Method of using a key to secure components of a drug delivery system during assembly

Abstract

A method of securing an assembly of a drug delivery system, comprising: configuring at least a first component and a second component of the assembly in a closed configuration ready for placement into the drug delivery system; installing an assembly key including a locking element on the assembly to secure the assembly in said configuration; and, transporting the assembly with the assembly key installed.

Claims

1. A method of securing a telescoping assembly of a drug delivery system, comprising: configuring at least a pushing nut screw and an internal screw of the telescoping assembly in a closed configuration ready for placement into the drug delivery system, the pushing nut screw and the internal screw being interconnected by a screw thread such that relative rotation of the pushing nut screw with respect to the internal screw causes linear extension of the telescoping assembly; securing the telescoping assembly in said closed configuration with a locking element, wherein the locking element prevents relative rotation of at least the pushing nut screw and the internal screw with respect to each other in the closed configuration, thereby preventing linear extension of the telescoping assembly in the closed configuration; and, transporting the telescoping assembly secured with the locking element in the closed configuration.

2. The method according to claim 1, wherein the transporting is to an end user.

3. The method according to claim 1, further including inserting at least one clip into a clip aperture of the telescoping assembly so as to attach the locking element to the telescoping assembly.

4. The method according to claim 3, wherein the at least one clip is inserted through a top of the pushing nut screw.

5. The method according to claim 3, wherein the at least one clip is inserted on an outside of the pushing nut screw.

6. The method according to claim 1, wherein the internal screw has a driver component applied thereto for rotating the internal screw.

7. The method according to claim 6, wherein the driver component includes a gear.

8. The method according to claim 1, wherein the telescoping assembly includes an actuating component configured for pushing a plunger of a syringe.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

(1) 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, are not to scale, and are 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.

(2) In the drawings:

(3) FIG. 1 is a block diagram illustrating a system for preventing unintended extension of a telescoping assembly of a drug delivery system, in accordance with an exemplary embodiment of the invention;

(4) FIG. 2 is an exploded perspective view of a telescoping assembly of a drug delivery system, in accordance with an exemplary embodiment of the invention;

(5) FIG. 3 is a perspective view of the telescoping assembly of a drug delivery system with an assembly key of FIG. 2 in a closed configuration, in accordance with an exemplary embodiment of the invention;

(6) FIG. 4 is a perspective, cross-sectional view of the closed telescoping assembly with assembly key of FIG. 3, in accordance with an exemplary embodiment of the invention;

(7) FIG. 5 is a perspective view of the closed telescoping assembly of FIG. 3 showing the top of the cartridge gear with the assembly key removed, in accordance with an exemplary embodiment of the invention;

(8) FIGS. 6A-6C are perspective views of the assembly key, in accordance with an exemplary embodiment of the invention;

(9) FIG. 7A is a perspective view of a telescoping assembly showing a key slot in a component of the assembly which acts as a counterpart to the assembly key, in accordance with an exemplary embodiment of the invention;

(10) FIG. 7B is a close-up, perspective view of the assembly key engaged with the key slot, in accordance with an exemplary embodiment of the invention;

(11) FIG. 8 is a flowchart of a method for assembling a telescoping assembly of a drug delivery system while also securing it for transport, in accordance with an exemplary embodiment of the invention;

(12) FIG. 9 is a flowchart of an alternative method for assembling a telescoping assembly of a drug delivery system while also securing it for transport, in accordance with an exemplary embodiment of the invention;

(13) FIG. 10 is a flowchart of a method for using an assembly key to secure a telescoping assembly of a drug delivery system, in accordance with an exemplary embodiment of the invention;

(14) FIG. 11A is a perspective view of an alternative telescoping assembly showing a key slot in a component of the assembly which acts as a counterpart to an alternative assembly key, in accordance with an exemplary embodiment of the invention;

(15) FIG. 11B is a perspective view of the assembled, closed alternative telescoping assembly of FIG. 11A, in accordance with an exemplary embodiment of the invention;

(16) FIG. 11C is a cross-sectional view of the alternative telescoping assembly with assembly key of FIG. 11B, in accordance with an exemplary embodiment of the invention; and,

(17) FIGS. 12A-12C are perspective views of the alternative assembly key, in accordance with an exemplary embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

(18) The present invention, in some embodiments thereof, relates to drug delivery systems and, more particularly, but not exclusively, to apparatuses and methods for securing components of a drug delivery system during transport.

(19) 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 of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the exemplary embodiments. The invention is capable of other embodiments or of being practiced or carried out in various ways.

(20) Referring now to the drawings, FIG. 1 is a block diagram illustrating a system 100 for preventing unintended movement of a telescoping assembly 101 of a drug delivery system, in accordance with an exemplary embodiment of the invention. In an embodiment of the invention, the system is comprised of the telescoping assembly 101, a plunger 112 advanced by the telescoping assembly 101, and an assembly key 150. In an embodiment of the invention, the assembly key 150 is a separate component from the telescoping assembly 101, provided with latches and/or clips to removably attach it to at least one component of the assembly and which substantially retains the telescoping assembly 101 in a set configuration by preventing the linear movement of at least a first component 102 of the telescoping assembly 101 with respect to at least a second component 104 of the telescoping assembly 101. In an embodiment of the invention, the set configuration is a closed configuration.

(21) In some embodiments of the invention, extension of the telescoping assembly 101 is achieved by rotation of at least one of the components of the assembly 101. For example, the assembly key 150 substantially prevents rotation of the assembly 101 by interlocking at least two components of the assembly 101, which in some embodiments has at least four components, as shown in FIGS. 2-4, to prevent their rotation with respect to each other.

(22) In some embodiments of the invention, the drug delivery system is a patch injector system. In some embodiments of the invention, the telescoping assembly 101 is an operative component of a cartridge of a patch injector system, wherein the disposable and/or interchangeable cartridge contains a pre-measured dose of a drug to be administered to a patient using the drug delivery system.

(23) It should be understood that in order to utilize a smaller, more economical motor, the force used to screw the telescoping assembly 101 in order to extend and retract it may optionally be minimized with low friction threading. This low friction threading allows for easier movement using the motor, but it is also what allows for easy unintended movement of the assembly 101 as a result of vibrations, for example during transport.

(24) FIG. 2 illustrates an exploded perspective view of a telescoping assembly 101 of a drug delivery system, in accordance with an exemplary embodiment of the invention. In an embodiment of the invention, telescoping assembly 101 is comprised of at least one second component/driver component, for example a cartridge gear 202, and/or at least one first componentthat is, at least one external screw, for example a pushing nut screw 204, and/or at least one mid screw 206, and/or an internal screw 208 and/or a actuating component, for example a pushing nut cover 210 (shown in FIG. 2 pre-attached to pushing nut screw 204) for pushing a syringe plunger 112, shown in phantom in FIGS. 2-4. Telescoping assembly 101 includes three elongated threaded elements (pushing nut screw 204, mid screw 206 and internal screw 208) which move longitudinally with respect to one another to telescope (extend or close) the assembly, in an embodiment of the invention. The elongated elements may be interconnected by screw threads which drive the longitudinal movement when the elongated elements are rotated relative to one another. Thus, as shown in FIGS. 2-4, each elongated threaded element (pushing nut screw 204, mid screw 206 and internal screw 208) is a component having screw threads: pushing nut screw 204 has internal screw threads 204a (FIG. 4); mid screw 206 has external screw threads 206a and internal screw threads 206b (FIGS. 2 and 4); and internal screw 208 has external screw threads 208a (FIG. 4). As shown in FIG. 4, pushing nut screw 204 is connected by screw threads 204a and 206a to mid screw 206, and internal screw 208 is interconnected by a screw threads 208a and 206b to mid screw 206, such that relative rotation of the first component of any two of the components with respect to a second component interconnected to the first component by a screw thread may cause extension of the telescoping assembly. Alternatively or additionally, a telescoping assembly may include two, four or more elongated elements that may move longitudinally with respect to each other and/or may be interconnected by screw threads and/or may be driven by relative rotation (for example, as shown in FIGS. 2-4, pushing nut screw 204, mid screw 206 and internal screw 208).

(25) In an embodiment of the invention, an assembly key 150 is provided to the telescoping assembly 101 to secure the telescoping assembly 101 for transport and to optionally assist with assembly of the telescoping assembly 101 into a syringe and/or a plunger of the syringe. In some exemplary embodiments of the invention, the telescoping assembly 101 is configured to interplay with assembly key 150 to secure the telescoping assembly 101 for transport and/or assembly. For example, the telescoping assembly 101 is configured to be secured by inserting a locking element, for example, locking bit 602, shown and described in more detail with respect to FIGS. 6A-7B, of the assembly key 150 into at least one component of the telescoping assembly 101 thereby locking it to prevent unintended extension of the assembly 101, in an exemplary embodiment of the invention. In some embodiments of the invention, the at least one component of the assembly 101 into which the locking bit 602 is inserted is pushing nut screw 204.

(26) In an embodiment of the invention, pushing nut cover 210 is attached to a plunger 112 (FIGS. 2-4) or stopper (not shown) in the cartridge of the patch injector. The plunger may provide a fluid proof seal against the liquid in the cartridge and which pushes the fluid out of the cartridge and into the patient when the telescoping assembly 101 extends and activates/instigates the pushing of the pushing nut cover 210.

(27) In an embodiment of the invention, at least one component is manufactured from a medical grade polymer, for example Polybutylene Terephthalates (PBTs), Ticona Celanex 2402MT, Ticona Celanex 2405MT, Delrin 500AL and Delrin 500P. In some embodiments of the invention, at least one component is manufactured from a plurality of materials, for example the gears are Ticona Celanex 2402MT but the threads are Ticona Celanex 2405MT.

(28) In an embodiment of the invention, the cartridge gear is approximately 12 mm in diameter. In some embodiments of the invention, the extension achieved by the telescoping assembly is approximately 11 mm (for example, the 11 mm is a total amount of extension of a plurality of individual components which extend and contribute to the total), although it should be understood that virtually any length of extension could be achieved by any number of components operatively connected to one another. In some embodiments of the invention, the assembly key diameter approximately matches that of the cartridge gear.

(29) FIG. 3 is a perspective view of a telescoping assembly 101 with an assembly key 150 of a telescoping assembly 101 of a drug delivery system 100 that is closed (in a closed configuration) and locked by assembly key 150, in a typical secured configuration for transport and/or assembly and/or use in accordance with an exemplary embodiment of the invention. The telescoping assembly 101 is attachable to the plunger 112 (shown in phantom) via the pushing nut cover 210.

(30) FIG. 4 is a perspective, cross-sectional view of the telescoping assembly 101 of FIG. 3 in a closed configuration, in accordance with an exemplary embodiment of the invention. In the example of FIG. 3, assembly key 150 is locked to cartridge gear 202 and/or locking bit 602 of the assembly key 150 is shown interfacing with the pushing nut screw 204 in a closed configuration. In an embodiment of the invention, assembly key prevents the turning of the pushing nut screw 204 with respect to cartridge gear 202, thereby preventing substantially or entirely the unintended extension of the telescoping assembly. A handle on the proximal end of assembly key 150 may provide a gripping point and/or locking bit 602 may provide a torque point for twisting pushing nut screw 204 and/or pushing nut cover 210 For example, nut cover 210 may be inserted into a syringe and assembly key 150 may be used to twist pushing nut cover 210, screwing it into the plunger 112 (shown in phantom).

(31) FIG. 5 is a perspective view of the telescoping assembly 101 of FIG. 3 in a closed configuration showing the top of the cartridge gear 202 with the assembly key 150 removed, in accordance with an exemplary embodiment of the invention. In some embodiments of the invention, in the closed configuration shown, locking bit 602 is inserted through a bit aperture 502 in the cartridge gear 202 before it engages with a slot in the pushing nut screw 204. The assembly key 150 is provided with at least one clip 604, shown and described in more detail in FIGS. 6A-6C, which is removably attached to telescoping assembly 101 by inserting the at least one clip 604 through at least one counterpart clip aperture 504 located on the cartridge gear 202, in some embodiments of the invention. Additionally or alternatively, clip 604 may serve as a locking element, for example locking assembly key 150 to cartridge gear 202 and/or pushing nut screw 204. Additional details are shown in FIG. 4, wherein the at least one clip 604 is shown passing through a clip aperture 504 and through cartridge gear 202, in an embodiment of the invention.

(32) FIGS. 6A-6C are perspective views of the assembly key 150, in accordance with an exemplary embodiment of the invention. Shown in more detail in the various views are the locking bit 602 and the at least one clip 604.

(33) FIG. 7A is a perspective view of a telescoping assembly 101 showing a key slot 702 in a component of the assembly 101 which acts as a counterpart to the assembly key 150, in accordance with an exemplary embodiment of the invention. In some embodiments of the invention, the key slot 702 is located on the assembly key 150 key side of the pushing nut screw 204. In some embodiments of the invention, the key slot 702 aligns with the bit aperture 502 of the cartridge gear 202 (not shown in FIGS. 7A-7B, but shown in FIG. 5) whereby the locking bit 602 can be inserted through the bit aperture 502 and into the key slot 702.

(34) FIG. 7B is a close-up, perspective view of the locking bit 602 of the assembly key 150 engaged with the key slot 702, in accordance with an exemplary embodiment of the invention. FIG. 7B does not show the cartridge gear 202 to make this configuration more visible, which in an embodiment of the invention would nominally surround the viewable portion of the pushing nut screw 204 and locking bit 602 in this Figure.

(35) FIG. 8 is a flowchart of a method for configuring a telescoping assembly 101 of a drug delivery system and/or securing it for assembly and/or transport and/or deployment, in accordance with an exemplary embodiment of the invention. In an embodiment of the invention, the mid screw 206 is threaded (804) onto the internal screw 208 so that the threads on the exterior circumference of the mid screw are positioned substantially towards the pushing nut screw cover 210. The cartridge gear 202 is applied (806) onto the internal screw 208 at the end opposite the pushing nut cover 210, in an embodiment of the invention. In an embodiment of the invention, the three components 202, 206, 208 are threaded (808) into the pushing nut screw 204 by engaging the threads on the exterior circumference of the mid screw 206 with threads located on the inner circumference of the pushing nut screw 204, which is already attached (802) to the pushing nut cover 210. In an embodiment of the invention, the three components are screwed into the pushing nut screw 204 so that the bit aperture 502 located on the cartridge gear 202 is aligned (810) with the key slot 702 on the pushing nut screw 204.

(36) The assembly key 150 is installed (812) onto the telescoping assembly 101 by inserting the locking bit 602 into the bit aperture 502 and further, into the key slot 702. Additionally and concurrently, the at least one clip 604 is inserted through the at least one counterpart clip aperture 504 located on the cartridge gear 202 to removably attach the assembly key 150 to the telescoping assembly 101. In an embodiment of the invention, the locking bit 602 inserted into the locking bit aperture 502 and into the key slot 702 substantially prevents rotation of the pushing nut screw 204 with respect to the cartridge gear 202. Assembly key 150 may optionally supply a way of aligning and/or gripping pushing nut screw 204 and/or cartridge gear 202, Assembly key 150 may optionally prevent the unintended extension and/or closing of telescoping assembly 101.

(37) In an embodiment of the invention, the assembly key 150 is removed (814) from the telescoping assembly 101 after transport to enable normal operation of the telescoping assembly 101 and the drug delivery system. Removal (814) of assembly key 150 may be by simple pulling away from the telescoping assembly. Simple removal (814) of assembly key may contribute to the ease of use of the device.

(38) FIG. 9 is a flowchart of an alternative method for configuring a telescoping assembly 101 of a drug delivery system while also securing it for transport, in accordance with an exemplary embodiment of the invention. In an embodiment of the invention, pushing nut screw 204 is attached (902) to the pushing nut cover 210. The mid screw 206 is threaded (904) into the pushing nut screw 204 by engaging the threads on the exterior circumference of the mid screw 206 with threads on the interior circumference of the pushing nut screw 204. In an embodiment of the invention, the internal screw 208 is threaded (906) into the mid screw 206. The internal screw 208 is optionally over rotated to make installation of the cartridge gear 202 easier. In an embodiment of the invention, the cartridge gear 202 is installed (908) onto the inner screw aligning the bit aperture 502 of the cartridge gear 202 with the key slot 702 of the pushing nut screw 204 and, if the inner screw 208 was over rotated, the inner screw 208 is returned to a stop position.

(39) In some embodiments of the invention, the pushing nut screw 204 is at least partially deformed (914) near or at the end opposite the pushing nut cover 210 to create (912) a stop for the mid screw 206. Optionally, the stop is created by driving a shot pin into the pushing nut screw 204, possibly heated or ultrasonic.

(40) FIG. 10 is a flowchart illustration of a method for assembling and using a drug delivery system, in accordance with an exemplary embodiment of the invention. In an embodiment of the invention, the telescoping assembly is configured (1002) for use, for example as described in FIGS. 8 and/or 9. In an embodiment of the invention, the assembly key 150 is installed (1004) on the telescoping assembly 101, securing the assembly 101. For example, securing may include removably attaching the assembly key 150 to at least one component of the telescoping assembly 101. The telescoping assembly is now secured, preventing unintended extension, for assembly and/or transport and/or deployment.

(41) In some embodiments, after telescoping assembly 101 is configured (1002) and secured (1004), it may be placed into a drug delivery system. Optionally, assembly key 150 assists attachment (1012) of the telescoping assembly 150 into the syringe. For example, pushing nut cover 210 may be attached to a plunger of a syringe. Assembly key, supply a convenient gripping point and/or alignment indication for a person and/or a machine to hold pushing nut cover 210 and/or to insert it into the syringe and/or to align threads of pushing nut cover 210 to threads in the plunger and/or to twist pushing nut cover 210 to screw it into the plunger.

(42) In some embodiments, the syringe and/or the telescoping assembly 101 may be transported (1006) to the end user. The assembly key 150 may optionally be left on the telescoping assembly 101 during transport (1006). For example, the telescoping assembly 150 may prevent the telescoping assembly from moving out of its proper configuration for example due to vibrations during transport (1006).

(43) In some embodiments, once the syringe and/or the telescoping assembly 101 reach the end user, the assembly key may be removed (1008) and/or the syringe and/or the telescoping assembly 101 may be deployed. For example deployment may include inserting the syringe and/or assembly 101 into a delivery device (for example a patch injector). Transporting (1006) the telescoping assembly 101 with the assembly key 150 may help prevent the telescoping assembly 101 from extending during transport (1006). Unwanted extension of the telescoping assembly beyond its closed configuration might, for example, make it difficult to fit the assembly 101 and/or the syringe/cartridge into the injector.

(44) The delivery device may optionally restrain the syringe and/or the plunger and/or pushing nut cover 210 from rotating while rotating cartridge gear 202 causing the telescoping assembly 101 to extend, pushing the plunger into the syringe and/or delivering the drug. In some cases, transporting (1006) telescoping assembly 101 with the assembly key 150 attached (1004) may prevent telescoping assembly 101 from closing up too much during transport. Over closing of the telescoping assembly 101 may for example cause thread lock within the telescoping assembly 101 which could cause failure of the delivery system.

(45) In an embodiment of the invention, the assembly key 150 and/or the entire drug delivery system is disposed of (1010). For example, the delivery key 150 and/or the telescoping assembly and/or the delivery device may be made of safe materials that may be disposed of (1010) in municipal garbage.

(46) With respect to the assemblies and methods described herein it should be understood that in an exemplary embodiment of the invention, the assembly 101, which is secured for transport as described herein, remains in a closed configuration and does not unintentionally linearly extend as a result of vibrations during transport. In an embodiment of the invention, transport is to be understood as moving from the manufacturer, through the distribution chain, and ultimately to the consumer. In some embodiments, transport is a sub-set of the chain described above. For example, as applied to transport on a truck from a port of entry to a distribution center. In an embodiment of the invention, such as any of those described herein, the assembly key provides sufficient locking force to ensure compliance under the ASTM D4169 performance testing of shipping containers and systems standards for combined air and rail transport. In some embodiments of the invention, the assembly key prevents unintended linear extension of the assembly while being subjected to extended vibrations up to 300 Hz. Optionally, extended vibration time is for hours, days or even weeks, for example in the case of cargo shipping overseas. In some embodiments of the invention, the assembly key prevents unintended linear extension of the assembly while being subjected to shocks up to 300 m/s2.

(47) The secured assembly 101 is placed into a drug delivery system, for example a patch injector like the SmartDose Electronic Patch Injector System offered by Medimop Medical Projects Ltd., a subsidiary of West Pharmaceutical Services, Inc. after the removal of the assembly key 150, in accordance with an exemplary embodiment of the invention.

(48) FIG. 11A is a perspective view of an alternative telescoping assembly 1101 showing at least one bit aperture 1102 in at least one component of the assembly which acts as a counterpart to at least one locking bit 1152 of an assembly key 1150, in accordance with an exemplary embodiment of the invention. In some embodiments of the invention, the bit aperture 1102 is located on the assembly key 150 key side of the cartridge gear 1104.

(49) FIG. 11B is a perspective view of the assembled, closed alternative telescoping assembly 1101 of FIG. 11A, in accordance with an exemplary embodiment of the invention.

(50) FIG. 11C is a cross-sectional view of the alternative telescoping assembly 1101 with assembly key 1150 of FIG. 11B, in accordance with an exemplary embodiment of the invention.

(51) In some embodiments of the invention, the bit aperture 1102 of the cartridge gear 1104 aligns with a key slot 1108 of the pushing nut screw 1106, enabling the locking bit 1152 of the assembly key 1150 to be inserted through the bit aperture 1102 and into the key slot 1108 preventing movement of the cartridge gear 1104 relative to the pushing nut screw 1106. In an embodiment of the invention, prevention of movement between the cartridge gear 1104 relative to the pushing nut screw 1106 prevents rotation of the assembly 1101, thereby preventing unintended extension of the assembly 1101.

(52) In an embodiment of the invention, assembly key 1150 has a pair of clips 1110 for removal of the assembly key 1150 from the telescoping assembly 1101. In an embodiment of the invention, the pair of clips 1110 are squeezed sufficiently to cause deformation of the assembly key 1150 and to release the assembly key 1150 from the bit aperture 1102 and the key slot 1108. The use of deformable clips 1110 may make removal of assembly key 1150 easier for a nervous end user who may be reluctant to use force to remove assembly key 150 and/or who may become nervous that he might have broken the telescoping assembly 101 when he feels a snap giving way upon removal of assembly key 150. In some embodiments, deformation is elastic. In some embodiments, deformation is plastic. In some embodiments, deformation is a combination of elastic and plastic.

(53) FIGS. 12A-12C are perspective views of the alternative assembly key 1150, in accordance with an exemplary embodiment of the invention.

(54) In an embodiment of the invention, the assembly key 150, 1150 uses the same interface to attach to the telescoping assembly 101, 1101 as an assembly machine used for assembling the components of the telescoping assembly 101, 1101. In some embodiments of the invention, assembly key 150, 1150 is used as a linkage between the assembly machine and the telescoping assembly 101, 1101 during manufacturing. In an embodiment of the invention, after the telescoping assembly 101, 1101 is assembled, it is attached to a plunger of the drug delivery system, optionally by screwing. In an embodiment of the invention, the assembly key 150, 1150 provides a handle for manual or automatic screwing of the pushing nut cover into the plunger without extending, collapsing, screwing and/or unscrewing the telescoping assembly 150, 1150.

(55) In an embodiment of the invention, the assembly key 150, 1150, used as a link between the telescoping assembly and the assembly machine during manufacturing, helps the assembly machine recognize the orientation of the telescoping assembly 101, 1101 during assembly, which can be important for proper assembly of the telescoping assembly 101, 1101 and insertion of it into the plunger. In an embodiment of the invention, mechanical sensing of the telescoping assembly's orientation using the assembly key obviates the need for more expensive optical sensing equipment.

(56) In some embodiments of the invention, assembly keys as described herein are provided with a distinguishing feature, for example color, for easy identification by the customer for easier removal and/or disposal.

(57) It is expected that during the life of a patent maturing from this application many relevant securing technologies will be developed and the scope of the terms securing is intended to include all such new technologies a priori.

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

(59) The term consisting of means including and limited to.

(60) 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.

(61) 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.

(62) 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.

(63) 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.

(64) 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.

(65) 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.

(66) 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.