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 1-2, 6-13, 22-23, 25-26, 50, 54-57, 63, 65-69, 71, 73-75 are currently pending.
Claims 80-83, 86 and 89 have been newly canceled and no claims have been newly added.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-2, 6-13, 22-23, 25-26, 50, 54-57, 63, 65-69, 71, 73-75) and species regenerative fibroblast cells that express CD39 or CD73 in the reply filed on 08/27/2025 is acknowledged.
Claims 22-23, 25-26, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected specie, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/27/2025.
Claims 1-2, 6-13, 50, 54-57, 63, 65-69, 71, 73-75 have been examined on their merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/10/2022 has been considered by the examiner.
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.
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.
Claims 1-2, 6-13, 50, 54-57, 63, 65-69, 71, 73-75 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 the treating of ovarian failure, does not reasonably provide enablement for preventing ovarian failure in an individual.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the methods of the invention commensurate in scope with these claims.
There are numerous causes for ovarian failure including genetic causes such as Turner’s syndrome, environmental exposures and autoimmune diseases which are not necessarily capable of being prevented by the claimed method (Man et al. ”, International Journal of Molecular Sciences, 2022, abstract, pages 3-4). Since ovarian failure happens unpredictably there is no way to prevent it.
Applicant has not provided any evidence that the claimed method would be able to prevent ovarian failure that was caused by any and all situations.
Further, the burden of enabling "prophylaxis" (i.e. prevention), of a disease is greater than that of enabling a treatment method due to the need to screen the subjects
susceptible to the respective condition and the difficulty of proof that the administration of the composition was the agent that acted to prevent the condition.
Given that the outcomes of practicing the claimed methods beyond the scope defined above are highly unpredictable, and that the disclosure does not provide sufficient direction, guidance or working examples, the experimentation left to those skilled in the art is extremely extensive. It would initially require experimentation in animal models of the numerous diseases which are within the scope of the claims, using numerous types and subtypes of cells derived from fibroblasts, under various dosing regimens. The number of possible permutations of these parameters is so large that, even in cases where the requisite methods are routine, the amount of experimentation is beyond the capacity of even the largest research institutions. Since the skilled artisan understands that, for the reasons addressed above, the chances of identifying a set of conditions resulting in a useful outcome are extremely low, the skilled artisan would reasonably view such experimentation as unnecessarily, and improperly, extensive and undue.
Therefore, the currently claimed methods are not fully enabled for their entire scope based on the specification and what is known in the art of ovarian failure.
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.
Claim(s) 1-2, 6-13, 50, 54-57, 63, 65-69, 71, 73-75 are rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al (US 2018/0015127-from IDS filed 11/10/2022) in view of Costa et al (Zygote 2017-from IDS filed 11/10/2022) and O’Heeron et al (US 2018/0195044-from IDS filed 11/10/2022).
Regarding claims 1, 74 and 50, Ichim teaches a method of treating or preventing ovarian failure in an individual (Claim 1 - "A method for addressing ovarian aging or premature ovarian failure in an individual through the steps of: a) Diagnosing an individual with premature ovarian failure or ovarian aging; b) Administering endothelial progenitor cells to said individual").
However, Ichim does not specifically teach the method comprising administering a therapeutically effective amount of a composition comprising fibroblasts or conditioned media therefrom to an individual in need thereof.
Costa teaches the method of producing germ cells and oocyte-like cells from fibroblasts (pg 2, col 2, para 2 - "The aims of this study were to investigate the expression of pluripotency markers (OCT4, NANOG, REX, SOX2) in bovine fibroblast treated with different concentration of 5-Aza. It also evaluates the effects of BMP2, BMP4 or follicular fluid on expression of mRNA of markers for germ cells (VASA, DAZL, cKIT), meiosis (SCP3) and oocytes (ZPA and GDF9) during culture of 5-Aza treated fibroblasts in vitro"; pg 2, col 2, para 3 - "Primary bovine skin fibroblast cultures were established from fresh biopsies from fetal ear skin."; pg 4, col 1. para 3 - "After the exposure to 2.0 uM 5-Aza for 72 h, cell phenotype changed and fibroblast elongated morphology (Fig. 1A) was replaced by an oval or round shape (Fig. 1B). Figure 1(C) show that the great majority of the cells remained viable"; Figure 7 Legend - "Morphology of bovine fibroblasts exposed to 5-Aza and cultured in differentiation medium for 14 days. Fibroblast cultured for 14 days in medium supplemented with BMP2 (line 1), BMP4 (line 2) and follicular fluid (line 3), (A, D, G). ... Arrows show oocyte-like structures formed after 14 days of culture.)"; pg 14, col 1, para 2 - col 2, para 1 - "In conclusion, 2.0 uM 5-Aza induces the expression of mRNASs for SOX2, ОСТ4, NANOG and REX in bovine skin-derived fibroblasts cultured for 72 h. The presence of BMP2, BMP4 or follicular fluid in differentiation medium induces cellular morphological changes and promotes expression of markers for germ cells (VASA, DAZL and cKIT), meiosis (SCP3) and oocyte (GDF9 and ZPA). This method can be effective to produce oocytes from somatic cells and can thus contribute, in the future, for the development of new biotechnologies to solve fertility problems in human species").
However, Costa does not specifically teach the use of regenerative fibroblasts.
O’Heeron teaches a method of producing and enhancing regenerative fibroblasts for cell-based therapeutics (Abstract - "Disclosed are compositions of matter, cells, protocols and procedures useful for augmentation of one or more therapeutic activities of fibroblast cellular populations. ...In another embodiment, fibroblasts are cultured under hypoxic conditions prior to administration to an individual."; para [0020] - "In one embodiment, methods are provided for augmenting efficacy of fibroblasts for regeneration of cells and/or tissues, comprising the steps of (optionally) obtaining fibroblast cells; contacting fibroblasts with one or more biologically active substances; and/or culturing the fibroblasts under conditions to enhance efficacy of the fibroblasts for regeneration of the cells and/or tissues... In particular embodiments, regeneration of cells and/or tissue by the fibroblasts comprises immune modulation, angiogenesis... and so forth."; para [0036] - "Methodologies for growth of mesenchymal stem cells, which may be modified for fibroblast specific use, are provided in the following reference that is incorporated by reference"). Given that Ichim teaches the use of regenerative cells for treatment of ovarian failure (para [0002] - "The invention pertains to the field of ovarian aging and premature ovarian failure. Specifically, this invention relates to regenerative cell-based therapies for treating women afflicted with premature ovarian failure or at-risk for developing said condition."; para [0013] - "As used herein, the term "regenerative cell" refers to EPC and/or MSC."), and given that Costa specifically teaches the method of culturing fibroblasts to produce germ cells for oocyte production, and given that O’Heeron specifically teaches the use of regenerative fibroblasts for cell-based therapeutics to regenerate cells or tissues, one with ordinary skill in the art would have found it obvious that regenerative cells can be used for ovarian failure treatment (as taught by Ichim), further comprising administering regenerative fibroblasts taught by O’Heeron for augmented efficacy of fibroblasts for cell-based therapeutics, further culturing fibroblasts (according to the method of Costa) for increased expression of germ cell markers for oocyte production and treating fertility problems in a patient.
Regarding claim 2, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, and Ichim teaches wherein the ovarian failure is age-related (para [0004] - "Premature ovarian failure (POF), also referred to as premature ovarian insufficiency (POI) or premature menopause, is characterized by a loss of ovarian function marked by cessation of ovarian function and premature ovarian follicle depletion before 40 years of age."; para [0014-0015] - "As used herein, the term "ovarian aging" may refer to a reduction in follicle numbers and/or reduced quality or quantity of oocytes, or other sequelae related to ovarian health that are associated with a loss of natural fertility in women...As used herein, the term "therapeutic activity" refers to any activity of cells and/or other agents that reverses or improves ovarian aging or POF").
Regarding claim 2, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, and Ichim teaches wherein the ovarian failure is idiopathic premature ovarian failure (para [0004] - "Premature ovarian failure (POF), also referred to as premature ovarian insufficiency (POI) or premature menopause, is characterized by a loss of ovarian function marked by cessation of ovarian function and premature ovarian follicle depletion before 40 years of age."; para [0014-0015] - "As used herein, the term "ovarian aging" may refer to a reduction in follicle numbers and/or reduced quality or quantity of oocytes, or other sequelae related to ovarian health that are associated with a loss of natural fertility in women...As used herein, the term "therapeutic activity" refers to any activity of cells and/or other agents that reverses or improves ovarian aging or POF").
Regarding claim 2, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, and Ichim teaches wherein the ovarian failure is associated with treatment (para [0006] - "Chemotherapeutic agents, including alkylating agents, antimetabolites, aneuploidy inducers, radiomimetics and topoisomerase Il inhibitors, can have variable impacts in precipitating POF. Mechanistically, these agents may cause ovarian cell apoptosis, impair local hormone regulation needed for follicular function, or they may prevent normal interactions between oocytes and granulosa cells, which provide physical support and microenvironment required for the developing oocyte. Chemotherapy-induced ovarian failure may be reversible; however, in other cases, the damage is progressive and dysfunction is permanent. Such ovarian failure is diagnosed by irreversible amenorrhea lasting for several months... following chemotherapy and a follicle stimulating hormone level").
Regarding claims 6, 9, 13 and 75, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, and O’Heeron teaches wherein the fibroblasts comprise regenerative fibroblasts (para [0020] - "In one embodiment, methods are provided for augmenting efficacy of fibroblasts for regeneration of cells and/or tissues, comprising the steps of (optionally) obtaining fibroblast cells; contacting fibroblasts with one or more biologically active substances; and/or culturing the fibroblasts under conditions to enhance efficacy of the fibroblasts for regeneration of the cells and/or tissues... In particular embodiments, regeneration of cells and/or tissue by the fibroblasts comprises immune modulation, angiogenesis... and so forth."). The fibroblast cells are exposed to factors such as FGF-alpha (FGF-1) and FGF-beta (FGF-2) which will then stimulate the fibroblast to express CD39 and/or CD73 ([0020]) as evidenced by Applicant’s specification (page 42 para [0139]).
Regarding claims 7 and 10-12, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, and O’Heeron teaches wherein the fibroblast cells are cultured under conditions sufficient to differentiate the fibroblasts into regenerative fibroblast cells (para [0020] - "In one embodiment, methods are provided for augmenting efficacy of fibroblasts for regeneration of cells and/or tissues, comprising the steps of (optionally) obtaining fibroblast cells; contacting fibroblasts with one or more biologically active substances; and/or culturing the fibroblasts under conditions to enhance efficacy of the fibroblasts for regeneration of the cells and/or tissues... In particular embodiments, regeneration of cells and/or tissue by the fibroblasts comprises immune modulation, angiogenesis... and so forth."). Wherein the conditions comprise hypoxia sufficient to induce nuclear translocation of HIF-1 alpha and growth factors are disclosed (para [0054-0055] and para [0020]).
Regarding claim 8, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 6 or 7, and O’Heeron teaches wherein the regenerative fibroblast cells comprise one or more of the following biological activities: (a) inducing of angiogenesis; (b) producing trophic factors; (c) suppressing inflammation; (d) stimulating maturation of immature oocytes; and (e) inducing folliculogenesis (para [0020] - "In one embodiment, methods are provided for augmenting efficacy of fibroblasts for regeneration of cells and/or tissues, comprising the steps of (optionally) obtaining fibroblast cells; contacting fibroblasts with one or more biologically active substances; and/or culturing the fibroblasts under conditions to enhance efficacy of the fibroblasts for regeneration of the cells and/or tissues... In particular embodiments, regeneration of cells and/or tissue by the fibroblasts comprises immune modulation, angiogenesis... and so forth.").
Regarding claims 54-57 and 63, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, but do not disclose increasing the number and activity of T regulatory cells and wherein the fibroblasts are capable of inducing generation of T regulatory cells to produce growth factors. However, this is deemed to be an inherent property of carrying out the Ichim method as modified by Costa and O’Heeron as described above.
Regarding claim 63, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, but do not disclose manipulation of the individual’s microbiome by administration of Lactobacillus reuti. However, this probiotic is well known to provide therapeutic benefits and often prescribed for health benefits.
Regarding claim 65-67, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, and O’Heeron teaches wherein the fibroblast cells are cultured with an agent such as TGF (para [0007], [0015], [0020], [0030], [0035], [0049]) which increases expression of fibroblast PD-1 ligand (Applicant’s specification (para 27]).
Regarding claims 68-69 and 71, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, but do not disclose the effects of increased expression of PD-1 ligand. However, this is deemed to be an inherent property of carrying out the Ichim method as modified by Costa and O’Heeron as described above.
Regarding claim 73, Ichim in view of Costa, further in view of O’Heeron make obvious the method of claim 1, and Ichim disclose wherein administration is intravaginally or into the uterus (peri-ovary area) (para 0042]).
Therefore, the combined teachings of Ichim et al, Costa et al and O’Heeron et al render obvious Applicant’s invention as claimed.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Haniffa et al., “Adult Human Fibroblasts are Potent Immunoregulatory Cells and Functionally Equivalent to Mesenchymal Stem Cells”, The Journal of Immunology, 2007, Vol. 179, pp. 1595-1604.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631