. .
`.. ..
`. . .
`•
`•
`j8 a
`
`. . . . . . . ..
`. ...... :
`. . . , . . . . . .
`. . . . . . . ..
`.
`... ..
`.. ..
`.. . .
`
`• •
`
`•
`
`: •
`
`: • I
`
`: ••: •
`
`composite heavy chain, 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
`5 and 95 to 102 at least are donor residues.
`
`An anti-CD3 antibody molecule having affinity for the
`4.
`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.
`
`An anti-adhesion molecule antibody molecule having
`35 6.
`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
`
`• •
`
`• •
`
`Board Assigned Page #848
`
`PFIZER EX. 1095
`Page 1001
`
`

`

`. .
`.. ..
`...
`. .
`
`691
`
`. . . . . .. .. . ..... ·:
`·: . . : :: : . . .
`. . . . . . . . . . . : . :
`. . . . . . .. . .
`... . . .. . .
`
`•
`
`tt
`
`• ..
`
`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,
`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.
`
`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 107 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,
`
`Board Assigned Page #849
`
`PFIZER EX. 1095
`Page 1002
`
`

`

`•
`
`.. ..
`. . .
`. .
`•
`1-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, so, 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:
`
`• •
`
`• •
`
`Board Assigned Page #850
`
`PFIZER EX. 1095
`Page 1003
`
`

`

`.. ....
`..
`• ....
`• . .
`. •
`• . . . .
`..
`.. ..
`. •
`. . . . . .
`. . . . . . . . ... • . ..
`• . .
`• • .
`.. ..
`•• .
`. • .
`••• ••
`
`'h l
`
`••
`
`~(
`
`•
`
`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;
`for an
`composite heavy chain
`a
`(3] providing
`said composite heavy chain having
`antibody molecule,
`residues and donor antigen binding
`acceptor
`framework
`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;
`[7] associating the heavy chain produced in step (6j
`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;
`the antibody
`the affinity of
`[11] determining
`molecule formed in step (10] for said predetermined antigen;
`
`25
`
`30
`
`• •
`
`• •
`
`Board Assigned Page #851
`
`PFIZER EX. 1095
`Page 1004
`
`

`

`.. ....
`.. ..
`. ....
`. . . • . .
`. .
`. .
`..
`.
`. • • . . •
`•• ..
`. . . . .
`. .. .
`• . . . • • . ... . • • .
`• . • . .
`.. ..
`.
`. ... ..
`
`•
`
`'h2
`
`~fo
`
`5
`
`(12) if the affinity determined in step (11) is not
`equivalent to that of the donor antibody, providinq 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) associatinq the heavy chain produced in step
`(12) with a complementary liqht chain to form an antibody
`molecule;
`the antibody
`the affinity of
`( 14) determininq
`10 molecule formed in step (13) for said predetermined antiqen;
`(15) if the affinity determined in step (14) is not
`equivalent to that of the donor antibody, providinq a heavy
`chain as described in [12) above but in which at least one
`of amino acid
`residues 36,
`107 are
`94, 104, 106,
`15 additionally donor residues;
`( 16) associatinq the heavy chain produced in step
`(15) with a complementary liqht chain to form an antibody
`molecule.
`the antibody
`the affinity of
`(17) determininq
`20 molecule formed in step (16) for said predetermined antiqen;
`(18) if the affinity determined in step [17) is not
`equivalent to that of the donor antibody, providinq 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) associatinq the heavy chain produced in step
`(18) with a complementary liqht chain to form an antibody
`molecule.
`
`30 20.
`of:
`
`The · method of claim 19, further comprisinq the steps
`
`•
`
`tt
`
`• •
`
`the
`the amino acid sequence of
`(1) determininq
`variable domain of the liqht chain of said donor antibody
`which has affinity for said predetermined antiqen;
`(2] determininq
`the amino acid
`the
`sequence of
`variable domain of
`the
`liqht chain
`of a non-specific
`acceptor antibody;
`[3) providinq
`
`35
`
`a
`
`composite
`
`liqht chain
`
`for an
`
`Board Assigned Page #852
`
`PFIZER EX. 1095
`Page 1005
`
`

`

`. .
`.. ..
`. . .
`•
`•
`:-3 :
`
`e
`
`• •. I
`
`... : ..
`: . : . : : ··: . . ....
`·: . . : :: :
`. . . ..
`.. . .
`
`e I
`
`e I
`
`I
`
`I
`
`I
`
`I
`
`•
`
`I I :
`
`•
`
`. .
`
`• ..
`
`light chain having
`said composite
`antibody molecule,
`acceptor
`framework residues and donor antigen binding
`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;
`[6)
`if the affinity determined in step [5) is not
`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;
`(9)
`if the affinity determined in step [8] is not
`equivalent to that of the donor antibody, providing a light
`25 chain as described in [ 6) 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;
`antibody
`the
`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]
`
`Board Assigned Page #853
`
`PFIZER EX. 1095
`Page 1006
`
`

`

`. .
`.... .
`. .
`
`14 :
`
`. . . . . . . ..
`. . . ...
`. .
`. . . . .
`. .
`. . . . . .
`. . .. . . . ..
`. . . . . . . .
`. . . . . . . .
`.
`. . .
`
`with a complementary heavy chain to
`molecule •
`
`form an antibody
`
`•
`
`• •
`
`• •
`
`Board Assigned Page #854
`
`PFIZER EX. 1095
`Page 1007
`
`

`

`~(\(\~~f.~E~ED:_ 05/2~/201 0 J-'1 ()!
`d~·twi ~~eUMENT NO. 42
`lY~}
`PATE~0 q· f
`·=" ~L~ ~~~~
`lf
`; ~ i)
`"< I
`.
`'
`IN THE \;;;~;:D STATES PATENT AND TRADEMARK OFFICE
`
`( f
`
`NO. ;
`
`'i
`
`,·
`
`re applica t ion of:
`
`Jolua R. Adair, et al.
`
`·serial No. : 07/743,329
`
`Group Art Unit: 1807
`
`Filed: September 17, 1991
`
`Examiner: L. Bennett
`
`For :
`
`HUMANISED ANTIBODIES
`
`I, Ooroon Yatko Truptlo, Roglslrfttlon No. 35,719 certify
`that this corraspondonoo Is being deposited with the U.S.
`Postal Service 11s f irst Closs moil In en onvolopo addressed
`the Commissioner of Potents and Trademarks,
`to
`Woshington, D.C. 2023 1,
`
`Honorab le Commis sioner of
`Pa tent s and Trademark s
`Washingt on, D.C.
`20231
`
`Dear Sir:
`
`AMENDMENT
`
`This arnendrne.nt is filed in r esponse to the Office
`
`Actio n ma i led September 7, 1993. A petition for extension of ~irne
`
`and the appropri ate fee is attached.
`
`In the claims:
`
`Please cancel claims 73 to 107, 109 to 113 and 115 to
`
`119, without pre judice.
`
`Carter Exhibit 2010
`Carter v. Adair
`Interference No. 105,744
`
`Board Assigned Page #855
`
`PFIZER EX. 1095
`Page 1008
`
`

`

`

`

`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. S 112, 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, 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 i n
`
`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 -
`
`Board Assigned Page #85t
`
`PFIZER EX. 1095
`Page 1010
`
`

`

`DOCKET NO. : CARP-0009
`
`PATENT
`
`th i s case,
`
`the claims could then be
`
`interpreted to cover a
`
`struc t ure 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 c himeric antibodies or any similar structures. As can be
`
`seen from the description, the superhurnanised 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 b e lieved 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 variabie domain.
`
`This
`
`acceptor domain must be of known sequence. Thus, the protocol
`
`starts with a variable domain in which gil the residues are
`
`acceptor residues.
`
`In the sentence bridging pages 16 and 17, it is
`
`stated that:
`
`- 4 -
`
`Board Assigned Page #851:S
`
`PFIZER EX. 1095
`Page 1011
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`"The CDR-gra f ted chai n
`start ing
`f rom
`t he basis
`s e quence " .
`
`is
`of
`
`then
`the
`
`designed
`acceptor
`
`On page 1 7, in the middle paragraph, it is stated that:
`
`"The positions at which donor residues a r e to
`be substituted for acceptor in the framework
`are then chosen as follows .... "
`
`This again shows that, unle ss a r e sidue is chosen for substitution,
`
`it will remain as in the acce ptor seque nce .
`
`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 o f using chime r ic antibodies had the
`
`disadvantage that they were more "foreign " than desirable. The
`
`problem of making CDR-grafted antibodies was that they generally
`
`did not provide good recovery of affinity. Thus, the aim of the
`
`present invention was t o minimise as far as possible the "foreign"
`
`nature of the antibody while maximising as far as possible its
`
`affinity.
`
`Beari ng the passages referred to above and the aim of the
`
`invention in mind, it would have been abundantly clear to the
`
`s.killed 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 -
`
`Board Assigned Page #859
`
`PFIZER EX. 1095
`Page 1012
`
`

`

`DOCKET NO. : CARP-0009
`
`PATENT
`
`I t woul d be plain to the skilled person that all other residues
`
`should not be cons idered for changing at all. It would therefore
`
`be obvious that any residue which is not specified as being under
`
`consideration for c hanging 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
`
`acceptor chain. However, the disclosure in a specification is not
`
`limited to t he explicit disclosure but also i ncludes that which i s
`
`implicit.
`
`It is implicit, in the recitation that the chain is
`
`based on the acceptor and that only certain residues are considered
`
`for changi ng,
`
`that all non-specified res i dues must rema in as
`
`acceptor r esidues. Subject matter which might be fairly deduced
`
`from t he d isclosure 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, 40 1 U.S . 956 (1971) .
`
`Another way to look at it i s to consider a different way
`
`in which the cla im could be drafted . It could be specified that in
`
`the composite chain, at least a certain minimum number of residues
`
`are donor residues (as in the present claims) and a t most a certain
`
`maximum nwnber of residues are donor residues . The maximum munber
`
`would b e derived by listing all the residues which are considered
`
`for ·changing. Such an amendment would have clear e xplicit basis in
`
`the descripti on because all those residues are mentioned as such.
`
`However, the e ffect o f such an amendment would be to produce claims
`
`of exactl y t he same scope as the present claims.
`
`It can thus be
`
`- 6 -
`
`Board Assigned Page #8tiU
`
`PFIZER EX. 1095
`Page 1013
`
`

`

`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.
`
`I t
`
`is therefore submitted that the claims are fully
`
`supported by the description, are commensurate in scope with the
`
`disclosure i n 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 Act ion,
`
`t he Examiner
`
`maintains the rejection of the claims for lack of enablement.
`
`It
`
`is submitted t hat this rejection cannot stand for the following
`
`reas o n s.
`
`The Examiner contends that the d e scription does not
`
`provi de a "representative• number of Examples falling within the
`
`scope of t he 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 doe s not depend on
`
`, __
`
`the number of examples provided. Sufficient disclosure can be
`
`provi ·ded by illustrative examples or terminology. Further, "It is
`
`well settled that patent applications are not required to disclose
`
`every spec i es encompassed by their claims , even in an unpredictable
`
`art."
`
`In re Vaeck, 20 u.s.P .Q.2d 1438, 1445 (Fed. Cir. 1991) .
`
`- 7 -
`
`Board Assigned Page #81:51
`
`PFIZER EX. 1095
`Page 1014
`
`

`

`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 n ot all embodiments wi l l work. Even
`
`if this were the case (and it is no t, 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
`
`Ja.nin, ·209 U.S.P.Q. 761, 763 (Bd. of App. 19 79).
`
`"The mere fact
`
`that 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, 124 7 (Bd. of Pat. App. & Int. 1988).
`
`Apart from the legal poi nts made above, it is submitted
`
`that the Examiner is incorrect on the technical facts. Before
`
`expanding on this, however, it would be worthwhil e 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 -
`
`Board Assigned Page #862
`
`PFIZER EX. 1095
`Page 1015
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`technology, also have varying affinities, again within the range
`
`~-
`
`given above . The variation in the affinity may in part be due to
`
`the structure of the antibody and in part to the struc ture of the
`
`antigen. It may ther efore be that a good antibody directed against
`
`antigen X has an affinity of only Hl 7 whereas a good antibody
`
`aga i nst antigen Y may have an affinity of 10 12 • These are both good
`
`antibod ies , e ven though they have very differe nt affinities.
`
`It can be seen that if an engineered antibody is produced
`
`against antige n 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 affin ity o f 108 ,
`
`this
`
`will be regarded as being an awful result as the affinity will have
`
`been reduc e d 10,000 fold.
`
`Thus ,
`
`the only sensible way
`
`t o determine whether an
`
`engineered antibody is successful is to compare its affinity with
`
`that of the p rototype antibody from which it is der ived.
`
`It is
`
`po~ntless 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 s uccess of the
`
`protocol described in the. appll.cation.
`
`Fur ther, in some cases, a residue which is selected for
`
`changing according to the protocol described in the application may
`
`- 9 -
`
`Board Assigned Page #8€r.5
`
`PFIZER EX. 1095
`Page 1016
`
`

`

`/ I
`
`DOCKET NO.: CARP-0009
`
`PATENT
`
`not need to be changed.
`
`It may be that, f o rtuitously, it is the
`
`same in the d o nor and acceptor chains. This does not mean that, if
`
`the res i dues had been different, it would n o t have b een changed.
`
`It merely me ans that, i n effect, the change had alre ady been made.
`
`As to the number of antibodies wh i ch have been shown to
`
`have b een succ essfully superhumanised using the protocol of the
`
`present invent i on, the Examiner is requested to look at the sheets
`
`attached
`
`to
`
`the previous
`
`response submitte d April 7, 1993.
`
`Although Applicants are not r equired to provide a "representative
`
`number of e xamples", the provision of so many ant i bodies in these
`
`attachments should have satisfied any doubts on the part of the
`
`Examine r . Yet the Examiner makes no reference t o t hese at·tachments
`
`and t he ev ide nce they provide.
`
`The Examiner is also referred to the passage beginning on
`
`page 17 throu gh page 19 of the last respo~~e. This shows in detail
`
`that a represent ative number of antibod i es- fa lling wi thin the terms
`
`of the pre s e nt claims were superhumanised successfully. Again the
`
`Examine r has not even referred to these pages.
`
`•rhe Examiner has
`
`not provide d any
`
`reasoning as
`
`to why
`
`these pages are not
`
`persuas,i.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
`
`allegati ons . MPEP § 706.02.
`
`As has been shown by the third shee t attached to the
`
`:r
`
`previous res ponse, the successful antibodies are representati ve not
`
`- 10 -
`
`Board Assigned Page #864
`
`PFIZER EX. 1095
`Page 1017
`
`

`

`DOCKET NO. : CARP-0009
`
`PATENT
`
`only in number, but also as regards to antigens recognized. The
`
`antigens i nclude cell surface antigens found on both healthy and
`
`cancerous cells, soluble cytokines and adhesion molecules . Thes e
`
`are ali ~ry different in structure and function, yet antibodies
`
`against e ach 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 hurnanised than
`
`others. However, the reasons for this were clearly set out in the
`
`previous response. Thus, evidence that the replacement scheme is
`
`not g enerally applicable has not been provid ed .
`
`The Examiner places much reliance on the prior art as, in
`
`her view,
`
`s howing
`
`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 t h ere wou l d have been no
`
`reasonable expectation of success. However, the skilled person
`
`trying to put the present invention into practice does not have to
`
`rely o n o nly the prior art. The skilled person has available the
`
`teac hing 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 l east . Thus, the
`
`s 'killed person wou ld not rely on Reichmann and Queen as teachings
`
`r elevant to whether the present description is enabling.
`
`I t is submitted that the skilled person would rely on the
`
`clear teaching given in the application and find that it is
`
`- 11 -
`
`Board Assigned Page #865
`
`PFIZER EX. 1095
`Page 1018
`
`

`

`DOCKET NO.: CARP- 0009
`
`PATENT
`
`enab l ing. The s pe cifica tion plainly sets out what a ctions need to
`
`be taken .
`
`I t is presumed t hat the Examiner agrees that t he skilled
`
`person cou ld have taken those actions. The applic ation a l so sets
`
`out t hat, contrary to the teachings of Reichmann and Queen, the
`
`protocol is generally appl icable. Th e applicat i on furt her shows
`
`th at it h a d been successfully implemented . Thus , it is submitted
`
`that the ski lled person would find that the pres.ent appl icatio n is
`
`properly e na bled the full extent of the claims.
`
`Rejections Unde r 35 u.s.c. § 103
`
`The Examiner re jected all the claims as being obvious
`
`over Reichmann and Queen. However, this rejection appears contrary
`
`to her previous assertion s. When attacking the e nablement of the
`
`c laims , the Examiner stated. that :
`
`.... .. .i.n light of the prior art (for instance , Reic hmann
`
`et al . , Queen et al. ,
`
`a nd Chothia et al. )
`
`suc h
`
`a
`
`u n iversal property appears to be unpredictable ... The
`
`prior art does DQ1;, teach that s.tandardized principle ...
`
`i s possible ."
`
`(emphasis added)
`
`The Applicants agree with the Examine r tha t the prior art
`
`provides no predictability of success and certainly no e xpec t a tion
`
`tha t
`
`a ge n e rally applicable principle can b e devised.
`
`It is
`
`subm~ tted that this is a clear indicati on that the surprising
`
`- 12 -
`
`Board Assigned Page #866
`
`PFIZER EX. 1095
`Page 1019
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`discovery that ther e is a generally applicable principle involves
`
`an i nvention.
`
`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 c ombined Reichmann and Queen in the first plac e. 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 procedur e
`
`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
`
`residue. Thus, the teaching of Reichmann is that, as long as you
`
`hqve 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.ference 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 -
`
`Board Assigned Page #867
`
`PFIZER EX. 1095
`Page 1020
`
`

`

`DOCKET NO.: CARP-0009
`
`PATENT
`
`Reichmann.
`
`Thus, there is no incenti ve t o try to combine the
`
`teachi ngs of Re ichmann and Queen.
`
`Even if one could find some motivation for combining
`
`Reichmann and Queen, it is submitted that Reic hma nn would not add
`
`to Que en suc h that Applicants invention would be rendered obvious.
`
`Reichmann teaches the skilled person to us e a normal acceptor
`
`seque nc e and merely to change the CDRs.
`
`If the a cceptor sequence
`
`is not normal, then the abnormal residues are t o be changed to
`
`normal acceptor residues. This is all disclosed in Queen. Since,
`
`at best, Queen incorporates all the teaching o f Re ichmann, even if
`
`Reichmann and Queen are combined, the tota l teaching is no mor