DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/25/2025 has been entered.
Claim Status
Claims 42-44, 46-48, 50-51, and 53-61 are pending.
Claims 1-41, 45, 49, 52 and 62, are cancelled.
Claims 53-61 are withdrawn as being directed to a non-elected invention, the election having been made on 11/27/2024.
Claims 42-44, 46-48, 50-51 have been examined.
Priority
This application is a CON of 16/838,348 04/02/2020 PAT 11712483
16/838,348 is a CON of 15/700,880 09/11/2017 PAT 10646593
15/700,880 is a CON of 14/773,240 09/04/2015 PAT 9789209
14/773,240 is a 371 of PCT/US2014/025683 03/13/2014
PCT/US2014/025683 has PRO 61/785,450 03/14/2013
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/25/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Rejection
The rejection of claim 62 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn because applicant canceled claim 62.
Non-Compliant Amendment
The claim filed on 10/27/2025 is a non-compliant amendment. In the claim filed on 10/29/2025, there is no claims 1-41, 49, and 52, and the claim status identifiers of claims 1-41, 49, and 52 are missing.
Appropriate correction is required.
Claim Objections
Claim 42 is objected to because of the following informalities:
A period “.” required at the end of every claim is missing in claim 42.
Furthermore, the phrase “wherein: X1a and/or X1b may be present or absent, and when present comprise a nucleophilic moiety;” should be revised to “wherein X1a and X1b is independently absent or a molecule comprising a nucleophilic moiety”.
Appropriate correction is required.
Modified Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 42-44, 46, 48, and 50-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention for the reasons as follows.
The specification does not disclose a sufficient number of a membrane-interacting polypeptide A linked to a counterpart inhibitor of polypeptide Z via a cleavable linker for the entire genus of the molecule of X1a-A-X2-Z-X1b as claimed.
The disclosed SEQ ID NO: 3 or Temporin-like peptides of SEQ ID Nos: 61-90 are insufficient to represent the entire genus of a variant sequence of SEQ ID NO: 3 modified by removal of one or two hydrophobic residues (interpreted as deletion of one or two hydrophobic residues).
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A single species of SEQ ID NO: 3 does not represent the entire genus of SEQ ID NO: 3 modified by removal of one (13 species) or two hydrophobic residues (78 species) marked by
“ * ” shown as follows.
Similarly none of the variants SEQ ID Nos: 61-90 listed in Table 1 [0094] is sufficient to represent removal of one or two hydrophobic residues at various positions of the corresponding variant reference sequences as claimed.
The disclosed SEQ ID No: 19 or 96 (SFLL(R/Q)(N/D)PND(K/Q)YEPFW) does not represent the entire genus of Z comprises an exosite recognition sequence derived from the thrombin exosite recognition sequence of a protease-activated receptor-1 (PAR-1) comprising 2 to 55 amino acids in length disclosed in the SPEC [00101] as evidenced by Seeley et al. showing peptide sequence alignment of an exosite recognition sequence derived from the thrombin exosite recognition sequence of a protease-activated receptor-1 across various species shown as follows (p1034, Fig 1A).
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The specification does not establish correlation between a membrane-interacting polypeptide portion comprising the amino acid sequence of FVQWFSKFLGKLL (SEQ ID NO: 3) or a variant sequence modified by removal of one or two hydrophobic residues and the inhibitory function of a peptide moiety Z comprising 2 to 55 amino. Even though the specification disclosed portion Z comprises an amino acid sequence derived from the analysis of screening of combinatorial peptide libraries that may or may not share similarity to physiologic substrates of the enzymatic activator [00104] further demonstrating lack of correlation between a membrane-interacting peptide derived from a known or unknown variant sequence of SEQ ID NO: 3 modified by removal of one or two hydrophobic residues and the function of a peptide moiety Z.
Claims 43-44, 46-48, and 50-51 are rejected as depending on claim 42.
The rejection may be overcome by distinctly claiming the polypeptide sequences of moiety A and moiety Z with their SEQ ID Nos.
Response to Arguments
Applicant's arguments of the amendment to claim 42 fully supported by the specification and able to overcome the rejection of record filed 11/25/2025 in Remarks (p, 5-6) have been fully considered but they are not persuasive because neither the amendment to a membrane-interacting polypeptide nor the amendment to a polypeptide of Z moiety overcomes 112(a) rejection. See the modified rejection above not repeated here.
New Ground of Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 42-44, 46, 48, and 50-51 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 42 is unclear with respect to the phrase “a variant sequence modified by removal of one or two hydrophobic residues”. The metes and bounds of the phrase are unclear because (a) the reference peptide sequence of “a variant sequence” before modification is indefinite and (b) the other phrase “by removal of one or two hydrophobic residues” is further unclear with respect to the positions of one or two hydrophobic amino acid deleted/removed from the indefinite variant sequence. Claims 43-44, 46, 48, and 50-51 are further rejected as depending on claim 42.
With respect to claim 43, claim 43 recites the limitation " the protease " in 42. There is insufficient antecedent basis for this limitation in the claim because claim 42 does not refers to a protease.
With respect to claim 48, claim 48 recites the limitation " the radioisotope " in 42. There is insufficient antecedent basis for this limitation in the claim because claim 42 does not refers to a radioisotope.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 42-44, 46, 48, and 50-51 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rinaldi et al. (Biochem. J. (2002) 368, 91-100, previously cited 8/25/2025) in view of STN CAS Registry (2008, previously cited 12/19/2024), Martin et al. (Pharmaceuticals. 2010; 3: 1456-1490), Han et al. (ONCOLOGY LETTERS 2: 599-608, 2011), Kuliopulos et al. (WO 2010/118435 A2, previously cited 12/19/2024), Foley et al. (J Biol Chem. 2012 Jul 13;287(29):24330-8, previously cited 8/25/2025), and Jiang et al. (US 8,110,554 B2, previously cited 12/19/2024).
Claim 1 is drawn to a conjugate comprising X1a-A-X2-Z-X1b as follows:
X1a and/or X1b may be present or absent, and when present comprise a nucleophilic moiety;
A is a membrane-interacting polypeptide portion comprising the amino acid sequence FVQWFSKFLGKLL (SEQ ID NO: 3) or a variant sequence modified by removal of one or two hydrophobic residues;
X2 is a cleavable linker linking moieties A and Z; and
Z is a polypeptide comprising an exosite recognition sequence derived from the thrombin exosite recognition sequence of a protease-activated receptor-1 (PAR-1) able to
to inhibit interaction of portion A with a phospholipid bilayer before cleavage of the linker X2.
Rinaldi et al. teach “Temporin L: antimicrobial, haemolytic and cytotoxic activities, and effects on membrane permeabilization in lipid vesicles.” (Title). Rinaldi et al. teach Temporin L consisting of the positively charged peptide sequence of FVQWFSKFLGRIL, 100% homology to the instant SEQ ID NO 2, (p91, Abstract, col 1) with an alpha helical structure (p93, Fig 1). Rinaldi et al. show Temporin L killing tumour cells at a dose-dependent manner (p96, Fig 7-8). Rinaldi et al. further show membrane permeabilization effect of Temporin L (p97, Fig 9-10), demonstrating Temporin L as a positively charged cell penetrating peptide (membrane
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interacting peptide). STN CAS Registry is cited to show conservative substitution of positively charged R to K and hydrophobic I to L as follows (p11). Furthermore, the functionally similar amino acids of R/K and I/L also have similar size; thus, it is expected to maintain the helical structure of FVQWFSKFLG(R/K)(I/L)L and its membrane interacting function.
Rinaldi et al. in view of STN CAS Registry do not teach a prodrug conjugate comprising Temporin L.
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Martin et al. teach “Building Cell Selectivity into CPP-Mediated Strategies” (Title) in response to a protease expression in cancer tissues shown as follows (p1067, last para; p1468, Fig 4), but did not specify a cancer protease cleavable sequence.
Rinaldi et al. in view of STN CAS Registry and Martin et al. do not specify a cancer protease cleavage sequence for control release of a drug conjugate.
Han et al. teach protease-activated receptors (PARs) in cancer (Title and Abstract). Han et al. teach thrombin activates PAR1 in two stages. Firstly, it binds to PAR1 on either side of the cleavage site. Secondly, it cleaves PAR1 between Arg41 and Ser42 to expose a new N-terminal tethered ligand domain, SFLLRN (p600, col 1, 2. Thrombin level in cancer and PAR activation, para 2). Han et al. teach malignant cells secrete thrombin, which affects prolif-eration and mediates metastatic processes, such as cellular invasion, extracellular matrix degradation, angiogenesis and tissue remodeling. Han et al. teach PAR1 is expressed by a wide range of tumor cells and play a role in the progression of epithelial tumors, including breast, colon, kidney, pulmonary tumor, melanoma and hepatocellular carcinoma (p602, col 2, para 2). Han et al. further teach PAR1 expression is associated with tumor progression in human breast cancer and it plays a role in bone metastasis in prostate cancer (p603, col 1, last para). Because (a) PAR1 is expressed by a wide range of tumor cells and (b) malignant cells secrete thrombin to activate PAR1 by binding and cleaving PAR1, one of ordinary skill in the art would have found it obvious to conjugate a cleavable linker comprising a PAR1 sequence to make a prodrug conjugate activated by cancer secreted protease such as thrombin cleavage. Kuliopulos et al. is cited to show (i) PAR1 is the major thrombin receptor [0007] consistent with Han et al. and (ii)
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an MMP-1 cleavage site is very close to the thrombin cleavage site in PAR1 known in the art as follows (Fig. 2B). Foley et al. is further cited to show common knowledge (a) MMP1 overexpression is associated with many cancer types, including lung, breast, and melanoma, and often correlates with a poor clinical prognosis and (b) elevated MMP-1 is associated with increased risk of development and metastasis of non-small cell lung cancer and with increased invasiveness in cutaneous melanoma (p24330, col 2, para 1).
Martin et al. suggest a bioactive compound (therapeutic or diagnostic agent; p1461, para 1) can be conjugate to a CPP (e.g., Rinaldi’s CPP peptide of Temporin L) in figure 4, but did not specify the use of a nucleophilic moiety for the conjugation.
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Similar to Martin’s teaching, Jiang et al. teach an enzyme cleavable prodrug conjugate. Jiang et al. show the cargo comprising a radioisotope chelated to the molecule through a metal binding moiety shown as follows (Fig 14a, 14e, 14f). Jiang et al. further teach the cargo molecule may bind to a nitrogen, such as a nitrogen of a lysine epsilon amino group, or a nitrogen of an alpha amino group of a membrane interacting peptide backbone, reading on the limitation (i) X1a as a nucleophilic moiety of amino group (Col 21, Example 7, line 14-17).
With respect to the limitation (ii), Rinaldi et al. teach Temporin L consisting of the positively charged peptide sequence of FVQWFSKFLGRIL, 100% homology to the instant SEQ ID NO 2, (p91, Abstract, col 1) with an alpha helical structure (p93, Fig 1). STN is cited to show the functionally similar amino acids of R/K and I/L also have similar size; thus, it is expected to maintain the helical structure of FVQWFSKFLG(R/K)(I/L)L and its membrane interacting function.
With respect to the limitations (iii) and (iv), Han et al. (a) PAR1 is expressed by a wide range of tumor cells and (b) malignant cells secrete thrombin to activate PAR1 by binding and cleaving PAR1. one of ordinary skill in the art would have found it obvious to conjugate a cleavable linker comprising a PAR1 sequence to make a prodrug conjugate activated by cancer secreted protease such as thrombin cleavage. Kuliopulos et al. is cited to show (i) PAR1 is the major thrombin receptor [0007] consistent with Han et al. and (ii) an MMP-1 cleavage site is very close to the thrombin cleavage site in PAR1 known in the art (Fig. 2B). Foley et al. is further cited to show common knowledge (a) MMP1 overexpression is associated with many cancer types, including lung, breast, and melanoma, and often correlates with a poor clinical prognosis and (b) elevated MMP-1 is associated with increased risk of development and metastasis of non-small cell lung cancer and with increased invasiveness in cutaneous melanoma (p24330, col 2, para 1).
Thus one of ordinary skill in the art would have found it obvious to combine the teachings of combined references to generate a cancer protease cleavable prodrug conjugate as follows.
Radioisotope-(nucleophilic moiety)-[Temporin L variant]-[PAR1 cleavable sequence].
Temporin L variant sequence as FVQWFSKFLG(R/K)(I/L)L
PAR1 cleavable sequence comprising SFLLRNPNDQYEPFW. See WT in Fig. 2B above.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Rinaldi et al. in view of STN CAS Registry with (ii) Martin et al. and (iii) Han et al. in view of Kuliopulos et al. and Foley et al. because (a) Rinaldi et al. teach a membrane-interacting peptide with anticancer activity, (b) Martin et al. teach “Building Cell Selectivity into CPP-Mediated Strategies” in response to a protease expression in cancer tissues (Title; p1067, last para; p1468, Fig 4), (c) Han et al. PAR1 is expressed by a wide range of tumor cells and malignant cells secrete thrombin to activate PAR1 by binding and cleaving PAR1 (p602, col 2, para 2; p603, col 1, last para), and (d) Kuliopulos et al. is cited to show (i) PAR1 is the major thrombin receptor [0007] and an MMP-1 cleavage site is very close to the thrombin cleavage site in PAR1 known in the art (Fig. 2B). Foley et al. is further cited to show common knowledge of MMP1 overexpression is associated with many cancer types, including lung, breast, and melanoma, and often correlates with a poor clinical prognosis and elevated MMP-1 is associated with increased risk of development and metastasis of non-small cell lung cancer and with increased invasiveness in cutaneous melanoma (p24330, col 2, para 1). The combination would have reasonable expectation of success because Kuliopulos et al. show a PAR1 peptide sequence comprising both MMP1 and thrombin cleavage sites able to be cleavage by tumor secreted proteases.
One of ordinary skill in the art would have found it obvious to combine (i) Rinaldi et al. in view of STN CAS Registry, Martin et al., Han et al., Kuliopulos et al. and Foley et al. with (ii) Jiang et al. because (a) Rinaldi et al. in view of STN CAS Registry, Martin et al., Han et al., Kuliopulos et al. and Foley et al. teach a prodrug conjugate activatable by cancer proteases and (b) Jiang et al. teach the cargo molecule may bind to a membrane interacting peptide in a prodrug conjugate activatable by cancer proteases via a nucleophilic moiety of an amino group (Col 21, Example 7, line 14-17). The combination would have reasonable expectation of success because Jiang et al. show the use of a nucleophilic moiety of an amino group for conjugating a bioactive compound to a prodrug conjugate activatable by cancer proteases (Col 21, Example 7, line 14-17).
With respect to claim 43, Kuliopulos et al. show PAR1 sequence further comprising MMp-1 tumor protease cleavage site in addition to thrombin (Fig. 2B).
With respect to claims 43-44, Jiang et al. teach a cleavable linker comprising the amino acid sequence of PLGLAG (SEQ ID NO: 1) cleaved by a cancer metalloproteinase enzyme MMP-2 (col 10, line 25-28).
With respect to claim 46, Kuliopulos show the PAR1 sequence comprising SFLLRNPNDQYEPFW. STN shows the amino acids of N, D, Q, N are functionally similar amino acids.
With respect to claim 48, Jiang et al. show a cargo comprising a radioisotope chelated to the molecule through a metal binding moiety (Fig 14a, 14e, 14f). Jiang et al. further teach the cargo molecule may bind to a nitrogen, such as a nitrogen of a lysine epsilon amino group, or a nitrogen of an alpha amino group of a membrane interacting peptide backbone, reading on X1a as a nucleophilic moiety of amino group (Col 21, Example 7, line 14-17). Jiang et al. suggest the radioisotopes to treat a cancer can be 131I, 125I, 90Y, 186Re, or 188Re (col 14, line 11-13).
With respect to claims 50-51, Jiang et al. show the cargo comprising a radioisotope of
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Technetium-99m or lndium-111 chelated to the molecule through a metal binding moiety (Fig 14a, 14f). Jiang et al. further teach the cargo molecule may bind to a nitrogen, such as a nitrogen of a lysine epsilon amino group, or a nitrogen of an alpha amino group of a membrane interacting peptide backbone, reading on X1a as a nucleophilic moiety of amino group (Col 21, Example 7, line 14-17).
Applicant’s Argument
None of the cited references, alone or in combination, disclose or suggest the elements of
amended claim 42 (Remarks, p7).
Response to Arguments
Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive for the reasons as follows. Applicant’s amendments to claim 42 are rejected under both 112(a) and 112(b). The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The reasons to combine cited references are articulated above not repeated here. One of ordinary kill in the art would be sufficiently taught and/or motivated to generate a prodrug conjugate activated by cancer protease. A person of ordinary skill in the art is well defined as a person of ordinary creativity able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at ___, 82 USPQ2d at 1396. See MPEP 2141.03 (I).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 42-44, 46, 48, and 50-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of U.S. Patent No. 8,110,554 B2 (the ‘554 patent) in view of Rinaldi et al. (Biochem. J. (2002) 368, 91-100), STN CAS Registry (2008, previously cited 12/19/2024), Martin et al. (Pharmaceuticals. 2010; 3: 1456-1490), Han et al. (ONCOLOGY LETTERS 2: 599-608, 2011), Kuliopulos et al. (WO 2010/118435 A2, previously cited 12/19/2024), Foley et al. (J Biol Chem. 2012 Jul 13;287(29):24330-8), and Jiang et al. (US 8,110,554 B2, previously cited 12/19/2024).
Claim 1 of the ‘554 patent disclosed a controlled release prodrug conjugate comprising a cargo conjugated to a basic (positively charged) membrane-interacting domain and linked to an acidic (negatively charged) inhibitory domain via a cleavable linker.
Claim 11 of the ‘554 patent disclosed the linker X is cleavable by a matrix metalloproteinase.
Claims 1 and 11 of the ‘554 patent did not disclosed a cargo as a radioisotope chelated to the molecule through a metal binding moiety.
The relevancy of Rinaldi et al. in view of Martin et al., Kuliopulos et al., Foley et al., and Jiang et al. as applied to claims 42-44, 46-48, 50-51 above not repeated here.
Because Rinaldi et al. show Temporin L is a positive charged anticancer membrane-interacting polypeptide killing human cancer cells at a dose-dependent manner, one of ordinary skill in the art would have found it obvious to beneficially replace Jiang’s positively charged membrane-interacting polypeptide with Rinaldi’s anticancer peptide of Temporin L for treatment of cancer via controlled release of conjugated radioisotope in response to a cancer metalloproteinase enzyme (e.g., MMP-2). See MPEP 2143 (I)(B) Simple substitution of one known element for another to obtain predictable results.
Thus, claims 1 and 11 of the ‘554 patent in view of Rinaldi et al., STN CAS Registry, Martin et al., Kuliopulos et al., Foley et al., and Jiang et al. are obvious to the instant claims 42-44, 46-48, and 50-51.
Response to Arguments
Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive. See response to arguments above.
Allowable Subject Matter
Claim 47 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The examiner did not find a prior art reference teaching the peptide sequence of SEQ ID NO: 19 in claim 47 as indicated in the prior office action dated 8/25/2025.
Conclusion
No claim is allowed.
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/J.L/Examiner, Art Unit 1658
01-January-2026
/LI N KOMATSU/ Primary Examiner, Art Unit 1658