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
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-9, drawn to a non-alcoholic fatty liver artificial tissue model, in the reply filed on 05/03/2026 is acknowledged.
Claims 10-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant further elects human induced pluripotent stem cells (hiPSC), cited in claims 4 and 6, as the species of the source of the liver organoid.
Claims 5 and 7 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 1-12 are pending.
Claims 5, 7 and 10-12 are withdrawn.
Claims 1-4, 6 and 8-9 are considered on the merits.
Priority
This application is a CON of PCT/KR2022/007325 (filed on 05/24/2022), which claims benefits from foreign applications KR10-2022-0062798 (filed on 05/23/2022) and KR10-2021-0066220 (filed on 05/24/2021). The priority claim of the instant application has been granted and the earliest benefit date is 05/24/2021 from the application KR10-2021-0066220.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/21/2023, 04/10/2025, and 08/06/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
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.
The factual inquiries 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 1-3 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al., (Adv. Funct. Mater. 2018, 28, 1801954, p. 1-15. IDS 08/06/2025) in view of Ouchi et al., (Cell Metabolism. 2019, 30, 374-384. IDS 08/06/2025).
With respect to claim 1, Jin teaches a 3D vascularized liver organoid composed of induced hepatic (iHep) cells and a decellularized liver extracellular matrix (LEM) hydrogel cultured in a microfluidic system (see e.g., abstract). Jin teaches the microfluidic device consists of two layers with five chambers interconnected through five microchannels (Figure 3a and Figure S3,Supporting Information) and the 3D hepatic-like tissues (liver organoids) can be formed and maintained inside the chambers, with continuous media perfusion provided by a rocker system (p. 5, section 2.3. “Generation of a Liver-Mimetic 3D Culture in a Microfluidic System Using a Coculture of iHep Cells and HUVECs”, right col, last para, see Figs 3a and 3b). Jin teaches the hepatic cells are cultured in a hepatic induction medium comprising 10% (v/v) FBS (p. 12, section 4. “Experimental Section”, para 1 “Cell culture”), and one of ordinary skill in the art would have immediately expected that the FBS comprises an amount of free fatty acids. Thus, Jin teaches a liver artificial tissue model comprising a hydrogel containing a decellularized liver tissue-derived extracellular matrix (i.e., LEM hydrogel), a liver organoid, a device (i.e., a microfluidic device) including a well (i.e., a chamber) in which the hydrogel (and the liver organoid) is located and a plurality of microchannels through which a free fatty acid flows, and a culture medium containing a free fatty acid (e.g., the hepatic induction medium containing FBS comprising free fatty acids).
However, although Jin acknowledges the induced hepatic (iHep) cells can be used for disease modelling, drug screening, and transplantation (e.g., p. 2, para 1), Jin is silent on the liver artificial tissue model being a non-alcoholic fatty liver artificial tissue model.
Ouchi teaches a method to generate multi-cellular human liver organoids (HLOs) from human iPSCs and teaches free fatty acid exposure induces the steatohepatitis phenotype in organoids (e.g., cover page, section “In Brief” and “Highlights”). Ouchi teaches free fatty acid (e.g., oleic acid) exposure triggers steatosis and results in an inflammatory response in HLOs (e.g., p. 377, subsection “Modeling Inflammatory and Fibrotic Responses in HLOs by Free Fatty Acid Exposure” and see Fig 2) and these steatohepatitis HLOs (sHLOs) have increased ROS production (see Fig 4H), which is a hallmark of the nonalcoholic steatohepatitis-related hepatocyte damage (e.g., see p. 381, para 1). One of ordinary skill in the art would have expected that the nonalcoholic steatohepatitis (NASH) is a type of nonalcoholic fatty liver disease (NAFLD) as evidenced by Ouchi referring to “NAFLD/NASH Patients” (see p. e3, para 1 “Cell culture”). Thus, Ouchi teaches free fatty acid exposure induces non-alcoholic fatty liver disease phenotype in human liver organoids.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the liver artificial tissue model disclosed by Jin, by combining adding free fatty acid in the culture medium to obtain a non-alcoholic fatty liver artificial tissue model as suggested by Ouchi with a reasonable expectation of success. Since Jin aims to develop a highly functional, standardized drug screening and toxicological analysis platform (e.g., abstract) and since Ouchi teaches the disease model facilitates the discovery of effective treatments (see e.g., Summary in p. 374), one of ordinary skill in the art would have had a reason to combine adding free fatty acid in the culture medium as suggested by Ouchi to generate a non-alcoholic fatty liver artificial tissue model in order to facilitate drug screening and to discover effective treatments.
With respect to claim 2 directed to the liver extracellular matrix having 95% to 99.9% liver tissue cells been removed, Jin teaches “this successful decellularization was also confirmed by a DNA quantification assay indicating that 99.7% cells were removed by the procedure (Figure 1b)” (p. 2, section 2.1 “Decellularized Liver Extracellular Matrix (LEM) for Use as a 3D Hepatic Tissue Scaffold”).
With respect to claim 3 directed to the liver organoid being derived from a human induced pluripotent stem cell (hiPSC), however, Jin teaches the induced hepatic cells are directly reprogrammed from primary mouse embryonic fibroblasts (see e.g., p. 3, section 2.2 “Nonviral Generation of iHep Cells from Primary Fibroblasts”), but is silent on the liver organoid being derived from a human induced pluripotent stem cell.
Nevertheless, Jin acknowledges that “iPS cells are more extensively studied with better understanding of mechanism and differentiation protocols, and iPS cell-derived hepatocytes have a great potential for drug screening and toxicity testing due to their mature hepatic phenotypes and metabolic activity” and “Considering huge potential and recent advance of iPS cell technology and immaturity of reprogrammed iHep cells, our microfluidic platform is worth being tested for the generation of liver organoids with iPS cell-derived hepatocytes in future study” (p. 10, para 1), thus contemplates generating the model using the liver organoid being derived from an iPS cell.
As stated supra, Ouchi teaches a method to generate multi-cellular human liver organoids (HLOs) using 11 different healthy and diseased pluripotent stem cell lines (see e.g., “Summary” in p. 374), including those generated from NAFLD/NASH patients (see p. e3, para 1 “Cell culture”). Ouchi teaches the method offers a new approach for studying a personalized basis for inflammation and fibrosis in humans, thus facilitating the discovery of effective treatments (see e.g., “Summary” in p. 374).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the non-alcoholic fatty liver artificial tissue model suggested by Jin in view of Ouchi, by choosing human induced pluripotent stem cell to generate liver organoids as suggested by Jin and Ouchi with a reasonable expectation of success. Since Jin contemplates generating liver organoids with iPS cell-derived hepatocytes in future study due to their mature hepatic phenotypes and metabolic activity (p. 10, para 1), and since Ouchi reduces to practice generating multi-cellular human liver organoids using healthy and diseased hiPSC lines that facilitates the discovery of effective personalized treatments (“Summary”), one of ordinary skill in the art would have had a reason to generate the liver organoid being derived from a hiPSC in order to take advantage of their mature hepatic phenotypes and metabolic activity and to facilitate the discovery of personalized treatments.
With respect to claim 8 directed to the free fatty acid having a concentration of 100 µM to 900 µM, as stated supra, Ouchi makes obvious adding free fatty acid (FFA) in the culture medium to induce non-alcoholic fatty liver phenotype. Ouchi teaches screening various FFA treatment conditions and HLOs display lipid accumulation in a dose-dependent fashion of oleic acid (OA) (p. 377, left col, see Figure 2A for OA treatment in a concentration of 200 µM, 400 µM or 800 µM, and see Figure 2B for the dose-dependent lipid accumulation). Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen adding the free fatty acid in a concentration of 100 µM to 900 µM as suggested by Ouchi with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since Ouchi has screened and thus reduced to practice adding free fatty acid in the claimed concentration range. Furthermore, because Ouchi teaches the concentration of free fatty acid is a result effective variable (see lipid accumulation in a dose-dependent fashion of oleic acid), it would have been obvious to one having ordinary skill in the art at the time the invention was filed to apply the claimed concentrations of free fatty acid, since it has been held that discovering an optimum value/dose of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
With respect to claim 9 directed to the liver organoid being co-cultured with vascular cells, as stated supra, Jin teaches the liver organoid comprises co-culturing induced hepatic cells with HUVECs (human umbilical vein endothelial cells, i.e., a type of vascular cells) (p. 5, section 2.3. “Generation of a Liver-Mimetic 3D Culture in a Microfluidic System Using a Coculture of iHep Cells and HUVECs”).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al., (Adv. Funct. Mater. 2018, 28, 1801954, p. 1-15. Cited in IDS 08/06/2025) in view of Ouchi et al., (Cell Metabolism. 2019, 30, 374-384. Cited in IDS 08/06/2025), as applied to claims 1 and 3 above, and further in view of Finkbeiner et al., (Biology Open. 2015; 4: 1462-1472).
With respect to claim 4 directed to the liver organoid being cultured on the hydrogel, Jin teaches the “iHep cells were encapsulated in the LEM hydrogel” (p. 5, section 2.3, para 2) and also teaches the “iHep cells cultured on the LEM-coated substrate” (p. 4, left col, last para), thus teaches two approaches for culturing hepatic cells, i.e., both in and on the LEM hydrogel. Ouchi teaches in free fatty acid exposure, the human liver organoids are first isolated from Matrigel and then cultured with free fatty acid on ultra-low attachment plates (p. e4, last para).
However, Jin and Ouchi are silent on culturing the organoid on the hydrogel.
Finkbeiner teaches a method of seeding human intestinal organoids (HIOs) derived from human iPSCs on the decellularized human small intestine extracellular matrix or a poly-glycolic acid scaffold (see Fig 1, Method B and Method C). Finkbeiner teaches to reseed HIOs, organoids are removed from Matrigel (similarly taught by Ouchi) and excess Matrigel is trimmed away from the HIOs. The organoid are placed onto the mucosal surface of the matrices using forceps (p. 1470, left col, last para), or are individually transferred by gentle pipetting onto the outer surface of the PGA/PLLA scaffolds (p. 1471, para 1). Finkbeiner teaches HIOs efficiently reseed acellular intestinal matrix in vitro (see e.g., p. 1465) and HIOs seeded onto PGA/PLLA scaffolds thrive in vivo (e.g., p. 1466, last para).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted Jin’s encapsulating liver organoids in the LEM hydrogel with seeding the organoids on the hydrogel as suggested by Finkbeiner with a reasonable expectation of success. Since Jin teaches two approaches for culturing hepatic cells, i.e., both in and on the LEM hydrogel (p. 5, section 2.3, para 2 and p. 4, left col, last para), since Ouchi teaches the human liver organoids are isolated from Matrigel for the following culture (p. e4, last para), and since Finkbeiner reduces to practice a method of removing organoids from Matrigel (similarly taught by Ouchi) and placing onto the surface of the decellularized matrices (p. 1470, left col, last para) or the PGA/PLLA scaffolds (p. 1471, para 1) with efficient reseeding, one of ordinary skill in the art would have had a reason to substitute with isolating and culturing the organoid on the surface of the hydrogel as suggested by Finkbeiner in order to obtain efficient culturing. Furthermore, since both Ouchi and Finkbeiner teach isolating organoids, and both Jin and Finkbeiner teach the cells (or organoids) can be cultured on the surface of the hydrogel, one of ordinary skill in the art would have had a reasonable expectation of success in isolating organoids, placing on the surface of hydrogel and achieving efficient culturing.
With respect to claim 6 directed to the well having a depth of 2 mm to 4 mm, Jin teaches casting a 2.2 mm thick PDMS layer featuring the chambers and microchannels, five holes are punched between microchannels to form cell cultivation chambers and the device consists of two microfluidic layers that are assembled on top of each other with a 2 mm thick PDMS sheet on the bottom (p. 13, para 1). Thus, Jin teaches the chambers (i.e., the well) have a thickness of 2.2 mm, within the claimed range.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Provisional Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4, 6 and 8-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1, 4 and 6-8 of copending Application No. 18/539,379 (‘379) in view of Jin et al., (Adv. Funct. Mater. 2018, 28, 1801954, p. 1-15. Cited in IDS 08/06/2025) and Finkbeiner et al., (Biology Open. 2015; 4: 1462-1472). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims 1, 3-4 and 6-8 of ‘379 recite a multi-organ model comprising a liver organoid well connected to other wells by microchannels (reference claim 1, related to instant claim 1), the liver organoid well includes a hydrogel containing decellularized liver tissue-derived extracellular matrix (LEM) and liver organoids (reference claim 4, related to instant claim 1), the liver organoids are derived from human induced pluripotent stem cell (hiPSC) (reference claim 6, related to instant claim 3), a non-alcoholic fatty liver multi-organ model in which the liver organoid well is treated with free fatty acid (reference claim 7, related to instant claim 1) and the free fatty acid has a concentration ranging from 100 µM to 900 µM (reference claim 8, related to instant claim 8).
However, the cited application claims are silent on the LEM is a matrix in which 95% to 99.9% of liver tissue cells have been removed recited in instant claim 2, the liver organoid is cultured on the hydrogel in instant claim 4, the well has a depth of 2 mm to 4 mm in instant claim 6 or the liver organoid is co-cultured with vascular cells in instant claim 9.
Jin teaches a 3D vascularized liver organoid composed of induced hepatic (iHep) cells and a decellularized liver extracellular matrix (LEM) hydrogel cultured in a microfluidic system (see e.g., abstract). Jin teaches “this successful decellularization was also confirmed by a DNA quantification assay indicating that 99.7% cells were removed by the procedure (Figure 1b)” (p. 2, section 2.1 “Decellularized Liver Extracellular Matrix (LEM) for Use as a 3D Hepatic Tissue Scaffold”), related to instant claim 2. Jin teaches casting a 2.2 mm thick PDMS layer featuring the chambers and microchannels, five holes are punched between microchannels to form cell cultivation chambers and the device consists of two microfluidic layers that are assembled on top of each other with a 2 mm thick PDMS sheet on the bottom (p. 13, para 1). Thus, Jin teaches the chambers (i.e., the well) have a thickness of 2.2 mm, within the claimed range in instant claim 6. Jin teaches the liver organoid comprises co-culturing induced hepatic cells with HUVECs (human umbilical vein endothelial cells, i.e., a type of vascular cells) (p. 5, section 2.3. “Generation of a Liver-Mimetic 3D Culture in a Microfluidic System Using a Coculture of iHep Cells and HUVECs”), related to instant claim 9. Jin teaches the “iHep cells were encapsulated in the LEM hydrogel” (p. 5, section 2.3, para 2) and also teaches the “iHep cells cultured on the LEM-coated substrate” (p. 4, left col, last para), thus teaches two approaches for culturing hepatic cells, i.e., both in and on the LEM hydrogel, related to instant claim 4.
Finkbeiner teaches a method of seeding human intestinal organoids (HIOs) derived from human iPSCs on the decellularized human small intestine extracellular matrix or a poly-glycolic acid scaffold (see Fig 1, Method B and Method C). Finkbeiner teaches to reseed HIOs, organoids are removed from Matrigel (similarly taught by Ouchi) and excess Matrigel is trimmed away from the HIOs. The organoid are placed onto the mucosal surface of the matrices using forceps (p. 1470, left col, last para), or are individually transferred by gentle pipetting onto the outer surface of the PGA/PLLA scaffolds (p. 1471, para 1), related to instant claim 4. Finkbeiner teaches HIOs efficiently reseed acellular intestinal matrix in vitro (see e.g., p. 1465) and HIOs seeded onto PGA/PLLA scaffolds thrive in vivo (e.g., p. 1466, last para).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the non-alcoholic fatty liver model recited in the copending application claims, by choosing the decellularization of Jin to remove 95% to 99.9% of liver tissue cells, by choosing Jin’s thickness of the well, by combining vascular cells to co-culture with the liver organoid as suggested by Jin and by choosing to culture the liver organoid on the hydrogel as suggested by Jin and Finkbeiner with a reasonable expectation of success. Since Jin and Finkbeiner have reduced to practice a liver model with the claimed decellularized LEM, well depth, coculturing with vascular cells, and culturing the organoid on the hydrogel, one of ordinary skill in the art would have had a reason to choose to apply the method and device suggested by Jin and Finkbeiner in order to obtain a functional non-alcoholic fatty liver model.
Since the instant application claims are obvious over cited application claims, in view of Jin and Finkbeiner, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (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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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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