“KJ9IKD967
`
`PCT/639M020”
`
`-59-
`
`Comparison of the 372.3 murine and EU heavy
`
`chain sequences reveals that the mouse and'
`
`human residues are identical at positions
`
`23, 24{ 71 and 78.
`
`Thus the'mutated CUR-grafted 872.3 heavy
`
`chain corresponds to a preferred embodiment
`
`of the present invention.
`
`FD
`
`Regeneron Exhibit 1024.0401
`
`
`
`PCT/639M020”
`
`-59-
`
`Comparison of the 372.3 murine and EU heavy
`
`chain sequences reveals that the mouse and'
`
`human residues are identical at positions
`
`23, 24{ 71 and 78.
`
`Thus the'mutated CUR-grafted 872.3 heavy
`
`chain corresponds to a preferred embodiment
`
`of the present invention.
`
`FD
`
`Regeneron Exhibit 1024.0401
`
`
`
`W0 91/09967
`
`PCT/GB90/02017
`
`-‘50 _
`
`
`EXAMPLE 4
`
`_______________________________________________________
`CDR-GRAFTING OF A MURINE ANTI-ICAM-l MONOCLONAL ANTIBODY
`
`A murine antibody, R6-5-D6 (RP 0314863) having specificity
`for Intercellular Adhesion Molecule 1 (ICAM-l) was
`
`'
`
`I
`
`CDR-grafted substantially as described above in previous
`
`examples.
`
`This work is described in greater detail in
`
`co-pending application, British Patent Application No.
`- 9009549.8,
`the disclosure of which is incorporated herein
`by reference.
`
`The human EU framework was used as the acceptor framework
`
`for both heavy and light chains.
`The CDR-grafted
`antibody currently of choice is provided by co-expression'
`of grafted light chain gL221A and grafted heavy chain
`
`gH341D which has a binding affinity for ICAM l of about
`
`75% of that of the corresponding mouse-human chimeric
`antibody.
`‘
`LIGHT CHAIN
`
`gL221A has murine CDRs at positions 24-34 (CDRl), 50-56
`
`(CDR2) and 89-97 (CDR3).
`
`In addition several framework
`
`residues are also the murine amino acid.
`
`These residues
`
`were chosen after consideration of the possible
`
`contribution of these residues to domain packing and
`stability of the conformation of the antigen binding
`region.
`The residues which have been retained as mouse
`
`are at positions 2, 3, 48 (2), 60, 84, 85 and 87.
`
`Comparison of the murine anti-ICAM 1 and human EU light
`chain amino acid sequences reveals that the murine and
`
`human residues are identical at positions 46, 58 and 71.
`
`HEAVY CHAIN
`
`,
`
`93341D has mnrine CDRs at positions 26-35 (CDRl), 50-56
`
`(CDR2) and94-100B (CDR3).
`
`In addition murine residues
`
`were used in gH341D at positions 24, 48, 69, 71, 73, 80,
`88 and 91.
`Comparison of the murine anti-ICAM 1 and
`
`human EU heavy chain amino acid sequences are identical at
`
`us
`
`2
`
`positions 23, 49 and 78.
`
`Regeneron Exhibit 1024.0402
`
`
`
`WO 91/09967
`
`PCT/GB90/02017
`
`- 51 -
`
`EXAMPLE 5
`
`COR-Grafting of murine anti-TNFa antibodies
`
`A number of murine anti-TNFa monoclonal antibodies were
`
`CDR-grafted substantially as described above in previous
`
`examples.
`
`These antibodies include the murine monoclonal
`
`antibodies designated 61 E71, hTNFl, hTNF3 and 101.4
`
`A
`
`brief summary of the CDR-grafting of each of these
`
`antibodies is given below.
`
`
`61E71
`
`A similar analysis as described above (Example 1, Section
`12.1.) was done for 61E71 and for the heavy chain 10
`
`residues were identified at 23, 24, 48, 49, 68, 69, 71,
`
`73, 75 and 88 as residues to potentially retain as
`
`murine.
`
`The human frameworks chosen for GER-grafting of
`
`this antibody, and the hTNF3 and 101.4 antibodies were R31
`
`for the light chain and KOL for the heavy chain.
`
`Three genes were built, the first of which contained 23,
`
`24, 48, 49, 71 and 73 [gH341(6)] as murine residues.
`
`The
`
`second gene also had 75 and 88 as murine residues
`
`[gH341(8)] while the third gene additionally had 68, 69,
`
`75 and 88 as murine residues [gH34l(10)].
`
`Each was
`
`the minimum grafted light chain
`co-expressed with gL221,
`(CDRs only).
`The gL221/gHS41(6) and gL221/gn341(8)
`antibodies both bound as well to THE as murine 61371.
`
`The gL221/98341(10) antibody did not express and this
`combination was not taken further.
`
`Subsequently the gL221/9H341(6) antibody was assessed in
`
`an L929 cell competition assay in which the antibody
`
`competes against the TNF receptor on L929 cells for
`
`binding to TNF in solution.
`
`In this assay the
`
`gL221/gH341(6) antibody was approximately 10% as active as
`murine 61E71.
`
`Regeneron Exhibit 1024.0403
`
`
`
`WO- 91/09967
`
`PCT/6390/02017
`
`_ 52 -
`
`
`hTNFl
`
`hTNFl is a monoclonal antibody which recognises an epitope .
`on human TNF— .
`The EU human framework was used for
`
`!
`
`CDR-grafting of both the heavy and light variable domains.
`
`Heagy Chain
`
`In the CUR-grafted heavy chain (ghTNFl) mouse CDRs were
`
`used at positions 26-35 (CDRl), 50-65 (CDR2) and 95-102
`
`(CDR3). Mouse residues were also used in the frameworks
`at positions 48, 67, 69, 71, 73, 76, 89, 91, 94 and 108.
`
`Comparison of the TNFl mouse and EU human heavy chain
`residues reveals that these are identical at positions 23,
`24, 29 and 78.
`
`Light Chain
`
`In the CDR-grafted light chain (thTNFl) mouse CDRs wre
`
`used at positions 24-34 (CDRl), 50-56 (CDR2) and 89-97
`
`(CDR3).
`
`In addition mouse residues were used in the
`
`frameworks at positions 3, 42, 48, 49, 83, 106 and 108.
`
`Comparison of the hTNFl mouse and EU human light chain
`residues reveals that these are identical at positions 46,
`58 and 71.
`
`The grafted hTNFl heavy chain was co-expressed with the
`chimeric light chain and the binding ability of the
`product compared with that of the chimeric light
`chain/chimeric heavy chain.product in a TNF binding assay.
`The grafted heavy chain product appeared to have binding
`ability for TNF slightly better than the fully chimeric
`product.
`
`Similarly, a grafted heavy chain/grafted light chain
`product was co-expressed and compared with the fully
`chimeric product and found to have closely similar binding
`properties to the latter product.
`
`(I!
`
`3
`
`Regeneron Exhibit 1024.0404
`
`
`
`WO 91/09967
`
`PCT/GB90/02017
`
`_ 53 -
`
`
`hTNF3
`
`The
`hTNF3 recognises an_epitope on human TNF—o(.
`sequence of hTNF3 shows only 21 differences compared to
`
`61371 in the light and heavy chain variable regions, 10 in
`
`the light chain (2 in the CDRs at positions 50, 96 and 8
`
`in the framework at 1, 19, 40, 45, 46, 76, 103 and 106)
`and 11 in the heavy chain (3 in the CDR regions at
`
`positions 52, 60 and 95 and 8 in the framework at 1, 10,
`
`The light and heavy chains
`‘ 3B, 40, 67, 73, 87 and 105).
`of the 61E71 and hTNF3 chimeric antibodies can be
`
`exchanged without loss of activity in the direct binding
`assay.
`However 61E71 is an order of magnitude less able
`
`to compete with the TNF receptor on L929 cells for TNF-a
`
`compared to hTNF3.
`
`Based on the 61E71 CDR grafting data
`
`gL221 and gHB41(+23, 24, 48, 49 71 and 73 as mouse) genes
`have been built for hTNF3 and tested and the resultant
`
`grafted antibody binds well to TNF-a, but competes very
`
`poorly in the L929 assay.
`
`It is possible that in this
`
`case also the framework residues identified for OKT3
`
`programme may improve the competitive binding ability of
`
`this antibody.
`
`
`101.4
`
`101.4 is a further murine monoclonal antibody able to
`recognise human TNF-a.
`The heavy chain of this antibody
`
`shows good homology to KOL and so the CDR-grafting has
`
`been based on REl for the light chain and KOL for the
`
`heavy chain.
`
`Several grafted heavy chain genes have been
`
`constructed with conservative choices for the CDR's
`
`(gH34l) and which have one or a small number of non—CDR
`
`'residues at positions 73, 78 or 77-79 inclusive, as the
`
`mouse amino acids.
`
`These have been co-expressed with cL
`
`or gL221.
`
`In all cases binding to TNF equivalent to the
`
`chimeric antibody is seen and when co-expressed with cL
`
`the resultant antibodies are able to compete well in the
`
`L929 assay.
`
`However, with gL221 the resultant antibodies
`
`Regeneron Exhibit 1024.0405
`
`
`
`WO 91/09967
`
`PCTI6890/02017
`
`- 54 -
`
`are at least an order of magnitude less able to compete
`
`for TNF against the TNF receptor on L929 cells.
`
`Mouse residues at other positions in the heavy chain, for
`example, at 23 and 24 together or at 76 have been
`‘
`
`i
`
`demonstrated to provide no improvement to the competitive
`
`ability of the grafted antibody in the L929 assay.
`
`A number of other antibodies including antibodies having
`
`specificity for interleukins e.g. ILl and cancer markers
`
`such as carcinoembryonic antigen (CEA) e.g. the monoclonal
`
`antibody A587 (ref. 21), have been successfully
`
`CDR-grafted according to the present invention.
`
`It will be appreciated that the foregoing examples are
`
`given by way of illustration only and are not intended to
`
`limit the scope of the claimed invention.
`Changes and
`modifications may be made to the methods described whilst
`still falling within the spirit and scope of the invention.
`
`Regeneron Exhibit 1024.0406
`
`
`
`WO 91/09967
`
`PCT/GB90/02017
`
`-55-
`
`References
`
`1.
`
`Kohler & Milstein, Nature, 265, 295—497, 1975.
`
`2.
`
`3.
`
`4.
`
`
`Chatenoud et a1,
`
`(1986), J.
`
`Immunol. 137, 830-838.
`
`
`Jeffers et a1,
`
`(1986), Transplantation, 2;, 572-578.
`
`
`Begent et al, Br. J. Cancer 62:
`
`487 (1990).
`
`5.
`
`
`‘ Verhoeyen et al, Science, 239, 1534-1536, 1988.
`
`6.
`
`
`Riechmann et al, Nature, 332, 323-324, 1988..
`
`7o
`
`Rabat, E-Ao’ Wu, TOTO! Reid-Miller, Mt, Perry, HoM-I
`
`Gottesman, K.S., 1987, in Sequences of Proteins of
`
`Immunological Interest, US Department of Health and
`
`”Human Services, NIH, USA.
`
`8.
`
`9.
`
`Wu, T.T., and Rabat, E.A., 1970, J. Exp. Med. 132
`211-250.
`
`
`(1989), Proc. Natl. Acad. Sci- USA, fig,
`Queen et a1,
`10029-10033 and WO 90/07861
`
`
`10. Maniatis et al, Molecular Cloning, Cold Spring
`
`Harbor, New York, 1989.
`
`11. Primrose and Old, Principles of Gene Manipulation,
`Blackwell, Oxford, 1980.
`'
`
`12. Sanger, 8., Nicklen, S., Coulson, A.R., 1977, Proc.
`
`Natl. Acad. Sci. USA, 13 5463
`
`Regeneron Exhibit 1024.040?
`
`
`
`wow/09967
`
`‘
`
`'
`
`,
`
`PCT/6390/02017
`
`- 55 _
`
`13. Kramer, W., Drutsa, V., Jansen, B.-W., Kramer, B.,
`
`Plugfelder, M., Fritz, H.-J., 1984, Nucl. Acids Res.
`
`g, 9441
`
`'
`
`14- Whittle, N., Adair, J., Lloyd, J.C., Jenkins, B.,
`
`Devine, J., Schlom, J., Raubitshek, A., Colcher, D.,
`
`Bodmer, M., 1987, Protein Engineering 1, 499.
`
`15. Sikder, S.S., Akolkar, P.N., Kaledas, P.M., Morrison,
`S.L., Rabat, E.A., 1985, J.
`Immunol. 135, 4215.
`
`._
`
`e
`
`16. Wallick, S.C., Rabat, E.A., Morrison, S.L., 1988,
`
`J. Exp. Med. 168, 1099
`
`17. Bebbington, C.R., Published International Patent
`
`Application WO 89/01036.
`
`'18. Granthan and Perrin 1986,
`
`Immunology Today 1, 160.
`
`19. Kozak, M., 1987, J. Mol. Biol. 196, 947.
`
`20.
`
`Jones, T.P., Dear, P.H., Foote, J., Neuberger, M.S.,
`Winter, 6., 1986, Nature, 321, 522
`
`
`21. Harwood et al, Br. J. Cancer, 24, 75—82 (1986).
`
`Regeneron Exhibit 1024.0408
`
`
`
`WO 91/09967
`
`PCT/GB9OI02017
`
`- 57 _
`
`CLAIMS
`
`1.
`
`A CDR-grafted antibody heavy chain having a variable
`region domain comprising acceptor framework and donor
`
`antigen binding regions wherein the framework
`
`comprises donor residues at at least one of positions
`
`6, 23 and/or 24, 48 and/or 49, 71 and/or 73, 75
`and/or 76 and/or 78 and 88 and/or 91.
`
`2.
`
`A CDR-grafted heavy chain according to Claim 1
`
`comprising donor residues at positions 23, 24, 49,
`
`71, 73 and 78, or at positions 23, 24 and 49.
`
`3.
`
`A CUR-grafted heavy chain according to Claim 2
`
`comprising donor residues at positions 2, 4, 6, 25,
`
`36, 37, 39, 47, 48, 93, 94, 103, 104, 106 and 107.
`
`4.
`
`A CDR-grafted heavy chain according to Claim 2 or 3,
`
`comprising donor residues at one, some or all of
`
`positions:
`
`1 and 3,
`
`p
`
`69 (if 48 is different between donor and acceptor),
`
`38 and 46 (if 48 is the donor residue),'
`
`67,
`
`82 and 18 (if 67 is the donor residue),
`
`91, and
`
`any one or more of 9, 11, 41, 87, 108, 110 and 112.
`
`5.
`
`A CUR-grafted heavy chain according to any of the
`
`preceding comprising donor CDRs at positions 26-35,
`50-65 and 95-100.
`
`6.
`
`A CDR-grafted antibody light chain having a variable
`
`region domain comprising acceptor framework and‘donor
`
`antigen binding regions wherein the framework
`
`comprises donor residues at at least one of positions
`.1 and/or 3 and 46 and/or 47.
`'
`
`Regeneron Exhibit 1024.0409
`
`
`
`W0 9] /09967
`
`'
`
`PCT/6390/02017
`
`- 68 -
`
`7.
`
`A CDR—grafted light chain according to Claim 6
`
`comprising donor residues at positions 46 and 47.
`
`8.
`
`A CDR-grafted antibody light chain having a variable
`
`region domain comprising acceptor framework and donor
`
`’
`
`antigen binding regions wherein the framework
`
`comprises donor residues at at least one of positions
`
`46, 48, 58 and 71.
`
`9,. A CDR-grafted light chain according to Claim 8
`
`comprising donor residues at positions 46, 48, 58 and
`71.
`
`10.
`
`A CDR-grafted light chain according to Claim 8 or 9,
`
`comprising donor residues at positions 2, 4, 6, 35,
`
`36, 38, 44, 47, 49, 62, 64-69, 85, 87, 98, 99, 101
`and 102.
`
`11. A CDR-grafted light chain according to Claim 9 or 10,
`
`comprising donor residues at one,
`
`some or all of
`
`positions:
`
`1 and 3,
`
`63,
`
`60 (if 60 and 54 are able to form a potential
`
`saltbridge),
`
`70 (if 70 and 24 are able to form a potential
`
`saltbridge),
`73 andel (if 47 is different between donor and
`
`acceptor),
`
`37 and 45 (if 47 if different between donor and
`
`acceptor), and
`
`any one or more of 10, 12, 40, 83, 103 and 105.
`
`12.
`
`A CDR—grafted light chain according to any one of
`
`Claims 6—11, comprising donor CDRs at positions
`
`24-34, 50-56 and 89-97.
`
`('v
`
`vi
`
`Regeneron Exhibit 1024.0410
`
`
`
`WO 91109967
`
`PCT/G890/02017
`
`_ 59 -
`
`13.
`
`A CDR-grafted antibody molecule comprising at least
`
`one CDR—grafted heavy chain-according to any one of
`Claims 1-5 and at least one CDR-grafted light chain
`
`according to any one of Claims 6-12.
`
`14.
`
`A CDR-grafted antibody molecule according to Claim
`
`13, which is a site-specific antibody molecule.
`
`15. _A CDR-grafted antibody molecule according to Claim 13
`
`which has specificity for an interleukin, hormone or
`
`other biologically active compound or a receptor
`therefor.
`
`16.
`
`A CDR-grafted antibody heavy or light chain or
`- molecule according to any one of the preceding claims
`
`comprising human acCeptor residues and non-human
`donor residues.
`
`17.
`
`A DNA sequence which codes for a CDR-grafted heavy
`
`chain according to Claim 1 or a CUR-grafted light
`
`chain according to Claim 6 or Claim 8.
`
`18.
`
`A cloning or expression vector containing a DNA
`
`sequence according to Claim 17.
`
`19.. A host cell transformed with a DNA sequence according
`to Claim 17.
`
`20.
`
`A process for the production of a CDR-grafted
`
`antibody sequence according to Claim 17 in a
`‘transformed host cell.
`
`21.
`
`A process for producing a CDR-grafted antibody‘
`product comprising:
`
`Regeneron Exhibit 1024.0411
`
`
`
`WO 91/09967
`
`.
`
`‘
`
`PCT/GB90/02017
`
`.. 7 o ..
`
`(a)
`
`producing in an expression vector an operon
`
`having a DNA sequence which encodes an antibody
`
`heavy chain according to Claim 1;
`and/or
`
`(b)
`
`producing in an expression vector an operon
`
`’
`
`having a DNA sequence which encodes a
`
`complementary antibody light chain according to
`Claim 6 or Claim 8;
`
`transfecting a host cell with the or each vector;
`
`(c)
`and
`
`(d)
`
`culturing the transfected cell line to produce
`
`the CUR-grafted antibody product.
`
`22.
`
`A therapeutic or diagnostic composition comprising a
`CDR—grafted antibody heavy chain according to Claim
`
`1, or a CDR-grafted light chain according to Claim 6
`or Claim 8, or a CDR—grafted antibody molecule
`
`according to Claim 13 in combination with a
`
`pharmaceutically acceptable carrier, diluent or
`
`excipient.
`
`23.
`
`A method of therapy or diagnosis comprising
`
`administering an effective amount of a CUR-grafted
`
`heavy chain according to Claim 1, or a CDR-grafted
`
`light chain according to Claim 6 or Claim 8, or a
`
`CDR-grafted antibody molecule according to Claim 13
`
`to a human or animal subject.
`
`Regeneron Exhibit 1024.0412
`
`
`
`Cf‘iPMAELS & RANSFo‘fiD
`
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`
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`The Patent Office,
`
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`
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`
`WIPO
`
`pcr
`
`”"’
`
`po727swo: CPM/m
`.
`23rd January, 1991.
`
`REQUEST FOR RECTIFICATION UNDER PCT RULE 91.1(f)
`
`Dear sirs,
`
`Re: International Patent Application No. PGTIGBSOI02017!
`Celltegn Lim1§§§ at al,
`
`I refer to your Invitation issued on 14th January 1991. The required
`Authorisations and Formal Drawings will be filed in due course.
`
`In checking the application, it has become apparent that there are
`three mistakes in the Request Form.
`
`Firstly,....
`
`Secondly,..;.
`
`Thirdly, for reasons which are not apparent, an old version of the
`Request Form (PCT/R0/101 of July 1987) was used instead of the most
`up-to-date version.
`As a result of this,
`some PCT states were not
`designated although it was
`the Applicant's
`intention that all
`possible states sh uld have been designated. As evidence of this,
`I attach a copy of the information sheet which was given to me by
`hand by the Applicant's Patent Manager on the date the application
`
`Regeneron Exhibit 1024.0413
`
`
`
`2
`
`It can be seen that this clearly indicates that all
`was filed.
`territories should have been designated.
`
`I also enclose evidence that the out-of-date Request Form was used
`inadvertently.
`at the same time as the present application was
`filed, I also filed two other PCT applications, Nos. PCT/6890702015
`and PCT/GBQO/OZOIB.
`I enclose copies of the Request Forms for these
`cases which, as you can see, are the most up-to-date versions of the ’
`forms.
`'
`
`*
`
`the Request Form be amended by adding
`I therefore request that
`thereto the designations of Canada and Spain as national applications
`and Greece, Spain and Denmark as designated states within the EPC
`designation.
`I note that it will‘not be necessary to pay any extra
`fees in respect of these inadvertently omitted designations.
`
`In order to effect all these corrections, I enclose a retyped, up-
`to-date (at the date of filing) Request Form and request that this
`be substituted for the present, out-of-date Request Form.
`
`Yours truly,
`
`We ’
`MERCER, Christopher Paul
`Authorised Representative.
`
`Regeneron Exhibit 1024.0414
`
`
`
`WO 91/09967
`
`Pcr/cn9o/02017
`
`1/ 1.5
`
`GAATTCCCAA AGACAAAatg gattttcaag tgcagatttt cégcttcctg
`
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`
`atcatgtctg catctccagg ggagaaggtc accatgacct
`
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`
`ggcacctccc
`
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`
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`
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`
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`
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`
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`
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`
`tgggacctct
`ccacttatta
`
`gcagaagtca
`
`tggcttctgg
`tactctctca
`
`ctgccagcag
`
`gggacaaagt
`
`tggaaataaa
`
`ccgggctgat
`
`actgcaccaa
`
`ctgtatccat
`
`cttcccacca
`
`agttaacaté
`
`tggaggtgcc
`
`tcagtcgtgt
`
`gcttcttgaa
`
`tccagtgagc
`caacttctac
`
`cccaaagaca
`
`tcaatgtcaa
`
`gtggaagatt
`
`gatgqcagtg
`
`aacgacaaaa
`
`tggcgtcctg
`
`aacagttgga
`
`ctgatcagga
`
`cagcaaagac
`
`agcacctaca
`
`gcatgagcag caccctcacg ttgaccaagg
`
`agctatacct
`
`gtgaggccac
`
`tcacaagaca
`
`gagcttcaac
`CCAGCTCCCA
`
`aggaétgagt
`GCTCCATCCT
`
`gtTAGAGACA
`
`acgagtatga
`tcaacttcac
`
`AAGGTCCTGA
`
`acgacataac
`
`ccattgtcaa
`GACGCCACCA
`
`.ATCTTCCCTT CTAAGGTCTT GGAGGCTTCC
`
`TGCGGTGCTC
`
`tAAACCTCCT CCCACCTCCT
`
`TTGGCTTTTA
`
`TCATGCTAAT ATTTGCAGAA
`
`51
`
`101
`
`151
`
`201
`
`251
`
`301
`
`351
`
`401
`
`451
`
`501
`
`551
`
`601
`
`651
`
`701
`
`751
`
`851
`
`901
`
`51
`
`101
`
`151
`
`201
`
`801
`
`CCACAAGCGC
`
`TCTCCTCCTC
`
`tTAQCACTGT
`CTCCCTTTCC
`
`AATATTCAAT AAAGTGAGTC TTTGCCTTGA AAAAAAAAAA AAA
`
`Fig.1(a)
`
`MDFOVOiFSF LLISASVIIS RGQIVLTQSP AIMSASPGEK VTMTCSASSS
`
`VSYMNWYQQK SGTSPKRWIY DTSKLASGVP AHFRGSGSGT SYSLTISGME
`
`AEDAATYYCQ QWSSNPFTFG SGTKLEINRA DTAPTVSIFP PSSEQLTSGG
`
`ASVVCFLNNF YPKDINVKWK IDGSERQNGV LNSWTDQDSK DSTYSMSSTL
`
`TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC*
`
`Fig. 1(b)
`
`suasfiTUTE SHEET
`
`Regeneron Exhibit 1024.0415
`
`
`
`WO 91/09967
`
`PCT/GB90/02017
`
`2/15
`
`1 GAATTCCCCT CTCCACAGAC ACTGAAAACT CTGACTCAAC ATGGAAAGGC
`
`51 ACTGGATCTT TC‘I‘ACTCCTG rJZ‘:'.I.‘GTCAGTAA CTGCAGGTGT CCACTCCCAG
`101 GTCCAGCTGC AGCAGTCTGG GGCTGAACTG GCAAGACCTG GGGCCTCAGT
`
`151 GAAGATGTCC TGCAAGGCTT CTGGCTACAC CTTTACTAGG TACACGATGC
`
`201 ACTGGGTAAA ACAGAGGCCT GGACAGGGTC TGGAATGGAT TGGATACATT
`
`251 AATCCTAGCC GTGGTTATAC TAATTACAAT CAGAAGTTCA AGGACAAGGC
`
`301 CACATTGACT ACAGACAAAT CCTCCAGCAC AGCC‘I'ACATG CAACTGAGCA
`
`351 GCCTGACATC TGAGGACTCT GCAGTCTATT ACTGTGCAAG ATATTATGAT
`
`401 GATCATTACT GCCTTGACTA CTGGGGCCAA GGCACCACTC TCACAGTCTC
`
`451 CTCAGCCAAA ACAACAGCCC CATCGGTCTA TCCACTGGCC CCTGTGTGTG
`
`501 GAGATACAAC TGGCTCCTCG GTGACTCTAG GATGCCTGGT CAAGGGTTAT
`
`551 TTCCCTGAGC CAGTGACCTT GACCTGGAAC TCTGGATCCC TGTCCAGTGG
`601 TGTGCACACC TTCCCAGCTG TCCTGCAGTC TGACCTCTAC ACCCTCAGCA
`
`651 GCTCAGTGAC TGTAACCTCG AGCACCTGGC CCAGCCAGTC CATCACCTGC
`701 AATGTGGCCC ACCCGGCAAG CAGCACCAAG GTGGACAAGA AAATTGAGCC
`
`751 CAGAGGGCCC ACAATCAAGC CCTGTCCTCC ATGCAAATGC CCAGCACCTA
`
`801 ACCTCTTGGG TGGACCATCC GTCTTCATCT TCCCTCCAAA GATCAAGGAT
`
`851 GTACTCATGA TCTCCCTGAG CCCCATAGTC ACATGTGTGG TGGTGGATGT
`
`901 GAGCGAGGAT GACCCAGATG TCCAGATCAG 'CTGGTTTGTG AACAACGTGG
`
`951 AAGTACACAC AGCTCAGACA CAAACCCATA GAGAGGATTA CAACAGTACT
`
`1001 CTCCGGGTGG TCAGTGCCCT CCCCATCCAG CACCAGGACT GGATGAGTGG
`
`1051 CAAGGAGTTC AAATGCAAGG TCAACAACAA AGACCTCCCA GCGCCCATCG
`
`1101 AGAGAACCAT CTCAAAACCC AAAGGGTCAG TAAGAGCTCC ACAGGTATAT
`
`1151 GTCTTGCCTC CACCAGAAGA AGAGATGACT AAGAAACAGG TCACTCTGAC
`
`1201 CTGCATGGTC ACAGACTTCA TGCCTGAAGA CATTTACGTG GAGTGGACCA-
`
`1251 ACAACGGGAA AACAGAGCTA AACTACAAGA ACACTGAACC AGTCCTGGAC
`
`1301 TCTGATGGTT CTTACTTCAT GTACAGCAAG 'C'I‘GAGAGTGG AAAAGAAGAA
`
`1351 CTGGGTGGAA AGAAATAGCT ACTCCTGTTC AGTGGTCCAC GAGGGTCTGC
`
`1401 ACAATCACCA CACGACTAAG AGCTTCTCCC GGACTCCGGG TAAATGAGCT
`
`1451 CAGCACCCAC AAAACTCTCA GGTCCAAAGA GACACCCACA CTCATCTCCA
`
`1501 TGCTTCCCTT GTATAAATAA AGCACCCAGC AATGCCTGGG ACCATGTAAA
`
`1551 AAAAAAAAAA AAAGGAATTC
`
`‘ Fig.2(a)
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0416
`
`
`
`WO 91/09967
`
`PCT/GB9OID2017
`
`on 3 HEAVY CHAIN PROTEIN SEQUENCE DEDUCED FROM DNA SEQUENCE
`
`3/15
`
`1 MERHWIFLLL LSVTAGVHSQ VQLQQSGAEL ARPGASVKMS CKASGYTFTR
`
`51 YTMHWVKQRP GQGLEWIGYI NPSRGYTNYN QKFKDKATLT TDKSSSTAYM
`101 QLSSLTSEDS AVYYCARYYD DHYCLDYWGQ GTTLTVSSAK T’I‘APSVYPLA
`
`151 PVCGDTTGSS VTLGCLVKGY FPEPVTLTWN SGSLSSGVHT FPAVLQSDLY
`201 TLSSSVTVTS STWPSQSITC NVAHPASSTK VDKKIEPRGP TIKPCPPCKC
`
`251 PAPNLLGGPS VFIFPPKIKD VLMISLSPIV TCVVVDVSED DPDVQISWFV
`
`301 N'NVEVHTAQT QTHRBDYNST LRVVSALPIQ HQDWMSGKEF KCKVNNKDLP
`
`351 APIERTISRP KGSVRAPQVY VLPPPEEEMT KKQVTLTCMV TDFMPEDIYV
`401 EWTNNGKTEL NYKNTEPVLD SDGSYFMYSK LRVEKKNWVE RNSYSCSVVH
`*
`
`451
`
`EGLHNHHT'IK SFSRTPGK
`
`Fig 2(b)
`
`1
`
`NN
`
`.
`
`23
`
`‘
`
`4 2
`
`N-
`
`N .
`
`N
`
`N
`
`RES TYPE
`
`SBspSPESssBSstSssPSPSPsPSsse*s*p*Pi“I'SsSe
`
`Okt3v1
`
`QIVLTQSPAIMSASPGEKVTMTCSASS . SVSYIQIWYQQKSGT
`
`REI _
`
`*******
`***********
`
`DIQMTQSPSSLSASVGDRVTITCQASQDIIKYLNWYQQEPGK
`? ?
`CDRl
`€3an
`
`(LOOP)
`kmyr)
`
`I
`
`5 6
`
`'
`
`85
`
`N N
`
`RES TYPE
`
`*IsiPpIeesesssSBEsePsPSBSSEsPspsPsseesSPePb
`
`Okt3vl
`
`SPKRWIYDTSKLASGVPAEFEGSGSGTSYSL'I'ISfiMEAEDAAT
`
`REI
`
`APKLLIYEASNLQAGVPSRFSGSGSGTDXTETISSLQPEDJZAT
`a
`a7
`'3
`2
`
`Hanan”
`
`CDRZ (LOOP/KABAT)
`
`102 ~ 108
`
`RES TYPE PiPIPies**iPIIsPPSPSPSS
`Okt3vl
`YYCQQWSSNPFTEGSSTKLEINR
`REIv1
`YYCQQYQSLPYTFGQGTKQQIZR
`. ?
`?
`
`,
`Hg 3
`
`_
`
`“NH
`
`CDR3
`
`(LOOP)
`
`******.***
`
`C1103
`
`(KABAT)
`
`SUBSTITUTE SHEET’
`
`Regeneron Exhibit 1024.0417
`
`
`
`wo 91/09967
`
`‘
`
`misuse/02017
`
`4/15
`
`NN_N
`
`23 26
`
`32 35 N39
`
`43
`
`RES TYPE SESPs‘SBssS‘sSSsSpSpSPsPSEbSBssBePiPIpiesss
`
`Okt3h
`
`QVQLQQ§GAELA§PGASVK§SCKASGYTFTRYTMHWVKQRPGQ
`
`KOL
`
`QVQLVESGGGEVQPGgSLRLSC§§SGF;FSSYAMYWVRQAPGK
`?
`??
`
`******
`
`CDRl
`
`(LOOP)
`
`*****CDR1(KABAT)
`
`52a
`
`60
`
`65
`
`N N N
`
`82abc
`
`89
`
`RESTYPE IIeIppp“ssssssss‘ps‘pSSsbSpseSsSseSp‘pSpsSBssS‘ePb
`
`Okt3vh GLEWIGYINPSRGYTNTNQKFKQKATLTTDKSSSTAYMQLSSLTSEDSAV
`KOL
`GLEWVAIIWDDGSDQHYADSVKGRFTISRDNSKNTLELQMDSLREEDTQV
`
`'2?
`
`-
`
`2? ?’?
`
`?
`
`************
`
`CDRZ
`
`(LOOP)
`
`*******************
`
`CDRZ
`
`(KABAT)
`
`92 N
`
`107
`
`113
`
`RES TYPE PiPIEissssiiisssbibi*EIPIP*spSBSS
`
`Okt3vh
`
`YYCARYYDDHY.......CLDYWGQGTTLTVSS
`
`KOL
`
`YECARDGGHGFCSSASCFGPDYWGQGTEVTVSS
`
`***************** CRD3
`
`(WAT/LOOP)
`
`Fig.4
`
`susémum SHEET
`
`Regeneron Exhibit 1024.0418
`
`
`
`WO 91/09967
`
`PCT/GB9W02017
`
`5/15
`
`OKT 3 HEAVY CHAIN CDR GRAFTS
`
`1. gh341 and derivatives
`
`1
`
`2 6
`
`3 5
`
`3 9
`
`4 3
`
`0kt3vh QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQ
`91-13 4 1
`QVQLVESGGGVVQPGRSLRLSCSSSGYTFTRYTMWVRQAPGK JA17 8
`
`9H3 4 1A QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGK JA1 8 5
`
`gH3 4 1E QVQLVQSGGGVVQPGRSIIRLSCKASGYTFTRYTMHWVRQAPGK JA19 8
`
`gH3 4 1 * QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGK JA2 07
`
`JA2 0 9
`QVQLVQSGGGVVQPGRSLRLS CKAS GYTFTRYTMHWVRQAPGK
`91-13 4 1 *
`
`9H3 4 1D 'QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMWVRQAPGK JA197
`, 9H3 4 l * QVQLVQSGGGWQPGRSLRLSCWQAPGK JA1 9 9
`
`9H3 4 1C QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGK JA184 '
`
`gHB41* QVQLVQSGGGVVQPGRSLRLSCSASGYTFTRYTm-IWVRQAPGK
`
`JAZ 03
`
`_ 933 41* QVQLVESGGGVVQPGRSLRLSCSéSGYTFTRYTMHWVRQAPGK
`
`JAZ 05
`
`9334113 QVQLVESGGGVVQPGRSLRLSCSSSGYTF'I'RYTMHWVRQAPGK
`
`JA183
`
`JA204
`gH341* QVQLVgSGGGVVQPGRSLRLSCSASGYTFTRYTMHWVRQAPGK
`93341,» QVQLVESGGGVVQPGRSIRLSCSWQAPGK JA206
`gI-I341* 'QVQLVQSGGGVVQPGRSLRLSCSWQAPGK JAZ 08
`KOL
`QVQLVESGGGVVQPGRSLRLSCSSSGFIFSSYAMYWVRQAPGK
`
`Fig-15(1)“
`
`SUBSTITUTE s’HEET
`
`Regeneron Exhibit 1024.0419
`
`
`
`WO 91/09967
`
`PCT/GB9W02017
`
`6/15
`
`44
`
`so
`
`65
`
`83
`
`Okt3vh GLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLT
`
`gH341
`
`GLEWVAYINPSRGYTNYNQKFKDRFTISRDNSKNTLFLQMDSLR JA178
`
`933412; GLEWIGYINPSRGYTNYNQKVQRFTIsgngsxgryLQmSLR JA185
`
`gH341E GLEWIGYINPSRGYTNYNQKVKQRFTISED§SK§TAFLQMDSLR JA198
`
`gH341* GLEWIGYINPSRGYTNYNQKVKQRFTISEDéSKNTAFLQMDSLR JAZO?
`
`gH341* GLEWIGYINPSRG!TNYNQKVKQRFTISRDNSKNTAFLQMDSLR JA209
`
`gH341D GLEWIGYINPSRGYTNYNQKVKQRFTISgD§SKNTLFLQMDSLR JA197
`
`gH341* GLEWIGYINPSRGYTNYNQKVEQRFTISRDNSKNTLFLQMDSLR JA199
`gH341C GLEWVAYINPSRGXIEgflQKFKDRFTISRDNSKNTLFLQMDSLR JA184 -
`
`gH341* GLEWIGYINPSRGYTNYNOKVEQRFTISED§SK§TAFLQMDSLR JA207
`
`gH341* GLEWIGYINPSRGYTNYNOKVKQRFTISEDLSKQIQFLQMDSLR JAZOS
`
`gH341B GLEWIGYINPSRGYTNYNOKVEDRFTISgD§SK§TéFLQMDSLR JA183
`
`gH341* GLEWIGYINPSRGYTNYNOKVKQRFTISEDgsxéTéFLQMDSLR JA204
`
`gH341* GLEWIGYINPSRGYTNYNOKVEQRFTISED§SK§T§FLQMDSLR JAZOS
`
`gH34l* GLEWIGYINPSRGYTNYNOKVEQRFTISgQ§SKNTéFLQMDSLR JA208
`
`KOL
`
`‘GLEWVAIIWDDGSDQHYADSVKGRFTISRDNSKNTLFLQMDSLR
`
`Fig. 5(ii)
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0420
`
`
`
`VW)9u0m%7
`
`PCT/GB90/020] 7
`
`7/15
`
`Okt3vh
`
`113
`102
`_ 95
`84
`SEDSAVYYCARYYDDHY.......CLDYWGQGTTLTVSS
`
`gH341
`
`PEDTGVYFCARYYDDHY ....... CLDYWGQGTTLTVSS
`
`JA178
`
`gH341A
`
`PEDTéVY¥CARYYDDHY ....... CLDYWGQGTTLTVSS
`
`JA185
`
`gH341E
`
`gH341*
`
`PEDTGVYfCARYYDDHY ....... CLDYWGQGTTLTVSS
`
`PEDTGVYFCARYYDDHY ....... CLDYWGQGTTLTVSS
`
`JA198
`
`JA207
`
`gH341D
`
`PEDTGVYFCARYYDDHY ....... CLDYWGQGTTLTVSS
`
`JA197
`
`gHB41*
`
`PEDTGVYFCARYYDDHY ....... CLDYWGQGTTLTVSS
`
`JAZOQ
`
`gH341*
`
`PEDTGVYFCARYYDDHY. ..... .CLDYWGQGTTLTVSS
`
`JA199
`
`gH341C
`
`PEDTGVYFCARYYDDHY ..... ..CLDYWGQGTTLTVSS
`
`JA184
`
`gH341*
`
`PEDTéVYECARYYDDHY ....... CLDYWGQGTTLTVSS
`
`JA203
`
`gH341f
`
`PEDT;VY;CARYYDDHY. ...... CLDYWGQGTTLTVSS
`
`JA205
`
`983418
`
`PEDT;VY¥CARYYDDHY..1....CLDYWGQGTTLTVSS
`
`JA183
`
`gH341*
`
`PEDTGVYFCARYYDDHY.......CLDYWGQGTTLTVSS
`
`JA204
`
`gH341*
`
`PEDTGVYFCARYYDDHY.......CLDYWGQGTTLTVSS
`
`JA206
`
`gH341*
`KOL
`
`PEDTGVYFCARYYDDHY ..... ..CLDYWGQGTTLTVSS
`PEDTGVYFCARDGGHGFCSSASCFGPDYWGQGTPVTVSS
`
`JA208
`
`Fl 9. 5 (n I)
`
`SUBST‘TUTE SHEET
`
`
`
`Regeneron Exhibit 1024.0421
`
`
`
`WO 91/09967
`
`PCT/GB90/02017
`
`8/15
`
`OKT3 LIGHT CHAIN CDR GRAFTING
`
`1. gL221 and derivatives
`
`1
`
`24
`
`34
`
`42
`
`Okt3vl
`gLZZi
`gLZZlA
`gLZZlB
`gL221C
`REI
`
`QIVLTQSPAIMSASPGEKVTMTCSASS.SVSYMNWYQQKSGT
`DIQMTQSPSSLSASVGDRVTITCSASS.SVSYMNWYQQTPGK
`QIXMTQSPSSLSASVGDRVTITCSASS.SVSYMNWYQQTPGK
`QIXMTQSPSSLSASVGDRVTITCSASS.SVSYMNWYQQTPGK
`DIQMTQSPSSLSASVGDRVTITCSASS.SVSYMNWYQQTPGK
`DIQMTQSPSSLSASVGDRVTITCQASQDIIKYfiNWYQQTPGK
`
`43
`
`50
`
`56
`
`85
`
`Okt3v1
`
`SPKRWIYDTSKLASGVPAHFRGSGSGTSYSLEISGMEAEDAAT
`
`gLZZl
`gL221A
`gLZZlB
`gLZZlC
`REI
`
`APKLLIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIAT
`APKEgIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIAT
`APKBEIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIAT
`APKEgIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIAT
`APKLLIYEASNLQAGVPSRFSGSGSGTDYTFTISSLQPEDIAT
`
`86
`
`91
`
`96
`
`108
`
`Okt3vl' YYCQQWSSNPFTFGSGTKLEINR
`
`gL221
`
`YYCQQWSSNPFTFGQGTKLQITR
`
`gL221A YYCQQWSSNPFTFGQGTKLQITR
`
`gLZZlB YYCQQWSSNPFTFGQGTKLQITR
`
`gLZZlC YYCQQWSSNPFTFGQGTKLQITR
`
`REI
`
`YYCQQYQSLPYTFGQGTKLQITR
`
`CDR'S ARE UNDERLINED
`
`FRAMEWORK RESIDUES
`
`INCLUDED
`
`IN THE
`
`GENE ARE
`
`DOUBLE
`
`UNDERLINED
`
`Fig. 6
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0422
`
`
`
`WO 91/09967
`
`PCT/GB90/02017
`
`‘9/15
`
`
`
`.5—xUPNNInn—ll
`
`8.x231.4:!
`
`
`
`hm—xofiu[CI
`
`omFXUFNNll
`
`009
`
`8.o—
`
`
`
`$335558:5.
`
`292336823-2%
`
`
`
`><mm<02525
`
`
`
`
`
`334mm:-35.95:82
`
`cow
`
`oo—
`09
`AllSNBlNI SDNBDSBUOf‘nd
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0423
`
`
`
`
`WO 91/09967
`
`PCT/GB9W02017
`
`02:60.5.0Am..:<mn_zu:35mI><mw<3:55
`
`
`
`
`
`
`
`
`.zo:<3<>m823-go
`
`1OI15
`
`
`
`wo—xo—NuID]:
`
`m9xu—NNIT
`
`
`
`8—x0—3'0'
`
`
`
`mm.xUFNNIII!_
`
`SN8N.8—.09
`
`om
`
`
`
`3335>oomzz<
`
`.8.
`
`00..
`AllSNBlNI BDNBDSBHOD'Id
`
`Do
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0424
`
`
`
`
`WO 91/09967
`
`PCT/GB90/02017
`
`11/15
`
`BLOCKING ASSAY
`(Mean Channel - HPBALL's)
`
`200
`
`
`
`221C x1es-1
`221cx197-
`
`221CX183-
`221cx 181.-
`
`221cx1as—2
`
`.
`250 '
`
`>-
`.—
`
`9E
`
`.2:
`
`g 15
`3
`0')
`g
`
`O 3l
`
`l.
`
`100
`
`'
`
`0
`
`so
`
`100
`
`150
`
`200 -
`
`ANTIBODY (ng ltube)
`
`Fig. 9
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0425
`
`
`
`WO 91/09967
`
`.
`FIg.IO
`
`: zoo
`E
`w
`g
`m
`%
`g
`g
`g
`d
`
`OKT3 — GRAFTED HEAVY CHAINS
`BINDING ASSAY
`(Mean Channel — HPBAALL’S)
`.
`
`PU/GB90/02017
`
`12/15
`
`A
`zchx 185 a
`221cx 199 c
`221C x 204 o
`2ch x 205 E
`221C x 207 F
`221C x 208 G
`
`me x 209 H
`
`.1
`
`1
`
`'
`
`100
`10
`ANTIBODY (ngltube)
`
`1000
`
`OKT3 - GRAFTED HEAVY CHAINS
`BLOCKING ASSAY
`(Mean Channel - HPBALL's)
`
`200
`
`
`
`FLUORESCENCEINTENSITY
`
`141 X 144
`221C X 185
`
`221C x 199
`
`221C x 201.
`
`me x 205
`
`221C X 207
`
`221C X 208
`
`221C X 209
`
`:1:o"nmUom>
`11.1 X 144
`
`0
`
`so
`
`100
`
`150
`
`I
`
`200
`
`ANTIBODY (nglfiube)
`
`(205)
`
`-.-_,24.48.49.71.73 .76 .78 .8831.
`
`(208)
`
`6,--.24.48.49.71,73,__,78._._.__,
`
`(201.)
`
`(199)
`
`6.--.24.48.49.71,73,76.78,-_._-.
`
`6.23 , 24.48%9 ._-._—;——.-__.__._ -9
`
`(207)
`
`6.23.24.48.49J1.73..-.78.__,--,
`
`(185)
`
`6.23.24.48.49.” .73.76.78.88.91 .
`
`(209)
`
`6,23,24,48,49,.-.__,__,78,__,-_,
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0426
`
`
`
`W09l/09967
`
`PCT/6390/0201 7
`
`13/15
`
`.6;
`
`F1911
`
`>. 200
`:
`0'1
`g
`g
`w
`g
`g.
`g
`g
`.1
`LL
`
`
`
`om - GRAFTED HEAVY CHAINS
`BINDING ASSAY
`(Mean Chahnel - HPBALL’s)
`B.c.D.
`_
`
`E
`G
`
`A —.—— 221cx 183
`8 ——ac— 221cx1al.
`c ’—o— 221cx185
`D —-—— 221cx198
`E ——o— 221cx 203
`F + 221cx 205
`G —¢-— 221cx 206
`
`
`
`. 1
`
`I
`
`10
`
`100
`
`1000
`
`'
`
`,
`
`> 175
`’—
`
`ANTIBODY (ngl tube)
`
`OKT3
`
`GRAFl'ED HEAVY CHAINS
`
`BLOCKING ASSAY
`(Mean Channel — HP'BALL’s.)
`.
`
`
`
`221C x 183
`221C x 181,
`221C x 185
`221C X198
`221C x 203
`221C x 205
`221C x 206
`
`a 5
`
`p—
`g 150
`1.1
`L2:
`8
`g 125
`g
`_l
`IL.
`
`100
`
`
`
`O
`
`50
`
`100
`
`150
`
`200
`
`250
`
`ANTIBODY (ng Itu be)
`
`6.23.24.48.49.”.73.76.78._..,_-,
`
`_.__.._,z.a,49,71.73,7s,7a,aa,91.
`_._-. 24,48.49,71 ,73,76 .78 ,88,91 ,
`15.23.24....__._.....__.......__,
`._,_... 24.48,“.7133 .76.78,__.-_,
`6.--.24.48.49.71.73 .76.7B.88,91.
`6.23.24.48.49.”.73.76.78.88.91,
`
`(183)
`I205)
`(184)
`(206)
`(203)
`(185)
`(198)
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0427
`
`
`
`WO 91/09967
`
`PCT/GB90/0201 7
`
`14/15
`
`
`
`_8528583gomkxovmtohomoo.m>EmEmwarn:a.9“.
`
`
`
`
` 8Hxmm*2;szm814]m3usim..m.22:2m8......+..3.u
`some5.3.85mT3522214--am
`
`
`m3
`
`08
`
`+mg
`
`US
`
`
`
`~<m_._mH30E_xoaau
`
`
`
`2:283:89:850:
`
`
`
`mcozuzcoucou5305x9F—.o8.0Sod
`
`03
`
`mod
`
`ood
`
`Regeneron Exhibit 1024.0428
`
`
`
`WO 91/09967
`
`PCI‘IGB90/02017
`
`
`
`m,.9“.
`
`mhxo
`usw+oho
`
`moo.m>Em3m9:52
`
`
`
`razzugtoumkxo
`
`15/15
`
`
`
`m9xURNmooIIOII
`
`Em3mIID|I_-
`
`
`
`
`
`Aguéxoanu52655885893
`
`
`
`2:3323200:33:83
`
`
`
`E65..85
`
`mad
`
`o3
`
`m0.0
`
`86
`
`221;; I punog
`
`SUBSTITUTE SHEET
`
`Regeneron Exhibit 1024.0429
`
`
`
`
`I‘
`
`'V
`
`INTERNATIONAL SEARCH REPORT
`'
`International Application No PCT/GB 90/0201]
`
`
`I. CLASSIFICATION OF SUBJECT HATTER (ll several classification symbols apply, indicate all)s
`According to International Patent Classlliation (IPC) or to both National Classification and IPC
`IPCS: C 12 P 21/08, C 12 N 15/13, A 61 K 39/395, C 07 K 15/05
`I
`I
`o
`
`
`
`
`II. FIBDS SEARCHED
`
`
`
`
`Minimum Documentation Searched’
`Classification System
`Classification Symbols
`
`
`
`
`C 12 P; C 12 N; A 61 K
`Documentation Searched other than Minimum Documentation
`
`to the Extent that such Documents are Included in Field: Searched“
`
`
`
`IPCS
`
`
`
`
`
`
`Relevant to Claim No.13
`
`
`III. DOCUMENTS CONSIDERED TO BE RELEVANT5
`Citation of Document." with indication, where appropriate, of the relevant passages"z
`EP, A1, 0403156 (GENZYME CORPORATION ET AL.)
`19 December 1990,
`see examples 8-12 and corresponding
`tables
`
`
`
`
`
`
`
`
`Proc. Natl. Acad. Sci. USA, vol. 86, December 1989,
`C- Queen et al.: "A humanized antibody that
`-
`binds to the interleukin 2 receptor ",
`see page 10029- page 10033
`see the whole document and in particular
`page 10031 right col. - page 10032; left
`col. and page 10033 left col.
`
`EP, A1, 0328404 (MEDICAL RESEARCH COUNCIL ET AL.)
`16 August 1989,
`see pages 1-3, page 9, lines 49-54 and
`the claims
`
`
`
`
`
`
`
`
`
`
`
`
`'T' Iatendocument publis
`d alter the intemationa tiling date
` " Special categories of cited documents: 1'”
`or pnonty date and not ltwnflld With the appl atton but
`'A' docu ent definin the eneml state 0! the art which is not
`-
`~
`consia
`. to be 3' paracular relevance
`fignmtgnderstand the principle or theory underlymg the
`
`
`'5' earlier document but published on matter the International
`'X' document at particular "gimme. the claimed invention
`
`
`tiling date
`cannot be considered novel or cannot be considered to
`
`
`'L' document which mag throw doubts _on gi'or‘ig claim(gzhg
`involve 3" inventive $189
`which Is
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