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 .
Election/Restrictions
Claims 50, 65, and 72 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/24/2025.
Claims Status
Claims 2, 4-5, 7, 9-11, 13-17, 19, 21-22, 29, 32-49, 51-64, 66-71, 73-77 is/are cancelled. Claim 78 is newly added. Claims 1, 3, 6, 8, 12, 18, 20, 23-28, 30-31, 50, 65, 72, 78 is/are currently pending with claims 50, 65, 72 withdrawn. Claims 1, 3, 6, 8, 12, 18, 20, 23-28, 30-31, 78 is/are under examination.
Claim Rejections - 35 USC § 112
112(a):
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 28 and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claim 28 recites a subject “at risk of developing insulin dysfunction”. The specification does not disclose how risk is determined, nor what degree or type of assessed insulin dysfunction risk is sufficient to qualify a subject as “at risk”. As such, the disclosure fails to provide a definition of a subject at risk of developing insulin dysfunction sufficient for an artisan to determine whether a subject qualifies as being at risk of developing insulin dysfunction such that the limitations of claim 28 are fulfilled.
Claim 30 recites that “the insulin resistance reporter comprises a nucleic acid sequence having at least 90% identity to SEQ ID NO:4”. In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, a sequence 100% identical to SEQ ID NO:4 is the only species of sequences at least 90% identical to SEQ ID NO:4 whose complete structure is disclosed. The specification describes SEQ ID NO:4 as comprising from 5’ to 3’: a 5’ PCK1 homology arm, a sequence encoding p2A self-cleaving peptide, mScarlet gene, a sequence encoding T2A self-cleaving peptide, luciferase gene, and a 3’ PCK1 homology arm (paragraph [0132]; Fig. 5A). While the genus encompasses a large number of variants and molecules that have the same activity (being operatively linked to an insulin-dependent gene, as required by claim 1), and the genus encompasses a large number of variants and molecules that have a different structure, the specification does not describe the complete structure of a representative number of species of the large genus of sequences at least 90% identical to SEQ ID NO:4 or functional equivalents thereof. Additionally, the specification does not describe the complete structure of a representative number of species of the large genus of modified sequences.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence, specific features, and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only functional attribute described is that the insulin resistance reporter is operatively linked to an insulin-dependent gene (claim 1). Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of the genus, all members of the claimed genus will that characteristic. It is unclear based on the provided disclosure what sequence elements can be changed or which sequence elements or functions must be maintained in sequences at least 80% but less than 100% identical to SEQ ID NO:4. No further identifying characteristics of the modified sequences are disclosed.
In conclusion, Applicant’s disclosure of one sequence (SEQ ID NO:4) of the claimed broad genus is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus at the time the application was filed. Thus it is concluded that the written description requirement is not satisfied for the claimed genus.
Response to Arguments
Applicant's arguments filed 03/26/2026 have been fully considered but they are not persuasive.
Applicant amended claim 28 to recite that the subject is a subject “having or at risk of developing insulin dysfunction”. However, while a subject having insulin dysfunction is reasonable for an artisan to identify and is sufficiently described by the art, the specification does not disclose the degree of risk or types of risk factors that must be or should be considered to determine whether a subject is at risk of developing insulin dysfunction. Applicant has not addressed this lack of written description of “risk” in the filed response.
Applicant amended claim 30 to recite “at least 90% identity to SEQ ID NO: 4”, supported by a recitation of 90% identity in the specification. However, the specification does not disclose which structural or sequence elements of SEQ ID NO: 4 must be maintained or can be altered to create a sequence with less than 100% identity to SEQ ID NO: 4 and maintaining the required functional attributes, and Applicant’s arguments do not address such structural features which can or cannot be altered in a sequence less than 100% identical to SEQ ID NO: 4.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 31 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McKimpson (2019, of record). This rejection is maintained.
Regarding claim 31, McKimpson teaches an insulin-responsive cell (a hepatocyte) comprising an insulin resistance reporter operably linked to the insulin-dependent gene FOXO1 (abstract; Figs. 3, 4C-D; page C143 “Materials and Methods”).
Response to Arguments
Applicant's arguments filed 03/26/2026 have been fully considered but they are not persuasive. In these arguments, Applicant did not directly address the above rejection under 35 USC 102 of claim 31 over McKimpson. McKimpson is considered to encompass the invention of claim 31 as “an insulin-dependent gene of the liver organoid” does not necessarily require that the insulin-dependent gene be comprised in the genome of the liver organoid, but merely that it be comprised in the liver organoid.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1, 3, 12, 18, 20, 23-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over McKimpson (2019, of record) in view of Takebe (WO2018085615A1, of record) and Kumashiro (2011). This rejection is maintained.
Regarding claims 1 and 3, McKimpson teaches a hepatocyte comprising an insulin resistance reporter operably linked to the insulin-dependent gene FOXO1 (abstract; Fig. 3; page C143 “Materials and Methods”).
Regarding claim 12, McKimpson teaches that the insulin resistance reporter comprises a gene encoding a fluorescent protein (RFP) (page C143 “Materials and Methods”).
However, McKimpson does not teach a liver organoid comprising the insulin resistance reporter operably linked to the insulin-dependent gene.
Takebe teaches that a liver organoid is a better model of liver function than primary hepatocytes.
Regarding claim 1, Takebe teaches a liver organoid (claim 1), and teaches that liver organoids better model in vivo liver function than primary hepatocytes, as hepatocyte cultures lack the complex structures (abstract; paragraphs [0002]-[0005]).
Regarding claims 18, 20, and 23-25, Takebe teaches a fatty liver organoid generated by contacting the liver organoid with oleic acid (paragraphs [0021], [0084]). Based on the drawings provided by the applicant in the instant application (specifically Fig. 8C), fatty liver organoids created by contacting a liver organoid with oleic acid inherently exhibit insulin resistance and reduced suppression of expression of PCK1. As such, the fatty liver organoid of Takebe, generated by contacting the liver organoid with oleic acid, is considered to inherently exhibit insulin resistance and reduced suppression of expression of PCK1. Furthermore, instant Fig. 7E teaches that fatty liver organoids created by contacting liver organoids with oleic acid (see paragraph [0040]) inherently exhibit increased expression of TNFa, TGFb, IL6, IL8, and IL1b (see instant Fig. 7E), and as such, the fatty liver organoids of Takebe are considered to inherently exhibit increased expression of TNFa, TGFb, IL6, IL8, and IL1b, as required by claim 25. Takebe teaches that the fatty liver organoid exhibits intense lipid accumulation (paragraph [0084]) (required by claim 24).
Regarding claims 26-27, Takebe teaches that the liver organoids are human liver organoids derived from human induced pluripotent stem cells (iPSCs) (claims 1-2, 6-7).
McKimpson teaches that hepatocytes comprising the insulin resistance reporter operably linked to the insulin-dependent gene are useful for investigating “cell-intrinsic and -extrinsic mechanisms” and “cell heterogeneity” in the liver with respect to insulin resistance, diabetes, and metabolism (page C149). Given that Takebe teaches that liver organoids better model in vivo liver function than primary hepatocytes (Takebe abstract; paragraphs [0002]-[0005]), it would have been obvious to an artisan at the time of filing that the hepatocytes of McKimpson should be replaced with the liver organoids of Takebe. Furthermore, Kumashiro teaches that it was known in the art that insulin resistance was associated with NAFLD in animal models, and that accumulation of hepatocellular lipids were a suggested cause of this insulin resistance (page 16381). Based on the teachings of Kumashiro, an artisan would have recognized at the time of filing that the fatty liver organoids of Takebe would exhibit insulin resistance, because these fatty liver organoids exhibited intense lipid accumulation and because Takebe teaches that the fatty liver organoids can model NAFLD (paragraph [0084]). As such, it would have been obvious to an artisan at the time of filing that in order to examine the “cell-intrinsic and -extrinsic mechanisms” and “cell heterogeneity” in the liver as these concern insulin resistance, as taught by McKimpson as an application for the insulin resistance reporter and operatively-linked insulin-sensitive gene, an insulin-resistant liver organoid, such as the fatty liver organoid of Takebe, should be used.
Response to Arguments
Applicant's arguments filed 03/26/2026 have been fully considered but they are not persuasive.
Applicant argues that the pending claims require that the insulin resistance reporter be integrated into the genome of the liver organoid cells, and that as McKimpson does not teach such genomic integration, McKimpson and Takebe combined do not teach this essential element of the claims. Claim 1 recites that “the insulin resistance reporter…is operatively linked to an insulin-dependent gene of the liver organoid” (emphasis added), wherein the “of the liver organoid” is interpreted by the Examiner to be the phrasing which the Applicants depend on to assert that the claimed invention requires genomic integration of the insulin resistance reporter. However, the broadest reasonable interpretation of a gene of a liver organoid encompasses that the gene sequence is one which is found in the liver organoid cells, but the gene which is referenced is not necessarily itself in the genome (for example, an extrachromosomal plasmid which comprises a gene identical in sequence to a gene found in the genome). In order for the claim to require genomic integration of the insulin resistance reporter, such genomic integration must be recited (for example, by reciting “an insulin-dependent gene comprised in the genomes of the cells comprised in the liver organoid”). Moreover, while the arguments reference the use of CRISPR-mediated homology directed repair as a method for genomic integration, CRISPR systems and methods are not recited in the pending claims. The only further argument which does not depend upon genomic integration not being taught by McKimpson is found on page 11 section 4, wherein Applicant argues that the claimed organoid system enables both “quantitative readout of insulin responsiveness” and modeling of the complexity of liver structures. As argued in the rejection, McKimpson teaches a cellular system which enables quantitative readout of insulin responsiveness, and Takebe teaches that liver organoids are superior to cellular models precisely for the ability to model complex liver structures. An artisan at the time of filing would know, based on the teachings of Takebe, that the system of McKimpson should be used in a liver organoid instead of hepatocyte cultures to improve the quality and complexity of the output of the system of McKimpson.
Allowable Subject Matter
Claims 6, 8, 78 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: Claims 6 and 8 require that the reporter genes be separated from the insulin-dependent gene by a self-cleaving peptide or an IRES. McKimpson does not provide any teaching or suggestion of a self-cleaving peptide or IRES separating the reporter gene and the insulin-dependent gene. A search of the art for other insulin reporter systems did not yield art teaching or suggesting systems wherein an insulin-dependent gene and a reporter gene were linked by a self-cleaving peptide or an IRES.
Claim 78 requires that the cells of the liver organoid be derived from a subject having diabetes, metabolic syndrome, fatty liver disease, steatohepatitis, obesity, cardiovascular disease, polycystic ovary syndrome, hyperglycemia, hyperinsulinemia, dyslipidemia, or any combination thereof. McKimpson teaches that “experiments can also be adapted for use in primary culture and mouse models”, McKimpson does not teach or suggest adapting the model for use in cells derived from subjects having any of the diseases recited in claim 78. The reporter system of McKimpson is the closest found in the prior art. Based on the teachings of McKimpson about the utility of such a reporter system, an artisan would not have an obvious reason for using an organoid derived from a subject having any of the diseases of pending claim 78 instead of an organoid derived from a subject not having insulin dysfunction or a disease caused by insulin dysfunction.
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 AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
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