DETAILED ACTION
Notice of New Examiner
This case has been transferred to a new examiner for continued examination. Any further communications regarding this case may be directed to the contact information included in the conclusion of this office 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 .
Priority
Acknowledgement is made of applicant’s foreign priority based on an application filed in Korea on August 10th, 2021 and a certified copy of the KR10-2021-0105661 application was filed on February 9th, 2023.
Response to Amendment
Applicant’s amendment of July 3rd, 2025 is acknowledged. Claims 7-10 are cancelled. Claims 1-6 and 11-18 remain pending in the application and are re-examined on the merits herein. In light of Applicant’s claim amendment of July 3rd, 2025, rejection of claims 1-2 under 35 USC § 102(A) have been withdrawn and new grounds of rejections under 35 USC § 103 have been made as described below. Applicant’s amendments to the Specification in response to the Office Action of April 7, 2025 have overcome each and every objection.
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 1-6, and 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al (Park et al. Comparing the Membrane-Interaction Profiles of Two Antiviral Peptides: Insights into Structure-Function Relationship. Langmuir. 2019 Jul 30;35(30):9934-9943. doi: 10.1021/acs.langmuir.9b01052. Epub 2019 Jul 19. PMID: 31291111. Listed in PTO-892 filed on April 7, 2025) and further in view of Hosseini et al (Hosseini R, Asef-Kabiri L, Yousefi H, Sarvnaz H, Salehi M, Akbari ME, Eskandari N. The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells. Mol Cancer. 2021 Jun 2;20(1):83. doi: 10.1186/s12943-021-01376-w. PMID: 34078376; PMCID: PMC8170799. Listed in the PTO-892 filed on April 7, 2025), Holler et al (WO2019/070645 A1, published on April 11, 2019, listed in the PTO-892 filed on April 7, 2025), and Fang et al (Fang Y, Xue J, Gao S, Lu A, Yang D, Jiang H, He Y, Shi K. Cleavable PEGylation: a strategy for overcoming the "PEG dilemma" in efficient drug delivery. Drug Deliv. 2017 Dec;24(sup1):22-32. doi: 10.1080/10717544.2017.1388451. PMID: 29069920; PMCID: PMC8812578.).
Regarding instant claim 1 and 2, Park teaches the sequence of SEQ ID NO: 1 (Figure 2A; AH), and that AH exhibits a partial alpha-helical structure in aqueous buffer solutions (pg. 9938, column 1, paragraph 2), which is increased in lipid membrane environments (pg. 9938, column 1, paragraph 2).
However, Park does not teach the peptide is modified with polyethylene glycol (PEG), wherein the peptide is linked to the PEG via a pH-sensitive cleavable linker that is selectively cleaved under acidic conditions of a tumor microenvironment.
Holler teaches the PEGylation of proteins (paragraph [00101]). Holler further teaches that PEG helps to increase its [the peptide] in vivo half-life, prolonging its circulation time, and enhancing extravasation into solid tumors (paragraph [00101]). Therefore, it would have been obvious to the person of ordinary skill in the art to modify the peptide taught by Park with PEG modification to increase circulation time, half-life and enhance drug targeting to the tumors as taught by Holler.
While, Park and Holler teach the peptide modified with PEG, they do not teach the pH-sensitive linker that is selectively cleaved under acidic conditions of a tumor microenvironment.
Fang et al teaches the PEG dilemma wherein the PEG is used to enhance permeability and retention of the drug but can make the drug difficult for the absorption of drugs and subsequent endosomal escape (pg. 1, abstract). Fang et al further discloses cleavable linkers that are pH sensitive and PEG-linked drugs can be cleaved under acidic conditions of a tumor microenvironment (pg. 1, column 1, “PEG derivatives conjugated with disulfide bonds can be cleaved in the cell by the glutathione-mediated reduction environment via thiol-disulfide exchange reactions (Wang et al., 2014). In addition, carries with vinyl ether bonds and ester bonds can also be cleaved under acidic or oxidative conditions (Terada et al., 2006). These cleavable PEG-lipids have corresponding fracture mechanisms, so the application of them can achieve long-term circulation and promote drug absorption at a specific location”). Therefore. It would have been obvious to the person of ordinary skill in the art to include cleavable linkers that are pH sensitive such as the tumor microenvironment that is acidic to release the peptide from PEG to overcome the PEG dilemma in drug development as taught by Fang et al.
Regarding instant claim 3, Park et al, Holler et al and Fang et al teach the peptide modified with PEG and has a pH-sensitive cleavable linker that is selectively cleaved under acidic conditions of a tumor microenvironment. Park teaches that the AH peptide can rupture lipid vesicles below ~160nm (pg. 9935, column 1, paragraph 1) but does not teach that the peptide disrupts tumor derived vesicles. Hosseini teaches tumor-derived exosomes that are 30-150nm in size (pg. 1, column 1, paragraph 1) and further teaches that the tumor derived exosomes play in multiple aspects of tumor development and growth, such as proliferation, angiogenesis, metastatic niche formation and immune escape and therefore are a target of interest (pg. 9, column 1, paragraph 2). AH, as taught in Park, would be able to disrupt tumor-derived vesicles because they are known to be in the appropriate size range, as taught by Hosseini (Hosseini; exosomes are 30-150nm in size; pg. 1, column 1, paragraph 1). Park further teaches that the AH selectively disrupts lipid vesicles below ~160nm through a membrane-curvature dependent mechanism and is independent of membrane surface charge that allows low cytotoxicity against larger mammalian cells (pg. 9935, column 1, paragraph 1 and column 2, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the peptide for disrupting vesicles taught by Park, Holler, and Fang to disrupt tumor-derived vesicles and expect reasonable expectation of success because the peptide is more selective at disrupting vesicles in a membrane-curvature dependent mechanism and has low cytotoxicity profile. MPEP 2145 II. States that "the fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." The MPEP section further states that "The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention." Hosseini teaches the motivation that adjunctive inhibition or removal of TDEs may add to the therapeutic benefits of currently available chemo and immunotherapies and could improve tumor regression (pg. 10, Fig. 4). Therefore, it would have been obvious to the person of ordinary skill in the art to us the peptide taught by Park, Holler, and Fang to target and disrupt tumor-derived exosomes that contribute to cancer progression and may enhance chemotherapies and immunotherapies as taught by Hosseini. A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02).
Regarding instant claim 4, 5 and 6, as described above in claims 1-3, Hosseini et al further teaches the tumor-derived exosomes that impede anti-tumor immune responses via their immunosuppressive cargo (pg. 1, abstract) and that targeting exosome from cancer cells could strongly induce anti-tumor immunity and improve the anti-cancer effects of chemotherapeutic or immunotherapeutic agents (pg. 9, column 2). Hosseini teaches that tumor derived exosomes harbor membrane-bound proteins (PD-L1) which directly inhibit the anti-tumor activity of T cells (pg. 9, column 2, paragraph 2). Hosseini further teaches that tumor derived exosomes function in favor of tumor progression and crucially participate in nearly all aspects of cancer development, such
as angiogenesis, proliferation, and metastasis (pg. 1, column 2, paragraph 1).
Regarding instant claims 11, 12, and 13, as described above in claim 1-3, Hosseini et al further teaches the method of targeting tumor derived exosomes to enhance cancer immunotherapy in a subject in need thereof (pg. 10, Fig. 4, “Adjunctive inhibition or removal of TDEs may add to the therapeutic benefits of currently available chemo and immunotherapies and could improve tumor regression”) and Park et al, Holler et al, and Fang et al teach the peptide that is modified with PEG and has a pH-sensitive cleavable linker that is selectively cleaved under acidic conditions of a tumor microenvironment. Hosseini teaches therapeutic effects of PD-1/PD-L1 antibodies and that targeting tumor exosomes could add to the benefits of immunotherapeutic interventions (pg 9, column 2, paragraph 1).
Regarding instant claims 17 and 18, as described above in claim 1-3, Hosseini et al further teaches the method of enhancing cancer immunotherapy sensitivity by administering the peptide taught by Park et al, Holler et al, and Fang et al in a subject thereof. Hosseini further teaches that “the most recent studies indicate that exosomal PDL1 plays a vital role in tumor immune escape as well as in tumor resistant to anti-PD-1/PD-L1 immunotherapy” and suggests that targeting tumor-derived exosomes may enhance the effects of anti-PD1/PD-L1 immunotherapy.
Regarding instant claims 14, 15, and 16, as described above in claim 1-3, Hosseini et al further teaches the method of treating cancer. Hosseini discloses that tumor-derived exosomes contain a protein (S100A9) that modifies the maturation of dendritic cells, which is shown to be at a high level in the TME and is associated with tumor-associated dendritic cells (TADCs)-mediated chemoresistance of breast cancer (pg. 6, column 2, paragraph 1 – pg. 5, column 1, paragraph 1). Hosseini further teaches that that tumor-derived vesicles TDEs play in multiple aspects of tumor development and growth, such as proliferation, angiogenesis, metastatic niche formation and immune escape, a strong interest has emerged in recent years to selectively inhibit the generation/release of tumor exosomes as an adjunctive therapy for cancer (pg. 9, column 2, paragraph 2) and targeting exosomes or
exosomal markers could inhibit tumor progression and improve anti-tumor immunity (pg. 11, column 2, paragraph 1).
Response to Arguments
Applicant's arguments filed on July 3rd 2025 have been fully considered but they are not persuasive.
Regarding applicant’s argument that Park et al alone never contemplates, teaches, or suggests attaching the peptide to PEG, employing any sort of linker, or rendering that linker selectively cleavable at pH 6.5 (page 11, paragraph 4) in the amended claim 1 of July 3rd, 2025 has been considered and the rejections under 35 USC 102 of claim 1 and 2 have been withdrawn. However, new grounds of rejections have been made under 35 USC 103 for claims 1-6, and 11-18 as unpatentable under Park et al and in further view of Holler et al, Fang et al and Hosseini et al. As described above, in combination, Park et al teaches the peptide SEQ ID NO: 1, Holler et al teaches the PEG modification and Fang et al teaches the pH-sensitive cleavable linker to target tumor-derived exosomes. Hosseini et al teaches the motivation of targeting tumor-derived exosomes to enhance cancer immunotherapy. As the references are prior to the earliest effective filing date of the invention, one skilled artisan would have been able to use the teachings from Park et al, Holler et al, Fang et al and Hosseini et al to combine the peptide with the PEG modification and pH cleavable linker to target tumor-derived exosomes and enhance cancer immunotherapy. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the cholesterol rich membrane of tumor-derived exosomes (page 12, paragraph 1), and that PEGylation is used specifically to suppress normal-cell toxicity while permitting tumor-selective activation in an acidic environment (page 12, paragraph 2) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding to applicant’s argument that one person of ordinary skill in the art would find no reason to expect that the AH peptide shown by Park to rupture only cholesterol-free viral liposomes-could be rendered safe for systemic use, delivered to tumors, released by pH-triggered linker hydrolysis and then overcome the cholesterol barrier that Hosseini never addresses (page 13, paragraph 1), Park et al teaches that the AH can disrupt lipid membranes independently of membrane surface charge and disrupts vesicles via a membrane-curvature-dependent mechanisms while exhibiting low cytotoxicity against larger mammalian cells ) (pg. 9935, column 1 paragraph 2 and column 2, paragraph 1) and that AH peptide can rupture lipid vesicles below ~160nm (pg. 9935, column 1, paragraph 1. In combination with Park, Hosseini teaches that tumor-derived vesicles are 30-150 nm in size (page 1, paragraph 1) and provides a teaching suggestion that targeting tumor-derived vesicles to treat cancer and enhance cancer immunotherapies (page 10, Fig 4.). It is therefore obvious that a person of ordinary skill in the art would be able to use the peptide taught by Park et al for enhancing cancer therapy with reasonable expectation of success as the peptide would be able to selectively disrupt tumor derived vesicles that are below 160 nm and the peptide exhibits low cytotoxicity against larger mammalian cells. A person of ordinary skill in the art would be motivated to use the peptide taught by Park because of Hosseini’s teaching suggestion that play in multiple aspects of tumor development and growth, such as proliferation, angiogenesis, metastatic niche formation and immune escape, a strong interest has emerged in recent years to selectively inhibit the generation/release of tumor exosomes as an adjunctive therapy for cancer (page 9, column 2).
Regarding the applicant’s argument that PEGylation is used specifically to suppress normal-cell toxicity while permitting tumor-selective activation in an acidic environment (page 12, paragraph 2), Fang et al teaches that the PEGylation has been widely used in drug and nanocarriers to enhance permeability and retention effect but that cleavable PEGylation in response to the acidic tumor environment allows the drug to overcome the PEG dilemma of for the cellular absorption of drugs and subsequent endosomal escape (page 1, abstract). Fang et al further teaches peptides that can suppress cancer cell growth but are easily oxidized and lose activity in vivo (pg. 26, column 1, paragraph 2). Fang further teaches that the peptides are then modified with PEG and is linked via an acid-lable hydrazone bond which allows the peptide to be stable in physiological condition but the peptide is cleaved upon entering an acidic tumor environment to accumulate (pg. 26, column 1, paragraph 2).Therefore, in combination with Park et al, Holler et al, Hosseini et al and Fang et al, it would have been obvious to the person of ordinary skill in the art to use PEG and the pH-sensitive linker to allow enhanced permeability and retention of the peptide because peptides can lose its activity in vivo before it reaches the target cancer cells as taught by Fang et al and once entering the acidic tumor environment, the pH-sensitive cleavable linker is activated to release the peptide in the tumor environment to allow drug absorption by cancer cells.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-3.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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