DETAILED ACTION
This Office action details a first action on the merits for the above referenced application No. Claims 1-3, 6-9, 15, 29, 31-33, 35, 37, 40, 51-53, 57, 60, 68-69, 71-72, and 74-75 are pending in this application.
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
This application is a 35 USC 371 National Stage filing of international application No. PCT/US2022/073964 filed on 20 Jul. 2022, and claims benefit to US provisional application Nos: 63/253,093 and 63/223,902 filed on 6 Oct. 2021 and 20 Jul. 2021, respectively.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5 Feb. 2024 has been considered by the examiner.
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 6-7, 9, 29, 31, 40 51-53, 57, and 72 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.
Each of claims 6-7, 9, 29, 31, 51-53, and 57 recite SEQ ID Nos inside parentheses. For example, claim 6 recites “(SEQ ID NO: 1)”. It is not clear if the recited SEQ ID Nos are required limitations or merely examples.
In claim 7, it is not clear if “(Cy7)” is an abbreviation for sulfo-Cy7-maleimide, an example, or a required limitation.
In claim 40, it is not clear if the recitations of “(Ara-C)” and “(VP-16)” are merely examples or required limitations.
In claim 72, the recitation of “(e.g., Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET)” is indefinite because it is not clear if it recites examples or required limitations.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 6-8, 15, 32-33 and 60 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tanaka et al. (J. Am. Chem. Soc.; published 2015; see IDS filed 5 Feb. 2024).
Regarding claims 1-2, 6-8, 15, 28, 32-33 and 60, Tanaka et al. teach the compound ER-C16
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(scheme 1) and NBD-G-12
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(Fig. 6a). ER-C16 reads on a plurality of self-assembly components to form a self-assembled nanomaterial, each of the plurality of self-assembly components comprising a hydrophobic self-assembly (N-palmitoyl-Gly-Gly-Gly-His-; comprises a saturated hydrocarbon and aromatic hydrocarbon; comprises palmitoyl-GGGH and palmitoyl-GGGh; linker having the sequence G) motif operatively connected to a hydrophilic motif (-Arg-Lys; hydrophilic peptide) through a spacer. NBD-G-12 reads on a plurality of self-assembling components to form a self-assembled nanomaterial each of the plurality of self-assembling components comprising a hydrophobic self-assembly motif operatively connected to a hydrophilic motif further comprising a functional molecule operatively connected to each of the plurality thereof wherein the functional molecule further comprises a fluorophore. Tanaka et al. teach that the TEM observation so the hydrogel revealed bundled nanofibers approximately 10 nm in width (self-assembling components form the self-assembled nanomaterial and wherein the self-assembled nanomaterial has a micellar structure 10 nm in diameter)(pg. 774).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-3, 6-9, 15, 29, 32-33, 35, 37, 40, 51-53, 57, 60, 68-69, 71-72, and 74-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (J. Am. Chem. Soc.; published 2015; see IDS filed 5 Feb. 2024), in view of Zhao et al. (Angew. Chem. Int. Ed.; published 2019; see attached 892) and Shah et al. (US 2019/0117786 A1; published 25 Apr. 2019; see attached 892).
Tanaka et al. teach as discussed above. Tanaka et al. teach cancer cell death induced by the intracellular self-assembly of an enzyme-responsive supramolecular gelator (see title). The gelator precursor was designed to form nanofibers via molecular self-assembly after cleavage by a cancer related enzyme MMP-7 leading to hydrogelation. The hydrogelation precursor exhibited remarkable cytotoxicity to normal cells (see abstract). Tanaka et al. teach ER-C16
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(scheme 1; comprises 16 carbons). ER-16 contained the following distinct motifs: (1) the 16 carbon chain to enhance self-assembly in aqueous solution by providing hydrophobic interactions; (2) the tetrapeptide segment (Gly-Gly-Gly-His) following the alkyl chain as the major building block because of its ability to act as both an acceptor and donor of hydrogen bonds; (3) the peptide sequence (Pro-Leu-Gly-Leu) whose cleavage by MMP-7 confers on the molecule the ability to self-assembly, leading to gelation; and (4) the cationic peptide (Arg-Lys) which prevents ER-C16 from forming nanofibers without having undergone enzymatic hydrolysis. The derivatives were synthesized by peptide solid phase synthesis using Fmoc chemistry (pg. 771). Tanaka et al. teach MCF-7 cancer cells (breast cancer).
Tanaka et al. do not expressly teach that the aromatic hydrocarbon comprises Fmoc. Tanaka et al. do not teach a fluorophore comprising an NIR dye such as ICG or a plurality of self-assembling components operatively connected to a drug wherein the drug is a anticancer drug such as 5-FU. Tanaka et al. do not further teach a method for detecting a tumor in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 33 to the subject and detecting the dye thereby detecting the tumor optionally wherein the tumor is less than 5 mm in diameter optionally wherein the tumor is a breast cancer tumor and the detection comprises (NIR) fluorescence imaging. Tanaka et al. do not teach treating a cancer in a subject comprising administering an effective amount of the pharmaceutical composition of claim 37 to the subject thereby treating cancer in the subject in need thereof, optionally breast cancer.
Zhao et al. teach in situ self-assembled nanofibers precisely target cancer-associated fibroblasts for improved tumor imaging (see title). Zhao et al. teach constructed a peptide based near-infrared probe that is responsive to FAP-α and specifically forms nanofibers on the CAFs in situ. The selective assembly of the probe results in a signal intensity over four- and fivefold higher in tumor than the liver and kidney. With enhanced tumor imaging capability, this probe can visualize small tumors around 2 mm in diameter (pg. 15287). FAP-a provides a prospective for both imaging and therapy (pg. 15287). Zhao et al. teach molecular design and chemical structures (Fig. 1). Zhao et al. teach NIR fluorescence imaging of tumor in vivo with 1 and 4 (Fig. 5). The imaging strategy offers diversity so that imaging can be achieved by NIR, MR, and PET/CT (pg. 15292).
Shah et al. teach self-assembling verteporfin amphiphiles (SAVA) for local cancer therapy (see title). Shah et al. teach compositions comprising verteporfin and other anticancer compounds linked to a hydrophilic peptide through a degradable linker molecule (abstract). Shah et al. teach local administration of one or more biologically active agents to a subject comprising in situ injection of a SAVA composition, and upon contact with body fluids the composition is capable of undergoing a change from solution state to nanofiber gelation state. The delivered SAVA compositions can sustainably release the encapsulated bioactive agents over a long period of time ([0032]-[0034]). The biologically active agents include 5-FU ([0049]). The biologically active agents can also be imaging agents such as Cy7 and 800Cw ([0053]-[0054]). Exemplary amino acid linkers include E and C( [0057]). The verteporfin and other biologically active agents are linkers to the Pep via a biodegradable bond ([0058]). The linker can be cleaved by an enzyme ([0030], [0044]-[0045]). Shah et al. teach methods for treating a tumor ([0011]-[0013]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify compositions of Tanaka et al. (plurality of self-assembling components to form a self-assembled nanomaterial each of the plurality of self-assembling components comprising a hydrophobic self-assembly motif operatively connected to a hydrophobic motif wherein the hydrophobic motif comprises a saturated hydrocarbon and a aromatic hydrocarbon (his) so that the aromatic hydrocarbon comprises Fmoc as taught by Tanaka et al. because the Fmoc would have been expected to advantageously enable solid phase peptide synthesis.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Tanaka et al. so that the plurality of self-assembling components further comprises a biologically active component at the hydrophilic peptide moiety wherein the biologically active component is a NIR dye such as Cy7 or 800CW or an anticancer drug such as 5-FU as taught by Zhao et al. and Shah et al. because those biological agents would have been expected to advantageously enable in vivo NIR fluorescence imaging or in vivo therapeutic treatment using a different treatment mechanism by allow release of the bioactive agent of a period of time. It would have been obvious to a person of ordinary skill in the art before the effective filing date further modify Tanaka et al. by further substituting the hydrophilic gelation preventing moiety (RK) with E and C to arrive short hydrophilic peptide sequences including ECEE, ecee, EE, RR, ECEE, KCKK, KCEK, and RCRR as taught by Tanaka et al. and Shah et al. because those sequences formed from exemplary amino acids would have been expected to provide equivalent sequence suitable for preventing gelation and advantageous hydrophilic sequences suitable in situ release of the biologically active agent. Stereoisomers are prima facie obvious due to a general expectation of similar properties. See In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Tanaka et al. by further detecting a tumor in a subject comprising administering a therapeutically effective amount of the obvious composition comprising the NIR fluorophore to a subject having a breast cancer tumor and detecting the dye thereby detecting the tumor in the subject optionally wherein the tumor is less than 5 mm in diameter and the detecting comprises NIR fluorescence imaging as taught by Tanaka et al., Zhao et al., and Shah et al. because the administering and detecting would have been expected to advantageously enable in vivo NIR fluorescence imaging and monitoring of tumor tissue including small tumor tissue of < 5 mm.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Tanaka et al. by further treating cancer such as breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of the obvious composition comprising the anticancer drug such as 5-FU to the subject thereby treating cancer in the subject as taught by Tanaka et al. and Shah et al. because the treating would have been expected to advantageously enable treating the cancer by different mechanisms over a sustained period of time by slow release.
Claim(s) 1-3, 6-9, 15, 29, 31-33, 35, 37, 40, 51-53, 57, 60, 68-69, 71-72, and 74-76 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (J. Am. Chem. Soc.; published 2015; see IDS filed on 5 Feb. 2024), in view of Shah et al. (US 2019/0117786 A1; published 25 Apr. 2019; see attached 892), in further view of Liu et al. (US 9,982,011 B2; issued 29 May 2018; see attached 892) and Wu et al. (Chem. Eur. J.; published 2011; see attached 892).
Tanaka et al. teach as discussed above.
Tanaka et al. do not further teach the peptide sequence having AANG such as GGGHAANG.
Shah et al. teach as discussed above.
Liu et al. teach legumain activated doxorubicin derivative as well as preparation method and application thereof (see title). Liu et al. teach that legumain is generally expressed in malignant tumor cells. Legumain is a proteolytic enzyme highly expressed at the tumor site. It is present in most solid tumors and tumor microenvironment. Overexpression of such an enzyme is highly associated with invasion of the tumor cells to normal histiocytes, tumor metastasis and apoptosis of tumor cells. The drug can be completely hydrolyzed by legumain (col. 5). Liu et al. teach that legumain can cleave the peptide by hydrolysis at the position before Asn to release compound A-Leu (col. 6). Liu et al. teach -AANL-DOX (col. 6).
Wu et al. teach the interplay of chemical microenvironment and redox environment on thiol-disulfide exchange kinetics (see title). Wu et al. teach that the electrostatic attraction/repulsion between charged peptides and reducing agents such as glutathione was found to have a very pronounced effect of thiol-disulfide exchange kinetics. Wu et al. teach drug delivery systems, sensors, etc (see abstract). Wu et al. teach the sequence 28 WEECEE has a PSSP half-life of 48.05 in 10 nM GSH (table 1). Positively charged amino acid residues increased the pKa of the thiol, whereas negatively charged residues such as glutamic acid displayed the opposite effect (pg. 10065). Interestingly, the difference between doubly and quadruply negatively charged peptides (19 and 28) was significant more pronounced at neutral pH versus acidic pH. This highlights the importance of this phenomenon in the conception of redox-sensitive biomaterials, sensor or drug delivery systems (pg. 10068).
It would have been further obvious to a person of ordinary skill in the art before the effective filing date to modify the self-assembling components of Tanaka et al. by further substituting the hydrophilic ionic peptide (Arg-Lys) with the hydrophilic ionic peptide ECEE as taught by Wu et al. because the substituting would have been expected to provide an equivalent ionic peptide which prevents self-assembly before enzymatic hydrolysis and advantageously exhibits a repulsive effective with thiolate reducing species such as GS- the tumor microenvironment.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Tanaka et al. by further substituting the peptide sequence cleaved by MMP-7 with AANG to arrive at a spacer sequence comprising GGGHAANG as taught by Tanaka et al., Shah et al., and Liu et al. because that spacer sequence would have been expected to advantageously enable cleavage by legumain overexpressed at tumor sites and present in most solid tumors and micro-metastases wherein the cleavage induces aggregation.
A compound and its properties are inseparable. The plurality of self-assembling components made obvious by Tanaka et al., Shah et al., Liu et al. and Wu et al. are the same as those disclosed in the instant specification forming a micellular structure 5-10 nm in diameter.
The size of the tumor diameter detected is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. MPEP 2144.05.II. A person of ordinary skill in the art would have arrived at a tumor diameter that is less than 5 mm in order to more precisely detect all microtumors.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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