DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application No. Claims 1, 4-9, and 12-22 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 26 May 2026 has been entered.
Status of Claims
Claims 1 and 21 are amended. Claims 2-3, and 10-11 are cancelled. Claim 22 is new.
Response to Amendment
The amendments filed on 26 May 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the objection to claim 1 because of minor informalities is withdrawn.
In view of Applicants arguments, the rejection of claim 21 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
The rejection of claims 1, 4-7, 12-15 and 17-20 under 35 USC 103 as being unpatentable over Chung et al. (US 2011/0262354 A1; filed 13 Jan. 2007), in view of Liu et al. (Bioorg. Med. Chem. Lett; published 2007) and Chen et al. (Bioconjugate Chem.; published 2005) is withdrawn.
The rejection of claims 1, 4-7, 12-15 and 17-20 under 35 USC 103 as being unpatentable over Chung et al. (US 2011/0262354 A1; filed 13 Jan. 2007), in view of Liu et al. (Bioorg. Med. Chem. Lett; published 2007) and Chen et al. (Bioconjugate Chem.; published 2005) is withdrawn.
The rejection of claim 1, 4-9, and 12-20 under 35 USC 103 as being unpatentable over Chung et al. (US 2011/0262354 A1; filed 13 Jan. 2007), in view of hung et al. (US 2011/0262354 A1; filed 13 Jan. 2007), in view of Liu et al. (Bioorg. Med. Chem. Lett; published 2007) and Chen et al. (Bioconjugate Chem.; published 2005), in further view of Vlahov et al. (WO 2007/022494 A1; published 22 Feb. 2007) and Safavy et al. (J. Med. Chem.; published 1999) is withdrawn.
New Grounds 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.
Claim 17 is 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. In this case, claim 17 recites “compound according to claim” which is indefinite because it is not clear what claim the compound is according to.
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, 4-7, 12-15, and 17-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chung et al. (US 2011/0262354 A1; filed 13 Jan. 2007), in view of Liu et al. (Bioorg. Med. Chem. Lett.; published 2007) and Brush et al. (US 5,986,086; published 1999; see IDS filed on 16 Aug. 2023).
Chung et al. teach cyanine containing compounds for cancer imaging and treatment (see title). Chung et al. teach methods of using cyanine containing compounds for cancer cell imaging, cancer cell growth inhibition, and detection of cells (see abstract). Chung et al. teach cyanine conjugates where the cyanine emits fluorescence in the NIR region (see [0003]). Chung et al. teach providing the desired level of active agent or conjugate in the bloodstream or tissue (see [0122]). Chung et al. teach examples of cyanine dyes of formula C
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such as MHI-148 (R5=H, R=(CH2)5COOH), MHI-25 (R5=H, R=(CH2)4SO3H), MHI-78 (R5=H, R=(CH2)2OH) and IR780 (R5=H, R=(CH2)2CH3). R5 may be selected from OH, NH2, COOH(conjugate amenable functional groups) (see [0046]). These compounds read on targeting ligands of formula
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wherein R1=H, and R2= C3 alkyl (IR780), C4 alkyl sulfur containing group (MHI-25), or a C5 alkyl substituted with an oxygen containing group (MHI-148, emission 850 nm, [0078]. Chung et al. teach MHI-148 can image lung cancer and lymphoma (see Fig. 4) and the preferential uptake of IR 780 by cancerous tissue but not normal cells (see Figs. 14-20). Uptake is completely abolished by BSP (inhibitor of organic anion transporters). Chung et al. teach N-hydroxysuccinimide (see [0010]). The compounds of the invention may be administered in combination with other antineoplastic therapeutic agents and may be administered in a fixed combination (see [00162]). Chemotherapeutic agents include paclitaxel and other taxanes and octreotide ([0164]). Chung et al. teach methods of treating cancer comprising administering a cytotoxic amount of a cyanine-containing compound to cancer cells ([0013]). Chung et al. teach that esters of the compounds of the present invention can be prepared by functionalization of a hydroxyl group present within the molecular structure of the compound…Esters can be made by reaction with a carbonylating agent, e.g. acetic anhydride ([0135]). Compounds of the invention may be tagged with radioactive groups or other functional groups as known in the art ([0020]).
Although Chung et al. teach a targeting ligands as defined by the structure in claim 1, Chung et al. do not exemplify a claimed conjugate compound further comprising anticancer drug, and a linker covalently tethering the targeting ligand to the anticancer drug optionally paclitaxel wherein the linker comprises a C1-C6 moiety optionally a C6 moiety and an amide moiety and optionally wherein the linker further comprises a succinic ester or a pharmaceutically acceptable composition thereof or the claimed method of treating cancer. Chung et al. do not teach a conjugate of one of the above compounds comprising anti-cancer drug and a linker comprising a carboxyl (C1) or succinic (C4) moiety and an amide wherein the linker connects one of the above compounds to the anticancer drug wherein the anticancer drug is paclitaxel.
Liu et al. teach the synthesis of 2’-paclitaxel methyl 2-glucopyranosyl succinate for specific targeted delivery to cancer cells (see title). Liu et al. teach that paclitaxel is a potent anticancer drug used for the treatment of breast, ovarian and lung carcinomas. Among the most notable paclitaxel derivatives synthesized so far are those in which the C-2’ and C-7’ hydroxyl groups of the molecule are engaged in a functional group that collapses, upon in vivo activation, releasing paclitaxel (see pg. 617). Liu et al. teach compound 5
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. Liu et al. teach that although modification on the 2’-hydroxyl group of paclitaxel with succinic acid appeared to reduce the toxicity of paclitaxel on MCF-7 cell growth, this linker maintained the activity of paclitaxel upon the concentration used and could be used for the next conjugation with 2’-glucopyranose (see pg. 618). Liu et al. teach that the conjugation of glucose could reduce the toxicity of paclitaxel and showed the safety on human epithelial cells. It also enhanced the selectivity of glucose uptake and cytotoxicity for cancer cells (see pg. 619). Liu et al. teach fluorescein labeled octreotide conjugated paclitaxel (see pg. 619).
Brush et al. teach non-sulfonated cyanine dyes for labeling nucleosides and nucleotides (see title). Brush et al. teach conjugates of formula
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(col. 2; Fig. 5). Brush et al. describe compound wherein R is (CH2)3OH, (CH2)5COOH, (CH2)3NH2 (col. 3; Figs. 2-4). The linker may contain an amide. Preferrable linkers including propyl-O2C-ethyl-CO and propyl-O2C-ethyl-CONH-hexyl (comprises a C6 group). Preferable linkers are between 3 and 25 carbons in length (col. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compounds of Chung et al. (above cyanine compounds of the claimed targeting ligand formula for cancer imaging and treatment) by further conjugating to compounds an anticancer drug such as paclitaxel using a linker comprising a C1-C6 moiety or C6 moiety and an amide and optionally further comprising a succinic ester as taught by Chung et al, Liu et al. and Brush et al. because the conjugation of an anticancer drug such as paclitaxel using a linker comprising a C1-C6 moiety or C6 moiety and an amide and optionally further comprising a succinic ester moiety would have been expected to enable imaging and selective combination therapy where the cyanine of the claimed targeting ligand formula selectively delivers the anticancer drug to the cancer cells whereby reducing non-selective toxicity of the anticancer drug and because the linker comprising the C1-C6 moiety or C6 moiety and amide and optionally further comprising a succinic moiety would have been expected to provide optimal distancing using well known conjugate linking groups suitable in vivo application and optionally drug release.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compound of Chung et al. by further reacting the OH groups on the (CH2)2OH groups with acetic anhydride to form (CH2)3OAc groups as taught by Chung et al. because it would have been expected to enable a functionally equivalent compounds suitable for targeting cancer cells. Homologs are prima facie obvious.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Chung et al. (method of treating cancer cells) by further administering the obvious conjugate such as a paclitaxel conjugate to a subject in need of treatment with an anticancer drug as taught by Chung et al. and Liu et al. because it would have been expected to advantageously enable treatment of cancer using a conjugate that reduces toxicity of the anticancer drug and enhance selectivity of the anticancer drug and treats the cancer using different mechanisms.
Claim(s) 1, 4-9, and 12-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chung et al. (US 2011/0262354 A1; filed 13 Jan. 2007), in view of Liu et al. (Bioorg. Med. Chem. Lett.; published 2007) and Brush et al. (US 5,986,086; published 1999; see IDS filed on 16 Aug. 2026), in further view of Vlahov et al. (WO 2007/022494 A2; published 22 Feb. 2007) and Safavy et al. (J. Med. Chem.; published 1999).
Chung et al. teach as discussed above.
Chung et al. do not further teach a ligand further comprises a ligand conjugate of recognizing tumor stroma, tumor cells and/or tumor matrices in a tumor microenvironment, optionally wherein the ligand is selected from a growth factor that recognizes cell surface growth factor receptors, or peptide or small molecule that recognizes functional cell surface plasminogen activator, bradykinin or PSMA receptors. Chung et al. do not further teach docetaxel.
Liu et al. teach as discussed above.
Brush et al. teach as discussed above.
Vlahov et al. teach multi-drug conjugates (see title). Vlahov et al. teach conjugates comprising a plurality of drugs (see abstract). Vlahov et al. teach treatment of cancers (pgs. 36, 40). Vlahov et al. teach suitable compounds including cytokines or immune cell growth factors such as interleukins 1-18 (pg. 42) and growth factors like insulin growth factors such as interleukins 1-18 (pg. 29).
Safavy et al. teach paclitaxel derivatives for targeted therapy of cancer (see title). Safavy et al. teach that docetaxel, a semisynthetic derivative of paclitaxel has shown exceptional clinical results and was approved by the FDA for the treatment of breast cancer in 1996 and is now in phase II and III clinical trials for lung cancer and ovarian cancer (see pg. 4919, Fig. 1). Safavy et al. teach that possible advantages for specific delivery include efficient delivery of the drug to micrometastatic tumors and reduction of the administered dose as a result of site-specific deliver of the drug. The latter advantage should lead to a reduction of toxicity, enhancement of efficacy, lower drug doses, and more economic formulation (see pg. 4920). The designated PTXPEGBBN[7-13] showed retention of the BBN/GRP receptor binding property of the its peptide moiety as well as growth inhibition effects and cytotoxicity. Analogues with the paclitaxel moiety substituted at different sites and using different peptides with affinities for different tumor cell surface receptors, as well as conjugates with other types of targeting moieties have been designed and are currently under investigation. The synthesis of these novel molecules may lead to new approaches to more effectively target tumors with the taxane class of antitumor agents (pg. 4922).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chung et al. by further conjugating a compound capable of recognizing tumor stroma, cells, and/or other matrices in the tumor microenvironment such as growth factor that recognizes cell surface growth factor receptors as taught by Vlahov et al. because it would have been expected to enable multivalent targeting providing a broader range of tumor uptake and enhancing solubility.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chung et al. by further substituting the paclitaxel anti-cancer agent of the obvious conjugate with docetaxel as taught by Safavy et al. because the substituting would have been expected to provide an equivalent taxane (structurally similar) advantageously FDA approved for the treatment of breast, lung and ovarian cancer.
Applicants Arguments
Applicants assert that as demonstrated by the Henary/Yadaf reference, chain length in similar compounds can impact cancer cell uptake. Chung’s disclosure is confined to cyanine dyes and their co-administration of “fixed combination” with chemotherapeutics. Chung does not disclose or suggest covalent conjugates in which a cyanine targeting ligand is covalently tethered to an anticancer drug via a linker comprising a C1-C6 moiety or an amide moiety. Lui does not evaluate conjugation to a bulky lipophilic cyanine scaffold. Chen fails to disclose or suggest conjugation of an anticancer to a cyanine dye via a linker comprising a C1-C6 moiety and an amide moiety. The cited references fail to disclose the specific combination of (a) a cyanine targeting ligand of the claimed structure, (b) an anticancer drug, and (c) a linker comprising a C1-C6 moiety and an amide moiety tethering these two components into a single conjugate. The Henary/Yadav reference reports that dyes with a six-carbon N-indolenine substituent exhibited the most favorable cancer cell uptake and selectivity for cancer theranosis, whereas dyes with shorter and longer N-alkyl chains showed inferior performance. The Henary/Yadav reference however demonstrates that even in the absence of a payload, the cyanine scaffold itself is highly sensitive to the length of its N-alkyl side chain, which the chain lengths significantly impacting cancer cell uptake and selectivity. The Henary/Yadav reference shows that the claimed conjugates occupy a structurally and functionally subset of possibilities that the prior art neither disclosed nor rendered obvious.
Applicant's arguments filed 26 Jun. 2026 have been fully considered but they are not persuasive. As an initial matter, the Yadav/Henary reference is not prior art and would not have informed one of ordinary skill in the art before the effective filing date. The Yadav/Henary reference discusses the effects of the N-alkyl chain length chain length of cyanin dyes corresponding to R2 of the targeting ligand in formula of claim 1. It is noted that both R1 and R2 of the targeting ligand of the formula in claim 1 can be a C1-C15 alkyl or alkoxy optional substituted with the defined groups. The Yadav/Henary reference asserts that a 6 carbon chain is optimal and the Yadav/Henary reference asserts that compound 3c would make an excellent probe to conjugate with other anti-cancer drugs and increase the effective. Accordingly, the Yadav/Henary reference does not teach away from the proposed modification to arrive at the claimed conjugates.
The Chung provides for cancer targeting ligands of the formula as defined by the structure in claim 1. At [0020], Chung teaches that the compounds of the invention may be tagged by radioactive groups or other functional groups. At [0005], Chung teaches the conjugation amenable N-hydroxysuccinamide group. At [0122], Chung teaches an active agent and/or conjugate in the blood stream or target tissue. At [0164, Chung teaches combining a targeting ligand of the structure as defined in claim 1 with paclitaxel. Liu teaches that combining a targeting ligand with paclitaxel by conjugation is advantageous as it reduces the off-target toxicity of paclitaxel and enables improved safety. Brush teaches and enables cyanine dye conjugates. 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 Chung by forming the conjugated compound comprising a claimed targeting ligand, an anticancer drug such as paclitaxel and a linker comprising a C1-6 moiety and an amide moiety as taught by Chung, Liu, and Brush because those conjugate compounds would have been expected to advantageously enable treating cancer by different mechanisms and improved safety by reducing off target toxicity.
Conclusion
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
Prosecution Insights