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US 20170203043A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0203043 A1 Rusch et al. (43) Pub. Date: Jul. 20, 2017

(54) MEDICAL DELIVERY DEVICE WITH (52) U.S. Cl. LAMINATED STOPPER CPC ...... A61M 5/31505 (2013.01); A6IL 31/048 (2013.01); A61M 2005/3101 (2013.01) (71) Applicant: W. L. Gore & Associates, Inc., Newark, DE (US) (72) Inventors: Greg Rusch, Newark, DE (US); (57) ABSTRACT Robert C. Basham, Forest Hill, MD (US) The present disclosure relates to a medical delivery device (21) Appl. No.: 15/404,892 that includes a barrel having an inner Surface, a plunger rod having a distal end inserted within the barrel, and a stopper (22) Filed: Jan. 12, 2017 attached to the distal end of the plunger rod and contacting at least a portion of the inner surface of the barrel. In at least Related U.S. Application Data one embodiment, the inner surface is hydrophilic. The (60) Provisional application No. 62/279,553, filed on Jan. stopper may include an elastomeric body, one or more 15, 2016. fluoropolymer layers, and two or more ribs laminated with the one or more fluoropolymer layers. In some embodi Publication Classification ments, the contact width between at least one rib having a (51) Int. Cl. sealing Surface and the portion of the inner Surface of the A6M 5/35 (2006.01) barrel measured at a compressibility of greater than about A6IL 3L/04 (2006.01) 7.9% of the stopper is less than about 1.0 mm.

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MEDICAL DELIVERY DEVICE WITH Surface of a barrel of a glass or resin Syringe to achieve high LAMINATED STOPPER levels of air and liquid impermeability while also maintain ing acceptably low break loose and slide forces (i.e., low FIELD friction slidability) but not so much contact that the fluo ropolymer film is distorted to create leak paths that decrease 0001. The present invention relates to a medical delivery air and liquid impermeability. device with a laminated stopper, and in particular, to a medical delivery device with a stopper laminated with a fluoropolymer film. SUMMARY 0006. One embodiment relates to a medical delivery BACKGROUND device that includes a barrel, a plunger rod having a distal 0002 Medical delivery devices such as syringes typically end inserted within the barrel, a stopper attached to the distal include a barrel, a plunger rod reciprocally movable in the end of the plunger rod and contacting at least a portion of the barrel, and a stopper attached to an end of the plunger rod. inner surface of the barrel. The stopper has an elastomeric The stopper to be used for the Syringe is typically air, and body, one or more fluoropolymer layers, and two or more liquid impermeable while also possessing low-friction slid ribs laminated with the one or more fluoropolymer layers. A ability. Air and liquid impermeability is important for elimi contact width between at least one of the two or more ribs nating liquid leakage within the barrel and the introduction having a sealing Surface and a portion of the inner Surface of of air between an outer face of the stopper and an inner wall the barrel measured at a compressibility of greater than of the barrel when charging or discharging the liquid inside about 7.9% of the stopper is less than about 1.0 mm. In at the syringe. Low-friction slidability is important for facili least one embodiment, the barrel has a hydrophilic inner tating the charging and discharging of the liquid inside the surface. Optionally, the hydrophilic inner surface is bare Syringe. In addition to these requirements, a medical glass (e.g., free or Substantially free of silicone oil). Syringe, in particular, must not, adversely affect any phar 0007. In some embodiments, the medical delivery device maceutical composition Such as biopharmaceuticals that further includes a sliding surface that is less than about 2.0 come in contact with the Syringe (e.g., a pre-filled Syringe mm, which is calculated based on a sum of the contact comprising a pharmaceutical composition). widths between at least one of the two or more ribs having 0003 Stoppers for conventional syringes are commonly a sealing Surface and the portion of the inner Surface of the made of a rubber material such as natural rubber, isoprene barrel measured at a compressibility of greater than about rubber or styrene-butadiene rubber which may be vulca 7.9%. nized. Although this type of conventional stopper, has sat 0008. In some embodiments, at least one of each rib of isfactory air and liquid impermeability, it does not have good the two or more ribs having a sealing Surface includes a low-friction slidability. Accordingly, silicone lubricants are radius of curvature at an apex of each respective rib that is typically applied to both the outerface of the stopper and the less than about 0.22 mm; and a ratio of a maximum outer inner wall of the barrel such that the stopper can slide within diameter of all the ribs having a sealing Surface to an inner the barrel. However, Syringes comprising silicone lubricants diameter of the inner surface of the barrel is nominally cannot be used for pharmaceutical composition and the like greater than about 1.08. because the silicone lubricant can cause inactivation or 0009. In some embodiments, a maximum outer diameter otherwise impact the efficacy of these pharmaceutical com of the ribs having a sealing Surface is greater than about 5.0 positions. Therefore, in order to maintain the stability of the mm, an inner diameter of the inner surface of the barrel is pharmaceutical composition, stoppers laminated with a fluo nominally between about 4.65 and about 11.85 mm, and a ropolymer film have been used. Since the air and liquid ratio of the maximum outer diameter of the ribs having a impermeability of stoppers may also have an impact on the sealing Surface to an inner diameter of the inner Surface of quality and stability of the pharmaceutical compositions, the the barrel is greater than about 1.08. stoppers laminated with a fluoropolymer film are required to 0010. In another embodiment, a plunger rod includes a have high levels of air and liquid impermeability. However, distal end that is insertable into a barrel and a stopper when stoppers laminated with a fluoropolymer film are used attached to the distal end. In one or more embodiment, the with a glass or resin Syringe having a hydrophilic or lubri barrel has a hydrophilic inner Surface. The stopper is con cant free inner surface, the stoppers undesirably exhibit figured to contact at least a portion of the inner Surface of the poorer air and liquid impermeability than conventional, barrel. The stopper includes an elastomeric body, one or non-laminated rubber stoppers. more fluoropolymer layers, and two or more ribs laminated 0004 Another problem associated with some fluoropo with the one or more fluoropolymer layers. Each rib of the lymer laminates is its ability to maintain air and liquid two or more ribs having a sealing Surface includes a radius impermeability while also possessing low-friction slidabil of curvature at an apex of each respective rib that is less than ity. For example, Some fluoropolymer laminates function about 0.22 mm, and a ratio of a maximum outer diameter of inconsistently and can distort during insertion of the plunger all the ribs having a sealing Surface to an inner diameter of rod into the barrel and/or during movement of the plunger the inner surface of the barrel is greater than about 1.08. The rod within the barrel, which can create leak paths for the plunger rod may be configured such that when the plunger liquid. Additional difficulties with some fluoropolymer lami rod is inserted in the barrel having an inner diameter of an nates include poor airtightness due to a rough outer Surface inner surface of the barrel, a contact width between at least especially when manufactured as a skived film. one of the two or more ribs having a sealing Surface and the 0005 Accordingly, the need exists for stoppers laminated portion of the inner surface of the barrel measured at a with a fluoropolymer film that are capable of achieving compressibility of greater than about 7.9% of the stopper is sufficient contact with a hydrophilic or lubricant free inner less than about 1.0 mm. US 2017/0203043 A1 Jul. 20, 2017

0011. In yet another embodiment, a stopper that is insert lymer laminates have good biocompatibility, have good able in a barrel having a hydrophilic inner Surface comprises mechanical integrity, are inert, and are processable. an elastomeric body, one or more fluoropolymer layers, and 0020. In some embodiments, the stopper has a compress two or more ribs. The at least one of the two or more ribs are ibility (C96) that is greater than about 7.9%, between about laminated with the one or more fluoropolymer layers and 9.5 and about 20.0%, between about 11.75 and about 18.5%, configured to contact at least a portion of the inner Surface between about 14.0 and about 14.5. In one exemplary of the barrel. each rib of the two or more ribs having a embodiment. the compressibility may be about 14.4%. In sealing Surface comprises a radius of curvature at an apex of addition, the stopper includes at least two ribs laminated each respective rib that is less than 0.22 mm, and a ratio of with a fluoropolymer layer. At least one rib with a sealing a maximum outer diameter of all the ribs having a sealing Surface preferably has a contact, width (w) measured at the surface to an inner diameter of the inner surface of the barrel compressibility (C96) of less than about 1.0 mm. In some is greater than 1.08, and wherein the stopper is configured embodiments, the contact width at the compressibility is Such that when the stopper is inserted in the barrel having an between about 0.05 mm and about 1.0 mm, between about inner diameter of an inner Surface of the barrel, a contact 0.1 and about 0.75 mm, or between about 0.2 and about 0.5 width between at least one of the two or more ribs having a sealing Surface and the portion of the inner Surface of the 0021. In some embodiments, the stopper also includes, a barrel measured at a compressibility of greater than 7.9% of sliding surface (S), which is a sum of the contact widths (w) the stopper is less than about 1.0 mm. of all the ribs having a sealing Surface. The sliding Surface 0012 Optionally, the one or more fluoropolymer layers may be less than about 2.0 mm, or between about 0.05 mm described herein may include a single layer of densified and about 1.9 mm, between about 0.1 mm and about 1.65 expanded polytetrafluoroethylene (ePTFE), or the one or mm, or between about 0.5 mm and about 1.25 mm. Option more fluoropolymer layers may include a composite fluo ally, at least one rib having a sealing Surface has a predefined ropolymer film having a barrier layer and a porous layer, the radius of curvature (r) at the apex of the rib of less than about barrier layer including densified ePTFE. polytetrafluoroeth 0.22 mm, between about 0.05 and about 0.20 mm, or ylene (PTFE), fluorinated ethylene propylene (FEP), poly between about 0.12 and about 0.17 mm. Additionally or ethylene, polypropylene, polyvinylidene fluoride, polyvinyl alternatively, the ratio of a maximum outer diameter (v) of fluoride, perfluoropropylevinylether, a perfluoroalkoxy at least one rib having a sealing Surface to an inner diameter polymer, and copolymers and combinations thereof. (y) of the inner surface of the barrel is greater than about 1.08, between about 1.10 and about 1.25, or between about BRIEF DESCRIPTION OF THE DRAWINGS 1.13 and about 1.23. 0022. In certain embodiments, the fluoropolymer layer 0013 The present invention will be better understood in may include a fluoropolymer film, Such as a polytetrafluo view of the following non-limiting figures, in which: roethylene (PTFE) or densified expanded polytetrafluoro 0014 FIG. 1 illustrates a partial cross sectional side view ethylene (ePTFE) film. Films based on PTFE or ePTFE can of a syringe in accordance with Some embodiments; provide thin and strong barrier layers to leachables and 0015 FIGS. 2-9 depict cross sectional side views of extractables. The superior strength of the expanded fluo stoppers in accordance with some embodiments; ropolymer structure allows these materials to form thin 0016 FIG. 10A depicts a cross sectional side view of a barriers, which remain intact during the forming process and non-compressed stopper in accordance with some embodi installation of the stopper into the Syringe barrel. ments; and 0023 The use of at least partially porous and advanta 0017 FIG. 10B depicts a cross sectional side view of a geously fibrilizing materials, such as ePTFE in combination compressed stopper in accordance with Some embodiments. with other materials, provides numerous advantages. In one aspect, the use of Such porous materials may provide a DETAILED DESCRIPTION scaffold that enables thin strong barrier layers to be made and improves the bond between the elastomer and the I. Introduction laminate. Laminate compliance is beneficial to maintaining a seal between the stopper and the barrel. Porous materials 0018 Persons skilled in the art will readily appreciate also provide for improved compliance of the stopper. that various aspects of the present disclosure can be realized Improved compliance may result from reduced film thick by any number of methods and apparatus configured to ness, flexural compliance, and/or the compressibility of one perform the intended functions. It should also be noted that or more layers of the porous material. Accordingly, by the accompanying drawing figures referred to herein are not providing a laminate that is at least partially porous to the necessarily drawn to Scale, but may be exaggerated to outside (e.g. external or outermost Surface) of the stopper, illustrate various aspects of the present disclosure, and in the seal between the stopper and Syringe barrel may be that regard, the figures should not be construed as limiting. improved while the sliding force is minimized. 0019. The present disclosure is directed to a medical 0024. The laminate may be of single layer or multiple delivery device (e.g., a syringe), a plunger rod and a stopper layer construction. As described herein, layers may be laminated with a fluoropolymer film. The fluoropolymer described functionally. However, the functional names of laminate provides a low friction barrier between an elasto the various layers in the descriptions of embodiments that meric stopper and a pharmaceutical composition (e.g., a follow may not, describe all of the potential functions of any drug, medicine or other therapeutic) in the medical delivery given layer. Accordingly, it will be understood that Such device, and may inhibit, materials from leaching from the functional nomenclature is not intended to be limiting of any elastomeric stopper or from extraction of compounds from layer property. For example, a laminate layer may have the pharmaceutical composition by the elastomer. Fluoropo additional properties and functions such as providing a low US 2017/0203043 A1 Jul. 20, 2017 friction Surface, increasing bond strength and the like. tion, and/or to otherwise protectively seal, engage or Sur Moreover, in multi-layer embodiments, each layer may round sharply pointed distal end 65 of needle cannula 55 and contribute to the reduction of leachable and extractable isolate same from the ambient environment. Thus, the cap 40 materials regardless of its designation as a barrier layer or prevents ambient air from communicating with the receiving otherwise. chamber 30 through needle cannula 55. (0029. The proximal end 25 of barrel 15 may include a II. Syringe flange 80 to be used as a finger stopper for pressing and 0025 FIG. 1 depicts a syringe 10 (optionally a prefilled pulling a plunger rod 85 reciprocally in the barrel 15. The Syringe) in accordance with at least one embodiment. As the plunger rod 85 has opposed distal and proximal ends 90 and skilled artisan will appreciate, although the present inven 95 with a stopper 100 attached to the distal end 90. Stopper tion is described hereafter as it relates to a syringe, other 100 includes opposed proximal and distal ends 105 and 110 types of medical delivery devices are contemplated. Such as, and a side surface 115 extending therebetween. The side for example, an auto-injector or cartridge, without departing surface 115 of stopper 100 may include two or more ribs 120 from the spirit and scope of the present disclosure. The Such as one or more circumferentially extending annular syringe 10 includes a barrel 15 having opposed distal and ribs. The stopper 100 is preferably'formed of an elastomeric proximal ends 20 and 25 and a receiving chamber 30 body 125 and one or more laminate layers 130. The elas positioned between the distal and proximal ends 20 and 25. tomeric body 125 may include any suitable elastomer, and The barrel 15 may be formed of a substantially rigid or hard more particularly, rubbers constructed from butyl, bromobu material. Such as a glass material (e.g., borosilicate glass), a tyl, chlorobutyl, silicone, nitrile, styrene butadiene, poly ceramic material, one or more polymeric materials (e.g., chloroprene, ethylene propylene diene, fluoroelastomers, polypropylene, polyethylene, and copolymers thereof), a thermoplastic elastomers (TPE), and combinations and metallic material, or a plastic material (e.g., cyclic olefin blends thereof. In some embodiments, the elastomeric body polymers (COC) and cyclic olefin copolymers (COP), and 125 may have an initial modulus (small strain) of between combinations thereof. about 2.5 MPa to about 5 MPa, or between about 3 MPa to 0026. In certain embodiments, the barrel 15 is formed of about 4 MPa. in one non-limiting embodiment, the initial glass (e.g., bare glass, without any lubricants thereon), resin, modulus may be, for example, about 3.5 MPa (plus/minus plastic, metal, or like materials and optionally has a hydro measurement and variability tolerance). The materials of the philic interior wall characterized by the absence of a lubri one or more laminate layers 130 are chosen, as described in cant such as, but not limited to, silicone or silicone oil. As detail herein, to provide a low coefficient of friction, com used herein, the term “hydrophilic interior wall” refers to a pliance, low extractables and leachables, and good barrier material (e.g., bare glass that is free or Substantially free of properties as they relate to extractables and leachables from silicone oil) that has a contact angle of deionized water on the elastomeric body 125, as well as good air and liquid a flat surface of the material of less than about 90°, which impermeability. For example, the one or more laminate indicates high wettability. layers 130 may include one or more fluoropolymer films, 0027. The distal end 20 of barrel 15 includes an elongated such as, but not limited to PTFE or ePTFE films. tip 35 extending through and communicating with the 0030 FIG. 1 also shows a material 135 provided in the receiving chamber 30. In some embodiments, a cap 40 is receiving chamber 30 of barrel 15 (e.g., a prefilled syringe). disposed at the distal end 20 of the barrel 15. The cap 40 For purposes of illustration but not of limitation, the material includes a proximal end 45 mated to the distal end 20 or to 135 is herein identified as a predetermined dose of a phar the elongated tip 35 and a closed distal end 50. Thus, the cap maceutical composition 135; however, it should be under 40 inhibits or prevents ambient air from communicating stood that the material 135 could be any type of liquid or with the receiving chamber 30 through the elongated tip 35. material capable of being expelled from a syringe, or the Optionally, a piercing element 55 is also disposed at the material 135 may be all together absent from the receiving distal end 20 of the barrel 15. The piercing element 55 chamber (e.g., an unfilled syringe). includes a proximal end 60 mated to the distal end 20 or to the elongated tip 35 and a distal end 65. It is within the III. Laminate Layers purview of the present disclosure that the piercing element 0031. In some embodiments, the one or more, laminate 55 may include a sharply pointed needle cannulae, or a layers 130 may include a single layer of a fluoropolymer. blunt-ended cannulae, such as those employed with “needle FIG. 2 depicts a stopper 100 that includes an elastomeric less’ systems. For purposes of illustration, the piercing body 125 and a single layer of fluoropolymer or barrier layer element 55 depicted and described herein is formed as a 140. Examples of elastomers that can be used to form the sharply pointed, elongate needle cannula 55 including the elastomeric body 125 include any elastomer suitable for the proximal end 60, a sharply pointed distal end 85 and a lumen application, most notably rubbers constructed from butyl, 70 extending between the proximal end 60 and the distal end bromobutyl, chlorobutyl, silicone, nitrile, styrene butadiene, 65. Proximal end 60 of needle cannula 55 may be rigidly polychloroprene, ethylene propylene diene, fluoraelasto mounted to the elongated tip 35 of the barrel 15. mers, thermoplastic elastomers (TPE), thermoplastic Vulca 0028. In some embodiments, the cap 40 is mounted over nizates (TPV), and materials sold under the trade name needle cannula 55 and is releasably engaged to the elongated VITONR), and combinations and blends thereof. Exemplary tip 35 of the barrel 15. The cap 40 may be formed from a elastomeric materials include, but are not limited to, butyl rigid material Such as plastic, or can be formed from a rubber, bromobutyl rubber, chlorobutyl rubber, silicone, flexible material such as rubber, or from like materials or nitrile, styrene butadiene, polychloroprene, ethylene propyl combinations known to the skilled artisan. The cap 40 may ene diene, fluoroelastomers and combinations thereof. be configured for closing the lumen 70 of the needle cannula 0032 Examples of fluoropolymers that can be used to 55 in fluid communication with a pharmaceutical composi form the fluoropolymer or barrier layer 140 include any US 2017/0203043 A1 Jul. 20, 2017 fluoropolymer Suitable for the application, most notably a and combinations thereof. The porous layer 150 may include densified expanded fluoropolymer, polytetrafluoroethylene ePTFE (for example, ePTFE as taught in U.S. Pat. No. (PTFE), densified ePTFE, fluorinated propylene (FEP), 6,541,589 to Bailie) or other porous expanded and fibrilizing polyethylene, polypropylene, polyvinylidene fluoride, poly fluoropolymers. The one or more laminate layers 130 having vinylfluoride, perfluoropropylevinylether, perfluoroalkoxy the barrier layer 145 and the porous layer 150 may be polymers, tetrafluoroethylene (TFE), and copolymers and constructed by coating or otherwise depositing the fluoropo combinations thereof. The barrier film may also include a lymer onto the porous layer to create the composite fluo composite fluoropolymer film having a barrier layer and a ropolymer film. One such example of this would be to porous layer. The porous layer, for example, maybe formed deposit granular or powdered fluoropolymers such as pow of ePTFE or other porous expanded and fibril Zing fluo dered PTFE onto a porous ePTFE surface in a coating ropolymers (for example, ePTFE as taught in U.S. Pat. No. process. The ePTFE support should be constructed to be 6,541,589). The ePTFE layers may be filled with an organic thermally stable enough to allow heat treatment of the or inorganic material to provide color, lubricity, or other deposited fluoropolymer for the creation of a barrier or for function. bonding of the deposited layer to the porous ePTFE support. 0033. In a some embodiments, the fluoropolymer or The ePTFE layer may be filled with an organic or inorganic barrier layer 140 may include a densified expanded fluo material to provide color, lubricity, or other functional ropolymer, preferably a densified expanded polytetrafluoro attributes. ethylene (ePTFE). A densified ePTFE film may be prepared 0037. In accordance with some aspects of the present in the manner described in U.S. Pat. No. 7,521,010 to invention, the elastomer material of the elastomeric body Kennedy, et al., U.S. Pat. No. 6,030,694 to Dolanet al., U.S. 125 may at least partially penetrate the porous layer 150. Pat. No. 5,792,525 to Fuhr et al., or U.S. Pat. No. 5,374,473 FIG. 4 illustrates a cross-section of a stopper depicting the to Knox et al. Expanded copolymers of PTFE, such as are barrier layer 145, the porous layer 150, and the elastomeric described in U.S. Pat. No. 5,708,044 to Branca, U.S. Pat. body 125. Specifically, FIG. 4 shows a region of partial No. 6,541,589 to Baillie, U.S. Pat. No. 7,531,611 to Sabolet penetration 160 of the elastomer material of the elastomeric al., U.S. Pat. No. 8,637,144 to Ford, and U.S. Pat. No. body 125 into the porous layer 150. Penetration of the 9,139,669 to Xu et a. may be utilized if they are densified. elastomer material of the elastomeric body 125 into the 0034. The barrier film may also include an expanded porous layer 150 may improve the bond between the elas polymeric material including a functional tetrafluoroethyl tomeric body 125 and the one or more laminate layers 130. erie (TFE) copolymer material having a microstructure 0038. In accordance with other aspects, the material of characterized by nodes interconnected by fibrils, where the the barrier layer 145 may at least partially penetrate the functional TFE copolymer material includes a functional porous layer 150. FIG. 5 illustrates a cross-section of a copolymer of TFE and PSVE (perfluorosuifonyl vinyl stopper depicting the barrier layer 145, the porous layer 150, ether), or TFE with another suitable functional monomer, and the elastomeric body 125. Specifically, FIG. 5 shows a such as, but not limited to, vinylidene fluoride (VDF), vinyl region of partial penetration 165 of the material of the barrier acetate, or vinyl alcohol. The functional TFE copolymer layer 145 into the porous layer 150. Penetration of the material may be prepared, for example, according to the material of the barrier layer 145 into the porous layer 150 methods described in U.S. Pat. No. 9,139,669 to Xu et al. or may improve the bond between the barrier layer 145 and the U.S. Pat. No. 8,658,707 to Xu et al. porous layer 150. The region of partial penetration 165 may 0035. The densified ePTFE film may be combined with also provide support for the barrier layer 145 to impart an elastomer to construct the stopper 100. In this embodi strength, toughness, compliance and stability, which may be ment, the densified ePTFE film is thermoformed to make a beneficial in both the forming process and in the application. preform. Thermoforming is done at process temperatures 0039. In another embodiment, as shown in FIG. 6, the sufficiently above the nodal melt temperature to ensure melt one or more laminate layers 130 may comprise a composite forming while preserving barrier and strength properties. fluoropolymer film having a densified expanded fluoropo The high strength of the resulting expanded film allows for lymer layer 170, a barrier melt fluoropolymer layer 175, and forming extremely thin films. The films can be made with a porous layer 180. The densified expanded fluoropolymer thicknesses ranging from about 0.5 micron to about 20 layer 170 can may include or be formed of a densified microns. In some embodiments, the films have a thickness ePTFE. The barrier melt fluoropolymer layer 175 may that is less than about 30 microns. The film can optionally be include a fluoropolymer Such as a densified expanded fluo pre-treated or post-treated with chemical etching, plasma ropolymer, PTFE, ePTFE, densified ePTFE, or fluorinated treating, corona, roughening, or the like to improve bonding propylene (FEIN), polyethylene, polypropylene, polyvi to the elastomeric body 125. The thermoformed, densified nylidene fluoride, polyvinylfluoride, perfluoropropyleviny ePTFE preform can be combined with the elastomeric body lether, perfluoroalkoxy polymers, and copolymers and com 125 by injection molding, compression molding, priming binations thereof. The porous layer 150 may include or be and post laminating around an elastomer perform, or by formed of ePTFE or other porous expanded and fibrilizing other suitable methods known to those of skill in the art. fluoropolymers. The one or more laminate layers 130 having 0036. In another embodiment, as shown in FIG. 3, the the densified expanded fluoropolymer layer 170, the barrier one or more laminate layers 130 may include a composite melt fluoropolymer layer 175 and the porous layer 180 may fluoropolymer film having a barrier layer 145 and a porous be constructed by coating or otherwise depositing the fluo layer 150. The barrier layer 145 can include a fluoropolymer ropolymer onto the porous layer to create the composite such as a densified expanded fluoropolymer, PTFE. ePTFE, fluoropolymer film. The densified ePTFE film, fluoropoly densified ePTFE, FEP polyethylene, polypropylene, poly mer, and porous layer may be thermoformed to make a vinylidene fluoride, polyvinylfluoride, perfluoropropylevi preform, and may be combined with the elastomeric body nylether, perfluoroalkoxy polymers, TFE, and copolymers 125 by injection molding, compression molding, priming US 2017/0203043 A1 Jul. 20, 2017

and post laminating around an elastomer perform, or other IV. Stopper Structure suitable methods known to the skilled artisan. 0044. In some embodiments, the stopper 100 is config 0040. In accordance with some aspects, the elastomer ured to achieve container closure integrity with high levels material of the elastomeric body 125 may at least partially of air and liquid impermeability while also maintaining penetrate the porous layer 180. FIG. 7 shows a cross-section acceptably low break loose and slide forces. FIGS. 10A and of a stopper depicting a densified expanded fluoropolymer 10B show such a stopper 100 that includes a body 205 layer 170, a barrier melt fluoropolymer layer 175, and a having opposed proximal and distal ends 210 and 215 and porous layer 180. Specifically, FIG. 7 shows a region of two or more ribs 220. A head portion 225 is formed partial penetration 185 of the elastomer material of the integrally with the distal end 215 of the body 205. One or elastomeric body 125 into the porous layer 180. Penetration more annular grooves 230 is formed in an outer surface of of the elastomer material of the elastomeric body 125 into the body 205, thus forming and connecting the two or more the porous layer 180 may improve the bond between the ribs 220. At least one of the two or more ribs 220 is elastomeric body 125 and the one or more laminate layers laminated with the one or more laminate layers 130. A cavity 130. 240 may extend from the proximal end of 210 of the body 0041. In accordance with other aspects, the material of 205 towards the distal end 215. The distal end 90 of the the barrier melt fluoropolymer layer 175 may at least par plunger rod 85 may be inserted and fixed inside the cavity tially penetrate the porous layer 180. FIG. 8 shows a 240 of the stopper. cross-section of a stopper according to an embodiment 0045. The two or more ribs 220 can be classified based on depicting densified expanded fluoropolymer layer 170, a whether they have a sealing Surface or a non-sealing Surface. barrier melt fluoropolymer layer 175 and a porous layer 180. As used herein, the term "sealing surface” refers to a rib Specifically, FIG. 8 shows a region of partial penetration 190 having a compressibility of greater than about 7.9%, and the of the material of the barrier melt fluoropolymer layer 175 term “non-sealing Surface' refers to a rib having a com into the porous layer 180. Penetration of the material of the pressibility of about 7.9% or less. For example, the two ribs barrier melt fluoropolymer layer 175 into the porous layer shown in FIGS. 10A and 106 as being the furthest towards 180 may improve the bond between the barrier melt fluo the distal end 215 of the body 205 have a compressibility of ropolymer layer 175 and the porous layer 180. The region of greater than about 7.9%, and thus are referred to as having partial penetration 190 may also provide support for the a sealing surface. In contrast, the one rib shown in FIGS. barrier melt fluoropolymer layer 175 to impart strength, 10A and 106 as being the furthest towards the proximal end toughness, compliance and stability, which is beneficial in 210 of the body 205 has a compressibility of about 7.9% or both the forming process and in use. less, and thus is referred to as having a non-sealing Surface. 0042. In accordance with some aspects, the material of As the skilled artisan will appreciate, although the present the barrier melt fluoropolymer layer 175 may at least par invention is described hereafter as it relates to rib arrange tially penetrate the densified expanded fluoropolymer layer ment shown in FIGS. 10A and 10B, other types of rib 170. FIG. 9 shows a cross-section of a stopper depicting a arrangements are contemplated, such as, for example having densified expanded fluoropolymer layer 170, a barrier melt three ribs with sealing Surfaces, without departing from the fluoropolymer layer 175, and a porous layer 180. Specifi spirit and scope of the present disclosure. cally, FIG. 9 shows a region of partial penetration 195 of the 0046 Each rib 220 having a sealing surface includes at material of the barrier melt fluoropolymer layer 175 into the least one a predefined outer diameter (X) measured from an densified expanded fluoropolymer layer 170. Penetration of apex of the respective rib with the stopper 100 in a non the material of the barrier melt fluoropolymer layer 175 into compressed State (see, e.g., FIG. 10A), a curvature (c) the densified expanded fluoropolymer layer 170 may having a predefined radius of curvature (r) at the apex of the improve the bond between the barrier melt fluoropolymer respective rib that is measured with the stopper 100 in a layer 175 and the densified expanded fluoropolymer layer non-compressed state (see, e.g., FIG. 10A), and a contact 170. The region of partial penetration 195 may also provide width (w) between each respective rib and an inner surface support for the barrier melt fluoropolymer layer 175 to 240 of the barrel measured at a compressibility (C96) of the impart strength, toughness, compliance and Stability, which stopper 100 in a compressed state (see, e.g., FIG. 106). In is beneficial in both the forming process and in use. some embodiments, at least one of the predefined outer 0043. The stopper 100 may include various degrees of diameter (X) of at least one rib 220 having a sealing Surface penetration of either the elastomer material or the barrier is greater than about 5.0 mm, between about 5.0 mm and polymer into the porous material or the densified expanded about 14.0 mm, or between about 5.5 mm and about 10 mm. fluoropolymer layer as shown in FIGS. 4, 5, and 7-9, and as In some embodiments, the predefined outer diameter (x) described in U.S. Pat. No. 8,722,178 to Ashmead, et al., U.S. may be, for example, about 7.42 mm or about 5.5 mm. The Patent Publication No. 2012/0251748 to Ashmead, et al., predefined radius of curvature (r) of at least one rib 220 and U.S. Patent Publication No. 2016/0022918 to Ashmead, having a sealing Surface is less than about 0.22 mm, between et al. It is to be appreciated that there are many variations of about 0.05 mm and about 0.20 mm. or between about 0.12 the processes described herein that could be utilized for mm and about 0.17 mm. The contact width (w) of, at least forming the stopper 100 without departing from the scope one rib 220 having a sealing Surface measured at the and/or spirit the invention. Some of these variations may compressibility (C96) is less than about 1.0 mm. In some include, but are not limited to, forming any of the fluoropo embodiments, the contact width at the compressibility is lymers used in the stopper 100 of the present invention with between about 0.05 mm and about 1.0 mm, between about an expanded fluoropolymer film based on PTFE, modified 0.1 and about 0.75 mm, or between about 0.2 and about 0.5 PTFE, and PTFE and TFE copolymers such as, for example, mm. A sliding surface (S) of the stopper 100 includes a sum the resins as described in U.S. Pat. No. 6,541,589 to Bailie of the contact widths (w) of all the ribs having a sealing and U.S. Pat. No. 8,637,144 to Ford. Surface that is less than 2.0 mm. The sliding Surface may be US 2017/0203043 A1 Jul. 20, 2017

less than about 2.0 mm, or between about 0.05 mm and position within the barrel) and slide forces (e.g., the amount about 1.9 mm, between about 0.1 mm and about 1.65 mm, of force required to move the stopper parallel along the inner or between about 0.5 mm and about 1.25 mm. surface of the barrel) particularly depend upon the contact 0047. As the skilled artisan will appreciate, the ribs 220 width (w) or sliding surface (S). Additionally, it was found can be structured in any number of configurations, and that distortion of the fluoropolymer film (both the portion of FIGS. 10A and 10B are provided for purposes of illustration the fluoropolymer film contacting the inner surface of the only, and are not intended to limit the present disclosure. For barrel and the portion of the fluoropolymer film not con example, in certain embodiments, all of the ribs 220 having tacting the inner surface of the barrel) of the stopper that is a sealing Surface may have a same predefined outer diameter in contact with a hydrophilic or lubricant free inner surface (X). In other embodiments, each rib 220 having a sealing of a barrel depends particularly upon the dimensions of the surface may have its own predefined outer diameter (x). For two or more ribs. Some of the conventional stoppers lami example, a distal or leading rib may have a predefined outer nated with a fluoropolymer film when compressed enough to diameter (1X) and a proximal or trailing rib may have a achieve a desired seal pressure have unacceptable break predefined outer diameter (2x) that is between about 75% loose and slide forces due to excessive contact area or and about 99.9% of the predefined outer diameter (1X). sliding Surface between the stopper and the inner Surface of 0048. The compressibility (C96) is defined in relation to barrel. Moreover, some conventional laminates tends to a maximum outer diameter (v) of the ribs 220 having a distort during movement of the plunger rod within the barrel sealing Surface of the stopper 100 in a non-compressed State during charging or discharging due to the structure of the and the inner diameter (y) of the inner surface 240 of the one or more annular grooves and the two or more ribs. barrel as follows: C 96-((v-y)/v)x100. For example, under 0051. However, it has been surprisingly and unexpect standing that each of the ribs 220 having a sealing Surface edly found that when the contact width (w) of at least one rib may have its own predefined outer diameter (X), and thus its with a sealing Surface measured at a compressibility (C96) own compression, compressibility (C96) of the stopper 100 of greater than 7.9% is less than about 1.0 mm, or between is defined in relation to the largest outer diameter (X) (i.e., about 0.05 mm and about 1.0 mm, between about 0.1 and the maximum outer diameter (v)) out of all of the ribs 220 about 0.75 mm, or between about 0.2 mm and about 0.5 mm having a sealing Surface of the stopper 100 in a non and a sliding surface (S) of the stopper 100 that includes a compressed State. In some embodiments, the maximum Sum of the contact widths (w) of all the ribs having a sealing outer diameter (v) of the ribs 220 having a sealing surface is surface is less than about 2.0 mm, or between about 0.05mm greater than about 5.0 mm, between about 5.0 mm and about and about 1.9 mm, between about 0.1 mm and about 1.65 14.0 mm, or between about 5.5 mm and about 10 mm. In mm, or between about 0.5 and about 1.25 mm, the stoppers Some embodiments, the sealing Surface may be, for of the present disclosure achieve a desired seal pressure with example, about 7.42 mm or about 5.5 mm; the inner diam acceptable break loose and slide forces. Moreover, it has eter (y) may be between about 2.5 mm and about 30.0 mm, been Surprisingly and unexpectedly found that when the between about 4.5 mm and about 20.0 mm, or between about predefined radius of curvature (r) of at least one rib having 5.5 mm and about 11.5 mm. In some embodiment, the inner a sealing Surface is at less than about 0.22 mm, or between diameter may be, for example, about 6.35 mm or nominally about 0.05 and about 0.20 mm, or between about 0.12 and (a tolerance of +/-0.1 on the 4.65 side and a tolerance of about 0.17 mm, and the ratio of the maximum outer diameter +/-0.2 on the 11.85) between about 4.65 mm and about (v) of at least one rib having a sealing Surface to the inner 11.85 mm; and the compressibility (C96) of the stopper may diameter (y) of the inner surface of the barrel is greater than be greater than about 7.9%, between about 9.5% and about about 1.08, between about 1.10 and about 1.25, or between 20.0%, or between about 11.75% and about 18.5%. In some about 1.13 and about 1.23, the fluoropolymer laminate of the embodiments, the compressibility may be, for example, stoppers do not distort under the compressibility (C '%), about 14.4%. In some embodiments, a ratio of the maximum which is necessary to achieve an adequate seal pressure outer diameter (v) of the ribs 220 having a sealing surface to while allowing for acceptably low break loose and slide the inner diameter (y) of the inner surface 240 of the barrel forces. may be greater than, for example, about 1.08, or between 0.052 Additionally, it has been surprisingly and unex about 1.10 and about 1.25, or between about 1.13 and about pectedly found that using the aforementioned one or more 1.23. laminate layers allows for improved geometry with respect 0049. In some embodiments, the stopper 100 may be to aforementioned properties of the two or more ribs without configured based on the aforementioned composition of the causing leak paths. Accordingly, the aforementioned aspects one or more laminate layers 130 and properties of the two or of the present invention allow for the construction of stop more ribs 220 to have a predetermined slide force and pers laminated with a fluoropolymer film that achieve suf predetermined seal pressure. In, Some embodiments, the ficient contact with the inner surface of the barrel of a glass predetermined slide force is a peak extrusion force of less or resin syringe (hydrophilic and/or lubricant free) to than about 20 Nat speeds of 50-250 mm/min using a syringe achieve high levels of air and liquid impermeability while filled with water. In some embodiments, the predetermined also maintaining acceptably low break loose and slide forces seal pressure is, a seal pressure adequate to achieve, a helium low-friction slidability) but not so much contact that the leak rate of less than 6x10 secs. fluoropolymer film surface is distorted to create leak paths 0050 Referring to FIGS. 10A and 10B, it was found that that decrease the air and liquid impermeability. the seal pressure of a stopper laminated with a fluoropoly 0053. In another aspect, the medical delivery device, mer film that is in contact with a hydrophilic or lubricant free plunger rod, and stopper described herein may be used in inner Surface of a barrel depends particularly upon com combination different therapeutic compounds such as, for pressibility (C96), and the break loose (e.g., the amount of example, drugs and biologics, including but not limited to, force required to begin moving the stopper from a stationary , antisense, RNA interference, therapy, pri US 2017/0203043 A1 Jul. 20, 2017

mary and embryonic stem cells, , and combinations Cholinergic neural cell, Adrenergic neural cell, Peptidergic thereof. For instance, the embodiments described herein neural cell; Sense organ and peripheral neuron Supporting may be utilized in combination with any or all of the cells including but not limited to: Inner pillar cell of organ following: of Corti, Outer pillar cell of organ of Corti, Inner phalangeal 0054 Cell therapy using cells that are derived primarily cell of organ of Corti, Outer phalangeal cell of organ of from endoderm such as Exocrine secretory epithelial cells Corti, Border cell of organ of Corti, Hensen cell of organ of and Hormone-secreting cells; ectoderm Such as Keratinizing Corti, Vestibular apparatus Supporting cell, Taste bud Sup epithelial cells, Wet stratified barrier epithelial cells, Sensory porting cell, Olfactory epithelium Supporting cell, Schwann transducer cells, Autonomic neuron cells, Sense organ and cell, Satellite glial cell, Enteric glial cell: Central nervous peripheral neuron Supporting cells, Central nervous system system neurons and glial cells including but not limited to: neurons and glial cells, Lens cells; mesoderm Such, as Astrocyte, Neuron cells, Oligodendrocyte, Spindle neuron; Metabolism and storage cells, Barrier function cells (lung, Lens cells including but not limited to: Anterior lens epi gut, exocrine glands, and urogenital tract), Extracellular thelial cell, Crystallin-containing lens fiber cell; Metabolism matrix cells, Contractile cells, Blood and immune system and storage cells including but not limited to: Adipocytes: cells, Germ cells, Nurse cell, Interstitial cells or a combi Liver lipocyte; Barrier function cells including but not nation thereof. Additionally cells that are genetically, chemi limited to: Kidney parietal cell, Kidney glomerulus podo cally or physically altered or modified are considered to be cyte, Kidney proximal tubule brush border cell, Loop of in the scope of the invention. Henle thin segment cell, Kidney distal tubule cell, Kidney collecting duct cell, Principal cells, Intercalated cells, Type 0055 Examples of Exocrine secretory epithelial cells I pneumocyte, Pancreatic duct cell, Nonstriated duct cell, include, but are not limited to, Salivary gland mucous cell, Principal cell, Intercalated cell, Duct cell, Intestinal brush Salivary gland number 1, Von Ebner's gland cell in tongue, border cell, Exocrine gland striated duct cell, Gall bladder Mammary gland cell, Lacrimal gland cell, Ceruminous epithelial cell, Ductulus efferens nonciliated cell, Epididy gland cell in ear, Eccrine Sweat gland dark cell, Eccrine mal principal cell, Epididymal basal cell: Extracellular Sweat gland clear cell, Apocrine Sweat gland cell, Gland of matrix cells including but not limited to: Ameloblast epi Moll cell in eyelid, Sebaceous gland cell, Bowman's gland thelial cell, Planum semilunatum epithelial cell of vestibular cell in nose, Brunner's gland cell in duodenum, Seminal system of ear, Organ of Corti interdental epithelial cell, vesicle cell, Prostate gland cell, Bulbourethral gland cell, Loose connective tissue fibroblasts, Corneal fibroblasts, Bartholinis gland cell, Gland of Littre cell, Uterus endome Tendon fibroblasts, marrow reticular tissue fibroblasts, trium cell, Isolated goblet cell of respiratory and digestive Other nonepithelial fibroblasts, Pericyte, Nucleus pulposus tracts, Stomach lining mucous cell, Gastric gland Zymogenic cell of intervertebral disc, Cementoblasticementocyte, cell, Gastric gland oxyntic cell, Pancreatic acinar cell, Odontoblastiodontocyte, Hyaline cartilage chondrocyte, Paneth cell of small intestine, Type II pneumocyte of lung, Fibrocartilage chondrocyte, Elastic cartilage chondrocyte, Clara cell of lung: Hormone-secreting cells including but not Osteoblastiosteocyte, Osteoprogenitor cell, Hyalocyte of limited to: Anterior pituitary cells, Intermediate pituitary vitreous body of eye, Stellate cell of perilymphatic space of cell, Magnocellular neurosecretory cells, Gut and respira ear, Hepatic stellate cell, Pancreatic stelle cell; Contractile tory tract cells, Thyroid gland cells, Parathyroid gland cells, cells including but not limited to: Skeletal muscle cell, Adrenal gland cells, Leydig cell of testes secreting testos Satellite cell, Heart muscle cells, Smooth muscle cell, Myo terone. Theca interns cell of ovarian follicle secreting estro epithelial cell of iris, Myoepithelial cell of exocrine glands: gen, Corpus luteum cell of ruptured ovarian follicle secret Blood and immune system cells including but not limited to: ing progesterone, Juxtaglomerular cell, Macula dense cell of Erythrocyte, Megakaryocyte, Monocyte, Connective tissue kidney, Peripolar cell of kidney, Mesangial cell of kidney, , Epidermal Langerhans cell. Osteoclast, Den Pancreatic islets; Keratinizing epithelial cells including but dritic cell, Microglial cell, Neutrophil granulocyte, Eosino not limited to: Epidermal keratinocyte, Epidermal basal cell, phil granulocyte, Basophil granulocyte, Hybridoma cell, Keratinocyte offingernails and toenails, Nail bed basal cell, Mast cell, Helper , Suppressor T cell, Cytotoxic T cell, Medullary hair shaft cell, Cortical hair shaft cell, Cuticular Natural Killer T cell, B cell, Natural killer cell, Reticulocyte, hair shaft cell, Cuticular hair root sheath cell, Hair root Stem cells and committed progenitors for the blood and sheath cell of Huxley's layer, Hair root sheath cell of immune system; Germ cells including but not limited to: Henle’s layer, External hair root sheath cell, Haft matrix Oogonium/Oocyte, Spermatid, Spermatocyte, Spermatogo cell; Wet stratified barrier epithelial cells including but not limited to: Surface epithelial cell of stratified squamous nium cell, Spermatozoon: Nurse cell including but not epithelium and basal cell of epithelia of cornea, tongue, oral limited to: Ovarian follicle cell, Sertoli cell, Thymus epi cavity, esophagus, anal canal, distal urethra and vagina, thelial cell; Interstitial cells including but not limited to: Urinary epithelium cell; Sensory transducer cells including Interstitial kidney cells and a combination thereof. but not limited to: Auditory inner hair cell of organ of Corti, 0056. Examples of antibodies, antisense, RNA interfer Auditory outer hair cell of organ of Corti, Basal cell of ence, or gene therapy made to targets or gene(s) of: olfactory epithelium, Cold-sensitive primary sensory neu Ataxia Telangiectasia Mutated, Tumor Protein p53, Check rons, Heat-sensitive primary sensory neurons, Merkel cell of point kinase 2, breast Susceptibility protein, Double epidermis, neuron, Pain-sensitive pri strand break repair protein, DNA repair protein RAD50 mary sensory neurons, Photoreceptor cells of retina in eye: Nibrin, p53-binding protein, Mediator of DNA damage Proprioceptive primary sensory neurons, Touch-sensitive checkpoint protein, HA histone family member X, Micro primary sensory neurons, Type I carotid body cell. Type II cephalin, C-terminal-binding protein 1, Structural mainte carotid body cell. Type I hair cell of vestibular system of ear, nance of protein 1A: Esterases; Phosphatases; Type II hair cell of vestibular system of ear. Type I taste bud Examples of Ion channels include but are not limited to: cell; Autonomic neuron cells including but not limited to: ligand-gated ion channels, Voltage-gated ion channels; US 2017/0203043 A1 Jul. 20, 2017

Examples of growth factors include but are not limited to: cine-rich repeat-containing G protein-coupled receptor fam nerve (NGF), vascular endothelial growth ily, horiogonadotropin receptor (LH), Leukotriene 84 recep factor (VEGF), platelet-derived growth factor (PDGF), tor (BLT1), Adenylate Cyclase Activating Polypeptide 1 C-fos-induced growth factor (FIGF), platelet-activating fac Receptor 1 (mPAC1), , Melanocortin recep tor (PAF), transforming growth factor beta (TGF-3), b, one tor family, Melanin concentrating hormone receptor 1 morphogenetic (BMPs), Activin, inhibin, fibroblast (TVICH1), Neuropeptide Y1 receptor (Y1), Neuropeptide growth factors (FGFs), granulocyte-colony stimulating fac Y2 receptor (NPY2R), family, Oxytocin tor (G-CSF), granulocyte-macrophage colony stimulating, receptor (OT), P2Y Purinoceptor 12 (mP2Y12), P2Y Puri factor (GM-CSF), glial cell line-derived neurotrophic factor noceptor 6 (P2Y6), Pancreatic polypeptide receptor family, (GDNF), growth differentiation factor-9 (GDF9), epidermal Platelet-activating factor receptor family, Prostaglandin E growth factor (EGF), transforming growth factor-O. (TGF receptor family, Prostanoid IP1 receptor (IP1), MAS-related C.), growth factor (KGF), migration-stimulating factor GPR, member family, (Rhodopsin), Relaxin (MSF), -like protein (HGFLP), family peptide receptor family, fam hepatocyte growth factor (HGF), hepatoma-derived growth ily, family, family, factor (HDGF). -like growth factors: Examples of G Urotensin receptor family, Vasoactive intestinal peptide ProteinCoupled Receptors (GPCR) include but are not lim receptor 1 (mVPAC1), (BB1), ited to: family, 1 (NMU1), Neuropeptides B/W family, Angiotensin H receptor, , family, Neuropeptide FF receptor 1 (NPFF1), neu receptor family, Brain-specific fam ropeptide S receptor 1 (NPS receptor), Neuropeptide Y ily, family, family, receptor family, 1 (NTS1), 5 Complement component 3a receptor 1, Complement com (OPN5), Opioid receptor-like receptor (NOP), Oxoeico ponent 5a receptor 1, family, Calcitonin sanoid (OXE) receptor 1 (OXE), Oxoglutarate (alpha-keto receptor-like family, Calcium-sensing receptor, Cholecysto glutarate) receptor 1 (OXGR1), family, kinin A receptor (CCK1), Cholecystokinin B receptor Pyrimidinergic receptor family, Prolactin releasing hormone (CCK2), Chemokine (C-C motif) receptor family, Sphin receptor (PRRP), family, Platelet acti gosine 1-phosphate receptor family. Succinic receptor, Cho vating receptor (PAF). family, linergic receptor family. Chemokine-like receptor family, Prostaglandin 12 (prostacyclin) receptor family, Parathyroid family, Corticotropin releasing hor hormone receptor family, muscarinic 4 (rM4), Prostanoid mone receptor family, prostaglandin D2 receptor, DP2 receptor (rGPR44), Prokineticin receptor family, Chemokine C-X3-C receptor family, Chernokine (C-X-C Relaxin family peptide receptor family, motif) receptor family, Burkitt lymphoma receptor, (secretin), , class receptor (Smooth Chemokine (C-X-C motif) receptor family, Cysteinyl leu ened), trace amine associated receptor family, Tachykinin kotriene receptor 2 (CYSLT2), (FY), family. Thromboxane A2 receptor (TP), Thyrotropin releas family, G protein-coupled receptor 183 ing hormone receptor (TRH1), Thyroid Stimulating Hor (GPR183), receptor family, Endothe mone Receptor (TSH); Examples of Protein kinases include lin receptor family, Coagulation factor (thrombin) receptor but are not limited to: AP2 associated kinase, Homo sapiens family, family, Formylpepticle ABL proto-oncogene 1-non-receptor tyrosine-protein kinase receptor family, Follicle stimulating hormone receptor family, c-abl oncogene 1 receptor family, (FSHR), gamma-aminobutyric acid (GABA) B receptor, V-abl Abelson murine leukemia viral oncogene homolog 2. family, , Growth hor activin A receptor family, chaperone—ABC1 activity of bc1 mone releasing hormone receptor (GHRH), Ghrelin receptor complex homolog (S. pombe) (ADCK3), aarF domain con (ghrelin), Growth hormone secretagogue receptor lb taining kinase 4 (ADCK4), V-akt murine thymoma viral (GHSR1b). Gastric inhibitory polypeptide receptor (GIP), oncogene homolog family, anaplastic lymphoma receptor Glucagon-like peptide receptor family, Gonadotropin-re tyrosine kinase family, protein kinase A family, protein leasing hormone receptor (GnRH), pyroglutamylated kinase B family, ankyrin repeat and kinase domain contain RFamide peptide receptor (QRFPR), G protein-coupled bile ing 1 (ANKK1), NUAK family—SNF1-like kinase, mito acid receptor 1 (GPBA), Hydroxycarboxylic acid receptor gen-activated protein kinase kinase kinase family aurora family, Lysophosphatidic acid receptor 4 (LPA4) Lysophos kinase A (AURKA), aurora kinase B (AURKB), aurora phatidic acid receptor 5 (GPR92), G protein-coupled recep kinase C (AURKC), AXL (AXL), tor 79 pseudogene (GPR79), Hydroxycarboxylic acid recep BMP2 inducible kinase (BIKE), B lymphoid tyrosine kinase tor 1 (HCA1), G-protein coupled receptor (C5L2, FFA4, (BLIP), bone morphogenetic protein receptor family, BMX FFA4, FFA4, GPER, GPR1, GPR101, GPR107, GPR119, non-receptor tyrosine kinase (BMX), V-raf murine sarcoma GPR12, GPR123, GPR132, GPR135, GPR139, GPR141, viral oncogene homolog B1 (BRAF), protein tyrosine kinase GPR142, GPR143, GPR146, GPR148, GPR149, GPR15, 6 (BRK), BR serine/threonine kinase family, Bruton agam GPR150, GPR151, GPR152, GPR157, GPR161, GPR162, maglobulinemia tyrosine kinase (BTK), calcium/calrnodu SPRIT GPR171, GPR173, GPR176, GPR18, GPR182, lin-dependent protein kinase family, cyclin-dependent GPR20, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, kinase family, cyclin-dependent kinase-like family, CHK1 GPR32, GPR35, GPR37L1, GPR39, GPR4, GPR45, checkpoint homolog (S. pombe) (CHEK1), CHK2 check GPR50, GPR52, GPR55, GPR6, GPR61, GPR65, GPR75, point homolog (S. pombe) (CHEK2), Insulin receptor, iso GPR78, GPR83, GPR84, GPR85, GPR88, GPR97, form A (INSR), Insulin receptor, isoform B (INSR), rho TM7SF1), Metabotropic family, Gastrin interacting serine/threonine kinase (CIT), v- Hardy releasing peptide receptor (882), family, Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), family, 5-hydroxytryptamine receptor CDC-Like Kinase family—Hepatocyte growth factor recep family, KISS1-derived peptide receptor (kisspeptin), Leu tor (MET), Proto-oncogene tyrosine-protein kinase receptor, US 2017/0203043 A1 Jul. 20, 2017 colony-stimulating factor family receptor, c-Src, tyrosine pim-3 oncogene (PIM3), phosphatidylinositol-4-phosphate kinase (CSK), casein kinase family, megakaryocyte-associ 5-kinase family, phosphatidylinositol-5-phosphate 4-kinase ated tyrosine kinase (CTK), death-associated protein kinase family protein kinase, membrane associated tyrosine? threo family, doublecortin-like kinase family, discoidin domain nine (PKMYT1), protein kinase N family, polo-like kinase receptor tyrosine kinase, dystrophia myotonica-protein family, protein kinase C family, protein kinase D family, kinase (DMPK), dual-specificity tyrosine-(Y)-phosphoiya cGMP-dependent protein kinase family, eukaryotic transla tion regulated kinase family, recep tion initiation factor 2-alpha kinase 2 (PRKR), X-linked tor family, eukaryotic translation initiation factor 2-alpha protein kinase (PRKX), Prolactin receptor (PRLR), PRP4 kinase 1 (EIF2AK1), EPH receptor family, type-A pre-mRNA processing factor 4 homolog B (yeast) (PRP4). receptor family, Ephrin type-B receptor family, v-erb-b2 PTK2B protein tyrosine kinase 2 beta (PTK2B), SIK family erythroblastic leukemia viral oncogene homolog family, kinase 3 (QSK), V-raf-1 murine leukemia viral oncogene mitogen-activated protein kinase family, endoplasmic homolog 1 (RAF1), Neurotrophic tyrosine kinase receptor reticulum to nucleus signaling 1 (ERN1), PTK2 protein type family, receptor (TNFRSF)-interacting serine-threo tyrosine kinase 2 (FAK), fer (fps/fes related) tyrosine kinase nine kinase family, dual serine/threonine and tyrosine pro (FER), feline sarcoma oncogene (FES), Fibroblast growth tein kinase (RIPK5), Rho-associated, coiled-coil containing factor receptor family, Gardner-Rasheed feline sarcoma protein kinase family, c-ros oncogene 1, receptor tyrosine viral (v-fgr) oncogene homolog (FGR), fms-related tyrosine kinase (ROS1), ribosomal protein S6 kinase family, SH3 kinase family. Fms-related tyrosine kinase family, fyn-re binding domain kinase 1 (SBK1), serum/glucocorticoid lated kinase (FRK), FYN oncogene related to SRC, cyan G regulated kinase family, Putative uncharacterized serine/ associated kinase (GAK), eukaryotic translation initiation threonine-protein kinase (Sugen kinase 110) (SgK110), salt factor 2 alpha kinase, Growth hormone receptor. G protein inducible kinase family, SNF related kinase (SHIRK), Src coupled receptor kinase 1 (GRK1), G protein-coupled recep related kinase SFRS protein kinase family, Spleen tyrosine tor kinase family, glycogen synthase kinase family, germ kinase (SYK), TAO kinase family. TANK-binding kinase 1 cell associated 2 (haspin) (HASPIN), Hemopoietic cell (TBK1), tec protein tyrosine kinase (TEC), testis-specific kinase (HCK), homeodomain interacting protein kinase kinase 1 (TESK1), transforming growth factor, beta receptor family, mitogen-activated protein kinase kinase kinase family, tyrosine kinase with immunoglobulin-like and EGF kinase family, hormonally up-regulated Neu-associated like domains 1 (TIE1), TEK tyrosine kinase, endothelial kinase (HUNK), intestinal cell (MAK-like) kinase (ICK), (TIE2), -1 receptor (Tie2), tousled-like kinase Insulin-like growth factor 1 receptor (IGF1R), conserved family, TRAF2 and ICK interacting kinase (TNIK), non helix-loop-helix ubiquitous kinase (IKK-alpha), inhibitor of receptor tyrosine kinase family, TNNI3 interacting kinase kappa light polypeptide gene enhancer in B-cells kinase beta (TNNI3K), transient receptor potential cation channel, tes family, insulin receptor (INSR), insulin receptor-related tis-specific serine kinase family, TTK protein kinase (TTK), receptor (INSRR), -1 receptor-associated kinase TXK tyrosine kinase (TXK), Tyrosine kinase 2 (TYK2), family, IL2-inducible T-cell kinase (ITK), Janus kinase TYRO3 protein tyrosine kinase (TYRO3), unc-51-like family, Kinase Insert Domain Receptor, v-kit Hardy-Zuck kinase family, phosphatidylinositol 3-kinase, vaccinia erman 4 feline sarcoma viral oncogene homolog, lympho related kinase 2 (VRK2), WEE1 homolog family, WNK cyte-specific protein tyrosine kinase (LCK), LIM domain lysine deficient protein kinase family, V-yes-1 Yamaguchi kinase family, serine/threonine kinase family leucine-rich sarcoma viral oncogene homolog 1 (YES), Sterile alpha repeat kinase family, V-yes-1 Yamaguchi sarcoma viral motif and leucine Zipper containing kinase AZK (ZAK), related oncogene homolog (LYN), male germ cell-associ Zeta-chain (TCR) associated protein kinase 70 kDa ated kinase (MAK) MAP/microtubule affinity-regulating (ZAP70); Examples of nuclear hormone receptors include kinase family, microtubule associated serine/threonine but are not limited to: Androgen receptor (AR), Estrogen kinase family, maternal embryonic leucine Zipper kinase, related receptor alpha (ESRRA), Estrogen receptor 1 c-mer proto-oncogene tyrosine kinase (MERTK), met proto (ESR1), Nuclear receptor subfamily 1 group H-member 4 oncogene (hepatocyte ), MAP kinase (NR1H4), Nuclear receptor subfamily 3 group C mem interacting serine/threonine kinase family, myosin light ber 1 (glucocorticoid receptor) (NR3C1), Nuclear receptor chain kinase family, mixed lineage kinase domain-like pro subfamily 1—group H member 3 (Liver X receptor C.) tein isoform, CDC42 binding protein kinase family, serine/ (NR1H3), Nuclear receptor subfamily 1 group H mem threonine kinase family, macrophage stimulating 1 receptor ber 2 (Liver X receptor B) (NR1H2), Nuclear receptor (c-met-related tyrosine kinase) (MST1R), mechanistic target subfamily 1 group H member 2 (Liver X receptor B) of rapamycin (serine/threonine kinase) (MTOR), muscle (NR1H2), Nuclear receptor subfamily 3 group C mem skeletal-receptor tyrosine kinase (MUSK), myosin light ber 2 (Mineralcorticoid receptor) (NR3C2), Peroxisome chain kinase family, NIMA (never in mitosis genea)-related Proliferator Activated Receptor alpha (PPARA), Peroxisome kinase family, serine/threonine-protein kinase NIM1 Proliferator Activated Receptor gamma (PPARG), Peroxi (NIM1), nemo-like kinase (NLK), oxidative-stress respon some Proliferator Activated Receptor delta (PPARD), Pro sive 1 (OSR1), p21 protein (Cdc42/Rac)-activated kinase gesterone receptor C. (PGR), Progesterone receptor B (PGR), family, PAS domain containing serine/threonine kinase, Retinoic acid receptor-alpha (RARA), Retinoic acid recep Platelet-derived growth factor receptor family, 3-phospho tor-beta (RARB), Retinoid X receptor-alpha (RXRA), Ret inositide dependent protein kinase-1 (PDPK1), Calcium inoid X receptor-gamma (RXRG), Thyroid hormone recep dependent protein kinase 1, phosphorylase kinase gamma tor-alpha (THRA), Thyroid hormone receptor-beta (THRB), family, Phosphatidylinositol 4,5-bisphosphate 3-kinase, Retinoic acid-related , Liver X receptor, phosphoinositide-3-kinase family, phosphatidylinositol Farnesold X receptor, Vitamin D receptor, Pregnane X 4-kinase family. phosphoinositide kinase, FYVE finger con receptor, Constitutive androstane receptor, Hepatocyte taining, Pim-1 oncogene (PIM1), pim-2 oncogene (PIM2), nuclear factor 4, Oestrogen receptor, Oestrogen-related US 2017/0203043 A1 Jul. 20, 2017

receptor, Glucocortioic receptor, -in unit 1-like 2nd bromodomain (TAF1L(2)), tripartite motif duced-B, Germ cell nuclear factor; Examples of Epigenetic containing 24 (TRIM24(Bromo.)), tripartite motif contain targets include but are not limited to: ATPase family AAA ing 24 (TRIM24(PHD-Bromo.)), E3 ubiquitin-protein ligase domain-containing protein 2 (ATAD2A), ATPase family— TRIM33 (TRIM33), tripartite motif containing 33 (TRIM33 AAA domain containing 28 (ATAD2B), ATPase family AM (PHD-Bromo.)), WD repeat 9-1st bromodomain (WDR9 domain containing 2B (ATAD2B), bromodomain adjacent (1)), WD repeat 9 2nd bromodomain (WDR9(2)); mem to Zinc finger domain-1A (BAZ1A), bromodomain adja brane transport proteins including but not limited to ATP binding cassette (ABC) superfamily, solute carrier (SLC) cent to zinc finger domain-1B (BAZ1 B), bromodomain Superfamily, multidrug resistance protein 1 (P-glycopro adjacent to Zinc finger domain-2A (BAZ2A), bromodomain tein), organic anion transporter 1, and protein Such as adjacent to Zinc finger domain 2A (BAZ2A), bromodomain EAAT3, EAAC1, EAAT1, GLUT1, GLUT2, GLUTS, adjacent to zinc finger domain-2B (BAZ2B), bromodomain GLUT10, rBAT, AE1, NBC1, KNBC, CHED2, BTR1. containing protein 1 (BRD1), Bromodomain containing NABC1, CDPD, SGLT1, SGLT2, NIS, CHT1, NET, DAT, protein 2-1 st bromodomain (BRD2), Bromodomain contain GLYT2, CRTR, BOAT1, SIT1, XT3, y+LAT1, BAT1, ing protein 2—1st & 2nd bromodomains (BRD2), bromodo NHERF1, NHE6, ASBT, DMT1, DCT1, NRAMP2, main-containing protein 2 isoform 1-bromodomain 2 NKCC2, NCC, KCC3, NACT, MCT1, MCT8, MCT12, (BRD2(2)), bromodomain-containing protein 3-bromodo SLD, VGLUT3, THTR1, THTR2, PIT2, GLVR2, OCTN2, main 1 (BRD3(1)), Bromodomain-contain ng protein 3—1st URAT1, NCKX1, NCKX5, CIC, PiC, ANTI, ORNT1, bromodomain (BRD3), Bromodomain-containing protein AGC1, ARALAR, Citrin, STLN2, aralar2, TPC, MUP1, 3—1st & 2nd bromodomains (BRD3) bromodomain-con MCPHA, CACT, GC1, PHC, DTD, CLD, DRA, PDS, taining protein 3-bromodomain 2 (BRD3(2)), Bromodomain Prestin, TAT1, FATP4, ENT3, ZnT2, ZnT 10, AT1, NPT2A, containing protein 4-1 st bromodomain (BRD4), bromodo NPT2B, HHRH, CST, CDG2F, UGAT, UGTL, UGALT, main-containing protein 4 isoform long bromodomains 1 UGT1, UGT2, FUCT1, CDG2C, NST, PAT2, G6PT1, and 2 (BRD4(1-2)), bromodomain-containing protein 4 iso SPX4, ZIP4, LIV4, ZIP13, LZT-Hs9, FPN1, MTP1, IREG1, form long-bromodomain 2 (BRD4(2)), bromodomain-con RHAG, AIM1 PCFT, FLVCR1 FLVCR2, RFT1, RFT2, taining protein 4 isoform short (BRD4(full-length-short RFT3, OATP1B1, OATP1B3, OATP2A1: structural proteins iso.)), Bromodomain containing protein 7 (BRD7), including but not limited to tubulin, heat shock protein, bromodomain containing 8-bromodomain 1 (BRD8(1)), Microtubule-stabilizing proteins. Oncoprotein 18, stathmin, bromodomain containing 8-bromodomain 2 (BRD8(2)), kinesin-8 and kinesin-14 family, Kip3, Kifl 8A: proteases bromodomain-containing protein 9 isoform 1 (BRD9), Bro including but not limited ADAM (a disintegrin and metal modomain containing testis-specific—1st bromodomain loprotease) family. Other molecule targets in signal trans (BRDT), Bromodomain containing testis-specific—1st & ductions include but are not limited to: Cell, division cycle 2nd bromodomains (BRDT), bromodomain testis-specific 25 homolog A (CDC25A), forkhead box O3 (forkhead box protein isoform b bromodomain 2 (BRDT(2)), bromodo O3), nuclear factor ofkappa light polypeptide gene enhancer main and PHD finger containing 1 (BRPF1), bromodo in B-cells inhibitor, alpha (NFKBIA), nuclear factor (eryth main and PHD finger containing 3 (BRPF3), bromodo roid-derived 2)-like 2 (NFE2L2), Natriuretic peptide recep main and PHD finger containing 3 (BRPF3), tor A (NPR1), Tumor necrosis factor receptor superfamily, Bromodomain and WD repeat-containing 3-2nd bromodo member 11a (TNFRSF11A), v-rel reticuloendotheliosis viral main (BRWD3(2)), Cat eye syndrome critical region protein oncogene homolog A (avian) (RELA), Sterol regulatory 2 (CECR2), CREB binding protein (CREBBP), E1A bind element binding transcription factor 2 (SREBF2), CREB ing protein, p300 (EP300), EP300 (EP300), nucleosome regulated transcription coactivator 1 (CRTC1), CREB regu remodeling factor subunit BPTF isoform 1 (FALZ), Nucle osome-remodeling factor subunit BPT (FALZ), lated transcription coactivator 2 (CRTC2), X-box binding Euchromatic histone-lysine N-methyltransferase 2 protein 1 (XBP1), Catenin (cadherin-associated protein), (EHMT2). Histone Acetyltransferase KAT2A (GCN5L2), beta 1 (CTNNB1), and combinations thereof. Euchromatic histone-lysine N-methyltransferase 1 0057 Examples of known biologics include but are not (EHMT1). Histone-lysine N-methyltransferase (MLL), limited to: Abbosynagis, Abegrin, Actemra, AFP-Cide, Polybromo 1—1st bromodomain (PB1(1)), Polybromo Antova, Arzerra, Aurexis, Avastin, Benlysta, BeXXar, 1-2nd bromodomain (PE31(2)), polybromo 1-bromodomain Blontress, Bosatria, Carripath, CEA-Cde, CEA-Scan, Cirn 2 (PBRM1(2)), polybromo 1-bromodomain 5 (PBRM1(5)), Zia, Cyramza, Ektomab, Erbitux, FibriScint, Gazy va, Her Histone acetyltransferase KAT2B (PCAF), PH-interacting ceptin, hPAM4-Cide, HumaSPECT, HuMax-CD4, HuMax protein-1st bromodomain (PHIP(1)), PH-interacting pro EGFr Humira, HuZAF, Hybri-ceaker, Ilaris, Indimacis-125, tein-2nd bromodomain (PHIP(2)). Protein kinase C-binding Kadcyla, Lemtrada, LeukArrest, LeukoScan, Lucentis, protein 1 (PRKCBP1), Protein arginine N-methyltransferase Lymphomurt, LymphoScan, LymphoStat-B, MabThera, 3 (PRMT3), SWI/SNF related matrix associated actin Mycograb, Mylotarg, Myosoint, NeutroSpec, Numax, dependent regulator of chromatin—Subfamily a member 2 Nuvion, Omnitarg, Opdivo, Orthoclone OKT3. OvaRex, (SMARCA2), SWI/SNF related matrix associated actin Panorex, Prolia; Prostascint, Raptiva, Remicade, Removab, dependent regulator of chromatin—Subfamily a member 4 Rencarex, ReoPro, Rexomun, Rituxan, RoActemra, Scin (SMARCA4), Nuclear body protein SP110 (SP110), timun, Sirriponi, Simulect, Soliris, Stelara, Synagis, Tac Nuclear body protein—SP140 (SP140), Transcription ini tress. Theracim, Theragyn, Theraloc, Tysabri, Vectibix, Ver tiation factor TFIID subunit 1 (TAF1(1-2)), TAF1 RNA luma, Xolair, Yervoy, Zenapax, and Zevalin or combinations polymerase II TATA box binding protein (TBP)-associated thereof. factor 250 kDa bromodomain 2 (TAF1(2)). Transcrip 0.058 Examples of known Monoclonal antibodies tion initiation factor TFIID subunit 1-like—1st bromodo include but are not limited to: , 8H9, , main (TAF1 L(1)), Transcription initiation factor TFIID sub , , , Actoxumab, Adalir US 2017/0203043 A1 Jul. 20, 2017

numab, Adecaturnumab, , Afasevikumab, Afe Naratuximab emtansine, , , Nav limomab, Afutuzumab, , ALD518, icixizumab, Navivumab, Nebacumab, , Nem ALD403, , , Altumomab pen olizumab, Nerelimomata, , Nirnotuzumab, tetate, , AMG 334, , , Nofetumomab merpentan, Obittoxaximab, Obi Anetumab ravtansine, , , Apoli nutuzumab, , Oorelizumab, , Zumab, Arcitumomab, AScrinvacumab, , , , , , , Atinumab, Atlizumab, , Ave , OntuxtZumab, , Oportuzumab lumab, , , , Bectu monatox, , , , Otiertu momab, Begelomab, Belitnumab, , Bertilim Zunlab, , Ozartezumab, , Pagibax umab, , , Beziotoximab, imab, Palivizumab, , , Biciromab, Birnagrumab, Birnekizumab, Bivatuzumab mer Pankomab, Panobacumab, , , tansine, , , Biontuvettinab, Bloso Pasotuxizumab, , , , Zumab, , , , Pemturnomab, Perakizumab, , , Briakimumab, , , Broritictuzumab, Pidilizumab, , Pintumomab, Placu , Cabiralizumab, , Cantuzumab lumab, , Pogalizumab, , mertansine, , , , Prezalizumab, , Pritaxaximab, Pritu Capromab pendetide, , , Catumax mumab, PRO 140; , Racoturnomab, Radre omab, cBR96-doxorubicin immunoconjugate, Cedeli tumab, Rafivirumab, Ralpancizumab, , Zumab, CergutuZumab amunaleukin, , , Raxibacumab, Refanezumab, Regavirumab, , , , Clazaki , Ritotumumab, , , Zurriab, , Clivatuzumab tetraxetan, Codritu , Rivabazumab pegol, , Role Zumab, Coltuximab ravtansine, , Conci dumab, , , RovalpituZumab tes Zumab, CR6261, , Crotedumab, , irine, , , , , , Dapirolizumab pegol, Daratu Sarnalizumab, Sapelizumab, , Satumomab pen mumab, Dectrekumab, Derncizumab, Denintuzumab deticle, , , Setoxaximab, mafodotin, , , Derlo Sevirumab, SGN-CD18A, SGN-CD33A, , tuximab biotin, , Dinutuxiinab, Diridavumab, Sifalirnumab, Sittuximab, Sirntuzumab, Siptizumab; Siru DornagroZumab, Dorlirnomab aritax, , Duligo kumab, Sofituzumab veslotin, , , tumab, , , , Ecroniex Sonepcizumab, Sontuzumab, , Sulesomab, imab, Edobacomab, , Suvizumab, , Tacatuzumab tetraxetan, Tadoci Efungumab, , Elgemtumab, , Elsili Zumab, , Tamtuvetmab, , Taplitu momab, , , Ernicizumab, Ena momab paptox, , Tefibazumab, Telimomab ari Vatuzumab, , Enlimomab pegol, Enobli toX, Tenaturnomab, , , tuZumab, Enokizumab, , , , Tesdolumab, Tetulomab, , Epitumomab cituxetan, , , Erli TGNI412, Ticilimumab, , , Zumab, , , , Evi Timolumab, Tisotumab vedotin, TNX-650, , nacumab, , Exbivirumab, Fanolesomab, Farali , Tosatoxumab, , , moniab, , , FBTA05, Felvizumab, , , Trastuzumab erntansine, , Fibatuzumab, , , TRBS07, , , , , Fletikumab, , , Fora TucotuZurriab celmoleukin, Tuvirumab, , Ulo virumab, , , , Galcan cuplumab, , Urtoxazumab, , Utomi eZumab, , , , Gavil lumab, Vadastuximab tallirine, Vandortuzumab vedotin, Van irnomab, , Gevokiztimab, tictumab, , , , , Giernbaturnumab vedotin, , , , , , Gomiliximab, , , Ibritumomab tiux Vesencumab, Visilizurriab, , , etan, , Iciarucizumab, lgovomab, IMAB362, , Votumumab, Xentuzumab, Zalu Imalumab, Imciromab, , , IndatuX tumumab, , Zatuximab, Ziralirnumab, and imab ravtansine, Indusatumab vedotin, , Inflix Zolimomab aritox or combinations thereof. imab, , , , 0059 Examples of vaccines developed for viral diseases , , , , Kelixir include but are not limited to: Hepatitis A , Hepatitis rab, , Lambrolizumab, , B vaccine, vaccine, HPV vaccine, Influenza , , Laprituximab emtansine, vaccine, Japanese encephalitis vaccine, MMR vaccine, LBR-101/PF0442g7429, , Lernalesomab, MMRV vaccine, , , Rotavirus Lendalizumab, , , , vaccine, , Shingles vaccine, Smallpox vac Libivirumab, , , Liloto cine, , , Coxsackie mab satetraxetan, , Liniumab, Lodelcizumab, B virus vaccine, , , , , for humans, Eastern Equine encephalitis virus vaccine for Lulizumab pegoi, , LY2951742, Mapatu humans, , Enterovirus 71 vaccine, Epstein mumab, , , , Mavn Barr vaccine, , HIV vaccine, HTLV-1 limumab, , , , Min T-lymphotropic leukemia vaccine for humans, Marburg retumomab, Mirvetuximab soravitansine, Miturnomab, virus disease vaccine, Norovirus vaccine, Respiratory syn , Monalizumab, hillorolirnumab, Motavi cytial virus vaccine for humans, Severe acute respiratory Zumab, Moxeturnomab pasudotox, Muromonab CD3, Naco syndrome (SARS) vaccine, West Nile virus vaccine for lomab tafenatox. , . humans; Examples of bacterial diseases include but are not US 2017/0203043 A1 Jul. 20, 2017

limited to: , OPT vaccine, vaccine, (Hyaluronidase Inj), Ammonul (Sodium Phenylacetate and , Tuberculosis (BCG) vaccine, Meningococcal Sodium Benzoate Injection), AnaproX, Anzemet Injection vaccine, , Pneumococcal , (Dolasetron Mesylate Injection), Apidra (Insulin Glulisine Pneumococcal polysaccharide vaccine, , rDNA origin Inj), Apomab, Aranesp (darbepoetin alfa), Caries vaccine, Ehrlichiosis vaccine, Leprosy Vaccine, Lyme Argatroban (Argatroban Injection), Arginine Hydrochloride disease vaccine, Staphylococcus aureus vaccine, Streptococ Injection (R-Gene 10, Aristocort, Aristospan, Arsenic Tri cus pyogenes vaccine, Syphilis vaccine, Tularemia vaccine, oxide Injection (Trisenox), Articane HCl and Epinephrine Yersinia pestis vaccine; Examples of parasitic diseases Injection (Septocaine), Arzerra (Ofatumumab Injection), include but are not limited to; , Schistoso Asclera (Polidocanol Injection), Ataluren, Ataluren-DMD, miasis vaccine, Chagas disease vaccine, Hookworm vac Atenolol Inj (Tenormin I.V. Injection), Atracurium Besylate cine. Onchocerciasis river blindness vaccine for humans, Injection (Atracurium Besylate Injection), Avastin, AZactam , Visceral leishmaniasis vaccine; Injection (Aztreonam Injection), Azithromycin (Zithromax Examples of non-infectious diseases include but are not Injection), Aztreonam Injection (AZactam Injection), limited to: Alzheimer's disease amyloid protein vaccine, Baclofen Injection (Lioresal Intrathecal), Bacteriostatic vaccine, Ovarian , Prostate Water (Bacteriostatic Water for Injection), Baclofen Injec cancer vaccine, Talimogene laherparepvec (T-VEC); also tion (Lioresal Intrathecal), Bal in Oil Ampules (Dimercar vaccines including but not limited to the following trade prol Injection), BayHepE, BayTet, Benadryl, Bendamustine names: ACAM2000, ActHIB, Adacel, Afluria, AFLURIA Hydrochloride Injection (Treanda), Benztropine Mesylate QUADRIVALENT, Agriflu, BCG Vaccine, BEXSERO, Injection (Cogentin), Betamethasone Injectable Suspension Biothrax, Boostrix, , Comvax, DAPTACEL, (Celestone Soluspan), Bexxar, Bicillin C-R 900/300 (Peni DECAVAC, Engerix-B, FLUAD, Fluarix, Fluarix Quadri cillin G Benzathine and Penicillin G Procaine Injection), valent, Flublok, Flucelvax, Flucelvax Quadrivalent, Flulla Blenoxane (Bleomycin Sulfate Injection), Bleomycin Sul val, FluMist, FluMist Quadrivalent, Fluvirin, Fluzone Qua fate Injection (Blenoxane), Boniva Injection (Ibandronate drivalent, FluZone, FluZone High-Dose and FluZone Sodium Injection). Botox Cosmetic (Onabotulinumtoxin.A Intradermal, , Gardasil 9, Havrix, Hiberix, Imovax, for Injection), BR3-FC, Bravelle (Urofollitropin Injection), Infanrix, IPOL, Ixiaro, JE-Vax, KINRIX, Menactra, IVIen Bretylium (Bretylium Tosylate Injection), Brevital Sodium Hibrix, Menomune-A/C/Y/W-135, Merweo, M-M-R II, (Methohexital Sodium for Injection), Brethine, Briobacept, M-M-Vax, Pediarix, PedvaxHIB, Pentacel, Pneumovax 23, BTT-1023, Bupivacaine HCl, Byetta, Ca-DTPA (Pentetate Poliovax, Prevnar, Prevnar 13, ProQuad, Quadracel, Qua Calcium Trisodium In), Cabazitaxel Injection (Jevtana), drivalent, Rab Avert, Recombivax HB, ROTARIX, RotaTeq, Caffeine Alkaloid (Caffeine and Sodium Benzoate Injec TENIVAC, TICE BCG, Tripedia, TRUMENBA, Twinrix, tion), Calcijex Injection (Calcitrol), Calcitrol (Calcijex TYPHIM Vi, VAQTA, Varivax, Vaxchora, Vivotif, YF-Vax, Injection), Calcium Chloride (Calcium Chloride Injection Zostavax, and combinations thereof. 10%), Calcium Disodium Versenate (Edetate Calcium Diso 0060 Examples of injectable drugs include but are not dium Injection), Campath (Altemtuzumab), Camptosar limited to: Ablavar (Gadofosveset Trisodium Injection), Injection (Irinotecan Hydrochloride), Canakinumab Injec Abarelix Depot, Abobotulinum toxin A Injection (Dysport), tion (Ilaris), Capastat Sulfate (Capreomycin for injection), ABT-263, ABT-869, ABX-EFG, Accretropin (Somatropin Capreomycin for Injection (Capastat Sulfate), Cardiolite Injection), Acetadote (Acetylcysteine Injection), Acetazoi (Prep kit for Technetium Tc99 Sestamibi for injection), amide Injection (Acetazolamide Injection), Acetylcysteine Carticel, Cathflo, Cefazolin and Dextrose for Injection (Ce Injection (Acetadote), Actemra (Tocilizumab Injection), fazolin. Injection), Cefepime Hydrochloride, Cefotaxime, Acthrel (Corticorelin Ovine Triflutate for Injection), Actum Ceftriaxone, Cerezyme, Carnitor Injection, Caverject, Cele mune, Activase, Acyclovir for Injection (Zovirax Injection), stone Soluspan, Celsior, Cerebyx (Fosphenytoin Sodium O137. Adacel, , Adenoscan (Adenosine Injec Injection), Ceredase (Alglucerase Injection), Ceretec (Tech tion), Adenosine Injection (Adenoscan), Adrenaclick, netium Tc99m Exametazine Injection), Certolizumab, AdreView (Iobenguane 1123. Injection for Intravenous Use), CF-101, Chloramphenicol Sodium Succinate (Chloram Afluria, Ak-Fluor (Fluorescein Injection), Aldurazyme (La phenicol Sodium Succinate Injection), Chloramphenicol ronidase), Alglucerase Injection (Ceredase), Alkeran Injec Sodium Succinate Injection (Chloramphenicol Sodium Suc tion (Melphalan Hel Injection), Allopurinol Sodium for cinate), Cholestagel (Colesevelam HCL), Choriogonadotro Injection (Aloprim), Aloprim (Allopurinol Sodium for Injec pin Aifa Injection (Ovidrel), Cimzia, Cisplatin (Cisplatin tion), Alprostadil. Alsuma (Sumatriptan Injection), ALTU Injection), Clolar (Clofarabine Injection), Clomiphine Cit 238, Amino Acid Injections, Aminosyn, Apidra, Apremilast, rate, Clonidine Injection (Duraclon), Cogentin (Benztropine Alprostadil Dual Chamber System for Injection (Caverject Mesylate Injection), Colistimethate Injection (Coly-Mycin Impulse), AMG 009, AMG 076, AMG 102, AMG 108, AMG M), Coly-Mycin M (Colistimethate Injection), Compath, 114, AMG 162, AMG 220, AMG 221, AMG 222, AMG 223, Conivaptain Hel Injection (Vaprisol), Conjugated Estrogens AMG 317, AMG 379, AMG 386, AMG 403, AMG 477, for Injection (Premarin Injection), Copaxone, Corticorelin AMG 479, AMG 517, AMG 531, AMG 557, AMG 623, Ovine Triflutate for Injection (Acthrel), Corvert (Ibutilide AMG 655, AMG 706, AMG 714, AMG 745, AMG 785, Fumarate Injection), Cubicin (Daptomycin Injection), AMG 811, AMG 827, AMG 837, AMG 853, AMG 951, CF-101, Cyanokit (Hydroxocobalamin for Injection), Cyt Amiodarone HCl Injection (Amiodarone HCl Injection), arabine Liposome Injection (DepoCyt), Cyanocobalamin, Amobarbital Sodium Injection (Amytal Sodium), Amytal Cytovene (ganciclovir), D.H.E. 45, Dacetuzumab, Dacogen Sodium (Amobarbital Sodium Injection), Anakinra, Anti (Decitabine Injection), Dalteparin, Dantrium IV (Dantrolene Abeta, Anti-Beta7, Anti-Bta20, Anti-CD4, Anti-CD20, Anti Sodium for Injection), Dantrolene Sodium for Injection CD40. Anti-IFNalpha, Anti-IL 13, Anti-OX40L, Anti-ox (Dantrium IV), Daptomycin Injection (Cubicin), Darbepoi LDS, Anti-NGF. Anti-NRP1, Arixtra, Amphadase etin Alfa, DDAVP injection (Desmopressin Acetate Injec US 2017/0203043 A1 Jul. 20, 2017 tion), Decavax, Decitabine Injection (Dacogen), Dehydrated gon, HAE1, Haldol (Haloperidol Injection), Havrix, Hec Alcohol (Dehydrated Alcohol Injection), Denosumab injec torol injection (Doxercalciferol Injection), Hedgehog Path tion (Prolia), Delatestryl, Delestrogen, Delteparin Sodium, way Inhibitor, Heparin, Herceptin, hCG-CSF. Humalog, Depacon (Vaiproate Sodium Injection), Depo Medrol Human Growth Hormone, Humatrope, HuMax, Humegon, (Methylprednisolone Acetate Injectable Suspension), Depo Humira, Humulin, Ibandronate Sodium Injection (Boniva Cyt (Cytarabine Liposome Injection), DepoDur (Morphine Injection), Ibuprofen Lysine Injection (NeoProfen), Ibutilide Sulfate XR Liposome Injection). Desmopressin Acetate Fumarate Injection (Corvert), Idamycin PFS (idarubicin injection (DDAVP Injection), Depo-Estradiol, Depo-Pro Hydrochloride Injection), Idarubicin Hydrochloride Injec Vera 104 mg/ml, Depo-Provera 150 mg/ml, Depo-Testoster tion (Idamycin PFS), Rads (Canakinumab Injection), Imi one, DexraZoxane for Injection, Intravenous Infusion Only penem and Cilastatin for Injection (Primaxin Imitrex, Inco (Totect), Dextrose/Electrolytes, Dextrose and Sodium Chlo botulinum toxin A for Injection (Xeomin), Increlex ride Inj (Dextrose 5% in 0.9% Sodium Chloride), Dextrose, ( rDNA origin Injection), Indocin IV (Indo Diazepam Injection (Diazepam Injection), Digoxin Injection methacin In), Indomethacin Inj (Indocin IV), Infanrix, (Lanoxin Injection), Dilaudid-HP (Hydromorphone Hydro Innohep, Insulin, Insulin Aspart rDNA origin Inj (Novo chloride Injection), Dimercarprol Injection (Bal in Oil Log), Insulin Glargine rDNA origin Injection (Lantus), Ampules), Diphenhydramine Injection (Benadryl injection), Insulin Glulisine rDNA origin Inj (Apidra), Interferon Dipyridamole Injection (Dipyridamole Injection), DMOAD. alfa-2b, Recombinant for Injection (Intron A), Intron A Docetaxel for Injection (Taxotere), Dolasetron Mesylate (Interferon alfa-2b, Recombinant for Injection), Invanz (Er Injection (Anzemet Injection), Doribax (Doripenem for tapenem Injection), Invega Sustenna (Paliperidone Palmi Injection), Doripenem for Injection (Doribax), Doxercalcif tate Extended-Release Injectable Suspension), Invirase (sa erol Injection (Hectorol Injection), Doxil (Doxorubicin Hel quinavir mesylate), Iobenguane 1123 Injection for Liposome Injection), Doxorubicin Hot Liposome Injection Intravenous Use (Adreview), Iopromide Injection (Ultra (Doxil). Duraclon (Clonidine Injection). Duramorph (Mor vist), Ioversol Injection (Optiray injection), Iplex (Mecaser phine Injection), Dysport (Abobotulinum toxin A Injection), min Rinfabate rDNA origin Injection), Iprivask, Irinotecan Ecallantide Injection (Kalbitor), EC-Naprosyn (naproxen), Hydrochloride (Camptosar Injection), Iron Sucrose Injec Edetate Calcium Disodium Injection (Calcium Disodium tion (Venofer), Istodax (Romidepsin for Injection), Itracon Versenate), Edex (Alprostadil for Injection), Erigerix. Edro azole Injection (SporanoX Injection), Jevtana (Cabazitaxel phonium Injection (Enlon), Eliglustat Tartate, Eloxatin Injection), Jonexa, Kaibitor (Ecallantide Injection), KCL in (Oxaliplatin Injection), Emend Injection (Fosaprepitant D5NS (Potassium Chloride in 5% Dextrose and Sodium Dimeglumine Injection), Enalaprilat Injection (Enalaprilat Chloride Injection), KCL in D5W, KCL in NS, Kenalog 10 Injection), Enlon (Edrophonium Injection), Enoxaparin Injection (Triamcinolone Acetonide Injectable Suspension), Sodium Injection (Lovenox), Eovist (Gadoxetate Disodium Kepivance (), Keppra Injection (Levetiracetam), Injection), Eribrel (etanercept), Enoxaparin, Epicel, Epi Keratinocyte, KFG, Kinase Inhibitor, Kineret (Anakinra), nepherine, Epipen, Epipen Jr., EpratuZumab, ErbituX, Kinlytic (Urokinase Injection), Kinrix, Kionopin (clonaze Ertapenem Injection (InvanZ), Erythropoieten, Essential pam), Kytril Injection (Granisetron Hydrochloride), Iacos Amino Acid Injection (Nephramine), Estradiol Cypionate, amide Tablet and Injection (Vimpat), Lactated Ringers, Estradiol Valerate, Etanercept, Exenatide Injection (Byetta), Lanoxin Injection (Digoxin Injection), Lansoprazole for Evlotra, Fabrazyme (Adalsidase beta), Famotidine Injection, Injection (Prevacid Lantus, Leucovorin Calcium (Leuco FDG (Fludeoxyglucose F 18 Injection), Feraheme (Feru Vorin Calcium Injection), Lente (L), Leptin, Levemir, Leu moxytol Injection), Feridex I.V. (Ferumoxides Injectable kine , Leuprolide Acetate, Levothyroxine, Solution), Fertinex, Ferumoxides Injectable Solution (Feri Levetiracetam (Keppra Injection), Lovenox, Levocarnitine dex I.V.), Ferurnoxytol Injection (Feraheme), Flagyll Injec Injection (Carnitor Injection), Lexiscan (Regadenoson tion (Metronidazole Injection), Fluarix, Fludara (Fludara Injection), Lioresal Intrathecal (Baclofen Injection), Lira bine Phosphate), Fludeoxyglucose F 18 Injection (FOG), glutide rDNA Injection (Victoza), Lovenox (Enoxaparin Fluorescein Injection (Ak-Fluor). Follistim AQ Cartridge Sodium Injection), Lucentis (Ranibizumab Injection), Lumi (Follitropin Beta Injection). Follitropin Alfa Injection (Go Zyme, Lupron (Leuprolide Acetate Injection), Lusedra (Fos nal-f RFF), Follitropin Beta Injection (Follistim AQ Car propofol Disodium Injection), Maci, Magnesium Sulfate tridge), Folotyn (Pralatrexate Solution for Intravenous Injec (Magnesium Sulfate Injection), Mannitol Injection (Manni tion), Fondaparinux, Forteo (Teriparatide (rDNA origin) tol IV), Marcaine (Bupivacaine Hydrochloride and Epineph Injection), Fostarnatinib, Fosaprepitant Dimeglumine Injec rine Injection), Maxipime (Cefepime Hydrochloride for tion (Emend Injection), Foscarnet Sodium Injection Injection), MDP Multidose Kit of Technetium Injection (Foscavir), Foscavir (Foscarnet Sodium Injection), Fosphe (Technetium Tc99m Medronate Injection), Mecasermin nytoin Sodium Injection (Cerebyx), Fospropofol Disodium IrDNA origin Injection (Increlex), Injection (Lusedra), Fragmin, Fuzeon (enfuvirtide), GA101, IrDNA origin Injection (Iplex), Melphalan Hel Injection Gadobenate Dimeglumine Injection (Multihance), Gadofos (Alkeran Injection), Methotrexate, Menactra, Menopur veset Trisodium Injection (Ablavar), Gadoteridol Injection (Menotropins injection), Menotropins for Injection (Re Solution (ProHance), Gadoversetamide Injection (Opti pronex), Methohexital Sodium for injection (Brevital MARK), Gadoxetate Disodium Injection (Eovist), Ganirelix Sodium), Methyldopate Hydrochloride Injection, Solution (Ganirelix Acetate Injection), Gardasil, GC1008, GDFD, (Methyldopate Hcl), Methylene Blue (Methylene Blue Gemtuzumab OZogamicin for Injection (Mylotarg), Geno Injection), Methylprednisolone Acetate Injectable Suspen tropin, Gentamicin Injection, GENZ-112638, Golimumab sion (Depo Medrol), MetMab, Metoclopramide Injection Injection (Simponi Injection), Gonal-fRFF (Follitropin Alfa (Reglan Injection), Metrodin (Urofollitropin for Injection), injection), Granisetron Hydrochloride (Kytril Injection), Metronidazole Injection (Flagyll Injection), Miacalcin, Gentamicin Sulfate, Glatiramer Acetate, Glucagen, Gluca Midazolam (Midazolam Injection), Mimpara (Cinacalet), US 2017/0203043 A1 Jul. 20, 2017

Minocin Injection (Minocycline Inj), Minocycline Inj (Mi penem and Cilastatin for Injection), Prochyrnal, Procrit, nocin Injection), Mipomersen, Mitoxantrone for Injection Progesterone, ProHance (Gadoteridol Injection Solution), Concentrate (Novantrone), Morphine Injection (Du Prolix (Denosumab Injection), Promethazine HCl Injection ramorph), Morphine Sulfate XR Liposome Injection (Depo (Promethazine Hydrochloride Injection), Propranolol Dur), Morrhuate Sodium (Morrhuate Sodium Injection), Hydrochloride Injection (Propranolol Hydrochloride Injec , Mozobil (Plerixafor Injection), Multihance (Ga tion), Quinidine Gluconate Injection (Quinidine Injection), dobenate Dimegiumine injection), Multiple Electrolytes and Quinidine Injection (Quinidine Gluconate Injection), Dextrose Injection, Multiple Electrolytes injection, Mylo R-Gene 10 (Arginine Hydrochloride Injection), Ranibi targ (Gemtuzumab OZogarnicin for Injection), Myozyme Zumab Injection (Lucentis), Ranitidine Hydrochloride Injec (Alglucosidase alfa), Nafcillin Injection (Nafcillin Sodium), tion (Zantac Injection), Raptiva, Reclast (Zoledronic Acid Nafcillin Sodium (Nafcillin Injection), Naltrexone XR In Injection), Recombivarix HB, Regadenoson Injection (Vivitrol), Naprosyn (naproxen), NeoProfen (Ibuprofen (Lexiscan), Reglan Injection (Metoclopramide Injection), Lysine Injection), Nandrol Decanoate, Neostigmine Meth Remicade, Renegel, Renvela (Sevelamer Carbonate), ylsulfate (Neostigmine Methylsulfate Injection), NEO Repronex (Menotropins for Injection), Retrovir IV (Zido GAA, NeoTect (Technetium Tc 99m Depreotide Injection), Vudine Injection), rhapo2L/TRAIL, Ringers and 5% Dex Nephramine (Essential Amino Acid Injection), Neulasta trose Injection (Ringers in Dextrose), Ringers Injection (), Neupogen (), Novolin, Novolog, (Ringers Injection), Rituxan, Rituximab, Rocephin (ceftri NeoRecormon, Neutrexin (Trimetrexate Glucuronate MD, axone), Rocuronium Bromide Injection (Zemuron), Rof NPH (N), Nexterone (Amiodarone HCl Injection), Norditro eron-A (interferon alfa-2a), RomaZicon (flumazenil), pin (Somatropin Injection), Normal Saline (Sodium Chlo Romidepsin for Injection (Istodax), wizen (Somatropin ride Injection), Novantrone (Mitoxantrone for Injection Injection), Sandostatin LAR (Octreotide Acetate Injection), Concentrate), Novolin 70/30 Innolet (70% NPH, Human Sclerostin Ab, Sensipar (cinacalcet), Sensorcaine (Bupiva Insulin Isophane Suspension and 30% Regular, Human caine NCI Injections), Septocaine (Articane HCl and Epi Insulin Injection), NovoLog (Insulin Aspart rDNA origin nephrine Injection), Serostim LQ (Somatropin (rDNA ori Inj). Nplate (romiplostim), Nutropin (Somatropin (rDNA gin) Injection), Simponi Injection (Golimumab Injection), origin) for Inj), Nutropin AQ, Nutropin Depot (Somatropin Sodium Acetate (Sodium Acetate Injection), Sodium Bicar (rDNA origin) for trip, Octreotide Acetate Injection (San bonate (Sodium Bicarbonate 5% Injection), Sodium Lactate dostatin LAR), , Ofatumumab Injection (Sodium Lactate Injection in AVIVA), Sodium Phenylac (Arzerra), Olanzapine Extended Release Injectable Suspen etate and Sodium Benzoate Injection (Ammonul), Somatro sion (Zyprexa Relprew), Orrmitarg, Omnitrope (Somatropin pin (rDNA origin) for Inj (Nutropin), Sporanox Injection IrDNA origin Injection), Ondansetron Hydrochloride Injec (Itraconazole Injection), Stelara Injection (Ustekinumab), tion (Zofran Injection), OptiMARK (Gadoversetamide Stemen, Sufenta (Sufentanil Citrate Injection), Sufentanil Injection), Optiray Injection (Ioversol Injection), Orencia, Citrate Injection (Sufenta), Sumavel, Sumatriptan Injection Osmitrol Injection in Aviva (Mannitol Injection in Aviva (Alsuma), Symlin, Symlin Pen, Systemic Hedgehog Antago Plastic Vessel 250), Osmitrol Injection in Viaflex (Mannitol nist, Synvisc-One (Hylan G-F 20 Single Intra-articular Injection in Viaflex Plastic Vessel 250), Osteoprotegrin, Injection), Tarceva, Taxotere (Docetaxel for Injection), Ovidrel (Choriogonadotropin Alfa Injection), Oxacillin Technetium Tc 99m, Telavancin for Injection (Vibativ), (Oxacillin for Injection), Oxaliplatin Injection (Eloxatin), Temsirolimus Injection (Torisel), Tenormin I.V. Injection Oxytocin Injection (Pitocin), Paliperidone Palmitate (Atenolol Inj), Teriparatide (rDNA origin) Injection (For Extended-Release Injectable Suspension (Invega Susterma), teo), Cypionate, Testosterone Enanthate, Tes Pamidronate Disodium Injection (Pamidronate Disodium tosterone Propionate, Tev-Tropin (Somatropin, rDNA Ori Injection), Panitumumab Injection for Intravenous Use gin, for Injection), tyAAC94, Thallous Chloride, (Vectibix), Papaverine Hydrochloride Injection (Papaverine Theophylline. Thiotepa (Thiotepa Injection), Thyroglobulin Injection), Papaverine Injection (Papaverine Hydrochloride (Anti-Thymocyte Globulin (Rabbit), Thyrogen (Thyrotropin Injection), Parathyroid Hormone, Paricalcitol Injection Tip Alfa for Injection), Ticarcillin Disodium and Clavulanate top Vial (Zemplar Injection), PARP Inhibitor, Pediarix, Potassium Galaxy (Timentin Injection), Tigan Injection PEGIntron, Peginterferon, Pegfilgrastim, Penicillin G Ber (Trimethobenzamide Hydrochloride Injectable), Timentin izathine and Penicillin G Procaine, Pentetate Calcium Tri Injection (Ticarcillin Disodium and Clavulanate Potassium sodium Inj (Ca-DTPA), Pentetate Zinc Trisodium Injection Galaxy), TNKase, Tobramycin Injection (Tobramycin Injec (Zn-DTPA), Pepcid Injection (Famotidine Injection), Per tion), Tocilizumab Injection (Actemra), Torisel (Temsimli gonal, Pertuzumab, Phentolamine Mesylate (Phentolamine mus Injection), Totect (DexraZOxane for Injection, Intrave Mesylate for Injection), Physostigmine Salicylate (Phys nous Infusion Only), Trastuzumab-DM1, Travasol (Amino ostigmine Salicylate (injection)), Physostigmine Salicylate Acids (Injection)), Treanda (Bendamustine Hydrochloride (injection) (Physostigmine Salicylate), Piperacillin and Injection), Trelstar (Triptorelin Pamoate for Injectable Sus TaZobactam Injection (ZoSyn), Pitocin (Oxytocin Injection), pension), Triamcinolone Acetonide, Triamcinolone Diac Plasma-Lyte 148 (Multiple Electrolytes Inj), Plasma-Lyte 56 etate, Triamcinolone Hexacetonide Injectable Suspension and Dextrose (Multiple Electrolytes and Dextrose Injection (Aristospan Injection 20 mg), Triesence (Triamcinolone in Viaflex, Plastic Vessel 250), PlasmaLyte, Plerixafor Injec Acetonide Injectable Suspension), Trimethobenzamide tion (Mozobil), Polidocanol Injection (Aselera), Potassium Hydrochloride Injectable (Tigan Injection), Trimetrexate Chloride, Pralatrexate Solution for Intravenous Injection Glucuronate Inj (Neutrexin), Triptorelin Pamoate for Inject (Folotyn), Pramlintide Acetate Injection (Symlin), Premarin able Suspension (Trelstar), Twinject, Trivaris (Triamcino Injection (Conjugated Estrogens for Injection), Prep kit for lone Acetonide Injectable Suspension), TrisenoX (Arsenic Technetium Tc99 Sestamibi for Injection (Cardiolite), Pre Trioxide Injection), Twinrix, Typhoid Vi, Ultravist (Iopro vacid I.V. (Lansoprazole for Injection), Primaxin I.V. (Imi mide Injection), Urofollitropin for Injection (Metrodin), US 2017/0203043 A1 Jul. 20, 2017

Urokinase Injection (Kinlytic), Ustekinumab (Stelara Injec The test speed of 250 mm/minute was established, after tion), Ultralente (U), Valium (diazepam), Valproate Sodium which force displacement data was obtained. The maximum Injection (Depacori), Valtropin (Somatropin Injection), Van force obtained was recorded. The force displacement instru comycin Hydrochloride (Vancomycin Hydrochloride Injec ment used was a TA XT Plus Texture Analyzer with a TA tion), Vancomycin Hydrochloride Injection (Vancomycin 27ON syringe test fixture (Hamilton, Mass.). Hydrochloride), Vaprisol (Conivaptain Hel Injection), 0066 Contact Width VAQTA, Vasovist (Gadofosveset Trisodium Injection for 0067. The contact width of the plunger interface with a Intravenous Use), Vectibix (Panitumumab Injection for glass barrel was measured under 30x magnification averag Intravenous Use), Venofer (Iron Sucrose Injection), Verte ing 3 measurements on each rib using a Keyence digital porfin (Visudyne), Vibativ (Telavancin for Injection), Vic micrometer VHX-5000 (Itasca, Ill.). toza (Liraglutide rDNA Injection), Vimpat (Iacosamicle 0068 Barrel ID Tablet and Injection), Vinblastine Sulfate (Vinblastine Sul 0069. The internal diameter of the syringe barrel was fate Injection), Vincasar PFS (Vincristine Sulfate Injection), measured by use of a digital three point internal micrometer Victoza, Vincristine Sulfate (Vincristine Sulfate Injection), (Mitutoyo series 468, Aurora, Ill.). Visudyne (Verteporfin Inj), Vitamin 8-12, Vivitrol (Naltrex (0070 Stopper Rib Diameter and Rib Radius one XR Inj), Voluven (Hydroxyethyl Starch in Sodium 0071. The rib diameter and rib radius of the stopper was Chloride Injection), Xeloda, Xenical (orlistat), Xeomin (In measured using an optical measurement system (Keyence cobotulinum toxin A for Injection), Xolair, Zantac Injection (Ranitidine Hydrochloride Injection), Zemplar Injection IM 6225, Itasca, Ill.). (Paricalcitol Injection Fliptop Vial), Zemuron (Rocuronium Examples Bromide Injection), Zenapax (daclizumab), Zevalin, Zido Vudine Injection (Retrovir IV), Zithromax Injection 0072 A series of stoppers was fabricated as described in (Azithromycin), Zn-DTPA (Pentetate Zinc Trisodium Injec U.S. Pat. No. 8,722,178 to Ashmead, et at using a halobutyl tion), Zofran Injection (Ondansetron Hydrochloride Injec with an initial modulus of 3.5 MPa. The stoppers were sized tion), Zingo, Zoledronic Acid for Inj (Zometa), Zoledronic for use with a 1 ml long bare glass (not siliconized or Acid Injection (Reclast), Zometa (Zoledronic Acid for Inj), otherwise treated) syringe barrel with a nominal inside Zosyn (Piperacillin and TaZobactam Injection), Zyprexa diameter of 6.35 mm. The stoppers differed in number, shape Relprevv (Olanzapine Extended Release Injectable Suspen and size of the ribs intended to form the seal against the sion) and a combination thereof. interior of the Syringe barrel. After processing was com pleted, the stopper was measured using non-contact mea Test Methods Suring equipment. The average results for each design are reported in Table 1. The stoppers were washed using warm 0061. It should be understood that although certain meth purified water with a small amount of detergent, then rinsed ods and equipment are described below, other methods or and dried to remove any residual contamination from fab equipment determined suitable by one of ordinary skill in rication. The stoppers were inserted into bare glass barrels the art may be alternatively utilized. and tested as described herein. The results are reported in 0062 Helium Leak Table 2. Rib 1 is the distal end rib and subsequent ribs count 0063. To evaluate the seal of the plunger to the barrel the up towards the proximal end. leak rate of helium from the internals of an assembled Syringe system to the external environment was performed. 0073. Example 1 and Example 2 in Tables and 2 are This was accomplished by placing a stopper into a dry bare stoppers which meet the intent, of this disclosure. glass barrel (no lubricant present) and restraining the 0074 Comparative Example 3 in Tables 1 and 2 is an plunger rod to prevent movement of the stopper during example of a stopper which has good slide force but is testing. The internal Volume of the assembled Syringe was insufficient in diameter to achieve the required seal and is evacuated through the needle by use of a vacuum and therefore insufficient. replaced with a helium atmosphere pressurized to approxi 0075 Comparative Example 4 in Tables 1 and 2 is an mately 1 prig. The space around the Syringe was monitored example of a stopper which achieves the required seal but by use of a Gas chromatography/mass spectrometry (GC/ has excessive slide force due to a larger than desired contact MS) tuned for helium (LACO's TitanTestTM Helium Leak between the stopper and the barrel and is therefore insuffi Tester, Salt Lake City, Utah). The area around the syringe cient. was evacuated, and analyzed for Helium concentration to (0076. In the Tables, OD represents outer diameter and ID determine a helium leak rate at 1 minute after helium represents inner diameter. differential pressure of approximately 15.7 psid was estab lished. TABLE 1. 0064. Slide Force Rib 4 0065. Slide force was measured by filling syringe with OD Rib 1 OD Rib 2 OD Rib 3 OD/rad, 0.96 ml of Water For Injection (WFI) and inserting stopper rib 1 radius rib 2 radius rib 3 radius Rib S using a vent tube stopper insertion machine. The Syringe Sample (mm) (mm) (mm) (mm) (mm) (mm) ODrad used was a staked needle design with a 29 gauge /2 inch Example 1 7.42 0.12 7.41 0.13 6.73 0.26 needle. An appropriate plunger rod to match the stopper Example 2 7.42 0.15 7.41 0.16 7.40 0.16 Comparative 6.62 0.90 6.62 0.89 6.62 0.89 was fitted into the assembled Syringe system without moving Example 3 or disturbing the stopper. The system was placed into a Comparative 7.35 0.07 7.27 0.14 7.21 0.16 7.20/0.173, holder on a force displacement analyzer and the cross head Example 4 7.23.O.21 moved at a rate of 25 mm/minute until contact was made between the crosshead and the plunger rod proximal end. US 2017/0203043 A1 Jul. 20, 2017 16

TABLE 2 of said ribs having a sealing Surface to an inner diameter of the inner surface of the barrel is greater than about 1.08. Total Maxi Contact l 10. The medical delivery device of claim 1, wherein the width extrusion one or more fluoropolymer layers comprise a single layer of Com- Contact (ribs He (break densified expanded polytetrafluoroethylene. Barrel pression width with leak loose) 11. The medical delivery device of claim 10, wherein each ID (Rib 1) rib 1 C > rate force rib of said two or more ribs comprises a radius of curvature Sample (mm) (%) (mm) 7.9%) (sccs) (N)) at an apex of each respective rib of less than about 0.22 mm. Example 1 6.35 14.42 0.37 0.73 827-8 9.8 Example 2 6.35 14.47 O.S6 1.62 47-8 12.5 12. The medical delivery device of claim 11, wherein a Comparative 6.35 4.06 O.S2 NA 15-5 5.2 ratio of a maximum outer diameter of all said ribs having a example 3 sealing Surface to an inner diameter of the inner Surface of Comparative 6.35 13.61 O.40 1.94 7.7–8 21.8 the barrel is greater than about 1.08. example 4 13. The medical delivery device of claim 11, wherein a maximum outer diameter of the ribs having a sealing Surface 0077. The invention of this application has been is greater than about 5.0 mm, an inner diameter of the inner described above both generically and with regard to specific surface of the barrel is between about 4.65 mm and about embodiments. It will be apparent to those skilled in the art 11.85 mm, and a ratio of the maximum outer diameter of that various modifications and variations can be made in the said ribs having a sealing Surface to an inner diameter of the embodiments without departing from the scope of the dis inner surface of the barrel is greater than about 1.08. closure. Thus, it is intended that the embodiments cover the 14. The medical delivery device of claim 1, wherein the modifications and variations of this invention provided they one or more fluoropolymer layers comprise a composite come within the scope of the appended claims and their fluoropolymer film having a barrier layer and a porous layer, equivalents. the barrier layer comprising at least one member selected What is claimed is: from densified ePTFE, PTFE, fluorinated ethylene propyl 1. A medical delivery device comprising: ene, polyethylene, polypropylene, polyvinylidene fluoride, a barrel having an inner Surface; polyvinylfluoride, perfluoropropylevinylether, or a perfluo a plunger rod having a distal end inserted within the roalkoxy polymer and copolymers and combinations barrel; thereof. a stopper attached to the distal end of the plunger rod and 15. The medical delivery device of claim 14, wherein each contacting at least a portion of the inner Surface of the rib of the said two or more ribs comprises a radius of barrel, the stopper comprising an elastomeric body, one curvature at an apex of curvature of each respective rib that or more fluoropolymer layers, and two or more ribs is less than about 0.22 mm. having a sealing Surface and being positioned on the 16. The medical delivery device of claim 15, wherein a one or more fluoropolymer layers; ratio of a maximum outer diameter of all said ribs having a wherein a contact width between at least one of said two sealing Surface to an inner diameter of the inner Surface of or more ribs and a portion of the inner surface of the the barrel is greater than about 1.08. barrel measured at a compressibility of greater than 17. The medical delivery device of claim 15, wherein a about 7.9% of the stopper is less than about 1.0 mm. maximum outer diameter of the ribs having a sealing Surface 2. The medical delivery device of claim 1, wherein said is greater than about 5.0 mm, an inner diameter of the inner inner Surface is a hydrophilic inner Surface. surface of the barrel is between about 4.65 mm and about 3. The medical delivery device of claim 1, wherein said 11.85 mm, and a ratio of the maximum outer diameter of inner surface free or substantially free of lubricants. said ribs having a sealing Surface to an inner diameter of the 4. The medical delivery device of claim 1, wherein said inner surface of the barrel is greater than about 1.08. two or more ribs are laminated with said one or more 18. A plunger rod comprising: fluoropolymer layers. a distal end that is insertable in a barrel having an inner 5. The medical delivery device of claim 1, wherein said Surface; and stopper further comprises a sliding Surface that is less than a stopper attached to the distal end and configured to about 2.0 mm. contact at least a portion of the inner Surface of the 6. The medical delivery device of claim 1, wherein the barrel, the stopper comprising an elastomeric body, one inner Surface is bare glass. or more fluoropolymer layers, and two or more ribs 7. The medical delivery device of claim 1, wherein each positioned on the one or more fluoropolymer layers, rib of said two or more ribs has a sealing Surface that wherein each rib of said two or more ribs having a sealing comprises a radius of curvature at an apex of each respective Surface comprises a radius of curvature at an apex of rib that is less than about 0.22 mm. each respective rib that is less than about 0.22 mm, a 8. The medical delivery device of claim 7, wherein a ratio ratio of a maximum outer diameter of all said ribs of a maximum outer diameter of all said ribs having a having a sealing Surface to an inner diameter of the sealing Surface to an inner diameter of the inner Surface of inner surface of the barrel is greater than about 1.08, the barrel is greater than about 1.08. and 9. The medical delivery device of claim 7, wherein a wherein the plunger rod is configured such that when the maximum outer diameter of said ribs having a sealing plunger rod is inserted in the barrel having an inner Surface is greater than about 5.0 mm, an inner diameter of diameter of an inner Surface of the barrel, a contact the inner surface of the barrel is between about 4.65 mm and width between at least one of said two or more ribs about 11.85 mm, and a ratio of the maximum outer diameter having a sealing Surface and the portion of the inner US 2017/0203043 A1 Jul. 20, 2017

surface of the barrel measured at a compressibility of wherein at least one of the two or more ribs is positioned greater than 7.9% of the stopper is less than about 1.0 on the one or more fluoropolymer layers and is con . figured to contact at least a portion of the inner Surface of the barrel; and 19. The plunger rod of claim 18, wherein said inner wherein each rib of said two or more ribs comprises a Surface is a hydrophilic inner Surface. radius of curvature at an apex of each respective rib that 20. The plunger rod of claim 18, wherein said inner is less than about 0.22 mm, a ratio of a maximum outer surface is free or substantially free of lubricants. diameter of all said ribs to an inner diameter of the 21. The plunger rod of claim 18, wherein said two or more inner surface of the barrel is greater than about 1.08, ribs are laminated with said one or more fluoropolymer and layers. wherein the stopper is configured such that when the stopper is inserted in the barrel, a contact width 22. The plunger rod of claim 18, wherein the one or more between at least one of said two or more ribs and the fluoropolymer layers comprise a single layer of densified portion of the inner surface of the barrel measured at a expanded polytetrafluoroethylene. compressibility of greater than 7.9% of the stopper is 23. The plunger rod of claim 18, wherein the one or more less than about 1.0 mm. fluoropolymer layers comprise a composite fluoropolymer 25. The stopper of claim 24, wherein said two or more ribs are laminated with said one or more fluoropolymer layers. film having a barrier layer and a porous layer, the barrier 26. The stopper of claim 24, wherein the one or more layer comprising at least one member selected from densi fluoropolymer layers comprises a single layer of densified fied ePTFE, PTFE, fluorinated ethylene propylene, polyeth expanded polytetrafluoroethylene. ylene, polypropylene, polyvinylidene fluoride, polyvinyl 27. The stopper of claim 24, wherein the one or more fluoride, perfluoropropylevinylether, perfluoroalkoxy fluoropolymer layers comprise a composite fluoropolymer polymers and copolymers and combinations thereof. film having a barrier layer and a porous layer, the barrier 24. A stopper insertable in a barrel having an inner layer comprising at least one member selected from densi Surface, the stopper comprising: fied ePTFE, PTFE, fluorinated ethylene propylene (FEP), polyethylene, polypropylene, polyvinylidene fluoride, poly an elastomeric body; vinylfluoride, perfluoropropylevinylether, perfluoroalkoxy one or more fluoropolymer layers; and polymers and copolymers and blends thereof. two or more ribs, k k k k k