Drug delivery device with gear module, and related method of assembly

Abstract

To provide a drug delivery device and a related method of assembly.SOLUTION: A drug delivery device 10 may include a main housing having: an interior surface defining an enclosed space; and an exterior surface releasably attachable to a patient. A container 14 may be disposed in the enclosed space and include a reservoir 30 containing a drug and a stopper 34. A drive assembly 24 may also be disposed in the enclosed space and may be configured to move the stopper within the reservoir to expel the drug from the reservoir. The drive assembly may include a rotational power source and a gear module. The gear module may include a mounting plate, and a plurality of gears rotatably connected to the mounting plate. Furthermore, the mounting plate may be separate from the main housing.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 536,911, filed July 25, 2017, the entire contents of which are expressly incorporated by reference herein.

[0002] The present disclosure relates generally to drug delivery devices, and more particularly to the construction and manufacture of drive assemblies for expelling a drug from a reservoir contained within a drug delivery device. [Background technology]

[0003] Drug delivery devices, such as injectors, are used to deliver liquid medication to a patient. Many drug delivery devices are configured to expel a drug stored in an internal reservoir through a needle, cannula, or other delivery member to a patient. Some drug delivery devices include a drive assembly to provide the actuation energy required to release the drug from the reservoir. Some drive assemblies include a rotary power source, such as an electric motor. In some cases, the torque and / or rotational speed output by the rotary power source may require adjustment before transmitting it to an element responsible for releasing the drug from the reservoir. For example, it may be necessary to increase the torque while decreasing the rotational speed output by the electric motor to achieve a desired drug delivery rate.

[0004] Some drug delivery devices incorporate multiple gears to provide speed and / or torque conversion from a rotary power source to an ejection element. In conventional designs, these gears are attached directly to the walls of the main housing of the drug delivery device. Handling of the drug delivery device by the patient during manufacture or transportation as well as other external forces can deform the walls of the main housing, especially since the walls are usually made of a hard but lightweight and semi-flexible material such as plastic. Because the gears of conventional drug delivery devices are attached directly to the walls of the main housing, warping and other shape changes of the walls of the main housing can result in misalignment of the gears. This problem is exacerbated by gears that have small teeth and / or require precise alignment, which is often the case in drug delivery devices.

[0005] Furthermore, mounting the gear directly to the wall of the main housing may make it difficult to inspect the gear after it is installed in the drug delivery device, since other components in the main housing may block the gear from view after it is installed. The reduced ability to inspect the gear may result in some manufacturing defects, such as misalignment of the gear, being overlooked. This further increases the risk that the drug delivery device will operate improperly when activated by the patient, potentially delivering an incorrect dose of drug.

[0006] The present disclosure describes a drug delivery device and associated assembly methods that embody advantageous alternatives to existing drug delivery devices and assembly methods and that can address one or more of the problems or needs discussed above, as well as provide other benefits and advantages. Summary of the Invention [Means for solving the problem]

[0007] One aspect of the present disclosure provides a drug delivery device including a main housing, a container, and a drive assembly. The main housing may include an interior surface defining an enclosed space and an exterior surface removably attachable to a patient. The container may be disposed within the enclosed space and may include a reservoir housing a drug and a stopper. The drive assembly may be disposed within the enclosed space and may be configured to move the stopper within the reservoir to expel the drug from the reservoir. The drive assembly may include a rotational power source and a gear module. The gear may include a mounting plate and a plurality of gears rotatably connected to the mounting plate. The mounting plate may be separate from the main housing.

[0008] Another aspect of the present disclosure provides an assembly method including: (a) connecting a plurality of gears to a mounting plate of a gear module; (b) mounting the gear module within a main housing of a drug delivery device after connecting the plurality of gears to the mounting plate; and (c) enclosing the gear module and a container having a reservoir for containing a drug within the main housing of the drug delivery device.

[0009] The present disclosure will be more fully understood from the following description taken in conjunction with the accompanying drawings, in which: Some of the drawings may be simplified by omitting selected elements to more clearly show other elements. The omission of such elements in some of the drawings does not necessarily indicate the presence or absence of the particular element in any of the illustrative embodiments, unless expressly described in the corresponding written specification. Additionally, none of the drawings are necessarily drawn to scale. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 is a schematic top view of one embodiment of a drug delivery device according to the principles of the present disclosure. [Diagram 2] 2 is a schematic partial cross-sectional side view of the drug delivery device shown in FIG. 1. [Diagram 3]2 is a perspective view of the drug delivery device of FIG. 1 omitting some components including the container, the fluid pathway assembly, the tether, and the upper portion of the wall of the main housing. [Figure 4] FIG. 1 is a perspective top view of one embodiment of a gear module according to the principles of the present disclosure; [Diagram 5] FIG. 6 is a top view of the gear module shown in FIG. 5 with the cover member omitted to reveal the gear receptacle within the gear module. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In general, the present disclosure relates to the construction and manufacture of an internal drive assembly for a drug delivery device. The drive assembly may be configured to provide the actuation energy required to release a drug from a reservoir contained within the drug delivery device. More specifically, the drive assembly may push a stopper in a controlled manner within the reservoir upon activation of the drug delivery device to expel the drug to a patient. According to the present disclosure, the drive assembly may include a gear module that is constructed and / or mounted independently from other elements of the drug delivery device. The gear module may include a number of gears that receive rotational power from a rotational power source and a mounting plate to which the gears are rotatably connected. The mounting plate may provide a rigid support structure for the gears and may be constructed as a separate component from the main housing of the drug delivery device. The mounting plate may thus protect the gears from any unintentional or intentional warping or bending of the walls that define the main housing. The mounting plate therefore advantageously reduces the likelihood of misalignment of the gears after they are mounted within the drug delivery device. Furthermore, the use of mounting plates allows for greater flexibility in the design and / or materials used to construct the main housing, without compromising the integrity of the drug delivery device. Additionally, the gear module disclosed herein can be pre-assembled and inspected for defects prior to installation within the drug delivery device. This can reduce the need for extensive inspection of the gears after installation within the main housing, where the gears may be partially or completely blocked from view.

[0012] Each of the aforementioned components of the drug delivery device and the method of assembly of such a device will now be described in more detail.

[0013] 1 and 2 are schematic diagrams of one embodiment of a drug delivery device 10 constructed in accordance with the present disclosure. The drug delivery device 10 may be operated to deliver a drug to a patient subcutaneously or transdermally. In the illustrated embodiment, the drug delivery device 10 is configured as a wearable drug delivery device, such as an on-body injector or a portable infusion pump, that is removably attached to the patient's tissue 11 (e.g., the patient's skin). In other embodiments (not shown), the drug delivery device 10 may be configured as a pen injector, such as an autoinjector or an injection pen, that is temporarily pressed against the patient's tissue 11 for the course of an injection. The drug delivery device 10 may be configured to automatically deliver a fixed or patient / operator settable dose of a drug over a controlled or selected time period. Additionally, the drug delivery device 10 may be for self-administration by the patient or may be operated by medical personnel or other caregivers formally trained to administer injections.

[0014] In general, the drug delivery device 10 may include an insertion mechanism 12, a reservoir 14, a fluid path assembly 22, a drive assembly 24, and a controller 26, each of which may be disposed within an interior enclosed space of a main housing 29. An input device 28 (e.g., a user-depressible button, a touch screen, a microphone, etc.) may protrude from or be disposed on an exterior surface 19 of the main housing 29 and may be configured to initiate operation of the drug delivery device 10 by activating the insertion mechanism 12, the fluid path assembly 22, the drive assembly 24, the controller 26, and / or other mechanisms and / or electronics by mechanical and / or electrical means (shown in dashed lines in FIG. 1). In embodiments in which the input device 28 is a button that is pressed or otherwise physically operated by a user or patient, the input device 28 may operate as an actuator that exerts the motive force necessary to activate the insertion mechanism 12, the fluid path assembly 22, the drive assembly 24, the controller 26, and / or other mechanisms. In such embodiments, the input device 28 may be physically connected, either directly or indirectly via a mechanical linkage, to the insertion mechanism 12, drive assembly 24, fluid path assembly 22, and / or other mechanisms such that manually pushing or otherwise interacting with the input device 28 provides the motive force necessary to activate the insertion mechanism 12, drive assembly 24, fluid path assembly 22, and / or other mechanisms. For example, in some embodiments, manually pushing the input device 28 may move the fluid path assembly 22 toward the fixed container 14, or move the container 14 toward the fixed fluid path assembly 22, thereby causing the container access needle to pierce the seal member and enter the reservoir or interior volume of the container 14. Additionally or alternatively, pushing or interacting with the input device 28 may send electrical and / or mechanical signals to the controller 26, which may further execute programmable instructions to control the operation of the insertion mechanism 12, drive assembly 24, and / or fluid path assembly 22.In such an embodiment, the controller 26 may include a processor (e.g., a microprocessor) and non-transitory memory for storing programmable instructions executed by the processor. Additionally, in such an embodiment, the drug delivery device 10 may include internal actuators (e.g., electric motors, pneumatic or hydraulic pumps, and / or pressurized gas or liquid sources) separate from the input devices 28 that apply the motive force necessary to activate the insertion mechanism 12, the drive assembly 24, the fluid path assembly 22, and / or other mechanisms in response to electrical control signals received from the controller 26. One example of such an internal actuator is the rotational power source for the drive assembly 24, described in more detail below.

[0015] 2, the main housing 29 may include a wall 15 having an interior surface 17 and an exterior surface 19. The wall 15 may be a single unitary structure or may be made of multiple separate structures interconnected to one another. The interior surface 17 of the wall 15 may define an enclosed space in which the insertion mechanism 12, the container 14, the fluid path assembly 22, the drive assembly 24, and the controller 26, and / or other mechanisms and / or components may be disposed. In some embodiments, the enclosed space may be sealed, for example to define an enclosed clean space having a sterile or aseptic internal atmosphere. The bottom exterior surface 19 of the wall 15 may be removably attachable to the patient's tissue 11. In some embodiments, this may be accomplished by a skin adhesive applied or disposed on the bottom exterior surface 19 of the wall 15 of the main housing 29. In some embodiments, the skin adhesive may be part of an adhesive patch attached to the bottom exterior surface 19 of the wall 15 of the main housing 29. The upper exterior surface 19 of the wall 15 may include one or more visual indicators 42 (e.g., lights, graphical displays, etc.) and / or a window 35 for viewing the container 14 and the medication 32 contained therein. The one or more visual indicators 42 may be used to convey information to a user regarding the operational status of the drug delivery device 10 and / or the status of the medication 32. An opening 31 may be formed in the bottom of the wall 15, and optionally a pierceable sterile barrier 33, such as a pierceable septum, may extend across the opening 31 to seal the interior of the main housing 29 prior to use. In some embodiments, the pierceable sterile barrier 33 may be omitted, and instead a removable sealing member (not shown) may cover the opening 31 and seal close prior to use.

[0016] More specifically, with regard to the window 35, this element may be constructed from a transparent or translucent material and may be generally aligned with the container 14 to allow the patient or user of the drug delivery device 10 to see the drug 32 in the container 14 and / or to confirm completion of administration. Suitable materials for constructing the window 35 include, but are not limited to, glass and / or plastic. Placing the window 35 on the outside of the drug delivery device 10 may expose the drug 32 to ambient light, including sunlight. Some drugs may be sensitive to certain wavelengths of light and may undergo undesirable molecular changes when exposed to such wavelengths of light. For example, some drugs may be sensitive to wavelengths of light in the ultraviolet (UV), visible, and / or infrared ranges. To protect drugs that are primarily sensitive to light in the UV and / or infrared ranges, the window 35 may be dark-tinted and / or sized to cover a relatively small surface area of ​​the housing 29. For drugs that are primarily sensitive to light in the visible range, it may not be necessary to add a dark tint to the window 35 and / or reduce the size of the window 35. Instead, the window 35 may be constructed with a polarizing filter. In some embodiments, the polarizing filter may be a film or other coating applied to the window 35. In other embodiments, the polarizing filter may be directly incorporated into the material of the window 35. The polarizing filter may allow for observation and identification of the drug 32 within the container 14 while blocking approximately (e.g., ±10%) up to and including 50% of light in the visible range. In some embodiments, the portion of visible light blocked by the window 35 may be within the range of approximately (e.g., ±10%) 0-50%, or 10-50%, or 20-50%, or 25-50%, or 0-40%, or 0-30%, or 0-25%, depending on the photosensitivity of the drug 32 and / or the acuity of the patient population for the drug 32, among other considerations. Instead of adding a dark tint to the window 35 and / or reducing the size of the window 35, adding a polarizing filter to the window 35 advantageously protects the drug 35 from light in the visible range without substantially impairing the ability of the patient or user of the drug delivery device 10 to see the drug 32 in the container 14.

[0017] After the bottom of the wall 15 of the main housing 29 is attached to the patient's tissue 13, the insertion mechanism 12 may be actuated to move the subcutaneous delivery member from a retracted position, in which the pointed tip of the subcutaneous delivery member is retracted into the main housing, to a deployed position, in which the pointed tip protrudes from the main housing 29 beyond the exterior surface 19 of the main housing 29. In this embodiment, this may include the insertion mechanism 12 inserting the trocar 21 and the hollow cannula 23 surrounding the trocar 21 through a pierceable sterile barrier 33 into the patient's tissue 11, as shown in FIG. 2. Immediately thereafter, or shortly thereafter, the insertion mechanism 12 may automatically retract the trocar 21, leaving the tip of the cannula 23 inside the patient for subcutaneous delivery of the drug 32. The trocar 21 may be solid and have a sharp end for piercing the patient's skin 11. Additionally, the trocar 21 may be made of a stiffer material than the cannula 23. In some embodiments, the trocar 21 may be made of metal and the cannula 23 may be made of plastic or another polymer. The relative flexibility of the cannula 23 may allow the cannula 23 to be subcutaneously placed within the patient's tissue 11 for a period of time without causing pain or significant discomfort to the patient. The tip of the cannula 23 may be sharpened to a sharp tip, but may be less sharp than the tip of the trocar 21. In other embodiments (not shown), the trocar 21 and cannula 23 may be omitted, and instead the insertion mechanism 12 may insert only a stiff hollow needle into the patient's tissue 13 for subcutaneous delivery of the drug 32. Also, in one or more of these embodiments, the subcutaneous delivery member may have a longitudinal axis that is perpendicular or non-parallel to the longitudinal axis A of the container 14.

[0018] 2, the insertion mechanism 12 may include an insertion biasing member 25 and a retraction biasing member 27. Prior to activation of the insertion mechanism 12, each of the insertion biasing member 25 and the retraction biasing member 27 may be held in a biased state. Upon activation of the insertion mechanism 12, for example by the input device 28, the insertion biasing member 25 may release its stored energy to move the subcutaneous delivery member from the retracted position to the deployed position. In the illustrated embodiment, this involves moving the trocar 21 and the cannula 23 from a position where their tips are within the main housing 29 to the position shown in FIG. 2. During the insertion procedure, the retraction biasing member 27 may be held in its biased state. After the insertion procedure, the retraction biasing member 27 may release its stored energy to leave the cannula 23 in the deployed position and move the trocar 21 from the deployed position to the retracted position again.

[0019] 2, the insertion biasing member 25 and the retraction biasing member 27 are each compression springs arranged concentrically with respect to one another. Other power sources for the insertion biasing member 25 and / or the retraction biasing member 27 are also contemplated, including, for example, a torsion spring, an electric motor, a hydraulic or pneumatic pump, or a canister that releases pressurized gas or liquid to provide the actuation energy. In some embodiments, the insertion biasing member 25 and the retraction biasing member 27 may be defined by a single electric motor that operates in a forward and reverse direction to provide the insertion and retraction motions. Also, in some embodiments, the retraction biasing member 27 may be omitted.

[0020] Referring again to FIG. 1 , the container 14, which in some contexts may be referred to as a primary container, may include a wall 38 having an interior surface 43 and an exterior surface 47 that define a reservoir 30 into which the drug 32 is loaded. In some embodiments, the reservoir 30 may be preloaded with the drug 32 by the drug manufacturer prior to mounting the container 14 on the drug delivery device 10. In some embodiments, the container 14 may be rigidly connected to the main housing 29 such that the container 14 cannot move relative to the housing, while in other embodiments, the container 14 may be slidably connected to the housing 29 such that the container 14 can move relative to the main housing 29 during operation of the drug delivery device 10. The container 14 may have an elongated barrel-like or cylindrical shape extending along a longitudinal axis A. In embodiments in which the drug delivery device 10 is configured as an on-body injector, the longitudinal axis A of the container 14 may be perpendicular, or substantially perpendicular, or non-parallel to the direction in which the insertion mechanism 12 inserts a subcutaneous delivery member, such as the cannula 23, into the patient. This configuration may allow the on-body injector to have a generally flat, low profile that can be worn by a patient without impeding patient movement. Initially, a stopper 34 or other piston member may be disposed within the reservoir 30 at the proximal end 36 of the container 14. The stopper 34 may sealingly and slidably engage an interior surface 43 of a wall 38 of the container 14 and may be movable relative to the wall 38 of the container 14 to expel the medication 32 therein.

[0021] The amount of drug 32 contained within reservoir 30 prior to delivery can be any amount within the range of about (e.g., ±10%) 0.5-20 mL, or any amount within the range of about (e.g., ±10%) 0.5-10 mL, or any amount within the range of about (e.g., ±10%) 1-10 mL, or any amount within the range of about (e.g., ±10%) 1-8 mL, or any amount within the range of about (e.g., ±10%) 1-5 mL, or any amount within the range of about (e.g., ±10%) 1-3.5 mL, or any amount within the range of about (e.g., ±10%) 1-3 mL, or any amount within the range of about (e.g., ±10%) 1-3 mL, or For example, the reservoir 30 may be filled completely or partially with a drug 32. The drug 32 may be one or more of the drugs described below, such as, for example, a granulocyte colony stimulating factor (G-CSF), a PCSK9 (human proprotein convertase subtilisin / kexin type 9) specific antibody, a sclerostin antibody, or a calcitonin gene-related peptide (CGRP) antibody.

[0022] During operation of the drug delivery device 10, the drive assembly 24 may push the stopper 34 within the reservoir 30 along the longitudinal axis A from a proximal end 36 of the container 14 to a distal end 37 of the container 14 to expel the drug 32. As described in more detail below, the drive assembly 24 may include a rotational power source, a gear module configured to convert the rotational speed and / or torque of the rotational motion output by the rotational power source, a stopper biasing member configured to be initially held in a biased state and to expand axially to move the stopper within the reservoir 30, and a tether configured to constrain or regulate the expansion of the stopper biasing member.

[0023] An opening 45 may be formed in the wall 38 at the distal end 37 of the container 14. At least prior to operation of the drug delivery device 10, the opening 45 may be covered and hermetically closed by a sealing member 40, such as a pierceable septum connected to the distal end 37 of the container 14. A proximal surface of the sealing member 40 and an interior surface 43 of the wall 38 of the container 14 may define the reservoir 30. Additionally, in some embodiments, a distal surface of the stopper 34 may define the reservoir 30.

[0024] In general, the seal member 40 may be configured to selectively allow access to the reservoir 30. During operation of the drug delivery device 10, the seal member 40 may be physically altered (e.g., pierced) to allow fluid communication with the drug 32 in the reservoir 30. In some embodiments, the seal member 40 may be constructed of a flexible or elastically deformable material, such as, for example, rubber, that can be penetrated or pierced by the sharp end or tip 63 of the vessel access needle 60 of the fluid pathway assembly 22. In some embodiments, the seal member 40 may be fastened or secured to the distal surface of the wall 38 of the vessel 14 by a fastener (e.g., a crimp ring) and / or may be directly attached to the distal surface of the wall 38 of the vessel 14.

[0025] With further reference to FIG. 1 , the fluid path assembly 22 may be configured to establish fluid communication between the container 14 and the insertion mechanism 12 via a sterile fluid path during operation of the drug delivery device 10. Prior to use of the drug delivery device 10, the fluid path assembly 22 may not be in fluid communication with the container 14. During setup of the drug delivery device 10 or during an initial stage of operation of the drug delivery device 10 prior to drug delivery, the necessary connections may be enabled, connected, or opened manually by a user or automatically by the drug delivery device 10 to establish fluid communication between the container 14 and the fluid path assembly 22. The drive assembly 24 may then move the stopper 34 distally against the wall 38 of the container 14 to push the drug 32 stored in the container 14 through the sterile fluid path of the fluid path assembly 22 and into the cannula 23 or needle or other delivery member of the insertion mechanism 12 for subcutaneous delivery to a patient.

[0026] In some embodiments, the fluid path assembly 22 may be rigidly connected to the wall 15 of the main housing 29 such that the fluid path assembly 22 cannot move relative to the main housing 29, while in other embodiments, the fluid path assembly 22 may be slidably or movably connected to the wall 15 of the main housing 29 such that the fluid path assembly 22 can move relative to the main housing 29 during operation of the drug delivery device 10. In the former embodiment, the container 14 may be slidably or movably connected to the wall 15 of the main housing 29 such that the seal member 40 can be moved toward and pierced by the tip 63 of a fixedly disposed container access needle 60 of the fluid path assembly 22. In the latter embodiment, the container 14 may be fixedly disposed relative to the main housing 29 while the fluid path assembly 22 is moved toward the container 14 to pierce the tip 63 of the container access needle 60 through the seal member 40 to access the reservoir 30.

[0027] The fluid pathway assembly 22 may include a first end 44 connected to the container 14, a second end 48 connected to the insertion mechanism 12, and a fluid pathway 50 extending between the first end 44 and the second end 48. The fluid pathway 50 may be sterile and may be made partially or completely from a flexible tube 52. Initially, there may be slack in the flexible tube 52 to allow the fluid pathway assembly 22 to move relative to the housing 29 and / or to allow the components of the insertion mechanism 12 to which the fluid pathway assembly 22 is attached to move relative to the housing 29. In some embodiments, the fluid pathway 50 may include a rigid fluid-restricting element (not shown) in addition to the flexible tube 52. The fluid-restricting element may have an inner diameter smaller than the inner diameter of the flexible tube 52 to regulate the flow rate of the drug 32 as it passes through the fluid pathway assembly 22. Additionally, the fluid-restricting element may be made from a material that is more rigid than the flexible tube 52. For example, the fluid restricting element may be made from metal and the flexible tube 52 may be made from a polymeric material such as plastic.

[0028] 1, the first end 44 of the fluid pathway assembly 22 may include a vessel access needle 60 and a connection hub or attachment member 62. The vessel access needle 60 may have a sharpened end or tip 63 corresponding to the proximal end of the vessel access needle 60 and a distal end 64 in fluid communication with the fluid passageway 50. The attachment member 62 may cover a length of the distal end 64 of the vessel access needle 60 and connect the distal end 64 of the vessel access needle 60 to the flexible tubing 52.

[0029] Reservoir access needle 60 may have a hollow tubular shape with one or more openings at each of tip 63 and tip 64. Reservoir access needle 60 may be constructed from a rigid material, including but not limited to metal (e.g., stainless steel) and / or plastic. In some embodiments, attachment member 62 may be constructed from a different material than reservoir access needle 60, such that attachment member 62 and reservoir access needle 60 are separate, rigidly connected components. In some embodiments, attachment member 62 may be constructed from a rigid plastic material, while reservoir access needle 60 may be constructed of metal. In other embodiments, attachment member 62 and reservoir access needle 60 may be made of the same material, such that they form a single, integral structure.

[0030] With continued reference to FIG. 1 and further to FIGS. 3-5, a further description of the drive assembly 24 will be provided. Generally, the drive assembly 24 may be configured to provide at least the motive force necessary to move the stopper 34 within the reservoir 30, thereby expelling the medication 32 through the container access needle 60. In some embodiments, the drive assembly 24 may be activated in response to a mechanical and / or electrical signal generated by a user pressing or other interaction with the input device 28, while in other embodiments, the drive assembly 24 may be activated in response to an electrical signal received from the controller 26. Furthermore, in some embodiments, in addition to activating the drive assembly 24, the controller 26 may monitor and / or control the operation of the drive assembly 24 to regulate the rate and / or timing at which the stopper 34 expels the medication 32 from the reservoir 30.

[0031] The drive assembly 24 may include a rotary power source 70 configured to output rotational motion, a gear module 72 configured to convert the speed and / or torque of the rotational motion output by the rotary power source 70, a stopper biasing member 74 configured to be initially held in a biased state and to expand axially to move the stopper 34 within the reservoir 30, and a tether 76 configured to inhibit or adjust the expansion of the stopper biasing member 74.

[0032] The rotary power source 70 may be any mechanism capable of converting stored energy into rotational mechanical motion, including, but not limited to, an electric motor, a torsion spring, and / or a hydraulic or pneumatic pump. In the case of an electric motor, the drug delivery device 10 may include a battery for storing electrical energy for use by the rotary power source 70. The rotary power source 70 may have a rotatable output shaft 78 for transmitting rotary motion to the gear module 72. As shown in FIG. 5, a screw or worm gear 80 may be attached to and axially aligned with the output shaft 78 and may include helically cut teeth that meshingly engage with the teeth of one of the spur gears included in the gear module 72. In operation, the worm gear 80 may rotate relative to a mounting plate 82 of the gear module 72. In some embodiments, the rotary power source 70 may be mounted to the wall 15 of the main housing 29 separately or independently from the gear module 72, while in other embodiments, the rotary power source 70 may be pre-mounted directly to the gear module 72 such that mounting the gear module 72 to the wall 15 of the main housing 29 results in mounting the rotary power source 70 within the main housing 29. In such latter embodiments, the rotary power source 70 and the gear module 72 may be separate components mounted as a single unit within the main housing 29. Additionally, in other embodiments, a bevel gear may be used in place of the worm gear 80.

[0033] In some embodiments, the worm gear 80 may have a self-locking configuration such that the worm gear 80 can drive the gear 84a, but the gear 84a cannot (or has great difficulty driving) the worm gear 80. The self-locking configuration may depend on the advance angle, pressure angle, and / or coefficient of friction between the worm gear 80 and the gear 84a. The self-locking configuration of the worm gear 80 via the tether 76 may help prevent premature stretching or creep of the stopper biasing member 74 prior to operation of the rotational power source 70.

[0034] 3-5, the gear module 72 may generally function as a gear box and include a mounting plate 82 and a plurality of gears 84a-g. Each of the gears 84a-g may be rotatably connected to the mounting plate 82 such that each gear 84a-g may rotate relative to the mounting plate 82. In some embodiments, the rotatable connection of any individual one of the gears 84a-g may be achieved by a pin or shaft rigidly attached to the gear and slidably received within a groove or recess formed in the top surface 92 of the mounting plate 82. In some embodiments, each of the gears 84a-g may be a spur gear having a plurality of teeth cut straight or helically on the outer periphery of the gear. During operation of the rotary power source 70, the teeth of each of the plurality of gears 84a-g may meshingly engage with the teeth of at least one other gear of the plurality of gears 84a-g. Gear 84a, which may serve as an input gear for gear module 72, may have teeth that meshingly engage with the teeth of worm gear 80 such that gear 84a receives rotational power from rotational power source 70. Gear 84g, which may serve as an output gear for gear module 72, may be connected to and axially aligned with winch drum 86 such that gear 84g outputs rotational motion to winch drum 86. Due to the gear reduction provided by gear module 72, the rotational motion output to winch drum 86 may have a lower rotational speed, and in some cases, higher torque, than the rotational motion output by rotational power source 70. Gear reduction may be achieved by configuring at least some of gears 84a-g with different outer diameters and / or different numbers of teeth.

[0035] Certain pairs of gears 84a-g may be arranged in parallel sharing a common axis of rotation, while other pairs of gears 84a-g may be arranged in series with offset and parallel axes of rotation, but with meshing teeth. As shown in FIG. 5, the following gear pairs may be arranged in parallel: (i) gear 84a and gear 84b, (ii) gear 84c and gear 84d, and (iii) gear 84e and gear 84f. In contrast, the following gear pairs may be arranged in series: (i) gear 84b and gear 84c, (ii) gear 84d and gear 84e, and (iii) gear 84f and gear 84g. In some embodiments, such as the one shown in FIG. 5, the number of gear pairs arranged in series may be equal to three, or in other embodiments, may be less than three to reduce components and increase reliability. Worm gear 80 and spur gear 84a are also gear pairs that may be arranged in series.

[0036] As seen in FIG. 3, the mounting plate 82 may be connected to the wall 15 of the main housing 29, but may be separate from the wall 15 of the main housing 29. In some embodiments, the mounting plate 82 may be connected to the wall 15 by fasteners such as screws or bolts. By being attached to the mounting plate 82, the gears 84a-g are not directly connected to the wall 15 of the main housing 29. Thus, bending or other deformation of the wall 15 of the main housing 29 is less likely to affect the alignment of the gears 84a-g. In some embodiments, the mounting plate 82 may be constructed of a stiffer and / or thicker material than the wall 15 of the main housing 29 to make the mounting plate 82 less likely to bend than the wall 15 of the main housing 29. Furthermore, because the mounting plate 82 provides a rigid support structure for the gears 84a-g, there may be more design freedom regarding the shape and / or material used to construct the wall 15 of the main housing 29. Additionally, the printed circuit board 88 associated with the controller 26 may be directly connected to the mounting plate 82 instead of the wall 15, as shown in FIG. 3.

[0037] 4 and 5, the mounting plate 82 may include a bottom surface 90 and a top surface 92. The bottom surface 90 may face the interior surface 17 of the wall 15 of the main housing 29 when the gear module 72 is mounted within the main housing 29. The gears 84a-g may be rotatably connected to the top surface 92 of the mounting plate 82. The gear module 72 may further include a cover member 94 for at least partially enclosing the gears 84a-g within the gear module 72. As shown in FIG. 4, the cover member 94 may be disposed above the top surface 92 of the mounting plate 82 such that the gears 84a-g are disposed between the cover member 94 and the top surface 92 of the mounting plate 82.

[0038] 1 and 3, the drive assembly 24 may include one or more components for operatively connecting the gear module 72 to the stopper 34. In some embodiments, these components may include a tether 76, a winch drum 86, and a pulley member 98. The tether 76 may be any flexible elongated member, such as, for example, a cord, a wire, and / or a chain. The tether 76 may include a first end connected directly or indirectly to the winch drum 86 and a second end connected directly or indirectly to the stopper 34 and / or the stopper biasing member 74. First, prior to operation of the rotary power source 70, a length of the tether 76 may be wound around the winch drum 86, as shown in FIG. 1. The winch drum 86 may be rigidly attached to the output gear 84g such that the winch drum 86 and the output gear 84g rotate together relative to the main housing 29 about a common axis of rotation. A portion of the tether 76 between the winch drum 86 and the stopper 34 may be pulled taught and pulled around a pulley member 98 to change the direction of the tether 76. As shown in FIG. 1, the pulley member 98 changes the direction of the tether 98 from a direction perpendicular or non-parallel to the longitudinal axis A of the container 14 to a direction parallel and / or aligned with the longitudinal axis A of the container 14. The pulley member 98 may include a cylindrical drum or wheel rotatable relative to the main housing 29 or a cylindrical pin fixed relative to the main housing 29.

[0039] Prior to activation of the rotary power source 70, the stopper biasing member 74 exerts a biasing force on the stopper 34, which may result in the tether 76 being pulled between the stopper 34 and the winch drum 86. At this time, the tether 76 is attached to the winch drum 86, which is not rotating to allow the tether 76 to be unwound, and thus the tether 76 may prevent the stopper biasing member 74 from moving the stopper 34 within the reservoir 30. Upon activation of the rotary power source 70, the winch drum 86 may rotate due to being attached to the gear 84g. As the winch drum 86 rotates, the tether 76 may be unwound, creating slack in the tether 76. This slack may allow the stopper biasing member 74 to push the stopper 34 within the reservoir 30, thereby expelling the drug 32 from the container 14. Thus, tether 76 may be configured to provide a damping function to regulate the extension of stopper biasing member 74. In another embodiment, tether 76 and stopper biasing member 74 may be omitted, and instead stopper 34 may be urged within reservoir 30 by a rack and pinion mechanism that receives rotational power via gear 84g.

[0040] Where appropriate, any of the above subassemblies, features, components, features, functions, methods of manufacture, methods of use, and other aspects of drug delivery device 10 may be substituted and / or combined with any of the subassemblies, features, components, features, functions, methods of manufacture, methods of use, and other aspects of drug delivery devices described in any or all of the following documents, which are incorporated herein by reference in their entirety for all purposes: U.S. Patent No. 9,061,097; U.S. Patent Application Publication No. 2017 / 0124284; U.S. Patent Application Publication No. 2017 / 0119969; U.S. Patent Application Publication No. 2017 / 0098058; U.S. Patent Application Publication No. 2017 / 0124285; U.S. Patent Application Publication No. 2017 / 0103186; U.S. Provisional Patent Application No. 62 / 460,501 entitled "INSERTION MECHANISM FOR DRUG DELIVERY DEVICE"; "INSERTION MECHANISM FOR DRUG DELIVERY DEVICE"; and U.S. Provisional Patent Application No. 62 / 460,501 entitled "INSERTION MECHANISM FOR DRUG DELIVERY DEVICE"; No. 62 / 469,226, entitled "INSERTION MECHANISM AND METHOD OF INSERTING A NEEDLE OF A DRUG DELIVERY DEVICE"; U.S. Provisional Patent Application No. 62 / 468,190, entitled "DRUG DELIVERY DEVICE WITH STERILE FLUID FLOWPATH AND RELATED METHOD OF ASSEMBLY"; U.S. Provisional Patent Application No. 62 / 460,559, entitled "DRUG DELIVERY DEVICE WITH STERILE FLUID FLOWPATH AND RELATED METHOD OF ASSEMBLY"; U.S. Provisional Patent Application No. 62 / 294,842, entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE"; No. 62 / 297,718, entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE"; U.S. Provisional Patent Application No. 62 / 320,438, entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE";International Application No. PCT / US2017 / 017627, entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE"; and International Application No. PCT / US2017 / 026524, entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE".

[0041] A method of assembly of the drug delivery device 10 will now be described. As a preliminary step, an empty container 14 and a seal member 40 may be connected together and sterilized. The container 14 and seal member 40 may then be aseptically transferred to a filling and capping environment, where the reservoir 30 of the container 14 may be filled with a drug 32, after which the proximal end 36 of the container 14 may be hermetically closed by a stopper 34. This filling and capping environment may operate as a sterile or aseptic assembly environment to ensure that microorganisms and other contaminants are not introduced into the reservoir 30. The drug-filled container 14 may then be packaged and shipped to a facility where final assembly of the drug delivery device 10 takes place.

[0042] Also, as a preliminary step, the gear module 72 may be assembled. This process may include rotatably connecting each gear 84a-g to the mounting plate 82 and aligning the teeth of adjacent ones of the gears 84a-g so that the teeth mesh with each other upon rotation. After rotatably connecting the gears 84a-g to the mounting plate 82, the gears 84a-g may be visually inspected automatically by sensors and / or cameras and / or manually by a human to ensure that the gears 84a-g meet one or more predetermined quality control measures. Such quality control measures may include, but are not limited to, proper alignment of the teeth of adjacent ones of the gears 84a-g, proper pitch, proper tooth thickness at the pitch circle, proper gear eccentricity, proper gear grade, among others. Inspecting the gears at this stage may be easier than inspecting them after they are installed in the main housing 29 of the drug delivery device 10, where the gears may be partially or completely blocked from view. After inspection of the gears 84a-g, a cover member 94 may be attached to the mounting plate 82 to cover the gears 84a-g and / or to enclose the gears 84a-g within the gear module 72. Assembly of the gear module 72 may occur at the final assembly facility or at an upstream assembly facility operated by a different entity or company than the operator of the final assembly facility.

[0043] At the final assembly facility, the prefilled drug container 14 and the gear module 72 may be installed in the main housing 29 of the drug delivery device 10. In addition, at the final assembly facility, other components and mechanisms of the drug delivery device 10, such as the fluid path assembly 22, the insertion mechanism 12, the controller 26, components of the drive assembly 24 other than the gear module 72, and / or other components and mechanisms, may be installed in the main housing 29. Installing the gear module 72 in the main housing 29 may include connecting the mounting plate 82 to the inner surface 17 of the wall 15 of the main housing 29. This connection may be achieved by fasteners such as bolts or screws and / or by adhesive. In some embodiments, the assembly process may include connecting the rotational power source 70 to the inner surface 17 of the wall 15 of the main housing 29 and then connecting the gear module 72 to the inner surface 17 of the wall 15 of the main housing 29. In other embodiments, the order of these two steps may be reversed. Regardless of the order of these two steps, mounting the rotary power source 70 and gear module 72 within the main housing 29 may include aligning the teeth of the worm gear 80 with the teeth of the input gear 84a such that they meshingly engage with one another when rotated. In another embodiment, the rotary power source 70 may be connected to the gear module 72 with the teeth of the worm gear 80 aligned with the teeth of the input gear 84a prior to mounting the rotary power source 70 within the main housing 29. In such an embodiment, the rotary power source 70 and gear module 72 may be mounted together as a single unit within the main housing 29, rather than being mounted separately.

[0044] Mounting the gear module 72 within the main housing 29 may also include operatively connecting the gear module 72 to a first end of a tether 76. In some embodiments, this may include wrapping a portion of the tether 76 multiple times around the outside of a winch drum 86 and connecting the output gear 84g to the winch drum 86 such that the two components can rotate together about a common axis of rotation. The assembly process may further include operatively connecting a second end of the tether 76 to the stopper 34. The tether 76 may also be partially pulled around a pulley member 98 such that there is tension on the tether 76.

[0045] After all components are attached to the walls 15 of the main housing 29, any openings in the walls 15 may be covered 15 to enclose the components within the main housing 29. In some embodiments, this process may include creating an air-tight and / or fluid-tight seal to maintain a sterile or aseptic atmosphere within the main housing 29. The partially or fully assembled drug delivery device 10 may also be subjected to a sterilization process, such as radiation sterilization and / or gas sterilization, such as ethylene oxide sterilization, before or after the components are enclosed within the main housing 29. Once the final assembly steps are completed, the drug delivery device 10 may be configured as a preloaded and prefilled drug delivery device.

[0046] Drug Information As mentioned above, the container can be filled with a drug, which can be any one or combination of the drugs listed below, although the following list should not be considered as all-inclusive or limiting.

[0047] For example, the syringe may be loaded with colony stimulating factors such as granulocyte colony stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the syringe may be used with various pharmaceutical agents such as erythropoietin stimulating agents (ESAs), which may be in liquid or lyophilized form.ESAs include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methyoxy polyethylene glycol epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (registered trademark), and cyclosporine. any molecule that stimulates red blood cell production, such as, for example, epoetin zeta, Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, as well as any molecule that stimulates red blood cell production, such as, for example, epoetin zeta, epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, as well as any molecule that stimulates red blood cell production, such as, for example, epoetin zeta, epoetin alfa, epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), ... and the following patents or patent applications, each of which is incorporated herein by reference in its entirety: U.S. Pat. No. 4,703,008; U.S. Pat. No. 5,441,868; U.S. Pat. No. 5,547,933; U.S. Pat. No. 5,618,698; U.S. Pat. No. 5,621,080; U.S. Pat. No. 5,756,349; U.S. Pat. No. 5,767,078; U.S. Pat. No. 5,773,569; U.S. Pat. No. 5,955,422; U.S. Pat. No. 5,986,047. Nos. 6,583,272, 7,084,245, and 7,271,689, and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 96 / 40772, WO 00 / 24893, WO 01 / 81405, and WO 2007 / 136752, or variants or analogs thereof.

[0048] The ESA may be an erythropoiesis stimulating protein. As used herein, "erythropoiesis stimulating protein" refers to any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to the receptor and causing receptor dimerization. Erythropoiesis stimulating proteins include erythropoietin and its variants, analogs, or derivatives that bind to and activate the erythropoietin receptor; antibodies that bind to and activate the erythropoietin receptor; or peptides that bind to and activate the erythropoietin receptor. Erythropoiesis stimulating proteins include, but are not limited to, epoetin alpha, epoetin beta, epoetin delta, epoetin omega, epoetin iota, epoetin zeta, and analogs thereof, PEGylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1 / hematide), and mimetic antibodies. Exemplary erythropoiesis stimulating proteins include erythropoietin, darbepoietin, erythropoietin agonist variants, and peptides or antibodies that bind to and activate the erythropoietin receptor (as well as the compounds reported in U.S. Patent Application Publication Nos. 2003 / 0215444 and 2006 / 0040858, the disclosures of each of which are incorporated herein by reference in their entireties), as well as the following patents or patent applications, the disclosures of which are each incorporated herein by reference in their entireties: U.S. Pat. No. 4,703,008; U.S. Pat. No. 5,441,868; U.S. Pat. No. 5,547,933; U.S. Pat. No. 5,547,933; Patent No. 5,618,698, U.S. Patent No. 5,621,080, U.S. Patent No. 5,756,349, U.S. Patent No. 5,767,078, U.S. Patent No. 5,773,569, U.S. Patent No. 5,955,422, U.S. Patent No. 5,830,851, U.S. Patent No. 5,856,298, U.S. Patent No. 5,986,047, U.S. Patent No. 6,030,086, U.S. Patent No. 6,310,078, U.S. Patent No. 6,391,633, U.S. Patent No. 6,583,272, U.S. Patent No. 6,586,398, U.S. Patent No. 6,900,292,U.S. Patent No. 6,750,369, U.S. Patent No. 7,030,226, U.S. Patent No. 7,084,245, and U.S. Patent No. 7,217,689, U.S. Patent Application Publication No. 2002 / 0155998, U.S. Patent Application Publication No. 2003 / 0077753, U.S. Patent Application Publication No. 2003 / 0082749, U.S. Patent Application Publication No. 2003 / 0143202, U.S. Patent Application Publication No. 2004 / 0009902, U.S. Patent Application Publication No. 2004 / 0071694, U.S. Patent Application Publication No. 2004 / 0091961, U.S. Patent Application Publication No. 2004 / 0143857, U.S. Patent Application Publication No. 2004 / 0157293, U.S. Patent Application Publication No. 2004 / 0175379, U.S. Patent Application Publication No. 2004 / 0175824, U.S. Patent Application Publication No. 2004 / 0229318, U.S. Patent Application Publication No. 2004 / 0248815, U.S. Patent Application Publication No. 2004 / 0266690, U.S. Patent Application Publication No. 2005 / 0019914, U.S. Patent Application Publication No. 2005 / 0026834, US Patent Application Publication No. 2005 / 0096461, US Patent Application Publication No. 2005 / 0107297, US Patent Application Publication No. 2005 / 0107591, US Patent Application Publication No. 2005 / 0124045, US Patent Application Publication No. 2005 / 0124564, US Patent Application Publication No. 2005 / 0137329, US Patent Application Publication No. 2005 / 0142642, US Patent Application Publication No. 2005 / 0143292, US Patent Application Publication No. 2005 / 0153879, US Patent Application Publication No. 2005 / 0158822, U.S. Patent Application Publication No. 2005 / 0158832, U.S. Patent Application Publication No. 2005 / 0170457, U.S. Patent Application Publication No. 2005 / 0181359, U.S. Patent Application Publication No. 2005 / 0181482, U.S. Patent Application Publication No. 2005 / 0192211, U.S. Patent Application Publication No. 2005 / 0202538, U.S. Patent Application Publication No. 2005 / 0227289, U.S. Patent Application Publication No. 2005 / 0244409, U.S. Patent Application Publication No. 2006 / 0088906,and U.S. Patent Application Publication No. 2006 / 0111279, and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 99 / 66054, WO 00 / 24893, WO 01 / 81405, WO 00 / 61637, WO 01 / 36489, WO 02 / 014356, WO 02 / 19963, WO 02 / 20034, WO 02 / 49673, WO 02 / 085940, WO 03 / 029291, WO 2003 / 055526, WO 2003 / 084477, WO 2003 / 094858, WO 2004 / 002417, WO 2004 / 002424, WO 2004 / 009627, WO 2004 / 024761, WO 2004 / 033 651, WO 2004 / 035603, WO 2004 / 043382, WO 2004 / 101600, WO 2004 / 101606, WO 2004 / 101611, WO 2004 / 106373, WO 2004 / 018667, WO 2005 / 001025, WO 2005 / 001136, WO 2005 / 021579 brochure, International Publication No. 2005 / 025606 pamphlet, International Publication No. 2005 / 032460 pamphlet, International Publication No. 2005 / 051327 pamphlet, International Publication No. 2005 / 063808 pamphlet, International Publication No. 2005 / 063809 pamphlet, International Publication No. 2005 / 070451 pamphlet, International Publication No. 2005 / 081687 pamphlet, International Publication No. 2005 / 084711 pamphlet, International Publication No. 2005 / 103076 pamphlet, International Publication No. 2005 / 100403 pamphlet,The erythropoietin molecules disclosed in WO 2005 / 092369, WO 2006 / 50959, WO 2006 / 02646, and WO 2006 / 29094, or variants or analogs thereof, are included.

[0049] Examples of other pharmaceuticals for use with the device may include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab) and Prolia™ (denosumab); other biologics such as Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, PEGylated filgastriam, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such as Sensipar® (cinacalcet). The device may also be used with therapeutic antibodies, polypeptides, proteins, or other chemicals such as iron, e.g., ferumoxytol, iron dextran, ferric gluconate, and ferric oxide. The pharmaceutical agent may be in liquid form or may be reconstituted from a lyophilized form.

[0050] Among certain exemplary proteins are the specific proteins described below, including fusions, fragments, analogs, variants, or derivatives thereof.

[0051] The present invention relates to OPGL-specific antibodies and antibody-related proteins, including OPGL-specific antibodies having either a light chain of SEQ ID NO:2 as set forth in Figure 2 of the following publications and / or a heavy chain of SEQ ID NO:4 as set forth in Figure 4 of the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, and with regard to OPGL-specific antibodies and antibody-related proteins, in particular those having the sequences described in the following publications, specifically but not limited to those shown in the following publications (9H7, 18B2, 2D8, 2E11, 16E1, and 22B3), including but not limited to the antibodies described in PCT Publication WO 03 / 002713, which is incorporated herein in its entirety, OPGL-specific antibodies (also referred to as RANKL-specific antibodies, peptibodies, etc.), peptibodies, and related proteins, including fully humanized and human OPGL-specific antibodies, in particular fully humanized monoclonal antibodies:

[0052] The following publications are individually and specifically incorporated by reference in their entirety as disclosed in the following publications: TN8-19-1 to TN8-19-40, TN8-19 con1, and TN8-19 myostatin binding proteins, peptibodies, and related proteins, including myostatin-specific peptibodies, particularly those described in U.S. Patent Application Publication No. 2004 / 0181033 and PCT Publication No. WO 2004 / 058988, which are incorporated by reference in their entireties, particularly in part with respect to myostatin-specific peptibodies, including, but not limited to, the mTN8-19 family of peptibodies, including those of SEQ ID NOs: 305-351, including con2; the mL2 family of SEQ ID NOs: 357-383, the mL15 family of SEQ ID NOs: 384-409, the mL17 family of SEQ ID NOs: 410-438, the mL20 family of SEQ ID NOs: 439-446, the mL21 family of SEQ ID NOs: 447-452, the mL24 family of SEQ ID NOs: 453-454, and the peptibodies of SEQ ID NOs: 615-631.

[0053] IL-4 receptor specific antibodies, including, but not limited to, L1H1, L1H2, L1H3, L1H4, L1H5, L1H6, L1H7, L1H8, L1H9, L1H10, L1H11, L2H1, L2H2, L2H3, L2H4, L2H5, L2H6, L2H7, L2H8, L2H9, L2H10, L2H11, L2H12, L2H13, L2H14, L3H1, L4H1, L5H1, L6H1, each of which is individually and specifically incorporated by reference in its entirety herein, as disclosed in the following publications: Antibodies such as those described in the following publications, particularly those that inhibit activity mediated by the binding of IL-4 and / or IL-13 to their receptors, including those described in PCT Publication No. WO 2005 / 047331 or International Application No. PCT / US2004 / 37242 and U.S. Patent Application Publication No. 2005 / 112694, the entireties of which are incorporated herein by reference, with particular reference in part to those set forth in the following publications, including IL-4 receptor-specific antibodies, peptibodies, and related proteins.

[0054] Interleukin 1-receptor 1 ("IL1-R1") specific antibodies, peptibodies, and related proteins, including, but not limited to, those set forth in the following publications, each of which is individually and specifically incorporated by reference in its entirety as disclosed in the following publications: 15CA, 26F5, 27F2, 24E12, and 10H7, in part, including IL1-R1 specific binding proteins, particularly those described in U.S. Patent Application Publication No. 2004 / 097712, which is incorporated by reference in its entirety, particularly with respect to monoclonal antibodies:

[0055] The sequences of the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, in particular those sequences described in the following publications: L1(N), L1(N)WT, L1(N)1K WT, 2xL1(N), 2xL1(N)WT, Con4(N), Con4(N)1K WT, 2xCon4(N)1K, L1C, L1C 1K, 2xL1C, Con4C, Con4C 1K, 2xCon4C Ang2 specific antibodies and peptibodies, including, but not limited to, those described in PCT Publication No. WO 03 / 057134 and U.S. Patent Application Publication No. 2003 / 0229023, each of which is incorporated by reference in its entirety in part with particular reference to Ang2 specific antibodies and peptibodies, including, but not limited to, those described in the following publications ... and Ang2 specific antibodies, peptibodies, and related proteins, including anti-Ang2 antibodies and formulations such as those described in PCT Publication WO 2003 / 030833, which is incorporated by reference in its entirety with respect to AblP, and the like.

[0056] NGF-specific antibodies, peptibodies, and related proteins, including but not limited to those described in U.S. Patent Application Publication No. 2005 / 0074821 and U.S. Patent No. 6,919,426, each of which is individually and specifically incorporated by reference in its entirety as disclosed in the following publications, each of which is individually and specifically incorporated by reference in its entirety herein, specifically including but not limited to the NGF-specific antibodies 4D4, 4G6, 6H9, 7H2, 14D10, and 14D11 set forth in the following publications:

[0057] For example, humanized and fully human antibodies, including but not limited to, humanized and fully human monoclonal antibodies, particularly including, but not limited to, human CD22-specific IgG antibodies, such as, for example, a dimer of human-mouse monoclonal hLL2 gamma chain disulfide linked to a human-mouse monoclonal hLL2 kappa chain, including, but not limited to, the human CD22-specific fully humanized antibody of epratuzumab (CAS Registry Number 501423-23-0), specifically, human CD22-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 5,789,554, the entirety of which is incorporated herein by reference with respect to CD22-specific antibodies and related proteins.

[0058] The IGF-1 specific antibodies L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, and the like are set forth in the following publications, each of which is individually and specifically incorporated by reference in its entirety herein: L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L 24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L3 and IGF-1 receptor specific antibodies, peptibodies, and related proteins, including but not limited to 4H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-1 R-binding fragments and derivatives thereof, such as those described in PCT Publication WO 06 / 069202, which is incorporated by reference in its entirety for IGF-1 receptor specific antibodies and related proteins.

[0059] Also among the non-limiting examples of anti-IGF-1R antibodies for use in the methods and compositions of the disclosure are each of those described below.

[0060] (i) Antibodies described in U.S. Patent Application Publication No. 2006 / 0040358 (published February 23, 2006), U.S. Patent Application Publication No. 2005 / 0008642 (published January 13, 2005), and U.S. Patent Application Publication No. 2004 / 0228859 (published November 18, 2004), including, but not limited to, Antibody 1A (DSMZ Accession No. DSM ACC 2586), Antibody 8 (DSMZ Accession No. DSM ACC 2589), Antibody 23 (DSMZ Accession No. DSM ACC 2588), and Antibody 18.

[0061] (ii) including, but not limited to, antibodies 2F8, A12, and IMC-A12, described in PCT Publication No. WO 06 / 138729 (published December 28, 2006) and PCT Publication No. WO 05 / 016970 (published February 24, 2005), and Lu et al. (2004), J. Biol. Chem. 279:2856-2865.

[0062] (iii) PCT Publication No. WO 07 / 012614 (published on February 1, 2007), PCT Publication No. WO 07 / 000328 (published on January 4, 2007), PCT Publication No. WO 06 / 013472 (published on February 9, 2006), PCT Publication No. WO 05 / 058967 (published on June 30, 2005), and PCT Publication No. WO 03 / 059951 (published on July 24, 2003).

[0063] (iv) including, but not limited to, antibody 7C10, chimeric antibody C7C10, antibody h7C10, antibody 7H2M, chimeric antibody *7C10, antibody GM607, humanized antibody 7C10 version 1, humanized antibody 7C10 version 2, humanized antibody 7C10 version 3, and antibody 7H2HM described in U.S. Patent Application Publication No. 2005 / 0084906 (published April 21, 2005).

[0064] (v) antibodies including, but not limited to, EM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164 v1.1, huEM164 v1.2, and huEM164 v1.3, as described in U.S. Patent Application Publication No. 2005 / 0249728 (published November 10, 2005), U.S. Patent Application Publication No. 2005 / 0186203 (published August 25, 2005), U.S. Patent Application Publication No. 2004 / 0265307 (published December 30, 2004), and U.S. Patent Application Publication No. 2003 / 0235582 (published December 25, 2003), and Maloney et al. (2003), Cancer Res. 63:5073-5083.

[0065] (vi) U.S. Pat. No. 7,037,498, issued May 2, 2006; U.S. Patent Application Publication No. 2005 / 0244408, published November 30, 2005; and U.S. Patent Application Publication No. 2004 / 0086503, published May 6, 2004; and Cohen, et al. (2005), Clinical Cancer Res. 11:2063-2073, including, but not limited to, each of the antibodies produced by hybridomas having ATCC Accession Nos. PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793, and antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3, e.g., antibody CP-751,871.

[0066] (vii) including, but not limited to, antibody 19D12, as described in U.S. Patent Application Publication No. 2005 / 0136063, published June 23, 2005, and U.S. Patent Application Publication No. 2004 / 0018191, published January 29, 2004, and antibodies comprising a heavy chain encoded by the polynucleotides of plasmid 15H12 / 19D12 HCA(gamma4), deposited with the ATCC under accession number PTA-5214, and a light chain encoded by the polynucleotides of plasmid 15H12 / 19D12 LCF(kappa), deposited with the ATCC under accession number PTA-5220.

[0067] (viii) With respect to the aforementioned antibodies, peptibodies, and related proteins specifically targeting the IGF-1 receptor, including, but not limited to, the antibodies PINT-6A1, PINT-7A2, PINT-7A4, PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1, PINT-11A2, PINT-11A3, PINT-11A4, PINT-11A5, PINT-11A7, PINT-11A12, PINT-12A1, PINT-12A2, PINT-12A3, PINT-12A4, and PINT-12A5, each of which is incorporated by reference in its entirety herein.

[0068] B-7 related protein 1 specific antibodies, peptibodies, related proteins and the like ("B7RP-1," also referred to in the literature as B7H2, ICOSL, B7h, and CD275), particularly B7RP specific fully human monoclonal IgG2 antibodies, particularly fully human IgG2 monoclonal antibodies that bind to an epitope in the first immunoglobulin-like domain of B7RP-1, particularly those that inhibit the interaction of B7RP-1 with ICOS, the natural receptor for B7RP-1, particularly on activated T cells, and ... as disclosed in the following publications, each of which is individually and specifically incorporated herein in its entirety by reference as disclosed in the following publications: 16H (within which the light and heavy chain variable region sequences have SEQ ID NOs: 1 and 7, respectively), 5D (within which the light and heavy chain variable region sequences have SEQ ID NOs: 1 and 7, respectively), and SEQ ID NOs: 2 and 3, respectively, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications: and SEQ ID NO:9), 2H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:3 and SEQ ID NO:10, respectively), 43H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:6 and SEQ ID NO:14, respectively), 41H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:5 and SEQ ID NO:13, respectively), and 15H (having therein light chain variable region sequences and heavy chain variable region sequences, SEQ ID NO:4 and SEQ ID NO:12, respectively) as disclosed in U.S. Patent Publication No. 2008 / 0166352 and PCT Publication No. WO 07 / 011941, which are incorporated by reference in their entireties with respect to such antibodies and related proteins, including, but not limited to, the antibodies set forth in the following publications:

[0069] IL-15 specific antibodies, peptibodies, and related proteins, particularly antibodies, particularly humanized monoclonal antibodies, such as those disclosed in U.S. Patent Application Publication Nos. 2003 / 0138421, 2003 / 023586, and 2004 / 0071702, each of which is incorporated herein by reference in its entirety for IL-15 specific antibodies and related proteins, including, inter alia, peptibodies, including, but not limited to, HuMax IL-15 antibody and related proteins, such as 146B7, and U.S. Patent Application Publication No. 7,153,507.

[0070] IFNγ-specific antibodies, peptibodies, and related proteins, etc., particularly human IFNγ-specific antibodies, in particular fully human anti-IFNγ antibodies, such as, for example, IFNγ-specific antibodies, in particular, fully human anti-IFNγ antibodies, such as those described in U.S. Patent Application Publication No. 2005 / 0004353, which is incorporated herein by reference in its entirety for the antibodies designated 1118, 1118*, 1119, 1121, and 1121* in the following patent publications: The entire sequences of the heavy and light chains of each of these antibodies, and the sequences of their heavy and light chain variable regions and complementarity determining regions, are each individually and specifically incorporated herein by reference in their entirety as disclosed in the aforementioned publications and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115. In addition, the descriptions of the properties of these antibodies described in the aforementioned publications are also incorporated herein by reference in their entirety. Specific antibodies include those having a heavy chain of SEQ ID NO:17 and a light chain of SEQ ID NO:18, those having a heavy chain variable region of SEQ ID NO:6 and a light chain variable region of SEQ ID NO:8, those having a heavy chain of SEQ ID NO:19 and a light chain of SEQ ID NO:20, those having a heavy chain variable region of SEQ ID NO:10 and a light chain variable region of SEQ ID NO:12, those having a heavy chain of SEQ ID NO:32 and a light chain of SEQ ID NO:20, those having a heavy chain variable region of SEQ ID NO:30 and a light chain variable region of SEQ ID NO:12, those having a heavy chain sequence of SEQ ID NO:21 and a light chain sequence of SEQ ID NO:22, those having a heavy chain variable region of SEQ ID NO:14 and a light chain variable region of SEQ ID NO:16, those having a heavy chain of SEQ ID NO:21 and a light chain of SEQ ID NO:33, and those having a heavy chain variable region of SEQ ID NO:14 and a light chain variable region of SEQ ID NO:31, as disclosed in the aforementioned publications. A specific antibody contemplated is antibody 1119, disclosed in the aforementioned U.S. Patent Application Publication, having a complete heavy chain of SEQ ID NO: 17, disclosed in the aforementioned U.S. Patent Application Publication, and a complete light chain of SEQ ID NO: 18, disclosed in the aforementioned U.S. Patent Application Publication.

[0071] TALL-1 specific antibodies, peptibodies, and related proteins, such as those described in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, and in particular U.S. Patent Application Publication No. 2003 / 0195156 and U.S. Patent Application Publication No. 2006 / 0135431, each of which is incorporated herein by reference in its entirety with respect to TALL-1 binding proteins, particularly the molecules in Tables 4 and 5B, as well as other TALL specific binding proteins.

[0072] Parathyroid hormone ("PTH")-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 6,756,480, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind PTH.

[0073] Thrombopoietin receptor ("TPO-R")-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 6,835,809, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind to TPO-R.

[0074] Hepatocyte growth factor ("HGF") specific antibodies, peptibodies, and related proteins, including those that target the HGF / SF:c-Met axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / scatter (HGF / SF), as described in U.S. Patent Application Publication No. 2005 / 0118643 and PCT Publication No. WO 2005 / 017107, huL2G7, as described in U.S. Patent No. 7,220,410, and OA-5d5, as described in U.S. Patent Nos. 5,686,292 and 6,468,529, and PCT Publication No. WO 96 / 38557, each of which is incorporated by reference in its entirety with particular reference in part to proteins that bind HGF.

[0075] TRAIL-R2 specific antibodies, peptibodies, related proteins, etc., such as those described in U.S. Pat. No. 7,521,048, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind TRAIL-R2.

[0076] Activin A-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent Application Publication No. 2009 / 0234106, the entirety of which is incorporated herein by reference, particularly in part, with reference to proteins that bind activin A.

[0077] Particularly relevant to proteins that bind TGF-β are TGF-β specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Pat. No. 6,803,453 and U.S. Patent Application Publication No. 2007 / 0110747, each of which is incorporated by reference in its entirety herein.

[0078] Amyloid β protein specific antibodies, peptibodies, related proteins, etc., including but not limited to those described in PCT Publication WO 2006 / 081171, which is incorporated herein by reference in its entirety with particular reference to proteins that bind to amyloid β protein. One contemplated antibody is an antibody having a heavy chain variable region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID NO:6, as disclosed in the aforementioned publication.

[0079] c-Kit specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Patent Application Publication No. 2007 / 0253951, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind c-Kit and / or other stem cell factor receptors.

[0080] OX40L-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent Application Publication No. 2006 / 0002929, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind OX40L and / or other ligands of the OX40 receptor.

[0081] Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon-beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-alpha4beta7mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Humatrope® (somatropin, human growth hormone), Humira® (adalimumab), insulin in solution, Infergen® (interferon alfacon-1), Natrecor® (nesiritide, recombinant human B-type natriuretic peptide (hBNP), Kineret® (anakinra), Leukine (sargamostim, rhuGM-CSF), LymphoCide® (epratuzumab, anti-CD22 mAb), Benlysta™ (lymphostat B, belimumab, anti-BlyS mAb), Metalyse® (tenecteplase, t-PA analog), Mircera® (methoxypolyethylene glycol-epoetin beta), Mylotarg® (gemtuzumab ozogamicin), (efalizumab), Cimzia® (certolizumab pegol, CDP870), Soliris™ (eculizumab), pexelizumab (anti-complement C5), Numax® (MEDI-524), Lucentis® (ranibizumab), Panorex® (17-1A, edrecolomab), Trabio® (lerdelimumab), TheraCimhR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem® (IDM-1), OvaRex® (B43.13), Nuvion® (vigilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Neulasta® (PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GP lIb / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alfa-2a), Simulect® (basiliximab), Prexige® (lumib racoxib), Synagis® (palivizumab, 146B7-CHO (anti-IL15 antibody, see U.S. Pat. No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax™, Vectibix® (panitumumab), Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein))), VEGF trap (Ig domain of VEGFR1 fused to IgG1 Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2RαmAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimibe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23 mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist), CNTO148 (golimumab, anti-TNFα mAb), HGS- ETR1 (mapatumumab, human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (zalutumumab), M200 (volociximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb, and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. difficile toxin A and toxin B CmAbs MDX-066 (CDA-1) and MDX-1388), anti-CD22 dsFv-PE38 conjugate (CAT-3888 and CAT-8015), anti-CD25mAb (HuMax-TAC), anti-CD3mAb (NI-0401), adecatumumab, anti-CD30mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38mAb (HuMaxCD38), anti-CD40LmAb, anti-Cripto mAb, anti-CTGF idiopathic pulmonary fibrosis stage 1 fibrogen (FG-3019), anti-CTLA4 mAb, anti-eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2 mAb, anti-ganglioside GM2 mAb, anti-GDF-8 human mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12mAb (ABT-874), anti-IL12 / IL23mAb (CNTO1275), anti-IL13mAb (CAT-354), anti-IL2RamAb (HuMax-TAC) , anti-IL5 receptor mAb, anti-integrin receptor mAb (MDX-018, CNTO95), anti-IP10 ulcerative colitis mAb (MDX-1100), anti-LLY antibody, BMS-66513, anti-mannose receptor / hCGβOther exemplary proteins include mAb (MDX-1307), anti-mesothelin dsFv-PE38 conjugate (CAT-5001), anti-PD1 mAb (MDX-1106 (ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβ mAb (GC-1008), anti-TRAIL receptor-2 human mAb (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, anti-ZP3 mAb (HuMax-ZP3), NVS antibody no. 1, and NVS antibody no. 2.

[0082] Sclerostin antibodies, such as, but not limited to, romosozumab, brosozumab, or BPS804 (Novartis), may also be included. Further therapeutic agents may be included, such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX, or XGEVA. Additionally, monoclonal antibodies (IgG) that bind to human proprotein convertase subtilisin / kexin type 9 (PCSK9) may be included in the device. Such PCSK9-specific antibodies include those described in the following patents or patent applications, each of which is incorporated herein by reference in its entirety for all purposes: U.S. Pat. No. 8,030,547, U.S. Pat. No. 8,563,698, U.S. Pat. No. 8,829,165, U.S. Pat. No. 8,859,741, U.S. Pat. No. 8,871,913, U.S. Pat. No. 8,871,914, U.S. Pat. No. 8,883,983, U.S. Pat. No. 8,889,834, U.S. Pat. No. 8,981,064, U.S. Pat. No. 9,056,915, U.S. Pat. No. 8,168,762, U.S. Pat. No. 9,045,547, U.S. Pat. No. 8,030,457, U.S. Pat. No. 8,030,457, U.S. Pat. No. 8,829,165, U.S. Pat. No. 8,981,064, U.S. Pat. No. 8,030,457, U.S. Patent Application Publication No. 2013 / 0064825, U.S. Patent Application Publication No. 2012 / 0093818, U.S. Patent Application Publication No. 2013 / 0079502, U.S. Patent Application Publication No. 2014 / 0357850, U.S. Patent Application Publication No. 2011 / 0027287, U.S. Patent Application Publication No. 2014 / 0357851, U.S. Patent Application Publication No. 2014 / 0357854, U.S. US Patent Application Publication No. 2015 / 0031870, US Patent Application Publication No. 2013 / 0085265, US Patent Application Publication No. 2013 / 0079501, US Patent Application Publication No. 2012 / 0213797, US Patent Application Publication No. 2012 / 0251544, US Patent Application Publication No. 2013 / 0072665, US Patent Application Publication No. 2013 / 0058944, US Patent Application Publication No. 201 3 / 0052201, U.S. Patent Application Publication No. 2012 / 0027765, U.S. Patent Application Publication No. 2015 / 0087819, U.S. Patent Application Publication No. 2011 / 0117011, U.S. Patent Application Publication No. 2015 / 0004174, U.S. Provisional Patent Application No. 60 / 957,668, U.S. Provisional Patent Application No. 61 / 008,965, U.S. Provisional Patent Application No. 61 / 010,630, U.S. Provisional Patent Application No. Application No. 61 / 086,133, U.S. Provisional Patent Application No. 61 / 125,304, U.S. Provisional Patent Application No. 61 / 798,970, U.S. Provisional Patent Application No. 61 / 841,039, U.S. Provisional Patent Application No. 62 / 002,623, U.S. Provisional Patent Application No. 62 / 024,399, U.S. Provisional Patent Application No. 62 / 019,729, U.S. Provisional Patent Application No. 62 / 067,637, U.S. Patent Application No. 14 / 777,371, International Application No. PCT / US2013 / 048714, International Application No. PCT / US2015 / 040211, International Application No. PCT / US2015 / 056972, International Publication No. WO 2008 / 057457, International Publication No. WO 2008 / 057458, International Publication No. WO 2008 / 057459, International Publication No. WO 2008 / 063382, International Publication No. WO 2008 / 133647, International Publication No. 2009 / 100297, International Publication No. 2009 / 100318, International Publication No. 2011 / 037791, International Publication No. 2011 / 053759, International Publication No. 2011 / 053783, International Publication No. 2008 / 125623, International Publication No. 2011 / 072263, International Publication No. 2009 / 055783, International Publication No. 2012 / 0544438 No. WO 2010 / 029513, WO 2011 / 111007, WO 2010 / 077854, WO 2012 / 088313, WO 2012 / 101251, WO 2012 / 101252, WO 2012 / 101253, WO 2012 / 109530, WO 200 Examples of suitable anti-inflammatory agents include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab), and molecules, variants, analogs, or derivatives thereof, as disclosed in WO 1 / 031007, WO 2009 / 026558, WO 2009 / 131740, WO 2013 / 166448, and WO 2014 / 150983.

[0083] Also included may be talimogene laherparepvec or another oncolytic HSV for the treatment of melanoma or other cancers. Examples of oncolytic HSV include, but are not limited to, talimogene laherparepvec (U.S. Pat. Nos. 7,223,593 and 7,537,924), OncoVEXGALV / CD (U.S. Pat. No. 7,981,669), OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143), G207, 1716, NV1020, NV12023, NV1034, and NV1042 (Vargehes et al. (2002), Cancer Gene Ther., 9(12):967-978).

[0084] Also included are TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) and are important in many natural processes. TIMP-3 is expressed by various cells and / or present in the extracellular matrix, inhibits all major cartilage-degrading metalloproteases, and may play a role in many degradative diseases of connective tissue, including rheumatoid arthritis and osteoarthritis, as well as in cancer and cardiovascular conditions. The amino acid sequence of TIMP-3 and the nucleic acid sequence of DNA encoding TIMP-3 are disclosed in U.S. Patent No. 6,562,596, issued May 13, 2003, the disclosure of which is incorporated herein by reference. Descriptions of TIMP mutations can be found in U.S. Patent Application Publication No. 2014 / 0274874 and PCT Publication No. WO 2014 / 152012.

[0085] Also included are antagonistic antibodies of the human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecules targeting the CGRP receptor and other headache targets. Further information regarding these molecules can be found in WO 2010 / 075238.

[0086] In addition, bispecific T cell-inducing antibodies (BiTe), such as blinatumomab, can be used in the device. Alternatively, APJ macromolecular agonists, such as apelin or analogs thereof, can be included in the device. Information regarding such molecules can be found in PCT Publication WO 2014 / 099984.

[0087] In some embodiments, the medicament comprises a therapeutically effective amount of anti-thymic stromal lymphopoietin (TSLP) or TSLP receptor antibody. Examples of anti-TSLP antibodies that may be used in such embodiments include, but are not limited to, those described in U.S. Patent Nos. 7,982,016 and 8,232,372, and U.S. Patent Publication No. 2009 / 0186022. Examples of anti-TSLP receptor antibodies include, but are not limited to, those described in U.S. Patent No. 8,101,182. In a particularly preferred embodiment, the medicament comprises a therapeutically effective amount of the anti-TSLP antibody designated A5 in U.S. Patent No. 7,982,016.

[0088] While the disclosure has been described in connection with various embodiments, it will be understood that the disclosure is capable of further modifications. The disclosure is generally intended to cover any variations, uses, or adaptations of the disclosed subject matter that are in accordance with the principles of the disclosure and that are within known and customary practice within the art to which the disclosure pertains, including departures from the disclosure.

[0089] It should be noted that the structure and configuration of the drug delivery device and its various components and assemblies as shown in the various exemplary embodiments are merely exemplary. Although the present disclosure describes in detail only a few embodiments of the subject matter at issue, those skilled in the art who review the present disclosure will readily appreciate that many modifications (e.g., variations in the size, dimensions, configuration, shape and proportions of the various elements, parameter values, mounting configurations, use of materials, colors, orientations, etc.) are possible without substantially departing from the novel teachings and advantages of the subject matter disclosed herein. For example, elements shown as integrally formed may be composed of multiple parts or elements, and vice versa. Also, the positions of elements may be reversed or otherwise changed, and the nature or number of separate elements or positions may be modified or changed. Accordingly, all such modifications are intended to be included within the scope of the present disclosure as defined in the appended claims. Furthermore, the order or sequence of any process or method steps may be changed or rearranged in accordance with alternative embodiments. Other substitutions, modifications, changes and omissions may be made in the design, operating conditions and arrangements of the various exemplary embodiments without departing from the scope of the present disclosure.

Claims

1. a primary housing including an interior surface defining an enclosed space and an exterior surface removably attachable to a patient; a container disposed within the sealed space and including a reservoir containing a drug and a stopper; a drive assembly disposed within the enclosed space and configured to move the stopper within the reservoir to expel the drug from the reservoir, the drive assembly including a rotary power source and a gear module, the gear module including a mounting plate and a plurality of gears rotatably connected to the mounting plate, the mounting plate being separate from the main housing; 13. A drug delivery device comprising:

2. The drug delivery device of claim 1 , wherein the mounting plate includes a bottom surface facing the interior surface of the housing and a top surface on which the plurality of gears are disposed.

3. 3. The drug delivery device of claim 1 or 2, wherein a first rotational axis of a first gear of the plurality of gears is offset from a second rotational axis of a second gear of the plurality of gears and is parallel to the second rotational axis of the second gear of the plurality of gears, and during operation of the rotational power source, teeth of the first gear meshingly engage with teeth of the second gear.

4. The drive assembly includes: a stopper biasing member configured to be initially held in a biased state and to expand upon release from the biased state to move the stopper within the reservoir; a tether connected between the stopper and the gear module and configured to adjust the tension of the stopper biasing member; The drug delivery device according to any one of claims 1 to 3, comprising:

5. 5. The drug delivery device of claim 4, wherein the rotational power source is operatively connected to the tether via the plurality of gears, and rotation of the plurality of gears creates slack in the tether, allowing the stopper biasing member to stretch.

6. The drug delivery device of claim 4 or 5, comprising a pulley member contacting a portion of the tether extending between the gear module and the stopper.

7. A drug delivery device as described in any one of claims 1 to 6, comprising a worm gear attached to an output shaft of the rotary power source and having teeth that meshingly engage with teeth of at least one of the plurality of gears during operation of the rotary power source.

8. 8. The drug delivery device of claim 7, wherein the rotational power source is directly connected to the mounting plate, and the output shaft is configured to rotate relative to the mounting plate.

9. 9. The drug delivery device of claim 1, comprising a subcutaneous delivery member having a tip, the subcutaneous delivery member having a retracted position in which the tip is retracted into the main housing and a deployed position in which the tip protrudes from the housing beyond the exterior surface of the main housing.

10. 10. The drug delivery device of claim 9, comprising an insertion biasing member configured to be initially held in a biased state and to move the subcutaneous delivery member from the retracted position to the deployed position upon release from the biased state.

11. 11. The drug delivery device of claim 9 or 10, wherein the subcutaneous delivery member has a longitudinal axis that is not parallel to a longitudinal axis of the reservoir.

12. The drug delivery device of any one of claims 1 to 11, comprising a skin adhesive disposed on the exterior surface of the main housing for releasably attaching the drug delivery device to a patient.

13. The drug delivery device of any one of claims 1 to 12, wherein the plurality of gears comprises three or less gear pairs arranged in series.

14. 1. A method of assembling a drug delivery device, comprising: connecting a plurality of gears to a mounting plate of a gear module; after connecting the plurality of gears to the mounting plate, mounting the gear module within a main housing of the drug delivery device; enclosing the gear module and a container having a reservoir for containing a drug within the main housing of the drug delivery device; A method comprising:

15. 15. The method of claim 14, comprising visually inspecting at least one gear of the plurality of gears to determine whether at least one gear meets at least one quality control measure before installing the gear module within the main housing of the drug delivery device and after connecting the plurality of gears to the mounting plate of the gear module.

16. 16. The method of claim 15, wherein inspecting the at least one gear of the plurality of gears to determine if the at least one gear meets the at least one quality control measure comprises determining if teeth of the at least one gear are aligned with teeth of another gear of the plurality of gears.

17. The method of any one of claims 14 to 16, wherein mounting the gear module within the main housing of the drug delivery device comprises operatively connecting a first gear of the plurality of gears to a first end of a tether.

18. The method of claim 17 , further comprising connecting a second end of the tether to a stopper disposed within the reservoir of the container.

19. 19. The method of claim 17 or 18, wherein mounting the gear module within the main housing of the drug delivery device comprises operatively connecting a second gear of the plurality of gears to a rotational power source disposed within the main housing of the drug delivery device.

20. A method according to any one of claims 14 to 19, comprising connecting a rotary power source to the mounting plate prior to mounting the gear module within the main housing.

21. 21. The method of claim 20, comprising aligning teeth of at least one of the plurality of gears with teeth of a worm gear mounted on an output shaft of the rotary power source.

22. The method of any one of claims 14 to 21, wherein the plurality of gears comprises three or less gear pairs arranged in series.

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