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 .
Detailed Action
This application is in response to papers filed on November 14 2025. A response to the restriction requirement filed on November 14 2025 is acknowledged. Claims 1, 12, 16, 18-19 and 21-23 are currently pending. Claims 1, 12, 16, and 18 are amended, claims 2-11 13-15, 17 and 20 have been canceled and claims 21-23 have been added by Applicants’ amendment filed on 11/14/2025.
Applicants’ election of the following species in the response filed on 11/14/2025 is acknowledged:
a. interleukin-10 (IL-10),
a. hydrogels
a. umbilical cord
The examiner notes that claim 1 has been amended to recite the elected species of umbilical cord -derived regenerative cells and interleukin -10.
Therefore, claims 1, 12, 16, 18, 19 and 21-23 are under examination to which the following grounds of rejection are applicable.
Priority
It is acknowledged that this application is claiming benefit under 35 U.S.C. 119(e) of prior-filed provisional application 63/343,832 filed on May 19/2022.
Thus, the earliest possible priority for the instant application is May 19, 2022.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the term Thermo Electro Cryomed Freezer, Thermo Electron Corporation, Cryocyte, and Baxter, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
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, 12, 16, 18, 19 and 21-23 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 applicant regards as the invention.
Claim 1 is indefinite is vague and indefinite because they recite the phrase "derived from" and the metes and bounds of how regenerative cells can be “derived from" the claimed umbilical cord and still meet the intended limitation of the claims are not clear. Without a clear statement of the process by which the starting material is derivatized, it is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization, especially since the claimed starting material encompasses umbilical cord comprising diverse cell types such as immune, mesenchymal and epithelial stem cells, for example. This rejection could be overcome by substituting "isolated" for "derived" in the claim.
Claims 19 is indefinite in its recitation of “ wherein said mesenchymal stem cells express IL-I
receptor antagonist when treated with interferon gamma”. Claim 19 ultimately depends on claim 1. Claim 1 requires that the umbilical cord derived regenerative cells are treated with IL-10 and not IL-1 receptor antagonist. Therefore, it is unclear as to whether claim 19 intended to be limited to methods for providing umbilical cord-derived regenerative cells that are mesenchymal stem cells expressing not IL-1 receptor antagonist or the phrase refers a latent ability that is not expressed. As such the metes and bounds of the claim are indefinite.
Claims 1 12, 16, 18 and 21-23 are indefinite insofar as they depend from claim 1.
Claim Rejections - 35 USC § 112: Written Description
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 1, 12, 16, 18, 19, 21-23 are rejected under 35 U.S.C. l 12(a) or 35 U.S.C. 112 (preAIA ), 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.
M.P.E.P. § 2163 recites, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A), above), reduction to drawings (see i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406." Further, the written description inquiry is limited to that which is contained within the four corners of the specification, not the extent to which the skilled artisan, given his or her knowledge of the art, would have considered it to expand with only routine experimentation. See Ariad Pharms. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane); see also id. At 1352 ("[I]t is the specification itself that must demonstrate possession. A description that merely renders the invention obvious does not satisfy the requirement.").
Claim 1 is directed to a generic method for treating degenerated ovarian follicles comprising: identifying a patient suffering from degenerated ovarian follicles, providing umbilical cord-derived regenerative cells, treating said umbilical cord-derived regenerative cells with interleukin-10 (IL- 10), administering said treated umbilical cord-derived regenerative cells to said patient, and further administering lyophilized platelet gel or platelet rich plasma to said patient. There is not structure/function correlation for the claimed genus of IL-10 treated umbilical cord-derived regenerative cells and the repair of degenerated ovarian follicles.
The term “umbilical-cord derived regenerative cells” can be broadly but reasonably interpreted as a genus encompassing multiple heterogeneous cell populations capable of tissue repair. Claim 1 further limits the genus by reciting treatment with interleukin-10 (IL-10), thereby defining a subgenus of biologically modified regenerative cells.
The specification fails to teach any species within the genus, nor does it define any structural or functional characteristics that distinguish IL-10 treated regenerative cells from untreated cells. The specification also mentions different growth factor treatments to the mesenchymal stem cells that could work in conjunction with IL-10 [para 0008-0018]. Although the specification suggests embodiments of growth factor treatments for regenerative cells with IL-10 [Specification, para 10], there are no working examples containing molecular weights, ratios, and/or concentrations of IL-10 that result in the regenerative cells derived from umbilical cord responsible for degenerating ovarian follicles. Accordingly, the specification does not reasonably convey possession of a genus of IL-10 treated umbilical cord-derived regenerative cells.
Nakajima et al. specifies that high concentrations of IL-10 significantly inhibits microglial activation and enhances immunosuppressive activity relative to untreated MSCs [Abstract, page 102 col 1 para 1, “IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase. “]. Furthermore, Nakajima suggests that IL-10 secretion inhibits T cell and macrophage production, further downregulating any pro-inflammatory effects [page 102 col 2 para 1, “Specifically, IL-10 inhibits macrophage activation, T cell proliferation, and pro-inflammatory cytokine release, including production of interferon-g (IFN-g), IL-2, and tumor necrosis factor alpha (TNF-a) from type-1 helper T cells.”]. Nakajima implies that different concentrations of IL-10 can enhance or inhibit inflammatory behavior within mesenchymal stem cells.
Therefore, the specification does not describe the claimed subject matter that would reasonably convey to one skill in the art that applicants are in possession of population of regenerative cells from umbilical cord treated with all varying concentrations of IL-10, or combinations thereof to treat the degeneration of ovarian follicles.
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.
Claims 1, 12, 16, 18, 19, 21-23 are rejected over 35 U.S.C. 103 as being unpatentable over Zheng et al. [Published 2019. BioMed research international, 653929] in view of Chugh et al. [Published 2021. Stem Cell Research & Therapy, vol. 12, no. 1] and Bijl et al. [Published 2019. Transfusion, vol. 59, no. 11, pp. 3492–3500].
Regarding claim 1, Zheng recites a method of repairing ovarian follicles [page 5 col 2 para 1], comprising the steps of identifying a patient suffering from degenerated ovarian follicles [page 2 col 1 para 3 & Figure 1]
PNG
media_image1.png
422
761
media_image1.png
Greyscale
, providing umbilical cord-derived regenerative cells [page 2 col 1 para 2, “Cell Culture and Identification. UCMSCs were provided by Jinhua Sidanmu Stem Cell Biotechnology Co., Ltd. (Jinhua, Zhejiang, China).”].
However, Zheng does not teach treating said umbilical cord-derived regenerative cells with interleukin-10 or further administering lyophilized platelet gel or platelet rich plasma to said patient.
Chugh teaches treating the umbilical cord derived regenerative cells with IL-1. Chugh states at page 1 para 3: “ BM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improved in metabolic and reproductive markers in our PCOS model and able to restore fertility.”
The combined teachings of Zheng and Chugh fail to disclose further administering lyophilized platelet gel or platelet rich plasma to said patient.
However, Bijl teaches administering platelet gel and states at page 3493 col 1 para 2, “Recently, there has been much interest in the use of platelet-enriched blood products, commonly referred to as platelet-rich plasma (PRP) to stimulate healing of acute and chronic wounds”. Bijl also teaches that platelet gel as stimulated angiogenesis at page 3496 col 2 para 2, bridging into page 3497, “These results indicate that plasma factors are more important than platelet factors in inducing sprouting angiogenesis and that no additional effect is observed by combination of these factors.”
It would have been obvious to a person with ordinary skill in the art to modify the method of Zheng, which teaches administering umbilical cord-derived regenerative cells to repair degenerated ovarian follicles, by treating regenerative cells with interleukin-10 as taught by Chugh, since Chugh teaches that IL-10 conditioning enhances anti-inflammatory, regenerative properties and restores fertility, thereby predictably improving therapeutic efficacy. It would have been further obvious to administer the regenerative cells with lyophilized platelet gel as taught by Bijl, as platelet derived products stimulate healing of acute and chronic wounds and promote angiogenesis. A person with ordinary skill in the art would have been motivated to combine the teachings to achieve improved ovarian tissue regeneration and improved follicular growth through complementary and predictable biological mechanisms with reasonable expectation of success.
Regarding claim 16, the combined teachings of Zheng, Chugh and Bijl render obvious claim 1. Moreover, Chugh teaches allogenic umbilical-cord derived stem cells are allogeneic [page 15 col 2 para 2, “Due to limited lifespan of the engrafted MSC, it is not possible to expect a long-term treatment by only single injection of MSC. However, the short life span and gradually degradation of engrafted cells might be beneficial for the safety point of view using allogenic stem cell-based therapy”]. Furthermore, allogeneic stem cells provide standardized expansion and are immune-evasive, which would motivate a person of ordinary skill in the art to use for stem cell therapies.
Regarding claim 18, the combined teachings of Zheng, Chugh and Bijl render obvious claim 1. Moreover, Zheng teaches that the umbilical cord- derived regenerative cells are mesenchymal stem cells [Abstract, page 1 para 1, The results indicated that UCMSC transplantation recovered disturbed hormone secretion and folliculogenesis in POF rats. NGF and TrkA levels increased, while FSHR and caspase-3 decreased. The pregnancy rate of POF rats was improved. Therefore, UCMSCs could reduce ovarian failure due to premature senescence caused by chemotherapy, and the NGF/TrkA signaling pathway was involved in the amelioration of POF].
Regarding claim 21, the combined teachings of Zheng, Chugh and Bijl render obvious claim 1. Moreover, Bijl teaches that the lyophilized platelet gel is administered to the patient [page 3493 col 1 para 2, “Recently, there has been much interest in the use of platelet-enriched blood products, commonly referred to as platelet-rich plasma (PRP) to stimulate healing of acute and chronic wounds”].
Regarding claim 22, the combined teachings of Zheng, Chugh and Bijl render obvious claim 1. Moreover, Bijl teaches that the lyophilized platelet gel is allogeneic [page 3498 col 2 para 3, “An evidence-based standardized allogeneic PRP preparation could improve wound healing.”].
Regarding claim 23, the combined teachings of Zheng, Chugh and Bijl render obvious claim 1. Moreover, Zheng teaches [page 2 col 2 para 2, “UCMSC surface marker expression was analyzed at passage three by flow cytometry, using fluorescein isothiocyanate (FITC) conjugated monoclonal antihuman CD90 and CD45 antibodies, phycoerythrin (PE)conjugated anti-human CD34, CD73, and CD105 antibodies.”].
***
Claim 12 is rejected over U.S.C. 103 as being unpatentable over Zheng, Chugh and Bijl as applied to claim 1 above, and in further view of Zhou et al. [Published 2021. Stem Cells and Development, vol. 30, no. 15, pp. 782–796].
With regard to claim 1, the combined teachings of Zheng, Chugh and Bijl render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 1. However, the combined references fail to teach that the umbilical-cord-derived regenerative cells are prepared in a hydrogel.
Zhou teaches that mesenchymal stem cells can be prepared in a hydrogel scaffold and repair ovarian function in a mouse model [Abstract, page 782 para 1 “After the transplantation of the MSC/Matrigel, the number of follicles was significantly increased in the mice with POF, and the tissue fibrosis ratio was reduced.”]. Furthermore, Zhou teaches that hydrogels and three-dimensional matrices provide structural support for cells and aid in tissue regeneration and a suitable microenvironment for transplanted regenerative cells [page 783 col 1 para 3-4, “Three-dimensional (3D) scaffolds are typically porous, biocompatible, and biodegradable materials that serve to provide structural support for cells and new tissue being formed, acting as a temporary extracellular matrix (ECM) to induce the natural processes of tissue regeneration and development [24]. Matrigel, a natural biomaterial and the main component of the ECM, has been widely used for tissue-enhanced engineering scaffolds [25] because it can provide physical support and a suitable microenvironment for transplanted stem cells [26].”].
A person skilled in the art would have been motivated to prepare the umbilical-cord derived regenerative cells in a hydrogel since they are well known carriers for stem cell delivery that provide a bioinert, structural three-dimensional matrix, enhancing the therapeutic efficacy of the regenerative cells. Furthermore, Zhou reveals that regenerative cells prepared in a hydrogel have improved the generation of ovarian follicles, as well as reducing tissue fibrosis. A person of ordinary skill would have modified those combined teachings of Zheng, Chugh and Bijl to incorporate the regenerative cells within a hydrogel of Zhou to have reasonable expectation of success and arrive at the claimed invention. Therefore, it would have been obvious to implement the Zhou’s teaching of the hydrogel to improve the therapeutic efficacy of the claimed invention.
***
Claim 19 is rejected over U.S.C. 103 as being unpatentable over Zheng, Chugh and Bijl as applied to claims 1 and 18 above, and in further view of Luz-Crawford et al. [Published 2015. Stem Cells, Volume 34, Issue 2, February 2016, Pages 483–492].
With regard to claims 1 and 18 , the combined teachings of Zheng, Chugh and Bijl render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 1. However, the combined references fail to teach that mesenchymal stem cells express IL-1 receptor antagonist when treated with interferon gamma.
Luz-Crawford teaches that mesenchymal cells express interleukin-1 receptor antagonist in the presence of interferon gamma [page 484 col 1 “ IL1RA is also secreted by mesenchymal stromal/stem cells… inhibit the polyclonal B cells activation in the presence of interferon (IFN)-γ”]. Moreover, Luz-Crawford teaches that the presence of interferon gamma subsequently inhibits B cell differentiation [page 491 col 1 para 1 “ The most striking role of IL1RA produced by IFN-γ-activated MSCs is the inhibition of B cell differentiation. “].
It would have been obvious to a person of ordinary skill in the art to modify the mesenchymal stem cells of Zheng by exposing them to interferon gamma as taught by Luz-Crawford in order to induce IL-1Ra expression, since Luz-Crawford teaches that such conditioning would predictably inhibits B cell differentiation. A person of ordinary skill in the art would have had a reasonable expectation of success in combining these teachings as it was well established in the art prior to the effective filing date.
Conclusion
Claims 1, 12, 16, 18, 19 and 21-23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 10-4p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634