Conditionally Stable Micelle Compositions for Cancer Treatments Utilizing Local Delivery Routes of

Administration

Related Applications

This application claims priority to U.S. Provisional Application Serial No. 61/975,420 filed April 4, 2014, which is hereby incorporated in its entirety into this application.

Field of the Invention

The present invention relates to conditionally stable nanoparticle compositions and methods of treatment of cancer patients, particularly those cancers which benefit from treatment by local delivery routes of administration including intraperitoneal or intravesicular infusions for treatment of ovarian cancer, gastric cancer and bladder cancer.

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. 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. Side effects are common although the symptoms are either grade 1 or 2 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 (polyoxyethylated 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. Taxol 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 the concomitant or prior medications 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 (MBC) 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 lyophilized 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 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 are more stable in protein-free medium and less stable or unstable in a protein containing medium. The present invention relates to cancer treatment compositions where the cancer treatment drug is contained within a micelle or nanoparticle and where the cancer treatment composition is stable in protein-free medium and less stable or unstable in a protein containing medium. The present invention relates to paclitaxel compositions where the paclitaxel is contained within a micelle or nanoparticle and where the paclitaxel composition is stable in protein-free medium and less stable or unstable in a protein containing medium. The present invention further relates to nanoparticle compositions where the composition comprises about 4ug/ml to about 6000 ug/ml of paclitaxel. The present invention relates to nanoparticle 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 nanoparticle compositions where the composition is at least 20% more stable or 50% more stable or 100% more stable in a protein-free solution than nab-paclitaxel. The present invention relates to nanoparticle 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 nab-paclitaxel.

The present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing nanoparticles by any local delivery route of administration where conditional stable nanoparticle would expect to outperform unstable nanoparticles. The methods also relate to nanoparticles which are stable in protein-free medium and unstable in a protein containing medium where the protein free medium may be serum free medium and where the serum free medium may include but is not limited to phosphate buffered saline or saline or 5% Dextrose or Ringer Lactate. The methods of the present invention also relate to methods of treating cancer patients by administering a cancer treatment drug containing conditionally stable nanoparticles by local delivery routes to the patient where the level of cancer treatment drug one hour post infusion is higher than a comparable infusion of a cancer treatment drug with a unstable nanoparticle delivery system. The methods of the present invention also relate to methods of treating cancer patients by administering paclitaxel containing nanoparticles by local delivery routes to the patient where the level of cancer treatment drug one hour post infusion is higher than a comparable infusion of paclitaxel with a unstable nanoparticle delivery system.

The present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing nanoparticles by intraperitoneal infusion to the patient, where the cancer treatment drug can be, among other drugs, paclitaxel. The methods also relate to nanoparticles which are stable in protein-free medium and unstable in a protein containing medium where the protein free medium may be serum free medium and where the serum free medium may include but is not limited to phosphate buffered saline or saline or 5% Dextrose or Ringer Lactate. The methods of the present invention also relate to methods of treating cancer patients by administering a cancer treatment drug containing conditionally stable nanoparticles by intraperitoneal infusion to the patient where the level of cancer treatment drug one hour post infusion is higher than a comparable infusion of a cancer treatment drug with a unstable nanoparticle delivery system. The methods of the present invention also relate to methods of treating cancer patients by administering paclitaxel containing nanoparticles by intraperitoneal infusion to the patient where the level of cancer treatment drug one hour post infusion is higher than a comparable infusion of paclitaxel with a unstable nanoparticle delivery system.

The present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing conditionally stable nanoparticles by intravesicular infusion to the patient, where the cancer treatment drug can be, among other drugs, paclitaxel. The methods also relate to nanoparticles which are stable in protein-free medium and unstable in a protein containing medium where the protein free medium may be serum free medium and where the serum free medium may include but is not limited to phosphate buffered saline or saline or 5% Dextrose or Ringer Lactate. The methods of the present invention also relate to methods of treating cancer patients by administering a cancer treatment drug containing nanoparticles by intravesicular infusion to the patient where the level of cancer treatment drug one hour post infusion is higher than a comparable infusion of a cancer treatment drug with a unstable nanoparticle delivery system. The methods of the present invention also relate to methods of treating cancer patients by administering paclitaxel containing conditionally stable nanoparticles by intraperitoneal infusion to the patient where the level of cancer treatment drug one hour post infusion is higher than a comparable infusion of paclitaxel with a unstable nanoparticle delivery system. 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 the concentration of IG-001 and nab-paclitaxel in intraperitoneal fluid when administered as an IP bolus versus time. Figure 4 - Plot of the concentration of IG-001 and nab-paclitaxel in plasma when administered as an IP bolus versus time.

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 present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing conditionally stable nanoparticles by intraperitoneal infusion to the patient, where the cancer treatment drug can be, among other drugs, paclitaxel. The present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing conditionally stable nanoparticles by intravesicular infusion to the patient, where the cancer treatment drug can be, among other drugs, paclitaxel.

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, Cynviloq™) which is a cremophor-free, polymeric micelle formulation of paclitaxel. IG-001 (Genexol-PM) 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. 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.

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 conditional stable- less stable once administered into blood such that the drug compound can be released from the nanoparticle and made available to the endogenous protein delivery system.

The nanoparticle formulations of the present invention are quite stable in protein-free media. 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.

The conditionally stable nanoparticle would still allow for the rapid breakdown once in plasma or blood or target tissue allowing the release of the drug. Compositions and formulations that are too stable, such as NK105 or Cremophor EL Paclitaxel will enable the drug to accumulate in blood and thus not permit the release of paclitaxel to its target in the tumor. Thus stability in administration fluid only facilitates local accumulation without impacting on activity.

The present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing conditionally stable nanoparticles to the patient, where the cancer treatment drug can be, among other drugs, paclitaxel. In the methods of the present invention administration of conditionally stable nanoparticles containing cancer treatment drugs exhibit enhanced levels of adsorption of the cancer treatment drug as compared to unstable nanoparticle containing cancer treatment drugs. In the methods of the present invention the administration of nanoparticles containing cancer treatment drugs exhibit levels of cancer treatment drugs in the intraperitoneal fluid that is at least 1.5 times, or 2 times, or three times or four times, or five times, or six time or seven time, or eight times, or nine times or ten times or 15 times, or 20 times or 50 times greater than the administration of unstable nanoparticle containing cancer treatment drugs at the same or similar level measured about 30 minutes or about 1 hour or about 2 hours after infusion. In the methods of the present invention administration of nanoparticles containing cancer treatment drugs exhibit levels of cancer treatment drugs that is from about 1.5 times to about 50 times, or 1.5 times to about 20 times, or from about 1.5 times to about 10 times, or from about 1.5 times to about 5 times, or from about 1.5 times to about 3 times or from about 1.5 time to about 2 times, or from about 2 times to about 50 times, or 2 times to about 20 times, or from about 2 times to about 10 times, or from about 2 times to about 5 times, or from about 2 times to about 3 times or from about 3 times to about 50 times, or 3 times to about 20 times, or from about 3 times to about 10 times, or from about 3 times to about 5 times, or from about 5 times to about 50 times, or 5 times to about 20 times, or from about 5 times to about 10 times, or from about 10 times to about 50 times, or from about 10 times to about 20 times more than administration of unstable nanoparticle containing cancer treatment drugs at the same or similar level measured about 30 minutes or about 1 hour or about 2 hours after infusion.

The present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing conditionally stable nanoparticles by intraperitoneal infusion to the patient, where the cancer treatment drug can be, among other drugs, paclitaxel. In the methods of the present invention intraperitoneal administration of conditionally stable nanoparticles containing cancer treatment drugs exhibit enhanced local drug exposure compared to intraperitoneal infusion of unstable nanoparticle containing cancer treatment drugs. In the methods of the present invention the intraperitoneal administration of nanoparticles containing cancer treatment drugs exhibit levels of cancer treatment drugs in the intraperitoneal fluid that is at least 1.5 times, or 2 times, or three times or four times, or five times, or six time or seven time, or eight times, or nine times or ten times or 15 times, or 20 times or 50 times greater than intraperitoneal infusion of unstable nanoparticle containing cancer treatment drugs at the same or similar level measured about 30 minutes or about 1 hour or about 2 hours after infusion. In the methods of the present invention the intraperitoneal administration of nanoparticles containing cancer treatment drugs exhibit levels of cancer treatment drugs in the intraperitoneal fluid that is from about 1.5 times to about 50 times, or 1.5 times to about 20 times, or from about 1.5 times to about 10 times, or from about 1.5 times to about 5 times, or from about 1.5 times to about 3 times or from about 1.5 time to about 2 times, or from about 2 times to about 50 times, or 2 times to about 20 times, or from about 2 times to about 10 times, or from about 2 times to about 5 times, or from about 2 times to about 3 times or from about 3 times to about 50 times, or 3 times to about 20 times, or from about 3 times to about 10 times, or from about 3 times to about 5 times, or from about 5 times to about 50 times, or 5 times to about 20 times, or from about 5 times to about 10 times, or from about 10 times to about 50 times, or from about 10 times to about 20 times more than intraperitoneal infusion of unstable nanoparticle containing cancer treatment drugs at the same or similar level measured about 30 minutes or about 1 hour or about 2 hours after infusion.

The present invention also relates to methods of treating cancer patients by administering a cancer treatment drug containing nanoparticles by intravesicle infusion to the patient, where the cancer treatment drug can be, among other drugs, paclitaxel. In the methods of the present invention intravesicular administration of nanoparticles containing cancer treatment drugs exhibit enhanced levels of adsorption of the cancer treatment drug as compared to intravesicular infusion of unstable nanoparticle containing cancer treatment drugs. In the methods of the present invention the intravesicular administration of nanoparticles containing cancer treatment drugs exhibit levels of cancer treatment drugs in the intravesicular fluid that is at least 1.5 times, or 2 times, or three times or four times, or five times, or six time or seven time, or eight times, or nine times or ten times or 15 times, or 20 times or 50 times greater than intravesicular infusion of unstable nanoparticle containing cancer treatment drugs at the same or similar level measured about 30 minutes or about 1 hour or about 2 hours after infusion. In the methods of the present invention the intravesicular administration of nanoparticles containing cancer treatment drugs exhibit levels of cancer treatment drugs in the intravesicular fluid that is from about 1.5 times to about 50 times, or 1.5 times to about 20 times, or from about 1.5 times to about 10 times, or from about 1.5 times to about 5 times, or from about 1.5 times to about 3 times or from about 1.5 time to about 2 times, or from about 2 times to about 50 times, or 2 times to about 20 times, or from about 2 times to about 10 times, or from about 2 times to about 5 times, or from about 2 times to about 3 times or from about 3 times to about 50 times, or 3 times to about 20 times, or from about 3 times to about 10 times, or from about 3 times to about 5 times, or from about 5 times to about 50 times, or 5 times to about 20 times, or from about 5 times to about 10 times, or from about 10 times to about 50 times, or from about 10 times to about 20 times more than intravesicular infusion of unstable nanoparticle containing cancer treatment drugs at the same or similar level measured about 30 minutes or about 1 hour or about 2 hours after infusion.

Cancer treatment drugs used in the compositions and formulations of the present include but are not limited to paclitaxel, docetaxel, epothilones, rapamycin, 17-AAG, 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, epothilones and other tubulin inhibitors.

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.

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 as dissociation curves plotting nanoparticle size versus paclitaxel concnetrations. 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 (Figures 1 and 2). In PBS, 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 (Figure 2).

Example 2

Comparison of Intraperitoneal!)/ Administered IG-001 and nab-Pac nab-Pac and IG-001 were administered as an IP Bolus at 30 mg/kg. IP fluid was collected at 5, 15, 30 min and 1, 4, 8, 12, 24 hour post dosing using 3 animals per time point and paclitaxel levels were quantified by LC/MS-MS. The results showed up to a 10-fold enhanced paclitaxel levels for IG-001 vs. nab-paclitaxel at 1 hour post administration. Quantification of differences beyond the 1 hour time point failed presumably due to complete absorption of the administered drugs See Figures 3 and 4. Despite higher IP drug exposure, the IV drug exposure remained the same as unstable nanoparticles (Abraxane).

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.