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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Status
Claims 1-6, and 8-15 were previously pending.
Applicant previously elected without traverse of the invention of group I (claims 1-6) in the reply filed on 09 June, 2025 and the restriction requirement issued 08 April, 2025, was still deemed proper and made FINAL.
Receipt is acknowledged of the amendments to the claims filed 10 November, 2025. Claims 1 and 2 are amended. Claims 3-4, 6, and 8-11 are cancelled. Therefore, claims 1-2, 5, and 12-15 are pending.
Claims 12-15 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1, 2, and 5 are pending and under examination in the present Official Action.
Claim Objections
The amendment to the claims filed on 11/10/2025 does not comply with the requirements of 37 CFR 1.121(c) because changes in the texts of claims 12-15 was not completely marked with respect to withdrawn claims as set forth the office action filed on 7/23/2025. Specifically, claims 8-15 were previously withdrawn from further consideration by the examiner pursuant to 37 CPR 1.142(b) as being drawn to a nonelected invention. Thus, clams 12-15 are not identified with the proper status in the claim listing. Amendments to the claims filed on or after 07/23/2025 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
Any further claim amendments must comply with 37 CFR 1.121(c) or they may not be entered.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2020/042898, filed 18 November, 2020, which claims priority to Japan Application No. JP2019-211990, filed 25 November, 2019. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Acknowledgement is made of applicant’s filing of certified untranslated copies of papers required by 37 CFR 1.55 in this application on 25 May, 2022.
The earliest possible priority for the instant application is 25 November, 2019.
Drawings
The drawings filed on 25 May, 2022 are accepted by the Examiner.
Claim Objections
Claim 5 remains objected to because of the following informalities: Rosiglitazone and Forskolin should be capitalized because they are proper nouns. Appropriate correction is required. Applicant has not addressed this objection in their response filed 10 November, 2025.
Withdrawn Rejections/Objections in view of Applicant’s Amendments/Arguments
Claim Objections
The objection to claims 1-5 because of the following informalities: abbreviations/acronyms must be spelled out upon their first encounter in the claims (e.g. PPARγ, cAMP, BMP7, ALK2/3, ALK6, ALK5) is withdrawn in view of Applicant’s amendments. Applicant has spelled out all abbreviations/acronyms.
Claim Rejections - 35 USC § 112
The rejection of claims 2-4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicants amendments to the claims.
Applicant has amended claim 2 to remove prior-raised issues of indefiniteness and cancelled claims 3-4.
Double Patenting
The rejection of claims 1-2, and 5 on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,459,546 in view of Takeda et al. (Scientific reports 7.1 (2017): 4304., hereinafter “Takeda”, of record), Totonchi et al. (International Journal of Developmental Biology 54.5 (2010)., hereinafter “Totonchi”, of record), and Tseng et al. (Nature 454.7207 (2008): 1000-1004., hereinafter “Tseng”, of record) is withdrawn in view of Applicant’s amendments to the claims.
Applicant has amended claim 1 to expressly exclude an ALK 2/3 inhibitor, an ALK 6 inhibitor and an ALK 5 inhibitor. Reference claim 1 expressly requires the presence of an ALK5 inhibitor, an ALK6 inhibitor, an AMPK inhibitor, an ALK2 inhibitor, and an ALK3 inhibitor. Therefore, the reference claims no longer render obvious the pending claims.
Maintained Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 103
Claims 1-2, and 5 remain rejected under 35 U.S.C. 103 as being unpatentable over Takeda et al. (Scientific reports 7.1 (2017): 4304., hereinafter “Takeda”, of record) in view of Totonchi et al. (International Journal of Developmental Biology 54.5 (2010)., hereinafter “Totonchi”, of record), and Tseng et al. (Nature 454.7207 (2008): 1000-1004., hereinafter “Tseng”, of record). This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Takeda discloses a method for direct conversion of fibrobasts to brown adipocyte-like cells comprising culturing the fibroblasts in DMEM supplemented with rosiglitazone and forskolin (Takeda, page 9, second and third full paragraphs). Takeda teaches that Rosiglitazone is a PPARγ agonist (Takeda, Abstract) and that Forskolin is a cAMP inducer (Takeda, page 2, first full paragraph). Takeda also teaches that their chemical induction method avoids undesired effects from gene induction procedures for generating iPSCs (Takeda, Abstract). Thus, Takeda teaches a method of inducing fibroblasts into brown adipocytes via chemical induction as an alternative to genetic induction medium methods. Takeda teaches various chemical cocktails for culturing the fibroblasts into brown adipocytes (Takeda, Table 2). All of the possible media contained Rosiglitazone and some contained Forskolin (F), SB-431542 (S), LDN-193189 (L), and/or Dorsomorphin (D) (Takeda, page 2, “Results” heading, first two paragraphs; Table 2). Takeda teaches 3 combinations which comprise Rosiglitazone and Forskolin and which do not comprise either S, L, or D alone or in combination and which efficiently convert fibroblasts into brown adipocytes (Takeda, Table 2) (see below).
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Note that the instant specification teaches that SB431542 is an ALK5 inhibitor, LDN193189 is an ALK2/3 inhibitor, and that Dorsomorphin is an ALK2/3/6 inhibitor (Instant specification, [0003]). Thus, Takeda teaches 3 media for culturing fibroblasts to produce brown adipocytes which comprise both Rosiglitazone and Forskolin and which do not comprise an ALK5 inhibitor, an ALK2/3 inhibitor, or an ALK6 inhibitor.
It is noted that Takeda teaches each of those 3 media facilitate conversion of fibroblasts into brown adipocytes with varying levels of efficiency (Takeda, Table 2).
Takeda does not teach the use of a serum-free base medium as required by instant claim 1.
Totonchi teaches serum and feeder-free culture conditions for human somatic cell reprogramming (Totonchi, page 878, second full paragraph). Totonchi teaches that their method greatly simplifies induction of pluripotency in human somatic cells and that their feeder-free method enhanced the efficiency of alkaline positive cells greater than 10-fold from human adult fibroblasts (Totonchi, page 878, second and fourth full paragraph). Totonchi also teaches that their method brings in vitro generated cells and tissues (generated from fibroblasts) one step closer to clinical applications by overcoming issues with scale of production, establishment of feeder-free cultures qualified for transplant, and long-term stability (Totonchi, page 878, first partial paragraph and second full paragraph). Thus, a person having ordinary skill in the art would have understood from Totonchi that the use of a serum-free medium simplifies cell therapy products and brings them one step closer to clinical applications.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have substituted a serum-free medium as taught by Totonchi for the base medium of Takeda and arrive at the invention claimed in instant claim 1 with a reasonable expectation of success because they would have been motivated to do so to simplify the method of producing brown adipocyte-like cells and bring it one step closer to clinical applications by overcoming issues with scale of production, establishment of feeder-free cultures qualified for transplant, and long-term stability. As use of serum free media facilitates human somatic cell reprogramming/differentiation including reprogramming/differentiation of fibroblasts, culture of somatic cells including fibroblast in serum free media would have been reasonably expected by a person having ordinary skill in the art to facilitate reprogramming/differentiation of fibroblasts into another types of cells, e.g., brown adipocytes.
Regarding claim 2, the combination of Takeda and Totonchi does not teach or suggest adding BMP7 to the medium.
Tseng teaches that while some members of the family of bone morphogenic proteins (BMP) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes (Tseng, Abstract). Tseng also teaches that BMP7 activates a full program of brown adipogenesis including increasing expression of the adipogenic transcription factor PPARγ among others (Tseng, Abstract). Tseng also teaches that BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage (Tseng, Abstract). Tseng also teaches adding BMP7 to a medium (Tseng, “METHODS” heading, first two paragraphs).
Therefore, upon viewing the teachings of Takeda, Totonchi, and Tseng, it would have been prima facie obvious to a person having ordinary skill in the art to have added BMP7 as taught by Tseng to the medium taught by Takeda and Totonchi and to have arrived at the invention claimed in instant claim 2 with a reasonable expectation of success because they would have been motivated to do so to more selectively drive differentiation towards the brown adipocyte lineage as taught by Tseng.
Regarding instant claim 5, Takeda teaches both Rosiglitazone and Forskolin.
Response to Arguments
Applicant argues against the asserted prima facie obviousness of claims 1-2, and 5 by arguing (1) that Takeda does not disclose a serum-free base medium, Totonchi does not teach a direct-conversion method, and there would not have been a reasonable expectation of success in eliminating serum from the medium of Takeda, (2) the instant method produces unexpected results. These arguments have been fully considered but have not been found persuasive for the following reasons.
(1) Applicant argues “Applicant respectfully disagrees. As admitted on page 7 of the office action, Takeda fails to disclose use of a serum-free base medium. Moreover, a person of ordinary skill in the art ("POSITA") would not have been motivated to combine Totonchi with Takada and would not have expected success from such combination. The claimed invention is directed at "process for producing brown adipocytes by direct differentiation induction from a fibroblast," but Totonchi is directed at generating pluripotent stem cells with artificial gene transfer and therefore lacks relevance. Accordingly, a POSITA would not have found any motivation to combine the serum free system of Totonchi-used for generating stem cells-to the process described in Takeda inducing fibroblasts to brown adipocytes. Further, a POSITA would not have expected to successfully generate brown adipocytes from fibroblasts by eliminating serum from the growth medium of Takeda simply because Totonchi used a serum-free medium for an unrelated process of generating stem cells.” (Remarks, page 4).
This argument has been fully considered but has not been found persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While it is true that Takeda teaches a direct conversion method and Totonchi teaches an iPSC method, these publications share the goal of producing cell therapy products. Further, both Totonchi and Takeda teach fibroblasts as the starting cell for reprogramming and Totonchi teaches that their serum-free culture method brings in vitro generated cells and tissues one step closer to clinical applications by overcoming issues with scale of production, establishment of feeder-free cultures qualified for transplant, and long-term stability. Thus, a person having ordinary skill in the art would understand the teaching of a serum-free base medium simplifying the product and bringing it one step closer to clinical applications (Totonchi) to be readily applicable to other such cell therapy product production methods, especially those aimed at fibroblasts as the starting cell type. The fact that Totonchi does not teach direct conversion and that Takeda does not teach a serum-free medium does not suffice to destroy the motivation plainly evident in the combination of Takeda and Totonchi. With regard to the argument that there would not have been a reasonable expectation of success, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In the instant case, the advantage to using a serum-free medium is generally applicable to cell therapy production methods and is not limited to only the context in Totonchi. A person having ordinary skill in the art would have reasonably expected the serum-free medium to have had similar properties in Takeda to those it possessed in Totonchi. Therefore, there would have been a reasonable expectation of obtaining similar properties in using a serum-free base medium in the method of Takeda. Accordingly, Applicant’s arguments have been fully considered but have not been found persuasive.
(2) Applicant argues “Moreover, evidence of unobvious or unexpected advantageous properties, such as superiority in a property the claimed compound shares with the prior art, can rebut prima facie obviousness. See M.P.E.P.§§ 716.02(a) and 2144.09. In the instant application, Applicants respectfully submit that the present claims are not rendered obvious by the cited references in view of the unexpectedly superior property of the claimed process, which are not present in the compositions of the cited references. Specifically, the presently claimed process results in an unexpectedly superior conversion of fibroblasts into brown adipocytes. Examples 3 and 4 shown in table 3 correspond to the claimed process because they include a PPARy agonist (Rosiglitazone) and a cAMP inducer (Forskolin) but do not include any of the AKL2/3, 5, and 6 inducers (i.e., LDN193189, Dorsomorphin, SB431542). These two examples demonstrate a higher expression level of Ucp1, a brown adipocyte-specific gene. See Table 3, Figures 4 and 5)” (Remarks, pages 4-5).
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This argument has been fully considered but has not been found persuasive because Applicant has merely directed the Examiner’s attention to figures already on the record without any direct or indirect comparison to the closest prior art method (the method of Takeda). Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. In fact, Takeda does present Ucp1expression data in a format identical to instant Figures 4 and 5 (See Takeda Figure 3 (left)). In comparison to the 5CD-GM medium which is presented with “++++” in table 2 of Takeda, the MF medium presents with a “++” in table 2. Thus, it would appear that the MF medium (which is the same as instantly claimed except without a serum-free base medium) would lay somewhere around 2500 relative mRNA expression for Udp1. The instant figures 4 and 5 present a relative expression of around 1/10th the level evident in the Takeda reference. Therefore, it is unclear how the results presented in instant figures 4 and 5 are “unexpected” or “superior” to those a person having ordinary skill in the art would have expected in combining the teachings of Takeda and Totonchi. In addition, the results referenced by Applicant here were generated from brown adipocytes which were produced from human fibroblasts cultured in DMEM medium supplemented with
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either 1μM Rosiglitazone, 7.5μM Forskolin, and 20ng/mL BMP7 or 1μM Rosiglitazone, and 7.5μM Forskolin for 3 weeks followed by a 1 week culture in DMEM medium supplemented with the ingredients in instant Table 4 (right) (Specification, [0067]-[0074]). The instant claims contain no such two-step culturing method, nor are the instant claims specific to the ingredients and quantities used in generating the data upon which the Applicant relies here. Accordingly, these arguments have been considered but are not found to be persuasive.
Provisional Double Patenting
Claims 1-2, and 5 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-12 of copending Application No. 18/692,497 (reference application) in view of Takeda et al. (Scientific reports 7.1 (2017): 4304., hereinafter “Takeda”, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims 8-12 are related to the instant claims 1-2, and 5 as species-genus and claims 1-2, and 5 are obvious over the reference claims in view of Takeda.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 8 claims “A method of producing low-molecular-weight compound-induced brown adipocytes by inducing differentiation directly from a somatic cell using a compound targeting a cell membrane receptor and having a browning-promoting effect on brown adipocytes, wherein the method comprises a step of culturing a somatic cell in a serum-free differentiation induction medium in which the compound, a selective PPARγ agonist, and a cAMP inducer are present.” This claim is a species of the genus of methods claimed in instant claim 1. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann , 572 F.2d 312, 197 USPQ 5 (CCPA 1978).
Dependent claim limitations found in instant claims 2, and 5 can be found throughout reference claims 9-12.
Insofar as claim 1 is a species of the reference claims as it requires the medium to be absent of an ALK2/3 inhibitor, an ALK5 inhibitor, and an ALK6 inhibitor, Takeda teaches these claim limitations and provides motivation to select such a medium. Therefore, instant claims 1-2, and 5 would have been prima facie obvious to a person having ordinary skill in the art in view of the reference claims and Takeda.
New Grounds of Rejection
Claim Rejections - 35 USC § 112- First paragraph- New Matter
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 1, 2, and 5 are rejected under 35 U.S.C. 112, 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(s), at the time the application was filed, had possession of the claimed invention. This is a new rejection necessitated by amendment of the claims in the response filed 11/10/2025.
Claim 1 has been amended to recite “the process directly induces differentiation from the fibroblast to the brown adipocytes without generating a pluripotent stem cell from the fibroblast”
Applicants at paragraph [0029] of the published application discloses “ Somatic cells at various stages of differentiation, e.g., terminally differentiated somatic cells (e.g., fibroblasts,….. somatic cells that have differentiated or are in the process of differentiation from iPS cells, can be used in the present invention process”. The Specification does not provide support for differentiation of fibroblast to brown adipocytes without generating a pluripotent stem cell from the fibroblast.
The prior art of Totonchi et al. (International Journal of Developmental Biology 54.5 (2010)., discloses differentiation of fibroblasts into induced pluripotent stem cells (hiPSCs).
Hence, is not clear that the Applicant was in possession of a genus of undefined “differentiation from the fibroblast to the brown adipocytes without generating a pluripotent stem cell from the fibroblast” before the effective filing date of the claimed invention.
Claims 1, 2, and 5 will remain rejected until Applicant cancels all new matter.
Conclusion
No claim is allowed.
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 BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MARIA G LEAVITT can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634