Electronic Acknowledgement Receipt
`
`EFSID:
`
`Application Number:
`
`14823126
`
`13750352
`
`International Application Number:
`
`Confirmation Number:
`
`5306
`
`Title of Invention:
`
`SYRINGE
`
`First Named Inventor/Applicant Name:
`
`Juergen Sigg
`
`Customer Number:
`
`1095
`
`Filer:
`
`Andrew K. Holmes/Andrea Jacquin
`
`Filer Authorized By:
`
`Andrew K. Holmes
`
`Attorney Docket Number:
`
`55157-US0NP
`
`Receipt Date:
`
`29-JAN-2013
`
`Filing Date:
`
`Time Stamp:
`
`17:08:21
`
`Application Type:
`
`Utility under 35 USC 111 (a)
`
`Payment information:
`
`Submitted with Payment
`
`I no
`
`File Listing:
`
`Document
`Number
`
`1
`
`Document Description
`
`File Name
`
`File Size(Bytes)/
`Message Digest
`
`Multi
`Part /.zip
`
`Pages
`(if appl.)
`
`- 55157-US-
`NP _SupplDS_2013Jan29.pdf
`
`403890
`
`f7 c44 76d6c580dad55fb 1f88a8fe369d 1 c8a
`624a
`
`yes
`
`2
`
`Novartis Exhibit 2227.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Multipart Description/PDF files in .zip description
`
`Document Description
`
`Start
`
`End
`
`Transmittal Letter
`
`Information Disclosure Statement (IDS) Form (SB08)
`
`Warnings:
`
`Information:
`
`1
`
`2
`
`1
`
`2
`
`4757333
`
`2
`
`Foreign Reference
`
`0l_W02007035621.pdf
`
`no
`
`45
`
`Warnings:
`
`Information:
`
`7 c4b087089bec5465 02e0881 d 5 5 004ed 69
`50de3e
`
`10020477
`
`3
`
`Non Patent Literature
`
`11 _Ausubel_ 1987 _.pdf
`
`no
`
`26
`
`dd4dcccc6396a6fb0fa46148908980b3116E
`dOdf
`
`Warnings:
`
`Information:
`
`Total Files Size (in bytes)
`
`15181700
`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New A~~lications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`Acknowledgement Receipt will establish the filing date of the application.
`
`National Stage of an International A~~lication under 35 U.S.C. 371
`If a timely submission to enter the national stage of an international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/DO/EO/903 indicating acceptance of the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International A~~lication Filed with the USPTO as a Receiving Office
`If a new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 181 O), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/RO/1 OS) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
`Novartis Exhibit 2227.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Case PAT055157.;U$0NP
`
`IN RE APPLICATION OF
`Sigg, Juergen et al.
`A:Pf>LICATION NO: 13n50352
`FILED: Janua.r.y 25, 2013
`fOR: SYRINGE
`
`MS: Amendr11e~t(cid:173)
`Commissioner for Pajents
`PO Box 1450.
`Afexandria, VA 22313•1450
`
`INFORMATION DISCLOSURE STATEMENT
`
`Sit:
`This paper is .~ i.r.ig filed:
`
`IZ1
`·rzJ
`
`su.p:plemental to the lrifurmatioh Disdosur~ Statement ft.led January 25, 2013.
`
`within three months of th.e filing date of lhe,applicatlon. Therefore, rto fees are required.
`
`f:81
`
`betore: t~ mailing date. of a,first Office Action on the merits, and so t.mder 37 C.F.R
`§1.97(b){3) no fees. a.re required .
`!fa fe.e is deemed to be r.eq'wired,. the Commissioner i$ herepy autnorized to ch~rge. suyh fee to
`Depostt Account No. 19-01 ~4 in the name of Novartis,
`In accordance w:lth 37 C.F.R §1 ,56: applicctnts·wisn to call the .E);($Tliner's attefition to the
`~ferenoos cited on the attached form(s} PTOJSB/08A/B.,
`
`l:Rl
`
`Copies of the refereTices ate enclosed her.ewit!l.
`
`The Exarniner is requested 10-consider t!)e foregoi11g Information in relation to this application
`and indicate that each reference was considered by returning a copy. of the initialed
`PlO/SB/08AlB form(:s).
`
`Novartiii Pharmaceuticals Corporati9n
`O!'le Health Plaza. Bldg. 101
`East Hanover. NJ 07936
`+1 8627785816
`
`Date: January 29, 2013
`
`Respectfully submitted.
`I Andrew Holmes I
`Andrew Holmes
`Agent for Applicant
`Reg, No, 51,813.
`
`Novartis Exhibit 2227.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`f.l!.ING BY "EXPRESS MAIL" UNOER.37 CF:~U~tG
`
`j DOCX€ll Number I PAT05,\1~7•US-NP
`··········1
`-------1
`
`Express Mail Label Number
`
`Commissioner for Pate,1is
`PO Box 1450
`Alexandria, VA 22313-·1450
`
`!
`__________ j
`Dale ot Deposit
`,
`
`UTILITY PATENT APPLICATION TRANSMffT.AL AND FEE SHEET
`
`Transmitted herewith for filing under 37 CFR §1.53(b) is the utility patent application of
`
`Applicant (or identifier): Sigg, Juergen et al.
`
`Title:
`
`SYRINGE
`
`Enclosed are:
`
`1. ~ Specification {Including Claims and Abstract) • 27 pages
`2. ~ Drawings • 1 sheets
`3. D Executed Declaration and Power of Attorney (original or copy)
`4. 0 Microfiche Computer Program {appendix)
`5.
`Nucleotide and/or Amino Acid Sequence Submission
`0 Computer Readable Copy
`[J PaperCopy
`D Statement Verifying Identity of Above Copies
`6. D Preliminary Amendment
`7. D Assignment Papers (Cover Sheet & Docurnent(s))
`8. 0 English Translation of
`t81
`Information Disclosure Statement
`9.
`10. 0 Certified Copy of Priority Document{s)
`fZl Return Receipt Postcard
`11.
`fZl Application Data Sheet
`12.
`13. ~ Other: a) Submission of Sequence Listing Including Statement of Verification (1
`Sheet)
`b) Unexecuted Declaration for Utility Application using an Application Data
`Sheet (5 Sheets)
`c) Transmittal for Power of Attorney to one or more registered Practitioners
`and Power of Attorney by Applicant (2 sl1eets}
`
`Filing fee calculation:
`0 Before calculating the filing fee. please enter the enclosed Preliminary Amendment.
`D Before calculating the filing fee, please cancel claims
`
`Novartis Exhibit 2227.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`FHed
`
`!
`
`·--·······- ..
`$
`·--···--·
`·i
`$
`$
`---·-·- ·· $
`
`"'
`·-----·
`:::
`
`i $
`I
`
`$
`
`380
`620
`250
`0
`0
`
`"'
`720
`
`0
`
`,..,.,.,-----,-------------.... ·- ·--···- - - - - - - - - - -
`8asic Filinq Fee
`... ,._, _______
`Search Fee
`Examination Fee
`···-------
`~!:l.!~21e Dependent Claim Fee($
`}
`-
`, Foreion Lan uaqe Surcharoe ($
`}
`i
`--·-~N""-'--u_m_b_e_r.......,__......,.. _____ ...--___ _
`For
`Number I
`Rate
`Extra
`j
`..
`: Extra
`)( s
`60
`-20
`Total Claims
`12
`32
`I Claims
`?------+--------------------+-- - -
`!
`Independent
`.3
`i
`250
`)( $
`0
`,
`Claims
`~E-xt-ra-~---N-u_m_b-er_o_f_e_a_ch- ad_d,_itior.al r
`...
`Aoolication Size Fee
`Total
`Sheets
`
`Sheets
`
`50 or fraction thereof
`(rounded up lo a whole number)
`
`Rate
`
`1----2_8_.........,._·_1_0_0......,__ __ 0 _ _,__/..c.5 .... 0....,_______ 0 -·
`
`310 = i $
`, $
`X
`TOTAL F!LlNG FEE $
`
`0
`
`1970
`
`0 Please charge Deposit Account No. 19-0134 ln the name of Novartis in the amount of
`$1970. An additional copy of this paper is enclosed. The Commissioner ls hereby
`authorized to charge any additional fees under 37 CFR §1.16 and §1.1 7 which may be
`required in connection with this application, or credit any overpayment. to Deposit
`Account No. 19-0134 in the name of Novartis.
`
`Please address alt correspo,,dence to the address associated with Customer No. 001095,
`which is currently:
`
`Novartis Pharmaceuticals Corporation
`One Health Plaza, Bldg. 101
`East Hanover, NJ 07936
`
`Please direct all telephone calls to the undersigned at the number given below, and al!
`telefaxes to +1 9737818265.
`
`Novartis Pharmaceuticals Corporation
`One Health Plaza, Bldg. 101
`East Hanover, NJ 07936
`+1 8627785816
`
`Date: January 25, 2013
`
`Respectfully submitted,
`
`I Andrew Holmes I
`
`Andrew Holmes
`Agent for Applicant
`Reg. No. 51 ,813
`
`2
`
`Novartis Exhibit 2227.005
`Regeneron v. Novartis, IPR2021-008 16
`
`

`

`TECHNICAL FIELD
`
`SYRIN(;E
`
`The present invention relates to a syringe, particularly to a small volume syringe such as a
`
`syringe suitable for ophthalmic injections.
`
`5 BACKGROUND ART
`
`Many medicaments are delivered to a patient in a syringe from which the user can dispense the
`medicament If medicament is delivered to a patient in a syringe it is often to enable the patient,
`or a caregiver, to inject the medicament. It is important for patient safety and medicament
`
`integrity that the syringe and the contents of that syringe are sufficiently sterile to avoid
`
`10
`
`infection, or other, risks for patients. Sterilisation can be achieved by terminal sterilisation in
`
`which the assembled product, typically already in its associated packaging, is sterilised using
`
`heat or a sterilising gas.
`
`For small volume syringes, for example those [or injections into the eye in which it is intended
`
`that about 0.1ml or less of liquid is to be injected the sterilisation can pose difficulties that are
`
`15
`
`not necessarily associated with larger syringes. Changes in pressure, internal or external to the
`
`syringe, can cause parts of the syringe to move unpredictably, which may alter sealing
`
`characteristics and potentially compromise sterility. Incorrect handling of the syringe can also
`
`pose risks to product sterility.
`
`Furthermore, certain therapeutics such as biologic molecules are particularly sensitive to
`
`20
`
`sterilisation, be it cold gas sterilisation, thermal sterilisation, or irradiation. Thus, a careful
`
`balancing act is required to ensure that while a suitable level of sterilisation is carried out, the
`
`syringe remains suitably sealed, such that the therapeutic is not compromised. Of course, the
`
`syringe must also remain easy to use, in that the force required to depress the plunger to
`
`administer the medicament must not be too high.
`
`25
`
`There is therefore a need for a new syringe construct which provides a robust seal for its content,
`
`but which maintains ease of use.
`
`DISCLOSURE OF THE INVENTION
`
`The present invention provides a pre-filled syringe, the syringe comprising a body, a stopper and
`
`a plunger, the body comprising an outlet at an outlet end and the stopper being arranged within
`
`30
`
`the body such that a front surface of the stopper and the body define a variable volume chamber
`
`-1 -
`
`Novartis Exhibit 2227.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`from ,vhich a fluid can be expelled though the outlet, the plunger comprising a plunger co11tact
`
`surface at a first end and a rod extending ber.veen the plunger contact surface and a rear portion,
`the plunger contact surface mi-anged to contact the stoppGr, such that the plunger can be used to
`force the stopper towards the outl.e:t end of the body, reducing the volume of the variable volume
`
`S
`
`chamber, characterised in !'hat the fluid comp.rises an ophthalmic sohition. ln one embodiment,
`the ophthalmic solution comprises a VEGF-antagonist.
`
`ln one embodiment, the syringe is suitable for ophthaimk ir.tiections, more particularly
`.intravitreal injections, and as such has a suitably small volume, The syringe may also be silicon.e
`oil free, or substantially silicone oil free, or ma.y comprise a !ov.: level of silicone oll as fobricant.
`In one embodiment, despite the low silicone oil level, the :itopper break loose and slide force is
`
`10
`
`less than 20N.
`
`For ophthalmic injections, it is particularly important for the ophthalmic solution to have
`particularly !ow particle content. In one embodiment, the syringe meets US Phannacopeia
`standard 789 (USP789).
`
`15
`
`Syringe
`
`The body of the syringe may be a substantiaHy cylindrical shell. or may inc1ude a substantially
`cylindrical bore with a non ci.r6,i!.ar outer shape. The outlet end of the body includes an outlet
`
`through which a Huid housed within the variable volume chamber can be expelled as the volume
`of sa.id chamber is reduced. The outlet may comprise a projection from the outlet end through
`20 which extends a channel having a smaller diameter than that of the variable volume chamber.
`The outlet may be adapted, for example via a luer lock type connection, for connection. to a
`needle or other accessory such as a sealing devfoe which is able to seal the variable volume
`chamber, but ca11 be operated, or removed, to unseat the variable volume chamber and allow
`connection of the syringe to another accessory, such as a needle. Such a connection may be
`25 made di.rect1y between the syringe and accessory, or via the sealing device. The body extends
`along a first axis from the outlet end to a rear end.
`
`The body may be made from a plastic material (e.g. a cyclic ckfin polymer) or from glass and
`
`may include indicia on a surface thereof to act as an injection guide. ln one embodiment the
`body ma.y comprise a primi.ng mark. This allows the physic,ia:n to aiign a pre-determined part of
`the stopper (such as the tip of the front surface or one of the c.ircumterential ribs, discussed later)
`or plunger with the mark, thus expelling excess ophthalmic solution and any air bubbl.es from the
`
`30
`
`-2-
`
`Novartis Exhibit 2227.007
`Regeneron v. N ovartis, IPR202 1-008 16
`
`

`

`syringe. The priming process ensures that an exact, pre-deter.mined dosage is administered to the
`
`pittient
`
`The stopper may be made from .rubber, silicone or other suitable resiliently deformable material.
`The stopper may be substantially cy.lindri.,,al and the stopper may include one or more
`circumferenHal ribs around an outer surface of fhe stopper, the stopper and ribs being
`
`5
`
`dimensioned such that the ribs form a substantially fluid tight seal with an internal surface of the
`syringe body. The front surface of the stoppeJ may be any suitable shape, for example
`substantially planar, substantially conical or of a domed shape.. The rear surfoce of the stopper
`
`10
`
`may include a substantially central recess. Such a central recess couid he used to connect a
`plunger to the stopper using a snap fit feature or thread connection in a known manner. The
`stopper may be substantially rotationally symmetric about an ax.is through the stQpper.
`
`·me plunger comprises a plunger contact surface and extending .from that a rod extends from the
`plunger contact surface to a rear portion. The rear portion may include a user contact portion
`adapted to be cont.acted by a user during an injection event. The 1,1ser contact portion may
`
`15
`
`comprise a substantially disc shaped po1tion, the radius of the disc extending substantially
`perpendicular to the axis along which the rod extends. The user contact portion could be any
`suitable shape. The axis along which the rod extends may be the first axis, or may be
`substantially parailel with the first axis.
`
`The syringe may include a backstop arranged at a rear portion of lhe body. The backstop may be
`
`20
`
`removable from the syringe. If the syringe body includes tem:iinal flanges at the end opposite the
`outlet end the backstop may be configured to substantiu11y sandwich tem1inal flanges of the body
`as this prevent movement of the backstop in a direction parallel to the first axis.
`
`25
`
`30
`
`The rod may comprise at least one rod shoulder directed awa.y from the outlet end and the
`backstop may include a backstop shoulder directed towards the outlet end to cooperate with the
`rod shoulder to substantially prevent movement of the rod away from the outlet end when the
`
`backstop shoulder and rod shoulder are in contact. Restriction of the move.ment of the rod away
`from the outlet end can help to m,aintain steri.lity during termi.nai sterilisation operations, or other
`operations in which the pressure within the variable volume (hamber or outside the chamber
`may change. During such operations any gas trapped within the variable volume chamber, or
`
`bubbles that may forrn in a liquid therein, may change in volurne and thereby cause the stopper
`to move. Movement of the stopper away from the outlet could result in the breaching of <1
`sterility zone created by the stopper. This is particularly imporranJ for low volume syringes
`
`-3··
`
`Novartis Exhibit 2227.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`·where there are much lower tolerances in the component sizes and less flexibility in the stopper.
`
`The term steril.ity zone as used herein is used to refer to the area within the syringe that is sealed
`by the stopper .from access from either end of the syringe, This may be the area between a se.al
`of the stopper, for example a circumferential rib, closest to the outlet and a seal of the stopper,
`for example a circumforential db, furthest from the outlet. The distance between these two seals
`defines the sterility zone of the stopper since the stopper is installed into the syringe barrel in a
`sterile environment
`
`To further assist in maintaining sterility during the operations noted above the stopper may
`comprise at a front circumforential rib and a rear circumferential rib and those ribs may be
`separated in a direction along the first axis by at !east 3mm, by at kast 3.5 mm, by at least
`3,75mm or by 4mm or more. One or more ndditional ribs (Ic)r example 2, 3, 4 or 5 additional
`ribs, or between .l-10. 2-8, 3-6 or 4-5 additional ribs) may be arranged between the front and .rear
`
`ribs. fn one embodiment there are a total oft'hree circumferential ribs.
`
`5
`
`10
`
`A stopper with such an enhanced sterility zone can a!so provide protection for the injectahk
`15 medicament during a terminal sterilisation pl'Ocess. More ribs on the stopper, or a greater
`distance betwee11 the fro11t and rear ribs can reduce the potential exposure of the medicament to
`the sterilising agent, However, increasing the number of ribs can .increase the friction between
`the stopper and syringe body, reducing ease of use. While this may be overcome by increasing
`the siliconisation of the syringe, such an increase in silicone oil !.evels is particularly undesirable
`
`20
`
`for syringes for ophthalmic use,
`
`The rod shoulder may be arranged within the external diameter of the rod, or may be ananged
`outside the external diameter of the rod, By providing a shoulder that extends beyond the
`externai di.ameter of the rod, but still fits within the body, the shoulder can help to stabilise the
`movement of the rod within the body by reducing .movement of the rod perpendicti!ar to the first
`axis. The rod shoulder may comprise any suitable shoulder fonning e.lements on the rod, but in
`one embodiment the rod shoulder comprises a substantially disc shap(~d portion on the rod,
`
`Ju one embodiment of the syringe, when arranged with the plu.nger contact surface in contact
`with the stopper and the variable volume chamber is at its intended maximum volume there is a
`clearance of no more than about 2mm between the rod shoulder and backstop shoulder. ln some
`embodiments there is a clearance of less than. about 1-5 mm and in some less than about 1 mm.
`T11is distance is i>'elected to substantially limit or. prevent excessiw .rearward (away from the
`outlet end} movement of the stopper,
`
`25
`
`30
`
`Novartis Exhibit 2227.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`In one embodiment the variable volume diamber has an int.erna1 diameter greater than 5mm or
`6mm, or less than 3mm or 4mm. The internal diameter may be between 3mm and 6mm, or
`
`between 4mm and 5mm.
`
`In another embodiment the syringe is dimensioned so as to have a nom.inal maximum fiU volume
`
`5
`
`of between about 0.1ml and about 1.5ml. In certain embodiments the nominal maximum fill
`volume is between about 0.5ml and a.bout 1ml. ln certain. ernbo<limenLs the nominal maximum
`fiil volume is about 0.5ml or about 1ml, or about 1.5ml.
`
`The length of the body of the syringe may be less than 70mm, kss than 60mm or less than
`50mm. In one embodiment the kngth of the syringe body is between 45mm and 50mm.
`
`lO
`
`In one embodiment the syringe is filled with between about 0.01ml and about 1.5ml (fo.r
`example between about 0.05ml and about Jm!, between about 0.J.ml and about 0.5ml, between
`about 0.15ml and abom 0.175ml) of a VEGF antagonist solutkm. rn one embodiment, the
`syringe is filled with 0.165m I of a VEGF antagonist solution. Of course, typically a S)'Tinge is
`filled with more than the des.ired dose to be administered to the patient, to take into account
`
`! 5 wastage due to "dead, space" within. the syringe and needle. There may also be a certain amount
`of wastage when the syringe is prime{l by the physician, so that it ls ready to inject !:he patient.
`
`Thus, in one embodiment, the syr.inge is filled with a dosage volume (Le. thi:l volume of
`medicament intended for ddivery to the patent) <if between about 0.01ml and about 1.5ml (e.g.
`
`20
`
`25
`
`between about 0.<}5ml and about 1ml, between about 0. 1ml and about 0.5ml) of a VEGF
`anlagon.ist solution. In one embodiment, the dosage volume is between about 0.03ml and about
`0.05ml. for example, for Lucent.is, the dosage volume is 0.05m! or 0.03ml (0.5mg or 0.3mg) of a
`l Omg/ml injectable medicament solution; for Eylea, the dosage volume is 0.05ml of a 40mg/ml
`injectable medicament solution. Although unapproved for ophthalmic indications, bevacizumab
`
`is used off--label ln such ophthalmic indications at a concentration of 25mg/ml; typicaHy at a
`dosage volume of 0.05ml ( 1.25mg). In one embodiment, the extractable volume from the syringe
`(that is the amount of produt.-1. obtainable from the syringe following fil ling, taking into accom1t
`
`loss due to dead space in the syringe and needle) is about 0.09ml.
`
`ln one embodiment the length oft.he syringe body is between about 45mm and about 50mm, the
`internal diameter i.s between about 4mm and about 5mm, the fiU volume is between about 0.12
`
`30
`
`and about OJmi and the dosage volume is between about 0,03mi and about 0.05ml.
`
`-5-
`
`Novartis Exhibit 2227.010
`Regeneron v. Novartis, IPR2021-008 16
`
`

`

`As the syringe contains a medic.ament solution, the outlet may be reversibly sealed to maintain
`
`sterility of the medicament. This sealing may be achieved through the use of a sealing device as
`is known in the art. For ex.ample the ovs™ system which is available from Vetter Pharma
`1.nterna:linnal OmbH.
`
`5
`
`10
`
`It .is typical to sHiconise t11e syringe in order to allow ease of use, i.e. to apply silicone oil to the
`inside of the barrel, which decreases the force required to move the stopper. H.owever, for
`ophthalmic use, it is desirable to <lecrnase the likelihood of si!icone oil droplets being injected
`into the eye. With multiple injections, the amount of silicone droplets can build up in the eye,
`causing potential adverse e.tfocts, including "floaters" and an incr(~ase in intra-oc.ular pressure.
`Furthermore, silicone oil ca11 cause proteins to aggregate. A typical 1ml syringe comprises l 00·
`
`800µg silicone oil in the barrel, though a survey of manufacturers reported that 500- iOOOµg was
`typically used in pre-fille<l syringes (Badkar et a!.2011 , AAPS PharmaSciTech, 12(2):564,-572).
`
`Thus, .in one embodiment. a syringe according to the invention comprises less than about 800µg
`(Le. about less than about 500µg, less than about 300Fg, less than about 200~tg, less than about
`
`15
`
`I 00i,g, less than about 75µg, less than about 50µg, !ess than about 25~tg, less than about I 511g.,
`
`less than about l0~tg) silicone oil in the barrel. If the syringe comprises a low level of silicone
`
`oil, this may be more than about 1µg, more than about 3iig, more than about 5~1g, more than
`about 7µg or more than about 1 0~lg silicone oi'l in the barrel. Thu:,;, in one embodiment, the
`syringe may comprise about lµg--about S00µg, about 3µg-about 200µ.g, about 5tlg-about IO0~tg
`
`or about i 0~tg-about S0µg silicone oil in the barrel. Methods for measuring the amount of
`silicone oil in such a syringe barre!. are known in the a.it and .include, for example, d.tfferential
`weighing methods and quantitation by infrared-spectroscopy of the oil diluted in a suitable
`
`solvent. Various types of silicone nil are avajlable, but typ.icaHy either DC360 (Dow Corning<ri>;
`with a viscosity of lO00cP) or DC365 emulsion (Dow Corningt'; DC360 oil with a viscosity of
`350cP) are used for syringe siliconisation. In 011e embodiimmt, th{: pre~filled syringe of the
`
`invention comprises DC365 emulsion.
`
`During testing it was surprisingly found that, for syringes having smali dimensions, such as those
`
`discussed above, and particularly those described in conjunction vvith the figures below, the
`
`break loose and siiding forces for the stopper within the syringe are t{ubstantially unaffocted by
`
`reducing the silkonisation levels far below the crnTent standard to the levels discussed here. This
`is in contrast t·o conventional thinking that wou"ld suggest that if you decrease the silicone oil
`level,. the forces required would i.ncrease (see e.g. Schoenknecht, AAPS National Biotechnology
`Conference 2007 - Abstract no. NBC07-000488, which indicates that ,vhik 400).lg silicone oil is
`
`20
`
`25
`
`30
`
`Novartis Exhibit 2227.011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`acceptable, usability improves when increased to 800µg). Having too great a force required to
`
`move the stopper can cause problems during use for some users, for example accurate dose
`
`setting or smooth dose delivery may be made more difficult if significant strength is required to
`
`move, and/or keep in motion, the stopper. Smooth administration is particularly important in
`
`5
`
`sensitive tissues such as the eye, where movement of the syringe during administration could
`
`cause local tissue damage. Break loose and slide forces for pre-filled syringes known in the art
`
`are typically in the region of less than 20N, but where the pre-filled syringes contain about
`1 00µg-about 800µg silicone oil. In one embodiment the glide/slide force for the stopper within
`the pre-filled syringe is less than about l lN or less than 9N, less than 7N, less than SN or
`
`IO
`
`between about 3N to SN. In one embodiment, the break loose force is less than about l lN or less
`
`than 9N, less than 7N, less than SN or between ·about 2N to SN. Note that such measurements are
`
`for a filled syringe, rather than an empty syringe. The forces are typically measured at a stopper
`
`travelling speed of l 90mm/min. In one embodiment, the forces are measured with a 30G x 0.5
`inch needle attached to the syringe. In one embodiment, the syringe has a nominal maximal fill
`volume of between about 0.5ml and 1ml, contains less than about l00µg silicone oil and bas a
`
`15
`
`break loose force between about 2N to SN.
`
`In one embodiment the syringe barrel has an internal coating of silicone oil that has an average
`
`thickness of about 450nm or less (i.e. 400nm or less, 3SOnm or less, 300nm or less, 200nm or
`
`less, 100nm or less, 50nm or less, 20nm or less). Methods to measure the thickness of silicone oil
`
`20
`
`in a syringe are known in the art and include the rap.ID Layer Explorer® Application, which can
`
`also be used to measure the mass of silicone oil inside a syringe barrel.
`
`In one embodiment, the syringe is silicone oil free, or substantially silicone oil free. Such low
`
`silicone oil levels can be achieved by using uncoated syringe barrels and/or by avoiding the use
`
`of silicone oil as a lubricant for product contacting machine parts, or pumps in the syringe
`
`25
`
`assembly and fill line. A further way to reduce silicone oil and inorganic silica levels in a pre(cid:173)
`
`filled _syringe is to avoid the use of silicone tubing in filling lines, for example between storage
`
`tanks and pumps.
`
`30
`
`The syringe according to the invention may also meet certain requirements for particulate
`content. In one embodiment, the ophthalmic solution comprises no more than 2 particles :::S0µm
`in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 5
`particles :::25µm in diameter per ml. In one embodiment, the ophthalmic solution comprises no
`more than 50 particles :::lOµm in diameter per ml. In one embodiment, the ophthalmic solution
`
`-7-
`
`Novartis Exhibit 2227.012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`comprises no more than 2 particles :::,50µm in diameter per ml, no more than 5 particles :::,25µm
`in diameter per ml and no more than 50 particles :::,IOµm in diameter per ml. In one embodiment,
`
`a syringe according to the invention meets USP789 (United States Pharmacopoeia: Particulate
`Matter in Ophthalmic Solutions). In one embodiment the syringe has low levels of silicone oil
`
`5
`
`sufficient for the syringe to meet USP789.
`
`VEGF Antagonists
`
`Antibody VEGF antagonists
`
`VEGF is a well-characterised signal protein which stimulates angiogenesis. Two antibody VEGF
`
`antagonists have been approved for human use, namely ranibizumab (Lucentis®) and
`
`10
`
`bevacizumab (Avastin®).
`
`Non-Antibody VEGF antagonists
`
`In one aspect of the invention, the non-antibody VEGF antagonist is an immunoadhesin. One
`
`such immuoadhesin is aflibercept (Eylea®), which has recently been approved for human use
`
`15
`
`and is also known as VEGF-trap (Holash et al. (2002) PNAS USA 99: 11393-98; Riely & Miller
`(2007) Clin Cancer Res 13:4623-7s). Aflibercept is the preferred non-antibody VEGF antagonist
`for use with the invention. Aflibercept is a recombinant human soluble VEGF receptor fusion
`
`protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to
`
`the Fe portion of human lgG 1. It is a dimeric glycoprotein with a protein molecular weight of 97
`
`kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total
`20 molecular mass, resulting in a total molecular weight of 115 kDa. It is conveniently produced as
`
`a glycoprotein by expression in recombinant CHO Kl cells. Each monomer can have the
`
`following amino acid sequence (SEQ ID NO: 1):
`
`SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATY
`
`KEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPS
`
`25
`
`SKHQHKKLVNRDLKTQSGSEMKKFLSTLT IDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPP
`
`CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
`
`YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK
`
`GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL
`
`SLSPG
`
`30
`
`and disulfide bridges can be formed between residues 30-79, 124-185, 246-306 and 352-410
`
`within each monomer, and between residues 211-211 and 214-214 between the monomers.
`
`-8-
`
`Novartis Exhibit 2227.013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Another non-antibody VEGF antagonist immunoadhesin curren1!y in pre-clinical development is
`a recombinant htJman soluble VEGF receptor fusion protein similar to VEGF-trap containing
`
`extracellular ligand-binding domains 3 and 4 from VEGFR2/KDR, and domain 2 from
`
`VEGFRl/Flt-1; tJ1ese domains are fused to a human IgG Fe protein fragment (Li et al., 2011
`5 Molecular Vision 17:797-803). This antagonist binds to isofom1s VEGr-A, VEGF-B and VEGF-·
`C. The molecule is prepared using two different product.ion processes resulti11g i.n different
`
`glycosy!ation patterns on the final proteins. The twz) glycoforms are reJerred to as KH902
`
`(conbercept) and KH906. Tile fusion protein can have the following amino add. sequence (SEQ
`
`ID N0:2):
`
`.lO
`
`l.5
`
`MVSYW0'1'GVLLCALLSCL'Ll/l'G.SSSCGRPFVEMYSEIPEIIlfMTEGRELVIPCRV"l'SPNITVTLKKFPLDT
`
`LIPDG¥'..RIHv1)SRKGFI ISNATYKEIGLLTCEA'.t'VNGHLYK'rNYT.,'.l'H..".Q.'i'NT.T. .T.DWLSPSHGIELSVGEK
`
`LVLNCTl'.R'l'ELNVGIDFm'iEYPSSKHQHKKLvtmDLK'l'QSGS.F.:.MKKFLSTL'rIDCNTRSDQCLYTCl>.ASSG
`
`LN'l'K!<NS'l'FVRVEEKPFVl>.FGSGMESLVEA'I·VGERVRLl?AKYLGYPPPEIKWYKtifGIPLESN"dTIK.<\.GH.VL
`
`TIMEVSERD't-GNYTVIL'l'NPISKEKQSl-:'VVSTNVYVPPGP(,DK'l'H'.l'C!.'LCPX,,PELLGGPSVFLI-'PPKPKDT
`
`LM1$R1~PE'IJ'l'CVVVDVSHEDPlWKFNWYVDGVEV!fN,\KTKPREEQY.NS'f·YRVVSVLTVLHQDw1.,NGKEYRC
`
`KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRPELTKNQVSLTCLVKGFYPSDI~.VE~-/ESNGQPENNYK
`
`A'!'PPVL.DS.DGSF'P L YSKL'.l'\IDKSP.~vQQGNVFSCSVMHEALHNllY'l'QKSLSLSP<.;K
`
`and, like VEOF-trap, can be present a.s a dimer. This fusion protcin and related molecules are
`further characterized i11 EPl 767546.
`
`20 Other non-antibody VEGF antagonists include antibody mimetks (e.g. Affibody® molecules,
`
`affilins, affi1ins, anticatins, avimers, Kunitz domain peptides, and monobodks) with VEOF
`
`antagonist activity. This includes recombinant binding proteins comprising an ankyrin repeat
`
`domain that