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
This action is in response to the papers filed October 27, 2025.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/27/2025 has been entered.
Claim Amendments
Applicant’s amendment to the claims filed 10/27/2025 is acknowledged.
Claims 10-21 are pending.
Claims 11, 13, 15, 17 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 10, 12, 14, 16, 18, 20-21 are under examination.
Election/Restrictions
The following is a summary of the restriction/election requirements in the application. See the Requirement for Restriction/Election mailed 09/17/2024.
Applicant elected without traverse Invention I, drawn to a method of generating a brown adipocyte, and ALK-5 inhibitor II, as the inhibitor molecule, in the reply filed 11/18/2024. As previously stated in the Office action mailed 12/23/2024, the non-elected species of SB431542 had been rejoined.
Claims 11, 13, 15, 17 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/18/2024.
Priority
The instant application 18/517,402 was filed on 11/22/2023. This application is a continuation (CON) of U.S. Application No. 15/750,285 filed 07/03/2018, which is a national stage of international application filed 08/08/2016, claiming priority based on Japanese patent application JP2015-157697 filed 08/07/2015.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 in U.S. Application No. 15/750,285. The international application was published as WO 2017/026462 A1 in a non-English language, and a translator’s declaration has been filed on 07/03/2018 in U.S. Application No. 15/750,285. While a certified copy of the foreign patent application (JP2015-157697) has been provided, a certified English translation of said foreign patent application has not been provided.
Terminal Disclaimer
The terminal disclaimer filed on 10/26/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on U.S. Application No. 18/394,085 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 06/26/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The previous nonstatutory double patenting (NSDP) rejection over copending U.S. Application No. 18/394,085 has been withdrawn in light of the terminal disclaimer filed on 10/26/2025. The previous NSDP rejection over claims 1-9 of U.S. Patent No. 11,459,546 B2 has been withdrawn in light of the amendment to the claims and applicant’s remarks filed on 10/27/2025. In particular, the present claims have been amended to exclude additional TGFβ/SMAD pathway inhibitors that fall outside the Markush grouping of claim 10 (“an ALK4 inhibitor, an ALK5 inhibitor, and an ALK7 inhibitor”). See, pg. 6 of applicant’s reply.
Claim Rejections - 35 USC § 112
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 10, 12, 14, 16, 18, 20-21 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.
This rejection is newly applied, necessitated by amendment. This is a new matter rejection.
Claim 10 has been amended to recite “wherein the TGFβ/SMAD pathway inhibitor consists of at least one selected from the group consisting of an ALK4 inhibitor, an ALK5 inhibitor, and an ALK7 inhibitor.” The amendment is considered new matter.
In this case, the phrase “at least one” indicates that any combination or mixture of two or more of an ALK4 inhibitor, an ALK5 inhibitor, and an ALK7 inhibitor may be present, i.e., a mixture consisting of an ALK4 inhibitor and an ALK5 inhibitor, or a mixture consisting of an ALK5 inhibitor and an ALK7 inhibitor, or a mixture consisting of an ALK4 inhibitor and an ALK7 inhibitor, or a mixture consisting of an ALK4 inhibitor and an ALK5 inhibitor and an ALK7 inhibitor. Applicant’s remarks filed 10/27/2025 do not clearly identify where written support for this new limitation may be found in the original disclosure. The examiner cannot identify written support for this new limitation in the original disclosure.
For these reasons, claim 10 is considered to recite new matter. Dependent claim 12, 14, 16, 18, 20-21 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend. Applicant may overcome this rejection by deleting the phrase “at least one” in claim 10, or by precisely identifying where in the original disclosure there is sufficient written description for the recited combinations/mixtures.
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.
Claims 10, 12, 14, 16, 18, 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/010746 A1 to Kishida et al.; in view of Zhu et al. (2012) “Direct Conversion of Porcine Embryonic Fibroblasts into Adipocytes by Chemical Molecules”, Cellular Reprogramming, Vol. 14, No. 2, pg. 99-105; and WO 2015/199097 A1 to Kiuchi et al. (filed: 06/23/2015; published: 12/30/2015).
This rejection is newly applied, necessitated by amendment. A response to applicant’s traversal follows this rejection.
Translations:
The Kishida disclosure (WO 2014/010746 A1) was published in a non-English language. This rejection relies on a European Patent Office (EPO) machine translation of the disclosure provided with this action.
The Kiuchi disclosure (WO 2015/199097 A1) was published in a non-English language. This rejection relies on a Google Patents machine translation of the disclosure provided with this action.
Grounds of rejection:
Kishida (WO 2014/010746 A1) discloses a method of producing a brown adipocyte by culturing a fibroblast cell in a “differentiation induction medium for differentiating brown adipocytes” comprising insulin, isobutylmethylxanthine (IBMX), dexamethasone, indomethacin, T3 and rosiglitazone. See pages 6 and 8 of the provided machine translation; see Figure 1.
Kishida does not teach that the cell culture medium further comprises SB431542, as recited in the claimed invention.
Zhu is relevant prior art for teaching that transforming growth factor-beta (TGF-β) signaling pathway inhibitor SB431542 promotes the differentiation of a fibroblast into an adipocyte. See Abstract; pg. 100, 103; fig. 1-2.
In addition, Kiuchi is relevant prior art for disclosing that uncoupling protein-1 (UCP-1) is highly expressed in brown adipocytes and that combining a PPARγ agonist, such as rosiglitazone, with a Smad3 inhibitor, such as SB431542, synergistically induces the expression of UCP-1 in a starting population of preadipocytes, thereby promoting differentiation into brown adipocytes. See Figure 8; see Abstract, “Specifically provided is a UCP-1 expression promoter obtained by combining a PPAR-γ activator and a SMAD3 inhibitor”; page 3, “Brown adipocytes, … specifically UCP-1 (uncoupling protein-1) is highly expressed”; page 4, “when using a PPARγ activator and a Smad3 inhibitor in combination, … it significantly promotes the expression of UCP-1 and promotes brown fatification”; page 6, “when a PPARγ activator and a Smad3 inhibitor are combined and added to rat subcutaneous fat-derived cultured cells, the expression of the UCP-1 gene is significantly increased, … It can be said that it is a synergistic effect that exceeds the additive effect obtained in some cases”; page 11, “The preadipocytes (n = 3) obtained above were seeded in a 12-well plate coated with type I collagen, and the next day PPARγ activator (rosiglitazone (Rosi) (Wake Pure Chemical Industries), 10 μM) and Smad3 An inhibitor (SIS3 (SIGMA) or SB431542 (SIGMA): 10 μM) was added. After culturing for 7 days, … FIG. 8 indicates that the expression level of UCP-1 increased synergistically by adding rosiglitazone to SIS3 or SB431542 and norepinephrine”. The quotations originate from the provided machine translation.
To summarize, Kishida discloses a medium for inducing brown adipocyte differentiation comprising rosiglitazone, and Kiuchi further discloses that combining rosiglitazone with SB431542 synergistically induces UCP-1 expression, thereby promoting brown adipocyte differentiation.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify a medium for inducing brown adipocyte differentiation, as found in Kishida, to further comprise SB431542, as taught by Zhu and Kiuchi, with a reasonable expectation of success because SB431542 promotes the differentiation of a fibroblast into an adipocyte (Zhu, Abstract; pg. 100, 103; fig. 1-2), and combining rosiglitazone with SB431542 synergistically induces UCP-1 expression, which is a marker highly expressed in brown adipocytes (Kiuchi, see citations above).
Claim 10 further recites that the fibroblast is cultured for “3 to 30 days” in the recited induction medium. Kishida cultures the fibroblast for 2 days in a medium comprising insulin, isobutylmethylxanthine, dexamethasone, indomethacin, T3 and rosiglitazone (pg. 8), and 2 days is close to the claimed range of 3-30 days. Zhu cultures the fibroblast in a medium comprising SB431542 for 5, 10, 15 and 20 days (Figure 1), and 5, 10, 15 and 20 days lie inside the claimed range of 3-30 days. Kiuchi cultures preadipocytes for 7 days in a medium comprising rosiglitazone and SB431542 (pg. 11), and 7 days lies inside the claimed range of 3-30 days. MPEP 2144.05 instructs that, where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). In this case, the cited references either teach a number of days that lies inside the claimed range (Zhu and Kiuchi), or a number of days that is merely close to the claimed range (Kishida). Moreover, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this case, the number of days is a result-effective variable that one of ordinary skill in the art would have been led to optimize by routine experimentation. For example, Figure 1 of Zhu shows that the number of days is a variable that effects the degree of Oil Red O staining and lipid accumulation of adipocytes derived from the process. For these reasons, absent a secondary consideration, the claimed range of “3 to 30 days” would have been prima facie obvious over the cited references.
Kishida further teaches that the fibroblast may be obtained from an adult, a child or a fetus. (See, pg. 3-4, joining paragraph, of the machine translation, “The somatic cells... include fibroblast... The origin of the somatic cell may be an adult, a child or a fetus;” and see, pg. 8, “Example 1... human normal skin fibroblast cell line aHDF [adult human dermal fibroblast]”). Kishida does not expressly teach that the fibroblast is obtained from an “infant,” as claimed in claim 21. However, one of ordinary skill in the art would have recognized that fibroblasts are found in infants, and Kishida teaches that the fibroblast may be obtained from a subject at a range of developmental stages, i.e., from an adult, a child or a fetus. Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to obtain the fibroblast from an infant with a reasonable expectation of success, e.g., for providing an infant subject with an autologous cell-based therapy (Kishida, pg. 6 of the machine translation, “it is desirable that the transplanted cells for prophylaxis or therapy are autologous cells established from the patients themselves”).
For these reasons, the process of claims 10, 12, 14, 16, 18, 20-21 would have been prima facie obvious over the cited references.
Response to arguments
In arguments filed on 10/27/2025, applicant argues that Zhu teaches use of embryonic fibroblasts, which are considered to retain a substantial degree of pluripotency and relatively high plasticity compared to adult fibroblasts. Therefore, the results in Zhu are not predictable for a method of culturing fibroblast derived from adult or infant tissue, as recited by the instant claims and as found in Kishida. Therefore, Zhu and Kishida cannot be combined to arrive at the instantly claimed invention. See, pg. 5 of applicant’s reply.
Applicant’s arguments have been carefully considered, but are not found persuasive for the following reasons:
As an initial matter, applicant is respectfully reminded that arguments cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). In this case, applicant’s argument regarding differences between embryonic fibroblasts and adult fibroblasts is not supported by objective evidence, e.g., by citation to the scientific literature available at the time of invention.
Kishida teaches that the fibroblast may be obtained from a subject at a range of developmental stages, i.e., from an adult, a child or a fetus (see, rejection above). Also, Osonoi et al. (2011) “Fibroblasts have plasticity and potential utility for cell therapy” Human Cell, 24:30-34, discloses that adult fibroblast possess plasticity and are able to differentiate directly to all three germ layer derivatives. See, e.g., Abstract, and pg. 30. Therefore, the preponderance of evidence fairly suggests that adult fibroblasts do possess a suitable degree of plasticity for adipocyte differentiation, and there would have been a reasonable expectation of success in using adult fibroblasts to generate adipocytes.
Moreover, Lu et al. (2013) “Regulation of adipocyte differentiation and gene expression-crosstalk between TGFβ and wnt signaling pathways” Molecular biology reports, 40(9), 5237-5245, discloses that the Wnt/β-catenin and TGFβ signaling pathways play a critical role in inhibiting adipogenesis. TGFβ inhibits adipogenesis by signaling through Smad3 which cooperatively binds to smad4 to repress the transactivation function of C/EBPβ and C/EBPδ thus preventing their transcriptional activity on the promoters of key adipogenic genes such as leptin and PPARγ. See, Introduction on pg. 5237-5238. Accordingly, one of ordinary skill in the art would have recognized that TGFβ signaling pathways inhibit adipogenesis, and thus one would have been led to inhibit TGFβ signaling pathways when seeking to generate adipocytes, as in Zhu.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D 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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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631