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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6th of October 2025 has been entered.
Status of the Application
Applicant’s response and amendment filed 6th of October 2025 are acknowledged and entered. Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
In the response filed 6th of October 2025, Applicant amended claim 1, and canceled claims 5-6, 11-12, and 15.
Claims 7-10 and 13-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Feb. 23, 2023.
Currently, claims 1-4 and 16-17 have been examined on their merits.
Withdrawn Objections & Rejections
The rejection of claims 1-4 and 16-17 under 35 U.S.C. 103 as being unpatentable over Spiegelman, et al. (WO2010/080985, see IDS filed 9/02/2020; previously presented), in view of Hirning, et al. (Cell differentiation and development; 27.3: 243-248, published 1989; previously presented) and Williams, et al. (WO2012112458A2; filing date is 2/13/2012; previously presented) is withdrawn due to amendments to the claims.
Information Disclosure Statement
Applicant is reminded of 37 CFR §1.56, which details Applicant's duty to disclose all information known to be material to patentability.
It is noted that the information disclosure statements (IDS) submitted on 2nd of September 2020 is in compliance with the provisions of 37 CFR 1.97. Notably, the disclosure statements filed lists a “Search Reports”. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
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 1-4 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al., (WO2011/050334A1, 2011; cited by IDS 9/2/2020), Ahfeldt T, et al. (Nat Cell Biol. Jan 15;14(2):209-19., 2012; cited by IDS 9/2/2020, hereinafter as “Ahfeldt”), Wu, Zhidan, et al. (Genes & development 9.19: 2350-2363, 1995; hereinafter as “Wu 1995”), Wu, Zhidan, et al., (Molecular and cellular biology 16.8: 4128-4136, 1996; hereinafter as “Wu 1996”), Nakagawa, Masato, et al. (Proceedings of the National Academy of Sciences 107.32: 14152-14157, 2010; cited by IDS 9/2/2020; hereinafter as “Nakagawa”), and Williams, et al. (WO2012/112458A2; filing date is Feb. 13, 2012; prior art of record).
This is a new rejection as necessitated by amendment to the claims. Any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Combinations: C/EBPβ (C) and c-Myc (M); and C/EBPβ (C) L-Myc (L), and c-Myc (M)
Regarding claim 1-4 and 16-17, Zhu discloses an in vitro or ex vivo method for generating a brown adipocyte from a somatic cells, such as fibroblasts (see e.g. abstract, para. 36, 56-58, 69-71, 74, Example 1 and 4) of a mammal (e.g. human)(see e.g. abstract, para. 2, 52-56 and 92, claims 1-26, Example 1-4), and introduces a group of polynucleotides (i.e. reprogramming) are selected from the group consisting of C/ΕΒΡ-β (C), c-Myc (M), and any combination thereof (see e.g. paras. 36, 47-49; pages 25-29; Examples 1 and 4; claims 6, and 9), corresponding to the claim limitation of discloses encoding at least one brown adipocyte-related gene or expression product thereof, such as C/EBPβ (C), and a polynucleotide encoding at least one reprogramming-related gene or expression product thereof, such as c-Myc (M)(i.e. combination CM) into the somatic cell in the mammal and the at least one brown adipocyte-related gene or expression product thereof and at least one reprogramming-related gene or expression product thereof do not include Prdm16 (see e.g. abstract, para. 2, 47-49, 52-56, 60, 67 79-82 and 92-92, claims 1-26, Example 1 and 4). Further, Zhu discloses the brown adipocyte comprising at least one exogenous brown adipocyte-related gene and at least one exogenous reprogramming-related gene that is introduced by infection with a viral vector or other types of plasmids (see e.g. para. 92-93;, pages 2 and 26; claims 1-26; Example 1; figs. 1 and 7).
Zhu does not explicitly teach that the brown adipocyte is directly induced from a fibroblast without first becoming an induced pluripotent stem (iPS) cell or an embryonic stem (ES) cell.
However, the prior art of Ahfeldt discloses that expression of peroxisome proliferator-activator receptor gamma (PPARγ) alone or in combination with C/EBPβ (i.e. CEBPB) and/or Prdm16 results in development towards white or brown adipocyte cell fate (see e.g. pages 2, 4-5, and fig. 2, supplemental fig. 6). Moreover, the prior art of Wu 1995 and Wu 1996 discloses that expression of C/EBPβ and PPARγ in fibroblasts (e.g. NIH-3T3 multipotential mesenchymal precursor cells) induces differentiation to adipocytes, which reads on the claim limitation of the brown adipocyte is directly induced from the somatic cell without first becoming iPS or ES cells (see e.g. abstracts, respectively). Further, Wu 1195 discloses that when C/EBPβ and PPARγ are present together they have a synergistic effect (see e.g. abstract). Further, Wu 1996 discloses that the induction of the PPARγ in fibroblasts is dependent on elevated levels of C/EBPβ (see e.g. page 4132).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the methods for generating brown adipocytes, as taught of Zhu, to incorporate inducing brown adipocytes directly from somatic cells, as taught by Ahfeldt, Wu 1995, and Wu 1996, with a reasonable expectation of success because one of ordinary skill in the art would know that obtaining brown adipocytes directly from somatic cells depends on the reprogramming-related gene expression of C/EBPβ. Further, a person of ordinary skill in the art would know that methods of obtaining brown adipocytes directly from somatic cells was known in the prior art because Ahfeldt discloses that expression of peroxisome proliferator-activator receptor gamma (PPARγ) in combination with C/EBPβ with results in fibroblast development towards a brown adipocyte cell fate (see e.g. pages 2, 4-5, and fig. 2, supplemental fig. 6). Moreover, an artisan of ordinary skill in the art of adipogenesis has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007). Furthermore, Zhu, Ahfeldt, Xu 1995, and Xu 1996 disclose methods of obtaining adipocytes, as discussed above. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Zhu is silent regarding a polypeptide comprising the reprogramming-related gene L-myc (L).
However, the prior art of Nakagawa discloses that the functional moieties of Myc proto-oncogene products are involved in transformation and promotion of direct reprogramming (see e.g. title, abstract. Additionally, the prior art of Williams teaches the family of Myc genes (i.e. c-myc and L-myc) enhance the efficiency of reprogramming non-pluripotent cells (see e.g. abstract, page 14, and para. 46).
In the instant case, it would have been obvious to combine C/EBPβ (C) and c-myc (M)(as taught by Zhu) with L-myc (L)(as suggested by Nakagawa and Williams) for fibroblast differentiation into brown adipocytes because MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the methods of generating brown adipocytes comprising C/EBPβ (C) and c-myc (M) (as taught by Zhu) and combine the reprogramming-related gene of L-Myc (as taught by Nakagawa and Williams), because one of ordinary skill in the art would know that adding additional reprograming-related genes would increase in reprogramming efficiency and ensure brown adipose tissue development (see Williams e.g. abstract and para. 46). Further, Zhu, Nakagawa, and Williams are directed to reprogramming methods (see e.g. abstracts, respectively). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues the obviousness rejection over Spiegelman et al. in view of Riming et al. and Williams et al. (Remarks, page 6-7).
Applicant’s arguments, with respect to the rejection of the claims over Spiegelman et al. in view of Riming et al. and Williams et al. have been fully considered and are persuasive due to the amendment to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Zhu et al., Ahfeldt T, et al., Wu, Zhidan, et al., Wu, Zhidan, et al., Nakagawa, Masato, et al., and Williams, et al., as discussed above.
Applicant asserts that Williams et al., does not teach what factors can be productively combined with c-Myc, and notes that there are combinations with c-Myc present in the application that result in generating no brown adipocytes (see Remarks, page 7).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicants are reminded that the test for obviousness is not whether the features of a secondary reference maybe bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413,208 USPQ 871 (CCPA 1981). The MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments.
In response to applicant's argument, Williams et al., is not cited for teaching C/EBPβ (C) or c-Myc (M) but adding L-Myc to produce the combination of C/EBPβ (C) L-Myc (L), and c-Myc (M), as discussed above, and the prior art of Zhu is cited for teaching a method for generating a brown adipocyte from a somatic cell in a mammal comprising introducing a polynucleotide encoding at least one brown adipocyte-related gene, as discussed above. As discussed above, Williams teaches the family of Myc genes (i.e. c-myc and L-myc) are important reprogramming factors (see e.g. page 14, para. 46). Therefore, a person of ordinary skill in the art would have used c-myc and/or L-myc as reprogramming factor, as discloses by Williams, in a method for generating a brown adipocyte from a somatic cell in a mammal, as taught by Zhu, to ensure the optimal amount of brown adipocytes are reprogrammed. Additionally, it is noted that the independent claim recites at least one brown adipocyte-related gene and at least one reprogramming-related gene.
Applicant argues unexpected results in providing a high number of brown adipocytes as well as high UCP1 mRNA levels in the brown adipocytes, generated with the claimed combinations (see present applications para. 53-55 and fig. 3 and 4)(Remarks, page 7-8).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicant arguments, there is not a claim limitation to an amount (e.g. a conversion rate) of somatic cells generated into brown adipocytes. Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., higher number of brown adipocytes) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to Applicants’ unexpected results, in submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964). It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992). It is noted that Applicant discloses unexpected results of the combination of CM(50), CLMG(9), CLM(36), CLG(37), or CMG(38), none of which contain P, as being comparable to or better than a combination involving both P and C, such as PC(43), PCM(25), PCL(24), or PCLM(19)(Figures 3 and 4), as taught by Spiegelman et al., in view of Hirning, and Williams et al. (Remarks, page 8). As discussed above, Zhu discloses an in vitro or ex vivo method for generating a brown adipocyte from a somatic cells, such as fibroblasts (see e.g. abstract, para. 36, 56-58, 69-71, 74, Example 1 and 4) of a mammal (e.g. human)(see e.g. abstract, para. 2, 52-56 and 92, claims 1-26, Example 1-4), and introduces a group of polynucleotides (i.e. reprogramming) are selected from the group consisting of C/ΕΒΡ-β (C), c-Myc (M), and any combination thereof (see e.g. paras. 36, 47-49, 97; pages 25-29; Examples 1 and 4; claims 6, and 9). Therefore, it is unclear how the results are not obvious over the current obviousness rejection (i.e. Zhu et al., Ahfeldt T, et al., Wu, Zhidan, et al., Wu, Zhidan, et al., Nakagawa, Masato, et al., and Williams, et al.).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., high expression of UCP1 mRNA levels in brown adipocytes) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As discussed above, the instant rejection is based on the claim independent claim that recites at least one brown adipocyte-related gene and at least one reprogramming-related gene. It is noted that the Applicant generated high UCP1 mRNA levels in the brown adipocytes but there is not a claim limitation directed to brown adipocytes generated by C/EBPβ and c-Myc with having high expression of UCP1 mRNA levels in the brown adipocytes.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Tontonoz P, Hu E, Spiegelman BM. (Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994 Dec 30;79(7):1147-56. doi: 10.1016/0092-8674(94)90006-x. Erratum in: Cell 1995 Mar 24;80(6):following 957. PMID: 8001151); Lefterova, Martina I., et al. "PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale." Genes & development 22.21 (2008): 2941-2952; Zhu, Jianguo, et al. "Direct conversion of porcine embryonic fibroblasts into adipocytes by chemical molecules." Cellular Reprogramming 14.2 (2012): 99-105; and Park, Byung Ouk, et al. "Consecutive positive feedback loops create a bistable switch that controls preadipocyte-to-adipocyte conversion." Cell reports 2.4 (2012): 976-990.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 10AM - 5:00PM (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, Tracy Vivlemore can be reached at 571-272-2914. 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.
Josephine Gonzales PhD
Examiner
Art Unit 1638
/JOSEPHINE GONZALES/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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