EP 02 70 3958.5
`Chugai Seiyaku Kabushiki Kaisha
`Our Ref.: H2624 EP $3
`
`1
`
`VOSSIUS & PARTNER
`PATENTANWALTE * RECHTSANWALTE
`SIEBERTSTR.4
`81675 MUNCHEN
`
`1%. Apri 2019
`
`AMENDED CLAIMS SET
`
`1.
`
`2.
`
`A method for removing contaminant DNAin a sample containing an antibody, which
`comprises the following steps:
`1)
`converting the sample containing an antibody into an aqueous solution of pH 4
`to 8 and of low conductivity having a molarity of 0 to 100 mM; and
`removingthe resulting particles.
`
`2)
`
`A method for removing contaminant DNAin a sample containing an antibody, which
`comprises the following steps:
`1)
`converting the sample containing an antibodyinto anacidic or alkaline aqueous
`solution of low conductivity having a molarity of 0 to 100 mM;
`adjusting the pH ofthe resulting sample to pH of 4 to 8, wherein the molarity of
`the adjusted sample is 0 to 100 mM; and
`
`2)
`
`3)
`
`removingthe resulting particles.
`
`3.
`
`A method for removing contaminant DNA in an antibody-containing sample, which
`comprises the following steps:
`1)
`applying the antibody-containing sample to affinity chromatography on
`Protein A or ProteinGto elute the antibody with an acidic aqueous solution of
`low conductivity having a molarity of 0 to 100 mM;
`adjusting the pH of the resulting eluate to pH 4 to 8 by addition of a buffer,
`wherein the molarity of the adjusted eluate is 0 to 100 mM; and
`removingtheresulting particles.
`
`2)
`
`3)
`
`4.
`
`The method according to claim 2 or 3, wherein the acidic aqueous solution of low
`conductivity has a molarity of 0 to 50 mM.
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 1 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 1 of 40
`
`

`

`
`
`2
`
`The method according to any oneof claims 2 to 4, wherein the acidic aqueoussolution
`is selected from aqueoussolutions of hydrochloricacid, citric acid and acetic acid.
`
`The method according to claim 5, wherein the acidic aqueoussolution has a pH of 1.5
`to 3.9.
`
`The method according to any one of claims 1 to 5, wherein the contaminant DNAis
`
`present at a DNA concentration of 22.5 pg/mlorless in the treated sample containing
`an antibody.
`
`The methodaccording to claim 3, wherein the buffer is an aqueous solution ofTris.
`
`The method according to claim 3, wherein the buffer is added to raise the pH to 4.3 to
`7.5.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`The method accordingto any one ofclaims | to 3, wherein the antibody is a humanized
`monoclonalantibody.
`
`The method according to claim 10, wherein the antibody is a humanized anti-IL-6
`receptor antibody.
`
`The method according to claim 10, wherein the antibody is a humanized anti-HM1.24
`antigen monoclonalantibody.
`
`The method according to claim 10, wherein the antibody is a humanized anti-
`parathyroid hormone-related peptide antibody (anti-PTHrP antibody).
`
`The method according to claim 10, wherein the antibody is a humanized anti-tissue
`factor antibody.
`
`The methodaccording to any one ofclaims 1 to 3, wherein the particles are removed by
`filtration througha filter.
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 2 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 2 of 40
`
`

`

`16.
`
`A method for manufacturing a purified antibody, which comprises the steps of the
`
`method accordingto any oneof claims | to 3.
`
`3
`
`
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 3 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 3 of 40
`
`

`

`ey
`
`VOSSIUS & PARTNER WY
`
`Patentanwdlte Rechtsanwalte
`
`Vossius & PARTNER °POB 86 07 67 * 81634 Minchen ° Germany
`
`European Patent Office
`
`80298 MUNICH
`
`EPO - Munich
`
`80
`19 April 2019
`
`EP 02 70 3958.5-2405
`Chugai Seiyaku Kabushiki Kaisha
`OurRef.: H2624 EP S3
`
`Miinchen, April 19, 2010
`UEX/MW/KSY
`
`to the Official Communication pursuant
`in response
`is
`This
`Article 94(3) EPC dated October 23, 2009.
`
`to
`
`Weherewith submit copies of an amendedclaimsset, whichis to serve as
`the basis for the further prosecution ofthe application.
`
`1.
`
`NATURE OF THE AMENDMENTS
`
`Claim 17 has been deleted.
`
`As none of the above amendments comprises subject-matter
`extending beyond the application as
`filed,
`they should be
`admissible within the meaning of Article 123(2) EPC.
`
`2.
`
`ARTICLE 123(2) EPC
`
`With the above amendments to the claims, the objection raised
`under Article 123(2) EPC should be rendered moot.
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 4 of 40
`
`PATENTANWALTE
`EUROPEAN PATENT ATTORNEYS
`EUROPEAN TRADEMARK ATTORNEYS
`OR. VOLKER VOSSIUS, DipI.-Chem.
`(bis 1992; danach in anderer Kanzlei)
`Dr. PAUL TAUCHNER, Dipl.-Chem. (of Counsel)
`Dr. DigTER HEUNEMANN, Dipl.-Phys. *
`DR. PETER A. RAUH, Dipl-Chem.
`Dr. GERHARD HERMANN, Dipl.-Phys.
`JOSEF SCHMIDT, Dipt.-ing.
`Dr. HANS-RAINER JAENICHEN, Dipl.-Biol.
`Dr. ALEXA Vv. UEXKULL, M.Sc.
`Dr. RUDOLF WEINBERGER, Dip!.-Chem.
`AXEL STELLBRINK, Dipt-ing.
`Dr. JOACHIM WACHENFELD, Biol.
`Dr. FRIEDERIKE STOLZENBURG, Dipl.-Biol.
`RAINER VIKTOR, Dipl.-Ing.
`DOr. NATALIA BERRYMAN, Dipl.-Chem.
`DR. JORGEN MEIER, Dipl.-Biol.
`DR. STEFAN FICKERT, Dipt.-Chem.
`ARNOLD ASMUSSEN, Dipl.-tng.(FH)
`ELARD SCHENCK ZU SCHWEINSBERG, Dipl.-Ing.
`Dr. DIRK HARMSEN, Dipt.-Chem.
`DR. KATHARINA HAAS, Dipl.-Chem
`DR. CHRISTIAN KILGER, Dipl.-Biot. *
`EUROPEAN PATENT ATTORNEYS
`Dr. RENATE BARTH, Dipt.-Chem.
`DR. URSULA HOFMANN, Dipi.-Chem.
`Dr. PETER EINMAYR, Dipt.-Chem.
`Or. WERNER BASTIAN, Oipl.-Biol. * *
`DR. OLAF MALEK, Dipt.-Biol.
`DR. MICHAELA WESSE, Apothekerin
`Dr. OLIVER SAR, Dipt.-Phys.
`Dr. AXEL LEINS, Dipl.-Phys.
`BARBARA BROSZAT, Dipt.-Phys.
`SILVAN LATSCHA, Dipl.-ing. ETH **
`Dr. ROGER ABSEHER, Biochem.
`RECHTSANWALTE
`DR. JOHANN PITz
`DR. THURE SCHUBERT
`DR. MATHIAS KLEESPIES, LL.M.
`BARBARA GUGGENMOS,Dipl -Chem.
`SIMONE SCHAFER
`JENNIFER CLAYTON-CHEN
`PAUL KRETSCHMAR
`DR. GEORG ANDREAS RAUH
`Dr. MARCUS V. WELSER, LL.M.
`Dr. STEFANIE NABROTZKI, LL.M.
`CONSULTANTS
`Or. CHRISTIAN GUGERELL,
`EUROPEAN PATENT ATTORNEY
`YOSHIKAZU ISHINO
`KIMIO TAKAHASHI
`JENNIFER L. ENMON, Ph.D., J.D.,
`REGISTERED U.S. PATENT ATTORNEY
`RICHARD ENMON, Ph.D. J.D.
`REGISTERED U.S. PATENT ATTORNEY
`
`MAIN OFFICE
`SIEBERTSTR. 3
`81675 MONCHEN/GERMANY
`
`POSTAL ADDRESS:
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`81634 MUNCHEN/GERMANY
`
`Tel.: +49-(0)89-413 04-0
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`/-400
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`
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`
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`trademarks@vossiusandpartner.com
`
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`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 4 of 40
`
`

`

`
`
`VOSSIUS & PARTNER 22
`
`3.
`
`ARTICLES83/84 EPC
`
`According to the Examiner, the invention of claims 1 and 2 is neither supported nor
`disclosedin the detailed description in the specification. Applicants respectfully disagree.
`
`In the examples of the present application, the affinity chromatographyis merely used to
`prepare a solution (an eluate) whose molarity is within the range of 0 to 100 mM but
`whose pHis not within the range of4 to 8. It should be noted that no particle is formed at
`this point. Then, the pH ofthe solution is adjusted to the range of pH 4 to 8, whereby
`particles containing contaminant DNAare formed.
`From the examples and the description in the specification,it is understood that the use of
`affinity chromatographyis not essential to form particles containing contaminant DNA,
`and that the specified conditions with regard to molarity and pH arecritical to particle
`formation.
`Furthermore, Applicants consider that a person skilled in the art could easily choose an
`appropriate means instead of affinity chromatography to carry out the method of the
`claims based onthe disclosure ofthe specification.
`Therefore,
`it is submitted that the specification of this application fully supports the
`claimed invention.
`
`Moreover, the Guidelines for Examination (Part C, ChapterIII, 6) state that
`
`“The Examiner shouldraise an objection of lack of support only if
`he has well-founded reasons. ... Where an objection is raised, the
`reasons should, where possible, be supported specifically by a
`published document.”
`
`It is thus submitted that the Examiner should providea rational evidence to support the
`assertion that the method of claims 1 and 2 is not enabled and hencethe invention of the
`claims is not supportedbythe specification, should she maintain this allegation.
`
`4,
`
`ARTICLE 54 EPC
`
`The Examiner asserts in the Official Communication that the method of claim 1 ofthis
`application lacks novelty over D3 (WO 95/22389), by referring to the observation
`submitted by a third party. However, Applicants submit that D3 does not disclose the
`feature of “a molarity of 0 to 100 mM”of claim 1.
`
`In the observation, the third party asserts that
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 5 of 40
`H264EPS3
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 5 of 40
`
`

`

`
`
`VOSSIUS & PARTNER 3ooSeSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSeseseeeeeeeeeee
`
`“The composition of said Elution Buffer is described on page 18,
`Table 1. It consists of 25 mM citrate, pH 3.5.”
`
`Thus, the third party asserts that the molarity of the citation satisfies the limitation of a
`molarity stipulated in the claimsof the present application.
`However,this assertion is not correct.
`
`D3 discloses the following:
`
`“After loading the column, it is washed with at least 3 column
`volumes of PBS containing 0.1 M glycine. The RSHZ-19 is
`eluted with a low pH buffer by applying approximately 3 column
`volumesof Elution Buffer.” (page 14, lines 20 to 23)
`
`and
`
`“The Protein A eluate is collected and adjusted to pH 3.5 by the
`addition of 2.5 M HCl.”(page 14, lines 32 to 33)
`
`Furthermore,it is shown in Table 1 of D3 that the PBS/glycine used to wash the column
`is composed of 20 mM sodium phosphate, 150 mM sodium chloride, and 0.1 M glycine.
`
`From these passages of D3, it can be derived that the citation discloses the following
`feature:
`
`Whenthe column was washed with the PBS/glycine, the columnis filled with a solution
`having a molarity of 270 mM (20 mM + 150 mM + 100 mM). Then, approximately three
`column volumes of Elution Buffer is applied to the column to elute RSHZ-19; and
`Table 1 showsthat the elution bufferis a solution of 25 mM citrate.
`
`At the endof eluting RSHZ-19,it is obvious that a part of the three column volumesof
`the Elution Buffer remains in the column, andtherest of the Elution Buffer is contained
`in the eluate. As a matter of course, the PBS/glycine buffer, which was in the column
`before the elution, is also contained in the eluate. Therefore, the eluate contains the 25
`mM Elution Buffer and the 270 mM PBS/glycine buffer.
`Then, 2.5 M of HCl is addedto the eluate to adjust the pH ofthe eluate to 3.5, Tris is also
`added to readjust the pH to 5.5, and the eluate having an adjusted pH of 5.5is filtered
`througha prefilter.
`From these above,it is self-speaking that the molarity of the eluate having an adjusted pH
`of 5.5 exceeds 100 mM.
`
`H2624 EP S3
`
`PFIZER,INC., IPR2017-01357, Ex. 1043, p. 6 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 6 of 40
`
`

`

`
`
`VOSSIUS & PARTNER 4aa
`
`Therefore, the molarity stipulated in the present invention clearly is not disclosed in the
`citation, and the present invention is novel over D3.
`
`5.
`
`ARTICLE 56 EPC
`
`One of the characteristic features of the present invention for removing contaminant
`DNAasparticles from an antibody-containing sample is that the antibody-containing
`sample is changed to an aqueoussolution containing the antibody and having a molarity
`of 0 to 100 mM,and a pH offrom4to8, at the sametime.
`Thus, satisfying each of the limitations at
`the same time is critical
`to the present
`invention, whereby contaminant DNA can be effectively removed as particles from a
`sample without the need to use a complicated process.
`The importance ofsatisfying the limitations at the same time is clearly understandable
`from the working examples ofthis application.
`
`D3 is silent about a method for removal of contaminant DNA as particles from a sample,
`especially, under the specified conditions.
`Furthermore, as D3 includes the description
`
`“the pH 5.5 adjustment prepares the solution for cation exchange
`chromatography (CEC)”
`
`on page15,lines 3 and4,it is understood that the procedure describedin D3 is merely to
`prepare a solution for further cation exchange chromatography but is not intended to
`remove contaminant DNA. Moreover, D3 doesnot provide any hint to adjust the molarity
`of a solution to form particles containing contaminants such as DNA.
`Thus, Applicants consider that D3 doesnot provide any motivation for a person skilled in
`the art
`to utilize the method of D3 to remove contaminant DNA from a solution.
`Applicants also considerthat a personskilled in the art would not be able to conceive of
`the importanceofthe limitations (molarity and pH)ofthe present invention.
`
`From these viewpoints, it is submitted that the presentinvention is inventive over D3.
`
`6.
`
`REQUESTS
`
`With the above explanations and amendmentsto the claims, Applicants havesatisfied all
`requirementsset forth in the Communication.
`
`H2624 EP $3
`
`PFIZER,INC., IPR2017-01357, Ex. 1043, p. 7 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 7 of 40
`
`

`

`
`
`VOSSIUS & PARTNER 5aae
`
`If, however, the Examining Division does not agree with the above, it is requested that
`either a further Communication pursuant to Article 94(3) EPC and Rule 71(2) EPC ora
`summons to attend oral proceedings according to Article 116(1) EPC be issued. If
`deemed expedient, an informal interview is requested. The undersigned is prepared to
`discuss minor amendmentsoverthe phone.
`
`r. Alexa von Vexkiill
`European Patent Attorney
`
`Encl:
`Amendedclaimsset
`
`H2624 EP S3
`
`PFIZER,INC., IPR2017-01357, Ex. 1043, p. 8 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 8 of 40
`
`

`

`Datum
`Date
`Date
`
`30.03.2011
`
`Blatt
`Sheet
`Feuille
`
`1
`
`Anmelde-Nr:
`Application No: O2 703 958.5
`Demande n°:
`
`The examination is being carried out on the following application documents
`
`Description, Pages
`
`1-17, 19-24, 26__filed with entry into the regional phase before the EPO
`
`18, 25
`
`received on
`
`27-10-2003
`
`with letter of
`
`24.10.2003
`
`Claims, Numbers
`
`1-16
`
`received on
`
`19-04-2010
`
`with letter of
`
`19-04-2010
`
`Reference is madeto the following documents; the numbering will be adhered to in
`the rest of the procedure.
`
`D2
`
`D3
`
`EP 1020 522A
`
`WO 95/22389 A1
`
`1
`
`Amendments(Article 123(2) EPC)
`
`Upon reconsideration, no basis can be foundin the application as originally
`filed for the feature "... wherein the molarity of the adjusted sample/eluate is O
`to 100 mM..." in combination with the methodsof claim 2, step 2) and claim 3,
`step 2).
`
`The application as originally filed does not disclose that the samplein the
`methodof claim 2 has a molarity of 0 to 100 mM after the neutralizing step.
`The application also does not disclose that the adjusted eluate in the method
`of claim 3 has a molarity of 0 to 100 mM. The application only disclosesthat
`the buffer used for elution of the antibody from the column must have a low
`conductivity.
`
`The following comments will not take the above objected amendmentinto
`account.
`
`2
`
`Novelty (Article 54 EPC)
`
`Due to the unallowable amendments mentioned above, the question of
`novelty is reconsidered. As a result, novelty of the claims is objected again in
`view of D2 and D3 for the reasons already outlined in the official
`communication of 09.08.2007 and in the third party observations filed with
`letter of 04.04.2008. According thereto, D2 is novelty-destroying for claims 3,
`
`EPO Form 2906 01.91TRI
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 9 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 9 of 40
`
`

`

`Datum
`Date
`Date
`
`30.03.2011
`
`Blatt
`Sheet
`Feuille
`
`2
`
`Anmelde-Nr:
`Application No: O2 703 958.5
`Demande n°:
`
`5-10, 12, 15 and 16 and D3 is novelty-destroying for claims 1-6, 8-10, 15 and
`16.
`
`3
`
`Inventive step (Article 56 EPC)
`
`Due to the unallowable amendments mentioned above, the question of
`inventive step is reconsidered. As a result, the claims are objected again as
`lacking an inventive step in view of D2 and D9 for the reasons already
`outlined in the official communication of 09.08.2007 andin the third party
`observations filed with letter of 04.04.2008. According thereto, the subject-
`matter of claims 3-15 is obvious in view of D2 and the subject-matter of claims
`1-16 is obvious in view of D3.
`
`4
`
`Sufficiency of disclosure and support in the description (Articles 83/84 EPC)
`
`The objection is maintained in its entirety that the application does not provide
`adequate guidance to perform the methodsof claims 1 and 2 for the reasons
`already outlined in detail in the previous communications. The specification
`does not show that the use of an aqueous solution of pH 4 to 8 with a low
`conductivity alone without a prior step of affinity chromatographyis sufficient
`to remove DNA contamination from an antibody-containing sample. Therefore,
`claims 1 and 2 are not enabled and also not supported by the description.
`
`5
`
`Non-Unity (Article 82 EPC)
`
`Due to the unallowable amendments mentioned above, the question of unity is
`reconsidered. As a result, the claims are objected again as lacking unity for
`the reasons already outlined in the official communication of 09.08.2007.
`Whenfiling new claims, the applicant is requested to establish unity among
`the claims.
`
`6
`
`The applicant is requested to file new claims which take account of the above
`comments. However, the attention of the applicant is drawn to the fact that the
`application may not be amendedin such a waythat it contains subject-matter
`which extends beyond the content of the application asfiled (Article 123(2)
`EPC).
`
`Handwritten amendments may be submitted, however, an additional retyped
`version of the amendedclaims is requested.The applicant is requested to
`clearly identify the amendments carried out, irrespective of whether they
`concern amendments by addition, replacement or deletion, and to indicate the
`passagesof the application as filed on which these amendments are based.
`
`EPO Form 2906 01.91TRI
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 10 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 10 of 40
`
`

`

`European
`Patent Office
`Office européen
`des brevets
`
`Europaisches Patentamt
`:
`| ll | I ll l ll | ll |ll
`
`
`
`
`
`
`
`Vossius & Partner
`Siebertstrasse 4
`81675 Munchen
`ALLEMAGNE
`
`L
`
`/
`
`|
`
`European Patent Office
`80298 MUNICH
`GERMANY
`Tel: +49 89 2399 0
`Fax: +49 89 2399 4465
`
`rei
`
`Name: Durand-Fleith, O
`Tel: +49 89 2399 - 8302
`or call
`#81 (0)70 840 48 00
`.
`.
`Name:SommerBirgit,
`Tel: +49 89 2399 - 7099
`
`
`
`
`
`
`
`Ref.
`H 2624 EP $3
`
`Date
`30.03.2011
`
`
`
`Application No.
`02 703 958.5 - 2405
`
`Applicant
`CHUGAI SEIYAKU KABUSHIKI KAISHA
`
`Communication pursuantto Article 94(3) EPC
`
`The examination of the above-identified application has revealed that it does not meet the requirements of the
`European Patent Convention for the reasons enclosed herewith. If the deficiencies indicated are not rectified
`the application may be refused pursuantto Article 97(2) EPC.
`
`You are invited to file your observations and insofar as the deficiencies are such asto be rectifiable, to correct
`the indicated deficiencies within a period
`
`of
`
`4 months
`
`from the notification of this communication, this period being computed in accordance with Rules 126(2) and
`131(2) and (4) EPC. One set of amendments to the description, claims and drawingsis to be filed within the
`said period on separate sheets (R. 50(1) EPC).
`
`If filing amendments, you mustidentify them and indicate the basis for them in the application asfiled. Failure
`to meet either requirement may lead to a communication from the Examining Division requesting that you
`correct this deficiency (R. 137(4) EPC).
`
`Failure to complywith this invitation in due time will result in the application being deemed to be
`withdrawn(Art. 94(4) EPC).
`
`
`Registered Letter
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 11 of 40
`EPO Form 2001 04.10CSX
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 11 of 40
`
`

`

`Date 30.03.2011
`
`Sheet 2
`
`Application No.: 02 703 958.5
`
`s Pate,
`
`"am,
`
`*-gor®
`
`
` xoSx
`ae.
`
`.
`
`o>2Uer04
`uead™x~
`
`>a
`
`: 0o
`
`“b
`% ‘3,
`a
`tng aoipO
`
`.
`
`a
`
`Sommer, Birgit
`Primary Examiner
`For the Examining Division
`
`Enclosure(s):
`
`2 pages reasons (Form 2906)
`
`
`Registered Letter
`EPO Form 2001 04.10CSX
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 12 of 40
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 12 of 40
`
`

`

`VOSSIUS & PARTNER ©)
`
`Patentanwaite Rechtsanwalte
`
`Vossius & PARTNER * POB 86 07 67 * 81634 Munchen * Germany
`European Patent Office
`~
`
`80298 MUNICH
`
`actww
`O° e®
`\.
`gos gt
`a
`
`EP 02 70 3958.5-2405
`Chugai Seiyaku Kabushiki Kaisha
`Our Ref.: H2624 EP $3
`
`Miinchen, November 22, 2012
`UEX/MW/KSY
`
`to
`in response to the Official Communication pursuant
`is
`This
`Article 94(3) EPC dated May 26, 2012 in the above-identified application.
`
`1.
`
`ARTICLE 123(2) EPC
`
`According to the Examiner, the feature “wherein the molarity of
`the adjusted eluate is 0 to 100 mM”included in present claim 1 is
`notbased onthespecification of the present application asfiled.
`
`Applicant disagrees and submits that the feature finds a clear and
`unambiguous basis in the specification as filed, particularly on
`pages 10 to 12, and in originalclaim 1.
`|
`As can be seen from original claim | and the. disclosure on
`page 10, lines 1 to 2, the conversion of the sample into a neutral
`aqueous solution of low conductivity is an essential feature of the
`method according to the present invention. Specific embodiments
`of the methodare described on pages 10 to 12 of the specification.
`From the description on pages 10 to 12,
`it can be. clearly
`understood that the adjusted eluate in present claim. 1 corresponds
`to “a neutral1papeous solution of low conductivity”. Lines 5 to 8 of
`ER,
`INC., IPR2017-01357, Ex. 1043, p. 13 of 4
`
`PATENTANWALTE - DEUTSCHLAND
`EUROPEAN PATENT ATTORNEYS
`EUROPEAN TRADEMARK ATTORNEYS
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`4) Japanese Patent Attorney
`2) Fachanwaltfiree esRechtsschutz
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`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 13 of 40
`
`

`

`
`
`a~VOSSIUS & PARTNER — 2eri
`
`
`
`page 10 clearly define that “a neutral aqueoussolution of low conductivity” has a pH of 4
`to 8 and a molarity of 0 to 100 mM.
`,
`
`Moreover, the feature “wherein the molarity of the adjusted eluate is 0 to 100 mM”in
`present claim 1 can also be derived from, for example, Table 2 on page 18 of the English
`text.
`—
`As explained, with respect to Table 2 on page 18, 0 mM, 50 mM,or 100 mM NaCl was
`added to 2.5 mM HCI sample solutions and the pH ofthe solutions were adjusted by
`using Tris. After pH adjustment, the turbidity of the sample solutions to which 0 mM or
`50 mM NaCl was added increased remarkably ‘because of formation of particles
`containing contaminant DNA. The removal ofthe particles by filtration provided ‘low-
`DNAsolutions. However, the increase in turbidity of the sample solution to which
`100 mM NaClwasadded was small compared with the above two samples and the DNA
`content of the solution after filtration was high. This is because the molarity of the
`sample solution to which 100 mM NaClwas added (2.5 mM HCI plus 100 mM NaCl)is
`over 100 mM.
`.
`oe
`|
`Thus, the feature “wherein the molarity of the adjusted eluate is 0 to 100 mM” in present
`claim 1 finds a clear basis in the above disclosure of the specification as filed.
`
`in view of the above explanations,
`Thus,
`Article 123(2) EPC should have been overcome.
`
`the objections raised with regard to
`
`2.
`
`NOVELTY
`
`Asdiscussed in detail above, the objectionsraised with regard to Article 123(2) EPC are
`clearly unjustified.
`
`lacks novelty over’ D3
`the method of claim 1
`According to the Examiner,
`(WO 95/22389), inter alia referring to third party observations filed on April 4, 2008.
`Applicant submits that D3 does notdisclose the feature of “a molarity of 0 to 100 mM”
`of claim 1.
`
`In the observation, the third party asserts that.
`
`“The composition of said Elution Buffer is described on page 18,
`Table 1. It consists of 25 mM citrate, pH 3.5.”
`
`Thus, according to the third party, the molarity of the citation satisfies the limitation of
`the molarity cited in the claimsof the presentapplication.
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 14 of 40
`
`H2624 EP $3
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 14 of 40
`
`

`

`
`
`ooVOSSIUS & PARTNER 3nn
`
`
`
`However,this assertion is not correct.
`D3 discloses the following: .
`
`“After loading the column, it is washed with at least 3 column
`volumes of PBS containing 0.1 M glycine. The RSHZ-19 is
`eluted with a low pH buffer by applying approximately 3 column
`volumesof Elution Buffer.” (page 14,lines 20 to 23)
`
`and
`
`“The Protein A eluate is collected and adjusted to pH 3.5 by the
`addition of 2.5 M HCI.”(page 14,lines 32 to 33)
`
`Furthermore, it is shown in Table 1 of D3 that the PBS/glycine used to wash the column
`is composed of 20 mM sodium phosphate, 150 mM sodium chloride, and 0.1 M glycine.
`
`it can clearly be derived that the citation discloses the
`
`From these passages of D3,
`following feature:
`When the column is washed with the PBS/glycine,the column is filled with a solution
`having a molarity of 270 mM (20 mM + 150 mM + 100 mM). Then, approximately three
`column volumes of Elution Buffer are applied to the column to elute RSHZ-19; and
`Table 1 showsthat the elution buffer is a solution of 25 mM citrate.
`
`At the end of eluting RSHZ-19, it is obvious that a part of the three column volumes of
`the Elution Buffer remains in the column,and therest of the Elution Buffer is contained
`in the eluate. As a matter of course, the PBS/glycine buffer, which was in the column
`before the elution, is also contained in the eluate.. Therefore, the eluate contains the 25
`mM Elution Buffer and the 270 mM PBS/glycine buffer.
`_
`Then, 2.5 M of HClis added to the eluate to adjust the pH ofthe eluate to 3.5, Tris is also
`added to readjust the pH to 5.5, and the eluate having anadjusted pH of5.5 is filtered
`through a prefilter.
`From the above,it is obvious that the molarity of the eluate having an adjusted pH of5.5
`exceeds 100 mM.
`
`Therefore, the molarity stipulated by the present invention clearly is not disclosed in the
`citation, and the present invention is novel over D3.
`
`As already noted in the Official Communication pursuant to Article 94(3) EPC dated
`October 23, 2009, the subject-matter as presently claimed should be novel over D2.
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 15 of 40
`
`H2624 EP S3
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 15 of 40
`
`

`

`~VOSSIUS & PARTNER
`
`an
`
`4
`
`3.
`
`INVENTIVE STEP
`
`As submitted previously, one of the characteristic features of the present invention for
`removing contaminant DNAasparticles from an antibody-containing sample is that the
`antibody-containing sample is converted to’ an aqueous solution containing the antibody
`
`and having a molarity of 0 to 100 mM,and a pH offrom4to 8, at the same time. .
`Thus, satisfying each of the limitations at the same time is critical
`to the present
`invention, whereby contaminant DNA can be effectively removed as particles from a
`sample without the need to use a complicated process.
`The importance of satisfying the limitations at the same time is clearly understandable
`from the working examples ofthis application.
`
`D3 is silent about a method for removal of contaminant DNA as particles from.a sample,
`especially, underthe specified conditions.
`©
`-
`Furthermore, as D3 cites on page 15, lines 3 and 4 that
`
`“the pH 5.5 adjustment prepares the solution for cation exchange
`chromatography (CEC)”,
`
`it is understood that the procedure described in D3 is merely to prepare a solution for
`further cation exchange chromatography but
`is not
`intended to remove contaminant
`DNA. Moreover, D3 does not provide any hint to adjust the molarity of a solution to
`form particles containing contaminants such as DNA.
`Thus, Applicant submits that D3 does not provide any motivation for a person skilled in
`the art to use the method of D3 to remove contaminant DNA from a solution. Applicant
`also submits that a person skilled in the art. would not be able to conceive the importance
`of the limitations (molarity and pH) of the present invention.
`
`Thus, the subject-matter as presently claimed is inventive over D3.
`
`4.
`
`REQUESTS
`
`With the above explanations, Applicant has satisfied all. requirements set forth in the
`Communication.
`
`If, however, the Examining Division does not agree with the above, it is requested that
`either a further Communication pursuant to Article 94(3) EPC and Rule 71(2) EPC or a
`summons to attend oral proceedings according to Article 116(1) EPC be issued. If
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 16 of 40
`H2624 EP $3
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 16 of 40
`
`

`

`- VOSSIUS & PARTNER
`
`5
`
`deemed expedient, an informal interview is requested. The undersigned is prepared to
`discuss minor amendmentsover the phone.
`
`ble
`
`Dr. Michaela Wefge
`European Patent Attorney
`
`H2624 EP $3
`
`PFIZER,INC., IPR2017-01357, Ex. 1043, p. 17 of 40
`,
`
`PFIZER, INC., IPR2017-01357, Ex. 1043, p. 17 of 40
`
`

`

`Datum
`Date
`Date
`
`24.01.2013
`
`Blatt
`Sheet
`Feuille
`
`1
`
`Anmelde-Nr:
`Application No: O02 703 958.5
`Demande n°:
`
`The examination is being carried out on the following application documents
`
`Description, Pages
`
`1-17, 19-24, 26
`
`filed with entry into the regional phase before the EPO
`
`18, 25
`
`received on
`
`27-10-2003
`
`__-with letter of
`
`24.10.2003
`
`Claims, Numbers
`
`1-14
`
`received on
`
`28-09-2011 with letter of
`
`28-09-2011
`
`Referenceis madeto the following documents; the numbering will be adheredto in
`the rest of the procedure.
`
`D2
`
`D3
`
`EP 1020 522A
`
`WO 95/22389 A1
`
`1
`
`Amendments(Article 123(2) EPC)
`
`The objection is maintained that no basis can be found in the application as
`originally filed for the feature "... wherein the molarity of the adjusted sample/
`eluate is 0 to 100 mM..." used in the method of claim 1, step 2).
`
`The applicant cited with letter of 22.11.2012 pages 10 to 12 of the description,
`page 18, table 2 of the description and original claim 1 as alleged basis for
`this feature.
`
`Only the passage at page 10, line 23 - page 11, line 6 deals with a method
`comprising all steps of the claimed method. Said passage doesnotdisclose
`that the sample in the method of claim 2 has a molarity of 0 to 100 mM after
`the neutralizing step. The neutralization step is further described e.g. on page
`11, line 28