lR_Claim(s)
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`f j - ( 0 ~) II? -
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`is/are pending in the application.
`
`-·,
`
`•
`
`Office Action Summary
`
`I Applicant(s)
`Application No.
`f9/(/ / //// 7"u'
`/ -; -
`Examin'er
`
`I Group Art Unit
`/t./, :>
`
`(
`
`-.The MAILING DATE of this communication appears on the cover sheet beneath the correspondence address-
`
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE < _ ~FROM THE MAILING DATE
`OF THIS COMMUNICATION. ~
`- Extensions of time may be available under the provisions of 37 CFR 1.136(a). In no event, however, may a reply be timely filed after SIX (6) MONTHS
`from the mailing date of this communication.
`- If the period for reply specified above is less than thirty (30) days, a reply within the statutory minimum cif thirty (30) days will be considered timely.
`- If NO period for reply is specified above, such period shall, by default, expire SIX (6) MONTHS from the mailing date of this communication .
`- Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`
`Status
`~Responsive to communication(s) filed on __ #J_,/'--">'?<0-/.....,/,.____~~~,.__ ________________ _
`D This action is FINAL.
`D Since this application is in condition for allowance except for formal matters, prosecution as to the merits Is closed in
`accordance with the practice under Ex parte Quayle, 1935 C.D. 1 1; 453 O.G. 213.
`
`Disposition of Claims
`
`1.2.. ~
`Of the above claim(s)---~------------------ is/are withdrawn from consideration.
`D Claim(s)
`i;t Claim(s)'-· _
`D Claim(s)
`
`is/are allowed.
`_.4,,__1 ~?~==--<-' ~o'--'c,___,7--l(l--'l...,,?.__-__,_l ..... G.""""8-Y---------'---- is/are rejected.
`is/are objected to.
`
`D Claim(s)
`
`Application Papers
`
`are subject to restriction or election
`requirement.
`
`~-
`
`D See the attached Notice of Draftsperson's Patent Drawing Review, PT0-948.
`0 The proposed drawing correction, filed on _______ is 0 approved D disapproved.
`D The drawing(s) filed on _______ is/are objected to by the Examiner.
`"'--- . D !he specification is objected to by the Examiner.
`D The oath or declaration is objected to by the Examiner.
`
`Priority under 35U.S.C.§119 (a)-(d)
`
`D Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 11 9(a)-(d).
`D All D Some* D None of the CERTIFIED copies of the priority documents have been
`D received.
`D received in Application No. (Series COde/Serial Number) _____________ _
`D received in this national stage application from the International Bureau (PCT Rule 1 7.2(a)).
`
`*Certified copies not received: _______________________ _
`
`Attachment(s)
`
`D Information Disclosure Statement(s), PT0-1449, Paper No(s). ___ _
`!Ji(Notice of Reference(s) Cited, PT0-892
`D Notice of Draftsperson's Patent Drawing Review, PT0-948
`
`D Interview Summary, PT0-413
`D Notice of Informal Patent Application, PT0-152
`D Other _____________ _
`
`U. S. Patent and Trademark Office
`PT0-326 (Rev. 9-97)
`
`Office Action Summary
`
`Part of Paper No . .. M
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`'U.S. GPO: 1998454-457197505
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`641 of 947
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`Celltrion, Inc., Exhibit 1002
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`••
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`Application/Control Number: 08/146206
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`Art Unit: 1642
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`Page 2
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`Effective February 7, 1998, the Group Art Unit location has been changed, and the
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`examiner of the application has been changed. To aid in correlating any papers for this
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`application, all further correspondence regarding this application should be directed to Minh-Tam
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`Davis, Group Art Unit 1642.
`
`Since this application is eligible for the transitional procedure of 37 CFR 1.129(a), and the
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`fee set forth in 37 CFR l. l 7(r) has been timely paid, the finality of the previous office action has
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`been withdrawn pursuant to 37 CFR 1.129(a). Applicant's amendment filed on 08/26/98 has been
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`entered.
`
`The text of those sections of Title 35, U.S. Code not included in this action can be found
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`in a prior Office action.
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`Applicant cancels claims 106'."1~2, and adds new claims 115-128, which are related to
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`claims 43-105, and are not new matter.
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`\
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`Accordingly, claims 43-105, 113-128 are being examined.
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`The following are the remaining rejections.
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`REJECTION UNDER 35 USC 112 FIRST PARAGRAPH, SCOPE, NEW REJECTION
`
`Claims 43-105, 113-128 are rejected under 35 U.S.C. 112, first paragraph, because the
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`specification, while being enabling for humanized antibody muMAb4D5, and an anti-CD3
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`antibody, or variable domains thereof, comprising CDR amino acids which bind specifically to
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`pl85, or CD3, does not reasonably provide enablement for any humanized antibody, or variable
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`642 of 947
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`Celltrion, Inc., Exhibit 1002
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`Application/Control Number: 08/146206
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`Art Unit: 1642
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`domain thereof, comprising CDR amino acids which binds non-specifically to any antigen,
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`wherein the framework region amino acids are substituted at a site selected from the group
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`consisting of 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H,
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`36H, 39H, 43H, 45H, 69H, 70H, 74H, and 92H, or of24H, 73H, 76H, 78H and 93H, for
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`treating any chronic diseases. The specification does not enable any person skilled in the art to
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`which it pertains, or with which it is most nearly connected, to make and use the invention
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`commensurate in scope with these claims.
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`Claims 43-105, 113-128 are drawn to a humanized antibody, or variable domain thereof,
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`comprising CDR amino acids which bind an antigen, or which bind pl g5HER2. The framework
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`region amino acids of said antibody or variable domain are substituted at a site selected from the
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`group consisting of 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H,
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`4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, and 92H, or of24H, 73H, 76H, 78H and 93H. Claim
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`105 is further drawn to a humanized antibody which lacks immunogenicity upon repeated
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`administration for treating a chronic disease, and wherein its non-human CDR amino acids bind an
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`antigen.
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`The specification discloses examples of humanized antibody muMAb4D5, anti-CD3, and
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`anti-CD18 antibody, or variable domain thereof, comprising CDR amino acids which bind
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`specifically to p 185, CD3, and CD 18, respectively. The substituted framework residues for the
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`heavy chain of antibody muMAb4D5 are amino acids number 71, 73, 78, 93, and for the light
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`chains are amino acid number 66 (table 3, and p.68). Only one humanized antibody, huMab4D5-8,
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`643 of 947
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`Celltrion, Inc., Exhibit 1002
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`Application/Control Number: 08/146206
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`Art Unit: 1642
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`•
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`Page4
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`with all of the above five substitutions in the framework region binds to pl85 3-fold more tightly
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`than the murine counterpart. The humanized antibodies, huMab4D5-2 and huMab4D5-3, with one
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`and four substitutions in the framework region, respectively, are, however, at least 10-fold less
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`potent than the murine counterpart, having a Kd of 4.7nM and 4.4nM, respectively, as compared
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`to a Kd value of 0.30nM of the murine counterpart. The substituted framework residues for the
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`heavy chain of antibody anti-CD3 are amino acids number 75 and 76. Although the specification
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`discloses that humanized anti-CD3 antibody enhances the cytotoxic effects of cytotoxic T cells 4-
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`fold against tumor cells expressing pl 85HER2, there is no disclosure in the specification concerning
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`the binding affinity of the humanized anti-CD3 or anti-CD18 as compared to the murine
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`counterpart. The claims however encompass any humanized antibody, without any specificity,
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`binding to p 185HERi or any antigen, with just any one of substitution at a site selected from the
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`group consisting of 41, 381, 431, 441, 581, 621, 651, 661, 671, 681, 691, 731, 851, 981, 2H,
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`4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, and 92H, of24H, 73H, 76H, 78H and 93H. The
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`claims further encompass any humanized antibody for treating any chronic disease.
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`One cannot extrapolate from humanizing one antibody, which binds to p185HERi 3-fold
`
`more tightly than the murine counterpart, to humanizing any antibody, wherein its affinity would
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`be up to 3-fold or at least 3-fold more tightly than the murine counterpart, or wherein its affinity
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`would be still intact for therapeutic purposes. In addition, one cannot extrapolate from
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`humanizing an anti-p185 antibody by substitution at all five framework amino acids number H71,
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`H73, H78, H93 and 166 in an anti-p 185 antibody, or from humanizing an anti-CD3 antibody by
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`644 of 947
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`Celltrion, Inc., Exhibit 1002
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`Art Unit: 1642
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`Page 5
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`substitution at both framework amino acids number H75 and H76 in an anti-CD3 antibody, with
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`humanizing any antibody by substitution at only any one amino acid selected from the group
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`consisting of 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H,
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`36H, 39H, 43H, 45H, 69H, 70H, 74H, and 92H, or of24H, 73H, 76H, 78H and 93H. Patent
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`'101 teach that different antibodies require different combinations of different substitutions in the
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`light chain and heavy chain (table 1 ). Even the specification discloses that only one variant,
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`huMab4D5-8, wherein all five framework amino acids number H71, H73, H78, H93 and L66 are
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`substituted, binds to pl85 3-fold more tightly than the murinecounterpart. Other variants, with
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`only one or even four substitutions have much less binding affinity than the murine
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`counterpart(table 3). Thus it is unpredictable that substitution at only one framework amino acid
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`in any antibody, or any kind of combination of framework amino acid substitutions would result
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`in a humanized antibody that binds to its antigen 3-fold more tightly than its murine counterpart,
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`or retains adequate affinity for therapeutic purposes. The specification does not disclose whether
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`subtitution at only one of the claimed amino acid positions would produce a humanized antibody
`
`that has 3-fold more in affinity as the murine counterpart, or retains adequate affinity for
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`therapeutic purposes. The specification does not disclose which combination of what substituted
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`framework amino acids, other than H71, H73, H78, H93 and L66 for anti-pl85 antibody, and
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`H75 and H76 in anti-CD3 antibody would produce a humanized antibody that has 3-fold more in
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`affinity as the murine counterpart, or retains adequate affinity for therapeutic purposes. It is well
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`known in the art that not any substitution at any amino acids would produce a humanized
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`645 of 947
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`Celltrion, Inc., Exhibit 1002
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`Art Unit: 1642
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`Page 6
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`antibody having an affinity similar to the murine counterpart, unless it is tested by binding assays.
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`The specification provides insufficient guidance with regard to the issues raised above and
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`provides no working examples which would provide guidance to one skilled in the art and no
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`evidence has been provided which would allow one of skill in the art to make the claimed
`
`humanized antibodies with a reasonable expectation of success. In view of the above, one of skill
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`in the art would be forced into undue experimentation to practice the claimed invention.
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`Moreover, a humanized antibody that does not have a specificity for a particular antigen
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`is of little practical use for treating a chronic disease, because said antibody would not target to
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`the target tissues. In addition, although the specification discloses that murine anti-pl 8SHER2
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`antibody has been suceessfully used in treating tumor cell growth in culture (p.5), p I 85HER2 and
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`CD-3 are not specific for any tissues responsible for chronic disease, e.g. chronic headache,
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`chronic lung inflammation, or chronic kidney disease. The specification does not disclose how to
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`treat any chronic disease using the ylaimed humanized antibody. In the absence of a teaching of a
`. ·.'
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`method of treating any chronic disease, using the claimed humanized antibody, one of skill in the
`
`art would be forced into undue experimentation to practice the claimed invention.
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`REJECTION UNDER 35 USC 102, NEW REJECTION
`
`I.
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`New claims 115-117, 123, 127 are rejected under 35 USC 102(e) or 102(b) pertaining to
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`anticipation by PN=S,530,101 or Queen et al, 1989, PNAS, USA, 86: 10029-10033.
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`646 of 947
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`Celltrion, Inc., Exhibit 1002
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`

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`Application/Control Number: 08/146206
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`Art Unit: 1642
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`•
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`Page 7
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`Claims 115-117, 123, 127 are drawn to a humanized antibody or its heavy chain variable
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`domain comprising non-human CDR amino acids, and a framework region amino acid wherein
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`amino acid position 93H is substituted, utilizing the numbering system of Kabat, and wherein the
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`substituted residue is the residue found in the corresponding location of the non-human antibody.
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`PN=5,530,101, teach humanized anti-Tac antibody, wherein amino acid 93 is substituted
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`in heavy chain, using the aligned Kabat Eu sequence to provide the framework for the humanized
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`antibody (column 45).
`
`Queen et al, PNAS, teach humanized anti-Tac antibody, wherein amino acid 93 is
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`substituted in heavy chain, using the aligned Kabat Eu sequence to provide the framework for the
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`humanized antibody (figure 2).
`
`Since anti-Tac antibody is a mouse antibody, its inherent heavy chain variable domain
`
`would comprise non-human CDR amino acids. Thus the humanized antibody and its heavy chain
`
`variable domain taught by patent '101 or Queen et al is the same as the claimed invention.
`
`2.
`
`Claims 43, 44, 48, 55, 67, 71, 10?, 115-117, 120, 127 are rejected under 35 USC 102(e)
`
`pertaining to anticipation by PN=S,530,101.
`
`It is noted that PN=5,530,101 is filed on Sept, 1990, which is within a year before the
`
`claimed filing date of 06/14/91.
`
`Claims 43, 44, 48, 55, 67, 71, 105, 115-117, 120, 127 are drawn to a humanized antibody
`
`or its heavy chain variable domain comprising non-human CDR amino acids, and a framework
`
`region amino acid wherein amino acid position 38L, 67L, 69H, 73H or 93H is substituted,
`
`647 of 947
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`Celltrion, Inc., Exhibit 1002
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`

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`Application/Control Number: 08/146206
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`Art Unit: 1642
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`•
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`Page8
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`utilizing the numbering system of Kabat, and wherein the substituted residue is the residue found
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`in the corresponding location of the non-human antibody. Claim 105 is further drawn to said
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`humanized antibody which lacks immunogenicity compared to a non-human parent antibody upon
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`repeated administration to a human patient.
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`PN=5,530,101 teaches humanized antibodies, wherein amino acid 38 or 67 are substituted
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`in light chain (table 1, antibody Fd79 and M195, respectively), and amino acid 69, 73 or 93 is
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`substituted in heavy chain (table 1, antibody CMV5, mik-beta-1, and Fd138-80, respectively),
`
`using the aligned Kabat Eu sequence to provide the framework for the humanized antibody. The
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`humanized antibodies in table 1 would comprise non-human CDR amino acids (Summary). Patent
`
`'101 further teaches that the humanized antibodies will be substantially non-immunogenic in
`
`humans (Abstract). Thus the humanized antibody taught by patent '101 and its variable domain is
`
`the same as the claimed invention.
`
`REJECTION UNDER 35 USC 102
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`1.
`
`Claim 128 is rejected under 35 USC 102(e) as being anticipated by PN=5,530,101, for
`
`the same reasons set forth in paper No.27 for the rejection of previous claims 23-24.
`
`Applicant amends the claim 128 to read that the humanized antibody binds the antigen up
`
`to about 3-fold more tightly than the parent antibody. The language "up to" 3.-fold reads on
`
`anything below 3-fold. Thus the structure and binding affinity of the claimed humanized antibody
`
`is the same as that of the humanized antibody taught by 'I 01.
`
`648 of 947
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`Celltrion, Inc., Exhibit 1002
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`•
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`Application/Control Number: 08/146206
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`·Art Unit: 1642
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`•
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`Page9
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`2.
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`Claim 113 is rejected under 35 USC 102(e) as being anticipated by PN=5,693,762, for the
`
`same reasons set forth in paper No.27 for the rejection of previous claims 22-25, 38 and 39.
`
`Applicant argues that the "consensus sequence" in '762 is the most homologous sequence
`
`from a single human immunoglobulin, and is thus different from the consensus sequence of the
`
`claimed invention.
`
`Applicant's arguments set forth in paper No. 39 have been considered but are not deemed
`
`to be persuasive for the following reasons:
`
`Although '762 uses the most homologous sequence from a single human immunoglobulin
`
`as an example, '762 also teach that as a principle, a framework is used from either a human
`
`immunoglobulin which is unusually homologous to the donor immunoglobulin, or a consensus
`
`framework from many human antibodies is used (column 13, first paragraph, lines 4-7). Thus the
`
`consensus sequence taught by '762 is the same as the claimed consensus sequence, as defined by
`
`the specification, i.e. the most frequently occurring amino acids, ~ased on immunoglobulin of a
`
`particular species (p.14).
`
`REJECTION UNDER 35 USC 103
`
`Claims 113, -115-118, 123, 127-128 are rejected under 3 5 USC 103 as being unpatentable
`
`over US PN=5,693, 762 in view of Kabat et al, for the same reasons set forth in paper No:27, for
`
`the rejection of previous claims 26-36 and 40-41.
`
`Applicant argues as follows:
`
`649 of 947
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`Celltrion, Inc., Exhibit 1002
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`Art Unit: 1642
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`•
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`Page 10
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`The rejection is made using hindsight reconstruction of the present invention. Patent '762
`
`actually teaches away from the invention. The term "consensus framework" from '762 patent was
`
`not intended to refer to a sequence representing the most frequently occurring amino acids in the
`
`present invention. Furthermore, Kabat et al do not use the term "consensus", but rather
`
`"occurrences of most common amino acid". Thus there is no motivation to combine "consensus
`
`framework" from '762 patent with "occurrences of most common amino acid", especially the
`
`term "consensus framework" from '762 patent was not intended to refer to a sequence
`
`representing the most frequently occurring amino acids. Moreover, the present invention produces
`
`humanized antibodies with unexpected results, such as 1) lack of significant immunogenecity, as
`
`disclosed in the Declaration by Dr. Shak, 2) higher increase in binding affinity as compared to that
`
`of humanized antibodies known in the art, and 3) the same consensus sequence could be used to
`
`generate many different strong affinity humanized antibodies.
`
`Applicant's arguments set forth in paper No. 39 have been considered but are not deemed
`
`to be persuasive for the following reasons:
`
`Although '762 uses the most homologous sequence from a single human immunoglobulin
`
`as an example, '762 also teach that as a principle, a framework is used from either a human
`
`immunoglobulin which is unusually homologous to the donor immunoglobulin, or use a consensus
`
`framework from many human antibodies is used (column 13, first paragraph, lines 4-7). Thus
`
`·the consensus sequence taught by '762 is the same as the claimed consensus sequence, as defined
`
`by the specification, i.e. the most frequently occurring amino acids, based on immunoglobulin of a
`
`650 of 947
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`Celltrion, Inc., Exhibit 1002
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`•
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`Art Unit: 1642
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`•
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`Page 11
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`particular species (p.14). It is only Applicant's interpretation that the term "consensus
`
`framework" from '762 patent was not intended to refer to a sequence representing the most
`
`frequently occurring amino acids in the present invention. Furthermore, although Kabat et al do
`
`not use the term "consensus", but rather "occurrences of most common amino acid", one oL
`
`ordinary skill in the art would readily understand that " a consensus sequence" from many
`
`antibodies is a sequence that occurs most frequently.
`
`In addition, .In re Kerkhoven (205 USPQ 1069, CCPA 1980) summarizes:
`
`"It is prima facie obvious to combine two compositions each of which is taught by prior
`
`art to be useful for same purpose in order to form third composition that is to be used for very
`
`same purpose: idea of combining them flows logically from their having been individually
`
`taugh~ in prior art. " .
`
`Applicant asserts that the claimed humanized antibodies are not obvious in view of
`
`the cited references because the cited prior art does not suggest such a combination.
`
`However, the instant situation is amenable to the type of analysis set forth in In re
`
`Kerkhoven,205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious
`
`to combine two compositions each of which is taught by the prior art to be useful for the same
`
`purpose in order to for a third composition that is to be used for the very same purpose since
`
`the idea of combining them flows logically from their having been individually taught in the
`
`prior art. Applying the same logic to the instant claims, given the teaching of the prior art
`
`that as a principle, a framework is used from either a human immunoglobulin which is unusually
`
`651 of 947
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`Page 12
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`,
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`I
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`\
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`Application/Control Number: 08/146206
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`Art Unit: 1642
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`homologous to the donor immunoglobulin, or a consensus framework from many human
`
`antibodies is used, and the structures of sequences that are most commonly occurred among
`
`many antibodies, it would have been obvious to humanize antibodies as taught by patent '762,
`
`using the most commonly occurred sequences taught by Kabat et al, because the idea of doing
`
`so would have logically followed from their having been individually taught in the prior art,
`
`and because patent '762 teaches the use of "consensus sequence", for the same purpose of
`
`producing humanized monoclonal antibodies for therapeutic purposes. One of ordinary skill in
`
`the art would have motivated to make humanized antibodies using the methods taught by '762
`
`and the sequences taught by Kabat et al with a reasonable expectation of success. In addition, the
`
`arguments that the claimed invention is unexpected are not applicable, because the claims are
`
`broad, and drawn to any antibodies, and not specifically the claimed antibodies, wherein their
`
`specific target antigens, and their binding properties are not disclosed in the claims.
`
`Any inquiry concerning this communication or earlier communications from the examiner
`
`should be directed to Minh-Tam B. Davis whose telephone number is (703) 305-2008. The
`
`examiner can normally be reached on Monday-Friday from 9:30am to 3:30pm, except on
`
`Wesnesday.
`
`If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor,
`
`Tony Caputa, can be reached on (703) 308-3995. The fax phone number for this Group is
`
`(703) 308-4227.
`
`652 of 947
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`Celltrion, Inc., Exhibit 1002
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`

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`Application/Control Number: 08/146206
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`Art Unit: 1642
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`•
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`Page 13
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`Any inquiry of a general nature or relating to the status of this application or proceeding
`
`should be directed to the Group receptionist whose telephone number is (703) 308-0916.
`
`Minh-Tam B. Davis
`
`October 13, 2000
`
`suh~~
`
`PRIMARY EXAMINER
`
`653 of 947
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`Celltrion, Inc., Exhibit 1002
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`..
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`---.,
`ft;
`i ~-
`Notice of References Cited
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`I
`I
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`\
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`AppliCam:{s) dJ.
`Application No.
`(4fe-t.
`dV/ /14 -~ 2JfJ 6
`Group Art Unit
`Examiner
`.M . 7 . Yxi- tJ / ~
`lto~z. Page -L- of -1-
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`U.S. PATENT DOCUMENTS
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`DOCUMENT NO.
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`DATE
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`NAME
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`CLASS SUBCLASS
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`DOCUMENT NO.
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`DATE
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`NAME
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`FOREIGN PATENT DOCUMENTS
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`'
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`NON-PATENT DOCUMENTS
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`,L
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`A
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`DOCUMENT (Including Author, Trtle, Source, and Pertinent Pages)
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`U.S. Patent and Trademark Office
`PT0-892 {Rev. 9-96)
`
`•A copy of this reference Is not being funished with this Office action.
`(See Man"81 of Pate~••>. Sect"'1707.05(8).)
`
`Part of Paper No. s-7
`
`"U.S. GPO: 1996-420-311/40176
`
`654 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Patent Docket
`
`Application of
`
`Group Art Unit:
`
`1642
`
`Paul J. Carter et al.
`
`Examiner: M. Davis
`
`Serial No.:
`
`,.08/146, 206
`
`Filed:
`
`November 17, 1993
`
`For: METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`CERTIFICATE OF MAILING
`I hereby certify that this correspondence is being deposited
`with the United States Postal service with sufficient postage
`as first class mail in an envelope addressed to: Assistant
`Commissioner of Patents, Washington, D.C. 20231 on
`
`1l.!~2)l
`t~Q
`
`Wendy M. Lee
`
`AMENDMENT UNDER 37 C.F.R. §1.111
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`Sir:
`
`Responsive to the Office Action dated 10/25/00, reconsideration of the
`present application is respectfully requested in view of the following
`amendments and remarks. A request for a 3 month extension of time and
`the requisite fee accompany this amendment.
`
`IN THE CLAIMS;
`~lease amend claims 113 and 114 as follows:
`113.
`(Amended) A humanized variant of a non-human g rent antibody which
`binds an antigen and comprises a consensus huma variable domain of a
`human heavy chain immunoglobulin subgroup wh ein amino acid residues
`forming Complementarity Determining Regioy
`(CDRs)
`thereof comprise
`non-human antibody amino acid residues, anci'further comprises a Framework
`Region
`(FR)
`substitution where
`substituted FR
`residue:
`noncovalently binds antigen direct
`(b)
`interacts with a CDR;
`(c)
`introduces a glycosylation site hi ch affects the antigen binding or
`affinity of the antibody; or
`participates in the VL-VH interface by
`affecting the proximity or
`of the VL and VH regions with
`
`(a)
`
`~I
`
`1
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`655 of 947
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`Celltrion, Inc., Exhibit 1002
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`

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`.
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`\
`
`iJ ~y respect to
`
`-·
`
`I\')..
`~
`
`1r ~s
`(Amended) T{le humanized,..y_ariant of claim lktf which binds the antigen
`:14'tl·.
`.r Up to
`l»Y ~~ 3-fold more t\.tiglr1ffy 'thani\'tfl'e parent antibody binds antigen.
`l~ -l-""- ~ ·.,,t;I\"' ~- ·.f,c..
`
`2
`
`/2l
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`656 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`Claims
`have been amended. Attached hereto is a marked-up version of the changes
`made to the claims by the current amendment.
`The attached page is
`captioned "Version with Markings to Show Changes Made".
`
`Claim 113 no longer requires that the humanized variant bind antigen with
`better affinity than the parent antibody, up to about 3-fold tighter
`binding than the parent antibody. Hence, claim 114 has been amended
`herein to depend on claim 128, which claim requires that the humanized
`variant bind antigen more tightly than the parent antibody.
`
`Prosecution Historv of the Present Application
`Applicants first wish to express their concern about the undue prejudice
`to them due to the repeated transfer of this case from patent examiner
`to patent examiner, and to explain that this is a case which has thrice
`previously been indicated to be in condition for allowance.
`
`The case was originally with Examiner Adams,
`then was transferred to
`Examiner Nolan.
`In the 8/13/98 interview, Examiner Nolan indicated that
`unexpected results would overcome the 103 rejection based on Queen Patent
`5, 693, 762
`(hereinafter "the
`'762 patent") .
`An amendment was filed
`8/24/98 presenting the unexpected results. Shortly thereafter, the case
`was transferred to the present Examiner. Pending claims 43-114 were
`discussed in an interview on 10/16/98 between the undersigned,
`the
`present Examiner and Examiner Feisee at which time the only outstanding
`issue in the case related to the clarity of the terms "binding of CDR"
`and "significant
`imrnunogenicity".
`An amendment was filed 11/6/98
`addressing those issues.
`The case was then transferred to Examiner
`Reeves, who issued a restriction requirement 3/29/99 at that late stage
`in prosecution. In an 8/23/99 interview, Examiners Reeves/Burke and
`Feisee indicated that the case would be in order for allowance with the
`filing of a terminal disclaimer for claim 111 and addition of an upper
`limit to affinity in claims 113 and 128. Claims 113 and 128 were amended
`as suggested by the Examiners and claim 111 was canceled to avoid the
`
`3
`
`657 of 947
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`Celltrion, Inc., Exhibit 1002
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`-·
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`obviousness-type double patenting rejection (see 8/30/99 amendment). Now
`the case has been transferred yet again to the present Examiner and
`prosecution has been re-opened on a case that was indicated to be in
`condition for allowance three times previously.
`
`To the extent that any issues remain following entry of this amendment,
`Applicants specifically request an interview with the present Examiner
`and her supervisor to discuss this case so as to ensure speedy resolution
`of the issues and allowance of the application.
`It is noted that this
`is a pre-GATT case and two 129(a) responses have previously been filed.
`
`Section 112, first paragraph, Scope, New Reiection
`Claims 43-105 and 113-128 are rejected under 35 USC Section 112, first
`paragraph on the basis that the specification, while being enabling for
`humanized antibody muMAb4D5 and an anti-CD3 antibody, or variable domains
`thereof, "does not reasonably provide enablement for any humanized
`antibody, or variable domain thereof, comprising CDR amino acids which
`binds non-specifically to any antigen, wherein the framework region amino
`acids are substituted at a site selected from the group consisting of 4L,
`38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H,
`36H, 39H, 43H, 45H, 69H, 70H, 74H and 92H, or of 24H, 73H, 76H, 78H and
`93H, for treating any chronic disease."
`
`The Examiner contends that the specification discloses examples of
`humanized muMAb4D5, anti-CD3 and anti-CD18 antibodies or variable domains
`thereof; that the substituted FR residues for muMAb4D5 are 71H, 73H, 78H,
`93H and 66L; and that only one humanized antibody (huMAb4D5-8} with all
`the above five substitutions binds to pl85 3-fold more tightly than the
`murine counterpart. The Examiner further contends that the substituted
`framework residues for the heavy chain of antibody anti-CD3 are FR
`residues 75 and 76, and that there is no disclosure concerning the
`binding affinity of the humanized anti-CD3 or anti-CD18 as compared to
`the murine counterpart.
`The Examiner contends
`that one cannot
`extrapolate from humanizing one antibody, which binds to p185HER2 3-fold
`more tightly than the murine counterpart, to humanizing any antibody,
`
`4
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`658 of 947
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`Celltrion, Inc., Exhibit 1002
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`

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`wherein its affinity would be up to 3-fold or at least 3-fold tighter
`than the murine counterpart, or wherein its affinity would still be
`intact for therapeutic purposes. The Examiner further argues that one
`cannot extrapolate from humanizing an anti-plSS antibody by substitution
`of all five FR residues at positions 71H, 73H, 7SH, 93H and 66L in an
`anti-plSS antibody, or
`from humanizing an anti-CD3 antibody by
`substitution at both framework residues 7SH and 76H, with humanizing any
`antibody by substitution at only one amino acid residue selected from the
`group consisting of 4L, 3SL, 43L, 44L, SSL, 62L, 6SL, 66L, 67L, 6SL, 69L,
`73L, SSL, 9SL, 2H, 4H, 36H, 39H, 43H, 4SH, 69H, 70H, 74H and 92H, or of
`24H, 73H, 76H, 7SH and 93H. The Examiner opines that the specification
`does not disclose whether substitution at only one of the claimed amino
`acid positions would produce a humanized antibody that has 3-fold more
`affinity, or which combination of what substituted FR residues (other
`than 71H, 73H, 7SH, 93H and 66L for an anti-plSS antibody or 7SH and 76H
`in an anti-CD3 antibody) would produce a humanized antibody that has 3-
`fold more affinity than the murine
`counterpart, or
`retains adequate
`affinity for
`therapeutic purposes.
`The Examiner
`contends
`that a
`humanized antibody that does not have specificity for a particular
`antigen is of little practical use for treating a chronic disease and
`that the specification does not disclose how to treat any chronic disease
`using the claimed humanized antibody.
`
`Applicants submit that claims 43-lOS and 113-12S are enabled by the
`present application.
`
`First, Applicants point out that none of the claims (other than claim
`114) require that the humanized antibody bind antigen about 3-fold more
`tightly than the parent antibody binds antigen, as the Office Action
`seems to imply.
`The independent claims herein merely recite that the
`humanized antibody variable domain comprises CDR residues which bind an
`antigen (claims 43, 104 and llS); the