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 Status
The amendment of 03/13/2026 has been entered. Claims 38-47 are currently pending in this US patent application and were examined on their merits.
Information Disclosure Statement
The information disclosure statement filed in this application on 03/13/3036 has been received and considered.
Withdrawn Rejections
The rejection of the claims under 35 U.S.C. 112(b) as set forth in the previous Office action is withdrawn in light of the amendment of 03/13/2026, which amended claims 38 and 43 to no longer recite a differentiation step.
Claim Interpretation
Claims 38 and 43 recite methods of making cell aggregates comprising steps of loading and centrifuging, “thereby forming” aggregates consisting of cells that express particular proteins. As such, the claims indicate that the formation of aggregates expressing the recited markers is the intended result of the positively recited steps of loading and centrifuging. A clause in a method claim does not receive weight when it simply expresses the intended outcome of a process step positively recited. See MPEP § 2111.04 (I). As such, any prior art that teaches the positively recited steps of claims 38 and 43 will be interpreted to read on the entirety of claims 38 and 43.
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.
Claims 38-39 and 43-44 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., Cytotherapy 16: 485-495 (2014), in view of US patent application 2015/0202234 filed by Gillette et al., published 07/23/2015, US patent application 2012/0321671 filed by Boyden et al., published 12/20/2012, and Ungrin et al., PLoS ONE 3(2): e1565 (2008).
Wang teaches the culture of adipose-derived stem cells in suspension culture by culturing them in ultra-low-attachment plates. The cells formed aggregates, which served to maintain cell survival. The stem cells were more efficiently induced to differentiate into adipocytes in suspension culture than in two-dimensional monolayer culture (see entire document, including page 485, abstract; cf. claims 38 and 43 [“…loading…adipose derived stem cells…into a non-adherent culture plate…thereby forming three-dimensional…adipose derived stem cell aggregates, wherein the aggregates consist of…adipose derived stem cells”]; please see above under Claim Interpretation for the Examiner’s interpretation of the intended result of particular protein expression recited in the claimed method). The cells were cultured in a 37°C incubator in a humidified atmosphere in a growth medium that did not contain dexamethasone, IBMX, or T3 in plates designed to prevent cells from adhering (page 486, right column, paragraphs 2-3; cf. claims 38 and 43; the Examiner notes that, because an “adipocyte differentiation medium” is not defined or limited in the instant claims, this medium can be interpreted as an “adipocyte differentiation medium”). The cells were observed to aggregate after one day of suspension culture, and, on days 3 and 5 of suspension culture, the aggregates had conjugated into larger spheres (page 488, right column, paragraph 2; cf. claims 39 and 44). The cells then underwent adipogenic differentiation (page 487, left column, paragraph 6, to right column, paragraph 1).
However, Wang does not teach that the adipose tissue from which the stem cells are derived is brown adipose tissue. Wang also does not teach centrifuging the non-adherent culture plate in which the 3D aggregates are formed or culturing the stem cells under 2D conditions prior to the formation of aggregates.
Gillette teaches the injection of brown adipose microtissues into patients (see entire document, including page 1, paragraph 0007). Stem cells used to make the microtissues can be isolated from a variety of tissues and organs, including adipose tissue (page 6, paragraph 0067). Adipose stem cells were cultured on a 2D culture surface (page 12, paragraph 0116; cf. claim 39). The ASCs were removed from the 2D culture surface and cultured in a non-adhesive microwell, allowing the cells to form a 3D aggregate in the microwell (page 12, paragraph 0118; cf. claims 38 and 43 [“…loading…stem cells grown in a two-dimensional (2D) culture into a non-adherent culture plate…thereby forming three-dimensional…adipose derived stem cell aggregates”]). The stem cells were then differentiated into brown adipocytes (page 12, paragraph 0118).
Boyden teaches that brown pre-adipocytes, which are stem cells that can differentiate into brown adipose tissue, can be isolated from brown adipose tissue (see entire document, including page 6, paragraph 0040; cf. claims 38 and 43 [“…brown adipose derived stem cells”]).
Ungrin teaches that, while stem cells can form aggregates without intervention, a forced aggregation strategy via the addition of a step of centrifuging the culture plates containing the stem cells allowed for the improved control of aggregate size (see entire document, including page 3, right column, paragraphs 1-2; page 4, left column, paragraph 2; cf. claims 38 and 43 [“…centrifuging the non-adherent culture plate to uniformly position the…stem cells in the non-adherent culture plate”]).
While Wang does not teach that the adipose tissue from which the stem cells are derived is brown adipose tissue, it would have been obvious to one of ordinary skill in the art to obtain the stem cells from brown adipose tissue because Wang teaches that the adipose stem cells can be obtained from adipose tissue and because Boyden teaches that stem cells that can give rise to brown adipocytes can be obtained from brown adipose tissue. While Wang and Boyden do not teach that the formation of brown adipose microtissues from brown adipose-derived stem cells by culturing the stem cells in a non-adherent culture plate rendered obvious by their teachings involves a step of centrifuging the culture plate as recited in instant claims 38 and 43, it would have been obvious to one of ordinary skill in the art to do so because Ungrin teaches that centrifuging culture plates in which 3D stem cell aggregates are forming allows for the improved control of the size of the aggregates. While Wang, Boyden, and Ungrin do not teach culturing the brown adipose-derived stem cells in a 2D culture prior to making the aggregates rendered obvious by their teachings, it would have been obvious to one of ordinary skill in the art to do so because Gillette teaches that adipose-derived stem cells can be cultured in a 2D manner prior to using them to make 3D aggregates. One of ordinary skill in the art would have a reasonable expectation that culturing the brown adipose-derived stem cells of Boyden under 2D conditions as taught by Gillette and then transferring them into a non-adherent culture plate as taught by Wang and centrifuging the plate as taught by Ungrin would successfully result in the production of aggregates of a controllable size that can be differentiated into brown adipose tissue.
Therefore, claims 38-39 and 43-44 are rendered obvious by Wang in view of Gillette, Boyden, and Ungrin and are rejected under 35 U.S.C. 103.
Claims 38-47 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., Cytotherapy 16: 485-495 (2014), in view of US patent application 2015/0202234 filed by Gillette et al., published 07/23/2015, US patent application 2012/0321671 filed by Boyden et al., published 12/20/2012, Ungrin et al., PLoS ONE 3(2): e1565 (2008), and Kuss et al., Acta Biomat. 71: 486-495 (2018).
As discussed above, claims 38-39 and 43-44 are rendered obvious by Wang in view of Gillette, Boyden, and Ungrin. In addition, Gillette teaches differentiating the 3D aggregates into brown adipose tissue by culturing the aggregates in a medium comprising dexamethasone, IBMX, T3, and rosiglitazone (page 12, paragraph 0118; cf. claims 40 and 45; the Examiner notes that claims 40 and 45 do not require the first and second differentiation steps or the first and second differentiation media to be distinct from each other in any way). The brown adipose microtissues can be encapsulated into hydrogel carriers and administered to patients for the treatment of obesity (page 8, paragraph 0076; cf. claims 40 and 45). However, Wang, Gillette, Boyden, and Ungrin do not teach differentiating the stem cell aggregates in an encapsulation system as recited in instant claims 40 and 45.
Kuss teaches loading brown adipocyte progenitors into polymer hydrogel precursor solutions that were then extruded through a bioprinter and cured (see entire document, including page 487, right column, paragraphs 3-5; cf. claims 40-42 and 45-47; the Examiner notes that the hydrogel of Kuss can be interpreted as “polymers” as recited in instant claims 41 and 46 and as an “encapsulation medical device” as recited in instant claims 42 and 47). The brown adipocyte progenitor-containing constructs were then placed in differentiation medium to induce differentiation into brown adipocytes (page 488, left column, paragraph 2; cf. claims 40 and 45).
While Wang, Gillette, Boyden, and Ungrin do not teach that the encapsulation of the 3D aggregates in hydrogel carriers for administration to patients for the treatment of obesity occurs prior to differentiation, it would have been obvious to one of ordinary skill in the art to encapsulate the 3D aggregates containing brown adipose-derived stem cells rendered obvious by Wang, Gillette, Boyden, and Ungrin in a hydrogel carrier prior to differentiation because Gillette teaches that the differentiated microtissues may be encapsulated in a hydrogel prior to administration and because Kuss teaches that brown adipocyte progenitors may be differentiated into brown adipocytes while inside of a hydrogel carrier. One of ordinary skill in the art would have a reasonable expectation that encapsulating the 3D aggregates containing brown adipose-derived stem cells rendered obvious by Wang, Gillette, Boyden, and Ungrin in a hydrogel carrier and then culturing the aggregates in the differentiation medium taught by Gillette would successfully result in the differentiation of the stem cells into brown adipocytes.
Therefore, claims 38-47 are rendered obvious by Wang in view of Gillette, Boyden, Ungrin, and Kuss, as evidenced by Seale, and are rejected under 35 U.S.C. 103.
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 variation…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).
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.
Response to Arguments
Applicant has traversed the above rejections of the claims under 35 U.S.C. 103 as being unpatentable over Wang in view of Gillette, Boyden, and Ungrin. Applicant states that Wang teaches adipogenic differentiation in a culture medium that contains the ingredients restricted from the medium in claims 38 and 43, and so one of ordinary skill in the art would not be motivated to culture the aggregates in an adipocyte differentiation medium that does not contain those ingredients based on Wang’s teachings (remarks, pages 6-7). This argument has been fully considered but has not been found persuasive.
The Examiner notes that claims 38 and 43 do not limit the culture medium in any way other than saying that it does not contain certain ingredients. Stating that the culture medium is for “adipocyte differentiation” merely limits the intended use of the medium, which does not constitute a structural limitation. As such, the “adipocyte differentiation medium” of the instant claims cannot be differentiated from the medium in which Wang’s aggregates were formed.
Therefore, the Examiner has maintained the rejections presented above.
Conclusion
No claims are 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 Erin M. Bowers, whose telephone number is (571)272-2897. The examiner can normally be reached Monday-Friday, 7:30-5:00.
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/Erin M. Bowers/Primary Examiner, Art Unit 1653 04/02/2026
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