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 .
1. Claims 1-17 are pending and being examined.
Specification
2. The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. Examiner suggests a title relevant to micelle constructs comprising curcumin.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
3. Claim(s) 1-7 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tang et al (Polymer Preprints, 2009, 50:322).
Tang et al made a pharmaceutical composition comprising curcumin micelle loaded with chemotherapeutic doxorubicin (DOX) or campothethin (CPT) (Scheme 1; Experimental section); wherein the micelle construct of the composition ranged in size from about 8 nm to about 100 nm with an average diameter of 33 nm (Figure 3; p. 2, col. 1-2). Tang et al demonstrate successfully killing human ovarian cancer cells contacted with curcumin micelle nanoparticles loaded with chemotherapeutics doxorubicin (DOX) or campothethin (CPT) (2nd page), and teach curcumin is an NF-kB inhibitor that is known to be cytotoxic against many cancer cell lines of human origin including breast cancer cells and colon cancer cells (Introduction). HCAPlus data base identifies Tang et al as disclosing curcumin 1,6-Heptadiene-3,5-dione, 1,7-bis(4-hydroxy-3-methoxyphenyl)-, (1E,6E)-(CA INDEX NAME) of instant Formula 2:
L69 ANSWER 37 OF 43 HCAPLUS COPYRIGHT 2022 ACS on STN
ACCESSION NUMBER: 2009:339264 HCAPLUS Full-text
DOCUMENT NUMBER: 151:107823
TITLE: Curcumin-polyethylene surfactant as anticancer
prodrugs and drug carriers
AUTHOR(S): Tang, Huadong; Murphy, Cattlin Jean; Zhang, Bo; Shen,
Youqing; Cremeans, Kellee Dawn; Van Kirk, Edward Alva;
Murdoch, William J.
CORPORATE SOURCE: Department of Chemical & Petroleum Engineering,
University of Wyoming, Laramie, WY, 82071, USA
SOURCE: Polymer Preprints (American Chemical Society, Division
of Polymer Chemistry) (2009), 50(1), No pp. given
CODEN: ACPPAY; ISSN: 0032-3934
URL: http://pubs.acs.org/cgi-
bin/preprints/display?div=poly&meet=237&page=181.pdf
PUBLISHER: American Chemical Society, Division of Polymer
Chemistry
DOCUMENT TYPE: Journal; (online computer file)
LANGUAGE: English
ED Entered STN: 20 Mar 2009
AB A curcumin-PEG surfactant was synthesized and shown to have higher
toxicity to human ovarian cancer cells than curcumin alone. Curcumin-PEG
surfactant could also form nanoparticles in water to carry anticancer
drugs such as doxorubicin and camptothecin. Thus, the surfactant has
roles as a carrier of antitumor drugs and prodrugs.
IT 458-37-7, Curcumin
RL: RCT (Reactant); RACT (Reactant or reagent)
(curcumin-polyethylene surfactant as anticancer prodrugs and drug
carriers)
RN 458-37-7 HCAPLUS
CN 1,6-Heptadiene-3,5-dione, 1,7-bis(4-hydroxy-3-methoxyphenyl)-, (1E,6E)-
(CA INDEX NAME)
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4. Claim(s) 1-9, 13, and 14 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent Application Publication 2013/0330412, Maitra et al, claiming priority to December 10, 2010.
Maitra et al teach a cancer-treating nanoparticle composition comprising a polymeric micelle, combination of doxorubicin + curcumin (“NanoDoxCurc” (NDC)) conjugated to the micelle (abstract, [4-8]; [12-17]; [34-35]; Figures 13-16; [52-58]; Examples 1-4 and 9; claims), wherein the nanoparticle is less than 50nm, which encompasses sizes less than 30nm as instantly claimed (Figures 1 and 4; [12]; [16]; [18]; [21]; [34]; [49]; claims 3, 5, 10, and 13); and is in a pharmaceutically acceptable carrier ([13]; claims). Maitra et al teach administering their composition to human cancer patients to treat multi-drug resistant (MDR) cancers, wherein NDC is able to overcome the multi-drug resistant phenotype, induce xenograft regression and significantly enhance survival compared to doxorubicin formulations alone. Maitra et al teach that the NDC formulation has the advantages of overcoming MDR phenotype in cancer cells and reduces systemic adverse effects of the chemotherapeutics in advanced cancer, allowing an increase in cumulative dose of chemotherapeutics without an amplification of adverse effects (abstract; [17]; [56]; [58]; Example 9). Maitra et al purchased curcumin from Sabinsa ([74]) and HCAPlus data base identifies Maitra et al as disclosing curcumin 1,6-Heptadiene-3,5-dione, 1,7-bis(4-hydroxy-3-methoxyphenyl)-, (1E,6E)-(CA INDEX NAME) of instant Formula 2.
L69 ANSWER 11 OF 43 HCAPLUS COPYRIGHT 2022 ACS on STN
ACCESSION NUMBER: 2012:847752 HCAPLUS Full-text
DOCUMENT NUMBER: 157:56328
TITLE: Smart polymeric nanoparticles which overcome multidrug
resistance to cancer chemotherapeutics and
treatment-related systemic toxicity
INVENTOR(S): Maitra, Anirban; Pramanik, Dipankar
PATENT ASSIGNEE(S): The Johns Hopkins University, USA
SOURCE: PCT Int. Appl., 64pp.
CODEN: PIXXD2
DOCUMENT TYPE: Patent
LANGUAGE: English
FAMILY ACC. NUM. COUNT: 2
PATENT INFORMATION:
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------------- --------
WO 2012078831 A2 20120614 WO 2011-US63870 20111208
WO 2012078831 A3 20121115
CA 2821109 A1 20120614 CA 2011-2821109 20111208
EP 2648760 A2 20131016 EP 2011-847391 20111208
US 20130330412 A1 20131212 US 2013-13992777 20130819
PRIORITY APPLN. INFO.: US 2010-61421709 P 20101210
WO 2011-US63870 W 20111208
PATENT STATUS PATENT INFORMATION:
PATENT NO. KIND STATUS STATUS DATE
--------------- ---- ------------- -----------
WO 2012078831 A2 Dead 20201202
WO 2012078831 A3 Dead 20201202
CA 2821109 A1 Dead 20201121
EP 2648760 A2 Dead 20201203
US 20130330412 A1 Dead 20201121
ASSIGNMENT HISTORY FOR US PATENT AVAILABLE IN LSUS DISPLAY FORMAT
OTHER SOURCE(S): CASREACT 157:56328; CASFORMULTNS 2012:847752
ED Entered STN: 15 Jun 2012
AB Polymeric nanoparticles with a hydrophobic core that encapsulates curcumin
and a hydrophilic shell with one or more chemotherapeutic agents (e.g.,
doxorubicin) assocd. with the shell surface are formed from
N-isopropylacrylamide (NIPAAM), acrylic acid (AA), and at least one vinyl
monomer selected from the group consisting of vinyl acetate,
4-vinylbenzoic acid, Me methacrylate, vinyl methacrylate,
N-vinylpyrrolidone, N-vinylpiperidone, N-vinylcaprolactam,
N-vinylcarbazole, and styrene, where the NIPAAM, the AA, and the vinyl
monomer are present at molar ratios of 50-70:10-30: 10-30 for
NIPAAM:AA:vinyl monomer. These nanoparticles effectively overcome
multidrug resistance and ameliorate cardiomyopathy in vivo.
IT 458-37-7, Curcumin
RL: BSU (Biological study, unclassified); THU (Therapeutic use); BIOL
(Biological study); USES (Uses)
(smart polymer nanoparticles which overcome multidrug resistance and
treatment-related systemic toxicity)
RN 458-37-7 HCAPLUS
CN 1,6-Heptadiene-3,5-dione, 1,7-bis(4-hydroxy-3-methoxyphenyl)-, (1E,6E)-
(CA INDEX NAME)
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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.
5. Claims 8-17 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2013/0330412, Maitra et al, claiming priority to December 10, 2010; in view of Tang et al (Polymer Preprints, 2009, 50:322), Ma et al (Journal of Biomedical Material Research, 2008, 86A:300-310); and Lim et al (Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 April 17-21; Washington, DC, Philadelphia (PA):AACR; Cancer research 2010; 70(8 Suppl): Abstract nr 440).
Maitra et al teach as set forth above. Maitra et al teach doxorubicin is widely used as a cancer chemotherapeutic in many cancer treating regimens ([58]). Maitra et al further demonstrate in Example 9 that NDC successfully treated MDR human prostate cancer xenografts in vivo. Maitra et al teach:
[0103] In conclusion, this Example shows that we designed an exemplary composite polymeric nanoparticle, which has doxrorubicin covalently bound to the surface of the nanoparticle, and curcumin encapsulated within its inner core. This composite nanoparticle (NDC) can unequivocally overcome multidrug resistance as demonstrated by monitoring expression of MDR proteins and drug uptake, which translates into significant improvements in in vivo efficacy against DOX-resistant xenografts and syngenic ascites. Additionally, NDC shows significantly reduced cardiotoxicity in mice receiving high cumulative doses due to the cardioprotection afforded both by the nanoparticle itself, and by the encapsulated highly-bioavailable curcumin. Such composite nanoparticles have great promise for clinical translation, as they directly address multiple challenges by both overcoming resistance and enhancing safety, effectively ‘killing two birds with one stone.”
Maitra et al do not teach the cancer treated is breast, colon, or brain cancer.
Tang et al demonstrate successfully killing human ovarian cancer cells contacted with curcumin micelle nanoparticles loaded with chemotherapeutics doxorubicin (DOX) or campothethin (CPT) (2nd page), and teach curcumin is an NF-kB inhibitor that is known to be cytotoxic against many cancer cell lines of human origin including breast cancer cells and colon cancer cells (Introduction). Tang et al teach the micelle construct of the composition ranged in size from about 8 nm to about 100 nm with an average diameter of 33 nm (Figure 3; p. 2, col. 1-2).
Ma et al teach curcumin augments chemotherapeutic responses to many chemotherapeutics including gemcitabine, paclitaxel, cisplatin, celecoxib and vinorelbine (p. 300, col. 2 to p. 301, col. 1). Ma et al produced curcumin micelles utilizing curcumin of instant Formula 2 (Materials) to successfully induce cell death of several different cancer cells including B16-F10 mouse melanoma cells, SP-53, JeKo-1 and Mino human mantle cell lymphoma cells (p. 305, col. 2 to p. 306, col. 2). Ma et al teach that micelle-encapsulated curcumin was significantly less toxic than free curcumin at higher doses (p. 309, col. 1).
Lim et al demonstrate nanoparticle-encapsulated curcumin successfully decreased cell growth of multiple human brain cancer cells including glioblastoma and medulloblastoma. Lim et al teach curcumin has been shown to target multiple pathways in different tumor types (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat breast, colon or brain cancer in the method of Maitra et al. One would have been motivated to because: (1) Maitra et al teach doxorubicin is widely used as a cancer chemotherapeutic in many cancer treating regimens; (2) Lim et al teach curcumin has been shown to target multiple pathways in different tumor types including brain cancer; and (3) Tang et al teach curcumin is an NF-kB inhibitor that is known to be cytotoxic against many cancer cell lines of human origin including breast cancer cells and colon cancer cells. One of ordinary skill in the art would have a reasonable expectation of success treating breast, colon or brain cancer in the method of Maitra et al given: (1) all of the cited references teach or demonstrate successfully killing a wide variety of cancer cell types by administering nanoparticle curcumin or curcumin micelle loaded with chemotherapeutic CPT or DOX; and (2) Ma et al teach it is known curcumin augments chemotherapeutic responses to many different types of chemotherapeutics.
6. Claim(s) 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 8,697,098, Perumal et al, claiming priority to February 2011; in view of US Patent Application Publication 2013/0330412, Maitra et al, claiming priority to December 10, 2010; and Gou et al (Nanoscale, 2011, 3:1558-1567).
Perumal et al patented in their claims:
1. A stable micelle comprising:
1) an amphiphilic copolymer containing at least one hydrophobic moiety covalently conjugated to at least one hydrophilic moiety, wherein said at least one hydrophobic moiety is a prolamine protein selected from the group consisting of zein, gliadin, hordein, kafirin, and combinations thereof; and
2) one or more cargo molecules,
wherein the critical micelle concentration (CMC) of the copolymer in water is between about 0.015 g/L to about 0.035 g/L, and wherein said stable micelle has a biodegradable hydrophilic shell-hydrophobic core structure.
2. The stable micelle of claim 1, wherein said amphiphilic copolymer is a block copolymer or a graft copolymer.
3. The stable micelle of claim 1, wherein the at least one hydrophobic moiety is a zein protein and the at least one hydrophilic moiety is a PEG, and wherein peglyation results in at least one PEG moiety per zein moiety.
6. The stable micelle of claim 3, wherein the molecular weight of PEG is between about 1 kpa and 270 kDa.
7. The stable micelle of claim 3, wherein the micelle particle size is from about 10 nm to about 300 nm.
8. The stable micelle of claim 1, wherein said one or more cargo molecules are encapsulated within the hydrophobic core, covalently or non-covalently complexed to the hydrophobic moiety, covalently or non-covalently complexed to the hydrophilic moiety, or a combination thereof.
9. The stable micelle of claim 8, wherein the one or more cargo molecules are selected from the group consisting of a drug, a protein, a nucleic acid, a hormone, a receptor, a diagnostic agent, an imaging agent, and a combination thereof.
10. The stable micelle of claim 9, wherein the drug is a hydrophobic drug having a Log P of about 1 to 7.
11. The stable micelle of claim 9, wherein the drug is an anti-oxidant, anti-inflammatory, or an anticancer drug, and wherein the drug delivered via the stable micelle exhibits lower toxicity and enhanced efficacy compared to the drug delivered in the absence of said stable micelle.
12. The stable micelle of claim 11, wherein the drug is curcumin or doxorubicin.
20. A method of treating a P-glycoprotein (P-gp)-dependent multidrug resistant (MDR) cancer, wherein said P-gp is over-expressed, a skin or follicular disorder in subject in need thereof comprising administering the stable micelle of claim 11, wherein said cancer exhibits over-expression of P-gp.
Perumal et al teach and successfully exemplify making PEGylated zein micelle constructs comprising doxorubicin (Example 2, Figure 1) or curcumin (Example 3) through thin film hydration methods (col. 3, lines 20-29; col. 25, lines 32-41; col. 26; Examples 2 and 3), resulting average particle sizes of 125±15 nm (Figure 23, col. 8, lines 32-37) and 90±10 nm (Figure 12, col. 7, lines 13-19), respectively. Perumal et al teach one can make smaller sized micelle constructs (nanomicelles) by lowering the drug to PEG-zein ratio (col. 26, lines 7-9; col. 12, lines 45-54; Figure 1).
Perumal et al teach the structure of curcumin comprises:
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Perumal et al teach and suggest the micelles comprise a plurality of cargo molecules that are one or more drugs, and suggest the drugs can be curcumin and doxorubicin (col. 2, lines 32-39; claim 12 and 19). Perumal et al teach the micelle construct is comprised in a pharmaceutical composition with a pharmaceutically acceptable carrier (col. 2, lines 46-50; col. 28, lines 18-46) Perumal et al teach and demonstrate the function of the micelle constructs is to: (1) inhibit p-glycoprotein (P-gp) efflux pumps; (2) enhance uptake of the encapsulated drug in a drug-resistant cancer cell; (3) enhance water solubility of lipophilic compounds by encapsulating them in the micelle for delivery; (4) enhance chemical stability of the encapsulated drug; and (6) enhance accumulation of the encapsulated drug in tumor tissue as compared to normal tissues (col. 3, lines 55 to col. 4, lines 7; col. 4, lines 30-54; col. 26, lines 17 to col. 27, line 15; Examples 2 and 3; Figures 30, 32-35). Perumal et al teach administering the micelle construct to subjects to treat cancer, including breast cancer, colon cancer, and glioblastoma, particularly multidrug resistant (MDR) cancer overexpressing P-gp. Perumal et al exemplify (1) successfully inhibiting P-gp in drug resistant cancer cells by administering their micelle constructs, (2) successfully increasing in vivo drug resistant breast tumor tissue uptake of micelle constructs containing doxorubicin, (3) successfully reducing tumor growth and increasing survival with micelle constructs containing doxorubicin as compared to free doxorubicin, (4) successfully enhancing efficacy of doxorubicin therapeutic effects by micelle encapsulation compared to free doxorubicin; and (5) successfully reducing the toxicity of doxorubicin by encapsulation in micelles (col. 5, lines 49-57; col. 26, lines 33-54; col. 30, lines 23-36; Example 2, Figures 30, 32-35; col. 37, lines 34-36; claim 20).
Perumal et al do not exemplify combining curcumin and doxorubicin together in the micelle construct and do not exemplify making smaller constructs in the 20-60 nm or 10-20 nm range.
Combining curcumin and doxorubicin in same construct:
Maitra et al teach a cancer-treating nanoparticle composition comprising a polymeric micelle and combination of doxorubicin + curcumin (“NanoDoxCurc” (NDC)) conjugated to the micelle (abstract, [4-8]; [12-17]; [34-35]; Figures 13-16; [52-58]; Examples 1-4 and 9; claims) and is in a pharmaceutically acceptable carrier ([13]; claims). Maitra et al teach administering their composition to human cancer patients to treat multi-drug resistant (MDR) cancers, wherein NDC is able to overcome the multi-drug resistant phenotype, induce xenograft regression and significantly enhance survival compared to doxorubicin formulations alone. Maitra et al teach that the NDC formulation has the advantages of overcoming MDR phenotype in cancer cells and reduces systemic adverse effects of the chemotherapeutics in advanced cancer, allowing an increase in cumulative dose of chemotherapeutics without an amplification of adverse effects (abstract; [17]; [56]; [58]; Example 9).
Maitra et al teach the motivation for combining curcumin with doxorubicin in a nanoparticle composition:
[17] Resistance to cancer chemotherapy is a major cause for treatment failure and disease progression in cancer. One of the most important reasons for treatment resistance is the development of multidrug resistance (MDR) phenotype, which arises as a result of upregulation of various drug efflux transporter proteins. There are three major drug efflux transport proteins in human cancers: MDR1/ABCB1 (a.k.a P-glycoprotein), MRP-1/ABCC1 and ABCG2/BCRP. Upregulation of various MDR proteins is observed in many human cancers, particularly in advanced disease, which results in efflux of commonly used chemotherapeutic agents administered in these cancers, such as the anthracyclines (doxorubicin, daunorubicin), paclitaxel and other taxanes, cisplatin and other platinum compounds, topoisomerase inhibitors, etc. While MDR can be overcome to some extent by using higher dosages of chemotherapeutics, this in turn, can lead to systemic side effects in other organs, such as cardiotoxicity, nephrotoxicity, gastrointestinal toxicity, and bone marrow suppression, amongst others. A formulation that can overcome the MDR phenotype in cancers, while at the same reducing systemic adverse effects (i.e. killing two birds with one stone), would be of considerable value in clinical oncology. An embodiment of this invention presents a formulation of a composite polymeric nanoparticle that comprises curcumin in its hydrophobic core, and doxorubicin conjugated to the hydrophilic surface (NanoDoxCurc). Curcumin, derived from the Indian spice turmeric, is a potent inhibitor of all three MDR proteins, and allows the doxorubicin to accumulate within its site of action (the nucleus) in cancer cells without being effluxed. In multiple cancer models with high MDR protein expression and specifically selected for doxorubicin resistance (human prostate cancer, human multiple myeloma, human ovarian cancer, and murine leukemia), NanoDoxCurc is able to overcome the MDR phenotype, and either induce xenograft regression or significantly enhance survival compare to doxorubicin formulation alone. Notably, the effects of NanoDoxCurc are observed irrespective of the MDR protein expressed, suggesting that curcumin is a potent “pan-inhibitor” of all three MDR proteins. Importantly, in addition to its effects on cancer cells, we also observe that NanoDoxCurc is able to significantly attenuate the systemic adverse effects of doxorubicin on other organs systems, particularly the heart and bone marrow. This is highly clinically significant because one of the most reasons for dose limiting toxicity with doxorubicin is its adverse effect on the myocardium, with long term cardiomyopathy developing in patients who receive greater than a certain cumulative dose of the drug. In animal studies, using equivalent doses of free doxorubicin, pegylated liposomal doxorubicin (Doxil) and NanoDoxCurc we observe unequivocal echocardiographic evidence of cardiac toxicity with both doxorubicin and Doxil, while NanoDoxCurc demonstrates no evidence of cardiac side effects. Similarly, we observe clear cut evidence of hematological toxicity with doxorubicin and Doxil, while NanoDoxCurc shows no effects on the bone marrow at equivalent doses. Investigations have also confirmed that curcumin attenuates reactive oxygen species (ROS) induced cardiomyocyte damage, which are a byproduct in the heart of doxorubicin administration. Thus, in a preferred embodiment, the invention is a composite nanoparticle that serves a dual purpose of (a) overcoming MDR phenotype in cancer cells induced by multiple MDR proteins, while at the same time (b) reducing systemic adverse effects of the chemotherapeutic (doxorubicin in the example) in non-cancerous tissues. In addition to improving the efficacy of chemotherapeutics in advanced cancer, this composite nanoparticle should allow an increase in cumulative dose of chemotherapeutics that can be administered without an amplification of adverse effects.
[56] The NanoDoxCurc embodiment of the invention solves two pervasive problems in clinical oncology. First, cancers overexpress a variety of MDR proteins that efflux chemotherapeutics out of the site of intracellular action, and lead to chemoresistance, resulting in treatment failure. Second, many of these chemotherapeutic agents cause incidental toxicity, such as cardiac and hematological side effects, leading to a threshold cumulative dose in humans that cannot be exceeded without the advent of side effects. Here, an advantage of this embodiment of the invention is that it “kills two birds with one stone” by the use of a novel composite polymer nanoparticle that bypasses chemoresistance and also overcomes many of the systemic side effects associated with chemotherapy, especially those on the heart and bone marrow.
[57] The novel features of NanoDoxCurc (as well as related embodiments which include curcumin in combination with other chemotherapeutic agents) are (a) a polymer nanoparticle comprised of three monomers that are used in many FDA-approved products; (b) the ability to deliver two agents simultaneously; (b) one of the agents is a hydrophobic drug (curcumin) and encapsulated in the hydrophobic core of the nanoparticle; (c) the second dug (doxorubicin in the exemplary embodiment (but which could be other chemotherapeutic agents, as a well as a plurality of different chemotherapeutic agents) is conjugated to the surface of the nanoparticle (in some embodiments, a chemotherapeutic agent may be present in the core with curcumin); (d) curcumin delivered within the composite nanoparticle inactivates multiple MDR proteins (including MDR-1/PgP, MRP-1 and ABCG2/BCRP1) in cancer cells, thus allowing the concomitantly delivered doxorubicin to reach its site of action; (e) curcumin ameliorates the reactive oxygen species (ROS) mediated adverse effects of doxorubicin in non-cancerous tissues, mainly through enhancing cellular anti-oxidant levels and reducing oxidative stress. Importantly, preclinical studies show that dose-for-dose, NanoDoxCurc performs better in terms of reduced adverse effects compared to not only free doxorubicin, but also Doxi® 1 (pegylated liposomal doxorubicin) which is marketed specifically for the purpose of reducing the adverse effects of the drug. Thus, the new formulation outperforms Doxil® in terms of its safety profile in the preclinical small animal setting.
[58] Doxorubicin is widely used as a cancer chemotherapeutic in many cancer regimens, both for solid malignancies as well as hematological cancers. It is especially used in many pediatric malignancy regimens like leukemias, where long term effects of cardiac toxicity can be devastating. The NanoDoxCurc formulation has a dual advantage, not only overcoming chemoresistance, but also reducing systemic adverse effects of the delivered chemotherapeutic. The scope of this invention extends to a substantial market that is currently occupied by doxorubicin or Doxil®, or where these two drugs failed to win regulatory approval due to toxicity issues.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine curcumin and doxorubicin in the construct of Perumal et al. One would have been motivated to because: (1) Perumal et al suggest combining more than one drug into the micelle construct and suggest the drugs can be specifically curcumin or doxorubicin; (2) Perumal et al teach the constructs gain the advantages of inhibiting p-glycoprotein (P-gp) efflux pumps in MDR cancer, enhancing uptake of the encapsulated drug in a drug-resistant cancer cell, enhancing water solubility of compounds by encapsulating them in the micelle for delivery, enhancing chemical stability of the encapsulated drug, reducing toxicity, and enhancing accumulation of the encapsulated drug in tumor tissue as compared to normal tissues; (3) Maitra et al teach motivation for combining curcumin with doxorubicin to treat the same drug resistant cancer patient population taught by Perumal et al and to gain the same advantages as taught by Perumal et al, wherein the combination of curcumin with doxorubicin has the advantage of “killing two birds with one stone” to bypass chemoresistance and overcome many of the systemic side effects associated with chemotherapy. One of ordinary skill in the art would have a reasonable expectation of success to combine curcumin and doxorubicin in the micelle construct of Perumal et al given: (1) Perumal et al demonstrate successfully loading doxorubicin or curcumin into the micelle constructs and successfully using them to treat cancer or drug resistant cancer cells; (2) Maitra et al demonstrate the success of combining the two drugs on a single construct to overcome the multi-drug resistant cancer phenotype, induce xenograft tumor regression and significantly enhance survival compared to doxorubicin formulations alone.
Smaller size constructs:
Perumal et al teach and recognize the accumulation of micelle constructs at tumor tissues is a result of selective passive targeting that is due to the enhanced permeability and retention effect, resulting from a leaky vasculature and a lack of lymphatic drainage in tumor tissues (Example 2).
Maitra et al suggest the nanoparticle size is less than 100 nm (Figures 1 and 4; [12]; [16]; [18]; [21]; [34]; [49]; claims 3, 5, 10, and 13); and demonstrate that a micelle construct of nanoparticulate size (~50 nm in diameter) enhanced bioavailability and circulation of a poorly water soluble drug compared to free drug ([65]). Maitra et al teach micellar drug delivery carriers have several advantages including biocompatibility, solubilization of hydrophobic drugs in the core, manometric size ranges which facilitate extravasation of the drug carrier at the site of inflammation, site-specific delivery ([5]). Maitra et al suggest the polymeric nanoparticles are preferably 50-100 nm or smaller in size which include curcumin on entrapped within the hydrophobic interior of the nanoparticles and one or more chemotherapeutic agents (e.g., anthracyclines (doxorubicin, daunorubicin), paclitaxel and other taxanes, cisplatin and other platinum compounds, topoisomerase inhibitors, etc.) ([12]). Maitra et al suggest medicinal compositions are prepared which comprise polymeric nanoparticles preferably of a size on average of less than 100 nm diameter entrapping curcumin in combination with one or more cancer chemotherapeutic agents ([16]; [34]).
Gou et al teach successful production of a micelle construct comprising curcumin (Cur/MPEG-PCL), ranging from about 9 – 50 nm in size (Figure 3), and having a mean particle size of about 24 - 34 nm (Table 1; p. 1561, col. 2). Guo et al teach the structure of curcumin (Figure 1) and that encapsulation of lipophilic, hydrophobic drugs, such as curcumin, in nanoparticles renders the drugs completely water soluble for administration (p. 1559, col. 1). Guo et al teach successful inhibition of colon cancer and angiogenesis in vivo by administration of the micelles (section 3.4; Figure 10), and that encapsulation of curcumin enhanced its anti-cancer activity in vivo (p. 1564, col. 1). Gou et al recognize the advantages of smaller micelles (p. 1565, col. 2):
Alternatively, angiogenic blood vessels in tumor tissues have gaps between adjacent endothelial cells. This defective vascular architecture coupled with poor lymphatic drainage induces enhanced permeability and retention (EPR) effect, which allows nanoparticles to extravasate through these gaps into extravascular spaces and accumulate inside tumor tissues. For such a passive targeting mechanism (EPR effect) to work, these nanoparticles must circulate for a long time in vivo. Monodisperse Cur/MPEG-PCL micelles were small enough (<30 nm) for this, while our Cur/MPEG-PCL micelles have a core-shell structure, in which hydrophilic PEG acts as a brush-like protective coating. Encapsulation of curcumin in MPEG-PCL micelles improved the t1/2 and AUC of curcumin in vivo, which may contribute to enhancing the accumulation of curcumin in tumor site due to the EPR effect, thus improving the anticancer activities of curcumin. To our knowledge, this work is the first report concerning the application of polymeric micelle-encapsulated curcumin in colon cancer therapy in vivo. These results suggest that i.v. application of Cur/MPEG-PCL micelles may have potential application in treating colon carcinoma.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce smaller nanoparticle sized micelle constructs in Perumal et al that range from 20 nm – 60 nm or from 10 nm – 20 nm. One would have been motivated to because: (1) Perumal et al patented claims for their micelle construct size to fall into the range of about 10 nm to about 300 nm; (2) Maitra et al suggest particle sizes are preferably 50-100 nm or smaller in size; (3) Perumal et al recognize micelle construct accumulation at tumor sites is a result of selective passive targeting that is due to the enhanced permeability and retention effect, resulting from a leaky vasculature and a lack of lymphatic drainage in tumor tissues; and (4) Guo et al teach micelles <30 nm can take advantage of the enhanced permeability and retention (EPR) effect in order to extravasate through these gaps into extravascular spaces and accumulate inside tumor tissues. One of ordinary skill in the art would have a reasonable expectation of success to make and use a smaller micelle construct of Perumal et al because: (1) Perumal et al teach and successfully demonstrate the known methods for making their micelle constructs and teach how to make smaller sized micelle constructs (nanomicelles) by lowering the drug to PEG-zein ratio; and (2) Guo et al demonstrate micelle constructs <30 nm effectively take advantage of EPR effect to accumulate at tumor tissues.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
7. Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 9,833,508; in view of Lim et al (Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 April 17-21; Washington, DC, Philadelphia (PA):AACR; Cancer research 2010; 70(8 Suppl): Abstract nr 440). Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims overlapping compositions and methods rending the instant claims obvious. The US Patent claims:
1. A method of treating breast cancer or colon cancer in a subject, comprising: providing a composition comprising a micelle construct attached to curcumin at a concentration of 4 mg/kg, wherein the micelle construct is attached to doxorubicin at a concentration of 0.4 mg/kg, wherein the micelle construct is targeted to bind to glut-1 by using a glut-1 antibody as a targeting agent; and administering a therapeutically effective dosage of the composition to the subject.
2. The method of claim 1, wherein the micelle construct is less than 30 nm.
3. The method of claim 1, wherein the subject is a human.
4. The method of claim 1, wherein the subject is a mouse.
5. The method of claim 1, wherein the cancer is colon cancer; and the micelle construct is 50 nm or less, wherein the combination of anti-glut-1 antibody linked to micelles containing doxorubicin and curcumin have a synergistic effect to treat the colon cancer.
6. The method of claim 1, wherein the cancer is a chemotherapy-resistant cell.
The US Patent does not claim treating a brain cancer.
Lim et al demonstrate nanoparticle-encapsulated curcumin successfully decreased cell growth of multiple human brain cancer cells including glioblastoma and medulloblastoma. Lim et al teach curcumin has been shown to target multiple pathways in different tumor types (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat brain cancer in the method of the US Patent. One would have been motivated to because: (1) the US Patent claims treating two very different types of cancers; and (2) Lim et al teach curcumin has been shown to target multiple pathways in different tumor types including brain cancer. One of ordinary skill in the art would have a reasonable expectation of success treating brain cancer in the method of the US Patent given Lim et al demonstrate that nanoparticle curcumin alone is cytotoxic to brain cancer cells.
8. Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,819,571. Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims overlapping compositions and methods rending the instant claims obvious. The US Patent claims:
1. A pharmaceutical composition comprising:
a micelle construct comprising
1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (PEG2000-PE);
curcumin or a pharmaceutical equivalent, analog, derivative, or salt thereof; and
a chemotherapy agent;
wherein the average diameter of the micelle construct is less than 30 nm.
2. The composition of claim 1, wherein the curcumin is a compound having the structure of formula 1:
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or compound having the structure of formula 2:
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3. The composition of claim 1, wherein the chemotherapy agent is doxorubicin or a pharmaceutical equivalent, analog, derivative, and/or salt thereof.
4. The composition of claim 1, wherein the average diameter of the micelle construct is between 10 nm and 20 nm.
5. The composition of claim 1, further comprising a pharmaceutically acceptable carrier.
6. The composition of claim 1, wherein the average diameter of the micelle construct is less than 20 nm.
7. A method of treating cancer in a subject, comprising administering a therapeutically effective dosage of the composition of claim 1 to the subject.
8. The method of claim 7, wherein the subject is a human.
9. The method of claim 7, wherein the cancer is colon cancer.
10. The method of claim 7, wherein the cancer is breast cancer.
11. The method of claim 7, wherein the cancer is brain cancer.
12. The method of claim 7, wherein the cancer is a chemotherapy-resistant cell.
13. A method of inhibiting cell growth of a tumor cell, comprising:
providing the composition of claim 1; and
inhibiting cell growth by administering a therapeutically effective dosage to the tumor cell.
14. The method of claim 13, wherein the tumor cell is a breast cancer cell.
15. The method of claim 13, wherein the tumor cell is a colon cancer cell.
16. The method of claim 13, wherein the tumor cell is a brain cancer cell.
9. Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11, 14-23 of copending Application No. 18/696,333 (copending application); in view of US Patent Application Publication 2013/0330412, Maitra et al, claiming priority to December 10, 2010; Tang et al (Polymer Preprints, 2009, 50:322), Ma et al (Journal of Biomedical Material Research, 2008, 86A:300-310); and Lim et al (Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 April 17-21; Washington, DC, Philadelphia (PA):AACR; Cancer research 2010; 70(8 Suppl): Abstract nr 440).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application is claiming compositions and methods overlapping with the instant claims, rendering them obvious. The copending application claims:
1. A pharmaceutical regimen comprising: a first micelle construct comprising a polykinase inhibitor and a chemotherapeutic agent;and
a second micelle construct comprising and a polykinase inhibitor.
2. The pharmaceutical regimen of claim 1, wherein the second micelle construct does not comprise a chemotherapeutic agent.
3. The composition pharmaceutical regimen of claim 1, wherein the polykinase inhibitor is selected from a curcuminoid or curcuminoid analog, derivative or salt thereof or combination thereof.
4. The composition pharmaceutical regimen of claim 3, wherein the wherein the curcuminoid or curcuminoid analog, derivative or salt thereof or combination thereof is a curcumin compound having the structure of formula 1:
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or a curcumin compound having the structure of formula 2:
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5. The composition pharmaceutical regimen of claim 1, wherein the chemotherapeutic agent is doxorubicin or a pharmaceutical equivalent, analog, derivative, and/or salt thereof.
6. The composition pharmaceutical regimen of claim 1, wherein the first and second micelle constructs are each formed by amphiphilic PEG2000-DSPE polymers.
7. The composition pharmaceutical regimen of claim 1 wherein the first and second micelle constructs are each between 10 nm and 20 nm.
8. The composition pharmaceutical regimen of claim 1, wherein the first and second micelle constructs are each between 20 nm and 60 nm.
9. The composition pharmaceutical regimen of claim 1, wherein the first and second micelle constructs are each less than 30 nm.
11. A method of treating a sarcoma in a subject, comprising administering a therapeutically effective dosage of the regimen of claim 1 to the subject.
14. The method of claim 11, wherein administration of the second micelle construct comprising a polykinase inhibitor precedes administration of the first micelle construct comprising a polykinase inhibitor and a chemotherapeutic agent.
15. The method of claim 11, wherein administration of the second micelle construct comprising a polykinase inhibitor follows administration of the first micelle construct comprising a polykinase inhibitor and a chemotherapeutic agent.
16. The method of claim 11, wherein the second micelle construct comprising a polykinase inhibitor is administered once per day.
17. The method of claim 11, wherein the second micelle construct comprising a polykinase inhibitor is administered twice per day.
18. The method of claim 11, wherein the second micelle construct comprising a polykinase inhibitor is administered three times per day.
19. The method of claim 11, wherein the method further comprises administering the second micelle construct comprising a polykinase inhibitor for up to 14 days after completion of the regimen of claim 1.
20. The method of claim 11, wherein the method further comprises administering the second micelle construct comprising a polykinase inhibitor for 15 to 28 days after completion of the regimen of claim 1.
21. The method of claim 11, wherein the method further comprises administering the second micelle construct comprising a polykinase inhibitor for 28 days or more after completion of the regimen of claim 1.
22. The method of claim 11, wherein the second micelle construct comprising a polykinase inhibitor is administered at a dosage of about 20mg/ml to about 200mg/ml per day.
23. A method of inhibiting cell growth of a tumor cell, comprising administering a therapeutically effective dosage of the regimen of claim | to the tumor cell.
The copending application does not claim treating breast, colon, brain cancer or chemotherapy-resistant cancer, and the subject is human.
Maitra, Tang, Ma, and Lim teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat human breast, colon or brain cancer in the method of the copending application. One would have been motivated to because: (1) Maitra et al teach doxorubicin is widely used as a cancer chemotherapeutic in many cancer treating regimens; (2) Lim et al teach curcumin has been shown to target multiple pathways in different tumor types including brain cancer; (3) Ma et al produced curcumin micelles utilizing curcumin of Formula 2 to successfully induce cell death of several different cancer cell types; and (4) Tang et al teach curcumin is an NF-kB inhibitor that is known to be cytotoxic against many cancer cell lines of human origin including breast cancer cells and colon cancer cells. One of ordinary skill in the art would have a reasonable expectation of success treating breast, colon or brain cancer in the method of the copending application given: (1) the copending application teaches methods of treating a cancer or inhibiting cell growth of a tumor cell by administering a micelle construct comprising curcumin and chemotherapeutic doxorubicin and micelle construct comprising curcumin; (2) all of the cited secondary references teach or demonstrate successfully killing a wide variety of cancer cell types by administering nanoparticle curcumin or curcumin micelle loaded with chemotherapeutic CPT or DOX; and (3) Ma et al teach it is known curcumin augments chemotherapeutic responses to many different types of chemotherapeutics.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
10. Conclusion: No claim is allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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