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 .
The amendment filed 3/20/2026 has been entered. Claim 144 are pending. Claim(s) 1, 6, 11, 15, 17, 19-20, 27, 29-30, 42, 69-72 and 142-144 is/are pending. Claims 142-143 are withdrawn. Claim 144 has been amended. Claim(s) 1, 6, 11, 15, 17, 19-20, 27, 29-30, 42, 69-72 and 144 are under examination.
Claim Rejections - 35 USC § 103 Maintained
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 6, 11, 15, 17, 19-20, 27, 29-30, 42, 69-72 and 144 is/are rejected under 35 U.S.C. 103 as being unpatentable over O’Heeron et al. US 20180195044 7-12-2018 in view of Jones et al. Advances in Wound Care, vol, 4, no. 7 p. 431-439, 2015.
Claim 1, 29, 30 and 42: O’Heeron et al disclose a method of preparing genetically modified fibroblasts, the method comprising culturing fibroblasts in incubation medium and wherein the incubation medium further comprises one or more mitogenic factors selected from EGF, FGF, HGF, VEGF etc. See paragraphs 38-39, 48-49, 54 and 62-68. O’Heeron et al disclose the genetically modified fibroblast incubation medium comprises lysate of a platelet plasma composition which is a source of pro-inflammatory cytokine e.g. IL-1, pro-fibrotic cytokine TGF-beta, platelet-derived epidermal growth factor (PDEGF), as growth factors for tissue regeneration. See paragraphs 30-50.
3 Claim 11, 19-20: O’Heeron et al disclose the fibroblasts are exposed to hypoxia conditions such as at 1%-5%, 1%-4%, 1%-3%, 1%-2%, 2%-5%, 2%-4%, 2%-3%, 3%-5%, 3%-4%, or 4%-5% oxygen. See paragraph 54. O’Heeron et al disclose the duration of the culture is 12 hours to 1 day. See paragraph 6.5.
4 Claim 27: O’Heeron et al disclose culturing fibroblasts in DMEM media (paragraph 61) which compries less than 5g/L of glucose i.e. 4.5 g/L or 1 g/L as evidenced by product information of Dulbecco’s Modified Eagle’s Medium Sigma-Aldrich® retrieved on 9/18/2025 from https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/product/documents/223/143/d6046for.pdf?srsltid=AfmBOor9rbEaxPQhf0LbC8rhHcMUNjycpEXSuIeoS6lW9W1SBBBHi0ez. See paragraph 61.
5 Claim 1, 69-72 and 144: O’Heeron et al disclose that the fibroblasts are genetically modified by transfecting with polynucleotides that encode one or more gene products such as to upregulate expression of angiogenic stimuli or anti-inflammatory activities, wherein the genes are growth factors such as EGF, FGF, HGF, VEGF or transcription factors or cytokines TGF-a, TGF-b, IL-4, IL-10, IL-13, IL-20 thrombospondin such that the genetically modified fibroblasts can be used for treatment of lower back pain/inflammation. See paragraph 38-39 and 54. In other instances, the fibroblasts are genetically modified by transfection to encode growth factors and cytokines including IFN-gamma (IFNG) or combinations thereof: “In particular cases, the fibroblasts are recombinantly manipulated to encode SSEA3, VEGF, FGF-1, FGF-2, FGF-4, EGF, HGF, HIF-1alpha, HIF-2, NET, NF-kB, TGF-a, TGF-b, IL-4, IL-10, IL-13, IL-20 thrombospondin, canstatin, IP-10, kringle 1-5, collagen XVIII/endostatin, IL-1, TNF-alpha, IL-2, IL-6, IL-8, IL-9, IL-11, IL-12, IL-15, IL-17, IL-18, IL-21, IL-23, IL-27, IFN-alpha, IFN-beta, IFN-gamma, p55, p60, STAT1, STAT5, STAT4, IRF-1, IFR-3, IFR-8, or a combination thereof”. See paragraph 62-68. These genetically modified fibroblasts are used for therapeutic application such as regeneration, wherein the regeneration comprises immune modulation, angiogenesis, regeneration of spinal discs or wound repair, See abstract and claims 1-15.
6 O’Heeron et al does not disclose that the pH of the incubation medium is acidic such as pH 5.2 to 6.5.
7 Jones et al disclose that in wound healing an acidic pH environment increases fibroblast proliferation and migration and also regulates bacterial colonization. Jones et al disclose that as wounds progress through the states of healing, studies have shown that a shift toward an acidic pH occurs. See p. 434 column 2 under relevant basic science context. Jones et al disclose that healthy skin can be maintained around pH 5.2 and that acute/normal wound healing can occur around pH 6.5. See ranges of pH disclosed in figure 1 and figure 2.
8 It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have incubated the fibroblasts in acidic pH medium before, concurrent or after genetic modification in acidic pHs ranges for normal to acute/wound healing skin including pH 5.2-6.5 as taught by Jones et al, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Jones et al disclose that in wound healing an acidic pH environment increases fibroblast proliferation and migration and also regulates bacterial colonization. Jones et al disclose that as wounds progress through the states of healing, studies have shown that a shift toward an acidic pH occurs and that healthy skin can be maintained around pH 5.2 and that acute/normal wound healing can occur around pH 6.5. Furthermore, Jones et al disclose targeting the pH and making the wound environment acidic could benefit the healing process (see p. 437 under take home messages).
9 Regarding claim 15 and 17, culturing the fibroblasts in a first acidic pH incubation medium, for example, before therapeutic application for wound healing i.e. before genetic modification, concurrent with genetic modification or after genetic modification or a combination thereof would have been prima facie obvious as normal skin is maintained at pH 5.2-6.5 and the fibroblast in culture proliferate at acidic pH and for subsequent therapeutic application Jones et al disclose in figure 1 that acute/normal wound healing can starts at non-acidic pH and thus incubating the genetically modified fibroblasts at a second non-acidic pH for up to a couple of weeks for therapeutic application for wound healing would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention. Jones et al discloses that as wound healing progresses pH will eventually fall to the normal/healthy skin acidic pH. See figure 1.
10 Applicants argue that O’Heeron concerns methods of augmenting efficacy of fibroblast for regeneration of cells and/or tissues by contacting fibroblasts with one or more biologically active substances; and/or culturing the fibroblasts under conditions to enhance efficacy of said fibroblast for regeneration. Applicants state that in some embodiments, the fibroblasts are transfected with polynucleotides that encode one or more gene products (at least claim 1 and paragraph 39) and in other embodiments, the biologically active substance(s) are platelet rich plasma (PRP) (examples 1, 2 and 3) or one or more cytokines including one or more growth factors (at least claims 2-3).
11 Applicants argue that Jones is merely a review that provides an overview of what was known about the role of pH and its effect on the extracellular matrix and biofilms within healing and nonhealing wounds.
12 Applicants argue that in considering the teachings of the combination of references the skilled artisan would have no indication whether to expose the fibroblasts to PRP or cytokine(s) or whether to expose the fibroblasts to acidic pH and that these exposures are not equivalent and it is self-evident that the skilled artisan would have no reason to consider one over the other. O’Heeron in the combination instructs the skilled artisan to use PRP and cytokines so there would be no reason to look to other teachings when PRP and cytokines were described as being sufficient to prepare the fibroblasts as required by the claims and that even if the skilled artisan were so inclined as to utilize an additional or alternative exposure, there is no apparent reason under the standard of KSR or the person to look to a review about inherent pH in wound among all of the possibilities or addition or alternative exposure for the cells.
13 Applicants argument has been carefully considered but is not found persuasive.
14 As stated in the above rejection, O’Heeron et al disclose a method of preparing genetically modified fibroblasts, the method comprising culturing fibroblasts in incubation medium and wherein the incubation medium further comprises one or more mitogenic factors selected from EGF, FGF, HGF, VEGF etc. See paragraphs 38-39, 48-49, 54 and 62-68. O’Heeron et al disclose the genetically modified fibroblast incubation medium comprises lysate of a platelet plasma composition which is a source of pro-inflammatory cytokine e.g. IL-1, pro-fibrotic cytokine TGF-beta, platelet-derived epidermal growth factor (PDEGF), as growth factors for tissue regeneration. See paragraphs 30-50.
15 When culturing fibroblasts cells the pH of the incubation or culture medium is a consideration as are other factors to be added to incubation medium. For example, O’Heeron et al disclose culturing the fibroblasts in one or more incubation media such as RPMI-1640, DMEM media, EMEM media, Optimem, Isocove’s Media or a combination thereof. See paragraph 61. All these media comprise factors that are necessary to ensure the growth of the fibroblasts. Thus, contrary to Applicants argument fibroblasts are not only exposed to PRP or cytokine(s) or other growth factors to prepare them. Other factors are comprised in incubation media RPMI-1640, DMEM media, EMEM media, Optimem, Isocove’s Media or a combination thereof, such as but not limited to glucose.
16 Furthermore, O’Heeron disclose that these genetically modified fibroblasts are used for wound repair assay (see abstract) suggesting the use of the genetically modified fibroblasts for wound repair. Furthermore, the sources of the fibroblasts are from the skin. See paragraphs 38-40.
17 Jones et al disclose that healthy intact skin has a slightly acidic pH ranging from 4-6 and that an acidic pH environment is considered to be beneficial by increasing fibroblast proliferation and migration. See under “pH and wounds”. Thus, since the fibroblasts of O’Heeron are sourced from the skin and Jones et al teach that healthy intact skin has a slightly acidic pH ranging from 4-6 and that an acidic pH environment is considered to be beneficial by increasing fibroblast proliferation, it would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date to have incubated the genetically modified fibroblasts at the pH of healthy skin which is acidic pH ranging from 4-6 either for maintaining the therapeutic skin fibroblasts in culture or for therapeutic applications including the suggestion of the use in wound healing. Skin fibroblasts are used in O’Heeron and therefore maintaining them in culture or for therapeutic applications at pH of healthy skin i.e. 4-6, would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention
Status of Claims
Claims 1, 6, 11, 15, 17, 19-20, 27, 29-30, 42, 69-72 and 144 is/are rejected. Claims 142-143 are withdrawn.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/OLUWATOSIN A OGUNBIYI/Primary Examiner, Art Unit 1645
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