DETAILED ACTION
This action is in reply to papers filed 04/13/2026.
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 23-30, 33-37 are pending. Claims 35-37 are new.
Claims 23-30, 33, and 35-37 are examined on the merits herein.
Election/Restrictions
Applicant previously elected with traverse of Group I, drawn to claims 23-30 and 33, in the reply filed on 10/16/2025. As noted on page 2 of the Office Action mailed 01/12/2026, the restriction requirement was still deemed proper and was therefore made FINAL.
Claim 34 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/16/2025.
Withdrawn Rejection(s) and Objection(s)
The objection to claim 28 regarding minor informalities is withdrawn in light of the amendment to the claim.
The rejection of claims 23-30 and 33 under 35 U.S.C. 112(a) as failing to comply with the written description requirement is withdrawn in light of the amendment to claim 23 to strike the limitation “providing a second cell population having an increased tissue regeneration capacity.”
The rejection claims 23-30 and 33 under 35 U.S.C. 112(b) is withdrawn in light of the amendment to claims 23, 24, 26, 27, 29, and 30.
The rejection of claim 23 on the basis that it contains an improper Markush grouping of alternatives is withdrawn in light of Applicant’s amendment to the claims, which sets forth each alternative within an improper Markush grouping in a series of new dependent claims 35-37.
The cancellation of claims 31 and 32 render any rejections thereof moot.
Claim Objections
Claim 24 remains objected to because of the following informalities: The phrase “the gene selected from the group” (line 8) should be corrected to “wherein the gene is selected from the group”. Appropriate correction is required.
Claim Interpretation
Claim 23 recites the phrase wherein the modified cell population is used for a cell therapy (line 3), which is a recitation of intended use for the modified cell population. The intended use does not impose additional limitations to the product, and therefore is not given patentable weight. See MPEP 2111.02(II).
New Grounds of Rejection, Necessitated by Amendment
Claim Rejections - 35 USC § 112(a)
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 23 and 27 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
The Nature of the Invention: The nature of the invention is a method of modifying a cell population to have an increased tissue regeneration capacity, comprising separating a cell population from a biological tissue to obtain a separated cell population, the separated cell population having a combination of healthy cells and senescent cells, and culturing the separated cell population in a 3D thermoreversible culture for at least 24 days to create a supply of cells enriched with the healthy cells, wherein senescent cells are removed from the separated cell population and average telomere length of the 3D cultured cell population is extended to 110% or more of the average telomere length of a control cell population of the separated cell population in a 2D culture (claim 23).
Claim 27 further comprises the limitation that the separated cell population includes pluripotent stem cells and somatic stem cells, and the pluripotent stem cells and somatic stem cells are maintained or increased in content in the 3D cultured cell population when compared to the separated cell population, and 1) measuring the amount of α1-2 fucose in the cell population to compare the maintaining or increasing the content of the pluripotent stem cells between the separated cell population and the 3D cultured cell population, 2) measuring the amount of α2-6 sialic acid to compare the maintaining or increasing the content of the somatic stem cells between the separated cell population and the 3D cultured cell population.
The State of the Prior and Post-Filing Art:
Yin (Stem Cell Research and Therapy, 2020, 11: 226; cited in IDS 04/13/2026) teaches a method for culturing adipose-derived mesenchymal stem cells (ADMSCs), which are used in cell therapies, in 3D and 2D cultures to determine the modes of culture on ADMSC senescence (Abstract; p 2, col 1, para 1). Yin teaches obtaining abdominal adipose tissue from healthy female subjects by liposuction surgery, and isolating lipoaspirate MSCs therein (p 2, col 2, para 2). Yin teaches that after 21 days of culture, the population in 3D culture had significantly fewer cells which were positive for senescence-associated-β-gal expression compared to the population in 2D culture (p 3, col 1, para 2; p 5, col 1, para 2; Fig 2B), as well as significantly longer telomere length compared to the population in 2D culture (p 3, col 2, para 3; p 6, col 2, para 2; Fig 5a). A population of adipose-derived mesenchymal stem cells, as taught in Yin, comprises somatic stem cells, but not pluripotent stem cells.
Arumugam (Journal of Orthopaedics, 2011, 8(3): e5) teaches a method of in vitro expansion of human chondrocytes using a 3D thermoreversible polymer gel culture, wherein the chondrocytes are cultured for up to 16 weeks in 3D culture (p 4, para 5). Arumugam teaches obtaining human cartilage biopsies from non-weight bearing knee cartilage of human patients (p 4, para 1), and isolating articular chondrocytes from the cartilage tissues (p 4, para 1-2). Arumugam teaches that cells harvested from 3D culture was positive for the chondrocyte-specific protein marker S-100 (Fig. 4) (p 5, para 3), indicating that the cells are chondrocytes.
Importantly, neither Yin nor Arumugam teaches culturing a cell population separated from a biological tissue, wherein the separated cell population includes pluripotent stem cells and somatic stem cells, and wherein the pluripotent stem cells are maintained or increased in content in the 3D cultured cell population compared to the separated cell population.
Takahashi (Nature Reviews Molecular Biology, 2016, 17: 183-193) teaches that OCT3/4, SOX2, KLF4, and MYC (collectively referred to as OSKM factors) are four genes that comprise the minimal set of bona fide reprogramming factors that induce pluripotency, and are necessary for iPSC generation (p 185, col 2, para 2).
Lach (Cells, 2022, 11(3): 529) teaches that somatic cells may be converted into pluripotent stem cells by using transcription factors encoded by four specific genes: c-Myc, octamer-binding transcription factor 4 (OCT4), SRY-box transcription factor-2 (SOX2), and Krüppel-like factor 4 (Klf4) (p 4, para 2).
Importantly, the prior and post-filing art, as exemplified by Takahashi and Lach, teaches that OCT3/4, SOX2, KLF4, and MYC are required to convert somatic cells to pluripotent stem cells.
The level of one of ordinary skill: One of ordinary skill in the art is a research scientist holding a postgraduate degree or equivalent experience.
Amount of Guidance and Working Examples: The specification recites that somatic stem cells and pluripotent cells may be used in the invention (e.g., para 33), but does not provide further guidance on how to carry out the claimed method of claim 27, not offer working examples using a separated cell population which comprises pluripotent and somatic stem cells.
The working examples in the specification utilize cells isolated from human cartilage tissue (para 144, 150), which are the same type of cells (i.e., chondrocytes) as the cells used in Arumugam. Example 3 of the specification shows that in 3D cultured cell population, signals of α2-6 sialic acid-binding lectins such as SNA, SSA and TJA-I, and α1-2 fucose-binding lectins such as UEA-1 are enhanced depending on number of days of culture (para 167). The specification recites that since α2-6 sialic acid, which reacts to SNA, SSA and TJA-I, is a marker of somatic stem cell with high differentiating capacity, and α1-2 fucose binding lectin, such as UEA-1, is a marker of pluripotent stem cell, “it has been evident that cell population containing a lot of somatic stem cells with high differentiating capacity and pluripotent stem cells can be obtained when cell population is 3D cultured with TGP gel” (para 167). In other words, Example 3 of the specification asserts that by culturing chondrocytes in a 3D TGP gel, a cell population comprising somatic and pluripotent cells can be obtained in the absence of Yamanaka factors.
There are several issues to note. First, the working examples do not demonstrate the method of claim 27, which comprises the limitation of culturing a cell population comprising somatic and pluripotent stem cells. Rather, the working examples utilize chondrocytes isolated from human cartilage tissue.
Moreover, the inventors assert, based on the results of Example 3, that a cell population comprising somatic and pluripotent cells can be obtained from a population of chondrocytes merely by culturing said chondrocytes in a 3D TGP gel. Although the conditions of Example 3 are different from those as claimed in claim 27, which requires that the starting population comprises somatic and pluripotent stem cells (whereas Example 3 utilizes chondrocytes, which are not stem cells), the guidance from Example 3 is not sufficient to carry out the method of claim 27 without undue experimentation.
The quantity of experimentation necessary: Based on the content of the disclosure and the state of the prior art, undue experimentation is required to carry out the invention of claim 27. As discussed above, the experimental examples disclosed in the specification are limited to embodiments of the invention wherein a population of chondrocytes, which does not comprise stem cells, are used as the starting cell population. The prior and post-filing art, as set forth above, teaches that OCT3/4, SOX2, KLF4, and MYC are required to convert somatic cells (such as chondrocytes) into pluripotent stem cells. Despite the assertion in the instant specification that a cell population comprising somatic and pluripotent cells can be obtained from a population of chondrocytes merely by culturing said chondrocytes in a 3D TGP gel, the prior art does not teach that somatic cells can be reprogrammed into pluripotent stem cells in the absence of Yamanaka factors. Thus, there was a high level of unpredictability regarding a method for culturing a population of somatic and pluripotent stem cells in 3D culture, such that the 3D culturing condition 1) extends the average telomere length of the cell population compared to a 2D culture, and 2) maintains or increases the content of pluripotent and somatic stem cells compared to a 2D culture.
In conclusion, the evidence provided in the disclosure, in light of the teachings available in the art, does not enable one skilled in the art to carry the claimed invention without undue or reasonable experimentation. Therefore, the method of 27, which depends from claim 23, is not enabled.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 23, 24, 25, 28, 29, 30, 33, and 35-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Arumugam (Journal of Orthopaedics, 2011, 8(3): e5), as evidenced by Lefebvre (Connect Tissue Res., 2017, 58(1): 2-14) and Schilling (Biomaterials, 2022, 282: 121430).
Regarding claim 23: Arumugam teaches a method of in vitro expansion of human chondrocytes using a Thermoreversible Gelation Polymer (TGP) (Abstract).
Arumugam teaches obtaining human cartilage biopsies from non-weight bearing knee cartilage of human patients (p 4, para 1), and isolating articular chondrocytes from the cartilage tissues (p 4, para 1-2). Primary chondrocytes are not immortal, and therefore, a population of chondrocytes isolated from cartilage comprise healthy and senescent cells.
Arumugam teaches culturing the isolated chondrocytes either in the TPG scaffold (called “group 1” therein; corresponds to 3D culture) or without the TGP scaffold (called “group 2” therein; corresponds to 2D culture). Arumugam teaches culturing the 3D chondrocyte-TGP hydrogel in DMEM-HAM-F12 medium for up to 16 weeks (112 days) (p 4, para 5).
Arumugam teaches that at the end of the 4th week, cells in the 2D culture lost their viability, whereas cells seeded in 3D culture showed good number and cell viability (reads on a supply of cells enriched with the healthy cells) for 16 weeks (p 5, para 3). Cells in the 3D culture at 16 weeks, which “showed good number and cell viability” (p 5, para 3), inherently have average telomere length of 110% or more compared to the dead cells in 2D culture.
Regarding claims 24 and 28: Following the discussion of claim 23, Arumugam teaches that cells in 3D culture showed good number and cell viability for 16 weeks (112 days), whereas cells in the 2D culture lost their viability at the end of the 4th week (28 days) (p 5, para 3).
Arumugam is silent regarding the expression of miR-21, miR-140, miR21-5p, miR-140-3p, miR-140-Sp, SOX9, and COL2A1 in the cells from 3D culture. Arumugam teaches that cells harvested from 3D culture was positive for the chondrocyte-specific protein marker S-100 (Fig. 4) (p 5, para 3), indicating that the cells are chondrocytes.
Lefebvre shows that SOX9 is a pivotal transcription factor in developing and adult cartilage (Abstract). SOX9 is expressed from the multipotent skeletal progenitor stage and is active throughout chondrocyte differentiation, and remains expressed throughout life in permanent chondrocytes of healthy articular cartilage (Abstract).
Therefore, the cells harvested from 3D culture of Arumugam, which are chondrocytes, would express SOX9. Any expression of SOX9 would be an “increase” compared to the dead cells in 2D culture because dead cells do not express genes.
Regarding claims 25 and 30: Arumugam teaches that TGP is thermoreversible and is in a liquid state below 8 ℃ and solidifies above 8 ℃ (p 4, para 5), indicating a cloud point of approximately 8 ℃. TPG is a copolymer composed of the thermoreversible polymer (Poly (N isopropylacrylamide-co-n-butylmethacrylate) (polyNIPAAM-c0-BMA)) (reads on N-substituted acrylamide derivatives, acrylate derivatives, and methacrylate derivatives) and the hydrophilic polymer (poly ethylene glycol (PEG)) (p 4, para 4). Schilling shows that polyethylene (PEG) is also called polyethylene oxide (p 6, col 2, Section 3.2.2).
Regarding claims 29 and 33: Arumugam teaches isolating chondrocytes from human cartilage tissue (p 4, para 1-2).
Regarding claims 35-36: Arumugam teaches that cells harvested from 3D culture was positive for Hematoxylin and Eosin (H&E) staining (p 5, para 3; Fig. 3). Fig. 3, which shows the H&E staining of cells from the 3D culture, shows that the cells therein have a polygonal or spherical shape (claim 35), with the nucleus (stained with hematoxylin in dark blue) located near the center of the cell (claim 36).
Regarding claim 37: Following the discussion of claim 23, Arumugam teaches that at the end of the 4th week, cells in the 2D culture lost their viability, whereas cells seeded in 3D culture showed good number and cell viability for 16 weeks (p 5, para 3). Cells in the 3D culture at 16 weeks, which “showed good number and cell viability” (p 5, para 3), inherently have a higher size ratio between the cell and the nucleus compared to the dead cells in 2D culture.
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.
Claim(s) 23 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Arumugam (Journal of Orthopaedics, 2011, 8(3): e5), in view of Yoshioka (US 2004/0203148 A1).
The teachings of Arumugam are set forth above. Arumugam anticipates claim 23.
Regarding claim 26: Arumugam teaches the use of TPG, which is a copolymer composed of the thermoreversible polymer (Poly (N isopropylacrylamide-co-n-butylmethacrylate) (polyNIPAAM-c0-BMA)) (reads on N-isopropylacrylamide and n-butyl methacrylate) and the hydrophilic polymer (poly ethylene glycol (PEG)) (p 4, para 4).
Arumugam does not teach a thermoreversible polymer comprising polyethylene glycol dimethacrylate.
Yoshioka teaches a carrier for cell or tissue culture to effectively regenerate an intended cell or tissue, and a method of culturing a cell or tissue by using said carrier (Abstract). The carrier comprises a hydrogel-forming polymer showing a thermo-reversible sol-gel transition such that it assumes a sol state at a lower temperature and assumes a gel state at a higher temperature (para 14), and includes a polymer comprising a plurality of blocks having a cloud point, and a hydrophilic block connected or combined therewith (para 21). Yoshioka teaches that tissue cultured on the hydrogel carrier includes cartilage tissue (para 207, 249-253). Yoshioka teaches that a hydrogel-forming polymer may be obtained by connecting materials such as one comprising polypropylene glycol and polyethylene glycol bonded to both terminals thereof (para 165). Yoshioka teaches an embodiment of the hydrogel carrier, wherein the carrier comprises N-isopropylacrylamide, n-butyl methacrylate, and polyethylene glycol dimethacrylate (para 254-262).
Given the teachings of Yoshioka, there was a reasonable expectation that polyethylene glycol and polyethylene glycol dimethacrylate would work equivalently as a hydrophilic block in a thermoreversible hydrogel-forming polymer gel for culturing cartilage cells. Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have substituted polyethylene glycol dimethacrylate, as taught in Yoshioka, in place of polyethylene glycol, as taught in Arumugam, with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
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 Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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