Cross-reference to Related Applications

This PCT application claims the benefit of priority to US Provisional Application No 61/960,552 filed September 20, 2013 which is incorporated by reference in its entirety.

Statement Regarding Federally Sponsored Research or Development Not applicable.

Field of the Invention

The present invention relates to conditionally stable compositions and methods of treatment of cancer patients, including ovarian cancer patients with cytotoxic drugs, in particular the use of cytotoxic drugs encapsulated in a diblock copolymer formulation where the composition is stable in protein free media and less stable in protein containing media such as serum

Background of the Invention

Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008. Prostate cancer is a leading cause of cancer among men. Ovarian cancer is the ninth most common cancer in women and the fifth leading cause of cancer-related deaths in women in the US. One of every 72 women will develop ovarian cancer and one of every 100 will die from this form of cancer. The American Cancer Society estimates that in 2013 22,240 women will be diagnosed with ovarian cancer and about 14,230 will dies from ovarian cancer. About 85% to 90% of ovarian cancers are epithelial ovarian carcinomas.

Treatment options include surgery, chemotherapy, and occasionally radiation therapy. Surgery usually involves the removal of one or both ovaries, fallopian tubes and the uterus. In advanced disease, surgically removing all abdominal metastases enhances the effect of chemotherapy and helps improve survival. For women with stage III ovarian cancer in which removal of cancerous tissue has been performed, studies show that chemotherapy administered both intravenously and directly into the peritoneal cavity improves survival.

Abraxane and Taxol are chemotherapeutic drugs. Both drugs are used to treat breast cancer. These cytotoxic medicines arrest the growth of cells in case of cancerous tissues. They essentially differ in the component they carry and their effectiveness. Taxol is an antineoplastic drug used in chemotherapy. It is an alkaloid derived from plants and prevents microtubule formation in cells. The drug has proven effects on breast, ovarian, bladder, prostate, esophageal, lung and melanoma cancers. The drug is solvent based and should be carefully administered since it is an irritant. The dosage and duration of administration of drug depends on the Body Mass Index and the severity of the disease. Side effects are common although the symptoms are either one or two in most cases. The most common side effects include hair loss, peripheral neuropathy, vomiting, diarrhea, myalagia, arthralagia, low blood counts and hypersensitivity.

Taxol is a first generation paclitaxel formulation in which Cremophor EL {po!yoxyethySated castor oil) is mixed with paclitaxel and given as an infusion for the treatment of ovarian cancer, lung cancer,, head and neck cancer, bladder cancer. Taxoi has adverse side effects such as anaphylactic shock. Abraxane is paclitaxel nanoparticle encapsulated by albumin. The delivery of drug to target cells is easier when not formulated with solvent such as Cremophor. The drug is built on a natural albumin platform devoid of chemical solvents and there is little need for concomitant or prior medication with anti- hypersensitive drugs. Abraxane is the drug of choice in first and second line of treatment in metastatic breast cancer and is approved in majority of the countries. Side effects of Abraxane include bone marrow suppression (primarily neutropenia) which is dose-dependent and a dose-limiting toxicity of Abraxane. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer ( BC) and 47% of patients with non-small cell lung cancer {NSCLC}. Abraxane also requires tedious reconstitution which may cause foaming or clumping of the reconstituted iyophi!ized powder.

Biodegradable polymeric micelle-type drug compositions, containing a water-soluble amphiphilic block copolymer micelle having a hydrophilic poly(alkylene oxide) component and a hydrophobic biodegradable component, can be used to develop formulations in which a hydrophobic drug is physically trapped in the micelle. This micelle-type composition, enveloping a hydrophobic drug, can solubilize the hydrophobic drug in a hydrophilic environment to form a solution. IG-001 is a polymer bound nanoparticle paclitaxel and can be used to treat difficult to perfuse hypoxic tumors such as pancreatic cancer and ovarian cancer.

While there are cytotoxic drug compositions that are useful in the treatment of various cancers there exists a need for methods of treatment and drug administration that reduce side effects, have improved stability and/or increase the efficacy of the treatment regimen. Summary of the Invention

The present invention relates to compositions comprising cancer drugs in a micelle where the composition is stable in a protein-free medium and less stable in a protein containing medium. The compositions of the present invention are conditionally stable in that they are more stable in one media than another, in particular the compositions of the present invention are more stable in protein-free medium and less stable in a protein containing medium. The present invention relates to paclitaxel compositions where the paclitaxel is contained within a micelle and where the paclitaxel composition is stable in protein-free medium and less stable in a protein containing medium. The present invention further relates to micellular compositions where the composition comprises about 4ug/ml to about 2000 ug/ml of paclitaxel. The present invention relates to micellular compositions where the composition is at least 20% more stable or 50% more stable or 100% more stable in a protein-free solution than in a solution containing protein. The present invention relates to micellular compositions where the composition is at least 20% more stable or 50% more stable or 100% more stable in a protein- free solution than Abraxane. The present invention relates to micellular compositions where the composition is at least 20% less stable or 50% less stable or 100% less stable in a protein containing solution such as serum than Abraxane.

The invention also relates to methods of treating patients with ovarian cancer by administering paclitaxel-containing micelles and carboplatin to patients. The invention relates to methods of treating patients with ovarian cancer by administering paclitaxel-containing micelles and carboplatin to patients where the micelles are comprised of a diblock copolymer including IG-001 which is a paclitaxel- containing micelle. The invention relates to methods of treating patients with ovarian cancer by administering paclitaxel-containing micelles and carboplatin where the amount of paclitaxel administered is 260mg/m ² and the carboplatin is 5 AUC. The invention relates to methods of treating patients with ovarian cancer by administering paclitaxel-containing micelles and carboplatin where the paclitaxel containing micelles and carboplatin are administered in 6 cycles over 3 weeks. The invention relates to methods of treating patients with ovarian cancer by administering paclitaxel-containing micelles and carboplatin where the overall response rate is greater than 70% or greater than 80% or greater than 90% or greater than 95% or where the overall response rate is about 70% to about 95%. Brief Description of the Figures

Figure 1 - Plot of particle size versus paclitaxel concentration for Abraxane in phosphate buffered saline (PBS) and O.lx serum and lx serum. Figure 2 - Plot of particle size versus paclitaxel concentration for IG-001 in phosphate buffered saline (PBS) and O.lx serum and lx serum.

Figure 3 - Plot of dose proportionality curve for Taxol, Abraxane and IG-001 Figure 4 - Plot of dose limiting toxicity curve for Taxol, Abraxane and IG-001. Figure 5 - Plot of paclitaxel concentration of delivery of 30 mg/kg bolus by Abraxane and IG-001 Figure 6A and B - Plots of paclitaxel versus time for Abraxane and IG-001 in mice.

Figure 7 - Plot of overall response rate for IG-001, Taxol and Abraxane in Phase III study of metastatic breast cancer.

Detailed Description of the Invention

The present invention relates to compositions comprising cancer drugs in a micelle where the composition is stable in protein-free medium and less stable in a protein containing medium. The present invention relates to paclitaxel compositions where the paclitaxel is contained within a micelle and where the paclitaxel composition is stable in protein-free medium and less stable in a protein containing medium.

The paclitaxel formulation includes amphiphilic block copolymer which may comprise a hydrophilic block (A) and a hydrophobic block (B) linked with each other in the form of A-B, A-B-A or B-A-B structure. Additionally, the amphiphilic block copolymer may form core-shell type polymeric micelles in its aqueous solution state, wherein the hydrophobic block forms the core and the hydrophilic block forms the shell.

In one embodiment, the hydrophilic block (A) of the amphiphilic block copolymer may be polyethylene glycol (PEG) or monomethoxypolyethylene glycol (mPEG). Particularly, it may be mPEG. The hydrophilic block (A) may have a weight average molecular weight of 500-20,000 daltons, specifically 1,000-5,000 daltons, and more specifically 1,000-2,500 daltons.

The hydrophobic block (B) of the amphiphilic block copolymer may be a water-insoluble, biodegradable polymer. In one embodiment, the hydrophobic block (B) may be polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA). In another embodiment, the hydrophobic block (B) may have a weight average molecular weight of 500-20,000 daltons, specifically 1,000-5,000 daltons, and more specifically 1,000-2,500 daltons. Hydroxyl end groups of the hydrophobic block (B) may be protected with fatty acid groups, and particular examples of the fatty acid groups include acetate, propionate, butyrate, stearate, palmitate groups, and the like. The amphiphilic block copolymer comprising the hydrophilic block (A) and the hydrophobic block (B) may be present in the composition in an amount of 20-98 wt %, specifically 65-98 wt %, and more specifically 80-98 wt % based on the total dry weight of the composition.

In another embodiment, the hydrophilic block (A) and the hydrophobic block (B) may be present in the amphiphilic block copolymer in such a ratio that the copolymer comprises 40-70 wt %, specifically 50-60 wt % of the hydrophilic block (A) based on the weight of the copolymer. When the hydrophilic block (A) is present in a proportion less than 40%, the polymer has undesirably low solubility to water, resulting in difficulty in forming micelles. On the other hand, when the hydrophilic block (A) is present in a proportion greater than 70%, the polymer becomes too hydrophilic to form stable polymeric micelles, and thus the composition may not be used as a composition for solubilizing taxane.

A preferred paclitaxel formulation is IG-001 (also referred to as Genexol-PM and Cynviloq™) which is a cremophor-free, polymeric micelle formulation of paclitaxel. IG-001 (Genexol-PM, Cynviloq™) utilizes biodegradable di-block copolymer composed of methoxy poly (ethylene glycol)-poly (lactide) to form nanoparticles with paclitaxel containing hydrophobic core and a hydrophilic shell. IG-001 comprises biodegradable di-block copolymer composed of methoxypoly (ethyleneglycol)-poly (lactide) to form nanoparticles with a paclitaxel-containing hydrophobic core, and a hydrophilic shell. The micellar composition may be made by dissolving an amphipathic co-polymer, monomethoxypolyethylene glycol-polylactide with an average molecular weight of 1766-2000 daltons at 80°C in ethanol. Paclitaxel is added to the dissolved co-polymer and the solution cooled to about 50°C where room temperature water is added. Anhydrous lactose may be added and dissolved. The solution may then be filtered and lyophilized. The amount of paclitaxel in the micelle formulation can be altered. Less or more paclitaxel will change the loading % and change the CMC and properties of the formulation. The size of the nanoparticles for IG-001 is a Gaussian distribution where the mean particle size is about lOnm to about 50nm

The micellular formulations of the present invention are quite stable in protein-free media. Sustained release micelles have been prepared in which polymers with very low CMC (< 0.1 μg/ml) can be used for prolonging the circulation time before the micelle degrades. Upon intravenous injection, the micelles undergo dilution in the body. If the CMC of the micelles is high, the concentration of the polymer or surfactant falls below the CMC upon dilution and hence, the micelles dissociate. Therefore, a higher concentration of the polymer or surfactant has to be used to prepare the micelles so that they withstand the dilution up to 5 I in the blood. However, the use of high concentrations might not be feasible due to toxicity related dose limitations. If the polymer or surfactant has a CMC lower than 0.1 μg/ml, concentrations as low as 5 mg/ml may be used to prepare a micelle formulation in order to counter the dilution effects in the blood. A variety of polymers including diblock copolymers, triblock copolymers and graft copolymers have been synthesized to be stable even after intravenous administration. The formulations of the present invention provide methodologies for constructing formulations in which the nanoparticles are less stable once administered such that the drug compound can be released from the nanoparticle and made available to the endogenous albumin delivery system. Nanoparticles of the present invention are more stable in protein-free solutions than in solutions containing proteins such as serum. The nanoparticles of the present invention may be at least 20% more stable or 25% more stable or 30% more stable or 35% more stable or 40% more stable or 45% more stable or 50% more stable or 55% more stable or 60% more stable or 65% more stable or 70% more stable or 75% more stable or 80% more stable or 85% more stable or 90% more stable or 95% more stable or 100% more stable or 125% more stable or 150% more stable or 175% more stable or 200% more stable or 500% more stable or 1000% more stable or 5000% more stable or 10000% more stable in a protein free solution than in a solution containing protein. The nanoparticles of the present invention may be between about 10% more stable to about 25000% more stable or about 10% more stable to about 15000% more stable or about 10% more stable to about 12500% more stable or about 10% more stable to about 10000% more stable or from about 10% more stable to about 9000% more stable or from about 10% more stable to about 8000% more stable or from about 10% more stable to about 7000% more stable or from about 10% more stable to about 6000% more stable or from about 1000% more stable to about 500% more stable or from about 10% more stable to about 400% more stable or from about 10% more stable to about 300% more stable or about 10% more stable to about 200% more stable or about 20% more stable to about 125% more stable or about 20% more stable to about 100% more stable or from about 20% more stable to about 90% more stable or from about 20% more stable to about 80% more stable or from about 20% more stable to about 70% more stable or from about 20% more stable to about 60% more stable or from about 20% more stable to about 50% more stable or from about 20% more stable to about 40% more stable or from about 50% more stable to about 2500% or from about 50% more stable to about 1250% more stable or from about 50% more stable to about 1000% more stable in a protein free solution than in a solution containing protein.

Nanoparticles of the present invention are less stable in solutions or media containing proteins such as serum than Abraxane. The nanoparticles of the present invention may be at least 20% less stable or 25% less stable or 30% less stable or 35% less stable or 40% less stable or 45% less stable or 50% less stable or 55% less stable or 60% less stable or 65% less stable or 70% less stable or 75% less stable or 80% less stable or 85% less stable or 90% less stable or 95% less stable or 100% less stable or 125% less stable or 150% less stable or 175% less stable or 200% less stable or 500% less stable or 1000% less stable or 5000% less stable or 10000% less stable in a protein free solution than in a solution containing protein. The nanoparticles of the present invention may be between about 10% less stable to about 25000% less stable or about 10% less stable to about 15000% less stable or about 10% less stable to about 12500% less stable or about 10% less stable to about 10000% less stable or from about 10% less stable to about 9000% less stable or from about 10% less stable to about 8000% less stable or from about 10% less stable to about 7000% less stable or from about 10% less stable to about 6000% less stable or from about 1000% less stable to about 500% less stable or from about 10% less stable to about 400% less stable or from about 10% less stable to about 300% more stable or about 10% more stable to about 200% more stable or about 20% more stable to about 125% more stable or about 20% more stable to about 100% more stable or from about 20% more stable to about 90% more stable or from about 20% more stable to about 80% more stable or from about 20% more stable to about 70% more stable or from about 20% more stable to about 60% more stable or from about 20% more stable to about 50% more stable or from about 20% more stable to about 40% less stable or from about 50% less stable to about 2500% or from about 50% less stable to about 1250% less stable or from about 50% less stable to about 1000% less stable in a protein free solution than in a solution containing protein.

The compositions of the present invention including IG-001 show similar or the same pharmacokinetics in mice and humans as Abraxane.

Table 1 (in mice)

Also see Figures 6A and 6B.

Table 2 shows a comparison of mean non-compartmental pharmacokinetic parameters of Abraxane and IG-001 of a 3 hour infusion, 135 mg/m ² dose.

Table 2 (in humans)

IG-001 and Abraxane also show similar or the same clinical efficacy as measured by overall response rate in Phase III clinical trials for metastatic breast cancer (See Figure 7).

The methods of the present invention provide methodologies for constructing nanoparticles which ideally release their contents in vivo but are stable in an iv bag, in an infusion solution or in a reconstitute vial. IG-001 exhibited significant instability in serum even at high paclitaxel concentrations of 2000 ug/ml. Conversely, Abraxane ceased to exist as a nanoparticle starting at 200 ug/ml paclitaxel concentrations. IG-001 has expanded PK proportionality and higher MTD as compared to Abraxane (See Figures 3 and 4). Moreover, IG-001 exhibits a remarkable stability in protein-free matrices even at low paclitaxel concentrations of 4 ug/ml. Conversely, Abraxane ceased to exist as a nanoparticle starting at 40 ug/ml paclitaxel concentrations. IG-001 is suitable for intraperitoneal and/or intravesicle modes of drug delivery due to higher nanoparticle residence time and the reduced likelihood of paclitaxel precipitation.

Cytotoxic drugs used in the compositions and formulations of the present include but are not limited to paclitaxel, docetaxel, 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10- desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N- dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel.

Cancer types for which the methods and formulations of the present invention may be useful include but are not limited to ovarian cancer, breast cancer, pancreatic cancer, liver cancer, non- small cell lung cancer (NSCLC) and other lung cancers.

The cancer drug micelles of the present invention may be used in combination with cytotoxic anticancer agents which include but are not limited to paclitaxel, docetaxel, 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7- glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, methotrexate, topotecan, vincristine and vinblastine. For example carboplatin can be used in combination with IG-001 to treat various cancers including ovarian cancer.

Carboplatin is used as a single agent therapy for use in the treatment of recurrent ovarian cancer for example as a 360 mg/m ² by intravenous injection on day 1 every 4 weeks (alternatively, the carboplatin dose may be calculated by the Calvert formula which is based on a patient's preexisting renal function or renal function and desired platelet nadir. The use of this dosing formula, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function). Calvert formula for carboplatin dosing: Total Dose (mg)=(target AUC) A— (GFR + 25) The target AUC of 4-6 mg/mL/min using single agent carboplatin may provide the most appropriate range for treatment.

Examples

Example 1

Comparison of Stability Abraxane and IG-001

A comparison of dissolution/instability profiles of nab-paclitaxel and IG-001 was conducted in serum-containing (IX FBS, 0.1 X FBS) and protein-free (IX PBS) matrices at 37°C using Dynamic Light Scattering (DLS) methodology (Malvern's Zetasizer Nano S and Wyatt's Nanostar). The results of the study are displayed in Figures 1 and 2. IG-001 has a 10-fold diminished stability versus Abraxane in serum. IG-001 exhibited significant instability in serum even at high paclitaxel concentrations of 2000 ug/ml. Conversely, Abraxane ceased to exist as a nanoparticle starting at about 200 ug/ml paclitaxel concentrations. This data may explain the observed expanded PK proportionality and the higher maximum tolerated does (MTD) of IG-001 vs. Abraxane. IG-001 has 10-fold enhanced stability compared to Abraxane in protein-free matrices. IG-001 exhibited remarkable stability (high CMC) in protein-free matrices even at low paclitaxel concentrations of 4 ug/ml. Conversely, Abraxane ceased to exist as a nanoparticle starting at 40 ug/ml paclitaxel concentrations. Significance of these findings is the better suitability of IG-001 for intraperitoneal and/or intravesicle modes of drug delivery due to higher nanoparticle residence time and the reduced likelihood of paclitaxel precipitation. IG-001 exhibits exceptional stability in protein-free fluid- suitable for intraperitoneal administration for ovarian cancer and intravesicle administration for bladder cancer. IG-001 is highly unstable in serum and therefore shows expanded PK-proportionality making a higher MTD possible.

Example 2

Phase 1 study of IG-OOlwith Carboplatin as a Primary Treatment in Patients with Advanced Ovarian

Carcinoma

A Phase 1 study of IG-001, a novel Cremophor-free, polymeric micelle formulation of paclitaxel with carboplatin as a primary treatment in patients with advanced ovarian carcinoma was conducted to determine the Maximum Tolerated Dose (MTD) and dosing for Phase 2 trial of IG-001 in combination with carboplatin. Other objectives included overall survival, progress free survival, time to progression, duration of overall response and safety and toxicity. Six patients/dose level were treated with 220, 260, and 300 mg/ in a manner shown in Table 1. MTD was not determined in this phase 1 trial (over 300mg/m ² )

Table 3

Dose Limiting Toxicity was shown as grade 4 myalgia in one patient at 300 mg/m ² . The result indicated a response rate of 94.12%, adverse events: 20.64% and LT toxicity: 7.83%. No death related to the disease or treatment. The recommended dose for Phase 2 trial of cremophor-free paclitaxel in combination with Carboplatin is 260mg/m ² .

Example 3

Phase 2 Trial to Evaluate Efficacy and Safety of Combination Therapy of IG-001 Plus Carboplatin Compared to Paclitaxel Plus Carboplatin as a 1st line Treatment in Patients with Epithelial Ovarian

Cancer

Phase II ovarian trial design: randomized, two-arm trial, primary advanced epithelial ovarian cancer consisting of 100 patients (50/each arm). Control Arm: Solvent based paclitaxel 175mg/m ² IV + Carboplatin 5 AUC IV, 3 weeks, 6 cycles and Experimental Arm: IG-001 260mg/m ² IV + Carboplatin 5 AUC IV 3 weeks, 6 cycles.

Table 4

Table 5

Total 35 (35.71) 88 98 (100.00)

IG-001 + Carboplatin 1 (2.00) 1 50 (51.02)

UAE Paclitaxel + 0 (0.00) 0 48 (48.98) 1.0000

Carboplatin

Total 1 (1.02) 1 98 (100.00)

The results indicate that the response rate was 88.00% vs. 77.8% (IG-001 vs. paclitaxel) and the primary endpoint of noninferiority to paclitaxel was met. The one-sided 95% upper confidence limit was 4.95, which is lower than the non-inferiority threshold (16.3%), indicating that the study group is not inferior to the control group. Adverse events were similar to paclitaxel despite the higher dose.

Within this disclosure, any indication that a feature is optional is intended provide adequate support (e.g., under 35 U.S.C. 112 or Art. 83 and 84 of EPC) for claims that include closed or exclusive or negative language with reference to the optional feature. Exclusive language specifically excludes the particular recited feature from including any additional subject matter. For example, if it is indicated that A can be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists of X alone, or that A does not include any other drugs besides X. "Negative" language explicitly excludes the optional feature itself from the scope of the claims. For example, if it is indicated that element A can include X, such language is intended to provide support for a claim that explicitly specifies that A does not include X. Non-limiting examples of exclusive or negative terms include "only," "solely," "consisting of," "consisting essentially of," "alone," "without", "in the absence of (e.g., other items of the same type, structure and/or function)" "excluding," "not including", "not", "cannot," or any combination and/or variation of such language.

Similarly, referents such as "a," "an," "said," or "the," are intended to support both single and/or plural occurrences unless the context indicates otherwise. For example "a dog" is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc. Non-limiting examples of qualifying terms that indicate singularity include "a single", "one," "alone", "only one," "not more than one", etc. Non-limiting examples of qualifying terms that indicate (potential or actual) plurality include "at least one," "one or more," "more than one," "two or more," "a multiplicity," "a plurality," "any combination of," "any permutation of," "any one or more of," etc. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.

Where ranges are given herein, the endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that the various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Further advantages of the present immunological compositions and adjuvants of the present invention can be achieved by those skilled in the art based upon the embodiments described herein and are thus specifically within the scope of the present invention.