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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/27/2026 has been entered.
Claim Status
Claims 2-9 are pending. Claims 6-9 have been added. Claim 2 has been amended. Claims 2-6 and 8 are being examined in this application. In the response to the restriction requirement, Applicants elected cu-538-1 and cu-538-2. Claims 7 and 9 are withdrawn as being drawn to a nonelected species.
Claim Objections
Claim 8 is objected to because of the following informalities: Claim 8 should be amended to recite “……cu538-1, cu538-2, NY-38, cu592, . Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
This is a new rejection.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 8 is drawn to a compound comprising a combination of compounds, whereas claim 2 is drawn to a single compound. Therefore, claim 8 fails to include all the limitations of claim 2. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This rejection has been modified.
Claims 2-6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (PLoS ONE 8(5): e62946, 2013) in view of Ines et al. (Peptides 71 (2015) 100-112) and Kim et al. (J Control Release. 2007 Jun 2;122(3):375–383), as evidenced by Kanda et al. (The Journal of Antibiotics (2017) 70, 691-694).
Li et al. teach xantholysin A having the following structure (Fig. 2):
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Please note that xantholysin A corresponds to the claimed compounds cu-538-1 and cu-538-2.
Li et al. do not teach promoting cell layer permeation.
Ines et al. teach that lipopeptides such as xantholysin have pore forming capacity (page 101, left column, 2nd para; page 101 right column, 2nd para).
Kim et al. teach that magainin, a peptide known to form pores in bacterial cell membranes, can increase skin permeability by disrupting stratum corneum lipid structure (abstract).
Kim et al. further teach that “[T]his study also introduces the novel concept of using a first chemical enhancer to increase penetration of a second chemical enhancer into the skin to synergistically increase skin permeability to a model drug”.
Kim et al. also teach that the combination of magainin and NLS-ethanol synergistically increases skin permeability, because NLS-ethanol increased magainin penetration into stratum corneum, which further increased stratum corneum lipid disruption and skin permeability. We believe this is the first study to use a pore-forming peptide as a skin penetration enhancer and the first study to use one chemical enhancer to increase penetration of another chemical enhancer into the skin (page 9, 2nd para).
It would have been obvious to one of ordinary skill in the art to administer xantholysin to the skin in order to promote cell layer permeation and thus increase skin permeability of a drug because Kim et al. teach that magainin forms pores in bacterial cell membranes, thus increasing penetration of a drug.
The skilled artisan would have reasonably expected xantholysin to promote cell layer permeation and thus increase skin permeability of a drug, just as magainin did, because Ines et al. teach that lipopeptides such as xantholysin have pore forming capacity.
With respect to the limitation “wherein the promotion of cell layer permeation by the compound of formula (2) is reversible”, it is noted that the promotion of cell layer permeation is an inherent property of the compound of formula (2).
Furthermore, as evidenced by Kanda et al. (The Journal of Antibiotics (2017) 70, 691-694), which teaches that “[U]nlike the mode of action of a reversible TJ opener, capsaicin, the permeability increase induced by MA026 was irreversible for at least 5 h” (page 694, left column, 1st para).
Therefore, the reference implies that the compound MAO26 (depicted below), which corresponds to the instantly claimed compounds cu-538-1 and cu-538-2, would eventually reverse TJ opening.
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With respect to claim 6, Ines et al. teach that “[C]andida acts as a commensal in animal hosts and colonizes in skin, nails, mucous membranes, gastrointestinal and genitourinary tracts.The available synthetic antifungal drugs show high toxicity to host tissues causing adverse effect. Lipopeptide surfactants are among the natural compounds reported to inhibit the growth of this pathogenic yeast” (page 108, left column, 4th para).
Therefore, one of ordinary skill in the art concerned with the treatment of Candidiadis, would have been motivated, with a reasonable expectation of success, to administer xantholysin A to mucous membranes in order to promote cell layer permeation and thus increase skin permeability of a drug such as for e.g. fluconazole, clotrimazole, etc.
Response to Arguments
Applicant’s arguments filed on 4/27/2026 have been fully considered but they are not persuasive.
Applicant argues that “[T]he prior art references teach irreversible mechanisms, such as damage-induced irreversible poring of the cell membrane and disruption of stratum corneum lipids. In contrast, the claimed invention temporarily opens cell gaps by temporary detachment of cell-layers' bonding and allows rapid recovery of tight junctions. Therefore, the prior art's cytotoxic, pore-forming mechanism does not inherently disclose "reversibly opening tight junctions" via a paracellular route”.
Applicant’s arguments are not persuasive because the Xantholysin A taught by Li et al. corresponds to the instantly claimed compound of general formula (2), thus, it would inherently promote reversible cell layer permeation.
The Examiner submits the reference of Kanda et al. (The Journal of Antibiotics (2017) 70, 691-694), which teaches that “[U]nlike the mode of action of a reversible TJ opener, capsaicin, the permeability increase induced by MA026 was irreversible for at least 5 h” (page 694, left column, 1st para).
Therefore, the reference implies that the compound MAO26, which corresponds to the instantly claimed compound of general formula (2), would eventually reverse TJ opening.
Therefore, since Ines et al. teach that lipopeptides such as xantholysin have pore forming capacity, and Kim et al. teach that magainin, a peptide known to form pores in bacterial cell membranes, can increase skin permeability by disrupting stratum corneum lipid structure, one of ordinary skill in the art would have been motivated to administer xantholysin to the skin in order to promote cell layer permeation and thus increase skin permeability of a drug.
The skilled artisan would have had a reasonable expectation of success because Ines et al. teach that lipopeptides such as xantholysin have pore forming capacity.
For the reasons stated above the rejection is maintained.
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/SERGIO COFFA Ph.D./
Primary Examiner
Art Unit 1658
/SERGIO COFFA/Primary Examiner, Art Unit 1658
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