throbber
.. • ... --.
`.. ..
`. ....
`. . ••
`• . .. . •
`.. ..
`. . . . . •
`. . ... • . ..
`.
`.
`• . .
`. . .
`. . I
`. .
`.. ..
`. . .
`... ..
`•
`•
`~8 I
`
`• •
`
`••
`
`L{l
`
`composite heavy chain, amino acid residues 5, 8, 10, 12 to
`1 7 I 19 I 2 1 I 2 2 I 4 0 I 4 2 tO 4 4 I 6 6 I 6 8 I 7 0 I 7 4 I 7 7 I 7 9 I 81 I 8 3
`to 85, 90, 92, 105, 109, 111 and 113 at least are acceptor
`residues and amino acid residues 23, 24, 31 to 35, 49 to 58
`5 and 95 to 102 at least are donor residues.
`
`4.
`An anti-CD3 antibody molecule having affinity for the
`CD3 antigen comprising a composite heavy chain and a
`complementary light chain, said composite heavy chain having
`10 a variable domain comprising acceptor antibody heavy chain
`framework residues and donor antibody heavy chain antigen(cid:173)
`binding residues, said donor antibody having affinity for
`said CD3 antigen, wherein, according to the Kabat numbering
`system, in said composite heavy chain, amino acid residues
`15 5, 8, 10, 12 to 17, 19, 21, 22, 40, 42 to 44, 66, 68, 70,
`74, 77, 79, 81, 83 to 85, 90, 92, 105, 109, 111 and 113 at
`least are acceptor residues and amino acid residues 23, 24,
`31 to 35, 49
`to 58 and 95 to 102 at least are donor
`residues.
`
`20
`
`25
`
`An anti-CD4 antibody molecule having affinity for the
`5.
`CD4 antigen and comprising a composite heavy chain and a
`complementary light chain, said composite heavy chain having
`a variable domain comprising acceptor antibody heavy chain
`framework residues and donor antibody heavy chain antigen(cid:173)
`binding residues, said donor antibody having affinity for
`said CD4 antigen, wherein, according to the Kabat numbering
`system, in said composite heavy chain, amino acid residues
`5, 8, 10, 12 to 17, 19, 21, 22, 40, 42 to 44, 66, 68, 70,
`30 74, 77, 79, 81, 83 to 85, 90, 92, 105, 109, 111 and 113 at
`least are acceptor residues and amino acid residues 23, 24,
`31 to 35, 49 to 58 and 95 to 102 at least are donor
`residues.
`
`35 6.
`An anti-adhesion molecule antibody molecule having
`affinity for an adhesion molecule and comprising a composite
`heavy chain and a complementary light chain, said composite
`heavy chain having a variable domain comprising human
`
`e
`e
`
`e
`e
`
`1001 of 1849
`
`BI Exhibit 1095
`
`

`

`. •
`•• ..
`• . •
`. •
`09
`
`I
`
`• ....
`• . .
`. .
`..
`. • .
`. . . .
`. . . . . ... • . ..
`.
`• . . • . . .. . .
`.. .
`..
`... ..
`•
`
`•
`• •
`••
`
`•
`
`""'\-
`
`acceptor antibody heavy chain framework residues and donor
`antibody heavy chain antigen-binding residues, said donor
`antibody having affinity for said adhesion molecule wherein,
`according to the Kabat numbering system, in said composite
`5 heavy chain, amino acid residues 5, 8, 10, 12 to 17, 19, 21,
`2 2 I 4 0 I 4 2 to 4 4 I 6 6 I 6 8 I 7 0 I 7 4 I 7 7 I 7 9 I 81, 8 3 to 8 5 I 9 0 I
`92, 105, 109, 111 and 113 at least are acceptor residues and
`amino acid residues 23, 24, 31 to 35, 49 to 58 and 95 to 102
`at least are donor residues.
`
`10
`
`The antibody molecule of any one of claims 2 to 6
`7.
`wherein amino acid residues 71, 73 and 78 in said composite
`heavy chain are additionally donor residues .
`
`The antibody molecule of any one of claims 1 to 7,
`15 8.
`wherein amino acid residues 26 to 30 and 59 to 65 in said
`composite heavy chain are additionally donor residues.
`
`The antibody molecule of any one of claims 1 to 8,
`9.
`20 wherein at least one of amino acid residues 1, 3, and 76 in
`said composite heavy chain are additionally donor residues.
`
`The antibody molecule of any one of claims 1 to 9,
`10.
`wherein at least one of amino acid residues 36, 94, 104, 106
`25 and i07 in said composite heavy chain are additionally donor
`residues .
`
`The antibody molecule of claim 10, wherein at least
`11.
`one of amino acid residues 2, 4, 6, 38, 48, 67 and 69 in
`30 said composite heavy chain are additionally donor residues.
`
`The antibody molecule of any one of claims 1 to 11
`12.
`wherein amino acid residues 7, 9, 11, 18, 20, 25, 37, 39,
`41, 45, 47, 48, 72, 75, 80, 82, 86 to 89, 91, 93, 103, 108,
`35 110 and 112 in said composite heavy chain are additionally
`acceptor residues.
`
`13.
`
`The antibody molecule of any one of claims 1 to 12,
`
`e •
`
`• •
`
`1002 of 1849
`
`BI Exhibit 1095
`
`

`

`•
`
`•
`
`.. ..
`. . .
`. .
`
`·j·o I
`
`. . . . . . .. . . . . . . ...... :
`. : . . . . . . . . .
`. .. : : ··: . . ·:. :
`. : . . . . . .. . .
`. . . .
`
`wherein said complementary light chain is a composite light
`chain having a variable domain comprising acceptor antibody
`light chain framework residues and donor antibody light
`chain antigen-binding residues, said donor antibody having
`5 affinity for said predetermined antigen, wherein, according
`to the Kabat numbering system,
`in said composite light
`chain, amino acid residues 5, 7 to 9, 11, 13 to 18, 20, 22,
`23, 39, 41 to 43, 57, 59, 61, 72, 74 to 79, 81, 82, 84, 86,
`88, 100, 104, 106 and 107 at least are acceptor residues and
`10 amino acid residues 24 to 34, 46, 48, 50 to 56, 58, 71 and
`89 to 97 at least are donor residues.
`
`The antibody molecule of claim 13, wherein amino acid
`14.
`residues 1, 3 and 47 in said composite light chain are
`15 additionally donor residues.
`
`20
`
`25
`
`30
`
`35
`
`The antibody molecule of claim 13 or claim 14,
`15.
`wherein amino acid residues 36, 44, 47, 85 and 87 in said
`composite light chain are additionally donor residues.
`
`The antibody molecule of any one of claims 13 to 15,
`16.
`wherein at least one of amino acid residues 2, 4, 6, 49, 62,
`64 to 69, 98, 99, 101 and 102 in said composite lightly
`chain are additionally donor residues.
`
`The antibody molecule of any one of claims 13 to 16,
`17.
`wherein at least one of amino acid residues 1, 3, 10, 12,
`21, 40, 60, 63, 70, 73, 80, 103 and 105 in said composite
`light chain are additionally donor residues.
`
`A therapeutic or diagnostic composition comprising
`18.
`the antibody molecule of any one of claims 1 to 17 in
`combination with a pharmaceutically acceptable carrier,
`diluent or excipient.
`
`A method for producing a recombinant antigen binding
`19.
`molecule having affinity for
`a predetermined antigen
`comprising the steps of:
`
`e •
`
`• •
`
`1003 of 1849
`
`BI Exhibit 1095
`
`

`

`.. ....
`..
`• ....
`• .
`• . .
`. • . . •
`..
`•• ..
`. . . . . . .
`. . . . . . •
`• ... • . ..
`. . . . .
`• .
`•• .
`... ..
`.. ••
`. •
`
`••
`
`•
`•
`
`lJl'1~
`
`11 I
`
`e
`e
`
`• e
`
`15
`
`the
`the amino acid sequence of
`(1] determining
`variable domain of the heavy chain of a donor antibody which
`has affinity for said predetermined antigen;
`the
`(2] determining
`the amino acid sequence of
`5 variable domain of the heavy chain of a non-specific
`acceptor antibody;
`composite heavy chain
`a
`providing
`for an
`(3]
`said composite heavy chain
`molecule,
`having
`antibody
`residues and donor antigen
`framework
`binding
`acceptor
`10 residues wherein, according to the Kabat numbering system,
`amino acid residues 5, 8, 10, 12 to 17, 19, 21, 22, 40, 42
`to 44, 66, 68, 70, 74, 77, 79, 81, 83 to 85, 90, 92, 105,
`109, 111 and 113 at least are acceptor residues and amino
`acid residues 23, 24, 31 to 35, 49 to 58 and 95 to 102 at
`least are donor residues;
`(4] associating the heavy chain produced in step (3]
`with a complementary light chain to form an antibody
`molecule;
`the antibody
`the affinity of
`( 5] determining
`20 molecule formed in step (4] for said predetermined antigen;
`(6]
`if the affinity determined in step (5] is not
`equivalent to that of the donor antibody, providing a heavy
`chain as described in [ 3] above but in which amino acid
`residues 71, 73 and 78 are additionally donor residues;
`(7j associating the heavy chain produced in step [6]
`with a complementary
`light chain to form an antibody
`molecule;
`the antibody
`the affinity of
`(8] determining
`molecule formed in step [7] for said predetermined antigen;
`(9]
`if the affinity determined in step [8] is not
`equivalent to that of the donor antibody, providing a heavy
`chain as described in [ 6] above but in which amino acid
`residues 26 to 30 are additionally donor residues;
`[10] associating the heavy chain produced in step [9]
`35 with a complementary light chain to form an antibody
`molecule;
`antibody
`the
`the affinity of
`[ 11] determining
`molecule formed in step (10] for said predetermined antigen;
`
`25
`
`30
`
`1004 of 1849
`
`BI Exhibit 1095
`
`

`

`.. ....
`.. ..
`. ....
`. .
`. . . . . .
`..
`.. ..
`. .
`.
`. . . . . .
`I . . . .
`...
`. • • . . ... . • • .
`.. . .
`.
`• . • •
`.
`..
`..
`. ... ..
`•
`•
`1:2 •
`
`•
`
`·~~
`
`5
`
`(12] if the affinity determined in step (11] is not
`equivalent to that of the donor antibody, providing a heavy
`chain as described in [9] above but in which at least one of
`amino acid residues 1, 3, and 76 are additionally donor
`residues;
`( 13] associating the heavy chain produced in step
`(12] with a complementary light chain to form an antibody
`molecule;
`antibody
`the
`the affinity of
`[ 14] determining
`10 molecule formed in step (13] for said predetermined antigen;
`(15] if the affinity determined in step (14] is not
`equivalent to that of the donor antibody, providing a heavy
`chain as described in (12] above but in which at least one
`of amino acid
`residues 36,
`94, 104,
`106,
`107 are
`~ 15 additionally donor residues;
`( 16] associating the heavy chain produced in step
`(15] with a complementary light chain to form an antibody
`molecule.
`antibody
`the
`the affinity of
`(17] determining
`20 molecule formed in step (16] for said predetermined antigen;
`(18] if the affinity determined in step (17] is not
`equivalent to that of the donor antibody, providing a heavy
`chain as described in (15] above but in which at least one
`of amino acid residues 2, 4, 6, 38, 48, 67 and 69 are
`25 additionally donor residues; and
`( 19] associating the heavy cha in produced in step
`(18] with a complementary light chain to form an antibody
`molecule.
`
`~
`
`e
`e
`
`30 20.
`of:
`
`The'method of claim 19, further comprising the steps
`
`35
`
`the
`the amino acid sequence of
`(l] determining
`variable domain of the light chain of said donor antibody
`which has affinity for said predetermined antigen;
`the
`(2] determining
`the amino acid sequence of
`variable domain of
`the
`light chain of a non-specific
`acceptor antibody;
`[3] providing
`
`a
`
`composite
`
`light chain
`
`for an
`
`1005 of 1849
`
`BI Exhibit 1095
`
`

`

`..
`• ....
`. .
`. . .
`..
`. . . . .
`..
`. . . . . .
`. .
`. . .
`. ..
`. . . . . ... •
`. • .
`. •
`. • . • . .
`.. . .
`••
`..
`. ... ..
`:w 3 •
`
`•
`•
`
`\-1. I
`
`light chain having
`said composite
`antibody molecule,
`residues and donor antigen binding
`acceptor
`framework
`residues wherein, according to the Kabat numbering system,
`amino acid residues 5, 7 to 9, 11, 13 to 18, 20, 22, 23, 39,
`5 41 to 43, 57, 59, 61, 72, 74 to 79 to 79, 81, 82, 84, 86,
`88, 100, 104 and 106 to 109 at least are acceptor residues
`and amino acid residues 24 to 34, 46, 48, 50 to 56, 58, 71
`and 89 to 97 at least are donor residues;
`(4] associating the light chain produced in step (3]
`10 with a complementary heavy chain to
`form an antibody
`molecule;
`antibody
`the
`the affinity of
`( 5] determining
`molecule formed in step (4] for said predetermined antigen;
`if the affinity determined in step (5] is not
`(6]
`15 equivalent to that of the donor antibody, providing a light
`chain as described in [3] above but in which amino acid
`residues 1, 2, 3 and 47 are additionally donor residues;
`[7] associating the light chain produced in step (6]
`with a complementary heavy chain to form an antigen-binding
`20 molecule;
`(8] determining the affinity of the antigen-binding
`molecule formed in step (7] for said predetermined antigen;
`if the affinity determined in step [8] is not
`(9]
`equivalent to that of the donor antibody, providing a light
`25 chain as described in [ 6 J above but in which amino acid
`residues 36, 44, 47, 85 and 87 are additionally donor
`residues;
`(10] associating the light chain produced in step (9]
`with a complementary heavy chain to
`form an antibody
`30 molecule;
`the antibody
`the affinity of
`( 11] determining
`molecule formed in step (10] for said predetermined antigen;
`(12] if the affinity determined in step (11] is not
`equivalent to that of the donor antibody, providing a light
`35 chain as described in [9] above but in which at least one of
`amino acid residues 2, 4, 6, 49, 62, 64 to 69, 98, 99, 101
`are additionally donor residues; and
`(13] associating the light chain produced in step (9]
`
`~
`
`e
`
`e
`e
`
`1006 of 1849
`
`BI Exhibit 1095
`
`

`

`. ..
`
`74
`
`..
`....
`.. .
`.
`.
`..
`.
`..
`. . ... . . .. .
`.. .
`.
`.
`.
`. .
`..
`• .
`. .
`• . . . . ..
`
`••
`
`•
`
`V\
`
`g
`4
`
`with a complementary
`molecule.
`
`heavy
`
`chain to
`
`form an antibody
`
`1007 of 1849
`
`BI Exhibit 1095
`
`

`

`DATE FILED: 05/28/2010
`DOCUMENT NO: 42
`
`re application of:
`
`Joh.Ii R. Adair, et al.
`
`·serial No.: 07/743,329
`
`Group Art Unit: 1807
`
`Filed: September 17, 1991
`
`Examiner: L. Bermett
`
`For:
`
`HUMANISED ANTIBODIES
`
`I, Doreen Yatko Trujillo, Registration No .. 35,719 certify
`that this correspondence is being deposited with the U.S.
`Postal Service 11s First Class mail in en envelope addressed
`to
`the Commissioner of Patents end Trademarks,
`Washington, D.C. 20231.
`
`On February 7, 1994
`
`dJ~
`
`Doreen Yatko Tr
`
`Honorable Commissioner of
`Patents and Trademarks
`Washington, D.C.
`20231
`
`Dear Sir:
`
`AMENDMENT
`
`This amendme.nt is filed in response to the Office
`
`Action mailed September 7, 1993. A petition for extension of time
`
`and the appropriate fee is attached.
`
`In the claims:
`
`Please cancel claims 73 to 107, 109 to 113 and 115 to
`
`119 1 without prejudice.
`
`Carter Exhibit 2010
`Carter v. Adair
`Interference No. 105,744
`
`1008 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`"f'lease amend claims 67 and 71 as follows:
`
`(Amended) An antibody molecule having affinity for
`
`a predetermin~ antigen and comprising a composite heavy chain and
`
`a complementar~ ·ght chain, said composite heavy chain having a
`
`\
`
`variable domain \o rising human acceptor antibody heavy chain
`
`[framework] residues
`
`nd donor antibody heavy chain [antigen-
`
`binding] residues, said onor antibody having affinity for said
`
`predetermined antigen,
`
`va iable domai
`
`com lementarit determinin
`
`wherein, according to the
`
`Kabat numbering system,
`
`composite heavy chain, said
`
`donor residues at
`
`=l=e~a=s~t::.-=a~t'--'r=e==s=i~d~u~e~s"'--~3~1,__t~o~~3~5<-1---"'5~0,__t~o::.-....~~>=<=--"-~5~t~o.__=1~0~2:..i...· amino acid
`\
`residues 5, 8, 10, 12 to 17, 19, 21, 22~40, 42 to 44, 66, 68, 70,
`~
`74, 77, 79, 81, 83 to 85, 90, 92, 105, 10'-,~ 111 and 113 at least
`\
`are acceptor residues~ and amino acid residu~ 23, 24, [31 to 35,]
`
`49 [to 58], 71, 73[,] and 78 [and 95 to 102]
`
`t least are donor
`
`residues.
`
`Claim 71, line 2, please delete "48" and insert --46--.
`
`REMARKS
`
`Claims 67-72, 108 and 114 are pending. The number of
`
`claims pending in the present application has been reduced in order
`
`to expedite the prosecution of the case.
`
`The deletion of some
`
`clai ms should not be taken to be an admission that the subject
`
`- 2 -
`
`1009 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`matter of the deleted claims is unpatentable.
`
`The Applicants
`
`reserve the right to file continuation applications directed to the
`
`deleted subject matter. The Examiner is thanked for bringing the
`
`typographical error in Claim 71 to the Applicants' attention.
`
`To the extent the rejections are maintained against
`
`amended claim 67, and the remaining claims, Applicants respectfully
`
`request reconsideration for the reasons set forth below.
`
`Rejections Under 35 u.s.c. § 112r First Paragraph
`
`In paragraph 16 of
`
`the present Office Action,
`
`the
`
`Examiner contends that the application does not contain any support
`
`for the recita.tion of acceptor residues in the light or heavy
`
`chains.
`
`It is submitted, for the following reasons 1
`
`that the
`
`Examiner's contention is incorrect.
`
`At a very helpful interview held at the beginning of
`
`1993, there was some discussion of the word "comprising" as used in
`
`the claims under consideration at that time .
`
`In those claims, it
`
`was only specified that certain residues should be donor residues.
`
`It was considered that it was not clear whether these were the only
`
`residues which could be donor residues. The alternative view was
`
`that these were only the minimum number of residues which must be
`
`donor but that any of the other residues could also be donor.
`
`If the second line of interpretation were taken, the
`
`claims could be read to cover a situation in which all except one
`
`of the residues in the variable domain were donor residues.
`
`In
`
`- 3 -
`
`1010 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`this case,
`
`the claims could then be
`
`interpreted to cover a
`
`structure similar to a "chimeric" antibody comprising a donor
`
`variable domain and a human constant region.
`
`Such chimeric
`
`antibodies were already well known at the priority date.
`
`It plainly is not the intention of the Applicants to
`
`claim chimeric antibodies or any similar structures. As can be
`
`seen from the description, the superhumanised antibodies of the
`
`present
`
`invention are compared
`
`to
`
`the prior art chimeric
`
`antibodies. Moreover, the present invention was intended to deal
`
`with the problem of chimeric antibodies in that chimeric antibodies
`
`were believed to be too "foreign" because of the presence of the
`
`complete donor variable domain.
`
`For the above reasons, it is clear that the wording of
`
`the claims needed to be changed so that the Applicants' intention
`
`of excluding chimeric antibodies was made effective. The language
`
`now present in the claims puts this intention clearly into effect.
`
`As to support for this wording, the Examiner is referred
`
`firstly to page 16, under the heading "Protocol". It can be seen
`
`from this paragraph that the first step in the process involves the
`
`choice of an appropriate acceptor chain variable domain. This
`
`acceptor domain must be of known sequence.
`
`Thus, the protocol
`
`starts with a variable domain in which all the residues are
`
`acceptor residues.
`
`In the sentence bridging pages 16 and 17, it is
`
`stated that:
`
`- 4 -
`
`1011 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`"The CDR-grafted chain
`starting
`from
`the basis
`sequence".
`
`is
`of
`
`then
`the
`
`designed
`acceptor
`
`On page 17, in the middle paragraph, it is stated that:
`
`"The positions at which donor residues are to
`be substituted for acceptor in the framework
`are then chosen as follows .... "
`
`This again shows that, unless a residue is chosen for substitution,
`
`it will remain as in the acceptor sequence.
`
`It must also be borne in mind that the purpose of the
`
`invention is to obviate some of the disadvantages of prior art
`
`proposals.
`
`The proposal of using chimeric antibodies had the
`
`disadvantage that they were more "foreign" than desirable. The
`
`problem of making CDR-graf ted antibodies was that they generally
`
`did not provide good recovery of affinity. Thus, the aim of the
`
`present invention was to minimise as far as possible the "foreign"
`
`nature of the antibody while maximising as far as possible its
`
`affinity.
`
`Bearing the passages referred to above and the aim of the
`
`invention in mind, it would have been abundantly clear to the
`
`skilled person reading the application that as many residues as
`
`possible should remain as acceptor residues. If this were not the
`
`case, it could hardly be said that the composite chain is based on
`
`the acceptor sequence.
`
`The skilled person reading the application can plainly
`
`see that certain residues have been considered for changing from
`
`acceptor to donor. These are clearly set out in the description.
`
`- 5 -
`
`1012 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATE.NT
`
`It would be plain to the skilled person that all other residues
`
`should not be considered for changing at all. It would therefore
`
`be obvious that any residue which is not specified as being under
`
`consideration for changing must remain as in the acceptor chain.
`
`It may be that there is no explicit statement in the
`
`description that the specified residues should remain as in the
`
`acc·eptor chain. However, the disclosure in a specification is not
`
`limited to the explicit disclosure but also includes that which is
`
`implicit.
`
`It is implicit, in the recitation that the chain is
`
`based on the acceptor and that only certain residues are considered
`
`for changing,
`
`that all non-specified residues must remain as
`
`acceptor residues. Subject matter which might be fairly deduced
`
`from the disclosure is not new matter. Acme Highway Products Corp.
`
`v. D.S. Brown Co., 431 F.2d 1074, 1080, 167 U.S.P.Q. 129, 132-133
`
`{6th Cir. 1970), cert denied, 401 U.S. 956 {1971).
`
`Another way to look at it is to consider a different way
`
`in which the claim could be drafted. It could be specified that in
`
`the composite chain, at least a certain minimwn number of residues
`
`are donor residues (as in the present claims) and at most a certain
`
`maximum nwnber of residues are donor residues. The maximum nwnber
`
`would be derived by listing all the residues which are considered
`
`for changing. Such an amendment would have clear explicit basis in
`
`the description because all those residues are mentioned as such.
`
`However, the effect of such an amendment would be to produce claims
`
`of exactly the same scope as the present claims.
`
`It can thus be
`
`- 6 -
`
`1013 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`seen that the present claims do not add subject matter but are
`
`plainly properly based on the disclosure in the description.
`
`It is therefore submitted that the claims are fully
`
`supported by the description, are conunensurate in scope with the
`
`disclosure in the description, and are properly delimited over the
`
`prior art.
`
`The rejections of Claims 73-107, 109-113, and 115-119
`
`under 35 U.S.C. §112 has been rendered moot by their withdrawal.
`
`In paragraph 26 of the Office Action,
`
`the Examiner
`
`maintains the rejection of the claims for lack of enablement.
`
`It
`
`is submitted that this rejection cannot stand for the following
`
`reasons.
`
`'I'he Examiner contends that the description does not
`
`provide a "representative" number of Examples falling within the
`
`scope of the claims. Even if this were the case (and it is not,
`
`for reasons set out below} this does not provide a proper basis for
`
`rejection under 35 U.S.S. §112.
`
`A "representative" number of
`
`Examples is not required to obtain a patent. All that is required
`
`is that the disclosure be enabling. Enablement does not depend on
`
`the number of examples provided. Sufficient disclosure can be
`
`provided by illustrative examples QI: terminology. Further, 11 It is
`
`well settled that patent applications are not required to disclose
`
`every species encompassed by their claims, even in an unpredictable
`
`art."
`
`In re Vaeck, 20 U.S.P.Q.2d 1438, 1445 (Fed. Cir. 1991).
`
`- 7 -
`
`1014 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`The Examiner also appears to be arguing that it may be
`
`that some antibodies will not be susceptible to the protocol of the
`
`present invention, i.e. that not all embodiments will work. Even
`
`if this were the case (and it is not, for reasons set out below).
`
`this also does not provide a proper basis for rejection under 35
`
`U.S.C. §112. That inoperative embodiments may be encompassed is
`
`not detrimental.
`
`"It is not
`
`the function of claims or the
`
`specification to exclude all inoperative substances." Ex parte
`
`Janin, -2 09 U.S. P. Q. 7 61, 7 6 3 ( Bd. of App. 19 7 9) .
`
`"The mere fact
`
`th.at a claim embraces undisclosed or inoperative species or
`
`embodiments does not necessarily render it unduly broad." Horton
`
`v. Stevens, 7 U.S.P.Q.2d 1245, 1247 (Bd. of Pat. App. & Int. 1988).
`
`Apart from the legal points made above, it is submitted
`
`that the Examiner is incorrect on the technical facts. Before
`
`expanding on this, however, it would be worthwhile to make a few
`
`points concerning affinity. There is no absolute value which can
`
`be set which defines good affinity. Affinity can be measured, for
`
`instance in reciprocal moles
`
`(M- 1
`
`).
`
`In this measurement system,
`
`affinity can vary from 106 to 1012
`
`•
`
`Natural antibodies, as produced in vivo, do not all have
`
`the same affinity, even for the same antigen. Thus, in the normal
`
`polyclonal antiserum produced on challenge by an antigen, the body
`
`will produce a variety of antibodies having affinities within the
`
`range given above. Monoclonal antibodies, as produced by hybridoma
`
`- 8 -
`
`1015 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`technology, also have varying affinities, again within the range
`
`e
`
`given above. The variation in the affinity may in part be due to
`
`the structure of the antibody and in part to the structure of the
`
`antigen. It may therefore be that a good antibody directed against
`
`antigen X has an affinity of only 107 whereas a good antibody
`
`against antigen Y may have an affinity of 10 12
`
`• These are both good
`
`antibodies, even though they have very different affinities.
`
`It can be seen that if an engineered antibody is produced
`
`against antigen X with an affinity of 108
`
`, this will be regarded as
`
`being exceptional, in that the affinity has gone up 10 fold
`
`compared to the good antibody. However, if an engineered antibody
`
`recognizing antigen Y is produced with an affinity of 108 ,
`
`this
`
`will be regarded as being an awful result as the affinity will have
`
`been reduced 10,000 fold.
`
`Thus,
`
`the only sensible way to determine whether an
`
`engineered antibody is successful is to compare its affinity with
`
`that of the prototype antibody from which it is derived.
`
`It is
`
`po:intless to look at the absolute value of the affinity because
`
`this does not tell you anything about the success or failure of the
`
`engineering operation. It is for this reason that the Applicants
`
`have provided such qualitative evidence of the success of the
`
`protocol described in the application.
`
`Further, in some cases, a residue which is selected for
`
`changing according to the protocol described in the application may
`
`- 9 -
`
`1016 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKE'l' NO.: CARP-0009
`
`PATENT
`
`not need to be changed.
`
`It may be that, fortuitously, it is the
`
`same in the donor and acceptor chains. This does not mean that, if
`
`the residues had been different, it would not have been changed.
`
`!
`
`I I
`
`It merely means that, in effect, the change had already been made.
`
`As to the number of antibodies which have been shown to
`
`have been successfully superhwnanised using the protocol of the
`
`present invention, the Examiner is requested to look at the sheets
`
`attached
`
`to
`
`the previous
`
`response submitted April 7, 1993.
`
`Although Applicants are not required to provide a "representative
`
`number of examples", the provision of so many antibodies in these
`
`attachments should have satisfied any doubts on the part of the
`
`Examiner . Yet the Examiner makes no reference to these attachments
`
`and the evidence they provide.
`
`The Examiner is also referred to the passage beginning on
`
`page 17 through page 19 of the last respon$e. This shows in detail
`
`that a representative number of antibodies falling within the terms
`
`of the present claims were superhwnanised successfully. Again the
`
`Examiner has not even referred to these pages. The Examiner has
`
`not provided any reasoning as
`
`to why
`
`these pages are not
`
`persuas).ve.
`
`It is submitted that mere allegation is not enough.
`
`The Examiner must also provide references or, if based upon
`
`personal knowledge, an affidavit, in support of the Examiner's
`
`allegations. MPEP § 706.02.
`
`As has been shown by the third sheet attached to the
`
`previous response, the successful antibodies are representative not
`
`- 10 -
`
`1017 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`only in number, but also as regards to antigens recognized. The
`
`antigens include cell surface antigens found on both healthy and
`
`cancerous cells, soluble cytokines and adhesion molecules. These
`
`are ali very different in structure and function, yet antibodies
`
`against each of them have been successfully superhumanised using
`
`the protocol of the present invention.
`
`It is no doubt the case that some of the antibodies
`
`referred to in the sheets were more successfully humanised than
`
`others. However, the reasons for this were clearly set out in the
`
`previous response. Thus, evidence that the replacement scheme is
`
`not generally applicable has not been provided.
`
`The Examiner places much reliance on the prior art as, in
`
`her view, showing that
`
`there would have been no reasonable
`
`expectation of success. The Applicants agree that, if there were
`
`only the prior art to go on,
`
`then there would have been no
`
`reasonable expectation of success. However, the skilled person
`
`trying to put the present invention into practice does not have to
`
`rely on only the prior art. The skilled person has available the
`
`teaching of the present application. It is specifically stated in
`
`the application that the present protocol represents a departure
`
`from the procedures of Reichmann and Queen, at least. Thus, the
`
`skilled person would not rely on Reichmann and Queen as teachings
`
`relevant to whether the present description is enabling.
`
`It is submitted that the skilled person would rely on the
`
`clear teaching given in the application and find that it is
`
`- 11 -
`
`1018 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`enabling. The specification plainly sets out what actions need to
`
`be taken. It is presumed that the Examiner agrees that the skilled
`
`person could have taken those actions. The application also sets
`
`out that, contrary to the teachings of Reichmann and Queen, the
`
`protocol is generally applicable. The application further shows
`
`that it had been successfully implemented. Thus, it is submitted
`
`that the skilled person would find that the present application is
`
`properly enabled the full extent of the claims.
`
`Rejections Under 35 U.S.C. § 103
`
`The Examiner rejected all the claims as being obvious
`
`over Reichmann and Queen. However, this rejection appears contrary
`
`to her previous assertions. When attacking the enablement of the
`
`claims, the Examiner stated that:
`
`" ... in light of the prior art (for instance, Reichmann
`
`et al. , Queen et al. , and Chothia et al. )
`
`such a
`
`universal property appears to be unpredictable. . .
`
`The
`
`prior art does not teach that standardized principle ...
`
`is possible."
`
`(emphasis added)
`
`The Applicants agree with the Examiner that the prior art
`
`provides no predictability of success and certainly no expectation
`
`that a generally applicable principle can be devised.
`
`It is
`
`submitted that this is a clear indication that the surprising
`
`- 12 -
`
`1019 of 1849
`
`BI Exhibit 1095
`
`

`

`DOC.KE'!- NO. : CARP-0009
`
`PATENT
`
`discovery that there is a generally applicable principle involves
`
`an invention.
`
`The Examiner indicated that the arguments previously
`
`presented by the Applicants were deemed to be non-persuasive
`
`because they did not address the combined effect of Reichmann and
`
`Queen. This, of course, assumes that the skilled artisan would
`
`have combined Reichmann and Queen in the first place. The Examiner
`
`has shown no reason why Reichmann and Queen would have been
`
`combined. It is submitted that there is no reason why they should
`
`be combined.
`
`The earlier publication is Reichmann.
`
`This shows a
`
`relatively simple procedure in which the six CDRs
`
`from a rat
`
`antibody against a leukocyte cell surface antigen are transferred
`
`onto human frameworks. The only additional residue change is in
`
`the heavy chain at residue 27. The reason that this residue is
`
`changed is because it was atypical in the human (acceptor) chain.
`
`The change was to replace residue 27 with the more normal acceptor
`
`re.sidue. Thus, the teaching of Reichmann is that, as long as you
`
`have normal human (acceptor) chain, all that is needed is for the
`
`CDRs to be changed.
`
`Queen does in fact refer to Reichmann.
`
`Reichmann is
`
`re;f erence 2 4 in Queen. However, this is only referred to in
`
`passing on page 10029 as being an example of the work of Winter and
`
`his colleagues. The teaching of Queen clearly goes beyond that of
`
`- 13 -
`
`1020 of 1849
`
`BI Exhibit 1095
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`Reichmann.
`
`Thus, there is no incentive to try to combine the
`
`teachings of R

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