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. 10,080,788
`Case No. IPR2019-00459
`
`DECLARATION OF DR. HUBERT METZNER
`
`Page 1 of 17
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`CSL EXHIBIT 1014
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`Page 1 of 17
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`CSL EXHIBIT 1014
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`

`

`TABLE OF CONTENTS
`
`Page(s)
`
`1.
`
`II.
`
`INTRODUCTION & QUALIFICATIONS .................................................. 1
`
`THERE WERE NO SOLUBILITY, VISCOSITY, OR STABILITY
`LIMITATIONS EXPECTED OR FOUND WHEN FORMULATING
`Cl-INH ........................................................................................................ 2
`
`III.
`
`CONCLUSION ..................................... . ...................................................... 7
`
`Page 2 of 17
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`Page 2 of 17
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`

`

`I.
`
`INTRODUCTION & QUALIFICATIONS
`
`1._
`
`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.
`
`2.
`
`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
`
`Appendix B.
`
`I have also considered the materials listed in Appendix A.
`
`3.
`
`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 about 30 years I was particularly involved in the
`
`process- and formulation/freeze—drying development of several plasma-derived or
`
`recombinant biotherapeutic products. Some of these were finally approved by the
`
`regulatory authorities and are now available commercially (e.g. 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, Fibrinogen, Cl -INH, recombinant Factor VIII).
`
`Page 3 of 17
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`Page 3 of 17
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`

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`4.
`
`During my employment at CSLB and its legal predecessor companies,
`
`I assisted in the development of CSLB’s plasma-derived Cl-esterase inhibitor (“C1 -
`
`INH”) products, Berinert® and CSL830. Berinert® is available for intravenous (“iv”)
`
`administration at a concentration of SOU/mL (Berinert 500) and of 500U/mL
`
`(Berinert 1500, approved for instance in Europe). CSL830 (Haegarda®) was
`
`developed for subcutaneous (“sc”) administration at a concentration of SOOU/rnL.l
`
`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 3 team of scientists and technicians that performed the necessary studies to
`
`evaluate the feasibility of a concentrated C1 —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 C 1 -INH formulation.
`
`II.
`
`THERE WERE NO SOLUBILITY, VISCOSITY, OR STABILITY
`LIMITATIONS EXPECTED OR FOUND WHEN FORMULATING
`Cl-INH
`
`5.
`
`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 Cl-INH.
`
`1 As used herein, the abbreviation “U/mL” refers to both U/mL and IU/mL.
`
`2
`
`Page 4 of 17
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`Page 4 of 17
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`6.
`
`Cl-INH 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 lOOkDa 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. Ex. 1042 [Harrison,
`
`p. 5001], 5. More recent literature even describes a total carbohydrate content of
`
`45% oftotal mass. Ex. 1099 [Ghannam, p. 161], 7.
`
`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 sc formulation of Cl-INH, since
`
`glycosylation was known to enhance protein solubility. Ex. 1100 [Lis, p. 13], 13;
`
`Ex. 1101 [Reuter, p. 400], 37; Ex. 1060 [801a, p. 1231], 15; Ex. 1102 [Hossler,
`
`p. 938], 10.
`
`8.
`
`I am also not aware of any reports prior to March 2013 of Cl -INH being
`
`particularly prone to aggregation.
`
`I expected Cl-INH to be relatively stable, with
`
`no unusual tendency to unfold and aggregate.
`
`In particular, I expected Cl-INH’s
`
`high glycosylation to reduce or prevent protein aggregation. Ex. 1 103 [Schellekens,
`
`p. 31], 7; Ex. 1060 [S013 2009 p. 1237], 21.
`
`In fact, many of the manufacturing
`
`processes for producing Cl-INH that were known in March 2013 involved high-
`
`Page 5 of 17
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`Page 5 of 17
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`

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`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.
`
`9.
`
`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. 1104 [Monkos 1996]; Ex. 1067 [Yadav]; Ex. 1052 [Monkos
`
`2000]; Ex. 1098 [Monkos 1997]. For example, BSA, which is also a medium-t0-
`
`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.
`
`10.
`
`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 Cl-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—INH.
`
`In fact, in our own
`
`work we expected development of a high—concentration-small-volume formulation
`
`of Cl -INH to be quite routine, and that was precisely what we experienced.
`
`Page 6 of 17
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`Page 6 of 17
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`

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`l 1.
`
`In the mid-2000s, a colleague and I evaluated the feasibility of a 10-
`
`fold concentrated preparation of Berinert® P (i.e., 500U/1nL). 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
`
`(Wfl) to both result in Cl-INH concentrations of approximately SOOU/mL. The
`
`Memo contained in Exhibit 1008 reveals that we encountered no difficulties in
`
`achieving such a 10-fold concentrated version of Berinert® P. Ex. 1008 [ZLB
`
`Behring Memo, p. 3—4], 3—4.2
`
`In particular using the excipient composition of
`
`regular Berinert® P 500, we obtained a concentrated C1 -lNH product resulting after
`
`reconstitution in a colorless and clear solution with no enhanced aggregate
`
`formation.
`
`[Ex. 1008 [ZLB Behring Memo, p. 2], 2. Stability of the concentrated,
`
`freeze—dried product was also very good as evidenced by the analytical size
`
`2 Exhibit 1008 also contains an e-mail that my colleague, Ernst-Jiirgen Kanzy, sent
`
`on March 31, 2006, to Bernhard Vohwinkel, Stefan Schulte, and Gerhard Seemann,
`
`copying me and attaching the Memo. Ex. 1008 [ZLB Behring Memo, e-mail], 16.
`
`The text of the email was written in German, and translates to the following in
`
`English: “Hello everybody, Attached is the memo on Berinert 10—fold concentrated,
`
`which summarizes the previous results on technical feasibility and stability. Best
`
`regards, Ernst-Jfirgen Kanzy.”
`
`'J’I
`
`Page 7 of 17
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`Page 7 of 17
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`

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`exclusion chromatography (SEC-HPIC) and poly-acrylamide gel electrophoresis
`
`(PAGE) data.
`
`In particular, freeze—dried C1 -1NH exhibited no obvious tendency to
`
`aggregate, except when stored under stress conditions (40°C). Ex. 1008, [ZLB
`
`Behring Memo, p. 2, Figures 1—3], 2, 6—8. And even under those stress conditions,
`
`the extent of aggregation did not cause concern or require further modifications of
`
`the preparation when stored for a limited period of time as the product inhibitory
`
`potency was essentially constant. Exhibit 1008 does not contain viscosity data for
`
`the 10-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. Ex. 1008, [ZLB Behring Memo, p. 3—4], 3—4.
`
`12.
`
`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 Berinert® 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 led to FDA approval for CSL830,
`
`which launched in July 2017 under the trade name Haegarda® as the first sc Cl-INH
`
`product
`
`for
`
`the management of HAE.
`
`Ex. 1024,
`
`[Haegarda® Prescribing
`
`Information, p. l], 1.
`
`Page 8 of 17
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`Page 8 of 17
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`HI. CONCLUSION
`
`13.
`
`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 true.
`
`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.
`
`14.
`
`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 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: ”7—0257 20/?
`
`By:
`
`{E 'm
`
`Page 9 of 17
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`Page 9 of 17
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`

`

`Appendix A
`
`Page 10 of 17
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`Page 10 of 17
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`

`

`APPENDIX A
`List of Materials Cited
`
`
`
` EXHIBIT
`
`DESCRIPTION
`Ex. 1008
`
`
`ZLB Behring Memo from Emst-Jiirgen Kanzy / Hubert Metzner
`to B. Vohwinkel et 31., Berinert P I 0-fold concentrated
`
`
`
`(500 U/mL) Feasibilitv /S'tabili 1, March 30, 2006.
`
`Haegarda® Prescribing Information, CSL BEI—IRING, Revised Jun.
`Ex. 1024
`
`2017.
`
`
`
`Jan Over et a1., CI-Inhibitor, in PRODUCTION OF PLASMA
`
`Ex. 1028
`
`
`
`PROTEINS FOR THERAPEUTIC USE 241 (Joseph Bertolini et al. eds,
`John Wile & Sons, Inc. 2013).
`
`Richard A. Harrison, Human CI Inhibitor: Improved Isolation
`and Preliminary Structural Characterization, 22 BIOCHEMISTRY
`5001 (1983).
`Karol Monkos, Viscometric study ofhuman, bovine, equine and
`ovine haemoglobin in aqueous solution, 16(1) INT. J. BIOL.
`MACROMOL. 31 (1994).
`
`Karol Monkos, Viscosity analysis of the temperature dependence
`oft/1e solution conformation ofovalbumin, 85 BIOPHYS. CHEM.
`7—16 (2000).
`
`Ricardo J. 80123 & Kai Griebenow, Effects ofGlycosylation on the
`Stability ofProtein Pharmaceuticals, 98(4) J. PHARM. SCI. 1223
`(2009).
`
`Sandeep Yadav et 31., Viscosity Analysis of High Concentration
`Bovine Serum Albumin Aqueous Solutions, 28 PHARM. RES. 1973
`(2011).
`
`Karol Monkos, Concentration and temperature dependence of
`viscosity in lysozyme aqueous solutions,
`1339 BIOCHIMICA ET BIOPHYSICA ACTA 304 (1997).
`
`Arije Ghannam et 211., CI Inhibitor as a glycoprotein: The
`influence ofpolysaccharides on its function and autoantibody
`tar_et, 71 MOL. IMMUNOL. 161 (2016).
`
`Halina Lis & Nathan Sharon, Protein glycosylation: Structural
`and functional aSIects, 218 EUR. J. BIOCHEM.
`1 (1993).
`G. Reuter & H.-J. Gabius, Eukaryotic glycosylation: whim of
`nature or multipurpose tool? , 55 CMLS, CELL. MOL. LIFE SCI.
`368-422 (1999).
`
`
`
`
`
`Ex. 1042
`
`Ex. 1049
`
`Ex. 1052
`
`Ex. 1060
`
`Ex. 1067
`
`Ex. 1098
`
`Ex. 1099
`
`Ex. 1100
`
`Ex. 1 101
`
`Page 11 of 17
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`Page 11 of 17
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`

`

`
` EXHIBIT
` DESCRIPTION
`
`Patrick Hossler et al., Optimal and consistent protein
`
`
`glycosylation in mammalian cell culture,
`
`
`19(9) GLYCOBIOLOGY 936 (2009).
`
`
`Huub Schellekens, Why some proteins have sugars? Epoetins,
`
`
`
`rom al a to zeta, 14(6) EJHP PRACTICE 29 (2008).
`Karol Monkos, Visoosity ofbovine serum albumin aqueous
`Ex. 1 104
`‘
`
`solutions as a function of temperature and concentration,
`
`18 INT. J. BIOL. MACROMOL. 61 (1996).
`
`Ex. “03
`
`Page 12 of 17
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`

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`Appendix B
`
`Page 13 of 17
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`Page 13 of 17
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`

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`CURRICULUM VITAE - SYNOPSIS
`
`Dr. rer. nat. Hubert J. Metzner
`
`Director Process Development
`
`Recombinant Product Development
`
`CSL Behring GmbH
`
`Emil—von-Behring Str. 76
`
`D-35041 Marburg
`
`Education:
`
`1977 -1983:
`
`1983 - 1987:
`
`1988:
`
`Occupational Career:
`
`Studies of Chemistry at the University of Karlsruhe
`
`(Germany) with graduation as Dipl. Chemiker
`
`Doctoral thesis at the Department of
`
`Biochemistry, Faculty of Chemistry, University of
`
`Karlsruhe on the mechanisms of protein biosynthesis
`
`Degree of Dr. rer. nat. by the University of Karlsruhe.
`
`Sept. 1988 - June 1995:
`
`Research Scientist at Behringwerke AG in the field of
`
`haemostaseology and protein biochemistry
`
`July 1995 — April 2004:
`
`Manager and Assoc. Director in Preclinical R&D at
`
`Centeon Phat-Ina GmbH and at Aventis Behring
`GmbH
`
`April 2004 — September 2007:
`
`Assoc. Director in Preclinical R&D at ZLB Behring
`
`GmbH and CSL Behring GmbH, respectively
`
`Director Process Development, Preclinical R&D at
`
`CSL Behring GmbH
`
`Since October 2007:
`
`Fields of Interest:
`
`Coagulation and fibrinolysis, clotting factors and related products, haemophilia treatments;
`
`protein biochemistry, development of plasma-derived and recombinant protein therapeutics.
`
`Page 1 of 4
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`Page 14 of 17
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`Page 14 of 17
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`

`

`Selected Publications/Abstracts
`
`- R. Hilgenfeld, A. Liesum, R. Storm, H.J. Metzner, H.E. Karges
`Crystallization of Blood Coagulation Factor XHI by an automated
`procedure
`FEBS Lett. 265 (1,2), 110-112 (90)
`
`» H.J. Metzner, K. Funk, U. Panzer, E.P. Paques
`Recombinant factor XIII - biochemical properties
`in "Factor XIII: Second International Conference Marburg",
`ed. J. McDonagh, R. Seitz, R. Egbring, 87—93 (1993) Schattauer
`
`- R. Hilgenfeld, A. Liesum, D. Mausil, H.J. Metzner, H.E. Karges
`Towards a high-resolution crystal Structure of the factor XIII a—
`chain dimer
`
`in "Factor X111: Second International Conference Marburg",
`ed. J. McDonagh, R. Seitz, R. Egbring, 106-109 (1993) Schattauer
`
`- P. Hermentin, R. Witzel, E.-J. Kanzy, G. Diderrich, D. Hoffmann,
`H. Metzner, J. Vorlop, and H. Haupt:
`The hypothetical N-glycan charge: a number that characterizes
`protein glycosylation
`Glycobiology 6, 217-230 (1996)
`
`— H.E. Karges and H.J. Metzner
`Therapeutic factor XHI preparations and perspectives for recombinant factor XIII
`Sem Throm Hem 22: 427-436 (1996)
`
`- H.J. Metzner, B. Watzka, H.-G. Miiller, U. Klockmann, P. Hermentin, R. Homghaus and G.
`Auerswald
`
`Stability of factor VIII concentrates - a precondition for continuous infusion
`Biomed Progr 10: 31-34 (1997)
`
`- M.S. Weiss, H. J. Metzner and R. Hilgenfeld
`Two non-proline cis peptide bonds may be important for factor XIII function
`FEBS Letters 423: 291-296 (1998)
`
`- H.J. Metzner, P. Hermentin, T. Cuesta—Linker, S. Langner, H.—G. Miiller and J. Friedebold
`Characterization of factor VIII/von Willebrand factor concentrates using a modified method
`of von
`
`Willebrand factor multimer analysis (Abstract, ASH-Meeting)
`Blood 92, No. 10 (Suppl. 1), 49a (1998)
`
`- H.J. Metzner, P. Hermentin, T. Cuesta-Linker, S. Langner, H.-G. Mfiller and J. Friedebold
`Characterization of factor VIII/von Willebrand factor concentrates using a modified method
`of von
`
`Willebrand factor multimer analysis
`Haemophilia 4 (Suppl. 3): 25-32 (1998)
`
`- H.J. Metzner, G. Dickneite and K.—H. Diehl
`
`Page 2 of 4
`
`Page 15 of 17
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`

`

`Faktor XIII und Wundheilung — praklinische Untersuchungen
`In: Klinische Aspekte des Faktor XIII-Mangels. Diagnostik, klinische Relevanz, klinische
`Forschung
`Eds. R. Egbring, R. Seitz, G. WoZniak
`Karger, 1999, pp 111-118
`
`- T. Noll, G. Wozniak, K. McCarson, A. Hajimohammad, H.J. Metzner, J. Inserte, W.
`Kummer, F.W. Hehrlein and HM. Piper
`Effect of factor XIII on endothelial barrier function
`
`J Exp Med 189 (9): 1373-1382 (1999)
`
`- G. Dickneite, H. Metzner and U. Nicolay
`Prevention of suture hole bleeding using fibrin sealant: Benefits of factor XIII
`J Surg Res 93: 201-205 (2000)
`
`- H.J. Metzner, K. Funk, H. Naumann, A. Eisberg, J. Miiller-Cohrs, and G. Witzke
`A new method to investigate the adhesive properties of fibrin sealant preparations in vitro
`Blood 98 (11, Part 2): 75b (2001)
`
`- G. Dickneite, H.J. Metzner, M. Kroez, B. Hein und U. Nicolay
`The importance of Factor XIII as a component of fibrin sealants
`J Surg Res 107: 186-195 (2002)
`
`- P. Lauer, H.J. Metzner, G. ZettlmeiBl, M. Li, A.G. Smith, R. Lathe und G. Dickneite
`Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: Hemostatic
`abnormalities in mutant mice and characterization of the coagulation deficit
`Thromb Haemost 88: 967-974 (2002)
`
`— H.J. Metzner, H. Naumann, and G. Witzke
`Comparison of the Fibrinogen Components of Commercial Fibrin Sealants: Biochemical
`Parameters
`
`Ann Heinatol 82 (Suppl 1): S62 (2003)
`(Abstract)
`
`- G. Dickneite, H.J. Metzner, M. Kroez, U. Nicolay
`Benefits of factor XIII as a component of fibrin sealants: Experimental surgery
`Biomed Progr 16 (Suppl. 1): 6-13 (2003)
`
`- M. Phillips, G. Dickneite, H. Metzner
`Fibrin sealants in supporting surgical techniques: strength in factor XIII
`Cardiovasc Surg 11: 13-16 (2003)
`
`- G. Dickneite, H. Metzner, T. Pfeifer, M. Kroez, G. Witzke
`A comparison of fibrin sealants in relation to their in vitro and in vivo properties
`Thromb Res 112: 73-82 (2003)
`
`- H. J. Metzner, E.-J. Kanzy, A. Kalbass, H. Lind, H.—G. Mfiller, G. Kumpe, S. Schulte
`Analytical characterization of infusion volume reduced Humate-P/Haemate P
`Blood 106(11): 122b (2005)
`ASH Abstract 2005
`
`Page 3 of 4
`
`Page 16 of 17
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`Page 16 of 17
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`

`

`- U. Budde, H.J. Metzner, H.-G. Miiller
`Comparative analysis and classification of von Willebrand factor/factor VIII concentrates:
`Impact on treatment of patients with von Willebrand disease
`Semin Thromb Hemost 32: 626-635 (2006)
`
`- HJ Metzner, T. Weimer, U. Kronthaler, W. Lang, S. Schulte
`Genetic fusion to albumin improves the pharmacokinetic properties of factor IX
`Thromb Haemost 102: 634-644 (2009)
`
`- Jambor C., Reul V., Sclmider T.W., Degiacomi P., Metzner H., Korte W.C.
`In vitro inhibition of factor XIII retards clot formation, reduces clot firmness, and increases
`fibrinolytic effects in whole blood
`Anesthesia & Analgesia 109: 1023-1028 (2009)
`
`— H.J. Metzner, T. Weimer, and S. Schulte
`Half-life extension by fusion to recombinant albumin
`In: Therapeutic Proteins
`Ed. R. Konterrnann
`
`Wiley-Blackwell, 2012, pp 223-247
`
`- T. Weimer, H.J. Metzner, and S. Schulte
`Recombinant albumin fusion proteins
`In: Fusion Protein Technologies for Biopharmaceuticals — Applications and Challenges
`Ed. S.R. Schmidt
`
`John Wiley & Sons, 2013, pp 163-178
`
`— S.B. Zollner, E. Raquet, J. Miiller-Cohrs, H.J. Metzner, T. Weimer, I. Pragst, G. Dickneite,
`S. Schulte
`
`Preclinical efficacy and safety of rVIlI-SingleChain (CSL627), a novel recombinant single-
`chain
`factor VIII.
`
`Thromb Res. 2013; 132(2): 280-287
`
`- HJ Metzner, S. Pipe, T. Weimer, S. Schulte
`Extending the pharrnacokinetic half-life of coagulation factors by fusion to recombinant
`albumin
`
`Thromb Haemost 110: 931-939 (2013)
`
`- S. Zollner, E. Raquet, P. Claar, J. Miiller-Cohrs, H.J. Metzner, T. Weimer, I. Pragst, G.
`Dickneite,
`S. Schulte
`
`Non-clinical pharmacokinetics and pharmacodynarnics of rVHI-SingleChain, a novel
`recombinant single-chain factor VIII.
`Thromb Res. 2014; 134: 125-131
`
`- S. Schmidbauer, R. Witzel, L. Robbel, P. Sebastian, N. Grammel, H.J. Metzner, and S.
`Schulte
`
`Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain
`factor VHI. Thromb Res. 2015; 136: 388-395
`
`Page 4 of 4
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