DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 2/12/2026 is acknowledged. The election of species of compound 4 of Example 1 is also acknowledged. Claims 1, 2, 4, 6, 8-17 and 20-25 are pending, of which claims 4, 6, 12, 15, 21 and 25 are withdrawn as being directed to a non-elected invention or species. Claims 1, 2, 8-11, 13, 14, 16, 17, 20 and 22-24 encompass the elected invention and species and are examined herein on the merits for patentability.
Claim Objections
Claims 9 is objected to because of the following informalities: the claim recites “ofF,” in line 2, rather than “of F,” as a minor typographical error. Appropriate correction is required.
Claims 22-24 are objected to because of the following informalities: the claims recite “odium” lauryl benzene sulfonate” in line 3, rather than “sodium” as a minor typographical error. Appropriate correction is required.
Claims 1, 2, 8-11, 13, 14, 16, 17, 20 and 22-24 are objected to because of the following informalities: the chemical structures in each of claims 1, 6, 8, 11, 15, 16 and 20 appear pixelated and are difficult to read. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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.
The following references, directed to a non-elected species, were found during the search for the elected species or provided in an Information Disclosure Statement, and is provided in the interest of compact prosecution. It should not be interpreted that a comprehensive search was performed for all non-elected species.
Claim(s) 1, 2, 9, 10, 22 and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wu et al. (Analytical Letters, 2004, 37, 711–723).
Wu discloses a hydrophobic near-infrared (NIR) cationic cyanine dye was synthesized and evaluated as a new reagent for the determination of anionic surfactant sodium dodecyl benzenesulfonate (SDBS). The cyanine dye with an absorption maximum at 770 nm reacted with SDBS, causing significant hypochromism. Under the optimal conditions, the decreased absorption is proportional to the concentration of SDBS over the range 2.9 x 1027 –1 x 1025 mol/L. The detection limit was 1.9 x 1027 mol/L. The relative standard deviation for 1.43 x 1026 mol/L SDBS was 1.3%(n = 9). The proposed method was applied to determination of anionic surfactant in the river with 93–106% recovery levels. Preliminary research shows that the hypochromism is due to the formation of dye aggregate facilitated by SDBS (page 711-12).
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Sodium dodecyl benzenesulfonate (95%), (sodium lauryl benzene sulfonate) and Sodium dedocanesulfonate (98%) were obtained from Tokyo Kasei Kogyo Co., Ltd (Tokyo, Japan). Sodium dodecylsulfate (99%) were all obtained from Acros Organics (NJ). An accurately weighed amount of SDBS was dissolved in doubly distilled water to give a 3 x 1023 mol/L stock solution, and the working solution was prepared by diluting the stock solution to the concentration required.
Appropriate volumes of standard SDBS or sample solutions, 1.0 mL of phosphate buffer (pH = 6.2) was transferred into a 10-mL volumetric tube and the mixture was diluted with water to 9.0 mL. Then, 1.0 mL of the dye working solution was added and mixed thoroughly (page 714). It is noted that sodium dodecyl benzenesulfonate is synonymous with sodium lauryl benzenesulfonate.
Such a dye is within the scope of the claims such that R1-8 are H, n1 and n2 are 1, L is a bond and R1 and R2 are alkyl.
It is noted that the recitation of the intended use of the composition as a contrast agent does not distinguish over Wu because the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See In re Casey, 152 USPQ 235 (CCPA 1967) and In re Otto, 136 USPQ 458, 459 (CCPA 1963).
Claim(s) 11, 14, 17 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (Nanoscale, 2019, 11, 2211).
Wang discloses a novel “mosaic type” nanoparticle system (GA-Cy7-NP) for selective drug release targeting hypoxic cancer cells. In this system, hypoxia-targeting near-infrared dye (Cy7) moiety with a positive charge is conjugated to an anti tumor agent, namely, gambogic acid (GA) (abstract). In scheme 1, compound 1 is shown (page 2215):
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The compound encompasses the instant claims such that R1-8 are H, n2 is 1, R21 is alkyl, n1 is 5, L is a bond and R22 is COOH.
GA-Cy7 is also disclosed (page 2215).
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The compound encompasses the instant claims such that R1-8 are H, n2 is 1, R21 is alkyl, n1 is 5, L is a linking group and R22 is a substituted 5 membered heteroaryl group.
GA-Cy7 : surfactin (anionic surfactant) mixtures are Taught in Table 1.
Claim(s) 11, 14 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang (CN 110075299).
Wang discloses pentamethine cyanine dye structure to human epidermal growth factor receptor (EGFR) targeting drug molecular structure obtained by splicing. the compounds of the present invention can be used as a low oxygen and EGFR-targeted near infrared fluorescent probe, a low oxygen state by targeting tumor marker EGFR and tumour cells can reach the purpose of malignant tumour focus accurate imaging of high expression of EGFR; in addition, the compounds of the present invention can also be used as a photosensitizer for cancer treatment. An exemplary compound is compound 14.
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The compound encompasses the instant claims such that R1-8 are H, n2 is 1, R21 is alkyl, n1 is 5, L is a linking group and R22 is a substituted aryl.
Claim(s) 11, 14 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Small (WO 20/190735).
Small discloses NIR dyes of general formula I, including the compound shown in Scheme II:
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(page 6).
The compound encompasses the instant claims such that R1-8 are H, n2 is 3, R21 is alkyl, n1 is 5, L is a bond and R22 is COOH.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 2, 8, 9, 10, 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (Analytical Letters, 2004, 37, 711–723) in view of Bazin (US 2010/0143960).
Wu teaches a hydrophobic near-infrared (NIR) cationic cyanine dye was synthesized and evaluated as a new reagent for the determination of anionic surfactant sodium dodecyl benzenesulfonate (SDBS). The cyanine dye with an absorption maximum at 770 nm reacted with SDBS, causing significant hypochromism. Under the optimal conditions, the decreased absorption is proportional to the concentration of SDBS over the range 2.9 x 1027 –1 x 1025 mol/L. The detection limit was 1.9 x 1027 mol/L. The relative standard deviation for 1.43 x 1026 mol/L SDBS was 1.3%(n = 9). The proposed method was applied to determination of anionic surfactant in the river with 93–106% recovery levels. Preliminary research shows that the hypochromism is due to the formation of dye aggregate facilitated by SDBS (page 711-12).
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Sodium dodecyl benzenesulfonate (95%), or sodium lauryl and Sodium dedocanesulfonate (98%) were obtained from Tokyo Kasei Kogyo Co., Ltd (Tokyo, Japan). Sodium dodecylsulfate (99%) were all obtained from Acros Organics (NJ). An accurately weighed amount of SDBS was dissolved in doubly distilled water to give a 3 x 1023 mol/L stock solution, and the working solution was prepared by diluting the stock solution to the concentration required.
Appropriate volumes of standard SDBS or sample solutions, 1.0 mL of phosphate buffer (pH = 6.2) was transferred into a 10-mL volumetric tube and the mixture was diluted with water to 9.0 mL. Then, 1.0 mL of the dye working solution was added and mixed thoroughly (page 714). It is noted that sodium dodecyl benzenesulfonate is synonymous with sodium lauryl benzenesulfonate.
Such a dye is within the scope of the claims such that R1-8 are H, n1 and n2 are 1, L is a bond and R1 and R2 are alkyl.
It is noted that the recitation of the intended use of the composition as a contrast agent does not distinguish over Wu because the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See In re Casey, 152 USPQ 235 (CCPA 1967) and In re Otto, 136 USPQ 458, 459 (CCPA 1963).
With regard to claim 8, Wu teaches an iodide salt of the cyanine rather than bromide.
Bazin teaches fluorescent cyanine derivatives of Formula I.
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The cyanine derivatives of formula (I) of the invention comprise a counterion "Z" (not represented) which counterbalances the positive or negative charge or charges of the cyanine derivative. The nature of the counterion is not essential according to the invention; it depends on the synthesis process employed or on the medium in which the cyanine derivatives occur.
For example, Z will be: I- in the case of an alkylation by an iodide, such as, for example, …CF3COO- or HCOO- in the case of purification by reverse phase HPLC in the presence respectively of trifluoroacetic acid or of formic acid.
Advantageously, the counterion Z is chosen from I-, Cl-, Br-, CF3COO-, HCOO- or Na+ (paragraph 0082-88).
It would have been obvious to substitute bromide for iodide as a functionally equivalent salt in the cyanine dye compositions taught by Wu when the teaching of Wu is taken in view of Bazin. One would have been motivated to do so, with a reasonable expectation of success, because Bazin teaches that a cyanine dye may be charge balanced by either bromide or iodide, and that the nature of the counterion is not essential according to the invention; it depends on the synthesis process employed or on the medium in which the cyanine derivatives occur.
Claim(s) 1, 2, 8-11, 13, 14, 16, 17, 20 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Nanoscale, 2019, 11, 2211) in view of Luo et al. (Biomaterials, 2013, 34, 2244-51).
Wang teaches a novel “mosaic type” nanoparticle system (GA-Cy7-NP) for selective drug release targeting hypoxic cancer cells. In this system, hypoxia-targeting near-infrared dye (Cy7) moiety with a positive charge is conjugated to an anti tumor agent, namely, gambogic acid (GA) (abstract). In scheme 1, compound 1 is shown (page 2215):
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The compound encompasses the instant claims such that R1-8 are H, n2 is 1, R21 is alkyl, n1 is 5, L is a bond and R22 is COOH.
GA-Cy7 is also disclosed (page 2215).
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GA-Cy7 : surfactin (anionic surfactant) mixtures are Taught in Table 1.
Wang does not teach wherein a Cy7 derivative is conjugated to an alkyl or phenyl as an anticancer agent through the carboxylic moiety of the precursor compound.
Luo teaches that certain indocarbocyanine, thiacarbocyanine, and oxacarbocya nine dyes (wavelength below 600 nm) in high concentration have been revealed with mitochondrial toxicity to preferentially inhibit the NADH-ubiquinone reductase. The increased mitochondrial cytotoxicity of these dyes is shownatleastpartiallyin correlation to the increased length of alkyl chains. Because mitochondria are encircled with two specialized (outer and inner) lipophilic membranes and lipophilic agents are more readily transported across bistratal membranes to reach a higher concentration. Therefore, increasing lipophilicity of a mitochondrial toxic compound with suitable lipid/water partition coefficient may also improve its cytotoxicity. Basing on these investigations, we hypothesized that the chemical modification of IR-808 by increasing the alkyl side-chains length and the lipophilicity could enhance its cytotoxic activity. To testify this hypothesis, we screened a series of IR-808 analogs and IR-808DB, a butyl ester derivative of IR-808, was identified with simultaneous cancer targeted NIR imaging and potent anticancer activities. Here, we describe the chemical synthesis and biological characterization of this newly developed multifunctional dye.
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The anticancer activity of each ester derivative was evaluated initially in vitro on A549 human lung cancer cells, which has been widely used for screening of anticancer drugs. Studies showed that these ester derivatives exhibited diverse anticancer activities on A549 carcinoma cells. Figure 3 shows in vitro anticancer activity, a) the IC50 values of IR-808, IR-808DB, IR-808DH, IR-808DCH, IR-808DP, Rho123, IR-783 on cultured A549 lung cancer cells for 48 h. Of these, IR-808DB displayed remarkable anticancer activity with an IC50 of 0.43 mM (page 2247).
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute an alkyl or phenyl ester as functionally equivalent anticancer agents conjugated to a cyanine dye as taught by Wang when the teaching of Wang is taken in view of Luo. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known anticancer moiety for another via an ester linkage, and the results of the substitution would have been predictable, that is provision of an anticancer agent linked to a cyanine derivative for use in cancer treatment and detection.
Claim(s) 11, 13, 14, 16 17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Small (WO 20/190735) in view of Luo et al. (Biomaterials, 2013, 34, 2244-51).
Small teaches the design, synthesis, and functionalization of a conjugate including a tumor-targeting near-infrared (NIR) dye and a therapeutic agent and/or a diagnostic agent, whereby the NIR dye can function to target the therapeutic agent and/or diagnostic agent to tumor cells.
Generally, the instant invention details the use of tumor-targeting near-infrared (NIR) dyes in conjunction with a variety of therapeutic agents. In particular, the instant invention discloses the use of metal nanoparticles, magnetic nanoparticles, so-called“lossy dielectric materials,” chemotherapeutic agents, nitroxide radicals, photodynamic therapy agents, and photothermal therapy agents conjugated with a tumor-targeting NIR dye as a potentially effective treatment for various cancers. The NIR dye can target only malignant, cancerous cells in the body, bypassing healthy tissues, and can deliver the therapeutic agent to the appropriate site in the body, thus preventing or minimizing the harmful side-effects of many conventional cancer treatments when used without tumor-targeting technology (page 1).
The instant invention may provide an effective and versatile delivery method which combines tumor-targeting near-infrared (NIR) dyes with various cancer therapeutic agents and/or cancer diagnostic agents for (i) targeting tumor cells and/or (ii) killing tumor cells and/or (iii) imaging tumor cells.
As to particular embodiments, the instant invention may combine tumor-targeting fluorescent NIR dyes with various agents to create conjugates for the treatment and/or detection of various cancers, whereby these conjugates could be delivered directly to the tumor site, in contrast to conventional agents which may be non-specifically delivered and thus, may cause significant adverse side effects (page 3).
NIR dyes of general formula I are taught
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including the compound shown in Scheme II:
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(page 6).
The NIR dye can be asymmetrical. As but one illustrative example, a particular embodiment of an asymmetrical NIR dye which may be useful with the instant invention can be synthesized according to Scheme II.
As to particular embodiments, one or more of Ri-Rs or Y as shown in Formula I can be used as a linking site to covalently attach the linker and the therapeutic or diagnostic agent to the NIR dye to form the instant conjugate. In other particular embodiments, the linking site can be via the nitrogen of an indole moiety, whereby the therapeutic or diagnostic agent can be either mono- or bis- linked, as shown in Formula III (page 9).
An anticancer agent, DOX linked to an asymmetrical NIR dye is shown on page 32.
Small does not teach wherein the carboxylic acid is conjugated as an alkyl or aryl ester as an anticancer moiety.
Luo teaches that certain indocarbocyanine, thiacarbocyanine, and oxacarbocya nine dyes (wavelength below 600 nm) in high concentration have been revealed with mitochondrial toxicity to preferentially inhibit the NADH-ubiquinone reductase. The increased mitochondrial cytotoxicity of these dyes is shownatleastpartiallyin correlation to the increased length of alkyl chains. Because mitochondria are encircled with two specialized (outer and inner) lipophilic membranes and lipophilic agents are more readily transported across bistratal membranes to reach a higher concentration. Therefore, increasing lipophilicity of a mitochondrial toxic compound with suitable lipid/water partition coefficient may also improve its cytotoxicity. Basing on these investigations, we hypothesized that the chemical modification of IR-808 by increasing the alkyl side-chains length and the lipophilicity could enhance its cytotoxic activity. To testify this hypothesis, we screened a series of IR-808 analogs and IR-808DB, a butyl ester derivative of IR-808, was identified with simultaneous cancer targeted NIR imaging and potent anticancer activities. Here, we describe the chemical synthesis and biological characterization of this newly developed multifunctional dye.
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The anticancer activity of each ester derivative was evaluated initially in vitro on A549 human lung cancer cells, which has been widely used for screening of anticancer drugs. Studies showed that these ester derivatives exhibited diverse anticancer activities on A549 carcinoma cells. Figure 3 shows in vitro anticancer activity, a) the IC50 values of IR-808, IR-808DB, IR-808DH, IR-808DCH, IR-808DP, Rho123, IR-783 on cultured A549 lung cancer cells for 48 h. Of these, IR-808DB displayed remarkable anticanceractivity with an IC50 of 0.43 mM (page 2247).
It would have been obvious to one of ordinary skill in the art to provide an alkyl or aryl moiety on the carboxylic acid moiety of Small’s conjugate precursor as a anticancer therapeutic agent when the teaching of Small is taken in view of Luo. One would have been motivated to do so because Small teaches that diagnostic or therapeutic moieties may be linked to a cyanine dye, and that the linking site can be via the nitrogen of an indole moiety, whereby the therapeutic or diagnostic agent can be either mono- or bis- linked. One would have had a reasonable expectation of success in doing so, because Luo teaches that increasing lipophilicity of a mitochondrial toxic compound with suitable lipid/water partition coefficient may also improve its cytotoxicity, and that alkyl or phenyl linked IR808 derivatives show anti-cancer activity.
Regarding alkyl chain length at positions R1 and R2, it would have been obvious to optimize alkyl chain length as providing homologous compounds as a matter of routine optimization. As a methyl group (C1) is homologous to an ethyl group (C2) as recited in the claim, it is considered that one of ordinary skill in the art would have found it obvious to provide the ethyl group homolog with the expectation of providing similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Claim(s) 1, 2, 8-11, 13, 14, 16, 17, 20 and 22-24 are rejected under 35 U.S.C. 103 as being unpatenable over Small (WO 20/190735) in view of Luo et al. (Biomaterials, 2013, 34, 2244-51), in further view of Ho (WO 14/028057).
The rejection over Small in view of Luo is applied as above.
Small and Luo do not specifically recite wherein a compound of Formula I in combination with an anionic surfactant.
Ho teaches a conjugate comprising a prostate specific antigen targeting moiety; and (iii) an optional Pharmacokinetic (PK) modifier chemically linked to the prostate specific antigen targeting moiety. In certain embodiments, the imaging reporter is a fluorescent moiety (paragraph 0012). Exemplary fluorochromes include but are not limited to a carbocyanine fluorochrome and an indocyanine fluorochrome (paragraph 0051 and claims 18+).
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more agents of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
In certain embodiments, the invention provides a pharmaceutically acceptable composition suitable for administration to a subject comprising a prostate specific antigen imaging agent and a pharmaceutically acceptable excipient (paragraph 0181-3).
The rejection over Small and Luo is applied as above. It would have been obvious to one of ordinary skill in the art to provide a compound of Formula I in combination with an anionic surfactant when the teachings of Small and Luo are taken in view of Ho. Small and Ho are directed to diagnostic/therapeutic cyanine dye conjugates. One would have been motivated to do so, with a reasonable expectation of success, as a means of formulating the cyanine conjugates using conventional pharmaceutical excipients because Ho teaches that cyanine dye conjugates are suitably formulated with wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate; and that the pharmaceutical compositions may be suitable for parenteral administration comprise one or more agents of the invention in combination with one or more acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618