(12) INI'ERNATIONAL APPLICATION PUBLISHED LINDER THE PATENf <."OOPERATION TREATY (PCf)
`
`<19> w..,,. 1-::=.:;-:..:, °"""',...00
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`•
`
`I IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII Ill llllllllllll llll llllHIII
`
`(43) lnRrnadonal Publication Dale
`29 March 2007 (29.03.2007)
`
`PCT
`
`(10) blkrnalional Publication Number
`WO 2007 /0 356 21 A 1
`
`(51) lnterullon11I Patent Classllkalkm:
`A61M5132 (2006.0L)
`A6JF 9/00 (2006.01)
`
`(21) lnlemaliolllll Applkalkln Number:
`JlCT/U S'.!.O!Xi/03 62 60
`
`(25) FIiing unguage:
`
`(22) lnlc.r1111lional Fling Dale:
`18 September 2006 (18.09.2006)
`Hnglish
`English
`
`(26) Pu blka lion Language:
`(30) Priori!)' Data:
`16 Scpa:mbcr 2005 (16.09.'.2005) US
`60/117,865
`(71) Applicant (/or di Jesigr1a1t'd States t>.xcq,1 US): (OSI)
`t:Yt::n:CH. INC. (US/USI; 31imes Square. 12th Floor,
`New York, NY I 0036 (US).
`
`(72) Inventors; and
`(7.5) Inventors/Applkants (for US only): SCYPINSKI,
`Stephen (US/US I; 71 lodgc Drive, B ridgcwatcr, NJ 08807
`(US). CAl,IAS, lhry IUS/US I; 3!JSwnins Pund Awnuc,
`
`:-
`
`:= (54) Title: OPlffllALMIC SYRING!!
`,_
`
`'!!!!!!!!
`iaiiii
`
`,_ ,_ ,_
`
`-- Melrose, MA <r!I 76 (US). t:n:Rt::1'1~ Kk-hard, K.
`-i= - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`[ ... ~
`= -~ I=
`
`[US/USI; 25 Timber Lane, Randolph, NJ 07869 l US).
`SHIMA, David, T. (USA'.JBI; 75 Lancaster Avenue, Bar(cid:173)
`nd. I Icr!s XX EN4 00S (GB). HRt:EGI, Wisam IUSAJSJ;
`1:!0 Bctlfon.l Rood, Wubum, MA 01801 (US). LITMAN,
`Dana, I~ IUS/llSI: 18 Maynard Street. Malden, MA
`01148 (US).
`(74) AIJ!lll: RA1''A, Uldlael, J.; (OSII Eyetech, Inc., 3 Tunes
`Square, L'.?th Floor, New York, NY 10036 (US).
`(81) Dcsigi1111cd Stales (u,,J,..,s nth,,nt.•is,. i11dir.D1eJ, fnr -.ry
`ki,1Jofnatimrolpmlt!Clinl1 m:ailahk): AE, AO, AL, AM,
`AT, AU, AZ, BA, BB. BG. BR. BW, BY, BZ. CA. 01, CN,
`CO, CR, CU, CZ, DE., DK, DM, DZ, EC, EE, F.G, ES, Fl,
`GB, GO, GE, Gil, GM, IIN, IIR, JIU, to, IL, IN, IS, JI~
`KP., KG, KM, KN, KP. KR, KZ. LA, I.C. UC, LR, LS, i:r,
`UJ, I.V, LY, MA, MD, MG, MK, MN, MW, MX, MY, M:t~
`NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU,
`SC. SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR,
`TI, TZ, UA, UG, US, UZ. VC, VN, ZA, ZM. ZW.
`(M) Des1g1U1lcd Slatei (Ull(l'.fS nthuwise i11Jir.areJ, fnr -ry
`li.i,,J nf regional prott!dinn avaifabJe'):. ARIPO (BW, GH,
`/Cmilim,,.,J o" ,urn pageJ
`
`(57) Abslract:
`The proscnt
`invc nlion provides a device
`for use in uphUtalm11k1gy.
`In
`particular, the present invention
`II device for use in
`provides
`inlnlvilJOOll'I
`admirisln1tion
`of ocular agcn ts. The prescn I
`inwnlklfl .slst1 pruvidcs methods
`or delivering one ur mure drugs
`lo a human eye a11r.l melhods fur
`ticating an ophthalmic disease,
`disoider, or condilion.
`
`Regeneron Exhibit 1017.001
`
`

`

`WO 2007/035621 Al
`
`I IIIII IIIIIIII II IIIIII IIIII IIIII IIIII IIII I II llllllll lllll lllll lllll lllll llll 1111111111111111111
`
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, RY, KG, KZ, MD, RlJ, TT, TM),
`European (AT, BE, BG, Cll, CY, CZ, DE, DK, EE, ES, 1-ll,
`FR, GB, GR, HU, IE, IS, IT, LT. LU. LV. MC, NL, PL, PT.
`RO, SE, SI, SK, TR), OAPI (BP, BJ, CP, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`-
`with internatinnal seardz reporl
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`Regeneron Exhibit 1017.002
`
`

`

`WO 2007/035621
`
`PCT /US2006/036260
`
`1
`
`OPHTHALMIC SYRINGE
`
`RELATED APPLICATIONS
`
`This application claims priority to U.S. Provisional Application Serial Number
`
`60/717,865 filed September 16, 2005, Attorney Docket No. EYE-036P, which is hereby
`
`5
`
`incorporated in its entirety by reference.
`
`FIELD OF THE INVENTION
`
`The present invention relates to methods of administering ophthalmic medicines and
`
`devices related thereto. In particular, the invention relates to intravitreous injection using an
`
`ophthalmic syringe and needle.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`Intravitreous (IVT) injection has been used in the treatment of human ocular disease
`
`for nearly a century beginning in 1911 as means to introduce air for retinal tamponade and
`
`repair of detachment (J. Ohm, Albrecht von Graefes Arch Ophthalmol 1911; 79:442-450).
`
`Over the past two decades, the use of intravitreous injection has gained increasing acceptance
`
`15
`
`in the therapeutic management of many intra ocular diseases, particularly disorders affecting
`
`the posterior segment of the eye (Jager et al., Retina 24:676-698, 2004). IVT injection is
`
`increasingly being incorporated into management of ocular diseases and the number of
`
`approved products for IVT injection is anticipated to grow on the basis of promising results
`
`from ongoing clinical studies. Currently fom1ivirsen sodium (Vitravene®, Novartis AG,
`
`20 Basel, Switzerland), ranibizumab injection (Lucentis™, Genentech, Inc., South San Francisco,
`
`CA) and pegaptanib sodium (Macugen®, (OSI) Eyetech, Inc. NY, NY) are three medicines
`
`approved by the Food and Drug Administration as IVT injections.
`
`Advantages ofIVT injection of medicines and diagnostics include the achievement of
`
`maximum vitreous concentrations while minimizing toxicity attributed to systemic
`
`25
`
`administration. While these advantages are becoming widely appreciated, the ophthahnology
`
`community turns its focus to various complications potentially associated with IVT injection.
`
`Risks of IVT injection, some vision threatening, include endophthalmitis, retinal detachment,
`
`iritis/uveitis, inflammation, intraocular hemorrhage, ocular hypertension, hypotony,
`
`Regeneron Exhibit 1017.003
`
`

`

`WO 2007/035621
`
`PCT/US2006/036260
`
`2
`
`pneumatic retinopexy, and cataract (R.D. Jager et al., Retina 24:676-698, 2004 and C.N. Ta,
`
`Retina, 24:699-705, 2004).
`
`Endophthalmitis is a condition in which the tissues inside the eyeball become
`
`inflamed and is generally caused by bacterial infection. The most common sources of
`
`5
`
`bacteria causing postoperative endophthalmitis are believed to be the patient's conjunctiva or
`
`eyelids. Unless treated effectively, endophthalmitis can rapidly lead to severe vision loss or
`
`blindness. The relative risks of developing postoperative endophthalmitis depend on a
`
`number of factors, including the presence of eyelid or conjunctival diseases, the patient's
`
`general health, the use of immunosuppressant medications, the type of intraocular surgery,
`
`10
`
`and intraoperative complications. Of these factors, intraoperative complications, particularly
`
`breaks in the posterior capsule with vitreous loss, carry the greatest risk for the development
`
`of endophthalmitis.
`
`Although intravitreous injection is a simple procedure with a small wound, it has been
`
`demonstrated that bacteria potentially introduced by the procedure are sufficient to induce
`
`15
`
`endophthalmitis, which is likely due to the inability of the vitreous to clear the infectious
`
`microorganisms. Other equally plausible explanations for the apparent high risk of
`
`endophthahnitis after intravitreous injections may be the very limited sample size as well as
`
`publication bias. It is important, nevertheless, to minimize the risk of developing
`
`endophthahnitis by reducing or eliminating bacteria from the ocular surface at the time of the
`
`20
`
`injection and to strictly adhere to aseptic technique. The use of topical antibiotics has been
`
`shown to reduce conjunctival and eyelid bacterial flora, which may in tum also decrease the
`
`risk of endophthalmitis.
`
`Because transient increases in intra-ocular pressure (IOP) may cause mild discomfort
`
`and can be associated in rare instances with irreversible damage to retinal ganglion cells
`
`25
`
`and/or retinal vascular occlusion, many investigators reported using prophylactic and/or
`
`therapeutic measures to prevent increases in IOP after IVT injection. These have included
`
`the use of aqueous paracentesis, preoperative treatment with pressure-lowering agents and
`
`digital massage or the use of a Honan IOP reducer.
`
`Particulate contaminants present in a drug, in a syringe, or in or on materials used at
`
`30
`
`the time of injection also may have the potential to induce detrimental effects when injected
`
`into the vitreous. This has been demonstrated in the case of glove lubricants, which are
`
`Regeneron Exhibit 1017.004
`
`

`

`WO 2007/035621
`
`3
`
`PCT /U S2006/036260
`
`highly inflammatory when injected into the posterior ocular chamber (H.S. Park, Korean J.
`
`Ophthalmol. 1997; 11:51-59).
`
`Other serious complications rarely occurred after IVT injection, making it difficult, in
`
`most instances, to detennine whether these were truly injection-related or simply sporadic,
`
`5
`
`um-elated comorbidities.
`
`Serious adverse events are for the most part transient and/or treatable, and the risks of
`
`serious adverse events reported after IVT injection is low. Even so, there is a need for
`
`improved devices and methods for IVT injection. The risks and benefits ofIVT injection will
`
`likely carry increased weight in patient and clinician treatment as more treatment options
`
`10
`
`become available.
`
`Guidelines for IVT injection are continuing to evolve (L.P. Aiello et al., Retina,
`
`24:S3-Sl9, 2004). For example, povidone iodine and an antibiotic are administered prior to
`
`IVT injection. Also, IVT injections are generally performed with a sterile surgical drape and
`
`lid speculum in place and a 27 or 30 gauge needle is typically used with an injection site
`
`15
`
`3.5-4.0 111111 posterior to the limbus.
`
`As new treatment modalities for macular diseases become available, the number of
`
`intravitreous injections administered is expected to increase dramatically. For example,
`
`intravitreous injection of the vascular endothelial growth factor (VEGF) inhibitor, Macugen®,
`
`has become available for the treatment of age-related macular degeneration. Also,
`
`20
`
`intravitreous injections of triamcinolone acetonide are now commonly used for the treatment
`
`of macular edema.
`
`The prevalence of endophthalmitis after intravitreous injection of anti-VEGF agents is
`
`unknown. Due to the very limited data regarding the rate of endophthalmitis after
`
`intravitreous injections, it is difficult to speculate about the true prevalence of
`
`25
`
`endophthalmitis after these types of procedures. The increased use of intravitreous injections
`
`for the delivery of these agents to the retina will provide data regarding the prevalence and
`
`risk factors for post-injection endophthalmitis and in the future define a more accurate rate of
`
`endophthalmitis.
`
`Drug delivery into the eye is challenging because the anatomy, physiology and
`
`30
`
`biochemistry of the eye includes several defensive barriers that render ocular tissues
`
`Regeneron Exhibit 1017.005
`
`

`

`WO 2007/035621
`
`PCT/US2006/036260
`
`4
`
`impervious to foreign substances. Techniques used for administering active agents into the
`
`eye include systemic routes, intraocular injections, injections around the eye, intraocular
`
`implants, and topical applications. Patient acceptance and safety are key issues that play a
`
`key role as to which treatments are used.
`
`5
`
`Ocular bioavailability of drugs applied topically in formulations such as eye drops is
`
`very poor. The absorption of drugs in the eye is severely limited by some protective
`
`mechanisms that ensure the proper functioning of the eye, and by other concomitant factors,
`
`for example: drainage of the instilled solutions; lacrhymation, tear evaporation; non(cid:173)
`
`productive absorption/adsorption such as conjunctival absorption, poor corneal permeability,
`
`10
`
`binding by the lachrymal proteins, and metabolism.
`
`Alternative approaches to delivery include in situ activated gel-forming systems,
`
`mucoadhesive formulations, ocular penetration enhancers and ophthalmic inserts. In situ
`
`activated gel-fo1ming systems are liquid vehicles that undergo a viscosity increase upon
`
`instillation in the eye, thus favoring pre-corneal retention. Such a change in viscosity can be
`
`15
`
`triggered by a change in temperature, pH or electrolyte composition. Mucoadhesive
`
`formulations are vehicles containing polymers that adhere via non-covalent bonds to
`
`conjunctival mucin, thus ensuring contact of the medication with the pre-corneal tissues until
`
`mucin turnover causes elimination of the polymer. Ocular penetration enhancers are mainly
`
`surface active agents that are applied to the cornea to enhance the permeability of superficial
`
`20
`
`cells by destroying the cell membranes and causing cell lysis in a dose-dependent manner.
`
`Ophthalmic inserts are solid devices intended to be placed in the conjunctival sac and to
`
`deliver the drug at a comparatively slow rate. One such device is Ocusert®, by Alza
`
`Corporation, which is a diffusion unit consisting of a drug reservoir enclosed by two release(cid:173)
`
`controlling membranes made of a copolymer. M.F. Saettone provides a review of continued
`
`25
`
`endeavors devoted to ocular delivery. ("Progress and Problems in Ophthalmic Drug
`
`Delivery", Business Briefing: Pharmatech, Future Drug Delivery, 2002, 167-171).
`
`Many types of ophthalmic surgeries such as cataract surgery require use of various
`
`fluids which are both delivered and removed from the eye over the course of the surgery.
`
`The simultaneous delivery of two or more therapeutics typically requires multiple separate
`
`30
`
`needle penetrations. In areas where bacterial infection and/or structural damage are a concern,
`
`the risks associated with multiple injections may become unacceptable. Multiple injections
`
`may be circumvented by using a multi-compartment syringe or a double-barrel syringe.
`
`Regeneron Exhibit 1017.006
`
`

`

`WO 2007/035621
`
`5
`
`PCT/US2006/036260
`
`Administration of multiple viscoelastic solutions with a multi-compartment syringe is
`
`described in US Patent Application Publication No. 2004/0167480. A double-barrel syringe
`
`for ophthalmic surgeries is described in US Patent Application Publication No. 2004/0064102.
`
`Such invasive intraocular administrations may not be favorable because they cause
`
`5
`
`patient discomfort and sometimes fear, while risking permanent tissue damage. A device
`
`which allows the simultaneous or sequential delivery of a therapeutic while requiring a single
`
`needle penetration would significantly reduce any needle associated complications.
`
`SUMMARY OF THE INVENTION
`
`10
`
`The present invention provides a device for use in ophthalmology. In particular, the
`
`present invention provides a device for use in intravitreous administration of ocular agents.
`
`The present invention also provides methods of delivering one or more drugs to a human eye.
`
`Tn one aspect, the invention relates to ophthalmic drug delivery devices and features a
`
`device for delivery of a therapeutic agent to the eye of a mammal.
`
`15
`
`The invention features a drug delivery device for delivering a therapeutic compound
`
`to the eye and drug delivery methods related thereto. The invention also features a syringe
`
`for intravitreal delivery and methods ofusing the syringe to treat an ophthalmic disease,
`
`disorder, or condition.
`
`Other features and advantages of the invention will be apparent from the
`
`20
`
`following description, the drawings, and the claims.
`
`Regeneron Exhibit 1017.007
`
`

`

`WO 2007/035621
`
`6
`
`PCT /U S2006/036260
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 is a schematic representation of a needle assembly comprising a luer hub, a
`
`cannula and a needle tip having a standard bevel.
`
`Figure 2 is a schematic representation of a needle assembly comprising a luer hub, a
`
`5
`
`cannula and a needle tip shield.
`
`Figure 3 is a schematic representation of a syringe and needle assembly comprising a
`
`low dead space hub assembly.
`
`Figure 4 shows drawings of a first embodiment of a double barrel syringe.
`
`Figure 5 shows drawings of a first embodiment of a double barrel syringe.
`
`10
`
`Figure 6 is a schematic representation of a fluid exchange device.
`
`Figui-e 7 is a schematic representation of a tandem syringe.
`
`Figure 8 is a graph showing penetration force required by various needles.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`15
`
`One aspect provides a syringe useful in ophthalmic applications for delivery of a
`
`material into the eye.
`
`Needle
`
`Any suitable needle may be used. Suitable needles provide facile penetration of the
`
`sclera with minimal injury. A needle typically includes an elongated tube with an outside
`
`20
`
`surface, a proximal end, a distal end and an open bore therethrough. As seen in Figure 1, the
`
`needle assembly 20 may have a hub 23 attached to the proximal end of the needle 22 that is
`
`used to attach the needle to a syringe. In one embodiment the hub is a Luer hub.
`
`The needle may be attached to the syringe permanently ( e.g., staked) or may be
`
`attached to the syringe by a Luer fitting. The Luer fitting may be a standard Luer fitting,
`
`25
`
`Luer slip fitting or a Luer lock fitting. The Luer fitting has either a tip (male) or hub (female)
`
`Regeneron Exhibit 1017.008
`
`

`

`WO 2007/035621
`
`PCT/US2006/036260
`
`7
`
`component, and provides the ability to insure leak-proof and mechanically secure comiections
`
`to any other device having a mating Luer fitting. Luer connectors can comprise round and
`
`tapered male and matching female mating surfaces. Luer connectors can fonn a locking
`
`configuration by adding a threaded locking collar to the male luer connector, which mates
`
`5 with ears on the female luer connector, thereby providing a positive "locked" connection.
`
`Luer fittings have several advantages. Luer fittings provide compatibility among various
`
`medical devices, offering the clinician the benefits of choosing a preferred needle. In
`
`addition, Luer-lock connections insure against possibility of needle coming off of the syringe
`
`during the injection procedure. Standards for Luer fittings are described in American
`
`10 National Standard ANSI/RIMA MD 70.1-1983 and the International Standard IS0-594-1 and
`
`ISO-7886-1.
`
`A non-standard Luer fitting may be used. Examples of non-standard Luer fittings
`
`include, but are not limited to, the Tru-Lok™ fluid transfer adaptor by Becton Dickinson.
`
`Other non-standard fittings include Tyco Health Care, Kendall Monoject® low dead space
`
`15
`
`(LDS) needles featuring tri bevel, anti-coring, stainless steel needles. Examples oflow
`
`waste space fittings are found in US Patent Nos. 6,840,291, 5,902,277 5,902,271, 5,902,270
`
`5,902,269 5,782,803, the contents of each are hereby incorporated by reference in its entirety.
`
`The needle may also be attached to the syringe via a ceramic coated tip (CCT)
`
`interface, i.e. 'press fit'.
`
`20
`
`In one embodiment, the needle is beveled and coated with a suitable silicone. In one
`
`embodiment, the needle is a PrecisionGlide® needle available from Becton-Dickenson.
`
`Suitable PrecisionGlide® needles include but are not limited to a Y:z inch 30 gauge needle
`and a Y2 inch 27 gauge needle. In one embodiment, the needle is a PrecisionGlide® shown in
`
`Figure 3. Referring to the figure, the needle comprises a polypropylene Luer hub 33 and a
`
`25
`
`stainless steel cannula 34, lubricated with silicone, having a three-bevel point, attached to the
`
`hub via an epoxy joint.
`
`The needle tip may have a standard bevel. In one embodiment, the needle may have
`
`more than one bevel. In one embodiment, the needle has three bevels. In one embodiment,
`
`the needle has five bevels. Examples of a five-bevel needle are described in US Patent No.
`
`30
`
`6,629,963, and 6,009,933, US patent Application publication Nos. 2044/0111066,
`
`2004/0030303 and PCT Application No. 2005/016420
`
`Regeneron Exhibit 1017.009
`
`

`

`WO 2007/035621
`
`PCT/US2006/036260
`
`8
`In one embodiment, the needle is a coated needle. In one embodiment, the needle is a
`
`lubricated needle. The needle optionally includes a lubricious coating applied to and
`
`adherent to the outside surface of the tube, as described in US Patent No. 5,911,711.
`
`In one embodiment, the coating is a silicone coating. Any suitable silicone coating
`
`5 may be used. Examples of suitable coatings include, but are not limited to, those available
`
`from SurModics, Eden Prairie, MN (see US Patent Nos. 6,706,408, 6,669,994, 6,254,634
`
`and 6,121,027).
`
`In one embodiment the coating is a medicated coating.
`
`Preferably the needle is a 27 gauge needle or smaller. In one embodiment the needle
`
`10
`
`is a 30 gauge needle.
`
`In one embodiment, the needle has a length ofless than 1 inch. In another
`
`embodiment, the needle has a length of about 0.5 inches.
`
`Needle tip shield
`
`As seen in Figure 2, the needle assembly 20 may comprises a needle tip shield 21
`
`15
`
`enclosing needle 22. Needle 22 is attached to luer hub 23 via epoxy joint 24. In one
`
`embodiment, the tip shield 21 is rigid. Examples of suitable rigid shields include but are not
`
`limited to those disclosed in US Patent No. 4,986,818. As depicted in Figure 2, the tip shield
`
`is not in contact with the needle tip. Needle tip shields in contact with the needle potentially
`
`dull the needle and wipe away any lubrication on the needle. In another embodiment, the tip
`
`20
`
`shield comprises one or more apertures or is permeable to sterilizing gases. The apertures
`
`may facilitate sterilization by allowing sterilizing gasses or steam to access the interior of the
`
`needle shield. In a particular embodiment, the tip shield is synthetic isoprene, ethylene
`
`oxide (EtO) or hydrogen peroxide (H20 2) penneable. In another embodiment, the S)Tinge
`
`barrels, stoppers and plunger rod components and assemblies can also be gamma irradiated.
`In one embodiment, the needle tip shield comprises a polypropylene. In another embodiment,
`
`25
`
`the needle tip shield comprises a styrene block thermoplastic elastomer.
`
`Penetration Force
`
`The needles of the present invention are used for penetration of the scleral tissue for
`
`administration of the syringe contents into the vitreous. Preferably the needles require a low
`
`Regeneron Exhibit 1017.010
`
`

`

`WO 2007/035621
`
`9
`
`PCT/US2006/036260
`
`penetration force. Preferably the needles require a low penetration force with low variability.
`
`In one embodiment, the needles require a penetration force ofless than 500 grams (g). In
`
`another embodiment, the needles require a penetration force ofless than 100 grams (g). In
`
`another embodiment, the needles require a penetration force ofless than 50 grams (g).
`
`5
`
`In one embodiment, the needles require a penetration force with a variability range of
`
`+/- 20 %. In one embodiment, the needles require a penetration force with a variability range
`
`of+/- 50 g. In another embodiment, the needles require a penetration force with a variability
`
`range of+/- 20 g
`
`In one embodiment, the penetration force is reduced by reducing the needles
`
`10
`
`coefficient of friction. In one embodiment the penetration force is reduced by using a
`
`lubricious coating on the needle.
`
`Syringe
`
`The syringe barrel is typically made of glass or a thermoplastic material. In one
`
`embodiment the syringe is a 1 mL Type I glass barrel syringe sealed with a bromobutyl
`
`15
`
`rubber stopper. Examples of pre-filled syringes are found in US Patent No. 4,252,118. In
`
`one embodiment the syringe is a BD Hypak SCF® syringe. In a particular embodiment, the
`
`syringe is a single dose, pre-filled syringe. In one embodiment, the syringe barrel has a
`
`volume of 1 mL or less. In a particular embodiment, the syringe barrel has a microliter
`
`volume. The syringe barrels of the present invention may further be provided with
`
`20
`
`graduations to assist in precision filling of the barrel.
`
`In one embodiment, the syringe is a plastic sytinge. In another embodiment, the
`
`syringe comprises a cyclic olefin copolymer (COC). In another embodiment the cyclic
`
`olefin copolymer is TopPac® (Schott).
`
`In another embodiment, the final Luer formation is made using a platinum wire. In a
`
`25
`
`particular embodiment, the sy1inge is substantially free of tungsten. Staked needle
`
`production requires a small hole and seat for gluing in the needle. The small hole requires a
`
`high temperature tungsten pin. Some of the tungsten pin material may shed into the glass
`
`during processing. Luer lock syringes are alternatively fonned using a platinum pin material.
`
`The platinum may not leave a significant residue in the glass as compared to tungsten.
`
`Regeneron Exhibit 1017.011
`
`

`

`WO 2007/035621
`
`to
`
`PCT/US2006/036260
`
`Optimal particulate matter concentrations may be achieved primarily through strict control of
`
`the enviromnent and material cleanliness.
`
`Volume
`
`The ophthalmic injection solutions of the present invention are useful as microliter
`
`5
`
`(µL)-volume injections. Microliter (µL)-volume injections may also be referred to as "ultra(cid:173)
`
`low volume injections". In one embodiment, the ophthalmic injection solution to be
`
`delivered has a volume of about 1.0 mL (1000 µL) or less. In another embodiment the
`
`ophthalmic injection solution to be delivered has a volume of about 200 µL or less. In
`
`another embodiment the ophthalmic injection solution to be delivered has a volume of about
`
`10
`
`100 µL or less. In another embodiment the ophthalmic injection solution to be delivered has
`a volume of about 90 µL. In another embodiment the ophthalmic injection solution to be
`
`delivered has a volume of about 50 µL.
`
`Sub-Visible Particulate Matter
`
`The ophthalmic injection solutions of the present invention, including solutions
`
`15
`
`constituted from sterile solids intended for parenteral use, as used herein are substantially free
`
`from particles that can be observed on visual inspection. There are also strict controls on
`
`sub-visible particulate matter for ophthalmic injections. The ophthalmic injection solutions of
`
`the present invention can be tested by a light obscuration procedure or may be tested by a
`
`microscopic procedure as described in USP Chapter <788>. United States Pharmacopoeia
`
`20
`
`(USP) Chapters <788> Particulate Matter in Injections and <789> Particulate Matter in
`
`Ophthalmic Solutions describe physical tests for the purpose of enumerating extraneous
`particles within specific size ranges. The United States Phannacopoeia, 28111 revision and the
`National Formulary, 23rd edition (USP28-NF23), The United States Pharmacopeial
`Convention, Inc (2005), is hereby incorporated by reference in its entirety.
`
`25
`
`In one embodiment, the ophthalmic solution contained within the syringe of the
`
`present invention has a lOµm-size or larger sub-visible particulate count ofless than or equal
`
`to about 60 particles per mL, a 25 µm-size or larger sub-visible particulate count of less than
`
`or equal to about 10 particles per mL, or a 50~im-size or larger sub-visible particulate count
`
`ofless than or equal to about 5 particles per mL. In one particular embodiment, the
`
`30
`
`concentration of sub-visible particulate matter is less than or equal to about 150 ppb.
`
`Regeneron Exhibit 1017.012
`
`

`

`WO 2007/035621
`
`11
`
`PCT /U S2006/036260
`
`In one embodiment the ophthalmic solution contained within the syringe of the
`
`present :invention is subject to the particulate matter limits set forth in USP <789> wherein
`
`the average number of particles present in the units tested does not exceed the values listed in
`
`Table 1.
`
`5
`
`Table 1.
`
`Diameter
`
`~lOµm ~25µm ~50µm
`
`Number of particles
`
`50 per mLIS per mLl2 permL
`
`In one embodiment, the ophthalmic solution contained within the syringe of the
`
`present invention has a 1 Oµm-size or larger sub-visible particulate count of less than or equal
`
`to about 20 particles per mL, a 25 µm-size or larger sub-visible particulate count of less than
`
`10
`
`or equal to about 5 particles per mL, or a SOµm-size or larger sub-visible particulate count of
`
`less than or equal to about 2 particles per mL. In one particular embodiment, the
`
`concentration of sub-visible particulate matter contained within the syringe of the present
`
`invention is less than or equal to about 150 ppb.
`
`15
`
`Waste volume
`
`As represented in Figure 3, the syringe assembly has a low waste space, which is
`
`defined as the volume located in the syringe tip 31 of syringe ban·el 32, needle hub 33 and
`
`needle cannula 34. The International Standard ISO-7886-1 identifies the maximum waste
`
`space for a 3ml syringe tip to be 0.07 mL.
`
`20
`
`In a particular embodiment, the needle/syringe combination of the present invention
`
`has a low waste space. Examples oflow waste space fitt:ings are found in US Patent
`
`Nos. 6,840,291, 5,902,277 5,902,271, 5,902,270 5,902,269 5,782,803, the contents of each is
`
`hereby incorporated by reference in its entirety. An example of a needle/syringe combination
`
`having a low waste space includes Trn-lok™ fluid transfer adaptors by Becton Dickinson
`
`Regeneron Exhibit 1017.013
`
`

`

`WO 2007/035621
`
`12
`
`PCT/US2006/036260
`
`(US Patent No. 6,840,291) and Monoject® low dead space (LDS) needles Tyco Health Care,
`
`Kendall ( catalog Nos. 1188005058 and 1188001112) featuring tri bevel, anti-coring, stainless
`
`steel needles.
`
`5
`
`The needle/syringe combination of the present invention has a waste space of less
`than 0.1 mL. In one embodiment, the waste space is less than 0.05 mL. In another
`embodiment, the waste space is approx. 50-60 µL. In one embodiment, the waste space for
`
`the 1 mL Hypak Luer tip syringe is from about 0.040 to about 0.050 mL. In another
`
`embodiment, the waste space is less than 0.001 mL.
`
`Syringe tip cap
`
`10
`
`The syiinge assembly may comprise a syringe tip cap. The syringe tip cap is used to
`
`seal the barrel of a prefilled syringe. In one embodiment, the syringe tip cap is a plastic rigid
`
`tip cap. Examples of suitable syringe tip caps include, but are not limited to, those found in
`
`US Patent Nos. 6,190,364; 6,196,998; 6,520,935 and 5,833,653; US patent Application
`
`Publication No. 2004/0215148 and US design patent Nos. 457954Sl and 493526S 1.
`
`In one
`
`15
`
`embodiment, the rigid tip cap is an elastomeric fonnulation comprising an elastomer,
`
`reinforcement and a curing system. In another embodiment, the elastomer is a synthetic
`
`isoprene blend, the reinforcement is an inert material, and the curing system is a resin. In
`
`another embodiment, the syringe tip cap comprises a chloro/bromobutyl rubber stopper.
`
`Multiple barrel syringe
`
`20
`
`Another aspect of the invention provides a syringe comprising more than one barrel.
`
`The multiple barrel syringe may permit simultaneous, selective or sequential delivery of one
`
`or more different materials.
`
`In one embodiment the syringe comprises a first and second barrel positioned in side(cid:173)
`
`by-side relationship including a first and second plunger for telescoping movement within
`
`25
`
`their respective chambers (see US Patent Application Publication No. 2004/0064102, which
`
`is herby incorporated by reference in its entirety). The plungers are optionally connected to a
`
`common handle allowing for the dispensing of the materials from the two chambers
`
`simultaneously at the same rate, as disclosed, for example, in US Patent No. 5,792,103. In
`
`another embodiment, the plungers are detachably connected to the plunger stopper.
`
`Regeneron Exhibit 1017.014
`
`

`

`WO 2007/035621
`
`13
`
`PCT /U S2006/036260
`
`Figures 4 and 5 show examples of dual barrel syringes for the simultaneous or
`
`sequential delivery of two or more therapeutic agents. The syringe includes a first barrel, a
`
`second barrel, and one or more needles. Each barrel contains a therapeutic agent dissolved or
`
`suspended in a liquid fommlation. Referring now to the drawings, there is seen in Figures 4
`
`5
`
`and 5 first and second embodiments of the double barrel syringe which differ in the respect
`
`that the first embodiment (Figure 4) is configured for direct filling of the first and second
`
`materials inside their respective barrels while the second embodiment (Figures 5) is
`
`configured for insertion of pre-filled first and second carpules into the first and second barrels,
`
`respectively.
`
`10
`
`Referring to the first embodiment shown in Figure 4, the syringe comprises first and
`
`second barrels 41, 42 each having an internal chamber 43, 44 for holding a quantity of first
`
`and second, liquefied materials therein, respectively. The first and second barrels 41, 42 are
`
`arranged in side-by-side relationship with each other. First and second plungers 45, 46 are
`
`positioned for sliding within the first and second barrels 41, 42 for telescoping mo