DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Preliminary amendment filed on 03/27/2024 has been entered. Claims 10, 12, 13, 24, and 25 are cancelled. Claims 1-9, 11, and 14-23 are pending in this application and are currently under examination.
Priority
This application is a 371 of PCT/US2022/044948 filed on 09/27/2022 and claims benefit of US PRO 63/261,730 filed on 09/27/2021.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/261,730, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 2 and 19-22 recite “second micelle construct does not comprise a chemotherapeutic agent”, “for up to 14 days (or for 15 to 28 days; or for 28 days or more) after completion of the regimen”, and/or “a polykinase inhibitor is administered at a dosage of about 20mg/m2 to about 200mg/m2 per day”, which are not disclosed or supported by the prior-filed application, Application No. 63/261,730. Thus, the priority date of claims 2 and 19-22 is 09/27/2022.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 03/27/2024 has been considered.
Claim Objections
Claims 1-9, 11, 14, and 15 are objected to because of the following informalities: In claims 1, 2, 14, and 15, change the incorrect recitation “a chemotherapeutic agent” (line 2 of claims 1 and 2; line 3 of claims 14 and 15) to “an additional chemotherapeutic agent” because the preceding “a polykinase inhibitor” encompasses chemotherapeutic agent; also in claim 1, delete the excessive conjunction “and” immediately after the recitation “comprising” (line 4). In claim 3, delete the excessive recitation “curcuminoid” immediately before the recitation “analog” (line 2) because the subsequent recitation “thereof” (line 3) refers back to the preceding “a curcuminoid”. In claim 4, change the redundant recitation “wherein the wherein the” (line 2) to “wherein the”; and delete the excessive recitation “curcuminoid” immediately before the recitation “analog” (line 2) for the reason described in claim 3 above. In claim 5, insert the missing word “additional” immediately before the recitation “chemotherapeutic” (line 2) to connect back to the amended claim 1 above. In claim 6, spell out abbreviated “DSPE” (line 2) to “distearoyl-phosphatidylethanolamine (DSPE)”. In claims 7-9, insert the missing phrase “average size of” immediately after the recitation “wherein” (line 2) to be consistent with scope of the “nm” in the specification. In claim 11, insert the missing phrase “in need thereof” immediately after the recitation “in a subject” (line 1) because treatment is required for those in need, not every subject. 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 3 and 4 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.
Claims 3 and 4 recite “derivative”, which is not defined in the specification and thus it is not clear the metes and bounds of the recitation. Applicant is advised to insert the word “structural” immediately before the recitation “derivative”.
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.
Claims 1-4, 8, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kumari et al. (European Journal of Pharmaceutics and Biopharmaceutics 130:185–199, 2018, hereinafter referred to as Kumari ‘2018) incorporated by Kumari et al. (European Journal of Pharmaceutics and Biopharmaceutics 117:346–362, 2017, hereinafter referred to as Kumari ‘2017) and Ling et al. (MOLECULAR PHARMACOLOGY, 49:832-841, 1996, hereinafter referred to as Ling ‘1996).
With regard to structural limitations “a pharmaceutical regimen comprising: a first micelle construct comprising a polykinase inhibitor (or a curcuminoid; formula 1 or formula 2) or and an additional chemotherapeutic agent; and a second micelle construct comprising a polykinase inhibitor (or does not comprise an additional chemotherapeutic agent)” (claims 1-4), “average size of the first and second micelle constructs are each between 20 nm and 60 nm” (claim 8), and “a method of inhibiting cell growth of a tumor cell, comprising administering a therapeutically effective dosage of the regimen of claim 1 to the tumor cell” (claim 23):
Kumari ‘2018 disclosed synthesis of CD44-targeted DOX loaded nanoparticles (PSHA-DOXNPs) and their anticancer efficacy in combination with curcumin loaded selenium nanoparticles (Se-Cur NPs), previously developed by Kumari et al., 2017. Loading of DOX in PEG-stearyl amine-hyaluronic acid conjugate. The dried PSHA-DOXNPs were obtained after lyophilization. Amphiphilicity is a prerequisite for micellar self-assembly. Conjugation of PEG-stearyl amine chain with HA indicates the introduction of hydrophobicity to the hydrophilic backbone of HA due to long stearyl chains of PEG-stearyl amine. Size of dry PSHA-DOXNPs was found to be ∼25 nm (Fig. 2A) as measured by TEM (page 185, Abstract; page 186, right col., para. 2; page 189, left col., para. 6; right col., para. 2). Cell viability of HCT116 cancer cells treated with individual and combinatorial doses of Se-CurNPs and PSHA-DOXNPs:
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(page 193, Fig. 4B). Kumari ‘2017 (cited here as incorporated by the reference #25) disclosed synthesis of curcumin loaded Se NPs (Se-CurNPs). Surface attachment of curcumin over Se NPs may provide stable NPs carrying a high surface negative charge and may offer sustained release of curcumin. In addition, the stable, nanosized, colloidal particles may facilitate the solubilization of curcumin in the aqueous media. TEM provides the exact size of dry NPs. Se-CurNPs measured ∼57.5 ± 9.6 nm as per the data obtained through TEM (page 358, left col., para. 2; right col., para. 1; page 350, right col., para. 3). Ling ‘1996 (cited here as incorporated by the reference #47) disclosed inhibition of p34cdc2 kinase activity in Dox-treated cells is associated with the prevention of dephosphorylation of this enzyme (page 837, left col., para. 1).
Thus, these teachings of Kumari ‘2018 incorporated by Kumari ‘2017 and Ling ‘1996 anticipate Applicant’s claims 1-4, 8, and 23 because Se-CurNPs meets the limitation of the first micelle construct and the PSHA-DOXNPs meets the limitation of the second micelle construct.
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.
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.
Claims 1-9, 11, and 14-23 are rejected under 35 U.S.C. 103 as being unpatentable over Senn et al. (US 2018/0055949, Mar. 1, 2018, hereinafter referred to as Senn ‘2018, also listed in IDS filed on 03/27/2024) in view of Dash et al. (Pharm Res 34:279–289, 2017, hereinafter referred to as Dash ‘2017).
With regard to structural limitations “a pharmaceutical regimen comprising: a first micelle construct comprising a polykinase inhibitor (or a curcuminoid; formula 1 or formula 2) or and an additional chemotherapeutic agent (or doxorubicin); and a second micelle construct comprising a polykinase inhibitor (or a curcuminoid; formula 1 or formula 2; or does not comprise an additional chemotherapeutic agent)” (claims 1-5), “the first and second micelle constructs are each formed by amphiphilic PEG2000-DSPE polymers; or average size of the first and second micelle constructs are each between 10 nm and 20 nm (or between 20 nm and 60 nm; or less than 30 nm)” (claims 6-8), “a method comprising administering a therapeutically effective dosage of the regimen of claim 1 (or administration of the second micelle construct precedes or follows administration of the first micelle; or the second micelle construct is administered once, twice, or three time per day; or further administering the second micelle construct for up to 14 days, for 15 to 28 days, or for 28 days or more after completion of the regimen of claim 1; or the second micelle construct is administered at a dosage of about 20mg/m2 to about 200mg/m2 per day) to a subject suffering from a sarcoma” (claims 11 and 14-22), and “a method of inhibiting cell growth of a tumor cell, comprising administering a therapeutically effective dosage of the regimen of claim 1 to the tumor cell” (claim 23):
Senn ‘2018 disclosed a method of treating cancer in a subject, comprising providing a composition comprising a micelle construct attached to an inhibitor of NF-kB, and administering a therapeutically effective dosage of the composition to the subject. In another embodiment, the inhibitor of NF-kB is curcumin (or Formula 1:
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; or Formula 2). In one embodiment, the micelle construct further comprises doxorubicin. In one embodiment, the micelle construct is targeted to bind to glut-1 by using a glut-1 antibody as a targeting agent. In one embodiment, the therapeutically effective dosage of the composition comprises 6 mg/kg of curcumin; or the therapeutically effective dosage of the composition comprises 1.5 mg/kg of doxorubicin. In another embodiment, the micelle construct is less than 30 nm. A nanoconjugate is between 20 nm and 50 nm; or less than 60 nm; or less than 20 nm; or the nanoconjugate is enclosed by a micelle (pages 13/28 to 14/28, [0019-0021 and 0024]). FIG. 6 depicts round B study of micellar combination treatment, with DOX constant, GLUT1-CUR variable, applied over 48 hours to HCT-116 cell line.
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. FIG. 7B depicts micellar combination treatment, with DOX constant, and GLUT1-Curcumin variable, applied over 48 hours to breast cancer (MDA-MB231 cell line).
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. FIG. 9 depicts a chart of a in vivo study of Glut1-CUR+DOX constructs using HCT-116 cell line. Nude mice bearing -250 mm3 HCT-116 tumors were treated every 2 days starting at Day 0 (7 total IV injections) at a dose of 4 mg/kg CUR and 0.4 mg/kg DOX.
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. The tumor volume in each group of animals was measured on Day 12. The Cur Micelles group showed a 140% increase in tumor volume. Glut1-Cur Micelles group showed a 46% increase in tumor volume size. Cur+Dox Micelles group showed a 86% increase in tumor volume and Glut1-Cur+Dox Micelles group showed just 6% increase in tumor volume. The combination of anti-Glut1 Ab and curcumin-loaded micelles was the second most potent formulation in tumor growth suppression (page 12/28, [0010, 0012, and 0014]; pages 14/28 to 15/28, [0041-0048]). CUR and/or DOX drug-loaded micelles were prepared by the thin film hydration method. Specific amounts of CUR (3 mg/mL in methanol stock solution) and/or DOX free base (0.5 mg/mL in methanol stock solution) were added to PEG2000-DSPE in chloroform. The 1,2-Di stearoyl-sn-glycero-3 -phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG2000-DSPE) was purchased. Targeted combination micelles were prepared by co-incubating drug-loaded micelles with GLUT1-modified micelles at a ratio of 2 mole % of the reactive polymer, pNP-PEG3400-PE, to PEG2000-DSPE (pages 24/28 to 25/28, [0152, 0153, and 0155].
Senn ‘2018 did not explicitly disclose “a pharmaceutical regimen comprising: a first micelle construct and a second micelle construct”, “administration of the second micelle construct precedes or follows administration of the first micelle; or the second micelle construct is administered once, twice, or three time per day; or further administering the second micelle construct for up to 14 days, for 15 to 28 days, or for 28 days or more after completion of the regimen of claim 1; or the second micelle construct is administered at a dosage of about 20mg/m2 to about 200mg/m2 per day) to a subject suffering from a sarcoma”, required by claims 1-9, 11, and 14-23.
Dash ‘2017 disclosed liposomal curcumin (CurL, 165 nm) and MPEG-PCL micellar curcumin (CurM, 18 nm). CurM was found to be most suitable for solubilization of curcumin whereas CurL can be considered as most suitable nano-formulation for reversal of DOX resistance. To assess safety limit of curcumin in the prepared nano-formulations, cyto-toxicity assay of formulations in curcumin concentration range of 5–40 μM was performed. As shown in the dose response curve (Fig. 4), nano-carrier based systems, CurL and CurM increased the safety levels of curcumin. Curcumin is reported to increase the effectiveness of DOX in breast cancer (cell lines: MDA-MB-468, MDA-MB-231, BT-549, and BT-20), ovarian sarcoma (cell line: M5076), liver cancer (cell line: HA22T/VGH). Furthermore, curcumin reversed DOX resistance in Ehrlich ascites carcinoma, breast cancer (cell lline: MCF7), liver cancer (HepG2), osteosarcoma (cell line: KHOS). CurM was the most amiable formulation for scaling up owing to its minimal preparatory steps and efficient encapsulation. Liposomes and micelles compromised cellular uptake to certain extent but they can provide stability in systemic circulation (page 279, Abstract; page 284, right col., para. 1; page 285, left col., para. 2; page 287, left col., para. 2).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine the teachings of Senn ‘2018 and Dash ‘2017 for treating a cancer or a sarcoma with a micellar curcumin and a micellar curcumin+doxorubicin to maintain the safety level of curcumin in multiple administrations that would also sensitize anticancer activity of doxorubicin at the safety level because (a) Senn ‘2018 teaches that micellar combination treatments, with DOX constant (0.1, 0.2, or 0.4 µM) and GLUT1-CUR at 20 or 15 µM for HCT-116 cell line (or at 40 or 30 µM for MDA-MB231 cell line), are more effective than others with the same amount of DOX but 10 µM or less GLUT1-CUR for HCT-116 cell line (or 20 µM or less GLUT1-CUR for MDA-MB231 cell line), and (b) Dash ‘2017 teaches that nano-carrier based system, CurM, increases the safety levels of curcumin and provides stability in systemic circulation but micelles compromised cellular uptake to certain extent, described above. Thus, one of skill in the art would have a reasonable expectation that by combining the teachings of Senn ‘2018 and Dash ‘2017 for treating a cancer or a sarcoma with a micellar curcumin and a micellar curcumin+doxorubicin to maintain the safety level of curcumin in multiple administrations that would also sensitize anticancer activity of doxorubicin at the safety level; and by optimizing the dosage, dosing schedule, or cycle of administration, one would achieve Applicant’s claims 1-9, 11, and 14-23. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05 [R-01.2024] [II.A].
Conclusion
No claims are allowed.
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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691
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