Notice of Pre-AIA or AIA Status
The present application, 17911112, US PG-Pub 20230118035, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-9, 11-13, 17-19, and 22 are pending. Claims 9, 19, and 22 are withdrawn by the examiner. Claims 1-8, 11-13, 17-18 are examined.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-9, 10-13, and 17-18 in the reply filed on 11/14/2025, is acknowledged. Applicant canceled claim 10, in the amendments to the claims, filed 11/14/2025. The traversal is on the ground(s) that the International Searching Authority, found unity of invention to present in corresponding international Application No. PCT/JP2021/010208 and so this instant application should also be found to have unity of invention. This is not found persuasive because the U.S. Patent and Trademark Office finds that that unity is not present because there is no special technical feature linking the claims. Furthermore, the U.S. Patent and Trademark Office is not bound to obey the particular decisions of an international search regarding specific matters of substance, but must responsibly decide those specific matters to which duly come to it in the course of examination. Therefore, requirement is still deemed proper, as it is in accordance with the rules governing PCT unity of invention for 371 Applications. Rejoinder remains a possibility.
Applicant's election with traverse of requirement for election of species, mailed 9/16/2025, of Species 3, condition 3, cells labeled with anti-CD99, fluorescence intensity 1.9 or less, without traverse, and Species A, a cell culture derived from cartilage tissue, without traverse, which applicant states is readable on claims 7 and 17 in the reply filed on 11/14/2025, is acknowledged.
Claims 9, 19 and 22 are considered to be an unelected species (claim 9) and unelected inventions (claims 19 and 22) and have been withdrawn by the examiner.
Claims 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, (i.e. cultures derived from stem cells), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/14/2025.
Priority
The filing receipt, mailed 1/11/2023, states that this application was filed 9/12/2022, and claims domestic priority benefit of as a 371 of PCT/JP2021/010208, filed 03/12/2021 and foreign priority benefit of Foreign Application JAPAN 2020-044265, filed 03/13/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/25/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The citation to #8, IDS filed 10/8/25, ‘Taiwan Bioresources Conservation and Research Center,” has been lined through and has not been considered because there is no publication year provided for the citation.
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.
1. Claims 1, 2, 6-8, 11-13, 17, 18 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi, Journal of the Japanese Orthopaedic Association, 2019, 6 pages, Vol. 93:8, (of record, IDS 9/12/2025) and Diaz-Romero, 2005, J. Cellular Physiol., Vol. 202, pp. 731-742 (2005), (of record, IDS, hereinafter Diaz-Romero 2005).
Takahashi states that PD sheets (polydactyly-derived allogeneic chondrocyte cell sheets) were prepared after 2 weeks of culture by harvesting cartilage tissue from surgical waste tissue of polydactyly donors, isolating chondrocytes therefrom, and then seeding third passage chondrocytes into temperature- responsive culture dishes; that the cells were isolated from the completed polydactyly-derived allogeneic chondrocyte (PD) sheets and analyzed for 242 cell surface markers using BD Lyoplate Screening Panels; that the PD sheets were then 3D cultured using an in vitro evaluation system; and that the COL2A1/COLI1AI1 gene expression ratio on day 7 was analyzed by qPCR, and the correlation between marker positivity and COL2A1/COLIA1 ratio was analyzed (section entitled "Method").
Takahashi further states the following: that a comprehensive analysis identified 32 positive markers (CD73/CD90/CD 105, etc.); that 6 markers with a strong positive correlation with the COL2A1/ COLIAI ratio (correlation coefficient 0.83 to 0.67) and 3 markers with a negative correlation (correlation coefficient -0.64 to -0.51) were identified (section entitled "Results"); that markers that varied depending on the donor were identified, and validity marker candidates with a strong correlation to hyaline chondrogenesis potential were narrowed down (section entitled "Discussion and Conclusion"); and that in the future, validation tests will be performed by sorting the marker candidates with the goal of establishing a quality evaluation index (section entitled "Discussion and Conclusion"). Takahashi teaches markers with strong hyaline chondrogenic potential.
In this case, although Takahashi does not state that the cell surface markers that were considered "positive" such as CD73/CD90/CD 105 were "markers that showed a strong positive correlation with the COL2A1/ COLIAI ratio,” since Takahashi does state that the markers were "positive," it is reasonable to conclude that the expression strength of those markers was "at or above the threshold (a predetermined level)." Moreover, it is clear that the PD sheets and the preparation method thereof are similar to the "sheet-like cell culture material" described in the examples in the present application. Said PD sheets can also be considered identical as a product to the "sheet-like cell culture material" described in the present application from the aspect that they are produced by culturing chondrocytes derived from surgical waste tissue of polydactyly donors.
Takahashi does not teach higher or lower regulation of various chondrocyte biomarkers for having cartilage-like tissue forming property.
Diaz-Romero 2005 discloses a phenotypic analysis of human articular chondrocytes. Changes in surface markers were found to be associated with cell expansion in monolayer culture. This study contributes to the definition of, and provides new potential markers to characterize chondrocyte differentiation stage in the context of issue engineering applications. Among the markers of the HAC phenotype are integrins and other adhesion molecules (CD16, CD166, CD44), tetraspanins (CD9, CD63, CD81, CD82, CO151), receptors (GD1O5), ectoenzymes (CD26), and other surface molecules (CD90, CD99), Table 1. Moreover, differential expression of certain markers in monolayer culture was identified depending on duration of culture and dedifferentiation. Immunofluorescence staining of chondrocytes using FITC was performed, (see p. 732). Up-regulation of markers on HACs regarded as distinctive for mesenchymal stem cells (CD10, CD90, CD105, CO166) were observed during monolayer culture. Normalized expression profiles are described, e.g. for CD26 (see Fig. 7). Diaz-Romero 2005, at the abstract, described characterization of the cell surface molecules on human articular chondrocytes, and identified differential expression of certain markers, including upregulation of markers as distinctive for mesenchymal stem cells, suggesting that dedifferentiation leads to reversion to a primitive phenotype in chondrocyte differentiation stages.
Diaz Romero 2005, at p. 732, Reagents, teach the use of D-MEM/F12 medium, and harvest of human articular cartilage samples from the lateral femoral condyles of cadaveric knee joints.
Diaz Romero 2005, at p. 732, contemplate the use of these cells to optimize tissue repair, and tissue engineering. Diaz-Romero 2005, at p. 741, state:
The identification of new markers to characterize chondrocyte differentiation stage based on cell surface marker expression opens an array of applications in cartilage tissue engineering, from quality control for cell expansion to the optimization of culture conditions. Ongoing studies aim to investigate the expression of these potential dedifferentiation markers in normal adult cartilage and to establish a time-course of marker expression in long-term monolayer culture. Further validation of these surface molecules as markers of differentiation status will require to establish whether the profile of cell surface proteins induced by monolayer culture can be reversed by using redifferentiation procedures.
Diaz-Romero 2005, at p. 741.
It would have been prima facie obvious before the application was filed, for one of ordinary skill in the art to have combined cell cultures with cartilage-like tissue forming property, as taught by Takahashi, with the chondrocytes with higher or lower regulation of various chondrocyte biomarkers for having cartilage-like tissue forming property as taught by Diaz Romero 2005
One of ordinary skill in the art would have been motivated to have made and used cell cultures with cartilage-like tissue forming property, as taught by Takahashi, with the chondrocytes with higher or lower regulation of various chondrocyte biomarkers for having cartilage-like tissue forming property because “the identification of new markers to characterize chondrocyte differentiation stage based on cell surface marker expression opens an array of applications in cartilage tissue engineering, from quality control for cell expansion to the optimization of culture conditions” and so are useful in the context of tissue engineering applications, as taught by Diaz-Romero 2005, at p. 741.
2. Claim(s) 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi, Journal of the Japanese Orthopaedic Association, 2019, 6 pages, Vol. 93:8, (of record, IDS 9/12/2025) and Diaz-Romero, 2005, J. Cellular Physiol., Vol. 202, pp. 731-742 (2005), (of record, IDS, hereinafter Diaz-Romero 2005). as applied to claims 1, 2, 6-8, 11-13, 17 above, and further in view of Chan, Tissue Engineering, Part C, Volume 19, Number 2, 2013, pages 156 to 165, Boyan, US 20140370111 and Rosowski, US 20150093428.
Chan, Tissue Engineering, Part C, Volume 19, Number 2, 2013, pages 156 to 165, throughout the publication and abstract, and at pp. 156, 3d para, 157, para 1-6, teach using normalized medium fluorescence intensity (nMFI) for flow cytometry analysis of hepatic, chondrogenic and neurogenic differentiation. Chan at p. 157-158, bridging paragraph, teaches that nMFI increases accuracy of differentiation measurements. See abstract and p. 157. nMFI, which Chan teaches, is calculated as the ratio of MFI(sample) to MFI(negative) offers increased robustness, accuracy.
Chan does not teach analysis for CD73, CD271 and CD45 and other markers of chondrogenic differentiation and expression.
Boyan, US 20140370111, throughout the publication, and abstract and at para [0131] contacting cells with culture medium that promote formation of cartilage. AT para [0196] Boyan teaches seeded adipose stem cells positive for CD73 and CD271 and negative for CD45.
Chen, US 20210198630, throughout the publication, and abstract and at para [0007] and [0028], CD166- CD105+, Because CD166 is minus, it cannot be higher than a threshold cell surface marker.
Rosowski, US 20150093428, throughout the publication, and abstract and at [0010], claims 18 and 31, 0128] In order to accomplish a complete phenotypic dedifferentiation the isolated chondrocytes were cultured for at least ten passages in monolayer. As described previously, the cells adopted the definite progenitor phenotype marked by the expression of MSC surface markers (CD105, CD106, CD44, CD73, CD90 and CD13) and a multiple differentiation potential (adipocyte and osteocyte) (FIG. 1) (Rosowski et al., 2006). According to surface expression a uniform population of dedifferentiated chondrocytes was observed.
It would have been prima facie obvious before the filing date of the instant application for one of ordinary skill in the art to have combined nMFI analysis of chondrocytic biomarkers, as taught by Boyen, Chen and Rosowski.
One of ordinary skill in the art would have motivated to have combined nMFI analysis with the actual fluorescence quantitation of chondrocytic markers, as taught by Boyen, Chen and Rosowski, and thereby arrived at nMFI values. The data to calculate the nMFI values, such as the negative MFI value, would have been inherently present in the data Boyen, Chen and Rosowski, and would have been, absent evidence to the contrary, obvious to the practitioner.
Conclusion
1. Claims 1-9, 11-13, 17-19, and 22 are pending. Claims 9, 19, and 22 are withdrawn by the examiner. Claims 1-8, 11-13, 17-18 are examined.
2. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark L Shibuya whose telephone number is (571)272-0806. The examiner can normally be reached M-F, 9AM-4:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz, can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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MARK L. SHIBUYA
Primary Patent Examiner
Art Unit 1631
/MARK L SHIBUYA/Primary Patent Examiner, Art Unit 1631