. •
`Serial No. 715272
`Art Unit 1806
`
`•
`
`5
`
`10
`
`§
`
`is
`12,
`No.
`in Paper
`Group
`o:f
`Applicant's election
`1,
`and
`did not
`distinctly
`acknowledged.
`Because
`applicant
`errors
`in the restriction
`speci:fically point
`out the supposed
`requirement, the election
`has been treated as
`an election without
`traverse.
`See M. P. E. P. 818. 03(a).
`112,
`second
`Claims 1-10
`are rejected
`under
`35 U. S. C.
`paragraph, as being
`inde:finite :for :failing
`to particularly
`point
`matter which applicant
`out and distinctly claim the subject,
`5 and 7 are inde:finite
`Claims 1, 3, 4,
`regards as the invention.
`in the use o:f the
`language "import
`antibody" in that
`it is not
`the
`what
`ie.
`clear what constitutes
`an
`important antibody,
`Claim l
`step a) is
`determines what
`is to be an
`import antibody.
`inde:finite in that it is not
`clear what is meant
`by a "consensus �
`Claim
`l step d> is inde:finite in that it
`human variable domain" .
`15 is not clear what
`is actually taking
`place when
`one aligns the
`physical or mental
`amino acid sequences of the F R ,
`ie. is this a
`step?
`step e>
`Claim l
`is unclear
`in what type of
`homology is
`indicated, ie. are conservative
`amino acids considered as homologs
`or should their be
`identical amino acid residues at
`the indicated
`portion of the framework.
`Claim l step f>, 3
`is indefinite in the
`use
`of the
`"participates"
`in
`that the
`nature
`of
`language
`Claim
`is indefinite
`l step f )
`in that
`participation is unclear.
`it is not clear how one d:f ordinary skill can determine the ef:fects
`which are listed in steps 1-3, ie. through antigen binding, through
`25 hybridization?
`Claim 1
`step g > is
`inde:finite in that
`it is not
`clea� what ef:fects are reasonably expected to
`occur.
`is
`Claim 2
`indefinite in that the antecedent
`basis for
`"the domain"
`is
`unclear.
`· Claim 3 is inde:finite in that it is not clear when in the
`:for the
`antibody
`one would
`the
`o:f making
`process
`search
`glycosylation sites.
`the same reason
`is inde:finite :for
`Claim 4
`that claim � is
`inde:finite.
`Claim 5
`is inde:finite in that
`it is
`believed that the claims up to this point were directed to making a
`2
`
`20
`
`30
`
`201 of 389
`
`BI Exhibit 1094
`
`

`

`Serial No. 7 1 5272
`Art Unit 1 806
`
`•
`
`5
`
`unclear how "preparing a humanized
`"humanized antibody", and it is
`the antibody
`antibody" in claim 5 differs from the preparation of
`up to this point.
`Furthermore, it is not clear what is intended in
`of the antibody of claim 5 .
`the preparation
`Claim 6 is vague in
`that it is not clear what the numbers are meant to designate.
`lt
`is suggested that applicant clarify
`the nature of the numbers or
`point to a figure.
`Claim 7 is indefinite in that it is not clear
`what the method is drawn to.
`it is suggested that
`the language "a
`method of making
`a humanized antibody"
`be inserted
`within the
`1 0 claim.
`The following is
`a quotation
`of the first paragraph
`of 3 5
`u. s. c. § 1 1 2 :
`
`shal l
`speci£ication
`The
`descri ption 0£ the invention,
`
`written
`a
`contain
`and 0£ the manner and
`
`proc7ss 0£ making and using it,
`
`in such £u11, clear,
`and exact terms as to enable any person skil led
`concise,
`i n the art to which. it pertains, or with which it is most
`nearly connected, to make and use the same and shal l set
`£orth the beat mode contemplated by the inventor 0£
`carrying out his invention.
`
`1 5
`
`2 0
`
`25
`
`The specification is objected to under 35 U. S. C. § 1 1 2 , first
`paragraph, as failing to
`adequately describe the
`invention
`and
`failing to adequately teach how to make and or use the invention,
`The following terms
`ie. failing to provide an enabling disclosure.
`lack enablement in the specification: .
`"at least a
`in the language
`Claims 1
`and 7 lack enablement
`Applicant has
`only
`portion
`of
`an
`import variable domain".
`indicated specific residues which may
`be transferred, but they are ·
`claiming an antibody wherein the a portion
`of the import antibody
`There is no guidance in the specification
`30 are to be transferred.
`which would enable one of skill
`in the art to make antibodies with
`
`3
`
`202 of 389
`
`BI Exhibit 1094
`
`

`

`Serial No. 7 1 5272
`Art Unit 1 806
`
`•
`
`5
`
`Applicant is aware
`other than CDRs.
`transferred variable domains
`that a portion of the variable domain can be any one of the CDRs as
`However, this language
`also reads
`well as the framework regions.
`on small amino acid sequences which are incomplete regions
`of the
`variable region
`There
`is no support
`in the
`antibody.
`· of the
`specification for linking
`the variable region
`of the antibody to
`any
`or all of the myriad "portions" which
`are encompassed within
`this language.
`One of skill
`in the art would neither expect nor
`predict the appropriate functioning of the antibody
`as broadly as
`1 0 is claimed.
`It is suggested that the specific portion of the human
`variable region which is described in the specification be recited
`/
`language be removed
`in order
`completely
`within the claim or this
`/
`to obviate this rejection.
`is not clear how
`Claim 1 step c) lacks enablement in that it
`1 5 one would determine which amino acids are to be subst�tuted.
`There
`is
`no specific recitation of
`what characteristics of the amino
`acids are necessary for deciding whether it
`is to be replaced
`or
`Without this description one of skill in the art would not be
`not.
`able to choose the
`appropriate amino
`acid residues
`without
`2 0 hindering the function of the antib.ody.
`c---
`1 step f > , lacks enablement in � the pro�ocol for
`Clai m
`-
`determining whether �he a�ino
`acid residues
`in the
`import amino
`acid sequence are reasonably expected to interact with the antigen
`There · is no
`is not described
`anywhere
`in the specification.
`
`4
`
`203 of 389
`
`BI Exhibit 1094
`
`

`

`Serial No. 7 1 5272
`Art Unit 1 806
`
`•
`
`5
`
`the art to
`ordinary skill in
`explicit step which enables one 0£
`' determine
`the e££ects which are recited.
`lt would require undue
`experimentation 0£ one
`0£ ordinary skill
`in the art
`to make the
`variations which may be made in
`order to test the e££ects 0£ the
`mutant antibodies.
`Claim 2 lacks enablement in that there is no description in
`the speci£ication 0£ how to determine which residues are exposed on
`the sur£ace or which residues are buried within the domain, is this
`through computer modeling or through x-ray crystallography or other
`1 0 methods'?
`Claim 3
`' lacks enablement in that there is no guidance in the
`speci£ication on how one would determine which .glycosylation site
`a££ects
`antigen
`or
`binding,
`what
`comprises
`"reasonable
`expectation" •.
`Claims 6 , 7 and 9 lack enablement in that it would appear that
`these amino acids are relevant to lgG and not to other
`isotypes.
`There
`is no
`indication
`that
`one
`0£
`skill
`in the art would
`extrapolate the use 0£ these amino acids
`to all or other isotypes
`of immunoglobulins.
`Furthermore, there is insufficient description
`2 0 and guidance in the speci£ication with regards to the properties of
`'
`'
`these amino acids which would enable one 0£ ordinary skill in the
`art to make humanized
`antibodies with other
`isotypes using lhese
`amino acid sequences.
`
`1 5
`
`5
`
`204 of 389
`
`BI Exhibit 1094
`
`

`

`Serial No. 7 1 5272
`Art Unit 1 806
`
`( 1 990 ) .
`
`1 1 1 :
`
`4 7 -5 4
`
`6
`
`5
`
`1 5
`
`( 1 988 ) .
`
`1 0 2 1 29 - 2 1 38
`
`been
`have
`which
`antibodies
`shown that
`not
`Applicant has
`of :functioning
`as
`modified as that
`which is claimed are capable
`that which is being disclosed, ie. maintaining the binding affinity
`of the parent antibody.
`Protein chemistry is probably one of the
`most
`unpredictable
`areas
`of
`biotechnology.
`For example,
`replacement
`of a single lysine
`residue at position
`1 1 8 of acidic
`:fibroblast
`growth :factor by glutamic acid led to the substantial
`loss of
`heparin binding, receptor binding and biological activity
`Burgess et.
`al. Journal of Cell
`biology,
`of the protein.
`In transforming growth :factor alpha, replacement
`asparagine did not
`of aspartic acid at position 47 with alanine or
`affect
`biological
`activity while replacement
`or
`with serine
`glutamic acid sharply reduced
`the
`biological
`activity
`of
`the
`mitogen.
`Lazar et. al. Molecular and Cellular Biology, 8 : 1 24 7 - 1 25 2
`Similarly
`it has
`been shown that
`aglycosylation
`of
`antibodies reduces the resistance of the antibodies to
`proteolytic
`degradation, while CH2 deletions increase the
`binding affinity of
`the antibodies.
`See Tao et. al. The Journal of Immunology,
`Vol.
`1 43, No. 8 . 2595 - 260 1
`< 1 989 > and Gillies et. al.
`Human Antibodies
`2 0 and Hybridomas,
`Vol 1 ,
`no. 1 ,
`These references
`( 1 990 ) •
`demonstrate that even
`a single amino acid
`substitution
`or what
`appears to be an inconsequential chemical modification, will
`often
`dramatically affect the biological activity and characteristic of a
`protein.
`Therefore,
`without
`su:f:ficient
`guidance
`in
`the
`
`205 of 389
`
`BI Exhibit 1094
`
`

`

`·�
`
`Serial No. 7 1 5272
`Art Unit 1 806
`
`•
`
`and for the
`the above terms
`specification to support the use of
`reasons mentioned above
`one of
`ordinary skill
`in the
`art would
`forced
`into undue experimentation
`in
`order
`to
`practice
`the
`invention as is claimed.
`under 35
`Claims
`1 - 1 1 are rejected
`for the reasons set forth
`in
`paragraph,
`specification.
`35 U. S. C. § 1 0 1 reads as follows:
`
`U. S. C.
`first
`§
`the objection to
`the
`
`1 1 2 ,
`
`Whoever invents or discovers any new and use£u1
`process,
`machine, manu£acture,
`or composition
`0£ matter or any new and use£u1
`improvement
`thereo£, may obtain a patent there£ore, subj ect
`to the conditions and requirements 0£ this
`tit.1e.
`
`5
`
`1 0
`
`1 5
`
`Claims 1 - 4 , 6 - 8 are rejected under 35 U. S. C. § 1 0 1 because the
`claimed invention is directed to non-statutory subject matter.
`The
`above claims are drawn to a
`method
`of preparing
`an
`antibody,
`there is no
`indication within the claims that
`actual
`however,
`there is no step
`For example,
`physical steps
`are taking place.
`rather obtaining
`an amino
`includes isolating
`20 which
`an antibody,
`All 0£ the steps which are listed in the claims can
`acid sequence.
`be done on paper as mental steps or on a computer terminal.
`The specification is objected to under 35 U. S. C. § 1 1 2 , first
`and claims
`9 - 1 3 are rejected under 35 U. S. C.
`paragraph,
`§ 1 1 2 ,
`25 first paragraph and 3 5 U. S. C. § 1 0 1 as the specification fails to
`adequately teach
`how to use
`the claimed monoclonal
`antibodies in
`the manner in which they
`are disclosed
`ie. for the therapeutic
`
`7
`
`206 of 389
`
`BI Exhibit 1094
`
`

`

`Ser i a l N o . 7 1 5272
`
`Art U n i t 1 806
`
`•
`
`r ·-
`
`p u r p o s e s .
`
`A p p l i cants c l a i ms
`
`a r e s u p p orted o n l y b y i n v i t r o d a t a
`
`s h o w i n g the
`
`a b i l i t y o f muMab 4DS,
`
`w h ich i s
`
`a human ized
`
`ant i - p 1 8S
`
`a n t i b o d y w h i c h reacts w i t h
`
`breast and
`
`ovarian cancer s , t o react
`
`w i t h d i f ferent c e l l l ines
`
`< see page 8 8 - 90
`
`of the spec i f i c a t i o n > .
`
`S
`
`A p p l i cant
`
`has made no s h o w i n g
`
`that
`
`these data correlate w i t h
`
`ut i l it y f o r i n v i v o ther a p y
`
`i n humans o f t h e c o m p l e x a r r a y o f
`
`d i seases encomp assed
`
`b y t h e c l a i m s .
`
`I n gener a l ,
`
`e:f:fec t i ve
`
`treatment o:f human cancers h a s not been r o u t i n e l y ach i eved i n t h e
`
`a rt
`
`u s i n g monocl o n a l a n t i b o d i e s .
`
`Further, i n v i t r o d a t a such a s
`
`1 0 t h a t reported
`
`i n t h e speci f i c at i on
`
`and
`
`a n i m a l m odel studies
`
`frequent l y do not c o r r e l at e w i th c l i ni c a l u t i l it y i n in v i v o t r i a l s
`
`i n p at ie n t s .
`
`Based o n t he ev i dence o :f record, the a l leged ut i l i t y
`
`o f t he c l a i me d c o mp o s i t i on f o r t he treatment o f c a ncer w ou l d n o t b e
`
`b e l i e v a b l e o n i t s :face t o the p e r s o n o:f ski l l i n the a r t i n v i e w o :f
`
`1 5 t h e c o ntemporary k n o w l edge i n t h e art .
`
`A p p l icant has n o t p r o vided
`
`a n y s h o w i n g
`
`o:f
`
`therapeutic ut i l i t y
`
`o :f the
`
`subj ect m o n o c l o na l
`
`a n t i b o d i es which w o u l d lead o n e o f ski l l i n the art t o bel ieve t ha t
`
`t h e ant i bodies a r e broadly
`
`a p p l i c a b l e :for t h e treatment o:f
`
`a l l
`
`t y p e s o f
`
`aut o i mmune d i seases.
`
`A p p l icant
`
`i s requ i red
`
`to p r o v i d e
`
`20 ev idence commensurate w i t h the sco pe o f the c l a ims, w h i ch w ou l d b e
`
`c o n v i nc i n g t o t h o s e
`
`sk i l led
`
`i n the
`
`art that
`
`the
`
`c l a i med
`
`c o m p o s i t i o n s have
`
`ut i l i t y for
`
`the treatment
`
`o f m a l ignant
`
`and
`
`aut o i mmune d i seases i n humans . See MPEP 608 . 0 1 < p > .
`
`8
`
`207 of 389
`
`BI Exhibit 1094
`
`

`

`Ser i a l N o . 7 1 5272
`
`Art Unit 1 806
`
`W al dmann, i n a
`
`recent review of the
`
`l i terature pert a i n i ng t o
`
`c l i n ic a l a p p li c a t io n s
`
`of mono c l o n a l
`
`a n t ib od i es f o r di a g n o s i s
`
`and
`
`therapy o f human d i sease,
`
`teaches t h a t effec t i v e ther a p y u s i n g
`
`mon o c l o n a l ant i b od i es h a s b een e l u s i v e and i n d i cates t h a t h o p e s f o r
`
`5
`
`a nt i b o d y - b ased
`
`t reatment met h o d s engendered
`
`by i n
`
`v it r o stud i e s
`
`have n o t c orre l ated
`
`w e l l w i t h
`
`i n v i v o c l i n i c a l
`
`t r i a l res u l t s
`
`i n
`
`pat ients w i th c ancer .
`
`I t does n ot
`
`a ppear that
`
`the exem p l ar y
`
`mater i a l p r o v ided i n t h e spec i f ic a t i o n i n s u p p or t o f t h e assert i on s
`
`that
`
`the c l a i med a n t i bod ies have t h e r a p e u t i c ut i l i t y w o u l d
`
`b e
`
`1 0 v iewed b y those s k i l led i n the art
`
`a s b e i n g pred i c t i v e
`
`o f t h e i r
`
`ut i l it y for treati n g huma n s .
`
`A p p l i c a n t h a s n o t exemp l i f i ed
`
`h o w t o
`
`use t he c l a i med
`
`ant i b odies i n v i v o and h a s n o t s h o wn
`
`t h a t t h e
`
`a n ti b od i es
`
`w o u l d
`
`be effec t i v e
`
`i n v i v o .
`
`I t a p pears t h a t undue
`
`experi ment a t i o n w o u l d be r e q u i red o f
`
`one ski l l ed
`
`in t he
`
`art t o
`
`1 5 pr act ice the c l a i med i n vent i o n f o r t he
`
`s i n g l e ut i l i t y d i s c losed i n
`
`the s p ec i f i c at io n .
`
`The f o l lo w i n g i s a q u o t a t i o n
`
`o f the a p p r o p r i at e p a r a g r a p h s o f
`
`3 5 U . S . C . § 1 02 t h a t f orm the
`
`b a s i s f o r the rej ect i on s under t h i s
`
`20
`
`25
`
`sec t i o n made i n t h i s Office Act i on :
`
`A person shall be entitled to a pa.tent un.less- -
`
`in
`by others
`< a > the invention was known or used
`patented or described in a
`this country, or
`a :foreign
`in this or
`printed publication
`before the invention thereof by the
`country,
`app.licant £or a patent .
`
`in a
`or descr ibed
`( b ) the invention was patented
`printed pub.lication
`in
`this country or a
`
`9
`
`208 of 389
`
`BI Exhibit 1094
`
`

`

`•
`
`Ser i a l N o . 7 1 5272
`
`Art Unit 1 806
`
`£oreign country or in public use or on sale in
`this country. more than one year prior to the
`date 0£ application £or patent in the United
`States.
`
`5
`
`The
`
`£ a l l ow i n g is a q u o t a t i o n
`
`0£ 35 U . S . C .
`
`§ 1 03 w h i ch £ arms
`
`the basis £or all
`
`ob v i ousness rej ecti on s set £orth i n
`
`this 0££ ic e
`
`a c t i o n :
`
`A patent may not be obtained though the invention is
`secti on 102 0£ this title. i£ the di££erences between the
`
`not identically disclosed or described as set £orth
`
`in
`
`subject matter sought to be patented and the prior art
`are such that the subject matter as a whole would have
`been obvious at the time the invention was made to a
`person having ordinary skill in the art to which said
`Patentabil ity shall not be
`subject matter pertains.
`negatived by the manner in which the i nvention was made.
`
`102 0£ this title.
`
`Subject matter developed by another person. which
`qua1i£ies as prior art only under subsection
`( £ ) or
`( g )
`0£ section
`shall not
`preclude
`patentabil ity under this section where the sub j ect matter
`and the claimed invention were. at the time the invention
`was made.
`owned by the same
`person or subj ect to an
`obligation 0£ assignment to the same person.
`
`being antici pated by Queen et . al .•
`
`C l a i m s 1 ,
`
`2 , 5 - 1 0 are
`
`rej ected under
`
`35 U . S . C . §
`
`1 02 ( b ) a s
`
`The a b ove c l ai ms are dra w n t o
`
`1 0
`
`1 5
`
`20 )
`
`2 5
`
`a met h o d 0 £ producing
`
`a humanized a n t i b ody w herein the
`
`amino a c i d
`
`seq uences
`
`0 £ an
`
`i m p ort a n t i b od y
`
`and
`
`a
`
`consensus
`
`a n t i body a r e
`
`c o m p a red , w h erein the CDRs
`
`o f t h e imp ort anti body
`
`a r e subst i tuted
`
`£or the anti bo dy of
`
`the c onsensus a n t i b o d y ,
`
`a n d w h erein cert a i n
`
`3 0 framework residues
`
`w h i ch
`
`a r e responsi b l e £ o r t h e
`
`binding
`
`0 £
`
`ant igen , interact i o n
`
`with CDR ,
`
`o r
`
`part i c i pating
`
`i n the V l - V h
`
`interact i o n
`
`are a l s o i mp o rted
`
`t o t h e c o n sensus a n t i b od y .
`
`I n
`
`essence , residues 0 £ the framework reg i o n are a l s o transferred w i t h
`
`1 0
`
`209 of 389
`
`BI Exhibit 1094
`
`

`

`Ser i a l N o . 7 1 5272
`
`Art Unit 1 806
`
`•
`
`the CDRs in
`
`order t o retain
`
`the ant igen b i nding
`
`aff i n i t y of t h e
`
`p arent a n t i b od y .
`
`Queen et . a l . describe the produc t i on o f human ized
`
`a n t i bod ies
`
`wherein the murine a n t i b ody i s comp ared t o human anti bodies and the
`
`5
`
`most h o m o l o g ous human a n t i body i s c h o sen a s the accep t o r m o l e c u l e .
`
`T h e C D R s of
`
`the mur i n e ant i b ody are then substi tuted f o r the CDRs
`
`o f the human
`
`ant i b od y and certain
`
`framework residues
`
`are
`
`a l s o
`
`c h anged .
`
`Queen ef .
`
`a l . desc r i b e computer mode l i ng
`
`a n d seq uence
`
`c o m p a r i s o n
`
`in order to determine the amino acid residues w h i ch are
`
`10
`
`t o
`
`b e substituted
`
`< see page
`
`1 003 1 - 1 0033 ) .
`
`A l though
`
`the steps o f
`
`the methods are n o t i n exact l y t h e same order,
`
`a l l o f t h e c l a i med
`
`e l ements are present w i th in the reference .
`
`C l a i ms 1 , 2 and 5 - 1 0 are rej ected under 35 U . S . C .
`
`§ 1 02 < a > as
`
`being antici pated b y C o et . a l . . See above d iscuss i o n .
`
`1 5
`
`C o et . al . s h o w t h e pr oduct ion o f h u m a n i zed a n t i - HSV
`
`using the gener a l concept
`
`of Queen et . al .
`
`( see Resu lts
`
`and T a b l e
`
`1 > .
`
`C l a ims 3 and
`
`4 are rej ected under 35 U . S . C .
`
`§ 1 0 3 a s
`
`being
`
`unpaten t a b l e over Queen et . a l . or Co et . a l . in
`
`view of W a l l ick
`
`20 et . a l .
`
`The above c l a ims
`
`are draw n t o a met hod o f making a huma n i ze d
`
`a n t i body
`
`w herein the C D R s of a n i m p o r t anti body a r e transferred t o
`
`a
`
`consensus human
`
`anti b o d y a l ong w i th
`
`certa i n residues of
`
`t h e
`
`framework .
`
`Furthermore, the cl a i ms require that the g l y c o sy l at i o n
`
`1 1
`
`210 of 389
`
`BI Exhibit 1094
`
`

`

`I
`
`Ser i a l N o . 7 1 5272
`
`Art Unit 1 806
`
`•
`
`• 'Ai
`
`s i t e s , i f a n y , 0 £ the
`
`import a m i n o acid a l s o be i mp orted w i t h t h e
`
`C D R s a n d framework reg i on s i £ t h e s e si tes
`
`have a n a££eci
`
`on t h e
`
`b i nding 0 £ antigen .
`
`Queen et . a l . and Co et .
`
`a l . both describe the product i o n
`
`0 £
`
`5
`
`h u ma n i zed anti bodies b y trans£erring the CDRs and cer t a i n £ ramework
`
`reg i on s
`
`0 £ the d o n o r ant i b od y to the human consensus a n t i b od y
`
`< see
`
`Queen et .
`
`a l . pages 1 0031 - 1 0033 and C o et . a l . page 287 1 ) . They
`
`f urther
`
`state t h a t any residue w h ich might have a n a £ f ect on t h e
`
`a n t igen b i nd i ng of
`
`t h e anti b ody s h o u l d
`
`be changed subst i t uted
`
`i n
`
`1 0 order
`
`t o mainta i n the b i n d i ng a £ £ i ni t y 0 £ the p arent a n t i b ody
`
`< see
`
`p a g e 1 0033
`
`0£ Queen et .
`
`a l . at the
`
`l as t paragraph on
`
`the page ) .
`
`They do n o t h owever , s pecif i ca l l y di scuss t h e g l ycosy l at i o n sites
`
`as
`
`p o t en t i a l targets £or
`
`trans£er .
`
`W a l l i ck
`
`e t . al .
`
`teach t h e
`
`i m portance 0 £ carb o hy d r ate i nteracti o n w i t h a n t i gen £ o r m a i n t a i n i n g
`
`1 5
`
`or i ncreasing a n t i g e n bin d1 ng
`
`a f £ i n i t y
`
`< see pages 1 1 07 - 1 1 08 > .
`
`I t
`
`w o u l d have been prima facie o b v i o u s to one of ordinary sk i l l i n t h e
`
`art at the t im e the inven t i o n w a s made to make human i zed anti b od i e s
`
`u s i n g the method 0 £ Queen et . a l .
`
`or C o et .
`
`a l .
`
`and further
`
`i nc o r p orating the concept
`
`taught
`
`by Wal l i ck et .
`
`al . .
`
`One
`
`of
`
`20
`
`ordinary sk i l l in t h e art w ou ld have been m o t i v ated t o c o m b i ne the
`
`teachings of the two references i n view o f the teach ing
`
`of Queen
`
`that
`
`ret a i n i n g high antigen
`
`b i n d i n g a f £ i n i t y i s des i r a b l e in t h e
`
`product i o n o f human ized
`
`anti b o d i e s .
`
`K n o w i ng
`
`t h e r o l e
`
`0 £
`
`carbohy drates in a n t i gen anti b o d y in teracti o n a s w a s p oi nted out by
`
`1 2
`
`211 of 389
`
`BI Exhibit 1094
`
`

`

`I
`
`•
`
`S er i a l N o . 7 1 5272
`
`Art U n i t 1 80 6
`
`W a l l ick et .
`
`a l . o n e o f o r d i n a r y sk i l l w o u l d have had t h e means and
`
`the mot i va t i on
`
`t o
`
`make huma n i zed
`
`a nt i b od i es u s i n g b o t h
`
`o f t h e
`
`teachings o f the p r i mary and secondary references .
`
`C l a i m
`
`1 1
`
`i s rej ected under 3 5 U . S . C .
`
`§
`
`1 03
`
`as
`
`b e i n g
`
`5
`
`unpat en t a b l e over Queen et . a l . o r Co et . a l . i n v i ew of Reichmann
`
`eL a l .
`
`The a b o ve c l a i m i s drawn t o a humanized anti b o d y
`
`wherein o n l y
`
`o n e a m i n o a c i d
`
`( l isted in c l a i m 9 > i n t h e framework
`
`a n d t h e CDRs
`
`have been substituted i n the co nsensus an t i b od y .
`
`1 0
`
`Queen e t .
`
`a l . a n d C o et .
`
`a l . b o t h teach the
`
`p r oducti o n 0£
`
`huma n i zed a n t i b o d i es b y transfer r i n g the CDRs o f a
`
`murine a n t ib o d y
`
`a l on g w i t h spec i f i c residues
`
`o f t h e f r amework reg i on
`
`to
`
`t h e
`
`a cceptor a nt i b ody m o l ecu l e .
`
`They d o n o t h ow ev e r teach
`
`o n l y
`
`s u b s t i t u t i n g o ne
`
`o f t h e framework residues among t h o se
`
`l i sted i n
`
`1 5 c l a i m 9 .
`
`Queen et . a l . introduce t h e gener a l c oncept o f a scaff o l d
`
`where i n certa i n
`
`a m i n o a c i d residues
`
`of t h e framew o r k must
`
`b e
`
`p resent
`
`and c er t a i n a re d is p e n sa b l e .
`
`Reichmann et . a l . teach t h a t
`
`a
`
`s i n g l e a m i n o a c i d subst i t u t i o n
`
`i n a n an t i b ody
`
`i s s u f f i ci ent t o
`
`r et a i n the ant i gen b i n d i n g s p ec i f i c i t y
`
`o f the p arent a n t i b o dy
`
`< see
`
`20 f i n a l paragraph > .
`
`I t w o u l d h a v e been p r i m e facie
`
`o b v i ou s t o one
`
`of ordinary s k i l l i n the art at the t i me
`
`t h e i n v e n t i o n w a s made t o
`
`make o n l y a s i n g l e subst itut i o n i n the a n t i bo d y o f Queen e t . a l . o r
`
`C o et . a l .
`
`i n p o s i t i o n s among those
`
`l i sted i n c l a i m 9 .
`
`I t w o u l d
`
`h a ve
`
`been o bv ious t o
`
`o n e
`
`o f
`
`o r d i n ar y sk i l l t o c o m plete t h e
`
`1 3
`
`212 of 389
`
`BI Exhibit 1094
`
`

`

`•
`
`•
`
`Seri a l N o . 7 1 5272
`
`Art Unit 1 80 6
`
`i nv e n t i o n i n
`
`l i ght 0 £ the success
`
`0 £ R e i c h m a n n et .
`
`mut a t i n g
`
`o n e amino
`
`a c i d 0 £ t h e f r amewo r k .
`
`a l . i n
`
`o n l y
`
`Kn o w i n g t h a t each
`
`a n t i b od y v a r i es s l i g h t l y i n the n o n - co n served reg i o n , a n d g i v en the
`
`c om puter model l i ng
`
`protoc o l set £orth b y Queen et . a l .
`
`o n e o f
`
`5
`
`o r d i nary s k i l l w o u l d h a v e been mot i vated t o make a s i n g l e mut at i o n
`
`i n t h e v a r i a b l e reg i on
`
`w i t h the expecta t i on
`
`o f o b t a i n i n g
`
`a
`
`£unct i o n a l a n ti b o d y .
`
`A n y
`
`i n qu iry c o n cer n i n g
`
`t h i s
`
`commu n i c a t i o n
`
`o r
`
`e a r l ier
`
`co mmun i ca t i o n s f r o m the examiner should be di rected to Lila Fei see
`
`1 0 w h o se telephone number is, -<703 ) 308 - 27 31 .
`
`A n y
`
`i n q u i r y 0£ a general n ature o r r e l a t i n g t o the status 0 £
`
`t h i s a p p li c a t i on s h o u l d b e d i rected t o the G r o u p recep t i o n i st w hose
`
`t e l e p h o n e n umber i s
`
`< 703 > 308 - 0 1 96 .
`
`Feisee/ 1 £ cJP"
`
`1 5 Sept ember 29, 1 992
`
`AV D L. EV
`SUPERVISORY PATENT EXAMINER
`
`GROUP180 �d}i--
`
`1 4
`
`213 of 389
`
`BI Exhibit 1094
`
`

`

`TO SEPARATE, Ht
`{
`
`.:. TOP ANO BOTTOM EDGES, SNAP-APART ANl .)ISCARO CARBON
`
`FORM PT0-692
`
`(REV. 3-78)
`NOTICE OF REFERENCES CITED
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT ANO TRADEMARK OFFICE
`
`APPl.I CANT(SI
`
`�
`
`�.&_ �'f\r..tef cl /Q9 I
`U.S. PATENT DOCUMENTS
`F ILING DATE JF
`SUB·
`
`A
`
`B
`
`c D
`E
`F
`G
`H
`
`K
`
`L.
`M
`N
`0
`p
`Q
`
`DOCUMENT NO.
`
`DATE
`
`NAME
`
`CLASS
`
`CLASS
`
`APPROPRIATE
`
`FOREIGN PATENT DOCUMENTS
`
`DOCUMENT NO,
`
`DATE
`
`COUNTRY
`
`NAME
`
`CLASS
`
`SUB·
`CLASS
`
`PEATINENT
`SHTS. PP.
`OWG SPEC.
`
`OTHE R R E F E R ENCES (Including Author, Title, Date, Pertinent Pages, Etc.)
`
`/
`
`' DATE h/Jk J
`-v
`9J . ,,,._,, IE n-
`
`* A copy of this reference is not being furnished with this office action.
`
`(See Manual of Patent Examining Procedure, section 707.05 Cal.)
`
`214 of 389
`
`BI Exhibit 1094
`
`

`

`'
`
`FORM PT0-1449
`L'JST OF PRIOR ART CITED BY APPLICANT
`(Use several sheets if necessary)
`
`Sheet _1_ of _3_
`
`Atty Docket No.
`709
`Applicant
`Paul J. Carter et al.
`Group 'f"}&
`Filing Date
`June 14, 1991
`Pertinent Pages, Etc.)
`
`*Examiner
`Initials
`
`N
`O
`
`OTHER PRIOR ART
`Chothia et al., J. Mol . Biol. 186:651-663 (1985)
`Novotny and Haber, Proc. Natl. Acad. Sci . USA 82:4592-4596 (1985)
`Morrison, s. L. et al., Proc. Natl. Acad. Sci . USA 81:6851-6855 (1984)
`Bout ianne, G. L. et al., Nature 312:643-646 (1984)
`Neuberger, M. S. et al., Nature 314:268-270 (1985)
`Bruggemann, M. et al., J. Exp. Med. 166:1351·1361 (1987)
`Riechmann, L. et al., Nature 332:323-327 ( 1988)
`Love et al. , Methods in Enzymology 178:515·527 (1989)
`Bindon et al., J. Exp. Med. 168:127·142 (1988)
`Jones, P. T. et al., Nature 321:522-525 (1986)
`Verhoeyen, M. et al ., Science 239:1534·1536 (1988)
`Hale, G. et al ., Lancet i:1394-1399 (1988)
`Queen, c. et al., Proc. Natl. Acad. Sci . USA 86:10029·10033 (1989)
`Co et al., Proc. Natl. Acad. Sci . USA 88:2869-2873 (1991)
`Gorman et al. , Proc. Natl. Acad. Sci. USA 88:4181·4185 (1991)
`Daugherty et al., Nucleic Acids Research 19(9):2471-2476 (1991)
`Brown et al., Proc. Natl. Acad. Sci . USA 88:2663-2667 (1991 )
`Junghans et al., Cancer Research 50:1495-1502 (1990)
`Davies, D. R. et al., Ann. Rev. Biochem. 59:439·473 (1990)
`
`• Mol. Biol. 196:901-917 (1987)
`
`citation is in conforma ce with MPEP 609; Draw line through citation
`Include copy of this form with next communication to applicant.
`USCOMM-DC 80·398
`
`215 of 389
`
`BI Exhibit 1094
`
`

`

`•
`
`,
`FORM PT0-1449
`LiST OF PRIOR ART CITED BY APPLICANT
`(Use several sheets if necessary)
`
`b:. r.
`�
`
`, , �QO 7°''''
`-
`U.S. Dept. of c
`Patent and Trad
`l\ '\ggt � J Filing Date
`-�
`U.S. PATENT DOCUMEliil.._8 TR�t>W
`63o
`
`Atty Docket No.
`709
`Applicant
`Paul J. Carter et al.
`June 14, 1991
`
`Sheet _2_ of _3_
`0111152n
`
`I Serial No.
`I Group {�
`�'23? ·I
`
`Subclass
`
`Fi ling Date
`
`Doc1.111ent Number
`4,816,567
`
`Date
`3/28/89 Cabilly et al.
`
`Name
`
`Class
`
`*Examiner
`
`Init�l� V!r VAA
`
`AB
`AC
`AD
`AE
`AF
`AG
`AH
`AI
`AJ
`AK
`
`.
`
`...
`...
`"'
`
`�
`
`Document Number
`
`Date
`
`FOREIGN PATENT DOCUMENTS
`Country
`
`Class
`
`Subclass
`
`Translation
`No
`Yes
`
`AL .
`AM '
`AN
`AO
`AP
`..
`...,.
`AR
`
`.,.
`
`.
`
`AT
`AU
`
`�
`'
`OTHER PRIOR ART (Including Author, Title, Date, Pertinent Pages, Etc.)
`'0/f '"'
`Chothia, c. et al., Nature 342:8n-883 (1989)
`rfr AS
`Tramontano, A. et al., J. Mol. Biol. 215:175-182 (1990)
`" .
`lf;
`Margolies et al., Proc. Natl. Acad. Sci . USA 72:2180-2184 (1975)
`v?i
`Pluckthun, Biotechnolog� 9:545-51 (1991)
`� AV
`Spiegelberg et al., Biochemistr� 9:4217-4223 ( 1970)
`(f/ All
`llallick et al., J. Exe. Med. 168:1099-1109 (1988)
`1a ,,,»:-
`Sox et al., Proc. Natl. Acad. Sci . USA 66:975-982 (1970)
`Examine{� �
`�
`I Date Considered °';/��11�
`*Examiner� 'Ji'i'ftial "it ref�...lconsidered, whether or not citation is in conformance with MPEP 609; Draw line through citation
`Include copy of this form with next corrmunication to applicant.
`if not in conformance and not considered.
`USCOMM-DC 80-398.
`
`216 of 389
`
`BI Exhibit 1094
`
`

`

`U.S. Dept. of C011111erce
`Atty Docket No.
`709
`Patent and Trademark Off ice
`�Applicant
`�\..�Oo�
`L\: _
`� "'�"(
`·��e 14, 1991
`Paul J . Carter et al.
`,
`PATENT DOCUMEN � �
`'\9'Jt.
`ling Date
`F
`.. e.
`• & ffuv-
`-:._, j
`'/'
`
`Sheet _3_ of _3_
`I Serial No.
`I Gf6?J b
`
`07/715272
`
`Class Subclass
`
`Filing Date
`
`U.S.
`
`Name
`
`I
`
`�
`FORM PT0-1449
`LJST OF PRIOR ART CITED BY APPLICANT
`.
`(Use several sheets if necessary)
`
`Document N�r
`
`Date
`
`*Examiner
`Initials
`
`BA
`BB
`BC
`BD
`BE
`BF
`BG
`BH
`Bl
`BJ
`BK
`
`FOREIGN PATENT DOCUMENTS
`Country
`
`Date
`7/11/91 PCT
`
`Class
`
`Subclass
`
`Translation
`No
`Yes
`
`,,. \fr Bl WO 91/09967
`
`Document N�r
`
`I
`
`BM
`BN
`BO
`BP
`
`� BR
`� BS LR' BT
`
`( rv BU -G� ' BV
`0 � �
`Ex�-4(
`
`BX
`
`OTHER PRIOR ART (Including Author, Title, Date, Pertinent Pages, Etc.)
`Margni et al., Ann. Rev. Immunol.6:535-554 (1988)
`Fendly, B. M. et al., Cancer Res. 50:1550-1558 (1990)
`Neuberger et al., Nature 312:604-608 (1984)
`Takeda et al., Nature 314:452-454 (1985).__....
`Snow and Amzel, Protein: Structure, Function, and Genetics
`(1986)
`Cheetham, J . , Protein Engineering, 2(3): 170-172 (1988)
`./")
`Date Considered °J/cX//CJ�
`\-
`Initial 1f �erence considered, whether or not citation is in conformance with MPEP S09; ore!.. �ine through
`er:
`*Ex
`Include copy of this form with next cOlllllUnication to applicant.
`if not in conformance and not considered.
`USCOMM-DC 80-398.
`
`-
`
`1:267-279, Alan R. Liss, Inc. pubs.
`
`citation
`
`217 of 389
`
`BI Exhibit 1094
`
`

`

`' __ , •
`
`IN THE UNITED STATES PATENT AND TRADEMARK
`
`OFFICE
`
`In re Application of
`
`Paul J. Carter e.t al .
`Serial No . 07/715, 272
`Filed: 14 JUNE 1991
`
`For: IMMUNOGLOB
`
`ULIN VAR IANTS
`
`Examin er: L .FEISEE
`
`__ .. ____ .. _..---..... ... .....
`f �·
`RECE\VED
`JAN 2 1 \99:S
`GROUP 180
`·-·�· ...... _..... ... _ .. � .... �� ...
`�--p, ... --
`
`SUPPLEMENTAL INFORMATION DISCLOSURE STATEMENT
`
`Honorable Conuni s sioner of Patents and Trademarks
`
`Washington, D . C . 20231
`
`Sir:
`
`The attached materials were received in connec tion with the
`
`prosecution of a
`f oreign patent application corresponding to the
`
`c aptioned case.
`
`These materials contain at least two ref e rence
`
`c itations, the
`
`relevance of which is apparent f rom the
`
`commu ni cation f rom the foreign patent office that is also enclosed.
`
`A PTO Form 1449 is submit t ed herewith to fac i l i tate c itation
`to the record of all references contained in these mat erials.
`
`Respect fully submitted,
`
`GE{!�l�f-A1�
`Ca�i?'7 R . Rdle r
`
`Reg. No. 32 , 324
`
`Decembe r 30, 1992
`460 Point San Bruno Boulevard
`S outh San Francisc o , CA 94080
`415 -225 -261 4
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`CERTIFICATE OF MAILING (37 CFR 1.Bal
`I hereby certify that this paper is being deposited with the United States Postal Service on the date shown
`below with sufficient postage as first class mai l in an envelope addressed to the: Conmissioner of Patents and
`Trademarks, Washington, D.C. 20231 .
`'"°' '"-' 3D . 1 992
`l
`
`d?t� � 4 fmJJ.rd1
`
`1s Strasbaugh
`
`'.·��'
`t�
`
`218 of 389
`
`BI Exhibit 1094
`
`

`

`' ---
`
`,•
`
`•
`
`•
`
`PATENT DOCKET 709
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of
`Paul J. Carter et al.
`Serial No. 07 /7 1 5,272
`Filed: June 1 4, 1