CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Patent Application No.

62/380, 183 filed August 26, 2016. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under SC0008947 awarded by the Department of Energy. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

1 . Field of the Invention

[0003] The present invention relates to labeled radiopharmaceuticals. In particular, the invention relates to improved methods and systems for rapid isolation of radionuclides produced using a cyclotron.

2. Description of the Related Art

[0004] Radiometals (e.g., ⁶⁴ Cu, ⁸⁹ Zr, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y and ^99m Tc) play a pivotal role in nuclear medicine as therapeutic and imaging agents for radiation therapy and labeling of biologically important macromolecules like proteins, peptides and antibodies.

[0005] In the recent past, a rapid increase has been noted in both clinical and preclinical studies involving ⁶⁸ Ga-labeled radiopharmaceuticals [Ref. 1 -5]. This increase can be attributed to the favorable physical characteristics of ⁶⁸ Ga (E max 1 .8 MeV, β ⁺

89%, Ti/2 = 67.7 minutes) for imaging various rapidly changing processes (proliferation, apoptosis, angiogenesis) and targets (growth hormones, myocardial and pulmonary perfusion, inflammation and infection), and to some extent, to newer, more reliable production and labeling methods [Ref. 1 -5]. Gallium-68 labeled somatostatin analogs have already shown their superiority over the existing agent ¹¹¹ In-DTPA-octreotide through enhanced sensitivity, specificity, accuracy and cost effectiveness for the diagnosis of patients with neuroendocrine tumors [Ref. 1 , 6-9].

[0006] The clinical promise of ⁶⁸ Ga-labeled radiopharmaceuticals clearly warrants growth of the supply of ⁶⁸ Ga to meet the increasing demand in various nuclear medicine facilities. Presently, ⁶⁸ Ga can be produced by two different approaches, (1 ) solid targetry [Ref. 10, 1 1 ] and (2) the ⁶⁸ Ge/ ⁶⁸ Ga generator [Ref. 12]. The former requires high capital cost and expertise and specialized cyclotron facilities that accommodate solid targets, whereas, the latter is more broadly accessible in nuclear medicine facilities not equipped with an on-site cyclotron. The simplicity and lower capital cost of the

⁶⁸ Ge/ ⁶⁸ Ga generator have made it more popular among the nuclear medicine facilities with relatively lower number of requirements for ⁶⁸ Ga labeled doses [Ref. 1 , 12].

However, the breakthrough of trace quantities of the long-lived ⁶⁸ Ge parent isotope (ti/2 = 271 days) into the eluted ⁶⁸ Ga remains a concern [Ref. 13]. Furthermore, with increasing applicability of ⁶⁸ Ga-labeled radiopharmaceuticals, one can foresee a need for alternative production methods to meet the increasing demand especially for the relatively busy nuclear medicine centers having an on-site cyclotron. There have been previous attempts to produce ⁶⁸ Ga using a cyclotron, initially employing a solid target method using ⁶⁸ Zn electrodeposition on a copper substrate [Ref. 10, 14] and more recently using a solution target containing an enriched ⁶⁸ ZnCl2 solution [Ref. 15]. The solid target methods require a lengthy separation step, which is not optimal for shortlived isotopes like ⁶⁸ Ga, as well as expensive solid target infrastructure.

[0007] The production of ⁶⁸ Ga from a cyclotron using a liquid target method has been reported [Ref. 16]. However, due to the longer processing time, use of caustic acid HBr, use of organic solvents, and the large quantity of eluent used, this method may not be optimal for use in routine production and application of ⁶⁸ Ga.

[0008] Thus, there is a need in the art for improved methods and systems for rapid isolation of cyclotron produced radionuclides, such as ⁶⁸ Ga.

SUMMARY OF THE INVENTION

[0009] ⁶⁸ Ga (T1/2 67.7 min) is a positron emission tomography (PET) isotope and is used to label peptides, proteins and small molecules for diagnostic PET imaging. ⁶⁸ Ga can be produced using a low energy cyclotron employing solid or liquid target methods. The processing of ⁶⁸ Ga produced in a cyclotron includes separation of ⁶⁸ Ga from the parent isotope ⁶⁸ Zn and other isotopes ( ¹³ N, ¹¹ C, ¹⁸ F) which may be formed during isotope production. Due to the 67.7 minute half-life of ⁶⁸ Ga, it is critical to have a simple and efficient processing method in order to minimize the loss of radioactivity by decay. The present disclosure provides a method for the separation of Gallium-68 from the parent Zinc-68 that reduces processing time and requires a smaller volume of final eluent. In one version of the invention, efficient trapping on a small volume of hydroxamate resin facilitates the reduction of final elution volumes to provide more concentrated solutions of Ga-68 for radiolabeling. In another version of the invention, more economical production of ⁶⁸ Ga from a cyclotron is achieved by efficient recycling of the parent isotope ⁶⁸ Zn using a method of recycling of ⁶⁸ Zn according to the present disclosure.

[0010] ⁶⁷ Ga may be used for SPECT imaging and/or therapeutic applications. One method of production of ⁶⁷ Ga requires separation of ⁶⁷ Ga from nonradioactive zinc cations.

[0011] In one aspect, this disclosure provides a method for producing a solution including a radionuclide. In the method, a target solution is bombarded with protons to produce a solution including a radionuclide, wherein the radionuclide is ⁶⁸ Ga. The solution including the radionuclide is passed through a column including a sorbent to adsorb the radionuclide on the sorbent, wherein the sorbent comprises a hydroxamate resin, and the radionuclide is eluted off the sorbent.

[0012] In another aspect, the disclosure provides a method for producing a solution including a radionuclide. In the method, a target solution including zinc cations is bombarded with protons to produce a solution including a radionuclide. The solution including the radionuclide is passed through a first column including a first sorbent to adsorb the radionuclide on the first sorbent, and the zinc cations are recovered from a recovery solution that has passed through the first column by passing the recovery solution through a second column including a second sorbent comprising a cation exchange resin.

[0013] In yet another aspect, the disclosure provides a method for producing a solution including a radionuclide. In the method, a solid target is bombarded with protons to produce a solid radionuclide, wherein the radionuclide is ⁶⁸ Ga. A solution including the radionuclide is created from the solid radionuclide. The solution including the radionuclide is then passed through a column including a sorbent to adsorb the radionuclide on the sorbent wherein the sorbent comprises a hydroxamate resin. The radionuclide is then eluted off the sorbent.

[0014] The foregoing and other aspects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings that form a part hereof, and in which there is shown by way of illustration certain embodiments of the invention. Such embodiments do not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is a schematic of an automated system for the separation of ⁶⁸ Ga radioisotope from a cyclotron produced solution including ⁶⁸ Ga.

DETAILED DESCRIPTION OF THE INVENTION

[0016] In one embodiment, the present disclosure provides a method for producing a solution including a radionuclide comprising the bombardment of a target solution with protons to produce a solution including a radionuclide, wherein the radionuclide is ⁶⁸ Ga; the passing of the solution including the radionuclide through a column including a sorbent to adsorb the radionuclide on the sorbent; and the elution of the radionuclide off the sorbent, wherein the sorbent comprises a hydroxamate resin. In one form, the target solution may comprise ⁶⁸ Zn-enriched zinc nitrate. The method may further comprise the elution of the radionuclide off the sorbent using hydrochloric acid, wherein an amount of eluent of 5 milliliters or less can be used. This method may take 30 minutes or less.

[0017] The method may further comprise adjusting pH of the solution including the radionuclide before passing the solution including the radionuclide through the column. In one version, these adjustments of the pH may comprise a dilution of the solution with water. The volume of water for dilution may range from 10 to 50 milliliters. In another version, the adjusting of the pH may comprise an addition of an organic or inorganic base to the solution. In this other version, the base may form a water soluble product with ⁶⁸ Ga and ⁶⁸ Zn. In one form of this other version, the base is sodium bicarbonate. The pH of the solution including the radionuclide before passing the solution including the radionuclide through the column may be between 5 and 7, preferably in a range of 5.5 to 6.5. [0018] In this first embodiment, at least one of the steps of the method may be completed by an automated process using a remotely controlled radiochemistry module for processing in a hot cell as depicted in Figure 1 . The yield of the radionuclide from the solution including the radionuclide may be greater than 80% by radioactivity, or greater than 85% by radioactivity, or greater than 90% by radioactivity, or greater than 95% by radioactivity. In another form, the hydroxamate resin may comprise

hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene. In one non-limiting form, the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase. The hydroxamate resin may have a particle size in a range of 10 to 100 microns, or in a range of 20 to 70 microns, or in a range of 30 to 60 microns. In one non-limiting form, the hydroxamate resin has a particle size in a range of 37 to 55 microns.

[0019] In a second embodiment, the present disclosure provides a method for producing a solution including a radionuclide comprising the bombardment of a target solution including zinc cations with protons to produce a solution including a

radionuclide; the passing of the solution including the radionuclide through a first column including a first sorbent to adsorb the radionuclide on the first sorbent; and the recovery of zinc cations from a recovery solution that has passed through the first column by passing the recovery solution through a second column including a second sorbent comprising a cation exchange resin. In one form, the method may comprise adjusting the pH of the recovery solution before passing the recovery solution through the second column. A beneficial pH range for the recovery solution before passing the recovery solution through the second column is a pH in a range of 3 to 7, or 4 to 6, or 4.5 to 5.5.

[0020] The first sorbent may be a hydroxamate resin comprising hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene. In one non-limiting form, the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase. The hydroxamate resin may have a particle size in a range of 10 to 100 microns, or in a range of 20 to 70 microns, or in a range of 30 to 60 microns. In one non-limiting form, the hydroxamate resin has a particle size in a range of 37 to 55 microns. The second sorbent may comprise a polymeric resin having sulfonic acid groups. The second sorbent may be a polystyrene-divinylbenzene sulfonic acid such as that sold under the tradename AG ^® 50W-X8. The second sorbent may be a styrene-divinylbenzene copolymer containing iminodiacetic acid groups such as that sold under the tradename Chelex ^® 100.

[0021] The method may further comprise washing the second column with deionized water before passing the recovery solution through the second column. The method may also comprise pushing air through the second column before passing the recovery solution through the second column. In yet another form, the target solution may comprise ⁶⁸ Zn-enriched zinc nitrate. The recovery of the zinc cations from the second column may be 90% or greater based on weight of the zinc cations in the target solution, or 93% or greater based on weight of the zinc cations in the target solution, or 95% or greater based on weight of the zinc cations in the target solution, or 98% or greater based on weight of the zinc cations in the target solution. In this second embodiment, at least one of the steps of the method may be completed by an automated process.

[0022] In a third embodiment, the present disclosure provides a method for producing a solution including a radionuclide comprising the bombardment of a solid target with protons to produce a solid radionuclide, wherein the radionuclide is ⁶⁸ Ga; the creation of a solution including the radionuclide from the solid radionuclide; the passing of the solution including the radionuclide through a column including a sorbent to adsorb the radionuclide on the sorbent; and the elution of the radionuclide off the sorbent, wherein the sorbent comprises a hydroxamate resin. In one form, the target solution may comprise ⁶⁸ Zn-enriched zinc nitrate. The method may further comprise the elution of the radionuclide off the sorbent using hydrochloric acid, wherein an amount of eluent of 5 milliliters or less can be used. This method may take 30 minutes or less.

[0023] The method may further comprise adjusting pH of the solution including the radionuclide before passing the solution including the radionuclide through the column. In one version, these adjustments of the pH may comprise a dilution of the solution with water. The volume of water for dilution may range from 10 to 50 milliliters. In another version, the adjusting of the pH may comprise an addition of an organic or inorganic base to the solution. In this other version, the base may form a water soluble product with ⁶⁸ Ga and ⁶⁸ Zn. In one form of this other version, the base is sodium bicarbonate. The pH of the solution including the radionuclide before passing the solution including the radionuclide through the column may be between 5 and 7, preferably in a range of 5.5 to 6.5.

[0024] In this third embodiment, at least one of the steps of the method may be completed by an automated process using a remotely controlled radiochemistry module for processing in a hot cell as depicted in Figure 1 . The yield of the radionuclide from the solution including the radionuclide may be greater than 80% by radioactivity, or greater than 85% by radioactivity, or greater than 90% by radioactivity, or greater than 95% by radioactivity. In another form, the hydroxamate resin may comprise

hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene. In one non-limiting form, the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase. The hydroxamate resin may have a particle size in a range of 10 to 100 microns, or in a range of 20 to 70 microns, or in a range of 30 to 60 microns. In one non-limiting form, the hydroxamate resin has a particle size in a range of 37 to 55 microns.

EXAMPLES

[0025] The following Examples are provided in order to demonstrate and further illustrate certain embodiments and aspects of the present invention and are not to be construed as limiting the scope of the invention.

Example 1

Introduction to Example 1

[0026] Hydroxamate mediated separation of Ga-68 from Zn-68 reduces processing time and provides a smaller volume of final eluent. Without limiting the present disclosure to a particular theory, it is contemplated that because Ga ³⁺ forms a hard Lewis acid in solution that it should form stable complexes with hard Lewis base groups, e.g., N, 0 groups of hydroxamate. In contrast, zinc forms a borderline Lewis acid, which has less of a chemical affinity for the hydroxamate resin. Efficient trapping on a small volume of hydroxamate resin should also facilitate the reduction of final elution volumes to provide more concentrated solutions of Ga-68 for radiolabeling.

Experiments were performed according to the following procedure.

Materials and Methods:

Chemicals

[0027] Zn-68 (99.23%) enriched metal was purchased from Cambridge Isotopes Laboratory (Tewksbury, MA). Hydrochloric acid (34-37% as HCI) and nitric acid (67- 70% as HNO3) both trace metals basis were purchased from Fisher Scientific

(Suwanee, GA). AG-50W-X8 (polystyrene-divinylbenzene sulfonic acid resin, 200-400 mesh, hydrogen form) resin was purchased from Bio-Rad (Hercules, CA). Accell Plus CM (300 A, WAT 010740) cation exchange resin (acrylic acid/acrylamide coated silica having a diol bonded phase - particle size: 37-55 pm - pore size: 300 angstroms) was purchased from Waters Inc. (Milford, MA). The activity readings were measured using a CRC dose calibrator (#416 setting, CRC-55tPET, Capintec, Ramsey, NJ).

Synthesis Of Hydroxamate Resin

[0028] Synthesis of hydroxamate resin was performed using a method developed by Pandey et al. [see Ref. 17 which is hereby incorporated by reference in the present disclosure]. Briefly, the hydroxamate resin was synthesized by stirring Accell Plus CM resin (2.00 g), methyl chloroformate (2.0 mL, 25.8 mmol) and triethylamine (2.0 mL, 14.3 mmol) in anhydrous dichloromethane (30 mL) at 0°C for 30 minutes and then at room temperature for additional 90 minutes. The temperature of the mixture was further lowered to 0°C before addition of hydroxylamine hydrochloride (0.6 g, 8.63 mmol) and triethylamine (2.0 mL, 14.3 mmol). The resultant mixture was stirred at room

temperature for an additional 15 hours. The solvent was removed under vacuum, and cold water was poured with constant stirring into the flask containing the functionalized resin. The resin was filtered, washed extensively with water, and dried under vacuum.

[0029] Hydroxamate resin can also be prepared on various types of backbone polymers/resins including but not limited to polystyrene, silica, polyacrylate, polymer coated with silica or any other organic / inorganic backbone materials. Furthermore, the high degree of hydroxamate functionalization on any back bone polymer with different mesh sizes (bead size) enhances the separation of Ga-68/67 from Zn-68.

Results and Discussion

Isolation of ⁶⁸ Ga

[0030] A solution including ⁶⁸ Ga was produced in a solution target via 30 minute proton irradiation (current = 20 μΑ) of a solution of 1 .7 M ⁶⁸ Zn-zinc nitrate (99.23% isotopic enrichment) in 0.2 N nitric acid using a method developed by Pandey et al. [see Ref. 16 which is hereby incorporated by reference in the present disclosure]. A column loaded with 100 mg of the hydroxamate resin as synthesized above was pre-washed with 1 ml_ of acetonitrile and 10 ml_ of water. After irradiation, the contents of the cyclotron target was delivered to a collection vial pre-loaded with 25 mL of 20 mM NaHC03. The pH of the resultant solution (after addition of acidic target solution) was found to be in the range 5.5-6.5 for effective trapping of ⁶⁸ Ga on the hydroxamate resin. The neutralized target solution was passed through the hydroxamate resin to trap ⁶⁸ Ga, while allowing ⁶⁸ Zn and shorter lived isotopes ¹³ N, ¹¹ C to pass through. Further rinsing of the parent ⁶⁸ Zn from the column was performed using 50 mL of water (pH 5.5). All ⁶⁸ Zn containing fractions were collected in a recovery vial for recycling of the parent ⁶⁸ Zn isotope. Finally, ⁶⁸ Ga was eluted from the hydroxamate resin with 2 mL 2 M hydrochloric acid and collected in a product vial for subsequent labeling.

[0031] This process was automated using a remotely controlled radiochemistry module for processing in a hot cell as depicted in Figure 1. A programmable

microprocessor-based controller was in electrical communication with valves V of the system 100 of Figure 1 to open and close the valves when necessary to transfer fluids in the fluid lines L of Figure 1 . Suitable timing of valve opening and closing was programmed in the controller. The processing was achieved in approximately 20 minutes with greater than 80% yield, decay corrected to start of processing.

[0032] Using the radiochemistry module as depicted in Figure 1 with the hydroxamate resin as synthesized above, processing times of 20-25 minutes can provide a trapping efficiency of 70-90%, an elution efficiency of 95-98%, and an overall efficiency of 70-90%. [0033] An analysis of metal impurities in the ⁶⁸ Ga product was as follows:

Ga: 0.3±0.1 pg, Cu: 10.2±7.3 pg, Zn: 33.3±21 pg, and Fe: 31 .9±26.2 pg for an ICP-MS analysis of ten different batches.

Recycling of ⁶⁸ Zn

[0034] Economical production of ⁶⁸ Ga from a cyclotron requires efficient recycling of the parent isotope ⁶⁸ Zn. A method of recycling of ⁶⁸ Zn was also developed. The pH of the recovered ⁶⁸ Zn solution (above) was adjusted to pH=5.0 by addition of nitric acid. The resultant ⁶⁸ Zn solution was passed through a column containing 1 .5 grams of cation exchange resin (Bio-Rad AG-50W-X8, 200-400 mesh, hydrogen form). Prior to use, the cation exchange resin was washed with 60 ml_ of water followed by 20 mL of air. ⁶⁸ Zn was trapped on the cation exchange resin. The resin was washed with an additional 10-15 mL of water (pH 5.0-5.5) with minimal loss of ⁶⁸ Zn. Finally, ⁶⁸ Zn was eluted from the resin with 15 mL of 8 M HNO3. The recovered ⁶⁸ Zn nitrate solution was dried under vacuum for subsequent use to produce ⁶⁸ Ga. ⁶⁸ Zn recovery was found to exceed 98%. ICP-MS analysis of the recovered ⁶⁸ Zn showed presence of insignificant quantities of metal ion impurities, such as sodium.

[0035] Thus, an improved method of Ga-68 purification and ⁶⁸ Zn recovery have been achieved. The developed method further simplifies a solution target approach of ⁶⁸ Ga production.

Example 2

[0036] Hydroxamate mediated separation of ⁶⁸ Ga from ⁶⁸ Zn is facilitated by a pH adjustment of the target solution. As will be detailed below, the separation of ⁶⁸ Ga from ⁶⁸ Zn has been accomplished in two different ways.

Non-base Mediated pH Adjustment

[0037] First, a non-base mediated pH adjustment was performed through dilution of post-irradiated ⁶⁸ Ga target solution with water. Various quantities of water were used to achieve different pH values before trapping ⁶⁸ Ga on hydroxamate resin. The amount of water used to adjust pH increases with increasing strength of the nitric acid and/or molarity of the ⁶⁸ Zn solutions used in target irradiation. Results are shown below in Table 1. Table 1 : Summary of the Non-Base Mediated Purification of Ga-68 from the Zn-68

Base Mediated pH Adjustment

[0038] Various organic and inorganic bases were employed to achieve a desired pH of the target solution before trapping ⁶⁸ Ga on hydroxamate resin. Herein, we demonstrated the use of sodium bicarbonate to achieve the desired pH. The amount of base (bicarbonate or appropriate organic/inorganic base) used to adjust pH is dependent upon the strength of the nitric acid and molarity of the ⁶⁸ Zn solutions used in target irradiation. Higher concentrations of nitric acid and ⁶⁸ Zn nitrate salt required higher strength of base solution to adjust the pH to the desired level (pH between 5.5 and 6.5). The selection of base also depends upon the solubility of the resultant species formed after neutralization. If the resultant species formed are insoluble in aqueous solution, then they cannot be used for automated separation of ⁶⁸ Ga from parent ⁶⁸ Zn. For example, if the acidic post-irradiation target solution is neutralized with sodium hydroxide, then the resultant species formed will be zinc hydroxide and gallium hydroxide. The hydroxides of Ga and Zn are poorly soluble in water and therefore, would not be appropriate. Similar rationale can be applied to other organic/ inorganic bases before their use in this hydroxamate based method of separation of ⁶⁸ Ga from ⁶⁸ Zn. Sodium bicarbonate was chosen because it yields sodium nitrate, carbonic acid and zinc bicarbonate after neutralization and allows ⁶⁸ Zn nitrate to be obtained effectively during the recycling process. Results are shown below in Table 2.

Table 2: Summary of the Base Mediated Purification of Ga-68 from the Zn-68

Note: 1 . Activity lost in the lines and collection flask have not been included in the calculation.

2. These runs are processed after 2.5 to 3 hours post irradiation.

Recycling of ⁶⁸ Zn

[0039] Recycling of recovered ⁶⁸ Zn(N03)2 was performed on a cation exchange column using 1.5-1 .6 grams of AG 50W-X8 resin. Prior to the recycling of ⁶⁸ Zn, an AG 50W-X8 resin column was washed with 60 mL of deionized water dropwise followed by 20 mL of air. Before passing the recovery solution through the column, the pH of the recycling solution was adjusted to <5 using dilute nitric acid, if needed. After passing the recovery solution through the column, 20 mL of air was also pushed through. The column was washed with 10 mL of deionized water, followed by 20 mL of air. ⁶⁸ Zn was eluted with 15 mL of 8N HNO3 into a fresh vial, and followed by 20 mL of air. The obtained ⁶⁸ Zn nitrate solution was concentrated on a rotary evaporator. The column was regenerated by passing an additional 2 mL of concentrated HNO3 (15.9 N). To reuse this column, a step of activation with 60 mL of deionized water and a step of 20 mL of air were performed. Results are shown below in Tables 3-4. Table 3

% of Zn-68 nitrate recovered in comparison with known starting mass of zinc nitrate

(Batch-1 )

Table 4

% of Zn-68 nitrate recovered in comparison with known starting mass of zinc nitrate

(Batch-2).

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[0040] Thus, the present invention provides improved methods and systems for rapid isolation of cyclotron produced radionuclides, such as ⁶⁸ Ga. The methods of processing ⁶⁸ Ga and recycling of ⁶⁸ Zn offer an economical alternative to ⁶⁸ Ge/ ⁶⁸ Ga generators.

[0041] Although the invention has been described with reference to certain embodiments, one skilled in the art will appreciate that the present invention can be practiced by other than the described embodiments, which have been presented for purposes of illustration and not of limitation. Therefore, the scope of the appended claims should not be limited to the description of the embodiments contained herein.