•
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`/0/7,
`Patent Docket P0709P1
`OfFl~L.
`?Le.'A~
`~
`p.JJ.
`to-4-11~
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Group Art Unit: 1816
`
`Examiner. P. Nolan
`
`In re Application of
`
`Paul J . Carter et al.
`
`Serial No.: 08/ 146,206
`
`Filed; November 17. 1993
`
`For:. METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`SUPPLEMENTAL INFORMATION DISCLOSURE STATEMENT
`
`Assistant Commissioner of Patents
`Washington . D.C. 20231
`
`Sir:
`
`Applicants submit herewith patents, publications or other information (attached hereto and listed on
`
`the attached Form PT0-1449) of which they are aware, which they believe may be material to the examination
`
`of this application and in respect of which there may be a duty to disclose in accordance with 37 CFR §1 .56.
`
`This Information Disclosure Statement:
`
`(a) [ ] accompanies the new patent application submitted herewith. 37 CFR §1 .97(a).
`
`(b) [ J is filed within three months after the filing date of the application or within three months after
`the date of entry of the national stage of a PCT application as set forth in 37 CFR§1.491 .
`
`(c) [ ) as far as is known to the undersigned, is filed before the mailing date of a first Office action on
`the merits.
`
`(d) [X)
`
`is filed after the first Office Action and more than three months after the application's filing date
`or PCT national stage date of entry filing but, as far as is known to the undersigned, prior to
`the mailing date of either a final rejection or a notice of allowance, whichever occurs first, and
`is accompanied by either the fee ($230) set forth in 37 CFR §1 .17(p) or a certification as
`specified in 37 CFR §1.97(e}, as checked below. Should any fee be due, the U.S. Patent and
`Trademark Office is hereby authorized to charge Deposit Account No. 07-0630 in the amount
`of $220.00 to cover the cost of this Information Disclosure Statement. Any deficiency or
`overpayment should be charged or credited to this deposit account. A duplicate of this sheet
`is enclosed.
`
`461 of 1033
`
`BI Exhibit 1002
`
`

`

`•
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`•
`
`08/ 146.206
`
`Page2
`
`(e) l ] is filed after the mailing date of either a final rejection or a notice of allowance, whichever
`occurred first, and is accompanied by the fee ($130) set forth in 37 CFR §1 .17(i)(1) and a
`certification as specified in 37 CFR §1.97(e), as checked below. This document is to be
`considered as a ~1etition requesting consideration of the infonnation disclosure
`statement. The U.S. Patent and Trademark Office is hereby authorized to charge Deposit
`Account No. 07--0630 in the amount of $130.00 to cover the cost of this Information Disclosure
`Statement. Any deficiency or overpayment should be charged or credited to this deposit
`account. A dupticat•e of this sheet is enclosed.
`
`Pf either of boxes (d) or (e) is clhecked above, the following "certification'' under 37 CFR §1 .97(e) may
`
`need to be completed.) The undersig1ned certifies that:
`
`[ ]
`
`[ )
`
`Each item of inform.ation contained in the information disclosure statement was cited in a
`communication mail1ed from a foreign patent office in a counterpart foreign application not
`more than three months prior to the filing of this information disclosure statement.
`
`No item of informatiion contained in this information disclosure statement was cited in a
`communication mailed from a foreign patent office in a counterpart foreign application or. to
`the knowledge of the undersigned after making reasonable inquiry, was known to any
`Individual designatecj in 37 CFR §1 .56(c) more than three months prior to the filing of this
`information disclosure statement.
`
`A list of the patent(s) or publiication(s) is set forth on the attached Form PT0-1449 (Modified) .
`
`A copy of the items on PT0-11449 is supplied hereWith:
`
`[x] each [ ] none [ ] only those listed below:
`
`Those patent(s) or publication(s) which are marked With an asterisk (•) in the attached PT0-1449 form are not
`
`supplied because they were previouslly cited by or submitted to the Office in a prior application Serial No. _
`
`_
`
`, filed
`
`and relied upon in this application for an earlier filing date under 35 USC §120.
`
`A concise explanation of rele1!t'ance of the items listed on PT0-1449 is:
`
`[x]
`
`{ ]
`
`[ ]
`
`[ ]
`
`not given
`
`given for each listed item
`
`given for only non-English language listed item(s} [Required)
`
`in the form of an Eniglish language copy of a Search Report from a foreign patent office,
`issued in a counterpart applicatlon, which refers to the relevant portions of the references.
`
`The Examiner is reminded that a "concise explanation of the relevance" of the submitted prior art "may
`
`be nothing more than identification of tlhe particular figure or paragraph of the patent or publication which has
`
`some relation to the claimed invention," MPEP §609.
`
`462 of 1033
`
`BI Exhibit 1002
`
`

`

`•
`
`08/ 146,206
`
`Page 3
`
`While the information and references disclosed in this Information Disclosure Statement may be
`
`"material" pursuant to 37 CFR §1 .56, it is not intended to constitute an admission that any patent, publication
`
`or other information referred to therein is "prior art" for this invention unless specifically designated as such.
`
`In accordance with 37 CFR §1 .97(g), the filing of this Information Disclosure Statement shall not be
`
`construed to mean that a search has been made or that no other material information as defined in 37 CFR
`§1.56(a) exists. It is submitted that the Information Disclosure Statement is in compliance with 37 CFR § 1.98
`
`and MPEP §609 and the Examiner is respectfully requested to consider the Hsted references.
`
`ully submitted,
`
`ECH, NC.
`
`Date: October J.a_, 1997
`
`460 Pt. San Bruno Blvd.
`So. San Francisco , CA 94080-4990
`Phone: (415) 225-1994
`Fax: (415) 952-9881
`
`463 of 1033
`
`BI Exhibit 1002
`
`

`

`EPO
`
`Document Number
`Date
`,,,_3 l)-i-?-38. 89 . 8"
`0 239 400
`/()-19 ~ 1' .18 . Hi
`0 620 276
`EPO
`WO 89/01783 J-9 -R') 0'9 . 8 :L ~ PCT
`PCT
`WO 89/06692 ?-c.ii ..... ,,fl'. 01~!1
`PCT
`WO 90/07861 7~ ~"26 . 81 . 90-
`WO 91/09967 "?-1/-~I 11197 p;i,
`PCT
`92/22654<=~ -72~~ . U.,l!
`PCT
`WO
`WO 93 / 0219 lQI---<,t_ ~. 82 . 9,..
`PCT
`
`Country
`
`Class
`
`Subclass
`
`Translation
`No
`Yes
`
`-
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`Examiner
`Initials
`
`l
`
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`
`Examiner
`Initials
`g..1/V
`
`I
`
`2
`3
`4
`
`5
`6
`
`1
`
`8
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`
`10
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`11
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`12
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`
`FORM PT0-1449
`
`,....:{\ \"'
`v,JJ./
`
`COJ t2L~"
`U.S. Dept. of Commerce
`
`I
`
`Patent and Trademark Office
`
`LIST OF DISCLOSURES CITED BY APPLICANT
`(Use several sheets tt necessary)
`
`.
`
`U.S. PATENT DOCUMENTS
`
`'f:
`Atty Docket No.
`P0709Pl
`Applicant
`Carter and Presta
`Filing Date
`17 Nov 1993
`
`4 --
`
`Sheet 1 -- of
`I Serial No.
`
`08/1 46.206
`
`I ~
`18-/1,
`
`Document Number
`4 ,816 , 567
`
`Date
`28 . 83 . 89
`.?-lr-8 /
`
`Name
`
`Class
`
`Subclass
`
`Filing Date
`
`Cabilly et al.
`
`FOREIGN PATENT DOCUMENTS
`
`OTHER DISCLOSURES (Including Author, Title, Date, Pertinent Pages, etc.)
`Amzel and Poljak, " Three ~dimensional structure of immunoglobulins • All.ll Be:x:
`lilias:hem. 48:961-967 (1979)
`
`Bindon e t al . , "Human monoclonal IgG isotypes differ in compleroent activating function at the level of
`C4 as well as Clq" Jgutaal gf EKDetimen;al Medicine 168(1):127-142 (July 1988)
`
`Boulianne, G. L. et al. ,
`646 (December 198 4)
`
`· Production of functional chimaeric mouse/hwnan antibody" ~ 312(5995):643-
`
`Brown et al .. • Anti-Tac- H. a humanized antibody to the interleukin 2 receptor. prolongs primate cardiac
`liii\tl. I Acag, Sci . ~sa 88:2663-2667 (1991)
`a llograft survival • f;r;:s;u;;,
`
`Bruccoleri , "Structure of antibody hypervariable loops reproduced by a conformational search a l gorithm"
`14 &.tlLt.e (erratum to articl e in Nature 335(6190):564-568 and) 336:266 (1988)
`
`· comparison of the effector functions of hum.an immunoglobulins using a matched
`Bruggemann, M. et al . ,
`set of chimeric antibodies• Jauroal gf EKDerimental Medi~ioe 166 : 1351-1361 (1987)
`
`Burgess et al. , "Possiole Dissociation of tne Heparin-oinoing ano Hitogenic Activities of Heparin-
`binding (Acidic Fibroblast) Growth Pactor-1 from Its Receptor-binding Activ.ities by Site-directed
`Hutaqenesis o f a Single Lysine Residue• "~·,~~~1 ~F roll A ;n1~~· 111:2129-2138 ( 1990)
`Carter et al., "Hwnanization of an anti-p l85KEA2 antibody for human cancer therapy• Proc
`Aclld. sci. 89 : 4285- 4289 (1992)
`
`tlAtl
`
`Cheetham, J., "Reshaping the antibody combining site by COR replacement-tailoting or tinkering to fit? "
`f;r;:gtein ~ngioee;r;:ing 2131 :110-112 (1988)
`' Canon ical Structures for the Hypervariable Regions• J Mal, Jli!:!l 196:901-917 (1987)
`
`Chothia and Lesk ,
`
`15
`
`16.
`
`17
`
`18
`
`19
`
`tb
`
`20
`
`Chothia et al. , "The predicted structure of immunoglobulin Dl.3 and its comparison with the crystal
`?N
`structure• Scieoee 233:755-758 (Aug. 15. 19861
`-
`"'Examiner ~~ I Dale Considered
`12//1/C/t
`'Examiner: Initial if reference cCr<sidered, whether or not cttation is in conformance with MPEP 609; draw line through citation
`if not in conformance and not considered. Include copy of this form with next communication to applicant.
`
`USCOMM·DC 80-398.
`
`464 of 1033
`
`BI Exhibit 1002
`
`

`

`, -
`
`r FORM PT0· 1449
`
`•
`
`U.S. Dept. of Commerce
`
`Atty Docket No.
`P0709Pl
`Applicant
`Carter and Presta
`Filing Date
`17 Nov 1993
`
`of
`
`4
`
`Sheet 2
`
`Serial No.
`08/146, 206
`
`Group
`1806
`
`-
`~~\\. ffOo
`37 APR ~ atent and Trademark Office
`LIST OF DISCLOSURES CITED BY APPi ~NT 17
`~199~~~
`"'ofl\''-
`{Use several sheets if necessary)
`OTHER DISCLOSURES (Including Author, Title, Date, Pertinent Pages, etc.)
`Chothia, c. et al., "Conformations of irnmunoglobulin hypervariable regions" lia..t..l.U.:.e 342(6252) :877-883
`(1989)
`
`21
`
`I
`1:r
`
`-
`
`Chothia, Cyrus, "Domain association in irnmunoglobulin molecules: The packing of variable domains" lL__
`11121. ~i2l. 186:651-663 (1985)
`
`Clark et al., "The improved lytic function and in vivo efficacy of monovalent monoclonal CDJ
`<mt il)oc;lies • J;;1,u;:12:r;iean .I2i.n:Da l Qf lll!!lll.!DQl!&i: 19:)81-388 (1989)
`
`Co et al., "Humanized anti bodies for antiviral therapy" fJ::Q~. r:il!itl. .&s;i!d.. S~i. l..'Sll. 88 :2869-2873 (1991)
`
`n
`
`23
`
`-- 24
`
`Coussens et al ., "Tyrosine Kinase Receptor with Extensive Homology to EGF Receptor Shares Chromosomal
`Location with neu Oncogene" Science 230:1132-1139 (1985)
`
`.. 5
`
`26
`
`-- 27
`,- 29
`
`1'28
`
`Daugherty, BL et al., "Polymerase chain reaction facilitates the cloning, CDR-graft 1ng, and rapid
`expression of a murine monoclonal antibody directed against the CD18 component of leukocyte integrins"
`l':IJ.J.~ls:is; .&dd:; Be:>ea~s;h 19!9) :2471-2476 (Mav 11, 1991)
`Davies , D. R. et al.. "Antibody-Antigen complexes • Ann, Bey Bi12chem 59:439-473 (1990)
`
`Epp et al., "The molecular structure of a dimer composed of the variable portions of the Bence-Jones
`protein REI refined at 2.0-A resolution" lli2s;l:um1iHn 14 !22) : 4943-4952 (1975)
`
`Fendly et al., ''Characterization of mu.rine monoclonal antibodies reactive to either the human epidermal
`growth factor receptor or HER2/neu gene product" S:ans;!ii:;t Bess:::ai::i::h 50:1550-1558 (1990)
`
`_,.....--..
`
`JO
`
`31
`
`FUrey et al . . "Structure of a novel Bence-Jones protein (Rhe) fragment at 1.6 A resolution .. .z' 1121 .
`.ai2l..... 167(3) :661-692 (July S, 1983)
`
`Gorman, SD et al., "Reshaping a therapeutic CD4 antibody" PrQs;. Na tl , Acad, Sci , USA 88 ( 10) : 4181-4185
`(May 15, 1991)
`
`. ~ - 32
`
`Gregory et al. , "The solution conformations of the subclasses of human IgG deduced from sedimentation
`and small angle X-ray scattering studies" MQle!::!.!l2.~ Imml.lm2l2m! 24(8):821-829 (August 1987)
`
`--
`
`·
`
`33
`
`... 34
`
`Hale et al., "Remission induction in non-hodgkin lymphoma with reshaped human monoclonal antibody
`caropa th- lH" ~ 1:139g-1399 (1988)
`Harris and Emery, "Therapeutic antibodies - the corning of age• :I il2t s:i:;b 11 : 42-44 (February 1993)
`
`.-
`
`·35
`
`Huber et al., "Crystallographic structure studies of an IgG molecule and an Fe fragment" ~ 264:415-
`420 (December 2, 1976)
`
`-~ .
`
`36
`
`... ~ =.. -3·7
`.... _.
`. - . --
`
`3~8
`
`39
`
`Hudziak et al., "pl8SllEIU Monoclonal Antibody Has Antiproliferative Effects In Vitro and
`Sensitizes Human Breast Tumor Cells to Tumor Necrosis FactQr" M2ls:s;J.J.l i\.U: i Cell!.!lax aiology 9(3):1165-
`1172 (1989)
`Jaffe.rs, G . .:1. et al .• "Monoclonal antibody therapy. Anti-idiotypic and non-anti-i diotypic antibodies
`to OKT3 arising despite intense irrununosuppression" Ixans~lantatiQD 41(5):572-578 (May 1986)
`
`Jones, P. T. et al., "Replacing the complementarity-determining regions in a human antibody with those
`from a mouse" ~ 321(6069):522-525 (1986)
`
`Junghans et al., "Anti-Tac-H , a humanized antibody to the interleukin 2 receptor with new features for
`immunotherapy in malignant and immune disorders" ~2ru;~~ R~~~2~s;h 50(5) :1495-1502 (Mar l, 1990)
`
`-
`' i/
`~ E
`.
`xam1ner
`
`Kabat et al. Sem.iimce:; Qf fXQt.fliD:> 12f IllllDll.IlQl!:lgis;al Int.s:u:st., Bethesda, MD:National Institutes of
`40 Health pps. iii-xxvi i, 41-176 (1987)
`
`!Oh.t }<;£
`d/1111>
`•Examiner:
`Initial if refefence considered, whether or not citation is in conformance with MPEP 609; draw line lhrou~ citation
`if not in conformance and not considered. Include copy of this form with next communication to applicant.
`
`I Date Considered
`
`USCOMM·DC 80-398.
`
`465 of 1033
`
`BI Exhibit 1002
`
`

`

`. ,,
`
`• ,...,
`
`, .
`
`Sheet _3 _
`
`of
`
`4
`
`FORM PT0·1449
`
`LIST OF DISCLOSURES CITED BY APPLICANT
`
`(Use several sheets ~ necessary)
`
`I Serial No.
`~11 ., r
`_ ~/~1 L!i, :
`I Group
`~lr)it:L 'I .· i~
`>'5
`'· u
`OTHER DISCLOSURES (Including Author, litle, Date, Pertinent Pages, etc.)
`~.;~; !·;·~-~~- .~
`King et al., "Amplification of a Novel v-erbB-Related Gene in a Hwnan HaJM\ary Carcinoma• Si::ieos;e
`229:974-976 (1985)
`
`U.S. Dept. of Commerce
`
`Patent and Trademark Office
`
`Atty Docket No.
`P0709Pl
`Applicant
`Carter and Presta
`Filing Date
`17 Nov 1993
`
`08/146,206
`
`l •
`
`.
`
`I
`
`.-
`
`I
`
`1
`
`'1-~'
`I
`I
`
`I
`
`I
`
`Ptv 41
`I
`I
`
`43
`
`44
`
`45
`
`46
`
`47
`
`48
`
`Lazar et al., •Transforming Growth Factor a: Mutation of Aspartic Acid 47 and Leucine 48 Results in
`42 Different Biological Activities• tlglecl.l l ar ~ Cellular Biology 8(3) :1247-1252 (l.988)
`
`Love et al, • Recombinant antibodies possessing novel effector functions • tletbgs;l.s in EDZll:I!!QlQsn:: 119:515-
`527 (1989)
`
`Lupu et al , , "Direct interaction of a l igand for the erbB2 oncogene product with the EGF receptor and
`plB5c•bB2• Si::iimce 249:1552-1555 (1990)
`
`Mai;gni AA and Binaghi RA,
`
`'Nonprecipitating asymmetric antibodies· ADD Bel.I:
`
`IllllDl.lD!ll
`
`6:535-554 (1988)
`
`Margolies et al . • "Diversity of light chain variable region sequences among rabbit antibodies elicited
`by the same antigens . · 1'.i::Qi;; .
`.si::i . !.lS.& 7'2;2180-84 (.Jun 1975)
`l'liH.l, ,&!:;ii!ll .
`Marquart et al.• •crystallographic refinement and atomic models of the intact immunoglobul1n molecule
`141(4) : 369-]91 (Aug
`Kol and its antigen-binding fragment at 3 . 0 A and 1.0 A resolution• J:
`tl!ll
`fliQl
`25, 1980)
`Mian, IS et al., •structure, function and properties of antibody binding sites" J.. l:l!ll
`217(1) :133·151 [Jan 5, 1991)
`
`liligl.
`
`I
`
`Miller, R . et al . , "Monoclonal antibody therapeutic trials in seven patients with T-cell lymphoma•
`49 ~ 62:988-995 (1983)
`
`Morrison, s. L. et al., *Chimeric hwnan antibody molecules: mouse antigen-binding domains with human
`l!Sll 81(21):6851- 6855 (Nov. 1984)
`constant region domains• 1'['21:
`l'latl
`lli::arl. Ss;i
`
`Neuberger et al., ' Recombinant antibodies possessing novel effector functions• ~ 312(5995):604 - 608
`(December 1984)
`
`Neuberger, M. s. et al., "A hapten-specific chimaeric IgE antibody with human physiological effector
`function• tia.t..l.lJ::e ]14(6008):268-270 (March 1985)
`
`Novotny and HaDer, "Structural invariants ot antigen DJ.nd1ng: comparison ot inununogloDulin Vi.-
`V" and Vi.- VL domain dimers· Proc . Natl. Acarl. Sci. USA 82 !14) :4592- 4596 (July
`1985)
`Pluckthun, Andreas, "Antibody engineering : advances from the use of escherichia coli expression
`systems • fli!l~ei::bn!l l !l~ 9:545-51 (1991)
`
`Queen, M. et al .. "A humanized antibody that binds to the interleukin 2 receptor • l:'[QC
`Si::i. LISA 86:10029- 10033 (1989)
`
`l::iatl a.cad
`
`Riechmann, L. et al. . "Reshaping hwnan antibodies for therapy• Na.t.w.:e. 332:323-327 (1988)
`
`Roitt et al. I mmunQl Qro!: (Gower Medical Publ ishing Ltd., London, England) pps. 5 . 5 (1985)
`
`Saul et al .• •Pr.el.111Unary reti.nement and structural analysis of the Fab fragment from human
`immonoglobulin new at 2 .. 0 A r e solution• iI!llU:Dal gf ~i!l l !l~ical CbemistD£ 253(2):585-597 (January 25,
`1978)
`Sc:hroff, R. et al.. "Human anti-murine immunoglobulin responses in patients receiving monoclonal
`antibody therapy• ~acce[ Besea[s:;b 45:879-885 (1985)
`
`50
`
`51
`
`S2
`
`53
`
`54
`
`SS
`
`56
`
`57
`
`58
`
`59
`
`Segal et al.• "The three-dimensional structure of a phosphorylc:holine- binding mouse iminunoglobulin Fab
`,ac;o,g , Si;;i YSA 71(11) : 4298-4302 (Nov 1974)
`and the noture of the ontigen b inding site • f cgc Hiltl
`
`60
`
`,Ri II
`Examiner~ J-Mt_
`
`/ 7 I~ 16
`"Examiner: Initial if reference considered, whether or not citation is in confonnance with MP-EP 609; draw line through citation
`if not in conformance and not considered. Include copy of this form with next communication to applicant.
`
`I Date Consid7'd 0,
`
`USCOMM·DC 80-398.
`
`466 of 1033
`
`BI Exhibit 1002
`
`

`

`-, , •
`
`, .
`37 APR
`. FOAM PT0-1449 ? 1995 ~·
`~ IRAD£1\\\.
`LIST OF DISCLOSURES CITED BY APPLICANT
`
`'
`
`, ~
`
`(Use several sheets if necessary)
`
`I
`
`-
`
`U.S. Dept. otComrnerce
`
`Patent.ano Trademark Office
`
`•
`
`Atty Docket No.
`P0709Pl
`Applicant
`Carter and Presta
`Filing Date
`17 Nov 1993
`
`Sheet _4 _
`
`of
`
`4
`
`I Serial No.
`
`08/146, 206
`
`Group
`1806
`
`I
`
`OTHER DISCLOSURES (Including Author, Title, Date, Pertinent Pages, etc.)
`Shalaby et al., ''Development ot humanized bispecJ.fic antibomes reactive with cytotoxic lymphocytes and
`
`I ~ - or- tumor cells overexpressing the HER2 protooncogene• iim.l01al Qf Exne.t.i.mental. Me!lici.rie 175(1) :217-225 (Jan
`-
`·- ·64-
`
`1 , 1992)
`Shepard and Lewis, "Resistance of tumor cells to tumor necrosis factor• J.. Cl.in. lmrn!.!mil 8(5) :333-395
`(1988)
`
`..&2-
`
`Sheriff et al., "Three-dimensional structure of an antibody-antigen complex" EJ:Q!: • ~atl. Al:ii!d. Sci USll
`~- - ,- :r- 6~- 84(22) : 8075-8079 (Nov. 1987)
`
`Sherman et al.. "Haloperidol binding to monoclom;i.l antibodies" J.Q1,u::m1l Qf .ei2J.2g.i.Sd:ll Cb!ilmi:.ta 263:4064 -
`4074 (1988)
`
`-
`
`'"''
`,_
`
`r r
`
`Silverton et al., "Three-dimensional structure of an int:act human ill11llunoglobulin" E.tQs;;, tla.tl. As;;a.g,
`Ii::.-; "''"' 74: 5140-5144 (1977)
`'Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-
`Slamon et al. ,
`2/neu Oncogene•• S!:iens;;e 235:177~182 (1987)
`
`Slaroon et al. , "Studies of the HER-2/neu proto-oncogene in human brea st and ovarian cancer• Ss;;i.ens;;e
`· :-"TO -6.7._. 244:707-712 (1989)
`
`1::>now and Amzel, "Calculating three-dimensional changes :Ln protein structure due to amino -acia
`· -~ -5-8-- substitutions: the variable re_gion of i1!11l1unoglobulins• J>.t2t.ein · s ~D.ls;; ti.u::e , i::i.ms;;ti2n. si!DQ !J!i:D!i:.tk:i, Alan
`R. Liss, Inc . Vol. 1:267-279 (1986)
`Sox et al., "Attachment of carbohydrate to the variable region of myeloma ill11llunoglubulin light chains •
`""' - f,r;:Q!:;' .Hii!tl. As;;a.g Ss;;.i., USA 66:975-82 (July 1970)
`Spiegelberg et al.. ' Localization of the carbohydrate within the variable region of light and heavy
`chains of human ')G myeloma proteins• ai2i;;bemi:ot.t::x: 9:4217-23 (Oct 1970)
`
`'"'
`
`Takeda et al., • construction of chimaeric processed imrntmoglobulin genes containing mouse variable and
`
`- -71:·-. human constant region sequences• ~ 314.(6010) :452-4!)4 (April 1985)
`-
`
`'72
`
`Tao et al .. "Role of Carbohydrate in the Structure and Effector Functions Mediated by the H uman IgG
`Imm!.!DQl 143(8):2595 - 2601 (1989)
`Constant Region• J.
`trameworit res:1.due Tl. is a maJor det.E~rminant ot the oosi~-ion ~n• conrormai:;ion ot tne
`l'l·ramoni:;ano et al..,
`,_ ·- " J¥
`--· .. -~•-"" ot immunou.lobulins • J.-MQl-Biol 215(1):175-182 (Sep s.
`............. -..,,...,;.L~ .L.- ~ ................................... v
`1990)
`Verhoeyen. M. et al. , "Reshaping human anti-bodl.es: graf t~ing an antilysozyme activity • Ss;;;i.ens::e
`-~ ~ _.,,4._ 239(4847) :1534 - 1536 (Mar :?5, 1988)
`
`I~
`
`~
`
`~-
`
`Waldmann, T., "Monoclonal antibodies in diagnosis and therapy" s,-•~n~~ 252:1657-1662 (199 1 )
`
`~,__ o-7-5,
`
`Wallick et al . , "Glycosylation of a VH residue of a monoclonal antibody against alpha (1----6) dextran
`
`Winte.r and Milstein. "Man-made antibodies• IDltYre 349 ( 6:107) : 293 -'299 (Jan 24 , 1991)
`
`- ~ increases its affinity for antigen" .1cu:r.:nal Qf J:;2'C!ei::im!illltal M!i:s:lii::ill!i: 168(3) :1099-1109 (Sep 1 988)
`-- ~1.:,-
`--- -.:.. .......... Yamamoto et al., •similar ity of protein encoded by the human c-erb-B- Z gene to epidermal growth factor
`
`78
`
`receptor• NiUJlll 319:230-34 (1986)
`
`II
`
`'
`
`Examiner
`
`/k£J;llb
`•Examiner: Initial if reference considered, whether or not citation is in conformance with MPEP 609; draw line throug~ citation
`if not in conformance and not considered. Include copy of this form with next communication to applicant.
`···- -'\...
`
`I Date Considered
`
`/(} fi; Jc;;-
`
`/ 2.. / ar.;/ 0 ·1
`
`USCOMM-DC 80-398.
`
`467 of 1033
`
`BI Exhibit 1002
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Patent Docket P0709P1
`
`Group Art Unit: 1816
`
`Examiner: P. Nolan
`
`In re Application of
`
`Paul J . Carter et al.
`
`Serial No.: 08/ 146,206
`
`Filed: November 17, 1993
`
`For: METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`AMENDMENT TRANSMITTAL
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`Sir:
`
`Transmitted herewith is an amendment in the above-Identified application.
`
`The fee has been calculated as shown below.
`
`or===,..---,,,,.~~
`
`OCT - 7 \197
`
`MAlrilA. UUi.iT~R
`· aEflV9CE ceNYEA
`
`Total
`
`Independent
`
`35
`
`8
`
`3 1
`
`10
`
`4
`
`0
`
`_ First Presentation of Multiple Dependent Claims
`
`x 88 =
`xBO=
`
`+ 260 =
`
`$88.00
`
`$0.00
`
`Total Fee Calculation ·
`
`$88.00
`
`x
`
`No additional fee is required.
`The Commissioner is hereby authorizea to charge Deposit Account No. 07-0630 in
`the amount of $88.00. A duplicate copv of this transmittal is enclosed.
`Petition for Extension of Time is enclosed.
`
`T he Commissioner is hereby authoriZed to charge any additional fees required under 37 CFR 1.16 and 1 17, or
`credit overpayment to Deposit Account No. 07-0630. A duplicate copy of this sheet is enclosed.
`
`ctfully submitted,
`Re
`N NTECH INC.
`
`By: ~-=~__;;;-=-~~~~~~
`Wendy M. Lee
`Reg. No. 40,378
`
`Date: October J_, 1997
`
`One DNA Way
`So. San Francisco, CA 94080-4990
`Phone: (415) 225-1994
`Fax: (415) 952-9881
`
`468 of 1033
`
`BI Exhibit 1002
`
`

`

`. ,
`
`•
`
`~Jzt
`
`"
`Patent Docket P0709P~
`;u/7/9 ·
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`/
`
`Group Art Unit: 1816
`
`Examiner. P. Nolan
`
`In re Application of
`
`Paul J . Carter et al.
`
`Serial No.: 08/146,206
`
`Filed: 17 November 1993
`
`For: METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`SUPPLEMENTAL AMENDMENT UNDER 37 C.F.R. §1:1~}~@c~~:v~2'
`OCi - 7 rw
`
`Sir:
`11At.1.'l~,, , ;-. ,
`~ VV'HA.\i,,,,.'.w ~t~ .. h
`Applicants respectfully request reconsideration of the above-identified appliaiti0'r.i~ln!viewJOf.::the
`
`.
`
`following amendments and remarks.
`
`IN THE SPECIFICATION:
`
`On page 8, lines 25-27 and page 15, lines 23-24, please replace the sequence in its entirety with
`
`the following sequence --
`
`EVQL VESGGG L VQPGGSLRLSCAASGFTFSDY AMSWVRQAPGKGLEWVAVISENGSDTYYADS
`
`VKGRFTISRDDSKNTL YLQMNSLRAEDTA VYYCARDRGGAVSYFDVWGQGTL VTVSS--
`
`On page 9, fine 30, please replace "huKI" with --hulfl-.
`
`IN THE CLAIMS:
`
`lO/lO/l'ffl ~ •r ~~erwW. humanize antibody variable domain having a non-human
`
`01 FC110J CompM~Rlarity Determining Region (C
`) incorporated into a human antibody variable
`1't\
`domain, wherein an amino acid resid \~been substituted for the human amino acid residue
`~\ at a site selected from the group c sistlng of:
`4L, [36L), 38L, 43L, 44L, 46L, 5
`I 62L, 65L, 66L, 67L, 68L, 69L, [70L,] 73L, 85L, [87L,) 98L, 2H,
`
`469 of 1033
`
`BI Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`Page 2
`
`Jf) 4H, (24H,] 36H, (37H,] 39H, 43f1/'~. [49H, 68H,] 69H, 70H, [73H,] 74H, 75H, 76H, 78H and
`~
`
`92H.
`
`/
`
`· Please add the following claims:
`
`-39. A humanized heavy chain variable domain comprising FR1- DR1·FR2-CDR2-FR3-CDR3-
`FR4, wherein FR1-4 comprise the four framework regions of a c sensus human variable
`
`domain of a human heavy chain immunoglobulin subgroup an CDR 1-3 comprise the three
`complementarity determining regions (CDRs) of a nonhuma
`import antibody, and further
`
`wherein consensus human framework region (FR) residue have been replaced by nonhuman
`import residues where the FR residue (a) noncovalently inds antigen directly; (b) interacts with a
`CDR; (c} comprises a glycosylation site which affects e antigen binding or affinity of the
`antibody; or (d) participates in the VL - VH interface.
`
`The humanized heavy chain variable d
`40.
`immunoglobulin subgroup is VH subgroup Ill.
`
`ain of claim 39 wherein the human heavy chain
`
`le domain of claim 40 wherein:
`The humanized heavy chain vari
`41 .
`FR 1 of the consensus human variable omain comprises the amino acid sequence:
`EVQLVESGGGLVQPGGSLRLSC
`
`FR2 of the consensus human var" ble domain comprises the amino acid sequence:
`WVRQAPGKGLEWVA (SEQ I N0:28);
`
`FR3 of the consensus huma ariable domain comprises the amino acid sequence:
`RFTISRDDSKNTL YLQMN RAEDT A VYYCAR (SEQ ID N0:29); and
`FR4 of the consensus hu an variable domain comprises the amino acid sequence:
`
`The huma zed antibody of claim 22 which lacks immunogenicity upon repeated
`42.
`administration t a human patient in order to treat a chronic disease in that patient.-
`
`7J}-
`
`470 of 1033
`
`BI Exhibit 1002
`
`

`

`Serial No. 08/146,206
`Page 3
`
`A.
`
`Amendments
`
`REMARKS
`
`The undersigned confirms having met with Examiners Nolan and Eisenschenk in the interview
`
`7 /23/97 and takes this opportunity to thank the Examiners for the courtesies extended in the
`
`interview. Claims 39-41 have been added herein which use language as proposed by Examiner
`
`Nolan in the interview. Independent claim 39 is similar to a combination of presently pending
`
`claims 22 and 23. Basis for the language "FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein FR1-
`4 comprise the four framework regions of a consensus human variable domain of a human heavy
`
`chain immunoglobulin subgroup and CDR1-3 comprise the three complementarity determining
`
`regions (CDRs) of a nonhuman import antibody" in claim 39 is found on page 1, lines 28-30 and
`
`page 25, lines 28-29, for example. Claim 40 finds specification basis on at least page 15, line
`
`18. Claim 41 finds specification support in Figure 1 B with respect to the framework regions of
`
`the HUVHlll consensus sequence therein. Claim 42 has also been added and finds specification
`
`basis on at least page 60, lines 25-32 and page 70, lines 6-8. With respect to the amendments
`
`to the specification, the sequence on pages 8 and 15 has been corrected (see Section B of this
`
`amendment) and the typographical error with respect to the Fig. 5 sequence has been corrected
`
`herein. In that the amendments do not introduce new matter, their entry is respectfully
`
`requested.
`
`B.
`
`Substitute Sequence Listing
`
`A further substitute sequence listing is submitted herewith. Applicants have found that SEQ ID
`
`N0:4 in the previous sequence listings did not correspond to the HUVHlll consensus sequence of
`Fig. 1 B (see page 9, lines 1-2) and hence SEQ ID N0:4 in the attached substitute sequence
`
`listing has been corrected accordingly. Furthermore, SEQ ID N0:4 is hereby corrected on pages
`
`8 and 15 of the application. In addition, separate sequence identifiers (SEQ ID NO's 27-30) have
`
`been given to the FR1-4 sequences in claim 41 added herein. In accordance with 37 C.F.R.
`§§1 .821 (f) and (g), the undersigned hereby states that the content of the paper and the computer
`
`readable sequence listings is the same.
`matter.
`
`I further state that this submission includes no new
`
`471 of 1033
`
`BI Exhibit 1002
`
`

`

`Serial No. 08/ 146,206
`Page 4
`
`C.
`
`Antibodies humanized ac:cording to the teachings of the instant application
`
`As discussed in the interview, the consensus human variable domain of the instant claims has
`
`been used to humanize a number of antibodies, including:
`
`1.
`
`Anti-p18~ERZ antibodies. See Example 1 of the application, including Table 3 on page 72
`
`(which describes humanized variants huMAb4D5-1-8) and page 65, lines 1-4 (concerning the use
`
`of a consensus human variable domain as recited in the claims herein). huMAb4D5-6 and
`
`huMAb4D5-8 had binding affinitie~; which were suprisingly superiorto that of the nonhuman
`
`antibody (muMAb4DS); see second to last column of Table 3. Repeated administration of the
`humanized anti-p185HER2 antibody huMAb4D5-8 has not lead to an immunogenic response in
`cancer patients treated therewith. See abstract of Baselga et al., J. Clin. Oncol. 14(3):737-744
`
`(1996), of record.
`
`2.
`
`Anti-CD3 antibodies. See Example 3 on pages 79-88 of the application; and Fig. Sas
`
`well as page 9, lines 25-31 concerning the use of a consensus human variable domain as
`claimed herein. [Note: In the Fig. 5 VH consensus sequence (hull I), the last residue of FR2 is S,
`i.e. A-S, and eighth residue of FR3 is N, i.e . D- N, because of changes in 1987 to 1991
`
`consensus sequence of Kabat et c~/.; such an equivalent consensus sequence and other
`
`changes in consensus sequences that result from the addition of further human antibody
`
`sequences to subseq~ent antibody compilations by Kabat et al. are clearly encompassed by the
`
`claims herein]. Humanized anti-C03 variant (v1) was found to enhance the cytotoxic effects of
`
`activated human cytotoxic T lymphocytes (CTL) 4-fold against SK-BR-3 tumor cells
`overexpressing p185HER2 (page 81 , lines 1-4). Variants of the humanized v1 antibody were made
`
`(v6 to v12; see page 82, line 22 and page 84, line 17 through to page 85, line 2 and page 86,
`
`lines 17-31), including the most pc1tent variant, v9, which bound Jurkat cells almost as efficiently
`
`as the chimeric BsF(ab'h (page 8fi, lines 20-22).
`
`3.
`
`Anti-CD18 antibody. See Example 4 on page 89 of the application and Figs. 6A and 68
`
`with respect to a consensus huma1n variable domain as claimed in the instant application. The
`
`binding affinity of the humanized anti-CD18 antibody (pH52-8.0/pH52-9.0; see Figs. 6A and 6 8 of
`
`472 of 1033
`
`BI Exhibit 1002
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`

`

`Serial No. 08/146,206
`Pages
`
`the application) was similar to the nonhuman H52 antibody; i.e. the humanized antibody has an
`
`affinity of 3.9 ± 0.9nM and murine H52 antibody has an affinity of 1.5 ± 0.3nM.
`
`4.
`
`Anti·lgE antibodies. See Presta et al. J. lmmunol. 151(5)2623-2632 (1993), of record.
`
`Use of a consensus human variable domain of the claims of the instant application is disclosed
`
`on page 2624 (column 1, first and third full paragraphs) and in Fig. 1. A number of humanized
`
`variants were made (see full paragraph 2 in column 1 on page 2624), including F(ab)-12 with only
`
`five framework region substitutions which exhibited binding comparable to the murine antibody
`(paragraph 2 on page 2631). Multidose administrations of full length anti-lgE variant 12 did not
`
`induce a human antihuman antibody response in allergic patients treated therewith (see column
`
`1, last paragraph on page 311 of Shields et al., Int. Arch. Allergy lmmunol. 107:308-312 (1995),
`
`of record).
`
`5.
`
`Anti·CD11a antibodies. See Werther et al. J. lmmnol. 157:4986-4995 (1996). of record.
`
`Use of a consensus human variable domain as taught and claimed in the instant application is
`
`discussed in the first sentence of the Results section on page 4988 and in Fig. 1 (see note in
`
`paragraph'2 above, with respect to changes in 1987 to 1991 consensus sequences. Eight
`
`humanized variants were made (see Table 1 on page 4989), including HulgG1 which had an
`
`apparent Kd similar to the parent murine antibody and comparable activity to the murine antibody
`
`in the celt adhesion and mixed leukocyte reaction (MLR) assays (see paragraph briging columns
`
`1 ·2 on page 4993).
`
`6.
`
`Anti-VEGF antibo