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 .
Status of Claims
Claims 1-17 are pending.
Priority
Claims 1-17 are a 371 of PCT/JP 2022/034540 filed on September 15, 2022, which has priority to foreign application JAPAN 2021-163080 filed on September 21, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on March 15, 2024, and on November 12, 2025, were filed before the mailing of the First Office Action on May 9, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7 are rejected 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.
Claim 1 recites “comprises a step of measuring the browning index of low-molecular-weight compound-induced brown adipocytes with and without a candidate compound applied to the brown adipocytes”. As written, the phrase “with or without a candidate compound applied” could be interpreted as either control cultures versus treated cultures or sequential measurements within the same culture. Because of this, a person of ordinary skill would not understand the context of the standard screening assays.
Claims 2-7 are also rejected based on their dependency to claim 1.
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.
Claims 1-17 are rejected under 35 U.S.C. §103 as being unpatentable over Takeda et al. [Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds, Nature Scientific Reports, 2017], in view of Ye et al. [TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis, Cell, 2012], in view of Tseng et al. [New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure, Nature, 2009].
Regarding claim 1, Takeda et al., discussing brown adipocytes’ role in energy metabolism, discloses low-molecular weight compound-induced brown adipocytes through measuring browning-associated gene expression, e.g. Ucp1, Fabp4 [Abstract]. Additionally, Takeda et al. also teaches “the measuring the browning index of low-molecular-weight compound-induced brown adipocytes” by comparing gene expression levels in ciBAs treated with forskolin versus DMSO [Functional Beta-adrenergic receptor signaling for thermogenesis in ciBAs ¶ 1]. Lastly, although Takeda et al. does not specifically disclose characterize these experiments as “screening”, the disclosed analysis conducted inherently constitutes a screening-compatible assay system, given the authors evaluated the biological activity of exogenous small molecules on defined cellular phenotypes using quantitative gene expression readouts [Fig. 1].
For claim 2 where the compound having a browning-promoting or browning-inhibiting effect acts on brown adipocytes via TRPV1 or TRPV4, Ye et al. teaches that TRPV4 is a key regulator of adipocyte thermogenesis and that modulation of TRPV4 activity using small molecules alters Ucp1 expression and oxidative metabolism in brown adipocytes [Introduction ¶ 3-4].
For claim 3 where brown adipocytes are differentiated directly from somatic cell cultured in serum-free differentiation induction in which a selective PPARγ agonist and a cAMP inducer are present, Takeda et al. teaches direct conversion of somatic cells, i.e. fibroblasts, into brown adipocytes using low-molecular weight compounds by activating adipogenic and thermogenic pathways [Abstract, Results ¶ 1]. Furthermore, the use of “serum-free differentiation induction medium” is a well-known method and has been in common practice in cell biology. Because of this, a person of ordinary skill in the art would have known that using a serum-free differentiation induction medium could be used.
For claim 4 where the screening method of claim 3 further comprises the step of culturing somatic cells in the presence of BMP7, Tseng et al., discussing the role of BMP7 in brown adipogenesis, teaches that BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normal required hormonal cocktail [Abstract]. Furthermore, Tseng et al. teaches that BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 and PGC-1, which is a PPARγ coactivator [Id.].
For claim 5 where the selective PPARγ agonist is rosiglitazone or the cAMP inducer comprises forskolin, Takeda et al. teaches the use of modified combinations of chemical compounds that included rosiglitazone, a PPARγ agonist, afforded direct conversion of human fibroblasts into brown adipocytes [Abstract].
Regarding claim 6 where the somatic cell is a fibroblast, again, Takeda et al. directly teaches the conversion of human fibroblasts, i.e. a somatic cell, into brown adipocytes [Abstract].
Regarding claim 7 where the browning index consists of Ucp1 gene expression, Fabp4 gene expression, Cidea gene expression, etc., Takeda et al. discloses that the chemical compound inducing brown adipocytes exhibited induction of brown adipocyte-specific genes such as Ucp1, Ckmt1, Cited1 and other adipocyte specific genes that also included Fabp4, ADipoQ, and Pparγ [Abstract].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Takeda et al. where fibroblasts were converted into functioning brown adipocytes using small molecule compounds with the additional teachings of Ye et al. and Tseng et al. where Ye et al. discussed how TRPV4 played a role in regulating oxidative metabolism and energy homeostasis with the Tseng et al. discussing how BMP7 activates a full program of brown adipogenesis. Taking together, a person of ordinary skill would have had a reasonable expectation of success of combining the teachings of Takeda et al. where chemically induced brown adipocytes from human fibroblasts, i.e. somatic cells, were evaluated for thermogenic gene expression with the teachings of Tseng et al. that teaches the Ucp1 and related markers are routinely used to identify compounds that modulate adipocyte browning with the further teachings of Ye et al. that taught TRPV4 is a key regulator of adipocyte thermogenesis and that modulation of TRPRV4 activity affects browning-associated gene expression.
Regarding claim 8 where a method of producing low-molecular-weight compound-induced brown adipocytes by inducing somatic cells, Takeda et al. discloses the induction of brown adipocytes from human fibroblasts using small-molecule combinations that include both PPARγ agonist activity and cAMP pathway activation that result in cells expressing brown adipocyte markers such as Ucp1 [Abstract, Results ¶ 1]. Additionally, the use of “serum-free differentiation induction medium” is a well-known method and has been in common practice in cell biology. Because of this, a person of ordinary skill in the art would have known that using a serum-free differentiation induction medium could be used.
For claim 9 where the compound having a browning-promoting effect comprises a TRPV1 agonist or a TRPV4 antagonist, Ye et al. discloses the use of the use of TRPV4 antagonists [Summary].
For claim 10, Tseng et al., discussing the role of BMP7 in brown adipogenesis, teaches that BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normal required hormonal cocktail [Abstract]. Furthermore, Tseng et al. teaches that BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 and PGC-1, which is a PPARγ coactivator [Id.].
For claim 11, Takeda et al. discloses the use of the PPARγ agonist rosiglitazone and cAMP inducer forskolin were both used [Results, Identification of chemical compounds for direct conversion from human fibroblasts to adipocyte-like cells].
For claim 12 where the somatic cells are fibroblasts, see analysis for claim 6.
For claim 13, see analysis for claim 8.
For claim 14 see analysis for claim 9.
For claim 15, see analysis for claim 10.
For claim 16, see analysis for claim 11.
For claim 17, see analysis for claim 6.
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Takeda et al. where fibroblasts were converted into functioning brown adipocytes using small molecule compounds with the additional teachings of Ye et al. and Tseng et al. where Ye et al. discussed how TRPV4 played a role in regulating oxidative metabolism and energy homeostasis with the Tseng et al. discussing how BMP7 activates a full program of brown adipogenesis. Taking together, a person of ordinary skill would have had a reasonable expectation of success of combining the teachings of Takeda et al. where chemically induced brown adipocytes from human fibroblasts, i.e. somatic cells, were evaluated for thermogenic gene expression with the teachings of Tseng et al. that teaches the Ucp1 and related markers are routinely used to identify compounds that modulate adipocyte browning with the further teachings of Ye et al. that taught TRPV4 is a key regulator of adipocyte thermogenesis and that modulation of TRPRV4 activity affects browning-associated gene expression for use in developing a method for inducing fibroblasts into brown adipocytes and further developing a composition for differentiating somatic cells, e.g. fibroblasts, into brown adipocytes.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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