Filed on behalf of: CSL Behring GmbH and CSL Behring LLC
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`CSL BEHRING GMBH and CSL BEHRING LLC,
`Petitioners,
`
`SHIRE VIROPHARMA INC.,
`Patent Owner.
`
`US. Patent No. 9,616,111
`
`
`
`DECLARATION OF DR. HUBERT METZNER
`
`CSL EXHIBIT 1014
`CSL v. Shire
`
`Page 1 of 25
`
`

`

`TABLE OF CONTENTS
`
`Page(s)
`
`INTRODUCTION & QUALIFICATIONS .................................................. .. 1
`
`THERE WERE NO SOLUBILITY, VISCOSITY, OR STABILITY
`LIMITATIONS EXPECTED OR FOUND WHEN F ORMULATING
`
`C 1 —INH .......................................................................................................... .. 2
`
`CONCLUSION ............................................................................................. .. 6
`
`Page 2 of 25
`
`

`

`INTRODUCTION & QUALIFICATIONS
`
`I am currently a Director of Process Development in Recombinant
`
`Product Development at CSL Behring GmbH (CSLB). In my role as a Director of
`
`Process Development,
`
`I
`
`am responsible for development of downstream
`
`manufacturing processes
`
`and development of
`
`formulations,
`
`freeze—drying
`
`processes and stability testing of recombinant development products.
`
`I received a Diploma degree in Chemistry and my Dr. rer. nat. degree
`
`(PhD equivalent) on a biochemical
`
`topic from the University of Karlsruhe,
`
`Germany. My curriculum Vitae and list of selected publications/abstracts is
`
`attached as Exhibit 1017.
`
`Prior to working at CSLB, I was employed by several of its legal
`
`predecessor companies (ZLB Behring, Aventis Behring, Centeon, Behringwerke)
`
`in Research and Development. During the time period with CSLB and its legal
`
`predecessor companies covering almost 30 years I was particularly involved in the
`
`process- and formulation/fi‘eeze-diying development of several plasma—derived or
`
`recombinant biotherapeutic products. Some of these were finally approved by the
`
`regulatory authorities and are now available commercially (Haemate® P / Humate®
`
`P with reduced reconstitution volume and Afstyla®). Part of the formulation and/or
`
`freeze-drying development work also resulted in corresponding patent applications
`
`(Factor XIII, F ibrinogen, C l -INH, recombinant Factor VIII).
`
`Page 3 of 25
`
`

`

`During my employment at CSLB, I assisted in the development of
`
`CSLB’S plasma—derived Cl-esterase inhibitor (“Cl-INH”) products, Berinert® and
`
`Berinert® is available for
`
`intravenous (“iv”) administration at a
`
`concentration of SOU/mL (Berinert 500) and 500U/mL (Berinert 1500, approved
`
`for instance in Europe), and CSL83O is developed for subcutaneous (“sc”
`
`administration at a concentration of SOOU/mL.1 My role in developing these
`
`products involved initial work to establish a concentrated formulation of Cl—INH.
`
`In particular, in the years from 2005 on I was heading a team of scientists and
`
`technicians that performed the necessary studies to evaluate the feasibility of a
`
`concentrated Cl—INH formulation. We were able to show in just a few experiments
`
`that Cl—INH could be concentrated at least 10-fold and that the regular excipient
`
`composition of Berinert 500 was also suitable for a 10-fold concentrated Cl-INH
`
`formulation.
`
`THERE WERE NO SOLUBILITY, VISCOSITY, OR STABILITY
`
`LIMITATIONS EXPECTED OR FOUND WHEN FORMULATING
`
`C 1—INH
`
`I have been asked to discuss whether I expected or observed any
`
`solubility, viscosity, or stability limitations in developing a high-concentration sc
`
`formulation of C l-INH.
`
`
`1 As used herein, the abbreviation “U/mL” refers to both U/mL and IU/mL.
`
`Page 4 of 25
`
`

`

`Cl-lNH is a medium-to—large protein (478 amino acids, MW of the
`
`amino acid portion is approximately 53 kDa) with an approximate apparent
`
`molecular weight of 1001<Da by SDS-PAGE. EX. 1028 [Over, p. 241], 3. Cl-INH
`
`is heavily glycosylated, with 6 N—linked carbohydrates and 14 potential 0-
`
`glycosylation sites, seven of which have been confirmed to be O—glycosylated. A
`
`total carbohydrate content of 33% by weight has been described. More recent
`
`literature even describes a total carbohydrate content of 45% of total mass. Ex.
`
`1042 [Harrison, p. 5001], 5; Ex. 1040 [Ghannam, p. 161], 7.
`
`I am not aware of any reports of a solubility threshold for Cl-INH as
`
`of March 2013. Based on the protein’s high level of glycosylation, I did not expect
`
`solubility to be a limiting factor for developing a so formulation of Cl-INH, since
`
`glycosylation was known to enhance protein solubility. Ex. 1045 [Lis, p. 13], 17;
`
`Ex. 1055 [Reuter, p. 400], 37; Ex. 1060 [Sola, p. 1231], 15; Ex. 1043 [Hossler, p.
`
`1 am also not aware of any reports prior to March 2013 of Cl—INH
`
`being particularly prone to aggregation.
`
`I expected Cl-lNH to be relatively stable,
`
`with no unusual tendency to unfold and aggregate.
`
`In particular, I expected C1—
`
`INH’s high glycosylation to reduce or prevent protein aggregation. Ex. 1058
`
`[Schellekens, p. 31], 8; Ex. 1060 [Sola 2009 p. 1237], 21.
`
`In fact, many of the
`
`manufacturing processes for producing Cl—INH that were known in March 2013
`
`Page 5 of 25
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`

`

`involved high—temperature steps, which indicated that Cl-INH is relatively stable
`
`and does not easily denature and aggregate when thermally stressed for shorter
`
`periods. Ex. 1028 [Over, Table 17.1], 7—8.
`
`I was also not aware of any viscosity limitations for Cl-INH as of
`
`March 2013. Based on the reported globular protein structure for Cl-INH’s serpin
`
`domain, I expected that Cl-INH would exhibit a concentration—viscosity profile
`
`similar to other globular proteins. In my experience, such globular proteins exhibit
`
`relatively low viscosities even at relatively high protein concentrations. EX. 1049
`
`[Monkos 1994]; Ex. 1050 [Monkos 1996]; Ex. 1067 [Yadav]; Ex. 1051 [Monkos
`
`1997]; Ex. 1052 [Monkos 2000]. For example, BSA, which is also a medium—to-
`
`large protein but does not contain significant solubility enhancing glycosylation,
`
`exhibits viscosities of around ScPs at concentrations of 200mg/mL. Ex. 1067
`
`[Yadav, p. 1979, Fig. 5], 11.
`
`In summary, Cl—INH does not have characteristics that posed unique
`
`challenges to developing a high—concentration sc formulation. There are no known
`
`solubility, viscosity, or stability limitations associated with C1—INH. Nor was
`
`there a long-held consensus prior to March 2013 that it would not be feasible to
`
`develop a high—concentration—small—volume sc formulation of Cl-lNH.
`
`In fact, in
`
`our own work we expected development of a high—concentration—smal1-volume
`
`Page 6 of 25
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`

`

`formulation of Cl—INH to be quite routine, and that was precisely what we
`
`experienced.
`
`In the mid 20003, a colleague and I evaluated the feasibility of a 10-
`
`fold concentrated preparation of Berinert® P (i.e., 500U/mL). We investigated
`
`freeze-dried 10—fold and 5—fold concentrated Cl-INH formulations (filling volumes
`
`of l and 2 mL, respectively) that were reconstituted in 1 mL of water for injection
`
`(WfI) to both result in Cl—INH concentrations of approximately 500U/mL. The
`
`report contained in Appendix A reveals that we encountered no difficulties in
`
`achieving such a 10—fold concentrated version of Berinert® P.
`
`In particular using
`
`the excipient composition of regular Berinert® P 500, we obtained a concentrated
`
`Cl—INH product resulting after reconstitution in a colorless and clear solution with
`
`no enhanced aggregate formation.
`
`[Appendix A, p. 2.]
`
`Stability of the
`
`concentrated,
`
`freeze—dried product was also very good as evidenced by the
`
`analytical size exclusion chromatography (SEC-HPLC) and poly—acrylamide gel
`
`electrophoresis (PAGE) data. In particular, freeze-dried Cl-INH exhibited no
`
`obvious tendency to aggregate, except when stored under stress conditions (40°C).
`
`[Appendix A, p. 2 and figures 1 to 3.] And even under those stress conditions, the
`
`extent of aggregation did not cause concern or require fithher modifications of the
`
`preparation when stored for a limited period of time as the product inhibitory
`
`potency was essentially constant. Appendix A does not contain Viscosity data for
`
`Page 7 of 25
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`

`

`the lO—fold concentrated preparation because we did not observe any appreciable
`
`increase in viscosity. Thus, the study confirmed that Cl—INH is a well—behaved
`
`protein that would be amenable to formulation at higher concentrations for
`
`subcutaneous administration.
`
`[Appendix A, Conclusions]
`
`Based on the successful results obtained from the feasibility studies,
`
`we proceeded to develop the CSL830 product.
`
`Because CSL830, once
`
`reconstituted, has the same concentration (SOOU/mL) and formulation as the 10—
`
`fold concentrated preparation of Berineit® P that was tested in the feasibility study,
`
`all that remained was to examine the safety and efficacy of its subcutaneous
`
`administration in clinical trials. Those studies have been conducted, and CSL
`
`expects FDA approval of CSL83O later this year.
`
`III. CONCLUSION
`
`I declare that all statements made herein of my own knowledge are
`
`true and the statements made herein on information and belief are believed to be
`
`I further declare that all statements made herein were made with the
`
`knowledge that willful false statements and the like are punishable by fine or
`
`imprisonment or both pursuant to 18 U.S.C. § 1001.
`
`In signing this declaration, I understand that the declaration will be
`
`filed as evidence in a contested case before the Patent Trial and Appeal Board of
`
`Page 8 of 25
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`

`

`the United States Patent and Trademark Office.
`
`I acknowledge that I may be
`
`subject to cross examination in the case and that cross examination will take place
`
`Within the United States. If cross examination is required of me, I will appear for
`
`cross examination within the United States during the time allotted for cross
`
`examination.
`
`Dated: May 24, 2017
`
`By; &’
`
`Page 9 of 25
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`

`

`
`
`Appendix A
`Appendix A
`
`Page 10 of 25
`
`Page 10 of 25
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`

`

`Von/From:
`Ernst-Jürgen Kanzy / Hubert Metzner
`RES & LCM
`Tel.: +49 (0)6421 39 2856 / 39 4417
`Fax: +49 (0)6421 39 4663
`
`
`
`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`
`Memo
`
`An/To:
`B. Vohwinkel
`S. Schulte
`G. Seemann
`
`
`
`March 30, 2006
`
`
`
`Berinert P 10-fold concentrated (500 U/mL)
`Feasibility / Stability
`
`
`
`In July 2005 research studies were started evaluating the feasibility of a 10-fold
`concentrated preparation of Berinert P (C1-esterase Inhibitor, C1-Inh), called Berinert P
`10-fold in the following. Such a concentrated preparation was considered a
`prerequisite for development of a subcutaneous, prophylactic home treatment of C1-
`Inh deficient patients. Two studies were performed so far and are summarized in this
`Memo covering altogether eight different formulations (Exp. no.: B-050706SB,
`B-050718SB, B-051209AK).
`
`Materials and Methods
`Different formulations were prepared based on the lyophilisate of a regular Berinert P
`batch (Lot NF3 62111) which was dissolved, concentrated 10-fold by ultrafiltration in a
`stirred UF-cell and transferred into various formulations (table 1) by conventional
`dialysis. 1 mL-fillings of concentrated C1-Inh solutions formulated as indicated in
`table 1 as well as 2-mL-fillings of semi-concentrated solutions (diluted 1:2 with WFI)
`were freeze-dried according to SOP 560498-02: recipe P5-02 (Berinert P program) in a
`controlled lab-scale freeze-drier. For reconstitution of the lyophilisates 1 mL of WFI
`was used for each filling size to obtain the 10-fold concentrated product.
`Analysis of reconstituted samples as well as of stability samples was performed using
`C1-Inhibitor activity measurement and polymer/oligomer determination by size
`exclusion chromatography (SEC) and native polyacrylamide gel electrophoresis (PAGE).
`
`
`Page 11 of 25
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`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 2
`
`Results
`Freeze-dried product cakes of the 1mL-fill sizes were more compact in comparison to
`those of the 2mL-fill sizes but on the other hand were more prone to cracking. The
`residual moisture of the preparations was in the range of 0.2% to 0.7%, what is very
`low in comparison to regular Berinert P (1.84%, mean value of 35 lots).
`Depending on the formulation, the dissolution times were in the range of 3 to 8
`minutes and always resulted in colorless and clear solutions.
`SEC-HPLC as well as native PAGE of the reconstituted samples did not show any
`enhanced aggregate formation of the C1-Inhibitor due to the concentration or freeze-
`drying process, respectively. But certain formulations (2, 4, 6, and 7) showed a
`tendency for the formation of bands with higher electrophoretic mobility.
`In general, it can be concluded that a 10-fold concentration and subsequent freeze-
`drying of C1-Inhibitor is technically feasible.
`
`Freeze-dried samples of formulations 1-8 were subjected to preliminary stability
`testing by storage of vials at 2°C to 8°C as well as at 40°C for up to 6 months
`(Exp: no.: B-050706SB, B-050718SB).
`After 6 months of storage at 2°C to 8°C no difference was detectable compared to
`samples at the beginning of storage regarding the inhibitor activity and regarding the
`polymer/oligomer content determined by SEC-HPLC and PAGE, respectively.
`However, depending on the formulation different degrees of polymer/oligomer
`formation were detected by SEC-HPLC in samples stored at 40°C (figure 1). In
`addition, the formation of higher molecular weight bands was also observed by PAGE
`(figure 2). The results suggest that higher concentrations of NaCl, the presence of
`sucrose or an appropriate combination of both are favorable with regard to
`polymer/oligomer formation but that polymer/oligomer formation under accelerated
`conditions cannot be avoided completely.
`No significant loss of activity could be determined upon concurrent testing of the
`frozen (<-70°C) stability samples stored for 0, 1, 3, and 6 months at 40°C (figure 3).
`Due to some inter-assay variability of the C1-Inh assay, results of samples tested on
`time could not be evaluated. As a result of the accelerated storage experiment it can
`be concluded that polymer formation up to the levels detected in these samples do
`not necessarily cause a measurable loss of activity in parallel.
`
` A
`
` comparative study of freeze-dried iso-osmotic formulation #8* (NaCl-concentration
`adapted to 4.0 g/L) and regular Berinert P (Exp. no.: B-051209AK) showed increased
`
`
`
`Page 12 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 3
`
`formation of polymers/oligomers (SEC-HPLC and PAGE) after 3 months at 40°C in the
`concentrated formulation (figure 4 and 5). Whether this increased formation of
`polymers/oligomers is due to the higher protein concentration and whether these are
`also formed in long-term stability studies at 2-8°C storage temperature will have to be
`evaluated in additional experiments.
`
`Iso-osmotic formulation #8* also was stored as a liquid preparation at 2-8°C, 25°C
`and 35°C for stability testing. After 3 months storage at 35°C an increased
`polymer/oligomer formation (figure 6 and 7) accompanied with a significant loss
`(~70%) of C1-Inh activity (figure 8) was detected. Therefore, it is assumed that
`significant efforts and real time storage data would be needed for the development of
`an appropriate liquid formulation.
`
`Comparative pharmacokinetic studies in rabbits using 10-fold concentrated samples of
`freeze-dried formulation #1 and #8* and regular Berinert P were performed by
`PDS/Pharmacology and Toxicology.
`The results of the first study with formulation #1 and Berinert P as a control (Study
`no.: PSK 06/05) showed that the courses of the plasma levels versus time were very
`similar (figure 9). It was concluded that the 10-fold concentrated formulation and the
`regular Berinert P are equally well resorbed from the subcutaneous space.
`The data of the second study (Exp. no. PSK 12/06, formulation #8* versus Berinert P)
`were statistically analyzed. Both products were absorbed at equal rates from the
`subcutaneous space (figure 10). The extent of absorption was slightly lower for the
`new formulation #8*: The average dose-adjusted AUC of Berinert® P 10-fold was
`about 15 % lower than the AUC of the standard formulation. However, this
`difference of absorption was not statistically significant (p-value of 0.33) and just may
`represent the regular variance of the model. It is therefore concluded that the
`bioavailability of the 10-fold concentrated product does not differ from present
`Berinert® P.
`
`Conclusions
`The results of the study demonstrate that 10-fold concentrated formulations of
`Berinert P of 500 U/mL after reconstitution can be prepared and that reasonably well
`soluble products are obtained. Due to the better appearance of the lyophilisate the 2
`mL filling size is currently preferred. Stability of different freeze-dried formulations up
`to 6 months under accelerated conditions with regard to C1-inhibitor activity could be
`
`
`
`Page 13 of 25
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`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 4
`
`demonstrated. However, a certain increase of the polymer/oligomer content was
`obtained for the concentrated formulations. Whether such polymers/oligomers will
`also be formed at 2-8°C upon long-term storage is not yet known.
`
`Comparative studies on pharmacokinetics after subcutaneous application showed a
`regular Berinert® P and 10-fold concentrated
`comparable bioavailability of
`formulations.
`
`
`
`Ernst-Jürgen Kanzy / Hubert Metzner
`
`
`
`Page 14 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`
`
`Table 1: Formulations of 10-fold concentrated Berinert P
`
`Formulation
`
`1
`(regular formulation)
`8.5
`10.0
`3.5
`
`
`
`7.0
`470
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`8*
`
`
`8.5
`
`10.0
`10.0
`10.0
`3.5
`
`3.5
`
`10
`
`2.1
`
`
`
`
`
`7.0
`7.0
`7.0
`170
`485
`180
`B-050706SB
`
`3.0
`10.0
`3.5
`
`
`10.0
`7.0
`310
`
`
`
`
`10
`2.1
`50.0
`7.0
`230
`
`
`
`3.5
`
`2.1
`50.0
`7.0
`220
`
`4.0
`3.0
`10.0
`10.0
`3.5
`3.5
`
`
`
`
`
`
`7.0
`7.0
`300
`280
`B-050718SB B-051209AK
`
`
`
`
`
`
`
`
`
`
`
`
`
`g/L
`NaCl
`
`g/L
`Glycine
`
`g/L
`Na3citrate x 2H2O
`
`g/L
`Histidine
`
`g/L
`Arginine x HCl
`
`g/L
`Sucrose
`
`
`pH
`Calculated osmolality mOsmol/L
`Study no.
`
`
`
`
`
`Page 15 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 6
`
`Figure 1:
`
`Accelerated stability study of Berinert P 10-fold, formulations #1 to #8, 2mL-fill sizes;
`content of polymers/oligomers after storage at 40°C determined by SEC-HPLC
`
`Berinert P s.c.
`OpNo. B-050706HL + B-050718SB
`2mL / Stability at 40°C
`SEC HPLC TSK 3000 SWXL - Oligomers + HMW -
`
`1 2 3 4 5 6 7 8
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`t (months)
`
`8,0
`
`7,0
`
`6,0
`
`5,0
`
`4,0
`
`3,0
`
`2,0
`
`1,0
`
`0,0
`
`HMW + Oligomers (%)
`
`
`
`
`
`Page 16 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 7
`
`Figure 2:
`
`Accelerated stability study of Berinert P 10-fold, formulations #1 to #8, 2mL-fill sizes;
`protein band patterns (PAGE) after storage for 6 months at 40°C.
`
`
`
`
`
`Formulation
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
` 1mL / 2mL
`
` 5 / 40 5 / 40 °C
`
`
`
` 2mL
`
` 5 / 40 °C
`
`Page 17 of 25
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`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Accelerated stability study of Berinert P 10-fold, formulations #1 to #8, 2mL-fill sizes;
`C1-Inhibitor activity after storage at 40°C (concurrent analysis of frozen samples at the end of the 6 months storage period).
`
`Berinert P s.c.
`OpNo. B-050706HL + B-050718SB
`2mL / Stability at 40°C
`Activity -C1-esterase inhibition-
`
`1 2 3 4 5 6 7 8
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`t (months)
`
`160
`
`140
`
`120
`
`100
`
`Activity (%)
`
`80
`
`60
`
`0
`
`Page: 8
`
`Figure 3:
`
`
`
`
`
`
`
`Page 18 of 25
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`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Comparative stability study of Berinert P 10-fold (formulation #8*) and regular Berinert P;
`content of polymers/oligomers after storage at 40°C determined by SEC-HPLC
`
`Berinert P s.c.
`Formulation 8* / Regular Formulation
`Stability OpNo. B-051209AK
`SEC HPLC TSK 3000 SWXL - HMW + Oligomers -
`
`8*
`Regular
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`t (months)
`
`Page: 9
`
`Figure 4:
`
`8,0
`
`7,0
`
`6,0
`
`5,0
`
`4,0
`
`3,0
`
`2,0
`
`1,0
`
`0,0
`
`HMW + Oligomers (%)
`
`
`
`
`
`Page 19 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Comparative stability study of Berinert P 10-fold (formulation #8*) and regular Berinert P;
`protein band patterns (PAGE) after storage for 3 months at 40°C.
`
`Page: 10
`
`Figure 5:
`
`
`
`
`
`Page 20 of 25
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`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Accelerated stability study of liquid Berinert P 10-fold (formulation #8*);
`content of polymers/oligomers after storage at 2-8°C, 25°C and 35°C determined by SEC-HPLC
`
`Berinert P s.c. 500 IU/mL
`OpNo. B-051205AK-01
`Liquid / Stability
`SEC HPLC TSK 3000 SWXL - HMW + Oligomers -
`
`2-8
`25
`35
`
`50
`
`40
`
`30
`
`20
`
`10
`
`HMW + Oligomers (%)
`
`Page: 11
`
`Figure 6:
`
`0
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`t (months)
`
`18
`
`21
`
`24
`
`27
`
`
`
`
`
`Page 21 of 25
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`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 12
`
`Figure 7:
`
`Accelerated stability study of liquid Berinert P 10-fold (formulation #8*);
`protein band patterns (PAGE) after storage for 3 months at 2-8°C, 25°C and 35°C
`
`
`
`
`
`Page 22 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Accelerated stability study of liquid Berinert P 10-fold (formulation #8*);
`C1-Inhibitor activity after storage at 2-8°C, 25°C and 35°C (activity related to corresponding control samples of Berinert P).
`
`Berinert P s.c. 500 IU/mL
`OpNo. B-051205AK-01
`Liquid / Stability
`Activity (%)
`
`2-8
`25
`35
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`27
`
`t (months)
`
`110
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Activity (%)
`
`Page: 13
`
`Figure 8:
`
`
`
`
`
`Page 23 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 14
`
`Figure 9:
`
`Study on the pharmacokinetics of Berinert P and Berinert P 10-fold (formulation #1);
`C1-Inhibitor plasma levels (% of baseline)
`
`Group I: Berinert P 200 U/kg s.c.
`
`Group II: Berinert P ten fold 200 U/kg s.c.
`
`0
`
`20
`
`40
`
`60
`
`100
`80
`Hours
`
`120
`
`140
`
`160
`
`180
`
`400
`350
`300
`250
`200
`150
`100
`50
`0
`
`% of Baseline (C1 INH )
`
`
`
`
`
`Page 24 of 25
`
`

`

`ZLB Behring GmbH
`P.O. Box 1230
`D 35002 Marburg
`www.zlbbehring.com
`
`
`Page: 15
`
`Figure 10:
`
`Study on the pharmacokinetics of Berinert P and Berinert P 10-fold (formulation #8*);
`C1-Inhibitor plasma levels (% of norm), dose adjusted
`
`Group I: Berinert P 200 U/kg s.c.
`
`Group II: Berinert P ten fold 200 U/kg s.c.
`
`0
`
`20
`
`40
`
`60
`
`100
`80
`Hours
`
`120
`
`140
`
`160
`
`180
`
`
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`C1 INH (% SHP)
`
`
`
`
`
`Page 25 of 25
`
`