Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/02—Solvent extraction of solids
  • B01D11/0288—Applications, solvents
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/02—Solvent extraction of solids
  • B01D11/0215—Solid material in other stationary receptacles
  • B01D11/0219—Fixed bed of solid material
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
  • B01D15/08—Selective adsorption, e.g. chromatography
  • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
  • B01D15/32—Bonded phase chromatography
  • B01D15/325—Reversed phase
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
  • B01D15/08—Selective adsorption, e.g. chromatography
  • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
  • B01D15/36—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving ionic interaction, e.g. ion-exchange, ion-pair, ion-suppression or ion-exclusion
  • B01D15/361—Ion-exchange

Definitions

• the present invention relates to methods for the extraction of cannabinoid compounds from plant tissue.
• THC and CBD are non-polar isoprenoid compounds that are frequently found modified with carboxylic acid groups that renders them both polar and inactive (THCA and CBD A).
• THCA and CBDA can be decarboxylated by heat, causing the compounds to be both activated and rendered non-polar (lipophilic).
• the activation, i.e. decarboxylation, of CBDA or THCA results in the active ingredients CBD or THC.
• the activation of THC and CBD limits the solubility of THC and CBD in water, while rendering them soluble in organic solvents.
• activated cannabinoids may be extracted from plant tissue using organic solvents such as chloroform, acetonitrile, butane, hexane, isopropanol, butanol, methanol and others.
• organic solvents such as chloroform, acetonitrile, butane, hexane, isopropanol, butanol, methanol and others.
• these non-potable solvents may be harmful themselves or be contaminated with trace amounts of harmful solvents.
• the invention comprises a method of extracting a cannabinoid from a plant tissue, comprising the steps of:
• the plant tissue may be dried and/or ground before the heat activation step.
• the polar solvent comprises water, a water/alcohol mixture, an organic acid, or a salt solution, and may optionally include a surfactant.
• the selective solvent is one which selectively extracts cannabinoid compounds.
• the heated, activated plant tissue may be extracted with the selective solvent to produce an intermediate resin before washing with a polar solvent in step (b).
• the selective solvent comprises ethanol or ethyl acetate.
• cannabinoids conversion of non-active, carboxylated forms of cannabinoids into their non-polar active ingredients allows for the subsequent, preferential removal of components which are soluble in a polar solvent.
• the cannabinoids may then be extracted using a selective solvent, such as ethanol, which is preferred due to its potability.
• a selective solvent such as ethanol
• Non-polar activated cannabinoids such as THC and CBD are not soluble in polar solvents, therefore polar contaminants may be washed away using the polar solvent.
• the polar solvent may be modified with salts, buffers or inorganic or organic acids or bases.
• the non-polar cannabinoids may then be extracted in a potable selective solvent, such as ethanol, that contains no harmful residues.
• the extracted cannabinoids may be purified by chromatography and/or quantified by spectroscopic methods.
• cannabis plant tissue is heated using an oven or a water bath to cause the conversion of the native acid forms of the cannabinoids, such as
• the plant tissue is heated at a temperature between about 100° to about 140° C, for between about 30 minutes to about 2 hours, preferably at about l20°C for about 1 hour.
• the washing step uses a polar solvent comprising water, a water/alcohol mixture, water modified by salt, buffers, inorganic or organic acids or bases, potable organic solvents, and/or combinations thereof.
• the tissue or intermediate resin is washed in a polar solvent comprising a potable surfactant or emulsifying agent, such as deoxycholate or n-octylglucoside or other amphipathic detergents.
• the washing step is done at a refrigerated temperature, such as below about 5° C, more preferably below about 0° C, but obviously above the freezing temperature of the polar solvent.
• the heated and washed cannabis tissue is subsequently extracted with a potable organic solvent, such as >40% ethanol and preferably 80% ethanol (v:v).
• a potable organic solvent such as >40% ethanol and preferably 80% ethanol (v:v).
• the extraction step occurs at a refrigerated temperature, such as between about -80° C to about 5° C, and more preferably between about -20° C and about 0° C.
• the active cannabinoids extracted from washed tissue by the selective solvent may be subsequently purified or separated from other extracted components by chromatography, the separation may be performed by liquid
• chromatography optionally DEAE, CMC, QA, PS, normal phase, or reversed phase chromatography.
• the chromatography may be isocratic, step gradient or a linear gradient.
• the purity of the purified active ingredient may be quantified by liquid chromatography such as high-performance liquid chromatography (HPLC).
• HPLC high-performance liquid chromatography
• the HPLC is nanoflow liquid chromatography.
• the HPLC can be reverse phase HPLC, ion exchange HPLC or normal phase HPLC.
• the chromatography mobile phase can for example be isopropyl alcohol (IP A), methanol, ethanol, propanol, or acetonitrile.
• the stationary phase can for example be silica based or polymer based, for example silica particles modified with octadecyl carbon chain (Cl 8).
• the step of detecting one or more ionizable products using mass spectrometry comprises ionizing the one or more ionizable products, optionally by electrospray ionization (ESI) or Atmospheric Pressure Chemical Ionization (APCI) to produce one or more product ions with a selected signal -to-noise ratio, and subjecting the one or more product ions to MS, optionally tandem MS (MS/MS).
• the ionizing is positive ionization (e.g. using an acidic buffer in the mobile phase).
• the ionizing is negative ionization (e.g using a basic buffer in the mobile phase).
• the step of ionizing the one or more ionizable products comprises Matrix-assisted laser desorption/ionization (MALDI).
• Figure 1 is an illustration of a scheme to activate, wash, selectively extract, purify, identify and quantify the cannabinoid compounds.
• Spectra depicts (A) 3x blank (B) external CBD standard curve from 0-200uM (C) detection of CBD (m/z 315) in hemp A HA1 extract,
• Figure 4A - CBD alone; 4B - THC alone; 4C - CBD and THC separation on a 6 cm column; 4D, CBD and THC separation on a 15 cm column over KinetexTM coreshell resin.
• Gradients - Samples were diluted in B buffer (65% AcN, 5%FA) with gradient 0 min at 70%, 10 min linear gradient to 80%, held for 5 min at 80% and equilibrate at 70%(base peak).
• Figure 6A CBD and THC reference standard; 6B, CBD alone; 6C, THC alone; 6D, Sample A spiked with CBD-D3; 6E, Sample B spiked with THC-D3.
• FIG. 7 Decarboxylation of CBDa at different temperatures.
• CBD external standard curve B, Internal versus external CBD curve.
• C Illustration spectra of the detection of CBD (m/z 315) in a hemp sample heated to l20°C spiked with CBD-D3 (m/z 318) measured by isocratic separation over C18 resin.
• FIG. 9 EtOH gradient extraction of CBD.
• C CBD and CBDa extracted in an ethanol gradient from a hemp sample heated to l20°C for 1 hour.
• Sample 1 0.1% TFA in 80% EtOH pH>2 (not adjusted); Sample 2, 0.1% FA in 80% EtOH pH2 (not adjusted); Sample 3, 0.1% Acetic acid in 80% EtOH pH3 (not adjusted); Sample 4, lOmM Citric acid in 80% EtOH pH4; Sample 5, lOmM Citrate in 80% EtOH pH5; Sample 6, lOmM Citrate in 80% EtOH pH6; Sample 7, lOmM Tris in 80% EtOH pH7; Sample 8, lOmM Tricine in 80% EtOH pH8; Sample 9, 0.1%
• CBD yields from 5 sequential extractions with and without pre-washing with H20 (n 3).
• O.lg hemp was heated to l20°C for 1 hour and extracted in A, 5x H20;
• B 5x Acetonitrile
• C 5x Ethanol
• D 5x Acetonitrile pre-washed with 5x H20
• E 5x Ethanol pre-washed with 5x H20
• Figure 14A ⁇ 7.5 mg CBD was extracted from 0.5g hemp in 100 % Ethanol, diluted to 20% ethanol and loaded onto a ⁇ l00ul HiQ column. The column was washed with loading solvent prior to elution with increasing amounts of Ethanol (25, 30, 32.5, 35, 37.5, 40,
• Figure 16 The wash of intermediate resin from cannabis sample A.
• a 0.1 g aliquot of cannabis sample A was washed heated to l20°C for 1 hour, extracted in ethanol and dried under vacuum to make a intermediate resin.
• the water soluble components of the resin were washed in water or water modified with organic acid, ethanol, or salt.
• Figure 17 The wash of intermediate resin from cannabis sample B. A 0.1 g aliquot of cannabis sample A was washed heated to l20°C for 1 hour, extracted in ethanol and dried under vacuum to make an intermediate resin. The water soluble components of the resin were washed in water, water with 0.5% acetic acid (v:v), ethanol, or salt.
• Figure 18 The extraction of intermediate resin from cannabis sample A.
• a 0.1 g aliquot of cannabis sample A was washed heated to 120° C for 1 hour, extracted in ethanol and dried under vacuum to make a intermediate resin.
• the water soluble components of the resin were washed in water with 0.5% acetic acid (v:v) and extracted with 1 ml of the solvent shown.
• FIG. 19 The extraction of intermediate resin from cannabis sample B.
• a 0.1 g aliquot of cannabis sample B was washed heated to l20°C for 1 hour, extracted in ethanol and dried under vacuum to make a intermediate resin.
• the water soluble components of the resin were washed in water with 0.5% acetic acid (v:v) and extracted with 1 ml of the solvent shown.
• the present invention comprises methods of selectively extracting and purifying cannabinoids from plant tissue, such as cannabinoid plant tissue.
• Cannabinoids are compounds which act on or modulate cannabinoid receptors in cells, which can alter neurotransmitter release in the brain. Cannabinoids were originally found in Cannabis saliva I... the origin of marijuana and hashish. Marijuana or its components have been reported in the scientific literature to alleviate the symptoms of a broad range of conditions including multiple sclerosis and forms of muscular spasm, including uterine and bowel cramps; movement disorders; pain, including migraine headache; glaucoma, asthma, inflammation, insomnia, and high blood pressure. There may also be utility for cannabinoids as an oxytoxic, anxiolytic, anti-convulsive, anti-depressant and/or anti-psychotic agent, anti-cancer agent, or an appetite stimulant.
• cannabinoids Many chemically related compounds, collectively classified as cannabinoids, have been isolated from Cannabis plants.
• the cannabinoids usually divided in the groups of classical cannabinoids, non-classical cannabinoids, aminoalkylindole derivatives and eicosanoids.
• Classical cannabinoids such as THC or CBD are isolated from Cannabis sativa L., or they can comprise synthetic analogs of these compounds.
• Non-classical cannabinoids may comprise bi- or tricyclic analogs of tetrahydrocannabinol (THC), while aminoalkylindoles form a group which differs structurally substantially from classical and non-classical cannabinoids.
• THC tetrahydrocannabinol
• cannabinoids can include, but are not limited to, cannabinoid compounds that may naturally occur in different combinations and relative quantities in the plant tissues of various species, subspecies, hybrids, strains, chemovars, and other genetic variants of the genus Cannabis, including material that may variously be classified as“marijuana” and“hemp” in accordance with various legal or technical definitions and standards.
• An exemplary cannabinoid comprises THC, having the formula (I):
• CBD cannabidiol
• IUPAC 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pentylbenzene- l,3-diol, having the formula (II):
• CBD is not known to have the psychotropic effects of THC, it is still considered to have a wide scope of potential therapeutic applications.
• CBD may be derived from industrial hemp which has negligible amounts of THC, and may be legally grown and consumed in Canada and the United States.
• Cannabinoid compounds may also include various other cannibinoids such as tetrahydrocannabinolic acid (THCA), delta-8-tetrahydrocannabinol (D8THC), cannabidiolic acid (CBD A), cannabinol (CBN), cannabinolic acid (CBNA),
• THCA tetrahydrocannabinolic acid
• D8THC delta-8-tetrahydrocannabinol
• CBD A cannabidiolic acid
• CBN cannabinol
• CBNA cannabinolic acid
• THCV tetrahydrocannabinovarin
• THCVA cannabidivarin
• CBDV cannabidivarin acid
• CBDA cannabigerol
• CBDA cannabigerolic acid
• CBC cannabichromene
• CBCA cannabichromenic acid
• CBND cannabinodiol
• CBNDA cannabinodiolic acid
• the term“selective” as used herein in reference to a solvent, a solid phase or chromatography system of a solvent or solid phase, is one that selectively extracts or purifies a target substance or compound, such as a cannabinoid, with greater specificity relative to another different substance or compound.
• the selective system purifies the target substance or compound by at least 2 fold, 3 fold, or 5 fold.
• Figure 1 is an illustration of a general scheme to activate, wash, selectively extract, purify, identify and quantify cannabinoid compounds from cannabis plant tissue.
• the invention may comprise a method of selectively extracting and purifying a cannabinoid from plant tissue comprising the steps of: a. preparing plant tissue in fresh or dried form;
• the cannabinoids from the extract can be purified by precipitation and/or partition chromatography drying.
• the cannabinoids can be detected by liquid chromatography electrospray or atmospheric pressure ionization and tandem mass spectrometry (MS/MS).
• the methods disclosed herein may be performed on finely divided plant tissue, such as fresh or dried tissue which has been cut, chopped, ground, mashed or otherwise processed to reduce particle size.
• the method may also be performed in solution in the absence of a solid phase, wherein the target substance is not in the solid phase but in a colloidal suspension or fine powder in water or otherwise suspended or emulsified in a liquid phase.
• the polar solvent comprises purified water, or water mixed with alcohol such as ethanol, preferably less than about 40% ethanol (v:v), or acetic acid, preferably less than about 5% acetic acid (v:v). It is preferred that all components are potable. As used herein, a potable component is one that is classified as“Generally Regarded as Safe” or“GRAS” by the United States FDA.
• Polar solvents have large dipole moments (“partial charges”); that is they contain bonds between atoms with very different electronegativities, such as oxygen and hydrogen.
• Non polar solvents contain bonds between atoms with similar electronegativities, such as carbon and hydrogen. Bonds between atoms with similar electronegativities will lack partial charges.
• the polar solvent is one with a dielectric constant greater than about 5.0 at 20° C, preferably greater than about 20, and more preferably greater than about 50.
• the washing polar solvent comprises a non-ionic, non polymeric detergent or a bile acid detergent, such as sodium deoxycholate.
• the wash solvent contains a potable buffer such as phosphate or carbonate buffer, such as Na 2 C03 or NaHCCri, an organic acid, such as acetic acid or formic acid, ammonia, ammonium hydroxide, methylamine trimethyl amine or the like.
• the polar solvent wash take place at a reduced temperature, preferably below about 5° C, and more preferably below about 0° C, but obviously above the freezing temperature of the solvent.
• a first wash in 0.5% acetic acid (v:v) may be repeated up to three times, followed by a second wash in 40% ethanol (v:v), repeated up to three times.
• v:v 0.5% acetic acid
• v:v 40% ethanol
• an initial wash in a weak organic acid may protonate water-soluble impurities, facilitating their dissolution in the aqueous phase.
• the subsequent washes in ethanol/water selectively removes additional polar impurities.
• the selective solvent is one which selectively extracts the activated
• the extract solvent comprises ethanol, or ethanol mixed in water, preferably greater than about 40% ethanol (v:v), more preferably 80% ethanol. Potable ethanol is intended for human consumption and contains no unacceptable residues of harmful solvents.
• the cannabinoid is selectively extracted with about 80% ethanol at a refrigerated temperature, preferably between about -80° C and about 5° C, and more preferably between about -20° C and 0° C.
• Extraction may be followed by precipitation or drying to recover the desired cannabinoid compounds.
• the extracted compounds may be purified by liquid partition chromatography as monitored by electrospray ionization or atmospheric pressure chemical ionization and tandem mass spectrometry (LC-ESI-MS/MS) is more sensitive and definitive than colorimetric, fluorescent, flame ionization, or electron capture detection and permits standards labelled with isotopes or isobaric tags. Since mass spectrometers can separate and analyze many analytes simultaneously using the methods described herein, it can allow identification and quantification of many different cannabinoids at the same time to levels far below that which is possible by direct mass spectrometric analysis.
• LC-ESI-MS/MS electrospray ionization or atmospheric pressure chemical ionization and tandem mass spectrometry
• hemp (mg).
• CBD (mg) (Mw x V(L) x M) x 1000. Standardize to 100.00 mg hemp:
• CBD yields from 5 sequential extractions with and without pre-washing with water (n 3). 0. lg hemp was heated to l20°C for 1 hour and extracted in:
• the mass yields and yield CBD of five fractions combined are shown in Table IIIA.
• the mass yields and yield CBD of the first three fractions combined are shown in Table IIIB.
• Samples were detected on a LC-ESI-MS using a 300 Angstrom 5 micron C18 porous resin. Mass is defined as the dry tissue product extracted.
• Table III The effect of multiple extracts of the yield and purity of CBD and THC from Cannabis tissue.
• 0.1 g of hemp was heated to 120° C and pre-washed 3x with PBS, PBS+600mM NaCl, 0.5% acetic acid (Hac), 0.5% ammonia or H 2 0, followed by 3 washes of 40% Ethanol.
• CBD was then extracted with 3x 500ul of 80% Ethanol and the three fractions were pooled.
• the samples pre-washed in EEO were extracted lx with lml of Ethanol.
• Pre-wash (mg) from from 0.100 from total in mass
• Figure 3 shows the separation and detection of CBD in hemp sample A on a 300 Angstrom 5 micron C18 porous resin by LC-ESI-MS with a isocratic HPLC in 70% AcN 0.1% formic acid.
• HA1 is a sample heated and extracted in 100% acetonitrile (AcN);
• HE8 is a sample heated and extracted in 80% EtOH; and
• Spectra depicts (A) 3x blank (B) external CBD standard curve from 0-200uM (C) detection of CBD (m/z 315) in hemp A HA1 extract, (D) HE8 extract (E) HE1 extract, (F) mix of HE8 and HE1 extract, (Cl) HA1 extract spiked with CBD-D3 (m/z 318), (Dl) HE8 extract spiked with CBD-D3, (El) HE1 extract spiked with CBD-D3 and (Fl) mix of HE8 and HE1 extract spiked with CBD-D3.
• Figure 5A shows the results for Sample 1 spiked with CBD-D3; and
• Figure 5B shows the results for Sample 2 spiked with CBD- D3;
• Figures 5C and 5D show CBD and THC reference standards respectively.
• Gradients - Samples were diluted in B buffer (65% AcN, 5%FA) with gradient 0 min at 70%, 10 min linear gradient to 80%, held for 5 min at 80% and equilibrate at 70% (base peak).
• Figure 6A shows the CBD and THC reference standard; 6B shows CBD alone; 6C shows THC alone; 6D shows sample A spiked with CBD-D3; 6E shows sample B spiked with THC-D3.
• Figure 7 shows the decarboxylation of CBDa at different temperatures.
• Figure 8A shows a CBD external standard curve.
• Figure 8B shows an internal versus external CBD curve.
• Figure 8C shows an illustration spectra of the detection of CBD (m/z 315) in a hemp sample heated to l20°C spiked with CBD-D3 (m/z 318) measured by isocratic separation over C18 resin.
• Figure 9 shows an EtOH gradient extraction of CBD.
• Figure 9A shows CBD extracted in ethanol gradient from a hemp sample heated to l20°C vs no heating control (0C);
• Figure 9B shows CBD and CBDa extracted in an ethanol gradient (from 0% to 100% vol in water) from the no heating control sample (0C);
• Figure 9C shows CBD and CBDa extracted in an ethanol gradient from a hemp sample heated to l20°C for 1 hour.
• Sample 1 0.1% TFA in 80% EtOH pH>2 (not adjusted); Sample 2, 0.1% FA in 80% EtOH pH2 (not adjusted); Sample 3, 0.1% Acetic acid in 80% EtOH pH3 (not adjusted); Sample 4, lOmM Citric acid in 80% EtOH pH4; Sample 5, lOmM Citrate in 80% EtOH pH5; Sample 6, lOmM Citrate in 80% EtOH pH6; Sample 7, lOmM Tris in 80% EtOH pH7; Sample 8, lOmM Tricine in 80% EtOH pH8; Sample 9, 0.1% Ethanolamine in 80% EtOH pH9; Sample 10, 0.1% Ethanolamine in 80% EtOH pHlO; Sample 11, 0.1% Ammonia in 80% EtOH rH ⁇ 10 (not adjusted); Sample 12, 80% EtOH in H20 (pH not adjusted).
• 0.1 g of hemp was heated to l20°C and extracted 3x in 100% ethanol. Extracts of 0.5 g total hemp per replicate were pooled and diluted with H 2 0 to the appropriate ethanol concentrations. Samples were loaded at 100% ethanol and decreasing to 10% ethanol onto the various resins (DEAE - Figure 13 A, CMS - Figure 13B, HiQ - Figure 13C, HiS - Figure 13D.
• the Flow Throughs (FT) were collected and analyzed by LC-ESI-MS.
• Figure 14A ⁇ 7.5 mg CBD was extracted from 0.5g hemp in 100 % Ethanol, diluted to 20% ethanol and loaded onto a ⁇ l00ul HiQ column. The column was washed with loading solvent prior to elution with increasing amounts of Ethanol (25, 30, 32.5, 35, 37.5, 40,
• Figure 16 shows the effect of a wash of intermediate resin from cannabis sample A.
• a 0.1 g aliquot of cannabis sample A was washed in water and heated to l20°C for 1 hour, extracted in ethanol and dried under vacuum to make an intermediate resin.
• the water soluble components of the resin were washed in water or water modified with 0.5% acetic acid (v:v), 40% ethanol, salt/ethanol and saturated salt.
• Figure 17 shows the results of a wash of intermediate resin from cannabis sample B.
• a 0.1 g aliquot of cannabis sample A was washed in water and heated to l20°C for 1 hour, extracted in ethanol and dried under vacuum to make an intermediate resin.
• the water soluble components of the resin were washed in water or water modified with 0.5% acetic acid, 40% ethanol, salt/ethanol and saturated salt. The results show that that 40% ethanol was a better polar solvent in removing soluble compounds compared to the other solvents from the resin in sample B.
• Figure 18 shows the results of a selective extraction of intermediate resin from cannabis sample A.
• a 0.1 g aliquot of cannabis sample B was washed in water and heated to 120° C for 1 hour, extracted in ethanol and dried under vacuum to make an intermediate resin.
• the water soluble components of the resin were washed in water modified with
• FIG. 19 shows the results of extraction of intermediate resin from cannabis sample B.
• a 0.1 g aliquot of cannabis sample B was washed in water and heated to l20°C for 1 hour, extracted in ethanol and dried under vacuum to make a intermediate resin.
• the water soluble components of the resin were washed in water modified with 0.5% acetic acid and extracted with 1 ml of a solvent: acetone, acetonitrile, ether, ethyl acetate, ethanol, hexane, isopropyl alcohol, and methanol.
• references in the specification to "one embodiment”, “an embodiment”, etc., indicate that the embodiment described may include a particular aspect, feature, structure, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to combine, affect or connect such aspect, feature, structure, or characteristic with other embodiments, whether or not such connection or combination is explicitly described. In other words, any element or feature may be combined with any other element or feature in different embodiments, unless there is an obvious or inherent incompatibility between the two, or it is specifically excluded.
• ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values.
• a recited range e.g., weight percents or carbon groups
• Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths.
• each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.

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• 2018
  • 2018-11-27 EP EP18880135.1A patent/EP3717093A4/de not_active Withdrawn

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