CANE-SUGAR SUBSTITUTE

RELATED APPLICATION

This application claims the benefit of priority of U.S. Provisional Patent Application No. 62/520,538, filed June 15, 2017, the contents of which are incorporated herein by reference in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to sugar substitutes and uses thereof, and more particularly, but not exclusively, to an all-natural cane-sugar substitute suitable for all uses.

Sugar substitutes are natural and/or synthetic food additives that simulate the sweet taste effect of sugar. Sweet tastes of natural and synthetic high-potency sweeteners are slower in onset and longer in duration than the sweet taste produced by sugar and thus change the taste balance of a food composition. Because of these differences, use of natural and synthetic high-potency sweeteners to replace a bulk sweetener, such as sugar, in a food or beverage, causes an unbalanced temporal profile and/or flavor profile. In addition to the difference in temporal profile, high-potency sweeteners generally exhibit lower maximal response than sugar, off tastes (e.g., bitter, metallic, cooling, astringent, licorice-like taste), tongue and oral cavity numbing/tingling, and/or sweetness that diminishes on iterative tasting. Some high potency sweeteners also exhibit dramatically different sweetness intensities as a function of temperature. It is well known to those skilled in the art of food/beverage formulation that changing the sweetener in a composition requires re-balancing of the flavor and other taste components. If the taste profile of natural and synthetic high-potency sweeteners could be modified to impart specific desired taste characteristics to be more sugar-like, the type and variety of compositions that may be prepared with that sweetener would be expanded significantly. Accordingly, it would be desirable to selectively modify the taste characteristics of natural and synthetic high- potency sweeteners.

Artificial sweeteners are synthetic sugar substitutes that may be derived from naturally occurring substances. Artificial sweeteners, such as Aspartame™, Sucralose™, and Saccharin™, are common alternatives to sugar because much less sweetener material is required as compared with the amount of sugar to achieve the same level of sweetness. Since many artificial sweeteners have higher levels of sweetness than sugar, they often have a different taste than that of sugar, frequently having a bitter or chemical aftertaste. In addition to not tasting like sugar, some sweeteners are made with glycemic, ingredients (such as maltodextrins) or synthetic additives or sugar alcohols or fructose in an effort to more similarly resemble sugar. However, artificial sweeteners still lack many of the properties and functions of sugar, such as sugar-like mouth feel and sugar-like binding and browning in baking, not to mention their adverse effects, such as their allergic and laxative effect.

Additionally, artificial sweeteners have been linked to an increase in diabetes, metabolic disease, neurotoxicity, carcinogenicity, and obesity as they have also been shown to adversely affect human gut bacteria. Artificial sweeteners have been specifically shown to increase the abundance of bacterial strains belonging to the Bacteroides genus and the Clostridiales order, both of which contain members linked to obesity, glucose intolerance, and opportunistic infections. In addition, artificial sweeteners are believed to interact with sweet taste receptors in the gut, which results in the release of insulin in the body. In addition to disrupting an individual's blood sugar levels, insulin spikes are known to increase fat stores and general inflammation resulting in a variety of health issues, associated with obesity and diabetes. As a result, high-volume artificial sweeteners are of particular concern to educate consumers and individuals that already have elevated insulin or blood sugar levels. Thus, sugar substitutes derived from natural ingredients have been proposed as healthier alternatives to artificial sweeteners.

Currently known sugar substitutes may be derived from plants, fruit, vegetables, herbs, roots, and grains. However, these sugar substitutes, some of which claim to be derived from natural sources, such as Isomalt™, Stevia™, Truvia™, and Monatin™, still lack many of the properties, usability and functions of sugar. Some of these sugar substitutes only have between about 40 % and 60 % of the sweetness of sugar and have a notable metallic aftertaste, such as that of many Stevia™ extracts. Other natural sugar substitutes, such as Palatinose™, have a lower glycemic index than sugar, but provide the same amount 20 of calories per gram as found in sugar. Some natural sugar substitutes, such as those containing sugar alcohol varieties, often cause laxative and bloating side effects and therefore are limited for use to only a small serving per day. Also, many natural sugar substitutes use ingredients derived from genetically modified organisms (GMO) and do not include a fiber component. Similarly, in the sugar substitutes that do utilize soluble fiber as a starting material, fiber production is often produced from GMO ingredients.

Hitherto, commonly found natural sugar substitutes have used several ingredients, such as digestion resistant soluble fiber, Luo Han Guo extracts, and steviol glycosides, to replicate the various properties and characteristics of sugar. However, these attempts have not been successful in replicating the properties and characteristics of sugar. As a result, these ingredients typically require a combination thereof with fructose and/or sucrose, artificial ingredients, sugar alcohol, or maltodextrin in order to simulate sugar.

Accordingly, there exists a need for a sugar substitute composition comprising natural ingredients that can provide the added human health benefits and properties and characteristics of sugar, without the caloric content and glycemic index of sugar and/or sugar additives and without causing adverse digestive side effects.

U.S. Patent Application Publication No. 2016/0165941 by the present inventor, which is incorporated herein by reference, discloses sugar substitute compositions comprising natural ingredients that provide added human health benefits and properties and characteristics of sugar, without the caloric content and glycemic index of sugar. Unlike artificial sweeteners, the sugar substitute compositions disclosed therein contain no chemicals or synthetic additives and taste and function similar to sugar. Specifically, the sugar substitute compositions comprise digestion resistant soluble fiber comprising an oligosaccharide matrix of glucose and/or fructose oligomers, which yield the sugar substitute digestion resistant property and allow it to simultaneously enhance the growth of beneficial bacteria in the human gut. In one embodiment, the sugar substitute comprises a digestion resistant soluble fiber, Luo Han Guo extract, and a flavor masking agent comprising rice extract. In another embodiment, the sugar substitute comprises a digestion resistant soluble fiber, Luo Han Guo extract, a flavor-masking agent comprising rice extract, and a steviol glycoside.

Additional prior art documents include, for example, WIPO Patent Applications WO 2015/042137, WO 2012/100991, WO 2017/075257 and WO 2017/176873, United States Patent Nos. 8,512,793 and 8,524,303, United States Patent Application Publication Nos. 2007/0116819, 2017/0143022, 2017/0119032, 2011/0200712, 2016/0198750, 2009/0011104, and 2016/0242439, and EP1815754 and EP1623630.

SUMMARY OF THE INVENTION

The present invention describes embodiments of an all-natural sugar substitute comprising specific compositions of botanical components with distinct ratios therebetween that yield respective levels of sweetness, ranging from sucrose level to a level that is about thirty times sweeter than sucrose, however with a lower calorie content and a lower glycemic index than that of sucrose. Specifically, in some embodiments, the composition of ingredients in the sugar substitute comprises three botanical components: a soluble fiber carrier, a fruit or herbal derived ingredient for sweetening and a grain-hull derived ingredient for flavor balancing, all of which are preferably GRAS, non-GMO and preferably devoid of maltodextrin, sugar alcohol, stevia Reb-A or any stevia derivative, glycerin, soy, milk, peanuts and wheat, and any known artificial sweetener.

In some embodiments, the sugar substitute may comprise some ingredients that would otherwise be excluded from the preferred composition but may be added due to, for example, common food processing methods. Such ingredients may include incidental additives in the manufacturing of the botanical components of the sugar substitute or incidental additives that are present in the botanical components with no technical function but are nevertheless present due to having been incorporated as an ingredient of another ingredient (such as a flavor for instance) where the additive substance have a function. Other examples of such ingredients may include processing aids that are often added during processing and may not have been fully removed, as well as otherwise excluded substances such as one or more of non-certified GRAS, non- certified non-GMO, maltodextrin, sugar alcohol, glycerin, soy, milk, peanut and wheat, each of which individually or in combination with others may be incorporated and listed on the label as making up no more than 2 % of the content of the composition.

The sugar substitute presented herein is nutritive in that each version provides phytonutrients to the diet without causing adverse effects on gut flora such as those commonly associated with non-nutritive sweeteners. The sugar substitute composition presented herein is based on specific ratios between the sweetening ingredient and the flavor balancing ingredient, each of which yields a specific level of sweetness while maintaining a clean taste with no bitter, metallic, cooling or licorice aftertaste such as that commonly associated with chemical sweeteners, stevia, sugar alcohol, allulose and Luo-Han Guo. It is the unique combination of properties - all natural, clean taste and range of sweetness, that confers the desired characteristic of the composition disclosed herein, which is distinctively unique compared to conventional sugar substitutes, as it the only sugar substitute capable of fully replacing natural sugar, such as cane sugar, and all types of sweeteners in all industrial and consumer recipes without added fillers or binders. The combined properties of some embodiments of the present invention of a sugar substitute composition, may include:

Clean pleasant taste with no bitter, metallic, cooling or licorice aftertaste;

Sweetness range from 1 to 30 sucrose equivalents;

Clean label available in 3 ingredient versions derived from non-GMO botanical sources; Available in version substantially devoid of maltodextrin, sugar alcohol, Stevia rebaudiana and derivatives thereof, soy, peanuts and wheat; Can replace sugar one-to-one in all consumer and industrial recipes without added carriers, fillers or binder;

Available in versions with sugar-like binding properties that can be useful in baking and chocolate manufacturing;

Can replace chemical sweeteners, sugar alcohols and stevia Rebaudioside A in all industrial recipes;

Least laxative;

Prebiotic, supports healthy gut bacteria;

Available in diabetic friendly versions;

Nutritive, promotes satiety;

High PH stability of 2-9 in some embodiments; and may reach 2-11 in other embodiments;

Heat stability at 200-250 °C in some embodiments; and

Low water activity (a _w ) of 0.5-0.7, or less in some embodiments.

Thus, according to an aspect of some embodiments of the present invention there is provided a composition-of-matter, which includes:

an indigestible fiber ingredient,

a natural high-potency sweetening ingredient,

a flavor-balancing ingredient; and

a grain hull ingredient.

According to another aspect of some embodiments of the present invention there is provided a composition-of-matter that consists exclusively of, consists essentially of, or consists substantially exclusively of:

an indigestible fiber ingredient,

a natural high-potency sweetening ingredient,

a flavor-balancing ingredient; and

a grain hull ingredient.

In some embodiments of the invention, the indigestible fiber ingredient is selected from the group consisting of an isomaltooligosaccharide, an inulin, a digestive resistant dextrin, and a digestive resistant maltodextrin.

In some embodiments of the invention, the natural high-potency sweetening ingredient is selected from the group consisting of a siraitia grosvenorii derived substance, a luo-han guo extract, a mogroside and esgoside. In some embodiments of the invention, the flavor-balancing ingredient is selected from the group consisting of a Vanilla planifolia derived substance, a natural vanillin and a citrus oil extract.

In some embodiments of the invention, grain hull ingredient is selected from the group consisting of rice hulls, medium roasted peanut shells, barley hulls, wheat hulls, dried grounded corncob and dried grounded sugar cane husks.

In some embodiments of the invention, the concentration of the indigestible fiber ingredient ranges from 93 to 98 weight percent; the concentration of the natural high-potency sweetening ingredient ranges from 0.5 to 2 weight percent; the concentration of the flavor- balancing ingredient ranges from 0.5 to 2 weight percent; and the concentration of the grain hull ingredient ranges from 0.5 to 2 weight percent of the total weight of the composition-of-matter.

In some embodiments of the invention, the indigestible fiber ingredient is tapioca isomaltooligosaccharide; the natural high-potency sweetening ingredient is luo-han guo extract; the flavor-balancing ingredient is natural vanillin; and the grain hull ingredient is rice hulls.

In some embodiments of the invention, the tapioca isomaltooligosaccharide is present at a concentration of 97 weight percent; the luo-han guo extract is present at a concentration of 1 weight percent; the natural vanillin is present at a concentration of 1 weight percent; and the rice hulls are present at a concentration of 1 weight percent of the total weight of the composition-of- matter.

In some embodiments of the invention, the concentration of the indigestible fiber ingredient ranges from 1 to 85 weight percent; the concentration of the natural high-potency sweetening ingredient ranges from 3 to 96 weight percent; the concentration of the flavor- balancing ingredient ranges from 2 to 35 weight percent; and the concentration of the grain hull ingredient ranges from 2 to 30 weight percent of the total weight of the composition-of-matter.

In some embodiments of the invention, the concentration of the indigestible fiber ingredient ranges about 3-30 weight percent; the concentration of the natural high-potency sweetening ingredient ranges about 55-75 weight percent; the concentration of the flavor- balancing ingredient ranges about 5-33 weight percent; and the concentration of the grain hull ingredient ranges about 5-10 weight percent of the total weight of the composition-of-matter.

In some or any of the embodiments of the invention, the composition-of-matter presented herein is substantially devoid of a sugar alcohol.

In some or any of the embodiments of the invention, the composition-of-matter presented herein is substantially devoid of an artificial or synthetic sweetener. In some or any of the embodiments of the invention, the composition-of-matter presented herein is substantially devoid of a steviol glycoside, or any Stevia rebaudiana-de /ed substance.

In some or any of the embodiments of the invention, the composition-of-matter presented herein is characterized by a glycemic index lower than 35.

In or any of the some embodiments of the invention, the composition-of-matter presented herein is characterized by inducing a glycemic response that is significantly lower than that induced by sugar in healthy human subjects.

In some or any of the embodiments of the invention, the composition-of-matter presented herein is packaged in a packaging material and identified in print for use as a sugar substitute.

In some embodiments of the invention, a mass and/or volume unit of the sugar substitute is equivalent to a mass and/or volume unit of sugar, such as tabletop sucrose.

According to another aspect of some embodiments of the present invention, there is provided a process of preparing the composition-of-matter presented herein; the process is effected by:

blending the indigestible fiber ingredient, the natural high-potency sweetening ingredient, and the flavor-balancing ingredient to thereby afford a mixture;

heating the above mixture; and

admixing the grain hull ingredient to the above mixture

wherein admixing the grain hull ingredient to the above mixture may be effected prior to, or subsequent to heating the above mixture.

In some embodiments of the invention, heating the above mixture is effected at a temperature that ranges from 65 °C to 120 °C for a time period that ranges respectively from 30 minutes to 0.5 minutes.

In some embodiments of the invention, heating the above mixture is effected in a dry oven.

In some embodiments of the invention, the process further includes, prior to heating the above mixture, mixing the mixture with water to thereby obtain a slurry; and subjecting the slurry to s spray drying procedure.

According to another aspect of some embodiments of the present invention, there is provided a food product that includes the composition-of-matter presented herein.

In some embodiments of the invention, the food product is substantially devoid of a sugar alcohol.

In some embodiments of the invention, the food product is substantially devoid of an artificial or synthetic sweetener. In some embodiments of the invention, the food product is substantially devoid of a steviol glycoside, or any Stevia rebaudiana-deriwed substance.

In some embodiments of the invention, the food product is characterized by a glycemic index lower than 35.

In some embodiments of the invention, the food product is selected from the group consisting of a pastry product, a dairy product, a beverage, and a cooked product.

According to another aspect of some embodiments of the present invention, there is provided a cosmetic or pharmaceutical composition that includes the composition-of-matter presented herein.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings:

FIGs. 1A-B present comparative spider diagrams of the sensory profile afforded for butter cookies category comparing BTS 101 to BTS90 (FIG. 1A) and comparing BTS 101 to Sugar (FIG. IB);

FIGs. 2A-B present comparative spider diagrams of the sensory profile afforded for chocolate cake category comparing BTS 101 to BTS90 (FIG. 2A) and comparing BTS 101 to Sugar (FIG. 2B); and

FIGs. 3A-B present comparative spider diagrams of the sensory profile afforded for cold coffee with milk category comparing BTS 101 to BTS90 (FIG. 3A) and comparing BTS 101 to Sugar (FIG. 3B). DESCRIPTION OF SOME SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to sugar substitutes and uses thereof, and more particularly, but not exclusively, to an all-natural cane-sugar substitute suitable for all uses.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

As discussed hereinabove, the present inventor has developed a preliminary composition- of-matter, disclosed in U.S. Patent Application Publication No. 2016/0165941, which afforded reasonable results compared to known sweeteners at the time.

While conceiving the present invention, the present inventor has contemplated a cane- sugar substitute that will have the visual appearance, texture, taste and usability of typical cane sugar, without sacrificing any of the desired properties of cane sugar. Serendipitously, a composition-of-matter was unexpectedly discovered by the inventor when a vanilla sugar substitute with a sweetness level of sucrose was mixed with a rice hulls excipient in an attempt to improve the mixture's flow. The resulting mix unexpectedly yielded a cane sugar flavor. The manufacturing of this cane sugar substitute version with sweetness level equivalent to that of sucrose, required a specific ratio between the sweetening component luo-han guo and the flavor component mix of vanillin and rice hulls. To yield a sucrose level of sweetness along with a clean taste, it was found that the natural high-potency sweetening ingredient, luo-han guo, should be of at concentration range of 0.6-2.0 wt.%, whereas to mask the aftertaste of luo-han guo, the flavor component was a 1: 1 combination of vanillin and rice hulls, present at the concentration range of 1.2-3 wt.% or 1-4.0 wt.% of the total weight of the composition. The ratio between the sweetening and the flavor components was found best at about 1/2.

While reducing the present invention to practice, the inventor has developed a composition-of-matter which comprises a sugar substitute variety where all embodiments thereof are based on four basic botanical components: an indigestible fiber ingredient, a natural high- potency sweetening ingredient, and a flavor-balancing ingredient, and a rice hulls ingredient. It was surprisingly found that the inclusion of rice hulls afforded a product with unprecedented resemblance to cane sugar. In addition it was found that the process of preparing the composition-of-matter presented herein also contributes to the performance of the final product. An indigestible fiber ingredient:

According to some embodiments of the present invention, the composition-of-matter presented herein includes an indigestible fiber ingredient. The indigestible fiber ingredient includes a substance referred to herein as an isomaltooligosaccharide, or IMO. In the context of embodiments of the present invention, IMO is a mixture of short-chain carbohydrates (fibers) that constitute a matrix of glucose oligomers (oligosaccharides) having a-D-(l,6) linkage ("iso" linkage) of various chain length, ranging from 2 to 9 saccharides linked together. In the context of embodiments of the present invention, IMO is digestion-resistant, namely a mixture of nutritional fibers that are ingestible yet indigestible; thus, ingestion of IMO is likely to contribute little to the caloric value of foods, and induce a low glycemic response in a subject (35+8 on a scale of 1-100). In general, a glycemic response refers to the changes in blood glucose after consuming/ingesting a carbohydrate-containing food, unlike available carbohydrates that are actually digested and absorbed into the blood, metabolized and induce a high glycemic response (>50 on a scale of 1-100).

IMOs are found naturally in all plants, and the raw material used for manufacturing IMO is typically starch, which is enzymatically converted into a mixture of isomaltooligosaccharides. According to some embodiments of the present invention, the IMO is a GRAS (Generally Recognized As Safe) food ingredient, which is afforded from crops like acacia, tapioca, corn, milk, banana, pulses (peas, beans, lentils), rice, potato and the likes.

In some embodiments, the indigestible fiber ingredient is IMO produced from corn, potato, acacia and/or tapioca.

Alternatively, in some embodiments, IMO can be replaced by an inulin as an indigestible fiber ingredient. Inulins constitute a group of naturally occurring fructose oligosaccharides produced by many types of plants, and are most often extracted from chicory or Jerusalem artichoke. Because of the β(2,1) linkages, inulins are not digested by enzymes in the human alimentary system, contributing to its functional properties: reduced calorie value, dietary fiber and prebiotic effects. Thus, inulins belong to a class of dietary fibers known as fructans, and are considered as indigestible fiber ingredient in the context of embodiments of the present invention. Inulin is used by some plants as a means of storing energy and is typically found in roots or rhizomes, and most plants that synthesize and store inulin do not store other forms of carbohydrate such as starch.

Alternatively and/or additionally, the indigestible fiber ingredient may include digestive resistant dextrin and digestive resistant maltodextrin. In some embodiments, the indigestible fiber ingredient may further include cellulose (e.g., from plants) and/or pectin (e.g., from apples) and/or IMO varieties derived from, for example, potato, pumpkin or banana, and in some cases also milk.

A natural high-potency sweetening ingredient:

According to some embodiments of the present invention, the composition-of-matter presented herein includes a natural high-potency sweetening ingredient.

As used herein, the phrase "natural high-potency sweetening ingredient" (NHPS ingredient) refers to any sweetener found in nature which may be in raw, extracted, purified, or any other form, singularly or in combination thereof and characteristically have a sweetness potency similar to, equal to or greater than sucrose, fructose, or glucose, yet have less calories. Non-limiting examples of NHPS ingredients include mogroside II, mogroside III, mogroside V, mogroside VI, isomogroside V, 11-oxomogroside, siamenoside, luo han guo extract in various concentrations of mogrosides, and other luo han guo extract components, monatin and its salts (monatin SS, RR, RS, SR), curculin, glycyrrhizic acid and its salts, abiziasaponin, abrusosides, in particular abrusoside A, abrusoside B, abrusoside C, abrusoside D, albiziasaponin, bayunosides, in particular bayunoside 1, bayunoside 2, brazzein, bryoside, bryonoside, bryonodulcoside, carnosifloside, carrelame, cyanin, chlorogenic acid, dihydroquercetin-3- acetate, dihydroflavenol, gaudichaudioside, gypenoside, hematoxylin, lugduname, magap, micraculin, naringin dihydrochalcone (NarDHC), pentadin, perillartine, polpodiosides, polypodoside A, scandenoside, selligueanin A, sucronate, sucrooctate, telosmoside D- tryptophane thaumatin, monellin, mabinlin, brazzein, hernandulcin, phyllodulcin, glycyphyllin, phloridzin, trilobatin, baiyunoside, osladin, polypodoside A, pterocaryoside A, pterocaryoside B, mukurozioside, phlomisoside I, periandrin I, abrusoside A, cyclocarioside I, modification or derivatives thereof rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside M (sometimes referred to rebaudioside X), dulcoside A, dulcoside B, rubusoside, stevia, stevioside, other steviol glycoside extract components, and the like. In an embodiment, the stevia glycosides can be stevia derived and/or produced through fermentation techniques. NHPS ingredients also includes modified NHPSs, which can include NHPSs which have been altered naturally or synthetically. For example, a modified NHPS includes NHPSs that have been fermented, contacted with enzyme, or derivatized or substituted on the NHPS. For the sake of brevity, in the description of embodiments, a modified NHPS is not expressly described as an alternative to an unmodified NHPS, but it should be understood that modified NHPSs can be substituted for NHPSs in any embodiment disclosed herein. Most NHPSs have taste defects, e.g., lingering sweetness, bitterness, metallic taste, and the like. In fact, all NHPSs, including artificial compounds such as aspartame, sucralose, acesulfame potassium, saccharin, cyclamate, and the like, all have significant taste defects and adaptation phenomena such as late sweetness onset relative to sucrose, lingering sweetness, bitterness, metallic taste, and astringency. While also used as sugar reducers or replacers, they have been accepted by subsets of the population in order to remove or significantly reduce sugar in their diets.

In some embodiments of the present invention the high-potency sweetening ingredient may comprise a fruit and/or herbal derived extract. The fruit extract may comprise luo han guo which is derived from the siraitia grosvenorii plant comprising 25-95 % mogrosides, and particularly mogroside V. Mogrosides constitute a family of glycosides of cucurbitane derivatives, or terpenoid glycoside phytonutrients, and include mogroside V (also referred to as mogroside 5), mogroside II Ai, mogroside II B , 7-oxomogroside II E, 11-oxomogroside Ai, mogroside III A ₂ , 11-deoxymogroside III, 11-oxomogroside IV A, 7-oxomogroside V, 11-oxo- mogroside V, and mogroside VI. The extract of such terpenoid glycoside phytonutrients is typically sweeter than sugar, yet induce very low glycemic response and very low calorie content.

In some embodiments of the present invention the high-potency sweetening ingredient is selected from the group consisting of: mogroside IV, mogroside V, Luo Han Guo sweetener, siamenoside, other components of Luo Han Guo sweetener, monatin and its salts (monatin SS, RR, RS, SR), curculin, glycyrrhizic acid and its salts, thaumatin, monellin, mabinlin, brazzein, hernandulcin, phyllodulcin, glycyphyllin, phloridzin, trilobatin, baiyunoside, osladin, polypodoside A, pterocaryoside A, pterocaryoside B, mukurozioside, phlomisoside I, periandrin I, abrusoside A, cyclocarioside I, modification or derivatives thereof, and a combination thereof.

In some embodiments, the high-potency sweetening ingredient is monk fruit extract, which is a natural product extracted from siraitia grosvenorii (luo han guo), and includes 25-95 % mogroside V, and is tested to be 150-200 time as sweet as sugar. Monk fruit extract (synonymously used herein with luo han guo extract) is also selected for being heat stable, non GMO, Kosher and GRAS certified. In addition, sweeteners made with monk fruit extract do not impact blood sugar levels, and carry substantially no calories. Unlike some artificial sweeteners, there is no evidence to date showing that monk fruit extracts has negative side effects, and they are recognized as safe for children, pregnant women, and breast-feeding women. Monk fruit extracts are available in liquid, granule, and powder forms. One of the few drawbacks of mogrosides and monk fruit extracts used as high-potency sweetening ingredient is a notable aftertaste, and the composition-of-matter presented herein provides a solution to this problem, in the form of a specific combination thereof with a flavor- balancing ingredient.

A flavor-balancing ingredient:

According to some embodiments of the present invention, the composition-of-matter presented herein includes a flavor-balancing ingredient. The flavor-balancing ingredient is included in the composition-of-matter presented herein to mitigate the aftertaste and undesired organoleptic response caused by the high potency sweeter. The flavor-balancing ingredient, according to some embodiments of the present invention, may comprise natural vanillin derived from vanilla pods, clove, eugenol, nutmeg, cinnamon or turmeric; and/or a combination of vanillin and other botanical ingredients; and/or a citrus extract from lemon oil or another type of citrus oil and/or combination of citrus oil extract and other botanical ingredients.

In some embodiments, the citrus extract may comprise a 5-10 folded citrus oil extract that may be mixed with a single strength citrus oil extract in a ratio of 9 to 1 or similar ratios.

Other flavor-balancing ingredient, according to some embodiments of the present invention, may comprise extracts or powders derived from ginger, cinnamon, pepper, allspice, nutmeg, rosemary, sage, thyme, oregano, rosemary, cardamom, chamomile, basil, bay leaf, banana, berries, papaya, melon, pineapple, coconut, cactus, peanuts, apple, pumpkin, carrot, beet, sweet potato, baobab, cassava, arrowroot, rice germ, rice bran, oat bran, lemon balm, lemon grass, cane sugar husk, pomegranate, acai, citrus, turmeric, coffee, cocoa, green tea, black tea and, the likes.

In some embodiments, the flavor-balancing ingredient is vanilla. The term "vanilla", as used herein, encompasses all sorts of vanilla flavoring products, such as natural vanillin derived from vanilla pods that is part of the vanilla orchid, vanilla extract, vanilla essence or any natural vanilla flavoring ingredient. It is noted herein that the vanilla-based flavor-balancing ingredient includes vanillin (4-hydroxy-3-methoxybenzaldehyde), which is characterized by an aldehyde functional group. Without being bound by any particular theory, it is assumed that the aldehyde functionality of vanillin interacts with certain functionalities found naturally in mogrosides and other terpenoids glycosides comprising compounds such as steviosides, whereas the product of such interaction confers the desirable taste-masking attribute to the composition-of-matter provided herein. In general, vanillin should be preferably derived from botanical sources such as vanilla orchids, clove, turmeric, nutmeg, plant eugenol and sugar. Wood lignins, microbial vanillin and petroleum-based eugenols are less desirable sources.

Grain hulls ingredient:

As discussed hereinabove, the composition-of-matter disclosed herein was found to be superior to previously disclosed compositions due to the inclusion of cereal grain hulls therein, and particularly rice hulls. In the context of embodiments of the present invention, cereal hulls, or husks, constitute the tough protective cover of the grain. It is noted herein that while grain bran is a byproduct obtained from the grain milling process, grain husk, or grain hull, is the grain's hard protecting cover. Both bran and hull are grain byproducts, which are often mistakenly considered to be the same, but are not.

According to some embodiments of the present invention the grain hulls ingredient includes any type of cereal hull, such as rice hulls, oat hulls, wheat hulls, barley hulls and the likes.

In some embodiments, the composition-of-matter includes rice hulls. Rice husks or rice hulls are the tough protective covers of the rice grain. The husks or hull is formed during the growing season, and include opaline silica and lignin content. The hull or husk is mostly indigestible to humans, hence these are typically used in the vermicomposting techniques wherein these husks are converted into fertilizers. Mostly, the husks are used for building material, insulation material, and fuel purposes.

Though both, rice bran and husk are similar in structure and nature, they differ in their properties. Rice bran and its products can be digested by human, while rice husk product cannot.

The differences between rice bran and rice hulls are summarized in the table below:

Rice product Bran Hulls

Description byproduct obtained from rice outer covering of the rice grain

mills

Definition Bran is the hard outer layers Rice hulls are the hard

of cereal grain. It consists of protecting coverings of grains of the combined aleurone and rice. In addition to protecting pericarp. Along with germ, it rice during the growing season, is an integral part of whole rice hulls can be put to use as grains, and is often produced building material, fertilizer, as a by-product of milling in insulation material, or fuel, the production of refined

grains.

Also known as: miller's bran rice husks

Consumption can be digested by humans cannot be digested by humans

and cattle

As discussed hereinabove, rice hulls were accidentally discovered to impart desired organoleptic properties to the composition-of-matter presented herein, similar to those of evaporated cane sugar juice. This effect may be correlated to the hull's composition which resembles that of sugar cane boagasse (husk). Both rice hulls and sugar cane boagasse comprise cellulose, hemicellulose, lignins and silica, which seem to contribute to the similarity between their organoleptic features. According to the existing data at the time this invention, rice hulls have never been used as a flavoring agent, neither was it ever discovered to function as such in sugar substitutes or any nutritional product.

A composition-of-matter:

Sucrose exhibits a sweet taste in which the maximal response is perceived quickly and where perceived sweetness disappears relatively quickly on swallowing a food or beverage. In contrast, the sweet tastes of essentially all high-potency sweeteners reach their maximal responses somewhat more slowly and they then decline in intensity more slowly than is the case for sucrose. This decline in sweetness is often referred to as "sweetness linger" and is a major limitation for high-potency sweeteners, whereas slow onset of sweetness also can be a problem.

Sucrose is not known to exhibit any bitterness or mouth/tongue coating, or numbing/tingling effect; all of these attributes are considered problematic, negative sensory effects, or "taste defects", in this discussion, particularly those of lingering or intensifying nature. NHPSs such as monk fruit extract and stevia, are known to have a number of taste defects and reduced sweetening power (maximum achievable sweetness intensity) relative to sugars and other high potency sweeteners, including delayed sweetness onset, bitterness, soapy taste, lingering sweetness, carryover sweetness, and recurring sweetness. In addition, a typical NHPS has a distinct sensory defect in that, in some subjects and in some instances, it leaves the tongue and overall oral cavity with a sticky, coated feeling and sometimes a numb sensation on the tongue that only subsides after significant water or other food exposure. In extreme cases, sweetness linger can last for more than 15 minutes. In extreme cases, minutes are required before the full sensation of the tongue returns. NHPSs are currently and most commonly used as sugar reduction tools and can work acceptably in products that contain some level of sugars or sugar alcohols. However, in order for NHPSs to be used to provide even more and eventually all of the sweetness in many consumer products, significant progress must be made to modify their taste profile, temporal profile and adaptive behaviors.

Embodiments of the present invention can address problems associated with taste defects of the natural high-potency sweetener. As a result, compositions-of-matter according to embodiments of the present invention exhibit significant improvement in taste defects, and have a temporal profile more similar to a sugar temporal profiles.

As used herein, "temporal profile" of a composition means the intensity of sweetness perceived over time in tasting of a composition by a human.

In some embodiments, the composition-of-matter presented herein can exhibit a more cane sugar-like temporal and/or sugar-like flavor profile by including rice hulls therein, thereby improving taste profile and can suppress, reduce or eliminate one or more of the undesirable taste defects of natural high-potency sweeteners and impart sugar-like characteristics to the composition-of-matter.

Some embodiments of the present invention provide methods for suppressing, reducing, or eliminating taste defects of a NHPS and impart sugar-like characteristics by including rice hulls in composition including the NHPS to form the composition-of-matter presented herein.

As used herein, the phrases "sugar-like characteristic", "sugar-like taste", "sugar-like sweet", "sugary", and "sugar-like" are synonymous and are used interchangeably. Sugar-like characteristics include any characteristic similar to that of sucrose and include, but are not limited to, maximal response, flavor profile, temporal profile, adaptation behavior, mouthfeel, concentration/response function behavior, tastant and flavor/sweet taste interactions, spatial pattern selectivity, and temperature effects. These characteristics are dimensions in which the taste of sucrose is different from the tastes of natural and synthetic high-potency sweeteners. Whether or not a characteristic is more sugar-like is determined by expert sensory panel assessments of sugar, whereas such assessments quantify similarities or differences of the characteristics of a composition with those comprising sugar. Suitable procedures for determining whether a composition has a more sugar-like taste are well known in the art.

As exemplified in the Examples section that follows below, the characteristics of the presently provided composition-of-matter are attributed to the ingredients and to the delicate balance therebetween, namely to the ratio of their content in the composition.

In general, unless specified otherwise, all ingredients are in a dry form, at least for the relative amount consideration, which is discussed in terms of weight percentage relative to the total weight of the composition. In some embodiments, one or more of the ingredients may be a liquid, a syrup, or a concentrated solution, and the amounts thereof refer to the weight percentage of the liquid, or to the total dissolved solid in the syrup/solution assuming the solvent is water or alcohol and that the solvent is releasable.

As demonstrated below, the composition-of-matter presented herein can be formulated to afford a product that resembles cane sugar in its sweetness, consistency and usability (functions); this particular embodiment of referred to herein as "sugar level substitute", "sucrose level substitute", or a "one-to-one" sugar substitute, namely 1 spoon (or gram) of sugar is replaceable with 1 spoon (or gram) of an embodiment of the composition-of-matter presented herein.

Alternatively and additionally, the composition-of-matter presented herein can be in a form having a high-volume sweetness equivalent of up to approximately 30-times sugar (sucrose) level. These embodiments are referred to herein as "high-volume sweetener substitute".

Thus, according to some embodiments of the present invention, the composition-of- matter presented herein in its sugar level substitute embodiment, includes:

an indigestible fiber ingredient, 94 - 98 wt.%;

a high-potency sweetening ingredient, 0.5 - 2 wt.%;

a flavor-balancing ingredient, 0.5 - 2 wt.%; and

a grain hull ingredient, 0.5 - 2 wt.%.

According to other embodiments of the present invention, the composition-of-matter presented herein in its high- volume sweetener substitute embodiment, includes:

an indigestible fiber ingredient, 1 - 85 wt.%, or 5 - 25 wt.%;

a high-potency sweetening ingredient, 3 - 96 wt.%, or 50 - 70 wt.%;

a flavor-balancing ingredient, 2 - 30 wt.%, or 15 - 20 wt.%; and

a grain hull ingredient, 2 - 30 wt.%, or 15 - 20 wt.%. It is to be understood that embodiments of the present invention encompass compositions-of-matter having all intermediate values of ingredients' contents, namely compositions-of-matter that are twice as sweet as sugar, 5-times, 10-times, 15-times, 20-times, 25-times, 30-times, 40-times and 50-times sweeter than sugar, wherein the ratio of the ingredients is maintained according to an interpolation between the "sugar level substitute" and the "high- volume sweetener" embodiments. For example, the ratio of the flavor-balancing ingredient and the grain hull ingredient is kept at a range of 0.1: 1 to 1: 1, whereas the content range of the high-potency sweetening ingredient goes from 0.5 - 2 wt.% to 50 - 90 wt.% of the composition, and the indigestible fiber ingredient makes up to Q.S. of 100 wt.%.

The composition can be supplemented with various optional and additional ingredients, which are used to confer particular properties to the composition-of-matter, such as flavoring agents, dairy-derived ingredients (e.g., dried milk), salts, thickeners, anticaking agent, and coloring agents. Such optional ingredients are selected and quantified so as not to augment the desired flavor and functionality of the composition-of-matter.

According to some embodiments, the composition-of-matter presented herein is substantially devoid of an artificial or synthetic sweetener. As used herein, the phrase "artificial or synthetic sweetener" refers to any substance that is not found in nature and characteristically have a sweetness potency greater than sucrose, fructose, or glucose, yet have less calories. Non- limiting examples of artificial or synthetic sweeteners relevant in the context of embodiments of the present invention include, without limitation, advantame, sucralose, potassium acesulfame, aspartame, alitame, saccharin, cyclamate, neotame, N-[N-[3-(3-hydroxy-4- methoxyphenyl)propyl]-L-a-aspartyl]-L-phenylalanine 1-methyl ester, N-[N-[3-(3-hydroxy-4- methoxyphenyl)-3-methylbutyl]-L-a-aspartyl]-L-phenylalanine 1-methyl ester, N-[N-[3-(3- methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-L-phenylalanin e 1-methyl ester, salts thereof, and the like.

According to some embodiments, the composition-of-matter presented herein is essentially devoid of a sugar alcohol, and more specifically, essentially devoid of sugar alcohol having 3-30 carbon atoms. Common sugar alcohols include, ethylene glycol (2-carbon), glycerol (3-carbon), erythritol (4-carbon), threitol (4-carbon), arabitol (5-carbon), xylitol (5- carbon), ribitol (5-carbon), mannitol (6-carbon), sorbitol (6-carbon), galactitol (6-carbon), fucitol (6-carbon), iditol (6-carbon), inositol (6-carbon; a cyclic sugar alcohol), volemitol (7-carbon), isomalt (12-carbon), maltitol (12-carbon), lactitol (12-carbon), maltotriitol (18-carbon), and maltotetraitol (24-carbon). It is noted herein that an IMO, as defined hereinabove, is not included in the category of sugar alcohols. According to some embodiments, the composition-of-matter presented herein is essentially devoid of any stevia derivative, stevioside, or other steviol glycoside extract components, including any natural, modified, derivative or a synthetic form thereof. In some embodiments, the high-potency sweetening ingredient is not selected from the group consisting of steviolbioside, stevioside, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside M/X, rubusoside, dulcoside A, dulcoside B, and a combination thereof.

According to an embodiment of the present invention, the composition-of-matter presented herein comprises, consists exclusively of, consists essentially of, or consists substantially exclusively of the following ingredients: an indigestible fiber ingredient, a natural high-potency sweetening ingredient, a flavor-balancing ingredient, and grain hull ingredient.

In some embodiments of the present invention, the composition-of-matter presented herein comprises, consists exclusively of, consists essentially of, or consists substantially exclusively of tapioca IMO, luo-han guo extract, natural vanillin, and rice halls.

According to an embodiment of the present invention, the composition-of-matter presented herein comprises, consists exclusively of, consists essentially of, or consists substantially exclusively of the following ingredients and amounts: an indigestible fiber ingredient at an concentration of about 94.0-97.4 wt.%, a natural high-potency sweetening ingredient at an concentration of about 0.6-2.0 wt.%, a flavor-balancing ingredient at an concentration of about 0.6-2.0 wt.%, and rice hulls at an concentration of about 0.6-2.0 wt.% of the total weight of the composition. In some embodiments, the indigestible fiber ingredient is tapioca IMO, the natural high-potency sweetening ingredient is Luo-Han Guo extract, and the flavor-balancing ingredient in natural vanillin.

Process:

While developing a protocol for preparing the composition-of-matter presented herein, it was contemplated that terpenoid glycosides, such as those found in lou-han guo-based NHPSs, and aldehydes, such as those found in many flavor-balancing ingredients such as vanillin, are polar molecules with lipophilic/hydrophilic tale ends that have a tendency to interact with each other and create a matrix in a process that may be accelerated by exposure to heat and/or exposure to moisture.

Indeed, it was found that dry heating (baking) the mixtures of the ingredients contributes to the elimination of taste defects (afternotes), possibly due to the heat effect on terpenoid glycosides and aldehydes, as well as on the removal of microbial oxidants and reduction of oxidized material which generally elicit bitter and astringent notes to degraded foodstuff. The same holds truth for spray drying protocols, which involve wetting and heating as part thereof.

It was found that a mixture comprising terpenoids glycosides and aldehyde, once exposed to a certain temperature per certain time range, forms a matrix with improved solubility and reduced foaming. It was further noticed that improvements in taste and function correlates with specific ratios between heating temperature and heating duration.

For example, the composition-of-matter presented herein is afforded after the following process protocols:

Open tray in a standard convection oven set to about 65 °C for about 5-30 minutes; or about 82 °C for about 1-10 or 1-5 minutes; or about 120 °C for about 0.5-3 or 0.5-1 minutes.

Spray drying is an alternative to the baking process, wherein the composition-of-matter is prepared by first mixing the NHPS ingredient with the flavor-balancing ingredient, thereafter mix in the indigestible fiber ingredient. Add the resulting mixture to water to afford a liquid slurry ready for spray drying/agglomeration under a temperature range of about 30-93 °C, through a single or two steps protocol until yielding a dry product. Optionally, rice hulls can be added to the dry product in a preferred concentration to afford the end product in the form of the composition-of-matter, according to some embodiments of the present invention.

Uses:

In general, the composition-of-matter presented herein can replace sugar in all food product categories, including tabletop products, cooking, baked goods, sweets, hot or cold drinks, dairy products, and the likes. It is noted that the composition-of-matter presented herein can replace sugar in a food product, while the food product is essentially devoid of any added sugars, devoid of any added sugar alcohols, or devoid of any added artificial or synthetic sweeteners.

While serving as a total sugar substitute, the composition-of-matter presented herein is capable of affording food products that are suitable for consumptions by subject that should be under a sugar-restrictive (low sugar) diet. As such, the composition-of-matter presented herein is characterized by inducing a low glycemic response. The combination of sugar-like properties and the low glycemic response induced in humans, renders the composition-of-matter presented herein an advantageous sugar substitute compared to all presently known sugar substitute products.

In some embodiments of the present invention, the composition-of-matter presented herein can be used in beverages, broths, and beverage preparations. In some embodiments of the present invention, the composition-of-matter presented herein can be used in carbonated, non- carbonated, frozen, semi-frozen ("slush"), non-frozen, ready-to-drink, concentrated (powdered, frozen, or syrup), dairy, non-dairy, herbal, non-herbal, caffeinated, non-caffeinated, alcoholic, non-alcoholic, flavored, non-flavored, vegetable-based, fruit-based, root/tuber/corn-based, nut- based, other plant-based, cola-based, chocolate-based, meat-based, seafood-based, other animal- based, algae-based, calorie enhanced, calorie -reduced, and calorie-free products. The amount of the composition-of-matter presented herein in the food product can vary depending on the desired sweetness and other characteristics of the product, so the amount of sweetener used can be adjusted accordingly. In an embodiment, the beverage can include the composition-of-matter presented herein and water, carbonated or non-carbonated water.

In some embodiments of the present invention, the composition-of-matter presented herein can be used in foods and food preparations (e.g., sweeteners, soups, sauces, flavorings, spices, oils, fats, and condiments) from dairy-based, cereal-based, baked goods, vegetable-based, fruit-based, root/tuber/corn-based, nut-based, other plant-based, egg-based, meat-based, seafood- based, other animal-based, algae-based, processed (e.g., spreads), preserved (e.g., meals-ready- to-eat rations), and synthesized (e.g., gels) products. The amount of the composition-of-matter presented herein can vary depending on the desired sweetness and other characteristics of the product, so the amount of sweetener used can be adjusted accordingly.

In some embodiments of the present invention, the composition-of-matter presented herein can be used in candies, confections, desserts, and snacks such as dairy-based, cereal- based, baked, vegetable-based, fruit based, root/tuber/corn-based, nut-based, gum-based, other plant-based, egg-based, meat-based, seafood-based other animal-based, algae-based, processed (e.g., spread;), preserved (e.g., meals-ready-to-eat rations), and synthesized (e.g., gels) products. The amount of the composition-of-matter presented herein can vary depending on the desired sweetness and other characteristics of the product, so the amount of composition-of-matter presented herein used can be adjusted accordingly.

In some embodiments, the composition-of-matter presented herein is used in bread, cakes, cookies, pastries and other baked goods, yogurt, coffee beverage, ice-cream and soft drinks.

In some embodiments of the present invention, the composition-of-matter presented herein can be used in prescription and over-the-counter pharmaceuticals, assays, diagnostic kits, and therapies. In an embodiment, the composition-of-matter can be used in weight control products, nutritional supplement, vitamins, infant diet, diabetic diet, athlete diet, geriatric diet, low carbohydrate diet, low fat diet, low protein diet, high carbohydrate diet, high fat diet, high protein diet, low calorie diet, non-caloric diet, oral hygiene products (e.g., toothpaste, mouthwash, rinses, floss, toothbrushes, other implements), personal care products (e.g., soaps, shampoos, rinses, lotions, balms, salves, ointments, paper goods, perfumes, lipstick, other cosmetics), professional dentistry products in which taste or smell is a factor (e.g., liquids, chewables, inhalables, injectables, salves, resins, rinses, pads, floss, implements), medical, veterinarian, and surgical products in which taste or smell is a factor (e.g., liquids, chewables, inhalables, injectables, salves, resins, rinses, pads, floss, implements), and pharmaceutical compounding fillers, syrups, capsules, gels, and coating products. The amount of the composition-of-matter presented herein can vary depending on the desired sweetness and other characteristics of the product, so the amount of composition-of-matter presented herein used can be adjusted accordingly.

In an embodiment, the composition-of-matter presented herein can be used in goods including table top sweeteners, sweeteners, co- sweeteners, coated sweetener sticks, frozen confection sticks, medicine spoons (human and veterinary uses), dental instruments, pre- sweetened disposable tableware and utensils sachets edible sachets potpourris, edible potpourris, artificial flowers, edible artificial flowers, clothing, edible clothing, massage oils, and edible massage oils. The amount of composition-of-matter presented herein can vary depending on the desired sweetness and other characteristics of the product, so the amount of composition-of- matter presented herein used can be adjusted accordingly.

In an embodiment, the composition-of-matter presented herein can include a tabletop composition that can optionally include bulking agent or anticaking agent or flow agent. In an embodiment, the tabletop composition-of-matter presented herein can be packaged in numerous different forms and it is intended that the tabletop composition-of-matter presented herein may be of any form known in the art. In an embodiment, the tabletop composition-of-matter presented herein can be in the form of a fine powder, a coarse powder, a granular form, packets, tablets, sachets, pellets, cubes, solids, and liquids (e.g., the composition-of-matter presented herein is included in a liquid carrier).

In an embodiment, the composition-of-matter presented herein is a liquid product with properties such that it can be sold commercially. In another embodiment, the liquid composition-of-matter presented herein is dried through a variety of techniques known to those skilled in the art including spray drying, freeze drying and vacuum drying, and foam-mat drying, stored for up to 3 years, then re-distributed into a food product such that the original taste characteristic of the liquid product is maintained.

It is expected that during the life of a patent maturing from this application many relevant variants of the sugar substitute presented herein will be developed and the scope of the terms "sugar substitute" and/or "cane-sugar substitute" are intended to include all such new technologies a priori.

As used herein the term "about" refers to ± 10 %.

The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

The term "consisting of means "including and limited to".

The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the phrases "substantially devoid of" and/or "essentially devoid of" in the context of a certain substance, refer to a composition that is totally devoid of this substance or includes less than about 5, 1, 0.5 or 0.1 percent of the substance by total weight or volume of the composition. Alternatively, the phrases "substantially devoid of" and/or "essentially devoid of" in the context of a process, a method, a property or a characteristic, refer to a process, a composition, a structure or an article that is totally devoid of a certain process/method step, or a certain property or a certain characteristic, or a process/method wherein the certain process/method step is effected at less than about 5, 1, 0.5 or 0.1 percent compared to a given standard process/method, or property or a characteristic characterized by less than about 5, 1, 0.5 or 0.1 percent of the property or characteristic, compared to a given standard.

The term "exemplary" is used herein to mean "serving as an example, instance or illustration". Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.

The words "optionally" or "alternatively" are used herein to mean "is provided in some embodiments and not provided in other embodiments". Any particular embodiment of the invention may include a plurality of "optional" features unless such features conflict.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

As used herein the terms "process" and "method" refer to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, material, mechanical, computational and digital arts.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental and/or calculated support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion. Example 1

Basic sweetness adjustment

The following is an experiment in which various parameters are tested to determine optimal ratios between lou-han guo extract and vanillin or citrus oil. Materials:

Food grade isomaltooligosaccharide tapioca powder (IMO) was obtained from Anhui Elite Industrial Co. LTD, China. Botanical source: Manihot esculenta;

Lou-han guo (Monk fruit) extract was obtained from Monk Fruit Corp's Fruit- Sweetness™ monk fruit extract division (MFC-E30P). Botanical source: Siraitia grosvenorii;

Natural vanillin was obtained from FoodArom™, (MET0000723). Botanical source: Syzygium aromaticum (clove);

Rice hull was obtained from RIBUS Inc., St. Louis, MO, USA (Nu-FLOW ^® ), marketed as a natural, free-flowing, fine powder used to replace silica (silicon dioxide, a synthetic anticaking agent) as an anticaking agent or as a flavor carrier. Particle size 200 mesh screen (74 micron). Nu-FLOW ^® is natural and organic and made from 100 % rice hulls that have been ground, steam sterilized, sifted and packaged; nothing is added and nothing is removed from the hulls; no enzymes, chemicals, solvents, extraction nor any other processes have been used in the manufacturing of Nu-FLOW ^® except as described herein. Botanical source: Oryza saliva;

High intensity sweetener with vanilla:

Different ratios between Lou-Han Guo Extract and vanillin were tested, and the following was found:

Option I - composition with lou-han guo extract comprising 30-55 % mogroside V glycosides (30MV-55MV);

Option II - composition with Lou-Han Guo Extract comprising 25 % mogroside V glycosides.

Option I yielded least taste defects at a ratio of 3: 1 between those ingredients; less preferred ratios ranged between 3: 1 and 10: 1. In all experiments lou-han guo 30MV, 50MV and 55MV exhibited virtually the same taste and sweetness qualities.

Option II yielded least taste defects at a ratio of 1: 1 between those ingredients, and less preferred ratios ranged between 1: 1 and 1:0.1.

Processing included placing the dry mixtures in an oven in a 3 mm layer over a baking tray. Different baking temperatures were tested and it was found that baking under 93 °C for 30 seconds was the minimum threshold required to notice initial improvements in solubility and taste, whereas baking under 93 °C for 3 minutes was the preferred threshold for achieving a peak in such improvements.

The effective range of baking temperature was between 60 °C to 93 °C, and the respective range of baking time was between 30 seconds to 3 minutes, beyond which there was no improvement in taste and solubility. The end product of both Option I and II, after the preferred baking threshold of 93 °C for 3 minutes, was a sweetener with instant solubility and least taste defects such as bitter, licorice, metallic or astringent compared to the starting material and equivalent Lou-Han Guo or Stevia based sweeteners, free of maltodextrin (sugar alcohols), polyols and added sugar.

Option I demonstrated the capacity to fully replace sugar in beverages, jelly, ice cream and yogurt applications. It is estimated to be about 30 times sweeter than sucrose. Recommended use of Option I is 0.3-1.5 % in a food product.

Option II demonstrated the capacity to replace sugar on a 50-100 % basis in beverages and fully replace sugar in ice cream and yogurt applications. It is estimated to be about 20 times sweeter than sucrose. Recommended use of Option II is 1-3 % in a food product.

High intensity sweetener with citrus:

Two exemplary compositions were prepared using same baking protocols as presented above, while replacing vanillin with lemon oil extract on a 1-to-l exchange; hence Option III and Option IV.

The end product in both Option III and Option IV was a high intensity sweetener with a citrus flavor, instant solubility and least taste defects such as bitter, licorice or metallic compared to equivalent Lou-Han and Stevia based sweeteners, free of maltodextrin, polyols and added sugar.

The high intensity sweeteners with citrus, Option III and Option IV, yielded no taste defects except for a hint of citrus when used in the recommended doses. Both Option III and Option IV demonstrated the capacity to fully replace sugar in fruity or citrusy beverages, jelly, ice cream and yogurt applications. Recommend use of Option III is 0.3-1.5 % in a food product, and Option IV 1-3 %. Example 2

Rice hulls

The following is an experiment in which rice hulls are used to further mitigate taste defects. This composition was accidentally discovered during the development process, while working on the vanilla composition and trying to increase the powder flow by adding an excipient in the form of rice hull. It was surprisingly found that the rice hulls unexpectedly afforded a cane sugar flavor to the composition. Thereafter, rice hulls were added at different concentrations to the abovementioned compositions Option I and Option II, and it was found that adding 3-10 wt.% rice hull yielded least taste defects to the end product. Option I and Option II with rice hulls are referred to herein as Option I-RH and Option II-RH, respectively. Experimenting with different ratios between lou-han guo, vanillin and rice hulls, it was found that when lou-han guo 30MV or 50MV were mixed with vanillin at a ratio of 30: 1, adding 1-4 wt.% rice hulls to that mix creates a more subtle and neutral flavor, whereas adding 4-10 wt.% rice hulls yields a more pronounced cane sugar-like flavor. Effective rice hulls concentration threshold ranged 1-10 wt.%. Effective vanillin concentration threshold ranged 0.1-5 wt.%. The preferred ratio range between lou-han guo 25MV and vanillin (Option II- RH was 30: 1 to 3: 1)

At a preferred concentration range of 3-10 wt.% rice hulls, the mixes of both Option I and Option II had a sugar cane flavor with least taste defects. After baking the compositions under the preferred threshold of 93 °C for 3 minutes, the end product of both Option I-RH and Option II-RH had least taste defects such as licorice, metallic or astringent, compared to equivalent lou-han or stevia based sweetener, free of maltodextrin, polyols and added sugar.

Option I-RH was tested to fully replace sugar in beverages, jelly, ice cream and yogurt applications; it is estimated to be about 30 times sweeter than sucrose.

Option II-RH was tested to replace sugar on a 50-100 % basis in beverages and fully replace sugar in ice cream and yogurt applications; it is estimated to be 20 times sweeter than sucrose.

Recommended use of Option I-RH is 0.2-1.5 % in s food product, and Option II-RH is 1.0-2 %.

Rice hull may be replaced by grounded peanut shell (medium roasted), and, or grounded hulls of barley and wheat, and/ or dried grounded corncob, and, or dried grounded sugar cane husk.

Example 3

Exemplary compositions

Sugar level substitute:

It was found that when mixing the abovementioned Option I-RH and Option II-RH with an indigestible fiber ingredient (IMO or Inulin) in a certain ratios, the resultant products yield a sweetness level close to that of sucrose. In the case of Option I-RH, a preferred ratio range of 0.6-2.5 wt.% NHPS to 99.4-97.5 wt.% indigestible fiber ingredient, yielded a sucrose equivalent level of sweetness with least taste defects. Effective ratio was 0.6-3 wt.% NHPS to 97-99.5 wt.% indigestible fiber ingredient.

The same ratio between ingredients applied to Option II-RH, however, this version had a lower level of sweetness, about 70-80 % equivalent to that of sucrose. Having a sugar-like binding capacity, all sugar level substitute compositions were capable of replacing sugar in baking applications without added binders or fillers.

Option I-RH demonstrated the capacity to fully replace sugar on a one-to-one basis in all industrial and consumers recipes including baking and can potentially serve as a tabletop item.

Option II- RH demonstrated the capacity to replace sugar on a 50-100 % basis in beverages, yogurt and ice cream, and fully replace sugar in baking; however, due to its lower level of sweetness, this version is a less preferred option for a tabletop item.

The preparation of the sugar substitute vanilla with sweetness level equivalent to that of sucrose, requires a specific ratio between the concentrations of the sweetening and the flavor components. To yield a sucrose level of sweetness along with a clean taste, the sweetening component luo-han guo should be at the concentration range of 0.6-2 wt.%, whereas to mask a aftertaste the flavor-balancing ingredient (e.g., vanillin) and the grain hulls ingredient (e.g., rice hulls) should be maintained at a 1: 1 ratio, and used as a single component at the concentration range of 1-1.5 wt.%. The ratio between the high-potency sweetening ingredient, the flavor- balancing ingredient, and the grain hulls ingredient is kept as about 1: 1: 1.

According to an embodiment of the present invention, the composition of the vanilla sugar substitute with sweetness level of sucrose ("sugar level substitute") may comprise, consist exclusively of, or consist substantially exclusively of the ingredients and amounts presented in Table 1 below.

Table 1

Ingredient wt. % Range wt.%

Tapioca IMO 97 94.0-97.4

Luo-Han Guo 1.0 0.6-2.0

Natural vanillin 1.0 0.6-2.0

Rice hulls 1.0 0.6-2.0

High-volume sweetener:

According to an embodiment of the present invention, the composition of the high- volume sweetener with sweetness level of approximately 30-times of sugar ("high-volume sweetener") may comprise, consist exclusively of, or consist substantially exclusively of the ingredients and amounts presented in Table 2 below. Table 2

Ingredient wt. % Range wt. %

Acacia gum fiber /IMO 5 3-30

Luo-Han Guo 60 55-75

Natural vanillin 30 5-33

Rice hulls 5 5-10

High intensity sweetener syrup:

Dry lou-han guo extracts with vanillin and 1-10 % rice hulls were added to solutions of alcohol and glycerin, and afforded the following syrup compositions.

Option I-RH a 10 % vanillin solution in alcohol, in a ratio of 1:2, produced a liquid sweetener with least taste defects. The concentrations of vanillin below 10 % were less effective. The liquid sweetener comprised 25 % lou-han guo and 7 % vanillin.

Option II- RH required more vanillin to yield least taste defects. It was found that mixing lou-han guo 25MV with a 25 % vanillin solution in alcohol, at a ratio of 1:2, produced a liquid sweetener with best taste qualities. The liquid sweetener comprised 25 % lou-han guo and 17 % vanillin.

Experimenting with baking the liquid products of both options under different temperatures for different durations, afforded that baking under 100 °C for 3 minutes or until noticing slight caramelization of the liquid, created a product with improved flavor and least taste defects. Effective range of baking temperature was between 65-120 °C, whereas the respective range of baking time was ranged over 30-1 minutes respectively.

The end product in both options after using the preferred baking threshold of 120 °C for 3 minutes, was a medium intensity liquid sweetener with a syrupy texture, a brown sugar caramel flavor, and the least taste defects such as bitter, metallic or licorice afternotes, compared to the starting material and equivalent syrup sweeteners, free of synthetic molecules, maltodextrin, sugar alcohol and added sugar.

An alcohol free syrup sweetener can be produced through the same protocol in both options upon substitution of the alcohol with glycerin on a 1-to-l basis. Glycerin should be derived from botanical sources, as non-botanical sources are less desirable.

Example 4

Spray drying preparation process

An alternative to baking the compositions in order to improve the taste thereof is spray drying, which confers the desired heating to the composition. High intensity sweetener cane sugar flavor:

The preparation of an exemplary composition-of-matter, according to some embodiments of the present invention, started by mixing lou-han guo 30MV or 50MV and vanillin at a ratio range of 30: 1 to 10: 1, and rice hull at a ratio of 1: 1-0.6: 1 with the lou-han guo, then blending that mixture with water to yield a liquid slurry ready for spray drying/agglomeration through a one step or two steps protocol.

The preparation of another exemplary composition-of-matter, according to some embodiments of the present invention, started by mixing lou-han guo 25MV with vanillin at a ratio of 4: 1 to 3: 1, and rice hull at a ratio of 1: 1-0.6: 1 with the lou-han guo, then blending that mixture with water to yield a liquid slurry ready for spray drying/agglomeration through a single step or two steps protocol.

The liquid slurry was spray dried alone or over a bed of acacia gum and/or cellulose under a temperature threshold ranging about 65-93 °C, until yielding a dry composition.

Optionally, the agglomeration process applies initially only to the composition of lou-han guo and vanillin at the ratios presented above; and after the mixture undergone spray drying, the dried composition was mixed with rice hulls at a final concentration of 3-10 % rice hulls, to afford the final composition-of-matter.

The spray drying temperature should be carefully adjusted to prevent formation of scorch particles. Though initial experiments have shown that spray drying under 120 °C can yield a viable product, a slower drying process utilizing a lower temperature range of 55-93 °C have shown to yield more desirable end products with lower scorch/ash content.

Sucrose level sugar substitute with vanilla:

The preparation of an exemplary composition-of-matter, according to some embodiments of the present invention, started by mixing lou-han guo 30MV or 50MV and vanillin at a ratio of 3: 1, and the mixture was blended with the indigestible fiber ingredient (IMO or inulin) at a ratio of 2.5 % lou-han guo/vanillin mixture to 97.5 % indigestible fiber ingredient.

The preparation of another exemplary composition-of-matter, according to some embodiments of the present invention, started by mixing lou-han guo 25MV and vanillin at a ratio of 1: 1, and the mixture was blended with the indigestible fiber ingredient (IMO or inulin) at a ratio of 2.5 % lou-han guo/vanillin mixture to 97.5 % indigestible fiber ingredient.

The ratio range between ingredients was 1-3 wt.% lou-han guo/vanillin mixture to 99-97 wt.% indigestible fiber ingredient. The dry blended mixtures were mixed with water to yield a slurry ready for spray drying/agglomeration under a temperature range of about 65-93 °C through a single step or two steps protocol until yielding the end product.

Sucrose level sugar substitute with citrus oil:

Following the same production protocol as that used for the sucrose level sugar substitute with vanilla, except that vanillin was replaced with lemon oil extract on a 1-to-l basis.

Sucrose level sugar substitute (cane sugar substitute):

The preparation of these exemplary compositions started with a mixture of lou-han guo and vanillin at a ratio range of 10: 1 to 3: 1 and rice hull at a ratio of 0.6: 1 to 1: 1 lou-han guo/rice hull for the mixture of lou-han guo 30Mv and 50MV, and a ratio range of 3: 1 to 2: 1 for the mixture with lou-han guo 25MV and vanillin and rice hull at a ratio of 0.6: 1 to 1: 1.

The indigestible fiber ingredient (IMO or inulin) was added to the mixtures at a ratio of 1.9-2.3 % mixture to 98.1-97.7 % indigestible fiber ingredient. Effective ratio ranged 1.5-2.5% mixture to 98.5-97.5 % indigestible fiber ingredient.

The resulting mixtures was blended with water to yield a liquid slurry ready for spray drying/agglomeration under a temperature range of 65-93 °C through a single or two steps protocol until yielding a dry product.

Optionally, the dry mixture of agglomerated lou-han guo, vanillin and indigestible fiber ingredient at the above ratios, was mixed with rice hulls at a concentration ranging 1-1.5 wt.% until yielding the end product composition-of-matter, according to some embodiments of the present invention. Effective rice hulls concentration ranged about 0.5-2.0 wt.%.

It is noted that the drying process should was carefully monitored to grant water movement below 5 (<5) for the end product.

The agglomerated composition-of-matter was afforded as granules in a preferred size of 20-80 mesh, similar to that of sugar granules.

Example 5

Organoleptic evaluations

In order to evaluate the effect of rice hulls on the performance of the composition-of- matter presented herein, compared to the performance of sugar substitutes disclosed in U.S. Patent Application Publication No. 2016/0165941, and compared to the performance of natural cane sugar, samples of various food products were prepared and evaluated by a of expert sensory (organoleptic) panel. As a standard for sugar-like characteristic, natural cane sugar was used to prepare the same products based on essentially the same recipe as those used for the sugar substitute samples.

The objectives of the organoleptic tests was to characterize sensory profiles for different products from three different food categories, in order to test whether the composition-of-matter presented herein has a similar sensory profile to cane sugar, and superior to the compositions disclosed in U.S. Patent Application Publication No. 2016/0165941.

The food product categories that were tested included:

Butter cookies;

Chocolate cake; and

Cold coffee with milk.

In each category, a sensory profile was built for three samples:

A composition-of-matter, according to some embodiments of the present invention, referred to herein as the "sugar level substitute", and denoted "BTS 101";

A sugar substitute composition similar to BTS 101 but without rice hulls (as disclosed in U.S. Patent Application Publication No. 2016/0165941), and denoted "BTS90"; and

Plain cane sugar, denoted "sugar".

The food products were tested among a "New Sense Research" (25 Efal St., Amot Platinum Tower, Kiryat Arie, Petach Tikva, Israel) expert panel, which included 10-12 professional tasters, all supertasters, who were screened according to the ISO standards for sensory sensitivity, consistency and sensory memory. The panelists met the following criteria:

Below the age of 65;

Without medical problems and nutritional limitations;

Not taking medications regularly;

Verbal, without language restrictions; and

Motivated.

The expert panel is a universal panel and therefore, for the purpose of adjusting for sugar substitutes tasting, the panel members were trained in training sessions for each category. The training sessions consisted the following subjects:

Building sensory vocabulary for the category;

Learning the tasting protocol for the category in order to calibrate all the tasters to a uniform taste;

Training the panel members on the different attributes intensities;

Calibration all the panel members on the scales; and Training on building a sensory profile for the products according to the attributes that were decided on the vocabulary.

After training and calibrating the panel members on each category held another meeting for each category in order to build a sensory profile (a "spider diagram") for the tested products in each category, according to the attributes that were decided on the sensory vocabulary.

Butter cookies category sensory profile:

Butter cookies were prepared as follows:

For a batch of 45 small cookies, 175 grams soft butter, 200 grams of BTS lOl, BTS90 or sugar, two egg-yolks, 2.5 cups of plain wheat flour, 0.5 ts of baking powder and a small amount of salt. The butter and BTS 101/BTS90/sugar were mixed in a food processor, and yolks were added thereto. Flour and salt were thereafter added and kneaded to afford homogeneous dough. The dough was flattened to a rounded dick, wrapped with plastic and refrigerated for half an hour. The cooled dough was thereafter cut into small round disks and placed on a baking sheet. The cookies were baked at 175 °C for 8-10 minutes.

Butter cookies were evaluated for properties that are relevant to the product category, and afford a comprehensive comparison relevant to all aspects of the sugar substitute samples, including all sensory attributes, which included color, size, hardness, thickness, crumbling, airiness, melt in mouth, stickiness to teeth, sweetness, butter taste, baking taste, and off-flavor (taste defects).

FIGs. 1A-B present comparative spider diagrams of the sensory profile afforded for butter cookies category comparing BTS lOl to BTS90 (FIG. 1A) and comparing BTS lOl to Sugar (FIG. IB).

As can be seen in FIGs. 1A-B, the sensory profile of the cookies with BTS lOl is very different from the sensory profile of the cookies with BTS90 in all the sensory attributes, except stickiness to teeth which was quite similar. The sensory profile of the cookies with BTS lOl was more similar to the profile of the cookies with sugar. However, they are some texture differences compare to the cookies with sugar. In terms of taste attributes, the cookies with BTS lOl are less sweet and having less baking taste, and they were darker then the cookies with the sugar.

Chocolate cake category sensory profile:

Chocolate cake was prepared as follows:

For a batch of 2 English cake forms, 2.5 cups of plain wheat flour, 300 grams of BTS 101, BTS90 or sugar, 2/3 cups of cocoa powder, 2 ts of baking powder, 1 tb sodium bicarbonate powder, 3 eggs, 1 cup of oil and 2 cups of water. All dried ingredients were premixed and eggs, oil and water were added thereto and mixed to afford homogeneous dough. The dough was poured into cake forms and places in an a preheated oven set at 170 °C, and baked at 170 °C for 30-35 minutes.

The chocolate cake was evaluated for properties that are relevant to the product category, and afford a comprehensive comparison relevant to all aspects of the sugar substitute samples, including all sensory attributes, which included color, smell, sweetness, bitterness, chocolate taste, crumbling, dryness/moisture, compressible/airiness, mashable, and off-flavor (taste defects).

FIGs. 2A-B present comparative spider diagrams of the sensory profile afforded for chocolate cake category comparing BTS lOl to BTS90 (FIG. 2A) and comparing BTS lOl to Sugar (FIG. 2B).

As can be seen in FIGs. 2A-B, the sensory profile of the cake with BTS lOl is different from the sensory profile of the cake with BTS90, in most of the sensory attributes. The sensory profile of the cake with BTS lOl was very similar to the profile of the cake with sugar in most of the sensory attributes; however, it is less dark, slightly less sweet and less dry than the product with sugar.

Cold coffee with milk category sensory profile:

Cold coffee with milk was prepared as follows:

For one liter of coffee, 5 tb of Taster's Choice instant coffee, 100 ml of hot water, 100 ml of cold milk, 800 ml of cold water, and 75 grams of BTS lOl, BTS90 or sugar. The dry ingredients were combined and dissolved in the hot water, and the cold water was added thereto. Cold coffee was served with ice cubes.

The cold coffee with milk was evaluated for properties that are relevant to the product category, and afford a comprehensive comparison relevant to all aspects of the sugar substitute samples, including all sensory attributes, which included color, smell, sweetness, sourness, bitterness, coffee taste, thickness, milkiness, body, and off-flavor (taste defects).

FIGs. 3A-B present comparative spider diagrams of the sensory profile afforded for cold coffee with milk category comparing BTS lOl to BTS90 (FIG. 3A) and comparing BTS lOl to Sugar (FIG. 3B).

As can be seen in FIGs. 3A-B, the sensory profile of coffee with BTS lOl has different sensory profile compare to the product with BTS90 and also compare to the product with sugar. Compare to the product with sugar, the coffee with BTS lOl is less sweet, less bitter and has less coffee taste. In addition, it is less thick, less milky and has less body. Compare to the product with BTS90, the product with BTS lOl is much less bitter and has less coffee taste. In addition it is less thick, has less body, less dark and has weaker smell.

Conclusions:

The results of the organoleptic sensory tests demonstrate that the composition-of-matter presented herein are capable of replacing sugar in all food categories, and in addition are superior to similar compositions known in the art.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.