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 .
Restriction/Election
Applicant’s election without traverse of Group I, claims 1-9 and 13-17 in the reply filed on 08/05/2025 is acknowledged.
Claims 1-2, 6-15, and 17-18 are pending. Claims 3-5 and 16 are cancelled. Claims 1, 10, 11, and 18 are amended.
Claims 10-12 and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/05/2025.
Claims 1, 2, 6-9, 13-15 and 17 are currently under examination.
Priority
This application is a 371 of PCT/EP2021/058809 filed on 04/02/2021, claims the priority of Foreign Applications EUROPEAN PATENT OFFICE (EPO) 20168012.1 filed on 04/03/2020. A certified copy of EP 20168012.1 was submitted of the record on 09/30/2022. The priority date of claim set filed on 08/05/2025 is determined to be 04/03/2020, the filing date of EP 20168012.1.
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.
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, 2, 6-9, 13-15 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Tavakol et al. (2018) (Tavakol et al., Human Endometrial Stem Cell Isolation from Endometrium and Menstrual Blood, Bio Protoc. 2018 Jan 20;8(2): e2693. doi: 10.21769/ BioProtoc.2693; listed as NPL #5 of IDS filed by Applicants on 12/06/2022) in view of Ai et al. (US 2014/0370515), Kao et al. (2011) (Kao et al., Comparative study of human eutopic and ectopic endometrial mesenchymal stem cells and the development of an in vivo endometriotic invasion model, Fertil Steril, 2011 Mar 15;95(4):1308-15.e1. doi: 10.1016/j.fertnstert. 2010.09.064. Epub 2010 Nov 3) and Masuda et al. (2012) (Masuda et al., A novel marker of human endometrial mesenchymal stem-like cells, Cell Transplant, 2012;21(10):2201-14. doi: 10.3727/096368911X637362. Epub 2012 Mar 27).
Claim 1 filed on 08/05/2025 is directed to “A composition: comprising endometrial stem cells for use in a method for the treatment of poor ovarian response, wherein said endometrial stem cells are endometrial mesenchymal stem cells from a human, wherein said endometrial mesenchymal stem cells are positive for CD90, CD146 and CD105 markers and negative for the CD34 and CD31 marker, and wherein said endometrial mesenchymal stem cells express Oct-4. CD146 and STRO-1”.
Claim interpretations: The limitation “for use in a method for treatment of poor ovarian response” recited in claim 1, and the limitation “is administered ---” recited in claims 6, 9, 15 and 17 are directed to the intended use of claimed composition comprising endometrial stem cells that do not affect the structure and characteristics of claimed composition, a product, which comprises endometrial mesenchymal stem cells from a human. Similarly, the limitation “autologous endometrial stem cells” recited in claim 2 is intended use of claimed “endometrial mesenchymal stem cells from a human” to be administered to the same human.
Regarding Claim(s) 1, 2, and 6, Tavakol et al. (2018) teaches that “Human endometrial stem cell/stromal cells (hEnSCs) are isolated from endometrium or menstrual blood and are recognized as a valuable cell type in tissue engineering and cell therapy. Furthermore, hEnSCs, which have CD90 (a mesenchymal marker), CD105 (endoglin), CD44, CD146 (endometrial stem cell markers) and lack CD31 (Endothelial marker), CD34 (hematopoietic marker) and CD133 on the cell surface, are a new source of mesenchymal stem/stromal cells. Additionally, these cells can be encapsulated into self-assembling peptide nanofibers as a 3D scaffold for applications in the treatment of neurodegenerative diseases. Here, we describe a protocol to isolate hEnSCs from endometrium or menstrual blood. (See Abstract, Tavakol et al. 2018).
Regarding limitations “PBS solution” and “cell number/ml” recited in instant claims 7-9, 13-15, and 17, Tavakol et al. (2018) teaches Figure 2. Schematic of isolation of hEnSCs from endometrium, which includes the steps “14. Add 4 ml pre-warmed PBS to the interface phase and centrifuge at 100 x g for 10 min. 15. Discard the supernatant, add 1 ml plating media (see Recipes) into the sediment and transfer them to T25 culture flasks. Add an additional 2.5 ml of plating media containing DMEM-F12, 15% FBS, 1% Pen/Strep. Incubate for 24 h in the cell incubator. A total volume of 3.5 ml cell culture media in T25 culture flasks for the first day can increase the frequency of cells adhering to the flask. Note that larger volumes may result in fewer cells adhering to the flask. 16. The next day, slowly add 3 ml more of plating media and keep it in the cell incubator for 1 week. Do not shake it or disturb it each day.17. When cells are 90% confluent, wash them with pre-warmed PBS, discard PBS, then add 0.25% trypsin-EDTA (1 ml). Incubate in the cell incubator for 5 min. After the cells dissociate from the flask, transfer the cells to a 15 ml Falcon and add 1 ml DMEM-F12 supplanted with 10% FBS, 1% Pen/Strep. Centrifuge at 300 x g for 10 min. 18. Add cell sediment to another T25 culture flasks (100,000 cells/ml) or T75 culture flasks (300,000 cells/ml) and for the rest of cell passages use 5 and 9 ml DMEM-F12 supplemented with 10% FBS, 1% Pene/Strep, respectively (Figure 2) (See page 5 of Tavakol et al., 2018).
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Figure 2. Schematic of isolation of hEnSCs from endometrium
Tavakol et al. (2018) further teaches in Figure 4. Isolation of hEnSCs from menstrual blood.
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Figure 4. Isolation of hEnSCs from menstrual blood. A. Sample collection. Sample
collection of menstrual blood during menstrual period in day 2 and 3 with Diva cup. This device
can be inserted in vaginal canal by donors and then, blood is transported into Falcon. B. Ficoll
separation.
Tavakol et al. (2018) does not explicitly teach endometrial mesenchymal stem cells express Oct-4 and STRO-1.
Regarding endometrial mesenchymal stem cells express Oct-4 and STRO-1, Ai et al. (2014) teaches that “Human endometrial stem cells (hEnSCs) are an easily accessible source of adult stem cells. The human endometrial stem cells, like other mesenchymal lineage stem cells,
have a low level of immunogenicity. Human endometrial stem cells are the most preferred type of cells arising from the mesenchymal stem cell lineage because of their high differentiation capacity, rapid growing and their functional development. Recent researches indicate the presence of endometrial stem cells in different layers of the uterus. Immunohistochemistry has helped in the identification of specific markers such as Oct-4, CD146, and STRO-1 expressed by the endometrial stem cells (See [0015] and [0016], Ali et al. US 2014/0370515).
Relevant to the imitations “PBS solution” and “cell number/ml” recited in instant claims 7-9, 13-15, and 17, consistent with the teachings by Tavakol et al. (2018), Ai et al. (2014) also teaches “Isolation of hEnSCs” (See [0135], Ali et al. US 2014/0370515); “Flow Cytometry Analysis of hEnSCs”, including step “The hEnSCs were then centrifuged at 500 g for 5 minutes at room temperature. The hEnSCs formed a pellet. The centrifugation step was repeated for resuspended in an appropriate volume of Flow cytometry Staining Buffer (See [0136], Ali et al. US 2014/0370515); and “After the hEnSCs were grown for 3 passages (in order to reach a desired cell density of l x106 cells/ml), the hEnSCs were transferred to culture plate inserts in a Home 6 well culture plate (See [0138], [0148], [0158], and [0178], Ali et al. US 2014/0370515)
Regarding endometrial mesenchymal stem cells express Oct-4, consistent with the teachings by Ai et al. (2014), Kao et al. (2011) teaches that “By flow cytometric analysis, the putative eutopic and ectopic endometrial MSC cell lines (EN18, EN19) were found to express the pluripotent stem cell marker, Oct-4, and several MSC biomarkers, CD9, CD29, CD44, CD49f, CD90, and CD105. These cells did not show the expression of CD34, CD45, and SSEA-4, which are specific markers for hematopoietic stem cells, leukocytes, and embryonic stem cells, respectively. Kao et al. (2011) further teaches that “We compared the characteristics of eutopic and ectopic endometrial MSCs from the same endometrial donor. Although both showed similar mesenchymal cell phenotypes, ectopic endometrial MSCs showed distinctly greater ability of cell migration and invasion. Furthermore, in an in vivo cell invasion model using cells grown in scaffold and transplantation in immune-deficient mice, the ectopic endometrial MSCs were found to form many new blood vessels and to invade surrounding tissue”. (See Abstract, page 1308)
Regarding endometrial mesenchymal stem cells express STRO-1, consistent with the teachings by Ai et al. (2014), Masuda et al. (2012) teaches that STRO-1 is a marker for nonhematopoietic stromal cells, and the analysis of surface phenotype of human endometrial W5C5+ cells indicate the expression of STRO-1 (60.3 ± 14.4%, n4) (Fig. 3A, B). (See page 2206, right column, second paragraph, and Fig. 3 on page 2208). Masuda et al. (2012) further teaches that “This study identified W5C5 as a single marker capable of purifying eMSCs possessing MSC properties and reconstituting endometrial stromal tissues in vivo. W5C5 enriches eMSCs to high purity and provides a simple protocol for their prospective isolation using magnetic bead selection rather than flow sorting. W5C5 selection may provide an alternate, readily available autologous source of MSC, obtainable with minimal morbidity using an office endometrial biopsy procedure for future cell-based therapies (See Abstract, Masuda et al., 2012).
It would have been prima facia obvious for a skilled artisan to incorporate the teachings of Ai et al. (2014), Kao et al. (2011) and Masuda et al. (2012) into the teachings of Tavakol et al. (2018) to reach the composition recited in instant claim 1 regarding “a composition: comprising endometrial stem cells for use in a method for the treatment of poor ovarian response, wherein said endometrial stem cells are endometrial mesenchymal stem cells from a human, wherein said endometrial mesenchymal stem cells are positive for CD90, CD146 and CD105 markers and negative for the CD34 and CD31 marker, and wherein said endometrial mesenchymal stem cells express Oct-4. CD146 and STRO-1” with reasonable expectation of success because Ai et al. (2014), Kao et al. (2011) and Masuda et al. (2012) are all directed to isolation, culture, and characterization of human endometrial mesenchymal stem cells, and potential therapeutic application of human endometrial mesenchymal stem cells in cell-based therapies.
A skilled artisan would have been motivated to incorporate the teachings of Ai et al. (2014), Kao et al. (2011) and Masuda et al. (2012) into the teachings of Tavakol et al. (2018) because (i) Ai et al. (2014) specifically teaches that “Recent researches indicate the presence of endometrial stem cells in different layers of the uterus. Immunohistochemistry has helped in the identification of specific markers such as Oct-4, CD146, and STRO-1 expressed by the endometrial stem cells (See [0016] Ai et al. US 2014/0370515); (ii) Kao et al. (2011) specifically teaches that “These results indicate unique invasion and angiogenesis characteristics of ectopic endometrial MSCs that may underlie the pathogenesis of ectopic endometriosis. The animal invasion model will be useful for future characterization of endometrial MSCs.” (See Conclusions, page 1308 of Kao et al., 2011), and (iii) Masuda et al. (2012) discloses that “This is the first report on the prospective isolation of eMSCs using a novel single marker, W5C5. Given that W5C5+ cells reside throughout endometrium, they offer an alternate readily available autologous source of MSC obtainable with minimum morbidity using an office-based endometrial biopsy procedure for future cell-based therapies in tissue engineering applications. Also, this study confirms eMSCs reside in a perivascular location in the stroma and play an important role in cyclical regeneration of this highly regenerative tissue. (See left column, page 2213 of Masuda et al., 2012).
Conclusion
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/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682