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 .
Response to Arguments
Applicant’s arguments, see Pages 1-2, filed 08/22/2025, with respect to the 103 rejection of claims 1-14 under Malik (US Patent No. 20040116511) in view of Halfon et al. Markers Distinguishing Mesenchymal Stem Cells from Fibroblasts Are Downregulated with Passaging, Stem Cells and Development, June 2010, Pages 53-66, Gillespie et al. Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts, Scientific reports, March 2019, Pages 1-17 and Tai et al. Minocycline modulates cytokine and chemokine production in lipopolysaccharide-stimulated THP-1 monocytic cells by inhibiting IκB kinase α/β phosphorylation, Transitional Research, February 2013, Pages 99-109 as well as claims 17-28 under Dugan et al. (US Patent No. 20170022135) in view of Larkin et al. (US patent No. 20130156742) and Wingo et al. Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury, Front. Neurol., July 2012, Pages 1-18 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Malik (US Patent No. 20040116511), Halfon et al. Markers Distinguishing Mesenchymal Stem Cells from Fibroblasts Are Downregulated with Passaging, Stem Cells and Development, June 2010, Pages 53-66, Gillespie et al. Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts, Scientific reports, March 2019, Pages 1-17, Tai et al. Minocycline modulates cytokine and chemokine production in lipopolysaccharide-stimulated THP-1 monocytic cells by inhibiting IκB kinase α/β phosphorylation, Transitional Research, February 2013, Pages 99-109 and Huang et al. Multilineage differentiation potential of fibroblast-like stromal cells derived from human skin, May 2010, Pages 1491-1501.
The teachings of Malik, Halfon and Tai from the previous office action in combination with the teachings of Huang on human skin fibroblasts expressing CD73 and CD105, reads to the limitations of claimed invention.
Applicant has additionally overcome the 112b rejection of claims 9, 13 and 22 by amending claims 9 and 13 and the cancelation of claim 22.
Claims 1, 4-5 and 17-28 has been canceled, claims 29-41 has been added. No new matter was added. Claims 2-3, 6-16 and 29-41 are now evaluated on its merits.
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.
Claims 2-3, 6-16 and 29-41 are rejected under 35 U.S.C. 103 as being unpatentable over Malik (US Patent No. 20040116511) in view of Halfon et al. Markers Distinguishing Mesenchymal Stem Cells from Fibroblasts Are Downregulated with Passaging, Stem Cells and Development, June 2010, Pages 53-66, Gillespie et al. Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts, Scientific reports, March 2019, Pages 1-17, Tai et al. Minocycline modulates cytokine and chemokine production in lipopolysaccharide-stimulated THP-1 monocytic cells by inhibiting IκB kinase α/β phosphorylation, Transitional Research, February 2013, Pages 99-109 and Huang et al. Multilineage differentiation potential of fibroblast-like stromal cells derived from human skin, May 2010, Pages 1491-1501.
Regarding claims 2-3, 6-16 and 29-41, Malik teaches compositions and methods that employ compounds that can promote skin cell renewal, wound healing, proliferation of fibroblasts and/or keratinocytes, and production of collagen or fibronectin by fibroblasts (abstract). The composition taught by Malik may contain an anti-microbial or anti-fungal compound from a list of agents that include minocycline, tetracycline, chlortetracycline, oxytetracycline and doxycycline (relevant to claims 6, 11, 32 and 37) (para. 0206-0207) as well as anti-inflammatory agents and Vitamin E (relevant to claims 12-13, 29, 38-39 and 41) (para 0027). Malik additionally teaches the in vitro testing of a human skin fibroblast cell line (relevant to claims 10 and 36) (para. 0251).
In terms of claims 9 and 35, The teachings of Malik is obvious to the limitation of administering the agent to an individual in need thereof prior to, in concurrent to and/or subsequent to administering the population of fibroblast to achieve the more effective steps of method.
Malik fails to teach the fibroblasts as plastic-adherent and express CD73 and CD105, addition of Metformin and NF-KappaB inhibitor minocycline suppressing the ability of fibroblasts to produce inflammatory cytokines of TNF-alpha, IL-1 beta and IL-6.
Halfon teaches mesenchymal stem cells from fibroblasts are plastic adherent when maintained in standard culture conditions and in recent years it has been recognized that stromal and even dermal fibroblasts, which are also plastic adherent, express most of MSC markers (relevant to claims 14 and 40) (Page 60, second column, first para.).
Tai teaches the tetracyclines antimicrobial group members of minocycline and doxycycline has been reported to possess anti-inflammatory effects, in part, by reducing TNF-a, IL-1b, IL-6, IL-8, and MCP-1 production (relevant to claims 2-3 and 30-31) (abstract, Page 100, 2nd column, 2nd para.).
Gillespie teaches metformin induced significant changes in the transcript profiles of normal human dermal fibroblasts, enrichment in AP-1 transcription factor and cytokine/chemokine expression and demonstrated increased FOXO3a promoter occupancy at these genes (relevant to claims 7-8 and 33-34) (abstract).
Huang teaches human foreskin tissue, which have fibroblast-like morphology stromal cells expresses CD90, CD105, CD166, CD73, SH3, and SH4, which is similar to the immunophenotypes of human bone marrow-derived mesenchymal stem cells (relevant to claims 15 and 16) (abstract, Page 1491).
Therefore, it would have been obvious to someone of ordinary skill in the art at the time of filling to have produced NF-KappaB inhibitors of minocycline and/or doxycycline along with additional agent of metformin to increase the regenerative activity of fibroblasts, wherein the NF-KappaB inhibitors are plastic-adherent, suppresses the ability of fibroblasts to produce inflammatory cytokines of TNF-alpha, IL-1 beta and IL-6 and fibroblasts express CD105 and CD73. One would have been motivated to do so from the teachings of Halfon on fibroblasts being plastic-adherent, Gillespie on metformin to promote dermal fibroblasts, Tai on minocycline and doxycycline suppresses and/or reduce TNF-a, IL-1b, IL-6 cytokines and Huang on skin fibroblasts expressing CD105 and CD73, in which Malik teaches NF-KappaB inhibitors of minocycline and doxycycline to increase the regenerative activity of skin fibroblasts. There is a reasonable expectation of increasing the regenerative activity of fibroblasts by NF-KappaB inhibitors of minocycline and doxycycline and AMPK activator of metformin, wherein the NF-KappaB inhibitors are plastic-adherent, suppresses the ability of fibroblasts to produce inflammatory cytokines of TNF-alpha, IL-1 beta and IL-6 and the fibroblasts express CD105 and CD73 from the teachings of Malik in view of Halfon, Gillespie, Tai and Huang.
Conclusion
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MIKHAIL O'DONNEL. ROBINSON
Examiner
Art Unit 1627
/MIKHAIL O'DONNEL ROBINSON/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627