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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/13/2025 has been entered.
Claims 1-35, 37-54 have been canceled, claim 65 is newly added, and claims 36 and 55-65 have been considered on the merits. All arguments have been considered.
Claim Rejections - 35 USC § 112 (New)
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 36 and 55-65 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 36 discloses the term “late passage human ABCB5+ stem cells”. The claim also discloses that the ABCB5+ stem cells are isolated from the primary human skin cells that have been through at least 10 passages. It is not clear if the “late passage” is intended to refer the passages of ABCB5+ stem cells or the primary skin cells. Clarification is required. If the term “late passage” is intended to refer human ABCB5+ stem cells, is this term meant to point out that ABCB5+ stem cells are isolated and then passaged? Furthermore, the term “late” would be considered a relative term under the interpretation of the ABCB5+ stem cells being passaged. Clarification is required.
Claim 36 discloses the term “tissue derived ABCB5+ cells” at the end of the claim. It is not clear what subject matter this term intends to point out. The claim discloses the ABCB5+ stem cells derived from the primary human skin cells, and how this cell is different from “tissue derived ABCB5+ cells” as they are derived the skin tissue. Clarification is required.
Claim 65 discloses the term “Mi-polarized macrophage”. It is not clear what this term intends to point out. Is it meant to be “polarized M1 macrophage”? Clarification is required.
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.
Claim(s) 36, 55-57 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Frank (US 8,455,245; of record) in view of Frank et al. (US 2016/0106782; IDS ref.), Uitto et al. (2016, J. Inves. Dermatol.; of record), Conget et al. (2010, Cytotherapy; of record).
Regarding claim 36, Frank teaches ABCB5 positive mesenchymal stem cells (ABCB5+ MSCs) that may be used for any purpose that MSCs from other course are used (Abstract). The ABCB5+ MSCs of Frank are purified, cloned, propagated and expanded among clonally-derived differentiating cultures for greater than 50 passages (col. 5, lines 41-46). The ABCB5+ MSCs can be obtained from skin and the skin may be derived from any subject having skin, preferably human skin (col. 6, lines 48-51). Frank teaches that clonally derived ABCB5+ dermal MSC possess multipotent differentiation potential (col. 26, lines 25-34). Frank teaches that the isolated ABCB5 positive immunomodulatory dermal MSCs are substantially pure, and the isolation is carried out by using antibody against ABCB5 (col. 28, claim 1).
Regarding the purity of “greater than 99%” (claim 36) or “greater than 99.998%” (claim 56), Frank teaches the ABCB5 positive MSCs are substantially pure isolated using an antibody against ABCB5, and teaches “at least 99 percent” (col.7, lines 47-53).
Regarding the wherein clause of claim 36 directed to the late passage human ABCB5+ stem cells being isolated, using an ABCB5 antibody, from the physiologically occurring primary human skin cells that have been cultured through at least 10 passages, Frank does not particularly teach the limitation.
This wherein clause is directed to a product-by-process limitation (see MPEP2113(I)) that limits the late passage human ABCB5+ stem cells utilized in the method of alleviating one or more symptoms of EB. Furthermore, the wherein clause would be considered optional but does not require steps to be performed (see MPEP2111.04(I)). In the absence of any evidence, the product-by-process limitation does not require any active step to be carried out for the claimed method, i.e. optional, and the limitation provides only the structure of the late passage human ABCB5+ stem cells utilized in the claimed method. For the instant case, the wherein clause provides the structure of the cells as ABCB5+ stem cells. As Frank teaches ABCB5+ MSCs, it is considered that Frank meets the limitation.
Regarding the wherein clause of claim 36 directed to the greater than or equal to 90% of the ABCB5+ MSCs maintain pluripotent properties of tissue derived ABCB5+ cells, as the human ABCB5+ MSCs of Frank are considered identical to the claimed cells, the properties of the human ABCB5+ MSCs of Frank would inherently possess identical properties as the claimed cells. Nevertheless, Frank et al. teach that the human ABCB5+ MSCs have capacity to differentiate all three germ layers, which would indicate that the human ABCB5+ MSCs of Frank would have identical feature indicative to pluripotent property of the cells (see the discussion on claim 57 below).
Regarding the method of treating EB, Frank does not teach the method of treating EB using their human ABCB5+ MSCs.
Uitto et al. teach that MSCs are used for treating RDEB citing various clinical trials reported. Uitto et al. teach that these clinical trials showed clinical improvements in wound healing, or reduction in skin inflammation, less skin pain and itching (p.355, 1st and 2nd col.). Conget et al., disclosed in Uitto et al., teach that allogeneic mesenchymal stromal cells replenished type VII collagen and re-epithelialization of chronically ulcerated skin in patients with RDEB (see entire document).
Frank et al. teach human ABCB5+ dermal MSC were able to produce regenerative wound healing by reducing inflammatory stroma thickness in wounded NSG mice (Example 4).
It would have been obvious to a person skilled in the art to use the human ABCB5+ MSCs of Frank for the method of treating EB taught by Uitto et al. and Conget et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to use the human ABCB5+ MSCs of Frank because one skilled in the art would recognize that the human ABCB5+ MSCs of Frank are suitable alternative to the bone marrow derived MSCs taught by Conget et al. The human ABCB5+ MSCs of Frank possess the necessary properties of MSCs (e.g. BM-MSCs) to provide immunomodulation (col. 28, claim 1). Furthermore, Frank et al. teach that the human ABCB5+ MSCs have capacity to provide regenerative wound healing as discussed above. Thus, one skilled in the art would recognize that the human ABCB5+ MSCs of Frank is suitable MSCs for treating EB for the method of Conget et al.
Regarding the late passage human ABCB5+ stem cells expressing higher levels of stem cell marker SOX2, NANO2 or SOX3 than tissue derived ABCB5+ cells (claim 36), the cited references do not teach the limitation. However, the limitation is directed to the characteristics of the claimed cells, and as the human ABCB5+ MSCs of Frank are considered identical to the claimed cells, the properties of the human ABCB5+ MSCs of Frank would inherently possess identical properties as the claimed cells.
Regarding claim 55, Frank does not teach the human ABCB5+ MSCs co-express CD90. However, Frank et al. teach that the ABCB5+ MSCs from human dermis express CD90 (para. 123). Thus, the human ABCB5+ MSCs of Frank would inherent co-express CD90.
Regarding claim 57 directed to the late passage human ABCB5+ stem cells possessing the capacity to differentiate all three germ layers, Frank does not particularly disclose the limitation. However, Frank et al. teach ABCB5+ dermal cells were capable of giving rise to all three embryonic lineages (para. 125). Thus, the human ABCB5+ MSCs of Frank would have the identical properties as claimed.
Regarding claim 65 directed to the late passage human ABCB5+ stem cells being capable of IL-1RA secretion after co-culture with Mi-polarized macrophages, the limitation is directed to the characteristics of ABCB5+ stem cells when they are used in the co-culture, which does not require any active step to be carried out for the claimed method of alleviating symptoms of EB in a subject. Thus, the wherein clause does not provide any weight in determining patentability of the claimed method.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 58-61 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frank in view of Frank et al., Uitto et al. and Conget et al. as applied to claims 36 and 55-57 above, and further in view of Chan et al. (2005, Stem Cells).
Regarding the limitations directed to the at least 5% (claim 58) or at least 70% (claim 59) of the late passage ABCB5+ stem cells comprising an exogenous gene, Frank teaches that the human ABCB5+ MSCs of Frank contains a biologically active agent which includes an exogenous genetic material (col. 3, lines 56-58; col. 19, lines 41-46; col. 29, claims 8 and 10). Regarding the percentage of the cells comprising the exogenous gene, as the genetically altered human ABCB5+ MSCs of Frank (col. 19, lines 41-46) can be stable changes by using retroviral vectors for high-efficiency transduction of genes, it is expected that the claimed percentage of the cells expressing the exogenous gene. It is noted that “high-efficiency” transduction of genes by using a retrovirus can be more than 90% according to Chan et al. (see Abstract).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 62-64 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frank in view of Frank et al., Uitto et al. and Conget et al. as applied to claims 36 and 55-57 above, and further in view of Larcher et al. (2015, Actas Dermosifiliogr.; of record) and Sebastiano et al. (2014, Sci. Transl. Med.; of record)
Regarding claims 62-64 directed to the human ABCB5+ MSCs comprising a CRISPR RNA-guided nuclease (cas9) and a gRNA that targets the gene, and the gene being Col7A, while Frank teaches that genetic alterations to have exogenous genetic material being expressed by any known gene therapy procedure to replace a mutated or non-expressed gene (col.19, lines 41-52), Frank in view of Frank et al., Uitto et al. and Conget et al. do not particularly teach the limitation.
Larcher et al. teach that there are three strategies to treat RDEB including protein therapy, cell therapy and gene therapy (Fig. 1). The cell therapy includes stem cells such as MSCs and iPSCs, and gene therapy involves gene editing to correct a COL7A1 mutation and the use of CRISPR/Cas9 system in the genetic modification of stem cells (p.380, 1st col.).
It would have been obvious to a person skilled in the art to genetically modified autologous human ABCB5+ MSCs as taught by Frank et al. using CRISPR/Cas9 system to correct COL7A in the human ABCB5+ MSCs for treating RDEB as taught by Larcher et al. A person of ordinary skilled in the art would have been motivated to do so because Larcher et al. recognize that both MSC-based cell therapy and gene therapy to correct the defective Col7A gene in the EB patients are suitable approaches to treat EB. Thus, one skilled in the art would combine two approaches to use autologous ABCB5+ MSCs corrective for the defective COL7A gene for treating EB. One skilled in the art would expect that the autologous ABCB5+ MSCs with corrected COL7A gene would be effective in treating EB because Sebastiano et al. teach the use of CRISPR/Cas9 system to correct autologous iPSC for treating RDEB (see entire document). As Larcher et al. teach that iPSC based cell therapy would be an alternative to MSC based cell therapy for treating EB, and Sebastiano et al. teach that the autologous iPSC with corrected COL7A gene would be able to produce keratinocytes producing wild type COL7A, one skilled in the art would expect that autologous ABCB5+ MSCs of Frank with corrected COL7A gene would be beneficial for treating EB.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant's arguments filed 11/13/2025 have been fully considered but they are not persuasive.
The Examiner has suggested to amend the claims to disclose the step of isolating ABCB5+ stem cells using an ABCB5 antibody as an active step instead of being as a wherein clause. It appears that applicant misunderstood the examiner as the amendment is not sufficient to make the isolation step as an active step required for the claimed method.
Applicant’s argument is based on the claim amendment that discloses the wherein clause directed to the late passage human ABCB5+ stem cells are isolated from the physiologically occurring primary human skin cells that have been cultured through at least 10 passages. While it is disclosed in the wherein clause that the isolation of the ABCB5+ cells is after the passaging the primary skin cells through at least 10 passages, however, the amended limitation is still considered as a product-by-process limitation. Upon the interpretation of the wherein clause as a product-by-process limitation and being as optional and not required by the claimed method, the wherein clause is interpreted as providing the structure of the cell being ABCB5+. The passage numbers, i.e. at least 10 passages, of primary human skin cells would not provide any structure to the ABCB5+ cells in the absence of any evidence to the contrary. Thus, it is the Examiner’s position that Frank teaches the limitation of ABCB5+ stem cells derived from skin cells. It is the Examiner’s position that the late passages of ABCB5+ stem cells of the cited references would have the same characteristics as the claimed cells because the cells of prior art as well as the claimed cells both went at least 10 passages, and thus, their property would be the same. The difference between the claimed invention and the cited reference is the time point when the ABCB5 selection is carried out. It is considered that if the isolation step is made active, this step would be obviated from the step taught by prior art.
Applicant is advised to amend the claim to disclose the steps disclosed in the wherein clause as active steps not as an optional or a product-by-process limitation.
In order to have the wherein clause directed to the isolating ABCB5+ stem cells, applicant is suggested to amend the claim to disclose this step as an active step required for the claimed method: for example;
Claim 36: A method of alleviating one or more symptoms of epidermolysis bullosa (EB) in a subject having EB comprising
providing a primary culture of human skin cells and culturing the primary human skin cells through at least 10 passages;
isolating ABCB5+ stem cells using an ABCB5 antibody from the primary human skin cells having been through at least 10 passages to obtain a population of late passage human ABCB5+ stem cells; and
administering to the subject having EB the late passage human ABCB5+ stem cells;
wherein greater than or equal to 90% of the late passage human ABCB5+ stem cells possess multipotent differentiation capacity.”
It is noted that Riekstina et al. is no longer cited as the claim rejection is based on the interpretation of the late passage human ABCB5+ stem cell being isolated, using an ABCB5 antibody, from the physiologically occurring primary human skin cells as a product-by-process limitation.
Upon the wherein clause of this limitation is disclosed as an active step as suggested above, the claim rejections would be overcome.
Conclusion
No claims are allowed.
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/TAEYOON KIM/ Primary Examiner, Art Unit 1631