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 .
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Misnumbered claim 26 has been renumbered 27.
Misnumbered claim 27 has been renumbered 28.
Misnumbered claim 28 has been renumbered 29.
Misnumbered claim 29 has been renumbered 30.
Misnumbered claim 30 has been renumbered 31.
Misnumbered claim 31 has been renumbered 32.
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.
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, 3-5, 7-9, 21-25, 28, 29, and 31 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, 2017) in view of Wang et al. (Evaluation and optimization of differentiation conditions for human primary brown adipocytes, 2018), Yu et al. (Stemness and transdifferentiation of adipose-derived stem cells using L-ascorbic acid 2-phosphate-induced cell sheet formation, 2014) and Kouro et al. (In Vitro Differentiation and Measurement of B Cell Progenitor Activity in Culture, 2005) as evidenced by FujiFilm Wako Pure Chemical Corporation (D-MEM (High Glucose) with L-Glutamine, Phenol Red, and Sodium Pyruvate)
Regarding claims 1 and 32: Takeda teaches a differentiation protocol using various small molecules to differentiate human fibroblasts into brown adipocytes. (Pg 1, Abstract) Specifically, the small molecules (which were added to a high-glucose DMEM base) include rosiglitazone and MK425, which contains ascorbic acid, biotin, pantothenic acid, triiodothyronine, octanoic acid, insulin, dexamethasone, 3-isobutyl-1-methylxanthine, FBS, and penicillin/streptomycin. (Pg 9, Methods) This reads on the use of fibroblasts as the somatic cell and the following in the culture media: a thyroid hormone receptor agonist, glucocorticoid receptor agonist, phosphodiesterase inhibitor, insulin, and an antibiotic.
Neither Takeda, Wang, nor Yu teach use of any gene introduction into the somatic cell being differentiated. In fact, Takeda specifies that it is preferable to carry out the differentiation process without use of genetically modified cells (in the instant case, iPSCs) in order to avoid undesired exogenous plasmids or effects from the transfection process. Therefore, use of non-edited cells is preferable. (Pg 1, Abstract)Takeda fails to teach use of specifically an ascorbic acid derivative or albumin.
Wang teaches a differentiation protocol for brown pre-adipocytes isolated from brown adipose tissue into mature brown adipocytes through use of an induction medium. (Pg 3, Fig 1A) Several differentiation cocktails were developed, one of which includes use of 2% fatty-acid free BSA (bovine serum albumin) (pg 2, Materials and Methods) and use of 3-isobutyl-1-methylxanthine (Pg 4, Results) This reads on use of an albumin and also a phosphodiesterase inhibitor.
While Takeda teaches use of ascorbic acid, both Takeda and Wang fail to teach use of specifically a derivative of ascorbic acid.
Yu teaches an adipocyte differentiation protocol which takes adipose-derived stem cells and uses L-ascorbic acid 2-phosphate to further enhance their markers of stemness and increase their transdifferentiation capabilities while being cultured in a tissue sheet. (Pg 3516, Abstract) Specifically, Yu teaches that use of L-ascorbic acid 2-phosphate is preferable to just ascorbic acid as it is significantly more stable than ascorbic acid and stimulates the growth of cells more effectively. (Pg 3517, Introduction) This reads on use of an ascorbic acid derivative. Takeda, Wang, and Yu all fail to teach use of a serum-free media.
Kouro teaches a serum free, feeder free differentiation protocol for the differentiation of B cells. (Pg 1-2, Basic Protocol 1) Specifically, Kouro teaches that the absence of serum allows for the direct effect of added cytokines to a media to be assessed and allows for single cell experiments to be performed. (Pg 1, Introduction)
Regarding claim 3: Takeda teaches us of the following, all found on page 9 in the Methods section:
Triiodothyronine (thyroid hormone receptor agonist)
Dexamethasone (glucocorticoid receptor agonist)
Isobutylmethylxanthine (phosphodiesterase inhibitor)
Insulin
Penicillin/streptomycin (antibiotic)
This reads on the claimed method of use of triiodothyronine as the thyroid hormone receptor agonist, dexamethasone as the glucocorticoid receptor agonist, isobutylmethlyxanthine as the phosphodiesterase inhibitor, insulin, and pen/strep as the antibiotic. Takeda fails to teach use of an ascorbic acid derivative or fatty-acid unbound albumin.
Wang teaches a differentiation cocktail containing fatty-acid free BSA. (pg 2, Materials and Methods) This reads on use of an albumin derivative. Wang fails to teach use of specifically an ascorbic acid derivative.
Yu teaches use of L-ascorbic acid 2-phosphate to further enhance their markers of stemness and increase their transdifferentiation capabilities while being cultured in a tissue sheet. (Pg 3516, Abstract) This reads on use of L-ascorbic acid 2-phosphate as the ascorbic acid derivative.
Regarding claims 4 and 5: Takeda teaches use of forskolin in the differentiation protocol to directly convert human fibroblasts into brown adipocytes. (Pg 9, Methods) This reads on the use of a cAMP inducer (claim 4) and use of forskolin as the cAMP inducer (claim 5).
Regarding claims 7-9: Takeda teaches use of a high-glucose DMEM media from the company Wako with the product number 043-30085 to be used as a base for their differentiation media. (Pg 9, Methods) This reads on the methods of claim 7 (use of DMEM medium) and claim 8 (use of a high glucose DMEM) but fails to explicitly state that the glutamine used in the DMEM media is L-glutamine. However, when the product number is pulled up on the manufacturer’s website, the product states use of L-glutamine as the source of glutamine in the media as seen by the screenshot below:
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It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Takeda with the teachings of Wang, Kouro, and Yu to create a high glutamine DMEM based serum free media to be used to induce fibroblasts to differentiate into brown fat comprising the following:
Triiodothyronine (thyroid hormone receptor agonist)
Dexamethasone (glucocorticoid receptor agonist)
Isobutylmethylxanthine (phosphodiesterase inhibitor)
Insulin
L-ascorbic acid 2-phosphate (ascorbic acid derivative)
Fatty-acid unbound albumin (albumin)
Penicillin/streptomycin (antibiotic)
Forskolin (cAMP agonist)
A person of ordinary skill in the art would have had motivation and a reasonable expectation of success at doing so based on the teachings of Takeda (use of triiodothyronine, dexamethasone, isobutylmethaylxanthine, insulin, pen/strep, forskolin in a high-glucose medium) in a fibroblast to brown adipocyte differentiation protocol, the teachings of Wang (use of fatty-acid unbound albumin in a brown adipocyte differentiation protocol), the teachings of Yu (use of L-ascorbic acid 2-phosphate due to its increased stability and ability to stimulate the growth of cells) and the teachings of Kouro, who state that use of serum-free media allows for observation of the impact of cytokines in the media and single-cell experiments to be performed.
Regarding claims 21, 22, 23, 24, 25, 26, 28, and 29: As discussed above, Takeda teaches use of a thyroid hormone receptor agonist, a glucocoritocoid receptor agonist, phosphodiesterase inhibitor, insulin, selective PPARy agonist, and cAMP inducer. Yu teaches use of an ascorbic acid derivative. While Takeda and Yu either fail to teach a concentration used or teach a different concentration used, it would be routine optimization for one skilled in the art to determine which concentration is best suited to their invention, as evidenced in MPEP 2144.05.II:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."
Regarding claim 27: As discussed above, Takeda teaches use of dexamethasone (Pg 9, Methods) as a glucocorticoid receptor agonist, which is not hydrocortisone.
Claim 6 is 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, 2017) in view of Wang et al. (Evaluation and optimization of differentiation conditions for human primary brown adipocytes, 2018), Yu et al. (Stemness and transdifferentiation of adipose-derived stem cells using L-ascorbic acid 2-phosphate-induced cell sheet formation, 2014), Hauner et al. (Methods in Molecular Biology, Chapter 20, Cultures of Human Adipose Precursor Cells), and Kouro et al. (In Vitro Differentiation and Measurement of B Cell Progenitor Activity in Culture, 2005) as evidenced by FujiFilm Wako Pure Chemical Corporation (D-MEM (High Glucose) with L-Glutamine, Phenol Red, and Sodium Pyruvate)
The teachings of Takeda, Wang, and Yu are described above. All sources fail to teach use of serum-free culture conditions.
Regarding claim 6: Hauner teaches a culture protocol for human adipose precursor cells which specifically uses serum-free media due to it being chemically defined and characterized as opposed to serum containing media, which can lead to unintended hormonal influences on the culture. In addition to this, Hauner states that the presence of serum in adipocyte differentiation media has been shown to “almost completely prevent[s]” the differentiation of adipose cells in the human system. (Pg 242, Introduction) Due to this teaching, a person of ordinary skill in the art therefore would have been motivated to incorporate the teachings of Hauner along with the previously discussed teachings of Takeda, Wang, and Yu to create a differentiation induction medium which is serum-free. Therefore, the teachings of claim 6 are rendered obvious.
Claims 30-31 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, 2017) in view of Wang et al. (Evaluation and optimization of differentiation conditions for human primary brown adipocytes, 2018), Yu et al. (Stemness and transdifferentiation of adipose-derived stem cells using L-ascorbic acid 2-phosphate-induced cell sheet formation, 2014), Tseng et al. (New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure, 2008) and Kouro et al. (In Vitro Differentiation and Measurement of B Cell Progenitor Activity in Culture, 2005)
The teachings of Takeda, Wang, Yu, and Kouro are discussed above. All fail to teach use of a BMP7.
Regarding claims 30 and 31: Tseng teaches that BMP7 singularly promotes the differentiation of brown preadipocytes regardless on if the normally required hormonal induction cocktail is present. In addition, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of said cells into nude mice led to the development of brown fat specifically. (Pg 1000, Abstract) Specifically, Tseng uses 3.3 nM rhBMP7 in culture (Pg 1005, Methods) which converts to roughly 100 ng/mL of BMP7, reading on the claimed range of 0.1 – 200 ng/mL of BMP7. Use of BMP7 as taught by Tseng further reads on claim 31 by virtue of use of “at least one selected” from a PPARy agonist, cAMP inducer, or BMP7.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Takeda, Wang, Yu, and Kouro with the teachings of Tseng to create a differentiation induction medium comprising, in addition to the aforementioned factors, BMP7. One skilled in the art would have had motivation and a reasonable expectation of success based on the teachings of Tseng, who demonstrate the BMP7 directly promotes the differentiation and development of brown adipose tissue both in culture and in mice.
Response to Arguments
Examiner recognizes Applicant has elected to cancel dependent claims 2 and 10 and has amended independent claim 1 and dependent claim 9.
Applicant's arguments filed 01/21/2026 have been fully considered but they are not persuasive. Applicant argues that claims 1-5 and 7-10 are not fully read on over Takeda in view of Wang and Yu due to the amendment of claim 1 stating use of serum-free culture conditions. As necessitated by amendments, prior art by Kouro et al. has been added to the rejection of claim 1, stating the benefit of use of serum-free culture conditions regarding B cell differentiation. While Kouro teaches specifically the differentiation of B cells, the teachings of use of serum free medium allowing for the observation of the direct impact of cytokines on the media throughout the differentiation process is applicable to any differentiation protocol for any cell type.
Examiner clarifies that the second rejection over Takeda, Wang Yu, Fujifilm, and Hauner contained a typo, and should be directed solely to claim 6. However, the argument that a person skilled in the art would be unmotivated to modify the protocol of Takeda because they would have no reason to is unpersuasive due to the fact that one of ordinary skill in the art is also one of ordinary creativity, as referenced in MPEP 2141.03.I:
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.”
As such, the 35 U.S.C. 103 rejections for claims 1, 3-9, and newly added claims 21-31 are upheld.
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 HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 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.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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