KCJNIG - SZYNKA - T||_|\/IANN - Von RENESSE
`
`PATENTANWALTE ' F’AFlTN:—lSCHAET rnbB
`
`Konig 0 Szynka - Tilrnann - von Penesse
`__
`Postfaon ‘I
`‘I D9 48 - 413509 Dusseldorf
`
`Europaisches Patentamt
`
`..
`Munchen
`
`Confirmation by mail
`
`Dr. Reirnar Konig, Dlpl.-|ng.1*1*
`Gregor S. Konig, Dipl.-Biol.
`Dr. Dirl< Szynl<a, Dip.-Ehys.
`Dr. D. v. Renesse, Dip|.—3lol.
`/Ix
`\/lax W. Tilmann, Dipl.-ng.
`
`2*
`
`4*
`
`Darla Roth, Dlpl.-Bio|.1*
`2
`Dr. Tobias Srnorodin, Dip .-Dhys.’|
`Dr. Lars Hemsath, Dipl.-Eiooflern.
`
`D.Rbtl_"l<,'.— .“
`F‘
`O er
`LJC 8 Dip Bloohernq
`Dr. Jorn Verhasselt, Dipl.-Dhys.
`
`German Patent Attorneys
`European Patent Attorneys
`European Trademark Attorneys
`
`European Design Attorneys
`Fame”
`3ussEI_Dol=aI=“
`
`l\/ICJNCHENE
`
`January 17, 2014
`
`Your reference:
`Our reference:
`
`54 546 K
`
`Re.:
`
`Opposition - European Patent 03 748 439.1—1412/ 1 528 933
`Patentee: AbbVie Biotechnology Ltd.
`
`OPPONENTS
`
`1.
`
`We herewith file Patentee’s response to the oppositions against EP 1 528 933. The
`
`oppositions were filed by four opponents, Ulrich Storz (Opponent 1), Alfred E.
`
`Tiefenbacher GmbH & Co. KG (Opponent 2), TEVA Pharmaceuticals Industries Ltd.
`
`(Opponent 3) and William Edward Bird (Opponent 4),
`
`(collectively referred to as
`
`“Opponents”).
`
`2.
`
`Patentee herewith files
`
`DOCUMENTS
`
`A consolidated list of all documents filed by all parties (D1 to D49)
`
`Auxiliary Requests 1A— 11B
`
`D38 Comparative study re D11 (Coriolis Report)
`
`D39 Salteld, J et al., ”GENERATlON OF FULLY HUMAN ANTl—TNF ANTIBODY
`
`D2E7”, Arthritis & Rheumatism, Vol. 41, No. 9 (Supplement), September 1998, S57
`
`0 TEL +49-21 ’| -130 ED EDD 0 FAX +49-2’! 1 -3D 2D 2D ’|
`’l
`D-4-D545 DUSSELDORF 0 |V|CJNCHENWEFlTHEFl STFL ’I
`WWW.KSVFl.NET 0 E-|\/|A||_: d@KSVFl.NET
`
`’|
`
`Eingetragen helm Amtsgerioht Essen unter Nummer PR ’l 538 0 Sitz: Dusseldorf
`Kanzlei l\/ltllnohenz D-B1479 l\/ltllnohen - Sollner Strssse 9
`
`
`
`Ex. 1053 - Page 1 of 58
`
`AMGEN INC.
`Exhibit 1053
`
`

`

`KC]N|(3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
`
`2
`
`D40 Kempeni, Joachim, “Update on D2E7: a fully human anti—tumor necrosis factor of
`
`monoclonal antibody”, Ann Rheum Dis 2000; 59 (Suppl I): 144-145
`
`D41 Rau, R, “Adalimumab (a fully human anti—tumor necrosis factor or monoclonal
`
`antibody) in the treatment of active rheumatoid arthritis: the initial results of five
`
`trials”, Ann Rheum Dis 2002; 61 (Suppl ll): ii70-ii73
`
`D42 Weinblatt, Michael E. et al., “Ada|imumab, a Fully Human Anti-Tumor Necrosis
`
`Factor of Monoclonal Antibody, for the Treatment of Rheumatoid Arthritis in Patients
`
`Taking Concomitant Methotrexate”, Arthritis & Rheumatism, Vol. 48, No. 1, January
`
`2003, pp. 35-45
`
`D43 Assignment of the priority rights
`
`D44 Certificate of Amalgamation
`
`D45 Request of the change of name of the applicant of January 12, 2005
`
`D46 Recordal of the name change of February 4, 2005
`
`D47 Extract of relevant results of D30
`
`D48 Expert opinion of Professor Dr. Gerhard Winter
`
`D49 EP1 406 656 B1
`
`REQUESTS
`
`3.
`
`4.
`
`5.
`
`6.
`
`Patentee requests the maintenance of the Opposed Patent on the basis of the claims as
`
`granted.
`
`As a measure of precaution, auxiliary requests 1
`
`to 11 are filed herewith. Patentee
`
`reserves the right to file further auxiliary requests.
`
`Any amendment made during the opposition proceedings is not to be understood as an
`
`act of abandoning any subject matter or request.
`
`Patentee requests Oral Proceedings under Article 116 EPC in the event the Opposition
`
`Division intends to revoke the Opposed Patent as granted.
`
`7.
`
`Claim 1 as granted in the Opposed Patent has the following features:
`
`FEATURES OF CLAIM 1 AS GRANTED
`
`A liquid aqueous pharmaceutical formulation
`
`Ex. 1053 — Page 2 of 58
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`Ex. 1053 - Page 2 of 58
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`

`

`KCJNIG ' SZYNKA ' TILIVIANN ' vom RENESSE
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`3
`
`having a pH of 4 to 8 and comprising
`
`(a)
`
`20 to 130 mg/ml of a human IgG1 anti—Tumor Necrosis Factor alpha
`
`(TNFor) antibody
`
`—
`
`comprising a light chain variable region comprising the amino acid
`
`sequence of SEQ ID NO:
`
`1 and a heavy chain variable region
`
`comprising the amino acid sequence of SEQ ID NO: 2,
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`(h)
`
`10-14 mg/ml of mannitol,
`
`0.1-5 mg/ml of Polysorbate 80,
`
`1-1.5 mg/ml of citric acid monohydrate,
`
`0.25-0.5 mg/ml of sodium citrate,
`
`1.25-1.75 mg/ml of disodium phosphate dihydrate,
`
`0.7-1.1 mg/ml of sodium dihydrogen phosphate dihydrate, and
`
`6.0-6.4 mg/ml sodium chloride.
`
`INTRODUCTION AND CONTRIBUTION TO THE ART
`
`8.
`
`The Opposed Patent claims a novel formulation for an lgG1 antibody. The antibody in the
`
`claim is further defined by its light chain and heavy chain variable region sequences. The
`
`skilled person understands this as defining a D2E7 antibody.
`
`9.
`
`D2E7 is a recombinant
`
`fully human anti—Tumor Necrosis Factor alpha (TNF alpha)
`
`antibody characterized by its specific light chain and heavy chain variable region
`
`sequences, and was well known at the priority date as being the first recombinant fully
`
`human anti—Tumor Necrosis Factor alpha (TNF alpha) antibody.
`
`10.
`
`The present formulation is a landmark formulation because it provides surprising storage
`
`stability for D2E7. Even more surprising is that the storage stability is provided at high
`
`antibody concentrations of at least 20 mg/ml and in addition even up to 130 mg/ml.
`
`Achieving stability of the pharmaceutical antibody at high concentrations is especially
`
`valuable for easy administration to the patient.
`
`11.
`
`The prior art cited by the Opponents confirms the contribution of the present invention. It
`
`shows all kinds of antibodies and various formulations, excipients and recommendations,
`
`none of which leads to the claimed combination. What is more, none provides even a hint
`
`to use the formulation as claimed, in particular a combination of a citrate and phosphate
`
`buffer, to achieve storage stability over a broad range of high antibody concentrations.
`
`Ex. 1053 — Page 3 of 58
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`Ex. 1053 - Page 3 of 58
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`KC]N|(3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
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`4
`
`I.
`
`ART. 123 (2), ART. 100 (C) EPC - NO ADDED MATTER
`
`12.
`
`The Opponents are of the opinion that the Opposed Patent extends beyond the content of
`
`the application as filed. Patentee sets out below why this position is not justified in the
`
`light of the disclosure of the original application as understood by the skilled person.
`
`13.
`
`We first show that the subject matter of claim 1 of the Opposed Patent has basis in the
`
`application as originally filed (Section A.). We then show that the antibody defined in claim
`
`1 has the light chain and heavy chain variable regions of D2E7 (Section B.). D2E7 is
`
`disclosed in the application as filed as the most preferred embodiment for the anti—TNFor
`
`antibody of the claimed formulation. This understanding is supported by the common
`
`general knowledge the skilled person had at the priority date regarding the existence and
`
`specific characteristics of the well—known D2E7 antibody including its published amino
`
`acid sequences as shown by a number of prior published documents.
`
`14.
`
`It cannot be disputed that “D2E7” is disclosed in the original application and in the priority
`
`document. Furthermore, both documents disclose D2E7 as being the most preferred
`
`embodiment. As D2E7 is another way of defining the sequences of claim 1
`
`(shown
`
`below), every aspect of the D2E7 disclosure in the original application (and in the priority
`
`document) supports claim 1 as granted.
`
`15.
`
`The strategy of the Opponents was to attack the performed correction of the antibody
`
`sequence as unallowable under Rule 139 EPC. However,
`
`it
`
`is a fact that the claim as
`
`granted relies on the sequence listing as corrected in the Opposed Patent and there is no
`
`longer a sequence error in the Opposed Patent. Consequently, the actual attack under
`
`Art. 123 (2) EPC is the allegation that the antibody defined in the claim has no basis in the
`
`original disclosure. The whole Art. 123 (2) EPC attack can be discussed (and rebutted)
`
`completely, irrespective of the originally filed sequence listing or any sequence error in the
`
`original application, because the original application already discloses the term D2E7 and
`
`the antibody features detailed in claim 1. The sequence information in claim 1
`
`is
`
`understood in the prior art as defining D2E7. Thus, there is no need for a sequence listing
`
`in the original application to start with.
`
`16.
`
`In addition, as shown below in Section C., the original application (as well as the priority
`
`document) validly incorporates D2E7 into their disclosure by reference (see, e.g. page 15,
`
`lines 19 to 22 of the original application) and thus the claimed features are the features
`
`attributed to D2E7 in the prior art. The result is that claim 1 of the Opposed Patent can
`
`rely on the initial disclosure (and priority disclosure) without any regard to the sequence
`
`listings.
`
`Ex. 1053 — Page 4 of 58
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`Ex. 1053 - Page 4 of 58
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`KC]N|(3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
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`5
`
`17.
`
`Nevertheless, we also show in detail below in Section D. why the sequence correction
`
`was allowable based on the information in the original application itself.
`
`18.
`
`Thus, the Examining Division was right in allowing correction of the sequence under Rule
`
`139 EPC for multiple reasons.
`
`19.
`
`Further arguments of the Opponents are addressed in Section E. and the disclosure of
`
`the citric acid monohydrate is shown in Section F.
`
`A. BASIS FOR THE COMBINATION OF FEATURES OF CLAIM 1
`
`20.
`
`The combination of
`
`features of claim 1
`
`of
`
`the Opposed Patent
`
`is directly and
`
`unambiguously disclosed in the application as originally filed. This becomes evident from
`
`the analysis of the general teaching of the application as filed as well as from the specific
`
`disclosure provided therein:
`
`21.
`
`The application as filed teaches a formulation for the well—known antibody D2E7 that is
`
`defined by certain technical features (|gG1 heavy chain constant region and specific
`
`sequences for the light chain and heavy chain variable regions). These features were
`
`known to the skilled person at the priority date as being attributed to D2E7.
`
`In addition
`
`these specific features form part of the disclosure of the application as filed due to the
`
`reference to D12 and D24 in the application as filed on page 12, lines 3-5 and lines 29-31,
`
`and page 15, lines 21 and 22. The disclosure of D12 and D24 includes the sequence
`
`information of D2E7. That D2E7, as understood by the skilled person at the priority date,
`
`includes the features of the antibody of claim 1
`C.
`
`is shown in detail below in Sections B. and
`
`22.
`
`In claim 1
`
`the applicant, rather than just using the name D2E7, simply used a more
`
`detailed way to identify the sequences of D2E7.
`
`23.
`
`The application discloses a new and inventive formulation for the well—known antibody
`
`D2E7 (and is not directed to a novel antibody compound). The few variations of the amino
`
`acid sequence disclosed in the application have no weight in the overall disclosure. D2E7
`
`is the most preferred antibody of the formulation that
`
`is specifically described in the
`
`application and, indeed, the antibody exemplified in the working examples.
`
`24.
`
`The focus of the application on D2E7 as the most preferred antibody of the formulation
`
`becomes clear upon analysis of the structure of the description, all examples and the
`claims.
`
`a.
`
`The summary section of
`
`the application focuses on D2E7 as the preferred
`
`embodiment by disclosing a certain aspect of the invention and then repeatedly and
`
`continuously tying this to D2E7 by repeating that this applies to D2E7:
`
`“In still
`
`Ex. 1053 — Page 5 of 58
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`Ex. 1053 - Page 5 of 58
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`KC]N|(3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
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`8
`
`another embodiment, the antibody is D2E7” (page 3, lines 27/28), — “In yet another
`
`embodiment, the antibody is D2E7” (page 3, line 35), “In a further embodiment, the
`
`antibody is D2E7’ (page 4 lines 3/4).
`
`b.
`
`A multitude of further sections relate specifically to D2E7 (e.g. page 7,
`
`line 15 or
`
`page 15, line 14).
`
`c.
`
`Page 16, lines 18 to 19 teach D2E7 as the preferred embodiment:
`
`“In another preferred embodiment, the antibody is D2E7”
`
`d.
`
`Page 16, lines 18 to 22 under “Preparation of the Formulation” teach D2E7 as the
`
`preferred embodiment then followed by the combination and details of the claimed
`
`excipients on page 17 and 18.
`
`e.
`
`Page 22, lines 2 to 3 explicitly state, that D2E7 is the most preferred embodiment:
`
`"In the most preferred embodiment, the antibody is D2E7 "
`
`f.
`
`This is repeated on page 22, line 10:
`
`“In the most preferred embodiment, the antibody is D2E7”
`
`g.
`
`h.
`
`Table 1, page 19 discloses a specific formulation with D2E7
`
`The working example for stability studies was conducted with D2E7 (page 29, lines
`
`31 and 33 and table 2) ,
`
`i.
`
`The specific antibody of original claims 12 and 22 is D2E7.
`
`25.
`
`The most preferred antibody of the original application is thus D2E7. There cannot be any
`
`serious doubt
`
`that
`
`the skilled person readily relates all statements and all specific
`
`information given elsewhere in the application in particular to D2E7.
`
`26.
`
`Thus, also the specific embodiments of the invention are disclosed in the application as
`
`preferred in combination with D2E7 (including |gG1 as heavy chain constant region). The
`
`combination of features as claimed is disclosed on page 17, last paragraph to page 18,
`
`last paragraph. This understanding of the disclosure is supported by the original claims
`
`and by example 1.
`
`27.
`
`The last paragraph on page 17 discloses that a preferred embodiment of the invention
`
`relates to a formulation with a “buffer system which contains citrate and phosphate” to
`
`maintain a pH range of about 4 to 8 (lines 29/30). In the same paragraph this citrate and
`
`phosphate buffer system is exemplified by three similar but distinct embodiments. The
`
`three embodiments all contain the same components and only differ in their respective
`
`quantities. One embodiment includes (page 18, lines 1 to 5)
`
`a.
`
`b.
`
`1-1.5 mg/ml of citric acid (i.e., citric acid monohydrate, supra),
`
`0.25 to 0.5 mg/ml of sodium citrate
`
`Ex. 1053 — Page 6 of 58
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`Ex. 1053 - Page 6 of 58
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`KC]N|(3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
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`7
`
`c.
`
`d.
`
`e.
`
`1.25-1.75 mg/ml of disodium phosphate dihydrate
`
`0.7 to 1.1 mg/ml of sodium dihydrogen phosphate dihydrate and
`
`6.0 to 6.4 mg/ml sodium chloride.
`
`28.
`
`This combination of buffer components and their respective quantities are identical with
`
`the respective features of claim 1 as granted.
`
`29.
`
`Notably,
`
`lines 5-6 of page 18 further disclose that the pH of the formulation can be
`
`adjusted with sodium hydroxide, meaning that the pH range can be varied. This statement
`
`refers back to the first sentence of this specific paragraph outlining that the pH of the
`
`formulation preferably ranges from 4 to 8.
`
`30.
`
`In the subsequent paragraphs of page 18 the formulation is further elaborated. The
`
`paragraphs describe which further excipients form part of the formulation. On page 18,
`
`line 7 it is said that a polyol is also included in the formulation. According to this section,
`
`therefore, the presence of the polyol is not optional, but mandatory. The polyol preferably
`
`is mannitol, preferably in a concentration range of 10 to 14 mg/ml (page 18, lines 14 et
`
`seq.).
`
`31.
`
`In line 21 of page 18 the description continues with outlining that the formulation further
`
`contains a detergent, and hence also that the presence of the detergent is not optional,
`
`but mandatory. The detergent most preferred is polysorbate 80. The content of
`
`polysorbate 80 preferably is between 0.1 to 10 mg, even more preferably between 0.5
`
`and 5 mg/ml. This disclosure encompasses the disclosure of the range from 0.1 to 5
`
`mg/ml.
`
`32.
`
`On pages 17 and 18, the original specification thus constitutes a specific disclosure of a
`
`preferred embodiment of the invention, namely a formulation with a pH between 4 and 8
`
`and a citrate/phosphate buffer comprising citric acid monohydrate,
`
`sodium citrate,
`
`disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate and sodium
`
`chloride, which further comprises mannitol and polysorbate 80 as defined in claim 1.
`
`33.
`
`This interpretation is fully in line with the disclosure of the original claims 13 and 14. The
`
`combination of features is further supported by page 17, lines 12 et seq. and by example
`
`1 (page 28, lines 15 et seq.) which disclose exactly the claimed combination. In addition,
`
`the features correspond to the features disclosed in the specific formulation of Table 1.
`
`34.
`
`The application taken as a whole also teaches that the formulation is preferred for high
`
`protein concentrations. This particularly holds true because a central aspect of
`
`the
`
`objective of the invention is to provide a formulation having surprising storage stability,
`
`which is
`
`easily administered even subcutaneously and thus
`
`in
`
`high
`
`antibody
`
`concentrations. This general objective of the invention is repeated on page 16, first
`
`Ex. 1053 — Page 7 of 58
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`Ex. 1053 - Page 7 of 58
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`KC]N|(3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
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`8
`
`paragraph of the chapter “Preparation of the formulation”. The antibody concentration,
`
`particularly D2E7, can be up to 150 mg/ml (e.g., page 4, line 8; page 7, lines 16 to 17;
`
`page 8, line 5; page 16, line 17 and line 33; page 17, line 4; page 21, line 30; page 22,
`
`line 5).
`
`35.
`
`Possible concentration ranges of the antibody are described in the last paragraph of page
`
`16 bridging page 17 and the first full paragraph of page 17. The broadest concentration
`
`range is 1 — 150 mg/ml (page 17, line 4). One individualized range is the claimed range of
`
`20 to 130 mg/ml (page 17, line 5).
`
`36.
`
`Thus,
`
`the formulation as claimed is directly and unambiguously derivable from the
`
`application as originally filed.
`
`B. D2E7 WAS WELL-KNOWN IN THE ART
`
`37.
`
`At the priority date the term D2E7 was well-known from the prior art. The human IgG1
`
`monoclonal anti—tumor necrosis factor alpha (TNF) D2E7 antibody (Knoll) was disclosed
`
`as early as 1998 in Broeder et al. Ann Rheum and Salfeld Ann Rheum both filed as D39.
`
`Salfeld et al. mention the “Generation of a fully human TNF antibody for the therapy of
`
`chronic inflammatory diseases” and “D2E7 was generated by phage display technology.
`
`The high affinity murine antiTNF monoclonal antibody MAK 195 was used as a template
`
`for guided selection, which involves complete replacement of the murine heavy and light
`
`chains with human counterparts and subsequent optimization of the antigen binding
`
`affinity. D2E7 is a TNF antibody with a fully human primary sequence.” Further, Broeder
`
`et al. note that D2E7 is “a new human IgG1 monoclonal anti—tumor necrosis factor or
`
`(TNF) antibody.”
`
`38.
`
`Further prior art disclosures of D2E7 are in D11; D12; D24; D25; D26; D29; Kempeni et
`
`al. 2000, D40; Rau et al. 2002, D41; Weinblatt et al. 2003, D42; EP 1 406 656 B1, D49.
`
`E.g. D25 defines D2E7 in the abstract and on page 311 as a fully human IgG1 anti-
`
`TNFalpha mAb and D40 Kempeni et al. states on page 44: “The high specificity
`
`neutralization potency of a previously perfected murine monoclonal antibody was
`
`transferred to a fully human IgG1 antibody format (D2E7)”.
`
`39.
`
`The sequences of D2E7 were disclosed as early as 1997 in the D2E7 antibody
`
`(compound) patent, D26 (cf. Fig. 1A/B, 2A/B, 7 and 8). D2E7 became known as the first
`
`fully human anti-TNF alpha antibody.
`
`40.
`
`The light chain variable sequence and the heavy chain variable sequence of D2E7 were
`
`further disclosed in D49, D12 and D24 as SEQ ID NOs:
`
`1 and 2 and unambiguously
`
`linked to the term D2E7 in the description of D49, D12 and D24 (cf. e.g. D24 col. 5, line 6
`
`Ex. 1053 — Page 8 of 58
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`KC]N|(3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
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`9
`
`and 21, col. 12, lines 48-51). D24 and D12 use the same Figs. 1A/B and 2A/B; and Fig. 7
`
`and 8 as the original D26. For example,
`
`a. D12 defines D2E7 in col. 4, line 51:
`
`FIGS. 1A and 1B show the amino acid sequences of the light chain variable
`
`region of D2E7 (D2E7 VL; also shown in SEQ ID NO: 1)
`
`and in col. 4 bottom:
`
`FIGS. 2A and 2B show the amino acid sequences of the heavy chain variable
`
`region of D2E7 (D2E7 VH; also shown in SEQ ID NO: 2),
`
`b. D24 defines D2E7 in col. 5, top:
`
`FIGS. 1A and 1B show the amino acid sequences of the light chain variable
`
`region of D2E7 (D2E7 VL; also shown in SEQ ID NO: 1)
`
`and:
`
`FIGS. 2A and 2B in D24 show the amino acid sequences of the heavy chain
`
`variable region of D2E7 (D2E7 VH; also shown in SE0 ID NO: 2),
`
`41.
`
`Consequently, the sequences of D2E7 can be considered common general knowledge.
`
`C. THE REFERENCE TO D12 AND D24 MAKES D2E7 AND ITS SEQUENCES A PRECISELY
`
`AND IDENTIFIABLY DISCLOSED FEATURE
`
`42.
`
`The application as filed incorporates an antibody or an antigen binding portion thereof by
`
`reference to the disclosure of D12 and D24 on page 15, lines 20 to 22 of the original
`
`application. The respective disclosure regarding D2E7 and its sequence information in
`
`D12 and D24 is thereby incorporated into the application as filed. The skilled person will
`
`find that in D12 and D24 D2E7 and its light chain and heavy chain variable regions and
`
`the heavy chain constant region (|gG1) are precisely and explicitly defined, identifiable (of.
`
`T 689/90) and even preferred.
`
`43.
`
`Opponent 4 states that it
`
`is questionable whether the features referenced in the U.S.
`
`patent clearly belong to the description of the invention in view of an alleged vagueness of
`the referenced antibodies.
`
`44.
`
`This ignores the way D2E7 and its sequences are disclosed in both documents. D2E7 is
`
`disclosed in both documents as a human anti—Tumor Necrosis Factor alpha (TNFor)
`
`antibody comprising light chain and heavy chain variable regions defined by the amino
`
`acid sequence of SEQ ID NO:
`
`1 and the amino acid sequence of SEQ ID NO: 2,
`
`respectively.
`
`Ex. 1053 — Page 9 of 58
`
`Ex. 1053 - Page 9 of 58
`
`

`

`KC]N|[3'SZYNKA'T|L|\/|ANN'vor1 RENESSE
`
`11:)
`
`45.
`
`The following extracts from D12 and D24 show that D2E7 is unambiguously linked to the
`
`correct sequence and precisely and identifiably disclosed with its sequences in D12 and
`D24:
`
`8..
`
`SEQ ID NO: 1 and 2 are defined as light chain and heavy chain variable regions of
`D2E7 in Col. 12 of D24:
`
`5(]
`
`In still another embodiment, the invention provides an
`i.s:.ti)lz1t<::«:1 hurnan antibody, or an agritignzn binding pcrtinn
`thereof, with a light chain varilalxalc region (LCVR) Cl;)'i'..’[1pI’iS«-'
`ing the amino acid sequence of SEQ ID N021 (i.e., the ISZE7
`VL) and a heavy chain variable region (HCVR) comprising
`the amino acid scqutcnnc: nil‘ SEQ III) NE); 2 (din, this DEE?
`r
`rum 1
`run
`VII).
`In c:cr£a.in cintbndimcmtn,
`tlitc: antibndy csomprisczs a
`
`The same applies to the definition by the nucleic acid sequence in col. 4, line 21 of
`
`D12 and col. 18, line 29 of D24:
`
`in View at the foregoing, anmhcr aspect of the invention
`pertains to l;‘l1l€3I€'«IC
`acid, vector and host cell ccntpoaitions
`that can be useci for recnmbinant expression of the antibnrh
`ice and antibody portions of the invention. The nucleotide
`30 scqucnw azncnding the D2137 light, chain varialnle region is
`shownt in Fifi}. '7 and ISEQ ID N0; 363. The CDRI cinrmain of
`1.1]:-3 LCVR nnnnmpassnts nur:1entidt:s 7(}-«I02,
`this CDR2
`dnmain encompasses nucleotides 1484.68 and the CD33
`domain encompasses nurrleoticles 265-291. The nuciemtnicie
`3,5 sequcttw nncncling the DBE7 heavy chain variable rcgion is
`shown in FIG. 8 and SEQ ID N0: 37. The: CDR1 riumairt of
`that
`I1(“‘\IT3 t;i¥IrIr'L*"r"vr\u*ir~n;J.aew wuwJa.mh'p«Imu (‘I1
`lfli
`Ham (‘T133’)
`
`The same applies to the brief description of the drawings in D12 and D24:
`
`BRIEF‘ DESCRIPTION DI?”
`
`DRAWINGS
`
`5
`
`FIGS. 1A and 1B show ths amino acid Saquencas of the
`light, chain variable rngiuta of I);2;l;3f'7 (DEE? VL; also shown
`in SEQ ID NI); 1), alanirw-scat] mutants of DIECE7 VI.
`/'l I\"H..”‘7=k A‘!
`I I“h"§[;?"‘l‘>fr~' A1
`I f'\"IL”7$ AA
`1
`I"§—'?«l..”“f=0E A4‘:
`
`1.3”’) domains are boxed,
`l;~‘l(lS. 213. am-:31 28 Show the amino mic} sequences of the
`heavy chain variable region of IJKZE7 (D2137 VII; zilrsn shown
`11 rr"m.mr“-L»
`1 4
`Y‘IT\.v\I”'t.M'!»L«
`A N
`11rx.»n‘rw-r-u
`a M
`lt‘Iw.n1“m-1»t.«
`L in
`in SEQ [ID N0: 2):, alanline-scan mutants of IDQE7 "VII
`
`gm
`
`The same applies to the sequence shown in Fig. 7 and 8 of D12 and D24
`
`EX. 1053 - Page ‘IO of 58
`
`Ex. 1053 - Page 10 of 58
`
`

`

`KONIG- SZYNKA-'flLMANN 'vonRENESSE
`
`11
`
`FIG. 7 shciws. the nuclentide sequence 0f the iighi chain
`variziblc regien of D2137, with the preiiicted amine acisii
`sequence balcsw the nuclmtidc sequen.ce. The CTEDR. LE,
`CDR L2 and (DR L3 regions are underlined.
`
`FIG. 8 shexvs the niuczleotide eeqiience Di’ the heavy chain
`variable region of i’.)2E7, with the predictecl amino acid
`eequencze below lhe mwleoliciez secltimcve. The CDR Hit,
`CIJR H2 and CTDR H3 regions are underiiincd.
`
`DZE7 VL
`
`GAC ATC CAG ATG ACC CAG TCT CCA TCC TCC CTG TCT GCA TCT GTA
`D
`I
`Q
`M
`T
`Q
`s
`9
`s
`s
`L
`s
`A
`s
`v
`
`CDR Isl
`GGG GAC AGA GTC ACC ATC ACT TGT GGG GCA AGT CAG GGC ATC AGA
`G
`D
`R
`V
`T
`I
`T
`C
`R
`A
`S
`Q
`G
`I
`R
`
`AAT TAC TTA GCC TGG TAT CAG CAA AAA CCA GGG AAA GCC CCT AAG
`N
`Y
`L
`A
`W
`Y
`Q
`Q
`K
`P
`G
`K
`A
`P
`K
`
`CDR L2
`CTC CTG ATC TAT GCT GCA TCC ACT TTG CAA TCA GGG GTC CCA TCT
`L
`L
`I
`Y
`A
`A
`S
`T
`L
`Q
`S
`G
`V
`P
`S
`
`CGG TTC AGT GGC AGT GGA TCT GGG ACA GAT TTC ACT CTC ACC ATC
`R
`F
`S
`G
`S
`G
`S
`G
`T
`D
`F
`T
`L
`T
`I
`
`AGC AGC CTA CAG CCT GAA GAT GTT GCA ACT TAT TAC TGT CAA AGG
`s
`s
`L
`Q
`P
`E
`D
`V
`A
`T
`Y
`Y
`c
`Q
`R
`
`CDR L3
`TAT AAC CGT GCA CCG TAT ACT TTT GGC CAG GGG ACC AAG GTG GAA
`Y
`N
`R
`A
`P
`Y
`T
`F
`G
`Q
`G
`T
`K
`V
`E
`
`ATC AAA
`I
`K
`
`FIGURE 7
`
`e.
`
`The same applies for Fig. 1A/B and 2A/B of D12 and D24 (Fig. 1A shown below)
`
`D2E’7VLDIQMTQSPSSLSASVGDRVTITC RASQGIRNYL
`LD2E'7*.A1
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`LD2E7*.A3
`.
`.
`.
`.
`.
`.
`.
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`LD2E7*.A4 .
`.
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`LD2E7*.A5 .
`.
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`LD2E7*.A7 .
`.
`.
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`LD2E7*.A8 .
`.
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`.
`
`.
`
`W
`
`Figure 1A
`
`EX. 1053 - Page ‘I1 of 58
`
`Ex. 1053 - Page 11 of 58
`
`

`

`KC]NlG'SZYNKA'TlLl\/lANN'vor1 RENESSE
`
`12
`
`46.
`
`Opponent 4 thus cannot establish any vagueness from a disclosure in the originally filed
`
`application that is so closely related to the referenced documents D12 and D24. Where
`
`D12 and D24 disclose alanine—scanning mutants of D2E7 as well as a few “D2E7—related”
`
`antibodies, this cannot be a source of the alleged vagueness since it does not affect the
`
`clear D2E7 statements in D12 and D24, which to a large extent correlate to the nearly
`
`identical text in the originally filed application. The same language correlation applies to
`
`the use of the term “D2E7—re|ated” antibody. Further, alanine scanning replaces an amino
`
`acid residue in the cognate antibody with an alanine residue, not with a proline residue.
`
`The skilled person thus cannot infer from D12 and D14 any proline addition to the D2E7
`
`sequences based on these alanine scanning experiments.
`
`47.
`
`The same applies to Opponent 4’s assertion that D12 and D24 discloses myriads of
`
`possible antibodies containing a great number of possible combinations. This is no more
`
`than a red herring because D12 and D24 with respect to the antibody disclosure of D2E7
`
`have the same simple structure and focus on D2E7 as preferred embodiment that is
`
`found in the original application.
`
`48.
`
`Opponent 1 points to T 689/90 and states that it requires the following conditions for
`
`features only described in a cross—referenced document: (i) Protection is sought, (ii) the
`
`features contribute and are comprised in the solution,
`
`(iii)
`
`the features belong to the
`
`description of the invention, (iv) the features are precisely defined and identifiable within
`the total technical information within the referenced document.
`
`49.
`
`In the present case, all these conditions are met for D2E7, an antibody of claim 1.
`
`It is
`
`claimed, disclosed in the original application as comprised in the solution and belonging to
`
`the description of the invention, and the antibody as recited in claim 1 and as understood
`
`at the priority date is precisely defined and identifiable within the technical information of
`
`D12 and D24, as already shown above.
`
`50.
`
`A closer look at T 689/90 provides additional guidance. The Board stated that features
`
`mentioned only in a cross—referenced document may be incorporated into the wording of a
`
`claim if the invention as filed leaves no doubt that such features contribute to achieving
`
`the invention and if such features are precisely defined and
`the technical aim of
`identifiable within the total technical information within the reference document. There is
`
`no dispute that the claimed sequences are precisely defined and preferred in D12 and
`
`D24 as the light chain and heavy chain variable region sequences of D2E7 and D2E7 as
`
`human IgG1 antibody. But the preceding statement shows more. An incorporation is even
`
`possible if a feature is only mentioned in a cross—referenced document.
`
`In the present
`
`case the link is much stronger. The light chain and heavy chain variable regions, which
`
`define the antibody in claim 1, are already inherently mentioned in the application as filed
`
`by the direct reference to D2E7 itself.
`
`EX. 1053 - Page 12 of 58
`
`Ex. 1053 - Page 12 of 58
`
`

`

`KC]NlG'SZYNKA'TlLl\/lANN'vor1 RENESSE
`
`13
`
`51.
`
`Opponents state that where the application refers to D12 and D24 on page 15, lines 20-
`
`22 of the original disclosure only the wording ‘‘like those described in U.S.
`
`is used
`
`which is asserted to not point to D2E7. This argument has no bearing because “like” is,
`
`however, a common term used by practitioners to refer to prior disclosed sequences
`
`without limiting their own disclosure, but it is clear that D2E7 is identified in the application
`
`as filed by its name as well as in D24 and D12 by its name and sequence. D12 and D24
`
`even use the same wording as the original application for the disclosure of the light chain
`
`and heavy chain variable regions of D2E7, and even the same sequence listing numbers
`
`for SEQ ID NO:1 and 2.
`
`52.
`
`Consequently, the original disclosure may validly rely on the incorporation by reference of
`
`the sequence information of D2E7 from D12 and D24.
`
`53.
`
`It follows from the above that all statements in the original application that relate to D2E7
`
`immediately apply to the antibody of claim 1 of the Opposed Patent. The Opponents’
`
`attack based on the allegation that certain features are only disclosed for D2E7 is thus
`
`void and rather supports the original disclosure of the claim because it exactly refers to
`
`this D2E7. The same applies to the allegation that the embodiment of Table 1 on page 19
`
`does not support the claimed formulation because it is undisputedly D2E7 related.
`
`54.
`
`The features of claim 1 are thus originally disclosed in the application as filed.
`
`D. SEQUENCE ERROR CAN BE IMMEDIATELY IDENTIFIED AND CORRECTED FROM THE
`
`APPLICATION AS FILED
`
`55.
`
`Whether the sequence error may be corrected or not has no bearing on the Art. 123 (2)
`
`EPC attack on the antibody of claim 1
`
`if the Opposition Division follows the above
`
`described common general knowledge and/or incorporation by reference evidence. The
`
`claimed antibody refers to the very sequences of D2E7, and these sequences were
`
`originally disclosed on the basis of the explicit disclosure of D2E7 itself without having
`
`regard to the sequence listing in the original application. For precaution we nevertheless
`
`show below the many reasons why the skilled person would have been able to identify
`
`and correct
`
`the sequence error in the application as filed without any reference to
`
`common general knowledge or the incorporated information of D2E7.
`
`56.
`
`The sequence listing in the application as filed lists a proline at position 1 of every
`
`sequence. This error has been corrected under Rule 139 EPC during prosecution. The
`
`Opponents assert that the correction of the sequence error in the application as filed is
`
`inadmissible under Rule 139 EPC because the skilled person would allegedly not have
`
`identified and corrected the error. To support the argument, the Opponents assert that the
`
`patent also discloses variations of D2E7 (D2E7—related antibodies) and the erroneous
`
`EX. 1053 - Page ‘I3 of 58
`
`Ex. 1053 - Page 13 of 58
`
`

`

`KC]NIG'SZYNKA'TILI\/IANN'vor1 RENESSE
`
`14
`
`sequence with a proline in position 1 would be understood as a variation of D2E7 (which
`
`already confirms that D2E7 is at the core of the disclosure). We will show that a proline at
`
`the beginning of every single sequence in the sequence listing is completely implausible
`
`and contradicts the disclosure in the description, where this type of alleged variation
`
`(amino acid addition) is not mentioned at all, much less at the beginning of a sequence.
`
`The position of the Opponents is, thus, completely artificial and cannot be maintained.
`
`57.
`
`The ski