`
`Europilsches
`Patentamt
`European
`PM! We
`Office euvopéon
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`Submission in opposition proceedings
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`Representative:
`.
`Hugh ROb'" GOODFELLOW
`Carpmaels & Ransford LLP
`Professional Association No. 182
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`One Southampton Row
`London WC1 B 5HA
`United Kingdom
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`Phone: 020-7242 8692
`Fax: 020-7405 4166
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`80298 Munich
`Germany
`Tel. +49(0)89 2399-0 | Fax 4465
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`PO. Box 5818
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`NL-2280 HV Rijswu‘k
`Nethenands
`Tel. +31(0)7o 340-2040 | Fax -3016
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`10958 Berlin
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`Germany
`Tel. +49(0)3o 25901-0 | Fax -840
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`' represen‘ingthe PVOP'iet°r(S)i
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`‘ shire viropharma incorporated
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`
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`Proprietor/representative‘s reference
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`0008044EP
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`The information given below is pertaining to the following patent in opposition proceedings:
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`Patent No.
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`Application No.
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`Title Of the invention
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`EP2968434
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`EP14762343.3
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`C1-INH COMPOSITIONS AND METHODS FOR THE
`PREVENTION AND TREATMENT OF DISORDERS
`ASSOCIATED WITH C1 ESTERASE INHIBITOR
`DEFICIENCY
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`Documents attached:
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`Description of document
`Original file name
`Assigned file name
`Reply of the patent proprietor to the notice(s) of
`0008044EP_Reply_as_filed.pdf
`OBSOdef
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`opposition
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`2 Any annexes (other than citation) to an opposition
`letter - 051 - Ruddy Confidentiality and NBA
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`051 - Ruddy Confidentiality and
`Non-Disclosure Agreement.de
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`Any annexes (other than citation) to an opposition
`letter - 052 - Gallaher ViroPharma Incorporated
`Employements
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`D52 - Gallaher ViroPharma
`Incorporated Employment
`Agreementpdf
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`OTHER-1.pdf
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`OTHER-2.pdf
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`D53 - Gallagher (CMC Framework
`Any annexes (other than citation) to an opposition
`_ViroPharma Consulting&COA).pdf
`letter - 053 - Gallagher (CMC
`Framework_ViroPharma ConsultingCDA)
`Any annexes (other than citation) to an opposition
`054 - Manning (Legacy and
`OTHER-4.pdf
`letter - 054 - Manning (Legacy and ViroPharma
`ViroPharma MSA)_Redacted.pdf
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`OTHER-Bepdf
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`MSA) Redacted
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`Any annexes (other than citation) to an opposition
`letter - 055 — Confirmatory Assignment
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`055 - Confirmatory Assignmentpdf
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`OTHER-5.pdf
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`0008044EP
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`Page 1 of 84
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`CSL EXHBIT 1058
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`D56 - PCT register.pdf
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`OTHER-6.pdf
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`letter - D56 - PCT register
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`D57 - Frank Prosecution Decl.pdf
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`OTHER-7.pdf
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`letter - D57 - Frank Prosecution Decl
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`D58 - Excerpt from AMA.pdf
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`OTHER-8.pdf
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`letter - D58 - Excerpt from AMA
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`D59 - Dey v Sunovion opinion.pdf
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`OTHER-9.pdf
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`letter - D59 - Dey v Sunovion opinion
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`D60 - USDC NJ judgment referred to in
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`D61 - Sanquin Report.pdf
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`OTHER-11.pdf
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`letter - D61 - Sanquin Report
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`D62 - Sanquin correspondence.pdf
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`OTHER-12.pdf
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`letter - D62 - Sanquin correspondence
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`D63 - Lee declaration.pdf
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`OTHER-13.pdf
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`letter - D63 - Lee declaration
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`D64 - Daugherty, 2006.pdf
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`OTHER-14.pdf
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`letter - D64 - Daugherty, 2006
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`D65 - Frost, 2007.pdf
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`OTHER-15.pdf
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`letter - D65 - Frost, 2007
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`17 Any annexes (other than citation) to an opposition
`D66 - ViroPharma Licenses Halozyme’s
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`letter - D66 - ViroPharma Licenses Halozyme’s
`Hyaluronidase.pdf
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`Hyaluronidase
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`18 Any annexes (other than citation) to an opposition
`D67 - Halozyme December 2012 press
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`letter - D67 - Halozyme December 2012 press
`release.pdf
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`release
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`D68 - ViroPharma Press Release, 1
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`August 2012.pdf
`letter - D68 - ViroPharma Press Release, 1 August
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`2012
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`D69 - Dunn, 2010.pdf
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`OTHER-19.pdf
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`letter - D69 - Dunn, 2010
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`D70 - Shapiro, 2010.pdf
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`OTHER-20.pdf
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`letter - D70 - Shapiro, 2010
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`D71 - Sasson, 2001.pdf
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`OTHER-21.pdf
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`letter - D71 - Sasson, 2001
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`D72 - Haller, 2007.pdf
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`OTHER-22.pdf
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`letter - D72 - Haller, 2007
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`D73 - Kling, 2014.pdf
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`OTHER-23.pdf
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`letter - D73 - Kling, 2014
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`D74 - Courthaudon, 1989.pdf
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`OTHER-24.pdf
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`letter - D74 - Courthaudon, 1989
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`D75 - UK_Berinert 2000 |U_SmPC.pdf
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`OTHER-25.pdf
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`letter - D75 - UK_Berinert 2000 |U_SmPC
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`D76 - Boylan, 2002.pdf
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`OTHER-26.pdf
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`letter - D76 - Boylan, 2002
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`D77 - Cinryze 500 SmPC.pdf
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`OTHER-27.pdf
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`letter - D77 - Cinryze 500 SmPC
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`D78 - Shapiro, 2012.pdf
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`OTHER-28.pdf
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`letter - D78 - Shapiro, 2012
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`D79 - Kramer, 2012.pdf
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`OTHER-29.pdf
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`letter - D79 - Kramer, 2012
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`D80 - Georgiou, 1994.pdf
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`OTHER-30.pdf
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`letter - D80 - Georgiou, 1994
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`32 Any annexes (other than citation) to an opposition
`D81 - Alford, 2007.pdf
`OTHER-31.pdf
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`OTHER-18.pdf
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`OOO8044EP
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`letter - D81 - Alford, 2007
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`33 Any annexes (other than citation) to an opposition
`D82 - Yadav, 2010.pdf
`OTHER-32.pdf
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`letter - D82 - Yadav, 2010
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`34 Any annexes (other than citation) to an opposition
`OTHER-33.pdf
`D83 - Burckbuchler, 2010.pdf
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`letter - D83 - Burckbuchler, 2010
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`letter - D84 - Jezek, 2011
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`D85 - Perkins, 1990.pdf
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`letter - D85 - Perkins, 1990
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`37 Any annexes (other than citation) to an opposition
`OTHER-36.pdf
`D86 - Baniel, 1992.pdf
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`letter - D86 - Baniel, 1992
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`38 Any annexes (other than citation) to an opposition
`OTHER-37.pdf
`D87 - Richter, 2012.pdf
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`letter - D87 - Richter, 2012
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`letter - D88 - Berinert prescribing information
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`letter - Consolidated list - opponent and proprietor
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`citations
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`D84 - Jezek, 2011.pdf
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`OTHER-34.pdf
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`OTHER-38.pdf
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`OTHER-39.pdf
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`35
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`D88 - Berinert prescribing
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`information.pdf
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`Consolidated list - opponent and
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`proprietor citations.pdf
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`Signatures
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`Place:
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`Date:
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`Signed by:
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`London
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`16 August 2018
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`/GOODFELLOW, Hugh Robin/
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`Representative name:
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`Hugh Robin GOODFELLOW
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`Capacity:
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`(Representative)
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`OOO8044EP
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`Page 3 0f 84
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`Page 3 of 84
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`CAQPMAELSSRANSFORD
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`PATENTEE’S OBSERVATIONS
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`ON THE OPPOSITIONS FILED AGAINST
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`EP 2 968 434 B1
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`IN THE NAME OF SHIRE VIROPHARMA, INC.
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`INTRODUCTION AND REQUESTS
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`This is the Patentee’s response to the communication dated 11th April 2018 inviting
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`observations and/or amendments in reply to the notices of opposition by Octapharma AG
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`(hereafter “opponent 1”) and CSL Behring GmbH (hereafter “opponent 2”) against
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`European Patent EP 2 968 434 (hereafter “the Patent”).
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`The Patentee’s Main Request is that the Opposition Division rejects the oppositions and
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`maintains the Patent on the basis of the claims as granted. Oral proceedings are requested
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`should the Opposition Division intend not to allow the Main Request.
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`If the Opposition Division intends not to allow the Main Request, the Patentee requests that
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`the patent be maintained on the basis of one of enclosed Auxiliary Requests 1-33.
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`A consolidated list of documents is provided in Annex 1.
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`SUMMARY
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`The patent should be maintained as granted, according to the Main Request.
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`The claimed subject matter is novel because:
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`D4, cited by opponent 1, discloses a formulation with a C1 esterase inhibitor
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`concentration of 100 U/ml. It therefore does not disclose treatment of hereditary
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`angioedema (HAE) by subcutaneous administration of a composition comprising C1
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`esterase inhibitor (C1-INH) at a concentration of 400 U/ml or more, as claimed.
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`D18 and D18a, cited by opponent 2, cannot be considered prior art under Article 54(2)
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`EPC. Their availability to the public has not been proven according to the necessary
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`standard of proof for documents which are under the exclusive control of the opponent
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`(“up to the hi] ”). In any event, D18 and D18a are not enabling disclosures.
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`Furthermore, D18 and D18a do not disclose use of a C1-INH formulation for treatment
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`of HAE and thus cannot be relevant to the novelty of the claimed subject matter even if
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`they were considered to be enabling prior art.
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`The claimed subject matter is inventive because none of documents cited by the
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`opponents suggests using a high concentration formulation as claimed for subcutaneous
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`administration. D4 relates to a C1-INH formulation in any possible concentration and does
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`not even mention subcutaneous administration, while both D5 and D26a relate to
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`formulations having a low C1-INH concentration and a high volume. Specifically, D5 and
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`D26a represent the general teaching in the field towards use of low concentration/high
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`.1
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`CAQPIVIAELSSRANSFORD
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`volume C1-INH formulations and would not have motivated the skilled person to develop
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`the claimed high concentration formulation. The rest of the cited documents are either
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`nearly identical to these three documents, or cannot be considered prior art.
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`The claimed subject matter is sufficiently disclosed in the patent. Most of the opponents’
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`objections are in effect objections under Article 84 EPC, which is not a valid ground of
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`opposition. In any event, neither of the opponents has presented any serious doubts
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`substantiated by verifiable facts that the claimed subject matter cannot be worked.
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`The subject matter of the claims is clearly and unambiguously disclosed in the application
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`as filed. The opponents base most of their arguments on a deliberate misreading of terms
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`in a manner which is not that taken by the skilled person, who reads the application as filed
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`with a mind willing to understand.
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`PRIORITY
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`Opponent 2 alleges a lack of priority on the basis of a purported failure of the priority right
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`to be transferred from the inventor-applicants of the priority document (Ruddy, Gallagher
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`and Manning) to the PCT applicant by the PCT filing date.
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`The Patentee encloses herewith evidence that the PCT applicant was the successor in title
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`to the inventor-applicants of the priority document on the PCT filing date. Priority is validly
`claimed in line with Article 87 EPC and Article 4C of the Paris Convention.
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`Transfer of priority right from inventor-applicant Ruddy
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`Ruddy was employed by ViroPharma Incorporated when the invention was made. His
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`employee invention agreement, which contains a present assignment of future rights, is
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`enclosed as D51, dated February 16th, 2012 (i.e. before the PCT filing date).
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`Thus ViroPharma Incorporated was the successor in title to Ruddy as of the PCT
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`application’s filing date.
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`Transfer of priority right from inventor-applicant Gallagher
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`2.4
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`Gallagher was also employed by ViroPharma Incorporated until slightly before the priority
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`document was filed. Her employment agreement with ViroPharma Incorporated, which also
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`contains a present assignment of future rights, is enclosed as D52. After leaving
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`employment by ViroPharma Incorporated, Gallagher set up a consultancy firm (called CMC
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`Framework, LLC) of which she was the principal. She agreed as principal of her firm that
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`any intellectual property generated during the course of the consultancy between her and
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`ViroPharma Incorporated would be owned by ViroPharma Incorporated. A copy of the
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`agreement made by Gallagher for her services through her company is enclosed as D53,
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`dated February 11th, 2013 (i.e. before the PCT filing date).
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`Page 5 0f 84
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`3.7
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`3.9
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`3.10
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`3.11
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`Thus ViroPharma Incorporated was the successor in title to Gallagher as of the PCT
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`application’s filing date.
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`ri htfrominventor-arioritTransferof licantMannin
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`Manning was a principal (co-owner) of Legacy BioDesign LLC with his wife Susan
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`Manning. Legacy BioDesign LLC is a consultancy firm which was instructed by ViroPharma
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`Incorporated to provide services to ViroPharma Incorporated. A redacted version of the
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`agreement for Manning’s services via his company is enclosed as D54, effective
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`September 23rd, 2011 (i.e. before the PCT filing date). As for the documents above, D54
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`also contains a present assignment of future rights.
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`Thus ViroPharma Incorporated was the successor in title to Manning as of the PCT
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`application’s filing date.
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`This transfer of rights has been confirmed by the inventor-applicants themselves
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`For completeness, the Patentee encloses D55, which sets out the understanding of the
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`inventor-applicants themselves. In this document, signed in 2015, Ruddy, Gallagher (and
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`CMC Framework, LLC) and Manning (and Legacy BioDesign, LLC) confirm their
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`understanding of the transfer of rights from them as inventor-applicants to ViroPharma
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`Incorporated as the PCT applicant and successor in title of their rights in the priority
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`application as of the PCT filing date. D55 reconfirms how the documents discussed above
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`transferred the rights from the inventor-applicants of the priority document to the PCT
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`applicant before the PCT filing date.
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`ViroPharma Incorporated was the original applicant for the PCT application
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`Opponent 2 also argues that a series of changes recorded in the named applicant for the
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`international application M the PCT application was filed somehow renders the priority
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`claim invalid. This argument is based on a mistaken understanding of the legal processes
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`that occurred during the international phase and a misinterpretation of documents in the
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`ViroPharma Incorporated was the original applicant for the PCT application, which alone is
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`decisive for the question of whether priority was rightly claimed. This fact is shown in the
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`file history of the PCT application — the originally filed request lists ViroPharma
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`Incorporated as the applicant. The file history of the international phase discloses three
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`changes to the applicant, which do not have any retroactive effect on the status as
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`ViroPharma Incorporated as the entity present on the PCT request as filed. There is no
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`retroactive effect because these changes were made pursuant to Rule 92bis.1 PCT.
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`Confirmation that the changes were understood to be requests under Rule 92bis PCT is
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`provided in the attached copy of the WIPO register for the PCT application (D56), with
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`each request under Rule 92bis PCT highlighted by a shaded arrow and each recordal
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`Page 6 0f 84
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`Page 6 of 84
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`under Rule 92bis PCT (as evidenced by issuance of an |B306 form) indicated with an
`unshaded arrow.
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`3.12
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`3.13
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`Changes recorded in the international phase under Rule 92bis.1 PCT are simply that:
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`changes. Opponent 2 appears to confuse changes recorded under Rule 92bis.1 PCT,
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`effective going fonNards following the request, with changes under Rule 91.3 (b) PCT
`which are made in the case of correction of obvious errors and which have a retroactive
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`effect. The different effect of the two rules is immediately evident from the fact that Rule
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`91.3 PCT expressly prescribes the retroactive effect on the date of filing in Rule 91.3 (c)(i)
`PCT, as set out below:
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`[...]
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`(0) Where the rectification of an obvious mistake has been authorized, it
`shall be effective:
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`in the case of a mistake in the international application as filed,
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`from the international filing date;
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`In contrast, Rule 92bis.1 PCT is silent on such a retroactive effect.
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`Opponent 2 misrepresents actions taken by the agents of record in the international phase
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`as actions by the international authorities
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`Finally, for completeness, opponent 2’s arguments are misleading with respect to the
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`behaviour of the international authorities. In particular, opponent 2 alleges that key
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`evidence for a supposed retroactive effect of the changes is that “substituted” pages of the
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`PCT request were “re-emitted’ by the international authorities following each change (page
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`12, 3rd full paragraph of opponent 2’s opposition statement). The international authorities
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`do not issue corrected forms in response to changes under Rule 92bis.1 PCT. Upon review
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`of the correspondence from the international file, it is instead evident that these sheets
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`originated from the agents of record in the international phase, and were fonNarded on the
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`seeming belief that this would assist the international authorities; no proactive generation of
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`replacement sheets by the international authorities occurred. lndeed, opponent 2’s
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`approach to interpreting the facts, and so its argument, is fatally undermined by the
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`documents it filed with its own submissions; both D28 and D29 even state that the updated
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`request sheets (D28a and D29a respectively) were enclosed by the agents of record in the
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`international phase‘. The changes under Rule 92bis.1 PCT are shown to have be
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`1 For completeness, if substitute sheets were issued by the international authorities as a correction of an
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`error in the PCT application as filed (i.e. with retroactive effect), they would not be issued under Rule 26
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`PCT. This PCT rule relates to formal defects, for instance, ifthe request is not signed, does not contain the
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`prescribed indications concerning the applicant, or is filed in a language in which the request is not accepted
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`by the receiving office (see, e.g., Section 325(a)(ii) of the Administrative Instructions under the Patent
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`Page 7 0f 84
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`Page 7 of 84
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`recorded by the international authorities based on issuance of the form |B306 in each
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`instance (see D56). No sheet of the PCT request was substituted under Rule 26 PCT in the
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`international phase, nor could it have been — the PCT request did not contain a formal error
`that Rule 26 PCT could be used to address.
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`Summary on priority entitlement
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`3.14
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`Opponent 2 misreads the actions of the international authorities. Contrary to the portrayal
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`of opponent 2, the actions of the authorities in the international phase correctly reflect the
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`fact that, although three changes of applicant were made afterthe PCT filing date under
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`Rule 92bis.1 PCT, ViroPharma Incorporated was always the applicant named on the day
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`that the PCT application was filed. Therefore, on the day that the PCT application was filed,
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`as ViroPharma Incorporated was the successor in title to all three applicants of the priority
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`document (as evidenced by D51-D55), the priority claim is valid.
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`The effective date of the claims is thus 15 March 2013.
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`4.2
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`4.3
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`4.4
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`NOVELTY
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`The opponents between them raise two arguments. However, neither is novelty-destroying.
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`Indeed, the weakness in respect of the lack of novelty arguments is belied by opponent 1’s
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`reliance on D1, in which a composition comprising 100 U/ml of C1-lNH is used, but yet
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`opponent 1 still alleges lack of novelty.
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`As the opponents are well aware, in order for a cited document to be considered as
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`novelty-destroying, it must be established that all elements of the contested claim have
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`been directly and unambiguously disclosed in the cited document. Neither of the
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`documents cited by the opponents discloses all elements of claim 1 and thus the claimed
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`subject matter is novel.
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`D1 (Jiang et al.)
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`D1 is a research paper discussing subcutaneous administration of C1-lNH to pigs.
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`As correctly noted by opponent 1, the C1-lNH used in the study described in D1 is
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`Cinryze®, which has a known concentration of 100 U/ml (see, for example, section 2 on
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`page 2 of document D25 cited by opponent 2). Therefore, D1 discloses administration of
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`C1-lNH at a concentration of 100 U/ml and not 400 U/ml or more, as claimed. D1 therefore
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`can never be novelty-destroying.
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`Cooperation Treaty, which notes sheets which are related to the formal defect corrections are marked Rule
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`26 PCT, but rectification of mistakes, under the retroactive provisions of Rule 91 PCT, would be marked
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`“RECTIFIED SHEET (RULE 91)” and Examination at the EPO as PCT Authority C-lll, 1 and H-IV, 1).
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`Page 8 0f 84
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`Page 8 of 84
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`CAQPMAELS&QANSFORD
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`In an attempt to brush over this fatal flaw, opponent 1 makes the allegation that there is a 2
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`ml limit to subcutaneous injections and thus concludes that the subcutaneous composition
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`administered in D1 is implied to be in a maximal volume of 2 ml and at a concentration of
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`400-575 U/ml. This is simply incorrect and contradicts the teaching of D1.
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`The skilled person reading D1 would interpret the use of Cinryze® in D1 to be “as-is” (i.e. at
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`a concentration of 100 U/ml). D1 discloses administration of Cinryze® to pigs weighing
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`16-23 kg at a dose of 50 U/kg, which translates to 800-1150 administered units. Thus the
`calculated administered volume disclosed in D1 is between 8-11.5 ml. As disclosed in the
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`first paragraph on page 325 of D1, the subcutaneous infusions were delivered by a
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`continuous pump over a 60 minute period, which is consistent with administration of a high
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`volume subcutaneously. If the administered volume were 2 ml, as argued by opponent 1,
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`then, when using a continuous pump over 60 minutes, this would translate to an absurdly
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`illogical administration of 33 pl per minute; if2 ml were used, at a realistic subcutaneous
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`injection rate, the administration time would have been significantly shorter than 60
`minutes.
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`For completeness, a declaration from Dr Michael Frank, a co-author of the Jiang paper, is
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`enclosed as D57. Here, Dr Frank confirms, as the skilled person would understand from
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`reading D1 without a mind desirous of misunderstanding that the administration was of
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`Cinryze® - at the standard 100 U/ml of C1-INH.
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`4.5
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`4.6
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`4.7
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`4.8
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`4.9
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`4.10
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`It is therefore wrong for opponent 1 to portray that there is a maximal volume of 2 ml for
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`subcutaneous administration (as a much higher volume was administered in D1, and, in
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`any case, no prejudice in the field existed that required all subcutaneous administrations to
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`be below 2 ml, as explained in detail at paragraphs 5.62-5.66 below). As a result, it is
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`wholly incorrect for opponent 1 to say that D1 discloses a composition for subcutaneous
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`administration that has the claimed concentration of C1-INH. Of note, opponent 2 agrees
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`with the skilled person’s reading of D1 and argues, contrary to opponent 1, that D1
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`discloses a C1-INH concentration of 100 U/ml (second paragraph on page 10 of opponent
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`2’s opposition statement). Thus, even another opponent will not support opponent 1’s tactic
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`of reading D1 with a mind desirous of misunderstanding.
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`Thus, the claims are novel over D1 as it does not disclose all elements of claim 1, and in
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`particular subcutaneous use of a composition having a C1-INH concentration of 400 U/ml
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`D18 and D18a (Informed Consent Formsj
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`Opponent 2 argues that D18 and D18a, which are informed consent forms that were
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`allegedly provided to trial subjects in CSL’s CSL830_2001 trial, constitute disclosures that
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`were available to the public before the priority date of the Patent. Opponent 2 further
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`argues that these documents anticipate the subject matter of claim 1. Opponent 2 is
`incorrect.
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`Page 9 0f 84
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`Page 9 of 84
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`CAQPMAELSSRANSFORD
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`As affirmed in recent case law from the Boards of Appeal, in cases concerning alleged
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`disclosure emanating from clinical trials, what is paramount is an assessment of the facts
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`of the case (reasons 4 of T 239/16, emphasis added):
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`“each case has to be assessed on its own facts
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`4.11
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`4.12
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`4.13
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`4.14
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`4.15
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`As explained in detail below, one key fact in the present case, which impacts on all of the
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`others, is that all information relating to D18 and D18a comes from opponent 2 and cannot
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`be verified independently by the Patentee. Established case law from the Boards of Appeal
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`sets out that in this instance, the standard of proof to be applied is “up to the hilt”.
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`Accordingly, in the present case, D18 and D18a cannot be considered as public
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`disclosures as their publication has not been proven “up to the hi] This standard has
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`consequences for the assessment of the publication of the document. Put simply, concrete
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`evidence is required. It means that the Opposition Division cannot operate in the realm of
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`theoretical possibilities or likelihood that the contents of these documents were public; a
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`mere unevidenced possibility is fundamentally incompatible with the “up to the hilt”
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`standard. In this regard, opponent 2’s reference to Boards of Appeal case law relating to
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`clinical trials cannot compensate for this profound lack of evidence to the required standard
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`to prove public access to D18 and D18a.
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`Furthermore, were the pertinent information in D18 and D18a even to have reached the
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`public, which is denied, still the skilled person would not have been able to work the
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`claimed subject matter. This inability derives from the lack of any teaching in D18 and
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`D18a with respect to the formulation to be used and the understanding in the art of
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`problems associated with the generation of high concentration C1-INH formulations that
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`possessed all the physical characteristics required for subcu