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 .
Claims 1-16 are pending.
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.
Written Description
Claims 1-16 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.
The specification lacks written description for performing the method of claim 1.
Claim 1 is drawn to a method for inducing dedifferentiation of adipocytes, comprising subjecting one or more adipocytes to a hypertonic solution; and inducing release of mitochondrial extracellular vesicles (MEVs) from the one or more adipocytes to an extracellular environment, wherein released MEVs enhance the secretion of a series of inflammatory genes from the one or more adipocytes, and wherein the series of inflammatory genes activates the Wnt/β-catenin signaling pathway, thereby driving adipocyte dedifferentiation.
The claim encompasses making any adipocyte precursor cells, preadipocytes, adipose-derived adult stem (ADAS) cells, adipose-derived stromal cells, adipose-derived adherent stromal cells (ADASC), processed lipoaspirate cells, and adipose-derived stem cells (ASCs) (Shen, International J. of Oral Sci., 2011, Vol. 3, pg 117-124; pg 117, 1st para). The claim also encompasses dedifferentiating adipose cells into pluripotent cells which has been done (Nie, Science Bull., 2015, Vol. 60, No. 20, pg 1752-1758) as well as MSCs which has not been done.
The claim encompasses performing the method in vivo or in vitro.
The specification teaches using the method of Li (Science Advances, 2020, Vol. 6, pg 1-13) who taught “squeezing” preadipocytes with PEG in DMEM such that “dedifferentiated” adipocytes are obtained, but Li did not teach the potency of the “dedifferentiated” adipocytes. Li did not teach they were any well-known adipose stem cell, MSC, pluripotent cell. Li sorted “dedifferentiated” adipocytes, but Li did not teach how they were sorted or what they were being sorted for. The “dedifferentiated” adipocytes were expanded and “redifferentiated” into myogenesis, osteogenesis, and adipogenesis. It is unclear how the “dedifferentiated” adipocytes correlate to any well-known adipose stem cell, MSC, pluripotent cell.
Example 1 (pg 12) teaches performing the method of Li using an adipocyte cell line instead of preadipocytes, but the specification does not teach how the teachings of Li were modified or explain the vagaries of the method of Li. Pg 12, para 64, says adipocytes were cultured with “the hypertonic medium” but does not teach what that is or correlate it to the teachings of Li. It also says the “dedifferentiated cells were isolated for osteogenic differentiation” but does not teach how they were sorted or what they were being sorted for. Example 2 (pg 13) says the “dedifferentiated adipocytes” could become osteogenic and chondrogenic lineages. Example 3 (pg 13-14) says extracellular vesicles were obtained from “dedifferentiated adipocytes” obtained from hypertonic treatments, but they have nothing to do with inducing differentiation as required in claim 1. The specification does not teach the potency of their “dedifferentiated adipocytes”, does not correlate them to well-known adipose stem cells, MSCs, pluripotent cells, and does not correlate them to the “dedifferentiated adipocytes” of Li capable of becoming osteogenic, adipogenic, or myogenic lineages. More importantly, the specification fails to teach how to select and sort for their desired “dedifferentiated adipocytes” after “squeezing” them using some hypertonic treatment.
The specification does not enable making/using any MEVs from any adipocyte as required in claim 1. Example 3, pg 13, is limited to obtaining EVs from “dedifferentiated adipocytes” obtained from hypertonic solution. The specification says EVs ejected mitochondria, but the specification does not how to make “MEVs” as claimed. The specification does not teach how to use EVs or MEVs as part of inducing dedifferentiation as required in claim 1 – perhaps the preamble of claim 1 should be “A method of making EVs from “dedifferentiated adipocytes,…”.
The specification does not teach how to induce any inflammatory genes that activate the Wnt/β-catenin signaling pathway in adipocytes using MEVs as required in claim 1. The specification does not teach dedifferentiating adipocytes using MEVs as required in claim 1. The specification does not teach inducing any inflammatory genes that activate the Wnt/β-catenin signaling pathway as broadly encompassed by claim 1. Example 4 (pg 15) discusses adipocytes treated with hypertonic solution, obtaining “dedifferentiated adipocytes” sorted by unknown means, making EVs from the “dedifferentiated adipocytes”, and observing inflammatory pathway genes represented within the EVs. Example 4 appears to be saying that inflammatory genes that activate the Wnt/β-catenin signaling pathway were observed in EVs obtained from adipocytes treated with a hypertonic solution which is not the same thing as what is being claimed. Example 4 does not teach every inflammatory gene that activates the Wnt/β-catenin is represented in the EVs. The specification does not teach activating IL1b, IFNα, IFNβ, ROS, NFκB, or any cross-talk cytokines as broadly encompassed by claim 1.
The specification does not correlate culturing adipocytes in a hypertonic solution to exposing adipocytes to a hypertonic solution in vivo as broadly encompassed by claim 1.
Accordingly, the specification lacks written description for the “dedifferentiated adipocytes” described in the specification specifically using the method of claim 1 to obtain the “dedifferentiated adipocytes” described in the specification. The specification lacks written description for how to obtain applicants “dedifferentiated adipocytes” using any method as broadly claimed. It is wholly unclear how/what the MEVs in claim 1 have anything to do with inducing dedifferentiation of adipocytes as claimed because they are obtained only after “dedifferentiated adipocytes” (pg 13, example 3).
The specification lacks written description for MCP1 activating the Wnt/β-catenin pathway as required in claim 2. Current evidence does not indicate that MCP1 (monocyte chemoattractant protein-1) directly activates the Wnt/β-catenin pathway in a general or universal way. MCP1 is a secreted chemokine best known for recruiting monocytes and other immune cells to sites of inflammation, injury, or infection. Its primary signaling is through G-protein-coupled receptors (e.g., CCR2), leading to immune cell migration and activation. The Wnt/β-catenin pathway, in contrast, is a conserved developmental and homeostatic signaling cascade that regulates cell fate, proliferation, and tissue regeneration biologyinsights.com+1. It is activated by Wnt ligands binding to Frizzled receptors and LRP5/6 co-receptors, which disrupt the cytoplasmic destruction complex, stabilize β-catenin, and allow it to enter the nucleus to regulate target gene expression biologyinsights.com+1.
The specification lacks written description for CEBPA activating the Wnt/β-catenin pathway as required in claim 2. CEBPA (CCAAT/enhancer-binding protein alpha) does not typically activate the Wnt/\(\beta \)-catenin pathway. In fact, CEBPA acts as a tumor suppressor and functions to restrict or inhibit the Wnt/\(\beta \)-catenin signaling cascade (Heuberger, Life Science Alliance, 2018, Vol. 2, No. 1, e20180017). The regulatory relationship works in the opposite direction and is characterized by a mutually antagonistic feedback loop (Tieri, PLOS, 2012, Vol. 7, No. 3, pg 1-11).
The specification is limited to adipose cell line and does not correlate them to any primary adipocytes, iPS-derived adipocytes, ES-derived adipocytes, or adipocytes derived from different anatomical locations as required in claim 3.
The specification lacks written description for increasing any “surface markers associated with” any “dedifferentiated adipocytes” by 10-20% as required in claim 7. The “dedifferentiated adipocytes” include any adipocyte precursor cells, preadipocytes, adipose-derived adult stem (ADAS) cells, adipose-derived stromal cells, adipose-derived adherent stromal cells (ADASC), processed lipoaspirate cells, and adipose-derived stem cells (ASCs) (Shen, International J. of Oral Sci., 2011, Vol. 3, pg 117-124; pg 117, 1st para), MSCs, and pluripotent cells. The surface markers used by applicants for sorting are not disclosed. The specification does not teach increasing any “surface markers associated with” any “dedifferentiated adipocytes” by 10-20% as required in claim 7.
The specification lacks written description for any small molecule capable of mitigating apoptosis as required in claim 11 other than “2-amino-4-[…]pyrimidine” as required in claim 12. The concept is contemplated on pg 3, para 19, but the only compound that has the function claimed is “2-amino-4-[…]pyrimidine”.
Enablement
Claims 1-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for culturing adipocytes using the technique described by Sugihara (Differentiation, 1986, Vol. 31, pg 42-49) cited by Shen (International J. of Oral Sci., 2011, Vol. 3, pg 117-124; pg 117, 1st para) such that adipose stem cells are obtained or culturing adipocytes using the method of Nie (Science Bull., 2015, Vol. 60, No. 20, pg 1752-1758) such that pluripotent cells are obtained, does not reasonably provide enablement for using microvesicles to dedifferentiate adipocytes into pluripotent cells, MSCs, or adipose stem cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Claim 1 and its breadth are summarized above.
The specification teaches using the method of Li (Science Advances, 2020, Vol. 6, pg 1-13) who taught “squeezing” preadipocytes with PEG in DMEM such that “dedifferentiated” adipocytes are obtained, but Li did not teach the potency of the “dedifferentiated” adipocytes. Li did not teach they were any well-known adipose stem cell, MSC, pluripotent cell. Li sorted “dedifferentiated” adipocytes, but Li did not teach how they were sorted or what they were being sorted for. The “dedifferentiated” adipocytes were expanded and “redifferentiated” into myogenesis, osteogenesis, and adipogenesis. It is unclear how the “dedifferentiated” adipocytes correlate to any well-known adipose stem cell, MSC, pluripotent cell.
Example 1 (pg 12) teaches performing the method of Li using an adipocyte cell line instead of preadipocytes, but the specification does not teach how the teachings of Li were modified or explain the vagaries of the method of Li. Pg 12, para 64, says adipocytes were cultured with “the hypertonic medium” but does not teach what that is or correlate it to the teachings of Li. It also says the “dedifferentiated cells were isolated for osteogenic differentiation” but does not teach how they were sorted or what they were being sorted for. Example 2 (pg 13) says the “dedifferentiated adipocytes” could become osteogenic and chondrogenic lineages. Example 3 (pg 13-14) says extracellular vesicles were obtained from “dedifferentiated adipocytes” obtained from hypertonic treatments, but they have nothing to do with inducing differentiation as required in claim 1. The specification does not teach the potency of their “dedifferentiated adipocytes”, does not correlate them to well-known adipose stem cells, MSCs, pluripotent cells, and does not correlate them to the “dedifferentiated adipocytes” of Li capable of becoming osteogenic, adipogenic, or myogenic lineages. More importantly, the specification fails to teach how to select and sort for their desired “dedifferentiated adipocytes” after “squeezing” them using some hypertonic treatment.
The specification does not enable making/using any MEVs from any adipocyte as required in claim 1. Example 3, pg 13, is limited to obtaining EVs from “dedifferentiated adipocytes” obtained from hypertonic solution. The specification says EVs ejected mitochondria, but the specification does not how to make “MEVs” as claimed. The specification does not teach how to use EVs or MEVs as part of inducing dedifferentiation as required in claim 1 – perhaps the preamble of claim 1 should be “A method of making EVs from “dedifferentiated adipocytes,…”.
The specification does not teach how to induce any inflammatory genes that activate the Wnt/β-catenin signaling pathway in adipocytes using MEVs as required in claim 1. The specification does not teach dedifferentiating adipocytes using MEVs as required in claim 1. The specification does not teach inducing any inflammatory genes that activate the Wnt/β-catenin signaling pathway as broadly encompassed by claim 1. Example 4 (pg 15) discusses adipocytes treated with hypertonic solution, obtaining “dedifferentiated adipocytes” sorted by unknown means, making EVs from the “dedifferentiated adipocytes”, and observing inflammatory pathway genes represented within the EVs. Example 4 appears to be saying that inflammatory genes that activate the Wnt/β-catenin signaling pathway were observed in EVs obtained from adipocytes treated with a hypertonic solution which is not the same thing as what is being claimed. Example 4 does not teach every inflammatory gene that activates the Wnt/β-catenin is represented in the EVs. The specification does not teach activating IL1b, IFNα, IFNβ, ROS, NFκB, or any cross-talk cytokines as broadly encompassed by claim 1.
The specification does not correlate culturing adipocytes in a hypertonic solution to exposing adipocytes to a hypertonic solution in vivo as broadly encompassed by claim 1.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make the “dedifferentiated adipocytes” described in the specification specifically using the method of claim 1 to obtain the “dedifferentiated adipocytes” described in the specification. It would also have required undue experimentation to determine how to obtain applicants “dedifferentiated adipocytes” using any method as broadly claimed without the hypertonic solution. It is wholly unclear how/what the MEVs in claim 1 have anything to do with inducing dedifferentiation of adipocytes as claimed because they are obtained after “dedifferentiated adipocytes” (pg 13, example 3).
The specification does not enable using MCP1 to activate the Wnt/β-catenin pathway as required in claim 2. Current evidence does not indicate that MCP1 (monocyte chemoattractant protein-1) directly activates the Wnt/β-catenin pathway in a general or universal way. MCP1 is a secreted chemokine best known for recruiting monocytes and other immune cells to sites of inflammation, injury, or infection. Its primary signaling is through G-protein-coupled receptors (e.g., CCR2), leading to immune cell migration and activation. The Wnt/β-catenin pathway, in contrast, is a conserved developmental and homeostatic signaling cascade that regulates cell fate, proliferation, and tissue regeneration biologyinsights.com+1. It is activated by Wnt ligands binding to Frizzled receptors and LRP5/6 co-receptors, which disrupt the cytoplasmic destruction complex, stabilize β-catenin, and allow it to enter the nucleus to regulate target gene expression biologyinsights.com+1.
The specification does not enable using CEBPA to activate the Wnt/β-catenin pathway as required in claim 2. CEBPA (CCAAT/enhancer-binding protein alpha) does not typically activate the Wnt/\(\beta \)-catenin pathway. In fact, CEBPA acts as a tumor suppressor and functions to restrict or inhibit the Wnt/\(\beta \)-catenin signaling cascade (Heuberger, Life Science Alliance, 2018, Vol. 2, No. 1, e20180017). The regulatory relationship works in the opposite direction and is characterized by a mutually antagonistic feedback loop (Tieri, PLOS, 2012, Vol. 7, No. 3, pg 1-11).
The specification is limited to adipose cell line and does not correlate them to any primary adipocytes, iPS-derived adipocytes, ES-derived adipocytes, or adipocytes derived from different anatomical locations as required in claim 3.
The specification does not enable increasing any “surface markers associated with” any “dedifferentiated adipocytes” by 10-20% as required in claim 7. The “dedifferentiated adipocytes” include any adipocyte precursor cells, preadipocytes, adipose-derived adult stem (ADAS) cells, adipose-derived stromal cells, adipose-derived adherent stromal cells (ADASC), processed lipoaspirate cells, and adipose-derived stem cells (ASCs) (Shen, International J. of Oral Sci., 2011, Vol. 3, pg 117-124; pg 117, 1st para), MSCs, and pluripotent cells. The surface markers used by applicants for sorting are not disclosed. The specification does not teach increasing any “surface markers associated with” any “dedifferentiated adipocytes” by 10-20% as required in claim 7.
The specification does not enable making/using any small molecule capable of mitigating apoptosis as required in claim 11 other than “2-amino-4-[…]pyrimidine” as required in claim 12. The concept is contemplated on pg 3, para 19, but the only compound that has the function claimed is “2-amino-4-[…]pyrimidine”.
Indefiniteness
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 1-16 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.
The metes and bounds of claim 1 cannot be determined because the steps rely on a well-known method of dedifferentiating adipocytes using the method of Li and then making extracellular vesicles (EVs) from them. While the method involves dedifferentiation of adipocytes using a hypertonic solution, the preamble does not capture the result of the active steps which is making EVs from dedifferentiated adipocytes. In the reverse, if the method is actually just “inducing dedifferentiation of adipocytes” as in the preamble, then releasing EVs from them is not an active step in the process of “inducing dedifferentiation of adipocytes”. The preamble does not correlate to the active steps in claim 1 and the active steps in claim 1 add up to more than just “inducing dedifferentiation of adipocytes”. This makes the claim indefinite because the metes and bounds cannot be determined.
The metes and bounds of an mitochondrial extracellular vesicle (MEV) in claim 1 cannot be determined. While an extracellular vesicle (EV) may contain mitochondria, it is unclear when an EV is a MEV as required in claim 1. This makes the claim indefinite.
It is unclear how “MEVs enhance the secretion of a series of inflammatory genes from the one or more adipocytes” as required in claim 1. The specification is limited to isolating EVs from dedifferentiated adipocytes; they are not derived from adipocytes as claimed. It is unclear how MEVs enhance secretion of anything in adipocytes or “dedifferentiated adipocytes” as required in claim 1, specifically of any inflammatory gene product. It appears that EVs from “dedifferentiated adipocytes” contain TNFα, IL6, et al. (Example 4), this is not what claim 1 says, and it is unclear what concept applicants are trying to capture. If the word “enhance” is attempting to say there is more TNFα, IL6, et al. in EVs from “dedifferentiated adipocytes” as compared to something else, that comparison is unclear and is missing from claim 1. The claim never clearly sets forth that the inflammatory proteins that activate the Wnt/β-catenin pathway are found in the EVs. The claim never clearly sets forth that the inflammatory proteins that activate the Wnt/β-catenin pathway are found in EVs isolated from adipocytes. The claim never clearly sets forth that inflammatory proteins that activate the Wnt/β-catenin pathway are found in EVs isolated from “dedifferentiated adipocytes” in amounts greater than EVs isolated from adipocytes. The claim is missing essential elements to determine what they mean by “MEVs enhance the secretion of a series of inflammatory genes from the one or more adipocytes” and the claim fails to correlate with any reasonable logic or science that is in the specification.
The CEBPA and MCP1 do not activate the Wnt/β-catenin pathway as required in claim 2. See written description and enablement rejections above. Therefore, CEBPA and MCP1 in claim 2 are broader than claim 1 and cannot be used to further limit claim 1.
The metes and bounds of stromal vascular fraction (SVF)-derived adipocytes in claim 4 cannot be determined. The claim never says the SFV is isolated from adipose tissue. The metes and bounds of the phrase are unclear because the specification does not teach whether mature adipocytes, preadipocytes, adipocyte progenitors, MSCs, and pluripotent cells are encompassed by phrase, or whether the phrase excludes mature adipocytes. It is unclear whether the phrase excludes MSCs and/or pluripotent cells found in the SFV of adipose. Therefore, those of skill would not be able to determine when they were infringing on the claim.
The phrase “the adipocyte count” in claim 5 lacks antecedent basis in claim 1.
The metes and bounds of the phrase “surface markers associated with dedifferentiated adipocytes” in claim 7 cannot be determined. The scope of “dedifferentiated adipocytes” appears to encompass preadipocytes, adipocyte progenitors, MSCs, and pluripotent cells. It is unclear when/whether a marker protein is “associated” with preadipocytes, adipocyte progenitors, MSCs, and pluripotent cells. It is unclear whether the marker must be exclusive to preadipocytes, adipocyte progenitors, MSCs, and pluripotent cells or if it is “highly” expressed. If it is “highly” expressed, then it is unclear when the threshold of being “highly” expressed has been met or when it was “associated” with the desired cell type.
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.
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 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Li (Science Advances, 2020, Vol. 6, pg 1-13) as supported by Liu (Stem Cell Res. & Therapy, 2023, Vol. 14, No. 333, pg 1-17).
Liu taught culturing adipocytes in hypertonic solution such that “dedifferentiated adipocytes” occur (pg 4, Fig. 3A; Materials and Methods, Results). The adipocytes inherently MUST create EVs that contain mitochondria and inflammatory proteins that activate the Wnt/β-catenin pathway as required in claim 1 because Liu taught reprogramming adipocytes in hypertonic conditions expressed TNF-α (“Hypertonicity induces mitochondrial extracellular vesicles (MEVs) that activate TNF-α and β-catenin signaling to promote adipocyte dedifferentiation”; Results). This is equivalent to claim 1.
The cells inherently MUST express TNF-α in the EVs as required in claim 2 as evidenced by Liu.
The adipocytes were primary as required in claim 3 (pg 8, “Cell Culture”).
The subcutaneous primary human adipocytes of Li are “stromal vascular fraction (SFV)-derived adipocytes” as required in claim 4.
The adipocyte count inherently must be that of claim 5 because applicants used the hypertonic conditions of Li (Example 1).
The expression marker percentage inherently must be that of claim 6 because applicants used the hypertonic conditions of Li (Example 1).
The expression marker percentage inherently must be that of claim 7 because applicants used the hypertonic conditions of Li (Example 1).
The hypertonic solution in claim 8 is the hypertonic solution of Li (pg 8, para bridging col. 1-2).
The hypertonic solution contains a preservative, stabilizer, or medication as required in claim 9 (pg 8, para bridging col. 1-2).
The dedifferentiated adipocytes were capable of osteogenesis and chondrogenesis as required in claim 10 (pg 8, 1st para).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Claims 11-16 are rejected under 35 U.S.C. 103 as being unpatentable over Li (Science Advances, 2020, Vol. 6, pg 1-13) as supported by Liu (Stem Cell Res. & Therapy, 2023, Vol. 14, No. 333, pg 1-17) as applied to claims 1-10 above and further in view of Narcisi (Tissue Engineering, 2016, Vol. 22, No. 21-22, pg 1264-1273).
Liu cultured adipocytes in hypertonic solution such that “dedifferentiated adipocytes” occur meeting all the limitations of claim 1 for reasons set forth above.
Liu did not teach adding a small molecule that “mitigates apoptosis” as required in claim 11.
However, it was well known to add AMBMP (2-amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine) to adipose precursor cells as described by Narcisi (abstract; Materials and Methods).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to culture adipocytes and “dedifferentiated adipocytes” under hypertonic conditions as described by Li and add AMBMP described by Narcisi. Those of ordinary skill in the art at the time of filing would have been motivated to do so because Li taught the hypertonic solution increased proteins expressed in the Wnt/β-catenin pathway (pg 5, “Genetic profiling of CIDAs”; pg 8, 1st para) and because adding AMBMP would prevent adipogenic differentiation as described by Narcisi.
AMBMP of Narcisi is the compound in claim 12.
The expression marker percentage inherently must be that of claim 13 because applicants used the hypertonic conditions of Li (Example 1).
The adipogenic genes inherently must be those in claim 14 because applicants used the hypertonic conditions of Li (Example 1).
The expression markers inherently must be those in claim 15 because applicants used the hypertonic conditions of Li (Example 1).
The dedifferentiated adipocytes were capable of osteogenesis and chondrogenesis as required in claim 16 (pg 8, 1st para).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights