DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application No. Claims 1-5, 7-8, 10, 12, 23, 33-37, 59, 61-63, 66, 69-72, 74-79, 94, 112, 117, 129, 133, 140, 150, and 153 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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6 Jun. 2025 has been entered.
Status of Claims
Claims 6, 9, 11, 13-22, 24-32, 38-58, 60, 64-65, 67-68, 73, 80-93, 95-111, 113-116, 118-128, 130-132, 134-139, 141-149, 151-152, and 154-158 are cancelled.
Response to Amendment
The amendments filed on 6 Jun. 2025 have been entered.
Response to Arguments
The rejection of claims 1-5, 7-8, 10, 12, 23, 33-37, 59, 61-63, 66, 69-72, 74-79, 94, 112, 117, 129, 133, 140, 150, and 153 under 35 USC 103 as being unpatentable over Gao et al. (US 2017/0143852 A1; published 25 May 2017), in view of Guo et al. (Biomaterials; published 2013) is withdrawn.
The rejection of claims 1-5, 7-8, 10, 12, 23, 33-37, 59, 61-63, 66, 69-72, 74-79, 94, 112, 117, 129, 133, 140, 150, and 153 on the ground of non-statutory double patenting as being unpatentable over claims 1-13 of US patent No. 10,098,971 B1, in view of Gao et al. (US 2017/0143852 A1; published 25 May 2017) and Guo et al. (Biomaterials; published 2013) is withdrawn.
The rejection of claims 1-5, 7-8, 10, 12, 23, 33-37, 59, 61-63, 66, 69-72, 74-79, 94, 112, 117, 129, 133, 140, 150, and 153 on the ground of non-statutory double patenting as being unpatentable over claims 1-14 of US patent No. 9,751,970 B1, in view of Gao et al. (US 2017/0143852 A1; published 25 May 2017) and Guo et al. (Biomaterials; published 2013) is withdrawn.
New Grounds of Rejection
Claim Objections
Claims 1-3, 12, 23, 37, and 74 are objected to because of the following informalities: in claims 1-3, 12, 23, 37, and 74, each instance of “selected from” should be replaced with “selected from the group consisting of”. Appropriate correction is required.
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 1-3, 12, 37, 62, and 78 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. Regarding claims 1-3, 12, and 37, the recitation of “or a substituted version of any of these groups” is indefinite because it is not clear what qualifies as a substituted version of any of these groups. The Examiner suggests possibly incorporating “substituted or unsubstituted” before each group. For example, at claim 1 the definition for X4 and X5 should possibly state “substituted or unsubstituted C1-C12 alkyl” or state “X4 and X5 are each substituted or unsubstituted and each independently selected from the group consisting of’. In claim 62, the recitation of “or any range derivable therein” is indefinite because it is not clear what qualifies as a derivable range therein. In claim 78, the recitation of “A micelle of a polymer of claim 1” is indefinite because it is not clear what qualifies as a micelle of a polymer. The Examiner suggest amending claim 78 to recited “A micelle comprising a polymer of claim 1”
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) 1-5, 7-8, 10, 12, 23, 33-37, 59, 61-63, 66, 69-72, 74-79, 94, 112, 117, 129, 133, 140, 150, and 153 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al. (US 2017/0143852 A1; published 25 May 2017), in view of Jensen et al. (Biomacromolecules; published 19 Mar. 2014; see attached 892).
Gao et al. teach a library of pH responsive polymers and nanoprobes thereof (see title). Gao et al. teach PDPA dyes of formula
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wherein x=71, 77, or 80 and y=3 or 6 (see figs. 14A-F, tables 1-3).
These probes read in part on probes of instant formula (I)
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wherein R1=Me (C1 alkyl); n=113; R2=R2’=Me (C1 alkyl); R11=R3=
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wherein X1=Me, X2=X3=H, nx=1; X4=X5=propyl (C3 alkyl)(consecutive to form a block), w=0, 1, or 2, and x=78, 79 or 80; R4=
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, Y1=Y2=Y3=H, and Y4=dye (ICG; [0025], [0043], [0309]), y=3; and R6=Me (C1 alkyl).
Gao et al. teach UPS6.9 (pH transition at 6.9)(see 40A). Gao et al. teach the polymer PEO-b-P(EPAx-r)ICG
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where ICG is the dye indocyanine green ([0043], [0079], [0309]),
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(pH transition 6.9) (R3 =
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). The hybrid UPS stays Off at neutral pH. When the pH is lowered, the PEG-b-(PR-r-dye) components disassemble and fluoresce sequentially to present different colors (see Fig. 85b). Gao et al. teach PEO-b-(PR1-r-PR2-t-Cy5)
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(w>0; random block from two different monomers; R11 and R3 are randomly incorporated in the polymer; in any order within the polymer)(see Fig. 58; [0147]). Gao et al. teach that that R1 may be H or
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or NOTA ([0013]). Gao et al. teach 64Cu2+ (see [0023], [0059, [0376]). Gao et al. teach a method of imaging the pH of a intracellular or extracellular environment (see [0030]-[0032]). Gao et al. teach a method of delivering a compound of interest to a target cell (see [0036]-[0038]). Gao et al. teach a method of resecting a tumor in a patient (see [0039]-[0042]). Gao et al. teach a method of treating a cancer susceptible to endosomal/lysosomal pH arrest in a patient (treating a disease or disorder in a patient) and identifying a tumor acidosis pathway ([0044], [0049]-[0053]). Gao et al. teach a method of imaging a patient to determine the presence of a tumor (see [0054]-[0058], [0238]-[0241]). Gao et al. teach monitoring treatment response (see [0218]). Gao et al. teach dual imaging methods with PET and fluorescence imaging (see [0347]-[0377]). Gao et al. compare the imaging efficacy of dual modality UPS and PET with FDG only (see [0378]-[0380]). By introducing 64Cu to the UPS nanoprobes, the distribution of the PET nuclides is anticipated to be shifted by targeting tumor acidosis and therefore eliminate false positive (see [0380]). Gao et al. the chemical structures of triblock copolymers PEO-b-(DEA40-b-D5A), PEO-b-P(D5A40-b-DEA40) (R11 and R3 are incorporated consecutively to form a block) and PEO-P(DEA40-r-D5A40)( R11 and R3 are randomly incorporated into the polymer; in any order within the polymer) (see Fig. 113A, [0202], [0459]). Gao et a. teach the polymer may further include a targeting moiety (see [0025], [0224], [0230]-[0230]). Gao et al. teach pH responsive applications such as (1) rapid dissociation of the micelle and high contrast sensitivity ([0222]-[0224]; [0227]-[0229]). Gao et al. teach efficacy and survival studies [0408]-[0410]).
Gao et al. do not teach a compound of instant formula (I) wherein z=1-5 and R5 is of formula (IV) or (VII) wherein Y4’=metal chelating group. Gao et al. do not disclose a compound of instant of instant formula (I) wherein Y4=ICG. Gao et al. do not disclose a compound of instant formula (I) wherein R1=H or
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. Gao et al. do not disclose a polymer comprising a targeting moiety. Gao et al. do not further teach determining the efficacy of cancer treatment therapy comprising (a) administering a pH responsive system comprising one or more micelles of claim 79 to a patient wherein the patient
Jensen et al. teach positron emission tomography-based analysis of long circulating cross-linked triblock polymeric micelles in U87MG mouse xenograft model and comparison of DOTA and CB-TE2A as chelators of copper-64 (see title). Jensen et al. teach that methods of labeling of nanoparticles with radionuclides that allow for PET imaging is attracting increasing attention. 64Cu is a particularly popular isotope due to its 12.7 h half-life allowing PET scans for up to 48 h after injection (pg. 1625). When conjugating chelators to nanoparticles, the location of the chelator may have importance. When chelators are placed near the surface of liposomes, protected by the PEG-layer, lower liver and spleen accumulation has been shown to occur in comparison with placement at the distal end of PEG. By conjugating the chelators in the shell-region, we envisioned that the chelators would be protected by the PEG-layer, thereby reducing/negating direct interaction of the chelators with blood components and possibly transchelation (pg. 1626). Jensen et al. teach conjugation of chelators to PEG-PHEMA-PCMA
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(scheme 2). Jensen et al. teach micelle preparation and radiolabeling with 64Cu (pg. 1628). The triblock polymeric micelles conjugated with CB-TE2A or DOTA in the micelle shell region were radiolabeled with 64Cu in good yields. Coumarin is fluorescent (pg. 1630). The micelles displayed long circulation half-life in blood and good tumor accumulation (pg. 1632). There is no or little tendency for Cu2+ dissociation both from nonspecifically bound 64Cu or due to chelator instability (pg. 16321).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Gao et al. (for example PDPA-dye, PEO-b-(PR1-r-PR2-r-CY5, PEO-b-P(EPAx-r)ICG or UPS6.9 and pH responsive micelles thereof wherein the micelles have a pH transition point and an emission spectra) by substituting at least one dye with a metal chelating group optionally complex with 64Cu such as DOTA or CB-TE2A as taught by Gao et al. and Jensen et al. because it would have been expected to advantageously enable in vivo PET imaging distribution and/or enable diagnosis of cancer and because positioning the metal chelating group at the methacrylate portion of the polymer would have been expected to advantageously reduce/negate direct interaction of chelators with blood components and possibly transchelation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Gao et al. by further using indocyanine green as the dye as taught by Gao et al. because it would have been expected to provide an equivalent dye for suitable for use in NIR fluorescence imaging. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of Gao et al. by substituting R1 wherein R1=Me with -H or
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as taught by Gao et al. because it would have been expected to provide an equivalent polymer capable of micelle formation and pH transition and/or enable conjugation to a targeting moiety. It would have been obvious to person of ordinary skill in the art before the effective filing date to modify Gao et al. so that the polymer further comprises a targeting moiety such as a small molecule or antibody as taught Gao et al. because it would have been expected to advantageously enable targeting to different tumor types.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Gao et al. (methods of imaging the pH or an intracellular or extracellular environment and/or imaging a patient to determine the presence of a tumor and/or treating a cancer susceptible to endosomal/lysosomal pH arrest in a patient and/or treating a disorder in patient in need thereof) by administering the obvious pH responsive micelle of the first polymer optionally wherein micelle encapsulates a therapeutic drug or other compound, which releases upon disassembly thereby treating cancer susceptible to lysosomal pH arrest in a patient and optionally detecting one more signal from the environment as taught by Gao et al. because it would have been expected to advantageously enable imaging and treatment where the optical signal indicates the micelle has reached its pH transition point. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Gao et al. (methods of resecting a tumor wherein the method comprises administering a pH responsive system, detecting one or more signals in a patient; and resecting the tumor via surgery) as taught by Gao et al. because it would have been expected to enable visualization of tumor margins ensuring a high percentage of tumor has been resected. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Gao et al. (method of identifying tumor acidosis) by contacting the obvious pH responsive system comprising one or micelles with a cell or cellular environment as taught by Gao et al. because it would have been expected to advantageously enable evaluation of inhibitors targeting different acidosis pathways. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Gao et al. (method of imaging comprising collecting one or more PET scans) by administering to the patient the obvious pH responsive system comprising one or more micelles to a tumor and collecting one or more PET scans and one or more optical scans as taught by Gao et al. because it would have been expected to advantageously enable localization and characterization of tumors by measuring metabolic activity. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Gao et al. (method for monitoring treatment response) by administering cancer therapy after the administration of the obvious pH responsive system and PET and optical image and then repeat as taught by Gao et al. because it would have been expected to advantageously enable determining the effect of treatment in the patient by PET and optical imaging.
Applicants Arguments
Applicants assert that neither Gao nor Guo teach the inclusion of the metal chelating group that would be buried within the hydrophobic body of the micelle. Gao describes attaching the metal chelating group attached at the R1 position. The attachment of the metal chelating group to this position would result in this group being one the surface of the membrane forming micelle. The presently claimed invention attaches the metal chelating group to the methacrylate portion of the polymer which will embed the metal chelating group into the heart of the membrane of the micelle. Only the presently claimed polymers contain the metal chelating group within the membrane. Neither reference teaches the particular configuration of the metal chelating group within the polymer nor suggests that the metal chelating group could be moved to this particular part of the polymer. Applicants assert unexpected activity. The specification on page 46 notes that the Applicant believed that the PET signal should always be ON, but contrary to that expectation, the presently claimed polymers showed an ON/OFF profile. The Applicants did not expect this activity profile for the PET signal given the known state of the art.
Applicant's arguments filed 6 Jun. 2025 have been fully considered but they are not persuasive. Applicants’ arguments regarding Guo are moot because Guo is no longer being applied in a rejection of claims. Gao provides for pH sensitive polymers that read in part on the instant formulas but differ from the instant formulas because none of the polymers contain an instant R5 having instant formula (IV) wherein Y4’ is a metal chelating group such as DOTA. As noted by Applicants, Gao separately teaches and suggests PET detectable labels including chelated 64Cu but Gao only teaches and suggest placing the PET detectable label on the PEG moiety that extends away from a formed micelle into a biological media. Gao is silent about incorporating the PET detectable at a methacrylate unit of the block copolymer. Jensen (cited above) however teaches that the position of the chelated metal matters when a metal chelator gets incorporated into micelle forming block polymer analogous to the block polymers of Gao. In addition, Jensen teaches that it is advantageous to incorporate a chelated 64Cu label on micelle forming block polymer analogous to the block polymer of Gao. Jensen teaches that when chelators are placed near the surface of liposomes, protected by the PET layer, lower liver and spleen accumulation has been shown to occur in comparison with placement at the distal end of PEG. Chelators that are placed on the distal end of PEG have significant effects on nanoparticle pharmacokinetics. Jensen envisioned that by conjugating the chelators in the shell-region, the chelators would be protected by the PEG layer thereby reducing/negating direct interaction of the chelators with blood components and possibly transchelation. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the micelle forming block polymers of Gao by incorporating at least acrylate monomer of instant formula (IV) that is bound to a metal chelator such as DOTA or CB-TE2A as taught by Jensen et al. because the incorporating would have been expected to enable dual PET and on/off fluorescence detection and because the position of the metal chelator would have been expected to reduce/negate direct interaction of the chelators with blood components and possibly transchelation.
The instant specification at pg. 46 asserts that the positron signal showed that a binary signal suppression and tumor activation similar to the fluorescence output and then provides some theory discussing that at different time points, different regions of the tumor can be acidified below the pH threshold 6.9. The transient signal in turn activates 64Cu-UPS micelles circulating at the tumor site into polycationic unimers, which are irreversibly leaving a stable imprint of the polymer signal. The irreversible capture resulted in increased dose accumulation over time for 64Cu-UPS as validated experimentally. In this case, the specification does not describe an unexpected on/off PET signal resulting from the incorporation of the incorporation of a chelated 64Cu onto a micelle forming polymer of Gao. None of the claimed micelle forming polymers contain a moiety that would quench the PET signal from the 64Cu that enables whole body PET imaging. Rather, the specification describes a selective accumulation of a USP micelle that transitions to unimers below a pH threshold of 6.9. The specification does not contain a comparison with the USP6.9 in Gao to show that the UPS6.9 does not exhibit a similar selective accumulation. Unexpected results must be reviewed to determine if the results occur over the entire claimed range. In this case, the formula (I) of claim 1 encompasses thousands of polymers and only a few of which may form micelles that transition at a pH threshold of 6.9. Accordingly, a person of ordinary skill in the art would not expect that the entire scope of formula I in claim to a have a positron signal that shows a binary pattern of signal suppression and tumor activation.
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 1-5, 7-8, 10, 12, 23, 33-37, 59, 61-63, 66, 69-72, 74-79, 94, 112, 117, 129, 133, 140, 150, and 153 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,098,971 B1, in view of Gao et al. (US 2017/0143852 A1; published 25 May 2017; see IDS filed on 31 Jul. 2023) and Jensen et al. (Biomacromolecules; published 19 Mar. 2014; see attached 892).
Claims 1-13 of U.S. Patent No. 10,098,971 B1 claim a polymer of formulas
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,
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, and
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wherein R3 has the formula
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, y may be 1-6, and R4 is of formula
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and Y4 is
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(an indocyanine green).
Claims 1-13 of U.S. Patent No. 10,098,971 B1 do not claim a polymer or a micelle comprising a polymer of instant formula (I) comprising at least one R5 of formula IV
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where Y4’ is a metal chelating group and wherein the dye is indocyanine green (ICG). Claims 1-13 of U.S. Patent No. 10,098,971 B1 do not claim a polymer of instant formula (I) comprising an R5 and optionally R11 and optionally wherein R11 and R3 are incorporated consecutively to form a block or randomly incorporated. Claims 1-13 of U.S. Patent No. 10,098,971 B1 do not claim a polymer of instant formula (I) wherein R1 is H or
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. Claims 1-13 of U.S. Patent No. 10,098,971 B1 do not claim a polymer further comprising a targeting moiety or UPS6.9 or a micelle of the instant polymer or a pH responsive system comprising a micelle of the instant polymers. Claims 1-13 of U.S. Patent No. 10,098,971 B1 do not claim a method of imaging the pH of an intracellular or extracellular environment or a method of delivering a compound of interest to a target cell or a method of resecting a tumor or a method of treating a cancer susceptible to endosomal or lysosomal pH arrest or a method of identifying the tumor acidosis pathway or a method of method of imaging a patient to determine the presence of a tumor or method of determining the efficacy of cancer treatment or a method of treating or preventing a disease or disorder in a patient.
Gao et al. teach as discussed above.
Jensen et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-13 of U.S. Patent No. 10,098,971 B1 by incorporating at least one of the instant R5 fragments wherein the R5 fragment is a derivative of the R4 fragment but substitutes the dye with metal chelating group such as DOTA or CB-TE2A as taught by Gao et a. and Jensen et al. because it would have been expected to advantageously enable in vivo PET and/or optical imaging distribution and optionally diagnosis of cancer and where position of the metal chelator advantageously reduces/negates direct interaction of the chelator with blood components and possibly transchelation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-13 of U.S. Patent No. 10,098,971 B1 by further using indocyanine green as the dye as taught by Gao et al. because it would have been expected to be an equivalent dye suitable for fluorescence imaging. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-13 of U.S. Patent No. 10,098,971 B1 by further incorporating one or more instant R11 fragments optionally wherein R11 and R3 are there consecutively as a block or randomly as taught by Gao et al. and Jansen et al. because it would have been expected to provide equivalent polymers suitable for use a pH responsive micelle. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-13 of U.S. Patent No. 10,098,971 B1 by substituting R1 with H or
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as taught by Gao et al. because it would have been expected to provide an equivalent polymer and/or advantageously enable conjugate to targeting moiety. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-13 of U.S. Patent No. 10,098,971 B1 by further incorporating a targeting moiety as taught by Gao et al. because it would advantageously enable targeted delivery and/or increased tumor accumulation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-13 of U.S. Patent No. 10,098,971 B1 by further arriving at UPS6.9 as taught be Gao et al. because a UPS6.9 would have been expected to advantageously enable phase transition as pH 6.9. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-13 of U.S. Patent No. 10,098,971 B1 by further forming a micelle or a pH responsive micelle comprising at least one of the obvious polymers as taught by Gao et al. because it would have been expected to advantageously enable PET detection and visualizing a change in fluorescence based on the pH of the environment. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of claims 1-13 of U.S. Patent No. 10,098,971 B1 by further using the obvious compositions in the methods of Gao et al. as taught by Gao et al. because it would have been expected to advantageously enable dual PET and optical imaging of pH sensitive environments thereby increasing sensitivity and reducing false positives.
Claims 1-5, 7-8, 10, 12, 23, 33-37, 59, 61-63, 66, 69-72, 74-79, 94, 112, 117, 129, 133, 140, 150, and 153 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US 9,751,970 B2, in view of Gao et al. (US 2017/0143852 A1; published 25 May 2017; see IDS filed on 31 Jul. 2023) and Jensen et al. (Biomacromolecules; published 19 Mar. 2014; see attached 892).
Claims 1-14 of U.S. Patent No. US 9,751,970 B2 claim a block copolymer and a pH-sensitive micelle formed from a block copolymer having the structure
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119
243
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wherein R is -NR1R2, y is 1-6 and L is a fluorescent label and wherein the following portion of the structure
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200
262
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may be arranged in any order and a block polymer having the formula
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380
485
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wherein L is a fluorescent label. In addition, claims 1-14 of U.S. Patent No. US 9,751,970 B2 claim a method of imaging a tumor in an individual.
Claims 1-14 of U.S. Patent No. US 9,751,970 B2 do not claim a polymer of instant formula (I) having an R4 of formula (III)
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160
119
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wherein Y4 is ICG and an R5 of formula (IV)
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179
126
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wherein Y4’ is a metal chelating group. Claims 1-14 of U.S. Patent No. US 9,751,970 B2 do not claim a polymer of instant formula (I) comprising an R5 and optionally R11 and optionally wherein R11 and R3 are incorporated consecutively to form a block or randomly incorporated. Claims 1-14 of U.S. Patent No. US 9,751,970 B2 do not claim a polymer of instant formula (I) wherein R1 is H or
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126
248
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. Claims 1-14 of U.S. Patent No. US 9,751,970 B2 do not claim an R3 having the structure
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216
148
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. Claims 1-14 of U.S. Patent No. US 9,751,970 B2 do not claim a polymer further comprising a targeting moiety or UPS6.9 or a micelle of the instant polymer or a pH responsive system comprising a micelle of the instant polymers. Claims 1-14 of U.S. Patent No. US 9,751,970 B2 do not claim a method of imaging the pH of an intracellular or extracellular environment or a method of delivering a compound of interest to a target cell or a method of resecting a tumor or a method of treating a cancer susceptible to endosomal or lysosomal pH arrest or a method of identifying the tumor acidosis pathway or a method of method of imaging a patient to determine the presence of a tumor or method of determining the efficacy of cancer treatment or a method of treating or preventing a disease or disorder in a patient.
Gao et al. teach as discussed above.
Jensen et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-14 of U.S. Patent No. US 9,751,970 B2 so that the L fluorophore is attached polymer by an amino alkyl group as in instant formula III and by incorporating at least one of the instant R5 fragments attached to a metal chelator such as DOTA or CB-TE2A as instant formula (IV) taught by Gao et a. and Jensen et al. because those modifications would have been expected to enable a pH sensitive transition polymer comprising an on/off NIR fluorophore and a PET detectable label such as 64Cu that advantageously enables whole body in vivo PET detection and/or diagnosis of cancer and because the position of the chelator would have been expected to reduce/negate direct interaction of the chelator with blood components and possibly transchelation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-14 of U.S. Patent No. US 9,751,970 B2 by using indocyanine green as the fluorescent label as taught by Gao et al. because it would have been expected to provide an equivalent dye advantageously capable of NIR fluorescence imaging. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-14 of U.S. Patent No. US 9,751,970 B2 further incorporating one or more instant R11 fragments optionally wherein R11 and R3 are there consecutively as a block or randomly as taught by Gao et al. and Jansen et al. because it would have been expected to provide equivalent polymers suitable for use as pH responsive micelles. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-14 of U.S. Patent No. US 9,751,970 B2 by substituting R1 with H or
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126
248
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as taught by Gao et al. because it would have been expected to provide an equivalent polymer and/or advantageously enable conjugate to targeting moiety. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymer of claims 1-14 of U.S. Patent No. US 9,751,970 B2 by substituting R11/R3 with
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216
148
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as taught by Gao et al. because it would have been expected to form an equivalent polymer composition suitable for forming a pH responsive micelle system. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-14 of U.S. Patent No. US 9,751,970 B2 by further incorporating a targeting moiety as taught by Gao et al. because it would have been expected to advantageously enable targeted delivery and/or increased tumor accumulation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-14 of U.S. Patent No. US 9,751,970 B2 by further arriving at UPS6.9 as taught be Gao et al. because it would advantageously enable phase transition as pH 6.9. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polymers of claims 1-14 of U.S. Patent No. US 9,751,970 B2 by further forming a micelle or a pH responsive micelle as taught by Gao et al. because it would have been expected to advantageously enable visualizing a change in fluorescence based on the pH of the environment. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of claims 1-14 of U.S. Patent No. US 9,751,970 B2 by further using the compositions in the methods of Gao et al. as taught by Gao et al. because it would have been expected to enable dual PET and optical imaging of pH sensitive environments thereby increasing sensitivity and reducing false positives.
Conclusion
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618