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 .
Election/Restrictions
Applicant’s election without traverse of Group I, (A) pheophorbide-a, (B) SEQ ID NO:1, (C) LXY30
in the reply filed on 7/14/2025 is acknowledged.
Claim 7, 15-23, 26-27, 29-33, 35, 60-61, 64 withdrawn from further consideration pursuant to 37
CFR 1.142(b) as being drawn to a nonelected Group II-V and species of A, B, and C, there being no
allowable generic or linking claim. Election was made without traverse in the reply filed on 7/14/2025.
Status of Claims
Withdrawn: 7, 15-23, 26-27, 29-33, 35, 60-61, 64
Examined Herein: 1-6, 8-14, 24-25, 28
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed
in PRO 62/886,698 on 8/14/2019, PRO 62/886,718 on 8/14/2019, and PCT/US20/46495 on 8/14/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/2/2022, 7/14/2025, and 2/18/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is
being considered by the examiner.
Drawings
The drawings received on 2/10/2022 are accepted.
Withdrawn Rejections
The rejection of claims 1-4 and 9-14 under 35 U.S.C. 103 over Hu and Qi is hereby withdrawn in view of Applicant’s amendments to claim 1 and Applicant’s persuasive arguments that Hu and Qi do not teach the claim limitations, as amended. [Remarks 12/8/2025, Page 11, Table 1]
The rejection of claims 1-6, 8-12, and 24 under 35 U.S.C. 103 over Shi, Anderson, and Qi is hereby withdrawn in view of Applicant’s amendments to claim 1 and Applicant’s persuasive arguments that Shi, Anderson, and Qi do not teach the claim limitations, as amended. [Remarks 12/8/2025, Page 11, Table 1 and Page 12, Paragraph 1]
The rejection of claims 1-6, 8-12, 24-25, and 28 under 35 U.S.C. 103 Shi, Anderson, Qi, and Lam is hereby withdrawn in view of Applicant’s amendments to claim 1 and Applicant’s persuasive arguments that Shi, Anderson, Qi, and Lam do not teach the claim limitations, as amended. [Remarks 12/8/2025, Page 11, Table 1 and Page 12, Paragraph 1]
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.
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.
Claims 1-8, 11, 12, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Choi (US 2020/0054751 A1, Filed 7/4/2017), in view of Hamblett (US 2021/0260210 A1, Filed 3/12/2019).
With respect to claim 1, Choi discloses a compound of formula (I):
A-B-C (I)
wherein
A is a hydrophobic moiety, chlorin e4,
B is a disulfide bond; and
C is a hydrophilic targeting ligand, GE11 peptide (YHWYGYTPQNVI), wherein the hydrophilic targeting ligand is an EGFR ligand. [Choi, 0122, 0137-Formula II]
With respect to claim 2, Choi discloses the hydrophobic moiety is chlorin e-4. [Choi, 0122, 0137-Formula II] Chlorin e-4 is a dye.
With respect to claim 3, Choi discloses the hydrophobic moiety is chlorin e-4. [Choi, 0122, 0137-Formula II] Chlorin e-4 is a fluorescent dye.
With respect to claim 4-5, Choi discloses the hydrophobic moiety is chlorin e-4. [Choi, 0122, 0137-Formula II] Chlorin e-4 is a porphyrin.
With respect to claim 6 and 8, Choi discloses the hydrophobic moiety is chlorin e-4. [Choi, 0122, 0137-Formula II] Choi discloses chlorin e-4 is a photosensitizer. Choi additionally discloses the photosensitizer may be pheophorbide. [Choi, 0070]
With respect to claim 24, Choi discloses the hydrophilic targeting ligand is GE11 peptide (YHWYGYTPQNVI). [Choi, 0122, 0137-Formula II] GE11 peptide (YHWYGYTPQNVI) is an EGFR ligand.
Choi discloses the linker (B) is a disulfide bond. [Choi, 0122, 0137 - Formula II] However, Choi further discloses the linker may be a peptide composed of 3 or less amino acid sequences. [Choi, 0017] Choi also discloses the linker may be degraded by an intracellular enzyme. [Choi, 0011, 0013, 0065, 0066]
Choi does not disclose B is a peptide, wherein the peptide forms a beta-sheet; and comprises (i) at least 50% sequence identity to SEO ID NO: 1, (ii) at least 50% sequence identity to SEO ID NO: 2, or (iii) at least 50% sequence identity to SEO ID NO: 3.
However, with respect to claim 1, Hamblett discloses a ligand-drug conjugate, wherein the linker is a tripeptide linker that is cleavable by an intracellular protease, like Phe-Phe-Lys (FFK). [Hamblett, 0263-0265]
With respect to claim 11-12, Hamblett discloses the peptide is FFK. [Hamblett, 0263-0265]
FFK comprises a peptide sequence, FF, from a beta-sheet peptide domain of beta-amyloid 40.
Modifying the compound disclosed by Choi by replacing the disulfide linker with Phe-Phe-Lys results in the compound of claim 1, 11, and 12, wherein B is a peptide (Phe-Phe-Lys) that forms a beta-sheet, comprises at least 50% sequence identity to SEO ID NO: 3, and comprises a peptide sequence, FF, from a beta-sheet peptide domain of beta-amyloid 40.
Further modifying the compound disclosed by Choi by replacing the photosensitizer with pheophorbide results in the compound of claim 6 and 8, wherein A is a hydrophobic moiety and porphyrin, pheophorbide.
It would be obvious to one of ordinary skill in the art to modify the compound disclosed by Choi by replacing the disulfide linker with Phe-Phe-Lys and have a reasonable expectation of success. Choi discloses a ligand-drug conjugate comprising a ligand, GE11 peptide (YHWYGYTPQNVI), linked to a drug chlorin e4, via a disulfide bond. Choi further discloses the linker may be a peptide composed of 3 or less amino acid sequences that is degraded by an intracellular enzyme. Hamblett discloses a ligand-drug conjugate, wherein the ligand and drug are linked via a tripeptide linker, Phe-Phe-Lys, which is cleavable by an intracellular protease. Thus, Hamblett establishes that Phe-Phe-Lys is a peptide linker for ligand-drug conjugates, is composed of 3 amino acids, and is degraded by an intracellular enzyme. Accordingly, the combined teachings of Choi and Hamblett suggest that Phe-Phe-Lys may serve as the linker in the ligand drug conjugated disclosed by Choi. Therefore, it is reasonable to expect the compound disclosed by Choi may be modified by replacing the disulfide linker with Phe-Phe-Lys. One would have been motivated to do so because the selection of a known material based on its suitability for its intended use is prima facie obvious. MPEP 2144.07 In the instant case, Choi discloses the linker in the ligand-drug conjugate may be a peptide composed of 3 or less amino acids that is degraded by an intracellular enzyme. Hamblett discloses Phe-Phe-Lys is a linker in a ligand-drug conjugate that is composed of three amino acids and is cleavable by an intracellular protease. Therefore, the selection of Phe-Phe-Lys based on its suitability as a tripeptide cleavable by an intracellular enzyme for use as a linker in the ligand-drug conjugate disclosed by Choi is prima facie obvious.
It would have been obvious to one of ordinary skill in the art to further modify the compound disclosed by Choi by replacing the photosensitizer with pheophorbide and have a reasonable expectation of success. Choi discloses a ligand-drug conjugate comprising a ligand, GE11 peptide (YHWYGYTPQNVI), linked to a drug chlorin e4. Choi discloses chlorin e4 functions as a photosensitizer. Choi additionally discloses the photosensitizer may be selected from multiple suitable compounds, including pheophorbide. In view of this express teaching by Choi, it is reasonable to expect the compound disclosed by Choi may be further modified by replacing the photosensitizer with pheophorbide. One would have been motivated to do so because it is prima facie obvious to modify a reference when the rationale for doing so is expressly contained in the prior art. MPEP 2144(I) In the instant case, Choi expressly states the photosensitizer may be selected from multiple suitable compounds, including pheophorbide. [Choi, 0070] Therefore, it is prima facie obvious to replace the photosensitizer (chlorin e4) with pheophorbide in the conjugate disclosed by Choi because Choi expressly teaches modifying the photosensitizer.
Claims 1-4, 9-14, 24, 25, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Xu (Bio-inspired metal ions regulate the structure evolution of self-assembled peptide-based nanoparticles, 6/22/2016, Nanoscale, 8:14078-14083), in view of Xiao (Discovery and characterization of a high-affinity and high-specificity peptide ligand LXY30 for in vivo targeting of α3 integrin-expressing human tumors, 2016, EJNMMI Research).
With respect to claim 1, Xu discloses a compound of formula (I), BP-KLVFFK-RGD:
A-B-C (I)
wherein,
A is a hydrophobic moiety, bis-pyrene,
B is a peptide, KLVFFK, that forms a beta-sheet; and
C is a hydrophilic targeting ligand, RGD, and
wherein, the peptide comprises at least 50% sequence identity to SEO ID NO: 1 and SEO ID NO: 2. [Xu, Page 14079, Scheme 1 and Figure 1]
With respect to claim 2-4, Xu discloses the hydrophobic moiety is bis-pyrene. [Xu, Page 14079, Scheme 1 and Figure 1] Bis-pyrene is a fluorescent dye.
With respect to claim 9-10, Xu discloses the peptide, KLVFFK, is a sequence 6 amino acids in length. [Xu, Page 14079, Scheme 1 and Figure 1]
With respect to claim 11-12, Xu discloses the peptide is KLVFFK. [Xu, Page 14079, Scheme 1 and Figure 1] KLVFFK comprises a peptide sequence, KLVFF, from a beta-sheet peptide domain of beta-amyloid 40.
With respect to claim 13-14, Xu discloses the peptide is KLVFFK. [Xu, Page 14079, Scheme 1 and Figure 1] KLVFFK comprises 100% sequence identity to SEQ ID: NO 1.
Xu further discloses RGD binds to αvβ3 integrin on U-87MG and MCF-7 cells. [Xu, Page 14078, Col. 2, Paragraph 2]
Xu does not disclose the hydrophilic targeting ligand is a LLP2A prodrug, LLP2A, LXY30, LXW64, DUPA, folate, a LHRH peptide, or a toll-like receptor agonist CpG oligonucleotides.
However, with respect to claim 1, 24, 25, and 28, Lam discloses a compound comprising (a) a hydrophobic moiety, FITC, and (c) a hydrophilic RGD targeting moiety, LXY30, that targets α3β1 integrin on U-87MG cells. [Xiao, Page 8, Figure 2 and Page 9, Figure 3]
Modifying the compound disclosed by Xu by replacing RGD with LXY30, results in the compound of claim 1, 24, 25, and 28 wherein the hydrophilic targeting ligand is LXY30.
It would be obvious to one of ordinary skill in the art to modify the compound disclosed by Xu by replacing RGD with LXY30 and have a reasonable expectation of success. Xu discloses a conjugate, BP-KLVFF-RGD, comprising a hydrophobic moiety and fluorescent dye (bis-pyrene), and a targeting ligand, RGD, that binds to integrin receptors on glioblastoma cells. Xiao discloses a conjugate, FITC-LXY30, comprising a hydrophobic moiety and fluorescent dye (FITC), and a targeting ligand, LXY30, that binds to integrin receptors on glioblastoma cells. Thus, Xu discloses a conjugate comprising a hydrophobic fluorescent dye and a targeting ligand that binds to integrin receptors on glioblastoma cells and Xiao discloses that LXY30 is a targeting ligand that binds to integrin receptors on glioblastoma cells and may be present in a conjugate comprising a hydrophobic fluorescent dye. Accordingly, the combined teachings of Xu and Xiao suggest that LXY30 can serve as the targeting ligand that binds to integrin receptors on glioblastoma cells in the conjugate comprising a hydrophobic fluorescent dye disclosed by Xu. Therefore, it is reasonable to expect the compound disclosed by Xu may be modified by replacing RGD with LXY30. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144 (II) Xiao discloses LXY30 is highly potent and selective and has great translational potential for systemic and intracranial delivery of imaging agents and/or cancer therapeutics to α3β1 integrin-expressing human tumors. [Xiao, Page 11, Col. 1, Paragraph 2] Therefore, one would have been motivated by the expectation that replacing RGD with LXY30 would enable the conjugate disclosed by Xu to deliver imaging agents and/or cancer therapeutics to α3β1 integrin-expressing human tumors.
Response to Arguments
Applicant’s arguments, filed 12/8/2025, with respect to the rejection of the pending claims under 35 U.S.C. 103 have been fully considered and are persuasive. Applicant’s arguments essentially state that the cited references do not teach the instant claims, as amended. [Remarks, Page 11, Table 1 and Page 12, Paragraph 1] Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of the references cited above.
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.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618