ([0156] of Rogiers).
MPEP § 2144.05 state Generally, differences in concentration by adjusting solution will not support the patentability of the subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955). In here, Tasnim teaches the hepatic macrophages derived can be expanded and maintained in culture to obtain larger cell numbers ([0018] of Tasnim), therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Tasnim to include the DMSO, DMS02, or TMSO at 281.6 mM, 140.8 mM, or 70.4 mM respectively, since discovering the optimum value of a result effective variable involves only routine skill in the art. The motivation for doing so would have been to derive hepatic macrophages ([0018] of Tasnim).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 1-4 and 16, 17-19, 21, 22 are rejected under 35 U.S.C. 103 as being unpatentable over Tasnim et al., (US20190352610A1; cited in IDS filed 05/28/2024; hereinafter “Tasnim”), in view of Oshimura et al. (US 2014/0241991; cited in IDS filed 05/28/2024; hereinafter, "Oshimura") and Kegel et al. (Journal of Visualized Experiments (JoVE), (109), p.e53069; cited in IDS filed 05/28/2024; hereinafter "Kegel").
As discussed previously, Tasnim discloses a method for preparing a conditioned medium from cultured human hepatocytes (HH) in a serum-free cell culture medium.
Regarding Claim 16, Tasnim is silent to the PHH cell density from 0.5x105 /cm2 to 5x105/cm2. However, such was known in the prior art.
Kegel teaches isolating primary human hepatocytes (Abstract) where PHH are cultured at a cell density from 0.5x 105 /cm2 to 5x105 /cm2 (plastic cell culture vessels at a density of 5x105 KC/cm2, (p. 3, 3rd ¶).
MPEP 2143 (B) states that simple substitution of one known element for another to obtain predictable results. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Accordingly, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Tasnim with the teaching of Kegel for the purpose of isolating PHH cells with higher density (p. 2, 1st ¶ of Kegel).
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is 571-272-0196. The examiner can normally be reached M-F 8-5 (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached on (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is (571)272-0196. The examiner can normally be reached M-F 8-5 (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic, can be reached on (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MASUDUR RAHMAN/ Patent Examiner, Art Unit 1633
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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