<j)MORNINGSIDE
`IP
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`Date: December 11, 2020
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`To whom it may concern:
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`This is to certify that the attached translation from German and into English is an accurate
`representation of the documents received by this office.
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`The document is designated as:
`International Application Number: PCT/EP97/02641
`•
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`Hannah Mendoza, Project Manager in this company, attests to the following:
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`“To the best of my knowledge, the aforementioned documents are a true, full and accurate translation
`of the specified documents.”
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`
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`_________________________________
`Signature of Hannah Mendoza
`
`
`
`
` The Leader in Global IP Solutions
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`www.morningsideIP.com
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` info@morningsideIP.com
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`CERT-05, 2019-Mar-21, V2
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`Novartis Exhibit 2054.001
`Regeneron v. Novartis, IPR2020-01317
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`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`PCT
`International Bureau
`PATENT COOPERATION TREATY (PCT) PUBLISHED INTERNATIONAL APPLICATION
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`(51) International patent classification6:
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`(11) International publication number:
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`WO 97/44068
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`A61L 2/04, 2/06, 2/12, 2/20, A61M 5/00
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`Al
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`(43) International
`Publication date:
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`November 27, 1997 (11/27/97)
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`(21) International application number:
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`PCT/EP97/02641
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`(22) International filing date:
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`May 23, 1997 (5/23/97)
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`(30) Priority dates:
`196 22 283.4
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`May 23, 1996 (5/23/96)
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`DE
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`(71) Applicant (for all designated states except US): SCHERING AG
`[DE/DE]; D-13342 Berlin (DE).
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`(72) Inventor(s); and
`(75) Inventor(s)/applicant(s) (US only): TACK, Johannes [DE/DE];
`Tharsanderweg 42, D-13595 Berlin (DE). SCHURREIT,
`Thomas [DF/DE); Matterhornstrasse 18, D-14163 Berlin (DE).
`ZÜRCHER, Jörg [DF/DE]; Bergstrasse 36, D-15711 Deutsch
`Wusterhausen (DE).
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`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DK, EE, ES, FI, GB, GE, HU, IL,
`IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD,
`SE, SG, SI, SK, TJ, TM, TR, TI, UA, UG, US, Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, DE, DK, ES, Fl, FR, GB, GR, IE, IT, LU,
`MC, NL, PT, SE).
`
`Published
`With international search report.
`Before the expiration of the period allowed for changes to the
`claims. Publication will be repeated in case of changes.
`
`(54) Title: METHOD OF TERMINALLY STERILIZING FILLED SYRINGES
`
`(57) Abstract
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`The invention concerns a method of producing a pre-filled sterile syringe. The syringe comprises a syringe body with a proximal end
`and a distal end, a syringe-outlet part at the distal end, a seal, a stopper, a fluid medium and a gaseous medium, the fluid medium being a
`liquid. The method comprises the following steps: preparing the syringe body, seal and stopper w hich is/are free from germs and/or
`endotoxins and low in particles; a lubricant is applied; the proximal end is sealed by inserting the stopper into the syringe body; the syringe
`is filled through the distal end; the syringe outlet part is sealed with the seal; the syringe is sterilized in a sterilizing chamber; the syringe is
`then packaged and the package container is then sterilized once again.
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`Novartis Exhibit 2054.002
`Regeneron v. Novartis, IPR2020-01317
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`Codes identifying PCT contracting states on the header sheets of the publications which publish international applications under the PCT.
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`FOR INFORMA T/ON ONLY
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`
`AL
`AM
`AT
`AU
`AZ,
`BA
`BB
`BE
`BF
`
`BG
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`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CJ
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`CM
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`CN
`Cu
`CZ
`DE
`
`DK
`EE
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`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia-Herzegovina
`Barbados
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`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
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`Switzerland
`Ivory Coast
`Cameroon
`China
`
`Cuba
`Czech Republic
`Germany
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`Denmark
`Estonia
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`ES
`Fl
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`FR
`GA
`GB
`
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`JS
`IT
`JP
`KE
`KG
`KP
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`
`KR
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`KZ
`LC
`LI
`LK
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`LR
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`Spain
`Finland
`France
`Gabon
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`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
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`Israel
`Island
`Italy
`Japan
`Kenia
`Kyrgyzstan
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`Democratic People's Republic
`Korea
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`Republic of Korea
`Kazakhstan
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`St. Lucia
`Liechtenstein
`Sri Lanka
`Liberia
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`LS
`LT
`LU
`LV
`MC
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`MD
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`MG
`MK
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`
`ML
`MN
`MR
`MW
`MX
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`NE
`NL
`NO
`NZ
`PL
`PT
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`RO
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`RU
`SD
`SE
`SG
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`
`Lesotho
`Lithuania
`Luxembourg
`M
`onaco
`Republic of
`Moldova
`Madagascar
`The former Yugoslavian
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`Republic of Macedonia
`Mali
`Mongolia
`Mauretania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Rumania
`Russian Federation
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`Sudan
`Sweden
`Singapore
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`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
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`Slovenia
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`Slovakia
`Senegal
`Swaziland
`Tchad
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`Togo
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`Tajikistan
`Turkmenistan
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`Turkey
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`Trinidad and Tobago
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`Ukraine
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`Uganda
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`United States of
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`America
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`uz
`Uzbekistan
`VN
`Vietnam
`YU
`Yugoslavia
`zw Zimbabwe
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`Novartis Exhibit 2054.003
`Regeneron v. Novartis, IPR2020-01317
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`WO 97/44068
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`1
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`PCT/EP97/02641
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`Method of terminally sterilizing filled syringes
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`The invention relates to a method of terminally sterilizing filled syringes. In particular, the focus is a
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`pyrogen-free and germ-free surface of the syringes. These syringes are preferably intended for the use of
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`injectable diagnostic agents, in particular contrast media, which are injected, for example, into blood
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`vessels, organs, organ parts, cavities and other vessels or have an imaging effect there.
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`Patent specification AT-E 68 979 describes a method of manufacturing a filled, terminally sterilized
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`syringe. The syringe is made of plastic. The syringe has a cylinder with a distal end having a syringe outlet
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`part. The syringe outlet part is closed by a seal. After the syringe is filled, it is closed with a flexible rubber
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`stopper that is slidable in the cylinder. The method begins by removing waste particles or other
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`contaminants from the seal and the plunger. Microbial contaminants on the seal and piston are destroyed.
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`The cylinder is washed with a variety of water jets to remove pyrogens and waste particles. Silicone oil is
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`then applied to the inner wall of the syringe. The seal is then attached to the syringe outlet part. The contrast
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`agent is filled into the syringe through the proximal end of the syringe. The syringe is then closed with the
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`stopper. This assembled and filled syringe is sterilized in an autoclave. In addition to the normal autoclave
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`pressure, an additional support pressure is generated in the autoclave. This makes the pressure on the outer
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`surface of the syringe equal to or greater than the pressure on the inner surface of the syringe.
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`From the publication by Venten and Heppert (E. VENTEN and J. HOPPERT (1978) Pharm. Ind. Vol. 40,
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`No. 6, pages 665 to 671), a terminal sterilization of pre-filled syringe ampoules is known. The syringe
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`ampoules, which have a stopper at the proximal end, are filled distally through the rolled rim. The rolled
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`rim is then sealed by a sealing disc, with a flange cap fixing the sealing disc to the rolled rim. (M. JUNGA
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`(1973) Pharm. Ind. Vol. 35, No. 11a, pages 824 to 829). The pre-filled syringe ampoules are then transferred
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`to an autoclave. This autoclave is adjustable with respect to temperature and pressure. To prevent the sealing
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`disc from loosening from the syringe ampoule, a support pressure is generated in the autoclave. The support
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`pressure is built up by an additional gas. This makes it possible to keep the pressure on the inside of the
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`sealing disc approximately equal to the pressure on the outside of the sealing disc. This also prevents
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`movement of the piston used. As a result of the good control, it is even possible to terminally sterilize dual
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`chamber syringe ampoules filled with two solutions without any unacceptable stopper movement or sealing
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`disc leakage.
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`Finnish patent application FI 93 0405 describes a method of terminally sterilizing a pre-filled plastic syringe
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`or glass syringe, the syringe containing a contrast agent. The syringe comprises a syringe cylinder with a
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`syringe outlet part at the distal end. In addition, syringe ampoules in the form previously described by
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`Novartis Exhibit 2054.004
`Regeneron v. Novartis, IPR2020-01317
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`

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`WO 97/44068
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`2
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`PCT/EP97/02641
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`Venten and Heppert are also listed. The syringes have an open proximal end, which can be closed by a
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`stopper which slides in the syringe. The stopper is connected to a plunger.
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`When the syringe or syringe ampoule is filled, the stopper is first inserted into the proximal end of the
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`syringe or syringe ampoule. Then the distal end is filled. The distal end is then sealed. In the case of syringe
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`ampoules, a sealing disc is fixed to the rolled rim with a flange cap. The syringes or syringe ampoules are
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`then sterilized, using a support pressure. This keeps the pressure on the outer surface of the syringe lower
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`than the pressure on the inner surface of the syringe or syringe ampoule. In the case of the syringe ampoules,
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`the pressure in the autoclave is equal to, greater than or less than the pressure in the syringe ampoule.
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`WO 95/12418 describes a terminal sterilization method for pre-filled syringes in which no autoclave is
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`used, but only a pressure-resistant sterilization chamber is used. The distally or proximally filled syringe is
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`placed in this sterilization chamber. The chamber is heated by means of heating gas. At the same time, this
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`heating gas also provides a pressure which is to compensate for the pressure increase in the syringe. In
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`order to prevent evaporation of liquid penetrating through the plastic, water vapor is introduced in addition
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`to the heating gas. It is described in the property right that the same safety is to be achieved as with
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`autoclaving.
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`WO 95/12482 describes a method for the production of pre-filled plastic syringes filled with a contrast
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`agent. The syringes are comprised of a cylinder, a syringe outlet part at the distal end, which is prepared
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`for a cannula attachment. Further, the syringe includes a stopper that can slide in the cylinder. It seals the
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`proximal end of the syringe. The syringe has been manufactured based on a method that results in pyrogen-
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`free objects. Likewise, no particles are present. The syringe is filled through the proximal end, and the
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`syringe outlet part is sealed with a stopper. The filled syringe is closed with the stopper. The particle status
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`of the spatialities corresponds to the conditions of class 100.
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`After the syringe parts come out of the mold, they are blown off with gas to remove particles. The syringe
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`is then washed. The syringe is then sterilized so that it can be further processed, stored or transported, as
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`desired.
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`The task is to offer a syringe which is pre-filled with a medium, whereby the medium is permanently present
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`in the syringe without any loss of quality. Particularly high demands are to be placed on safety with regard
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`to sterility and the absence of particles inside and outside the syringe.
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`The task is solved by a manufacturing method of a pre-filled, sterile syringe made of glass or plastic or a
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`mixture of glass and plastic, further a glass syringe with a plastic foil connected thereto and a plastic syringe
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`with a glass coating connected thereto, the syringe comprising
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`a cylindrical syringe body with a closable proximal end and a closable distal end,
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`Novartis Exhibit 2054.005
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 97/44068
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`3
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`PCT/EP97/02641
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`a syringe outlet part at the distal end,
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`a closure sealing the syringe outlet part,
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`a stopper slidable in the syringe body,
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`the stopper being movable by a plunger,
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`and
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`a fluid and a gaseous medium,
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`the fluid medium being a liquid, a solution, a suspension or an emulsion,
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`the method comprising the steps of:
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`- Providing the syringe cylinder which is freed from germs, pyrogens and/or endotoxins and is low
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`in particles,
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`- Providing the closure which is freed from germs, pyrogens and/or endotoxins and is low in
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`particles,
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`- Providing the stopper which is freed from germs, pyrogens and/or endotoxins, as well as low in
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`particles,
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`- Applying a lubricant,
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`- Sealing the proximal end by inserting the stopper into the syringe body and filling the syringe
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`through the distal end, and closing the syringe outlet part with the seal or welding the syringe outlet part,
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`or alternatively,
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`Sealing the distal end with the seal or welding the syringe outlet part and filling the syringe through the
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`proximal end and sealing the proximal end by inserting the stopper into the syringe body,
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`- Thermal sterilization in a sterilization chamber, in particular an autoclave or sterilizer, with steam,
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`hot air and/or microwave,
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`-
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`if necessary, build-up of a support pressure by a gas in the sterilization chamber, the pressure on
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`the outer surface of the syringe being equal to, greater than or less than the pressure on the inner surface of
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`the syringe,
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`- Packing the sterilized syringe in a container, in particular a secondary packaging means, and
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`- Sterilizing the packaged syringe with a substance that permeates at least portions of the container,
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`in particular the secondary packaging means.
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`The term syringe includes the terms cartridge (large volume syringe with at least 100 ml volume), ampoule
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`syringes, disposable syringes, disposable syringe ampoules, disposable syringes, injection ampoules,
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`syringe ampoules, ready-to-inject ampoule, cylinder ampoule, dual chamber syringe ampoule, dual
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`chamber syringe ampoule, dual chamber disposable syringe and instantaneous syringe.
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`Glass syringes and plastic syringes are described in detail in the publication by Junga (M. JUNGA (1973)
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`Novartis Exhibit 2054.006
`Regeneron v. Novartis, IPR2020-01317
`
`

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`WO 97/44068
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`4
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`PCT/EP97/02641
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`
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`Pharm. Ind. Vol. 35, No. 11a, pages 824 to 829). A mixture of glass and plastic is presented in WO 96/00098
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`(filing date June 23, 1995).
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`Plastics are described in detail in Römpp Chemistry Encyclopedia, publishers Jürgen FALBE and Manfred
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`REGITZ, 9th edition, Stuttgart, 1990 on pages 2398 ff. Preferred are COC, PP and polymethyl pentene.
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`[COG = cycloolefin copolymer with the brand names CZ (manufacturer: Nihon Zeon) and TOPAS
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`(manufacturer: Mitsui Chemicals and Hoechst)]. These plastics are particularly suitable for use with pre-
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`filled, terminally sterilized syringes, because their high melting point (at least 130°C) permits steam
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`sterilization (standard procedure 121°C). In addition, the optical properties are sufficient for one hundred
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`percent visual inspection in accordance with the pharmacopoeia.
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`The terms proximal and distal are defined from the point of view of the treating physician. At the distal end
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`is the syringe outlet part, to which, for example, the cannula or a tube leading to a cannula is connected. At
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`the proximal end is the stopper, which pushes the medium through the distal end during application. The
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`movement of the stopper can be manual or mechanical. The term stopper also includes plunger. For manual
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`operation of the syringe, it is helpful to the operator if the syringe carries finger holders at the proximal end.
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`In this case, the finger holders usually have at least one surface as an abutment for the index finger and
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`middle finger, the surface of the finger holder being substantially perpendicular to the axis of the syringe
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`cylinder. Various models are known for mechanical pumping devices. A syringe then preferably carries
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`one or more device holders at the preferably proximal end. Such a mechanical pump is particularly well
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`described in EP 0 584 531 (Reilly et al. filing date July 21, 1993). Mixed forms of finger holder and device
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`holder are also possible.
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`The syringes are usually rotationally symmetrical, only the finger holders and device holders and sometimes
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`also the syringe outlet part deviate from the symmetry. Thus, the syringe outlet part can be arranged
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`eccentrically. The Luer lock is particularly preferred, since it is used exclusively for the application of
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`contrast media when mechanical pumping devices are used. Also in manual application, the Luer lock and
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`the associated tubing avoid unintended movements of the physician being directly transmitted to the
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`cannula. Furthermore, the simple Luer approach and also the record approach are known.
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`It is also possible to weld the syringe outlet part and thereby seal it. It is then advantageous for a syringe
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`outlet part to have a predetermined breaking point, which allows the syringe outlet part to be opened without
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`difficulty before use.
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`The proximal and distal ends of the syringe must be sealable. The distal end is sealed by a closure that is
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`attachable to the syringe outlet part. In this property right, the syringe outlet part comprises the cover of the
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`Novartis Exhibit 2054.007
`Regeneron v. Novartis, IPR2020-01317
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`

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`WO 97/44068
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`5
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`PCT/EP97/02641
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`
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`syringe cylinder. Further, the syringe outlet part comprises a tube leading to the needle or tube, an end part,
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`which is in contact with the needle or tube, and a threaded cylinder on the inside, the cylinder surrounding
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`the end part and carrying a thread for a Luer lock, for example. The syringe outlet part can be one-part or
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`multi-part. The cover can be curved, flat or pyramid-shaped. Mixed forms are also conceivable. The stopper
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`closes the proximal end of the syringe. It must be slidable in the cylinder and must safely retain the medium
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`from the environment. It should be as impermeable as possible to gases and fluids. It must also be able to
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`absorb temperature fluctuations without malfunctioning. Usually, the stopper is not provided with its own
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`plunger during the mechanical emptying of the syringes. Rather, a plunger that is part of the pumping device
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`engages a closure inside the stopper so that movement of the stopper is easily possible (cf. EP 0 584 531).
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`The medium in the filled syringe is a mixture of a fluid medium and at least one gas. The medium can be a
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`liquid, a solution, a suspension or an emulsion. These manifestations are described in W. SCHRÖTER et
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`al., (1987) Chemie; Fakten und Gesetze, 14th edition, Leipzig on pages 23 and following.
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`Preferred is a fluid medium which is a contrast agent.
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`These are the following contrast media with the
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`generic names: Amidotrizoic acid, gadopenteic acid, Gadobutrol, Gadolinium EOB-DTPA, iopamidol,
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`iopromide, iotrolan and iotroxic acid.
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` syringe must be cleaned from foreign bodies. Foreign bodies are all the particles that are not from the
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` A
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`material of the syringe and the medium and the detached fragments of the syringe.
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`Pyrogens are substances which, as fragments of bacteria, provoke an immune response in humans. In
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`particular, they are lipopoly saccharides.
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`Sterile and pure production processes are described in DAB 1996 or Ph.Eur.
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`Publications on sterilization and microbial count reduction are listed in the following references:
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`K.H. WALLHÄUSSER (1990) The microbial purity of drug raw materials and drugs, Pharma Technology,
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`Vol. 11, No. 4, pages 2 - 9;
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`H. SEYFARTH (1990) Critical comments on the hygiene requirements of the EC Guide to Good
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`Manufacturing Practice for Medicinal Products, Pharma Technology, Vol. 11, No. 4, pages 10 - 19;
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`W. Hecker and R. MEIER (1990) Determination of the airborne bacterial count in the production area with
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`newer devices, Pharma Technology, Vol. 11, No. 4, pages 20 - 28;
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`G. SPICHER (1990) Possibilities and limitations of sterilization with gases and ionizing radiation in
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`comparison with classical sterilization methods, Pharma Technology, Vol. 11, No. 4, pages 50 - 56;
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`
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`Treatment with ethylene oxide, propane-3-olide and diethyl dicarbonate, furthermore hydrogen peroxide
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`Novartis Exhibit 2054.008
`Regeneron v. Novartis, IPR2020-01317
`
`

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`WO 97/44068
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`6
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`PCT/EP97/02641
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`
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`and an ozone/steam mixture are known as chemical sterilization methods. Such methods are described in:
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`G. SPICHER (1990) Possibilities and limitations of sterilization with gases and ionizing radiation in
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`comparison with the classical sterilization methods, Pharma Technology, Vol. 11, No 4, pages 50 - 56;
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`H. HÖRATH (1990) Legal framework of sterilization with ethylene oxide and formaldehyde, Pharma
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`Technology, Vol. 11, No 4, pages 57 – 64;
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`J. SCHUSTER (1990) The practice of operational ethylene oxide sterilization and attempts to optimize it,
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`Pharma Technology, Vol. 11, No 4, pages 65 – 71;
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`M. MARCZINOWSKI (1990) Practical
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`implementation of formaldehyde sterilization, Pharma
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`Technology, Vol. 11, No. 4, pages 72 – 76;
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`The method using hydrogen peroxide is particularly preferred.
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`
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`Sterilization with high-energy radiation is also possible. Gamma rays and X-rays are known here. Neutron
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`beams, beta beams and alpha beams are also used.
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`Lubricants are used to ensure that the stopper can be moved within the cylinder without great force. Silicone
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`oil is preferred, which has the following properties: viscosity at least 1,000 cSt; quality: medical grade.
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`After the syringe has been partially assembled, it may be possible to clean the syringe again from foreign
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`bodies. Foreign bodies are all the particles that are not composed of the material of the syringe and the
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`medium and are loose fragments of the syringe.
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`The most suitable sterilization methods are: Radiation sterilization and chemical sterilization methods,
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`respectively.
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`
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`Known chemical sterilization methods include treatment with ethylene oxide, propane 3-olide and diethyl
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`dicarbonate, as well as hydrogen peroxide and an ozone/steam mixture.
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`
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`Sterilization with high-energy radiation is also possible. Here gamma rays and X-rays are known.
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`If necessary, the parts of the syringe are sterile-wrapped in bacteria-proof but gas-permeable foil or
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`aluminum. Sterilization is carried out by means of thermal and/or chemical sterilization, with gamma rays
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`or X-rays, neutron rays or beta rays or a mixture of the previously mentioned rays. Preferred treatment is
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`with hydrogen peroxide or ozone/steam mixture.
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`
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`The syringe body is then filled through the distal or proximal end, with either the stopper or closure sealing
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`the opposite end. Subsequently, the filling orifice is closed by the closure or the stopper.
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`Novartis Exhibit 2054.009
`Regeneron v. Novartis, IPR2020-01317
`
`

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`WO 97/44068
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`7
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`PCT/EP97/02641
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`The distal end is closed with a closure or by welding the distal end. When welding, the distal end has a
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`predetermined breaking point proximal to the weld. This allows the distal end to be easily opened after
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`welding.
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`In the next step, the syringe or cartridge is thermally sterilized in an autoclave or sterilizer using hot air or
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`a microwave.
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`To prevent the stopper from migrating inside the cylinder, it is advantageous if the stopper is fixed during
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`sterilization.
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`If necessary, it is possible to build up a support pressure in the sterilization chamber of the autoclave or
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`sterile chamber by means of a gas in the sterilization chamber, the pressure on the outer surface of the
`
`syringe being greater than, equal to or less than the pressure on the inner surface of the syringe. The support
`
`pressure is to be defined as the pressure which is equal to the sum of the partial pressures in the sterilization
`
`chamber minus the partial pressure of the steam.
`
`
`
`It is advantageous if the stopper is readjusted after sterilization. This ensures that the stopper is in an
`
`optimum position. Sometimes the friction between the stopper and the cylinder is so great that the stopper
`
`does not automatically adjust to the stable position in which there is no pressure difference between the
`
`inside and outside of the syringe.
`
`
`
`At this point, visual inspection is advantageous. This ensures that particles present in the syringe are
`
`detected. Syringes with particles must be discarded.
`
`
`
`It is particularly essential to pack the sterilized syringe in a container and sterilize the filled container. This
`
`process can be performed in a sterile room. This step is particularly advantageous because it alone provides
`
`a guarantee of offering the attending physician a syringe that is also externally sterile. This can reduce the
`
`risk of contamination. This advantage also applies to syringes that are to be emptied mechanically, since
`
`the physician also touches the syringe in this case. Mechanical syringes are often used in sterile operating
`
`rooms. Only sterile or disinfected materials may be introduced into these rooms. This means that the syringe
`
`to be emptied mechanically must also be sterile on the outside.
`
`
`
`It is further advantageous that the filled and terminally filled syringe is wrapped in sterile plastic foil and /
`
`or aluminum foil under aseptic conditions, if necessary. Advantageously, the syringe is packed in possibly
`
`sterile blisters, with aseptic conditions prevailing, if necessary.
`
`Subsequently, the syringe, which is in the container, is externally sterilized again by treating the syringe
`
`with ethylene oxide, propane-3-olide and/or diethyl dicarbonate. Furthermore, hydrogen peroxide and an
`
`Novartis Exhibit 2054.010
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 97/44068
`
`8
`
`PCT/EP97/02641
`
`
`
`ozone/vapor mixture are known.
`
` preferred embodiment is further shown by way of example.
`
` A
`
`A syringe according to the invention is shown in Fig. 1 as a perspective drawing.
`
`In Fig. 2, a sectional drawing of the syringe is shown.
`
`In Fig. 3, a flow chart can be seen depicting the process of manufacturing, sterilization, filling and terminal
`
`sterilization.
`
`
`
`Figures 1 and 2 show a plastic syringe 100 comprising a syringe body 1 with a syringe cylinder 2. The
`
`syringe 100 has a proximal end 3, which is closed by a stopper 4. The stopper has a pyramid-shaped distal
`
`stopper portion 5 and a cylindrical-shaped proximal stopper portion 6, which sealingly contacts the inner
`
`wall of the syringe cylinder 2. Contact between the proximal stopper part 6 and the inner wall of the cylinder
`
`is made via a plurality of rubber beads 7.
`
`At the proximal end, device holders 8 are arranged on the outer wall of the syringe cylinder, consisting of
`
`a device holder ring 9 and two device holder projections 10 and 10'. The device holders 8 are used to clamp
`
`the syringe into a mechanical pumping device.
`
`At the distal end 11 of the syringe is a pyramid-shaped syringe outlet piece 12, which includes a tube 13
`
`and an end piece 14. The pyramid-shaped distal stopper portion 5 fits complementarily into the pyramid-
`
`shaped syringe outlet part 12. The tapered tube 13, which terminates in the end piece 14, is arranged
`
`centrally of the syringe outlet part 12. This end piece 14 is surrounded by a cylinder 15, which carries a
`
`thread 16 for a Luer lock on the inner side. The end piece 14 can be closed either by a syringe closure part
`
`in the form of a tip cap or by a syringe closure part with a Luer lock. The syringe closure part is not shown
`
`in the drawing.
`
` flow chart is shown in Fig. 3.
`
` A
`
`
`
`51414AWOM1XX00-P
`
`May 21, 1997
`
`
`
`
`
`Novartis Exhibit 2054.011
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 97/44068
`
`
`
`9
`
`Claims
`
`PCT/EP97/02641
`
`
`
`1.
`
`Method of producing a pre-filled sterile syringe made of glass or plastic or a mixture of glass and
`
`plastic, further a glass syringe with a plastic film connected thereto and a plastic syringe with a glass coating
`
`connected thereto,
`
`wherein the syringe comprises
`
`a cylindrical syringe body with a closable proximal end and a closable distal end,
`
`a syringe outlet part at the distal end,
`
`a seal sealing the syringe outlet piece,
`
`a stopper slidable in the syringe body,
`
`wherein the stopper is movable by a plunger,
`
`and
`
`a fluid and a gaseous medium,
`
`wherein the fluid medium is a liquid, a solution, a suspension or an emulsion,
`
`the method comprising the following steps:
`
`-
`
`Providing the syringe body which is freed from germs, pyrogens and/or endotoxins, as well as
`
`low in particles,
`
`-
`
`Providing the stopper which is freed from germs, pyrogens and/or endotoxins, as well as low in
`
`particles,
`
`-
`
`Providing the stopper which is freed from germs, pyrogens and/or endotoxins, as well as low in
`
`particles,
`
`- Applying a lubricant,
`
`- Sealing the proximal end by inserting the stopper into the syringe body and filling the syringe through the
`
`distal end and closing the syringe outlet part with the closure or welding the syringe outlet part,
`
`or alternatively
`
`Sealing the distal end with the closure or welding of the syringe outlet part and filling the syringe through
`
`the proximal end and sealing the proximal end by inserting the stopper into the syringe body,
`
`-
`
`-
`
`-
`
`
`
`2.
`
`Thermal sterilization in a sterilization chamber,
`
`Packaging the sterilized syringe in a container, and
`
`Sterilizing the packaged syringe with a substance that permeates at least portions of the container.
`
`Manufacturing method according to claim 1, wherein the sterilization chamber is an autoclave or
`
`sterilizer, with steam, hot air and/or microwave.
`
`
`
`3.
`
`Manufacturing method according to any one of the preceding claims, wherein a support pressure
`
`is established by a gas in the sterilization chamber, wherein the pressure on the outer surface of the syringe
`
`Novartis Exhibit 2054.012
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 97/44068
`
`10
`
`PCT/EP97/02641
`
`
`
`is equal to, greater than or less than the pressure on the inner surface of the syringe.
`
`
`
`4.
`
`Manufacturing method according to any one of the preceding claims, wherein the syringes
`
`comprise: Cartridges, ampoule syringes, disposable syringes, disposable syringe ampoules, disposable
`
`syringes, injection ampoules, ready-to-inject ampoules, cylinder ampoules, dual chamber syringe
`
`ampoules, dual chamber syringe ampoules, dual chamber disposable syringes, or instantaneous syringes.
`
`
`
`5.
`
`Manufacturing method according to any one of the preceding claims, wherein the plastic of the
`
`polyolefins is selected from the group consisting of COC, polymethyl pentene and PP.
`
`
`
`6.
`
`Manufacturing method according to any one of the preceding claims, wherein the syringe has a
`
`Luer lock at the distal end.
`
`
`
`7.
`
`Manufacturing method according to any one of the preceding claims, wherein the medium in the
`
`filled syringe is a mixture of a fluid medium and at least one gas.
`
`
`
`8.
`
`Manufacturing method according to claim 7, wherein the medium is a liquid, a solution, a
`
`suspension or an emulsion.
`
`
`
`9.
`
`Manufacturing method according to claim 8, wherein the medium is a contrast agent.
`
`
`
`10. Manufacturing method according to claim 9, wherein the contrast agent comprises a substance or
`
`a mixture selected from the group consisting of the following substances: Amidotrizoic acid, gadopenteic
`
`acid, Gadobutrol, Gadolinium EOB-DTPA, iopamidol, iopromide, iotrolan and iotroxic acid.
`
`
`
`11. Manufacturing process according to any one of the preceding claims, wherein the sterilization
`
`process with gas comprises treatment with ethylene oxide, propane-3-olide and diethyl dicarbonate, further
`
`hydrogen peroxide and an ozone/vapor mixture.
`
`
`
`12. Manufacturing method according to claim 11, wherein the treatment comprises hydrogen peroxide.
`
`
`
`13. Manufacturing method according to any one of the preceding claims, wherein the stopper is fixed
`
`during sterilization.
`
`
`
`14. Manufacturing method according to any one of the previous claims, wherein the stopper is
`
`readjusted after sterilization.
`
`Novartis Exhibit 2054.013
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 97/44068
`
`11
`
`PCT/EP97/02641
`
`
`
`
`
`15. Manufacturing method according to any one of the preceding claims, wherein the filled and
`
`terminally filled syringe is packaged in sterile plastic film and/or aluminum foil under optionally aseptic
`
`conditions.
`
`
`
`16. Manufacturing method according to claim 15, wherein the syringe placed in the container is
`
`externally re-sterilized again by treating the syringe with ethylene oxide, propane-3-olide, hydrogen
`
`peroxide, an ozone/vapor mixture and/or diethyl dicarbonate. Also known are.
`
`
`
`Novartis Exhibit 2054.014
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 97/44068
`
`
`
`PCT/EP97/02641
`
`
`
`
`
`
`
`
`1/3
`
`100
`~
`7
`
`l. --...
`
`'\1 ---
`
`\"'10'
`