~fA'rci DEPARTM~~~c::.·
`
`Patent and T~emark Office
`Address:-COMMISSIONER OF PATENTS AND TRADEMARKS
`•
`Waahinaton. DC 20231
`
`r
`
`.JANET E. HASAK
`INC.
`GENENTECH,
`460 POINT SAN BF<UNO BOULEVARl)
`SOUTH SAN FRANCISCO CA 94080-4·;i90
`
`1:=:MlI1223
`
`ATTORNEY DOCKET NO.
`J"..'1 1 .
`
`EXAMINER
`NuLAN,P
`
`ART UNIT
`1 ::::11;.
`
`PAPER NUMBER
`
`DATE MAILED:
`
`12/23/96
`
`Please find below and/or attached an Office communication concerning this application or
`proceeding.
`
`Commissioner of Patents and Trademarks
`
`.. ,
`
`PTO.BOC HY. 2/MI
`\~-- ~---------_,·-!!.._" .....:i.._ ________ -tni.S.OOVEllNMJ!NI' PIUHTINO O~CE 19"-319-826
`
`!
`
`321 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Office Action Summary
`
`•
`
`_ Applicant(s)
`
`Application No.
`081146,206
`
`Examiner
`
`Patrick Nolan
`
`Carter et al.
`
`Group Art Unit
`1816
`
`IX! Responsive to communication(s) filed on Dec 3, 1996
`~-~--------------------------
`0 This action is FINAL.
`D Since this application is in condition for allowance except for formal matters, prosecution as to the merits is closed
`in accordance with the practice under Ex parte Quayle, 1935 C.D. 11; 453 O.G. 213.
`month(s), QF it:iirt1 ae9s, urhjche><&r
`3
`A shortened statutory period for response to this action is set to expire
`~er, from the mailing date of this communication. Failure to respond within the period for response will cause the
`application to become abandoned. (35 U.S.C. § 133). Extensions of time may be obtained under the provisions of
`37 CFR 1.136(a).
`
`Disposition of Claims
`IX! Claim(s) 1-12, 15, and 19-25
`
`is/are pending in the application.
`
`I
`
`Of the above, claim(s) - - - - - - - - - - - - - - - - - - - - - is/are withdrawn from consideration.
`D Claim(s)
`is/are allowed.
`------------------------------
`IX! Claim(s) 1-12, 15, and 19-25
`D Claim(s) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - i s /a re objected to.
`D Claims
`are subject to restriction or election requirement.
`
`is/are rejected.
`
`Application Papers
`D See the attached Notice of Draftsperson's Patent Drawing Review, PT0-948.
`D The drawing(s) filed on
`is/are objected to by the Examiner.
`---------
`is D approved D disapproved.
`0 The proposed drawing correction, filed on
`- - - - - - - - -
`0 The specification is objected to by the Examiner.
`D The oath or declaration is objected to by the Examiner.
`
`Priority under 35 U.S.C. § 119
`D Acknowledgement is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d).
`D All D Some* D None of the CERTIFIED copies of the priority documents have been
`D received.
`D received in Application No. (Series Code/Serial Number)
`D received in this national stage application from the International Bureau (PCT Rule 17.2(a)).
`*Certtt~d copies n~received: - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`0 Acknowledgement is made of a claim for domestic priority under 35 U.S.C. § 119(e).
`
`~-------~
`
`Attachment(s)
`D Notice of References Cited, PT0-892
`IX! Information Disclosure Statement(s), PT0-1449, Paper No(s). 19, 24,26
`D Interview Summary, PT0-413
`D Notice of Draftsperson's Patent Drawing Review, PT0-948
`D Notice of Informal Patent Application, PT0-152
`
`U. S. Patent and Trademark Office
`PT0-326 (Rev. 9-95)
`
`Office Action Summary
`
`Part of Paper No.
`
`27
`
`--- SEE OFFICE ACTION ON THE FOLLOWING PAGES ---
`
`322 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`
`Art Unit 1816
`
`•
`
`2
`
`1. Claims 1-12, 15 and 19-25 are pending.
`
`2. Claims 19-21 stand rejected under 35 U.S.C. § 112, second
`paragraph, as being indefinite for failing to particularly point
`out and distinctly claim the subject matter which applicant regards
`as the invention.
`Claims 19-21 are substantial duplicates of claim 1. There
`appears to be no difference in scope between these claims, see MPEP
`706.03(k).
`
`3. The following is a quotation of 35 U.S.C. § 103 which forms the
`basis for all obviousness rejections set forth in this Office
`action:
`
`A patent may not be obtained though the invention is not
`identically disclosed or' described as set forth in section 102
`of this title, if the differences between the 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 subject matter pertains. P~tentability
`shall not be negatived by the manner in which the invention
`was made.
`
`Subject matter developed by another person, which qualifies as
`prior art only under subsection (-f) or (g) of section 102 of
`this
`this title, shall not preclude patentability under
`section where the subject matter and the claimed invention
`were, at the time the invention was made, owned by the same
`person or subject to an obligation of assignment to the same
`person.
`
`In
`inventors.
`joint
`This application currently names
`4.
`considering patentability of the claims under 35 U.S.C. § 103, the
`~xaminer presumes that the subject matter of the various claims was
`commonly owned at the time any inventions covered therein were made
`absent any evidence to the contrary. Applicant is advised of the
`obligation under 37 C. F. R. § 1. 56 to point out , the inventor and
`invention dates of each claim that was not commonly owned at the
`in order for the examiner to
`later invention was made
`time a
`consider the applicability of potential 35 U.S.C. § 102(f) or (g)
`prior art under 35 U.S.C. § 103.
`
`5. Claims 1, 2, 4-12, 15, and renumbered claims 19-22 and 24-25
`stand rejected under 35 U.S.C. § 103 as being unpatentable over
`Winter [EP 0239400], Riechmann et al. [Nature 332:323-327 (1988}]
`
`323 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`
`Art Unit 1816
`
`•
`
`3
`
`and Queen et al. [Proc. Natl. Acad. Sci. 86:10029-10033 (1989)],
`all of record for the same reasons set forth in paper No. 18.
`to a method for producing
`Briefly the claims are drawn
`humanized antibodies and humanized antibodies. Winter, teaches the
`the
`production of altered, chimeric, antibodies by replacing
`complementarily determining regions (CDRs), see abstract. Winter,
`teaches the requirements for CDR fusions, see page 6 to page 8,
`line 29. Particularly, page 8, lines 11-18, where Winter, teaches
`that "merely by replacing one or more CDRs with complementary CDRs
`may not always result in a functional altered antibody ..... it will
`be well within the competence of the man skilled in the art, either
`by carrying out routine experimentation or by trail and error
`testing to obtain a functional altered antibody. Note at page 8,
`framework region
`last full paragraph that Winter states that
`replacement ·and sequence changing may be necessary to obtain a
`lines 13-16, Winter
`On page 9,
`functional humanized antibody.
`suggests that the antibodies would be of importance for use in
`human therapy. Winter, teaches a method of producing the antibody,
`see page 10, paragraph 3 to page 15, paragraph 2. Consistent with
`teach a method of reshaping human
`Winter, Riechmann et al.
`antibodies for therapy by CDR grafting, see whole document and
`Queen et al. teach the humanization of antibodies by CDR grafting,
`see entire document. Riechmann et al. teach altering the sequence
`of the antibody to restore packing or to increase binding affinity,
`see page 326, first column, first full paragraph. Queen et al.
`teach the use of computer modeling to assist in the production of
`humanized antibodies, specifically to predict which amino acids to
`change thereby effecting molecular interactions, note that of the
`identified by
`those
`include
`amino acids predicted to change
`applicant in claims 7 and 10. A person of ordinary skill in the
`· art would have realized that dependent upon the framework region
`selected and the sequence of the CDR regions amino acid changes
`would need to be made and they would depend upon the precise amino
`acid interactions of the polypeptide. The combination of Winter,
`Riechmann et al. and Queen et al. teach a comprehensive method for
`producing humanized antibodies which include the steps outlined in
`applicant's claims. Therefore, it would have been prima facia
`obvious to a person of ordinary skill in the art at the time the
`to take the combined teachings of Winter,
`invention was made
`Riechmann et al. and Queen et al. to produce a method of making a
`humanized antibody and to have a humanized antibody for either
`diagnostic or therapeutic use.
`
`Applicant's arguments filed 6/12/95 have been fully considered
`but they are not persuasive. Applicant argues that the claimed
`invention is distinct from that taught by the above combination of
`
`324 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`
`Art Unit 1816
`
`•
`
`4
`
`further
`references because a consensus sequence is used and
`modifications are not necessary. Applicant further argues that the
`combination of references do not teach a humanized antibody with
`reduced immunogenicity.
`
`the combination of references
`Regarding the consensus sequence,
`framework regions having a significantly high
`teach the human
`degree of sequence homology (conservative regions). Queen et al.
`in particular point to Kabat as demonstrating that this was known
`see
`in advance of applicant's filing date,
`the art well
`in
`In essence there is no
`reference 38, cited by Queen et al.
`functional/structural distinction from what applicant has claimed
`and that taught by the combination of references. Ex parte C, 27
`U.S.P.Q.2d 1492 (BPAI 1993). Applicants recitation of Co et al. is
`unclear, it was not used in the prior art rejection. Applicant
`the
`that
`to several other references concluding
`then points
`techniques of the prior art and the technique of the instant
`the minor
`However,
`application are "certainly different".
`differences between the prior art and the claimed invention are
`obvious differences. Modifications in the framework regions which
`affect the proximity or orientation of the VL-VH interface regions
`is the same as substituting that FR residue from the import regions
`that is involved in the effects set forth in paragraph (f) of claim
`reduced
`teach
`references clearly
`combination of
`The
`1.
`See e.g.
`immunogenicity associated with the humanized antibody.
`lip.es 5-8. Applicant's
`Riechmann et al. page 323, column 2,
`comments have been fully considered and were as a whole not found
`persuasive.
`
`6. Claims 1, 2, 4-12 and 15, and renumbered claims 19-22 and 24-25
`stand rejected under 35 U.S.C. § 103 as being unpatentable over
`Winter [EP 0239400], Riechmpnn et al. [Nature 332:323-327 {1988)]
`and Queen et al. [Proc. Natl. Acad. Sci. 86:10029-10033 (1989)] in
`view of In re Durden 226 U.S.P.Q. 359 (Fed. Cir. 1985), all of
`record, for the same same reasons set forth in paper No. 18.
`to a method for producing
`the claims are drawn
`Briefly
`humanized antibodies and humanized antibodies. As discussed above
`the combination of Winter, Riechmann et al. and Queen et al. teach
`humanized antibodies and methods for their production. Applicant's
`from what has
`to differ
`invention does not appear
`claimed
`previously known in the art.
`
`Applicant cites the above comments in their response to this
`rejection.
`
`Applicant's comments were fully considered as described above and
`
`325 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`
`Art Unit 1816
`
`•
`
`5
`
`were not found persuasive, to the extent that they apply to this
`rejection.
`
`7. Claim 3 and renumbered claim 23 stand rejected under 35 U.S.C.
`§ 103 as being unpatentable over Winter [EP 0239400], Riechmann et
`al. [Nature 332:323-327 (1988)) and Queen et al. [Proc. Natl. Acad.
`Sci. 86:10029-10033 (1989)] as applied to claims 1, 2, 4-12 and 15
`and further in view of Raitt [Immunology, published 1985, by Gower
`Medical Publishing Ltd. (London, England) page 5.5], all of record
`for the same reasons set forth in paper No. 18.
`Briefly the claim is drawn to a method for producing humanized
`antibodies having the additional steps of searching the import
`variable domain sequence for glycosylation sites, determining if
`any such glycosylation site is reasonable expected to affect the
`antigen binding or affinity of the antibody and if so substituting
`the glycosylation site into the consensus sequence. As discussed
`above the combination of Winter, Riechmann et al. and Queen et al.
`teach humanized antibodies and methods of producing humanized
`antibodies. The combination of Winter, Riechmann et al. and Queen
`importance of carbohydrate residues.
`teach the
`et al. do not
`that antibodies contain carbohydrate
`teaches
`However, Roitt
`residues in the variable region. A person of ordinary skill in the
`art would realize that carbohydrate residues can produce steric
`the folding characteristics of polypeptides.
`in
`modifications
`Therefore it would have been prima facia obvious to a person of
`ordinary skill in the art at the time the invention was made to
`include a step in the method taught by the combination of Winter,
`Riechmann et al. and Queen et al. which determines if the presence
`of carbohydrate residues occur in the variable region that can
`affect antigen binding and then include in the antibody sequence
`the appropriate glycosylation signal, by adding the appropriate
`consensus sequence. A person of ordinary skill in the art would
`have been motivated to add the additional step of identifying
`glycosylation that may affect antigen binding to ensure that the
`antibody produced will have the appropriate binding affinity. A
`person of ordinary skill in the art would have been motivated to
`produce such an method to produce antibodies having diagnostic or
`therapeutic utility.
`
`The bulk of applicant's argument is that the references relied
`on in the above rejection do not render the invention obvious
`and Roitt adds nothing to these references to overcome the
`deficiency.
`
`From the above discussion, the references used render the claimed
`invention obvious. Roitt fulfills the deficiency of the references
`
`326 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`
`Art Unit 1816
`
`•
`
`6
`
`discussed above to the extent that Roitt teaches antibodies contain
`carbohydrate residues in the variable region. A person of ordinary
`skill in the art would realize that carbohydrate residues can
`produce steric modifications in the folding characteristics of
`polypeptides.
`
`THE FOLLOWING REJECTIONS ARE NEW GROUNDS OF REJECTIONS
`
`Double Patenting
`
`The non-statutory double patenting rejection, whether of the
`obviousness-type or non.-obviousness-type, is based on a judicially
`created doctrine grounded in public policy (a policy reflected in
`the statute) so as to prevent the unjustified or improper timewise
`extension of the "right to exclude" granted by a patent.
`In re
`(CCPA 1969); In re Vogel,
`Thorington, 418 F.2d 528, 163 USPQ 644
`(CCPA 1970); In re Van Ornum, 686
`422 F .2d 438, 164 USPQ 619
`(CCPA 1982); In re Longi, 759 F.2d 887, 225
`F.2d 937, 214 USPQ 761
`USPQ 645 (Fed. Cir. 1985); and In re Goodman, 29 USPQ2d 2010 (Fed.
`Cir. 1993).
`A timely filed terminal disclaimer in compliance with 37
`to overcome an actual or
`(c) may be used
`and
`CFR 1. 321 (b)
`provisional rejection based on a non-statutory double patenting
`ground provided the conflicting application or patent is shown to
`be commonly owned with this application. See 37 CFR 1.78,(d).
`Effective January 1, 1994, a registered attorney or agent of record
`may sign a terminal disclaimer. A terminal disclaimer signed by
`the assignee must fully comply with 37 CFR 3.73(b).
`
`Claims 1-12, 15 and 19-25 are provistonally rejected under the
`8.
`judicially created doctrine of obviousness-type double patenting as
`being unpatentable over claims 1-12, 15 and 19 of . copending
`application Serial No. 08/439,004. Although the conflicting claims
`are not identical, they ·are ·riot patentably distinct from each other
`invention claimed in claims 1-12, 15 and 19 of
`the
`because
`the
`encompasses
`08/ 439, 004
`copending appl.ication Serial No.
`the instant
`invention claimed in claims 1-12, 15 and 19, of
`application.
`is a provisional obviousness-type double patenting
`This
`rejection because the conflicting claims have not in fact been
`patented.
`
`327 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`
`Art Unit 1816
`
`•
`
`7
`
`Claim Rejections - 35 USC § 102
`
`The following is a quotation of the appropriate paragraphs
`of 35 U.S.C. § 102 that form the basis for the rejections under
`this section made in this Office action:
`A person shall be entitled to a patent unless --
`the invention was described in a patent granted on an
`el
`application for patent by another filed in the United States
`before the invention thereof by the applicant for patent, or
`on an international application by another who has fulfilled
`( 2) , and ( 4) of section
`the requirements of paragraphs ( 1) ,
`371 (c) of this title before the invention thereof by the
`applicant for patent.
`
`Claims 1-12, 15 and 19-25 are rejected under 35 U.S.C.
`9.
`§ 102(e) as being anticipated by U.S. Patent 5,530,101 (82).
`
`Claims 1-2 and 19-25:
`the production of
`for
`teaches methods
`'101 patent
`The
`humanized antibodies wherein the CDR amino acid sequences from the
`import (i.e. donor) a're exchanged for the human (i.e. acceptor) CDR
`'101 patent
`amino acid sequences (abstract, in particular). The
`regions and
`framework
`import and human
`teaches alignment of
`selection of substituted human framework antibody residues based on
`the following effed:s; the import framework residue non-covalently
`in
`column 14,
`three,
`(i.e. Category
`binds antigen directly
`particular), interacts with a CDR (i.e. Category three or four,
`column 14-15, in particular), or participates in the VL-VH interface
`(i.e. Category 3,4 or 5, column 14-15, in particular).
`'101 patent teaches that if a residues is exposed on the
`The
`surface of the domain (i.e. interacts with CDR) and doesn't have
`one of the effects of step f in claim 1, then to leave the human
`residue intact (column 13-14, in particular) . The term "consensus"
`import
`has been interpreted to include the aligning of murine
`in
`residues,
`framework
`to human acceptor
`residues
`framework
`addition to the aligning of all human framework resiudues ·and
`compiling a single "consensusf/ human framework to be used as a
`in every humanized antibody. Since "consensus" has
`template
`limitless interpretations as vaguely defined in the specification,
`the prior art reads on the claimed invention.
`
`Claims 3 and 4:
`a
`step of determining whether or not
`The additional
`substituted residue is glycosylated is determined by the residue
`makeup of the import peptide, a fact well known in the art prior to
`
`328 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No:
`
`08/146,206
`
`Art Unit 1816
`
`•
`
`8
`
`the invention and therefore lends no patentable import to the
`invention.
`
`Claim 5:
`'101 patent teaches retaining those residues that are
`The
`in the human framework region
`highly conserved (i.e. not rare)
`(Category 2 and 5, Column 14-16, in particular).
`
`Claims 6-8:
`'101 patent teaches which human and import residues are
`'The
`likely to be selected for substitution. In addition the '101 patent
`teaches corresponding import for human substitution at specific
`sites (Column 15, in particular) .
`
`Claim 9:
`'101 patent teaches a method employing a consensus human
`The
`variable domain based on human variable domains and additionally
`in
`(Column 13,
`variable domains from species other than human
`particular) .
`
`Claims 10-12:
`'101 patent teaches a humanized antibody variable domain
`The
`having a non-human CDR incorporated into a human antibody variable
`domain, wherein the improvement comprises~the substitution of only
`specific corresponding hum.an and import amino acid residues (column
`15, in particular) .
`
`Claim 15:
`'101 patent teaches a method for engineering a humanized
`The
`antibody comprising introducing residues from an import ant~body
`representing - a
`into an amino acid sequence
`variable domain
`consensus of mammalian antibody variable domain sequences (column·
`12-13, in particular).
`The prior 1art teachings anticipate the claimed invention.
`10. The references crossed out in the form PT0-1449 filed on
`12/3/96 are the duplicates of the references stated in the formn
`PT0-1449 filed 8/30/96.
`
`11. The lengthy specification has not been checked to the extent
`necessary to determine the presence of all possible minor errors.
`Applicants cooperation is requested in correcting any errors of
`which applicant may become aware of in the specification.
`
`communication or earlier
`this
`concerning
`inquiry
`12. Any
`communications from the examiner should be directed to Patrick
`
`329 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`
`Art Unit 1816
`
`•
`
`9
`
`Nolan whose telephone number is (703) 305-1987. The examiner can
`normally be reached on Monday through Friday from 8:30 am to 4:30
`pm.
`
`the
`the examiner are unsuccessful,
`to reach
`If attempts
`13.
`examiner's supervisor, Christina Chan, can be reached at (703) 305-
`3973. The FAX number for our group, 1816, is (703) 305-7939. "Any
`the status of this
`inquiry of a general nature relating to
`the Group
`to
`application or proceeding should be directed
`receptionist, whose telephone number is (703) 308-0196.
`
`Patrick J. Nolan, Ph.D.
`December 19, 1996
`
`Cd~CI~
`
`CHRISTINA Y. CHAN
`SUPERVISORY PATENT EXAMINER
`GROUP 1800
`
`330 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`... I~ 1.-.,fi-f_/_ ~) nd/2,., I /.Y L
`
`,
`
`.
`
`1""'1
`
`- "I ,
`.
`U.S. Dept. of Commerce
`
`FORM PT0·1449
`
`LIST OF DISCLOSURES CITED BY APPLICANT
`(Use seve~I sheets if necessaiy)
`
`Patent and Trademark Olfic:e
`
`U.S. PATENr DOCUMENTS
`
`I Atry Docket No.
`l·u·1oy 1:1
`Applicant
`Carter et: ill.
`filing Date
`17 Nov 1993
`
`Sheet _1 _
`
`Of _t_
`
`Serial No.
`08/1-16,?.06
`
`Group
`~/?lb
`
`Document Number
`5,
`/ --
`5 _ ........
`- --
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`-
`r
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`
`-
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`et al.
`
`Class
`
`,
`
`"
`
`Subclass
`~- --
`. --
`
`~
`
`Filing Date
`
`J!5.1B.§J
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`1:9. ~ ·~t>
`, 2-/
`
`Examiner
`nhials
`Pf1/
`pt/· 82
`
`fll
`
`Examiner
`nmats
`
`1.//V
`
`83
`
`Document Number
`
`c -· .. -·
`
`.::>.-~
`
`l fl4 ~--
`
`1
`
`85
`06
`87
`BO
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`---·
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`
`89
`
`, , , , , -tel.
`
`.at-
`
`.::II
`
`'
`
`1 n. •
`
`FOREIGN PATENT DOCUMENTS
`
`Country
`
`Date
`-~ -
`·-·-
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`·-
`
`~
`
`..,
`
`l!:PO
`
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`- '
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`
`l'ranslation
`No
`Yes
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`l
`~ (J rY Dato C/idered
`/2-c J1e/tft/?
`•El!amlner: Initial if reteVence considered, whether or not citation is in ¢0nf9~awith MPEP 809; draw line through caalion
`if not in confonnance and not Col'ISidered. Include copy ~I une ~with 'ne
`communication lo applicant.
`0
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`
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`
`lJSCOMM-DC 80-398.
`
`331 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`' .'l
`
`.... .,. . • Patent Docket P0709P1
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE !..._")
`'f,f!r'\
`
`Group Art Unit: 1816
`
`Examiner: P. Nolan
`
`In re Application of
`
`Paul J. Carter et al.
`
`Serial No.: 08/146,206
`
`Filed: November 17, 1993
`
`For: METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`AMENDMENT TRANSMITTAL
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`Sir:
`
`Transmitted herewith is an amendment in the above-identified application.
`The fee has been calculated as shown below.
`
`Total
`
`Independent
`
`31
`
`7
`
`24
`
`10
`
`7
`
`0
`
`_First Presentation of Multiple Dependent Claims
`
`x22 =
`x80 =
`+ 260 =
`
`$154.00
`
`$0.00
`
`Total Fee Calculation
`
`$154.00
`
`x
`x
`
`No additional fee is required.
`The Commissioner is hereby authorized to charge Deposit Account No. 07-0630 in
`the amount of $154.00. A duplicate copy of this transmittal is enclosed.
`Petition for Extension of Time is enclosed.
`
`The Commissioner is hereby authorized to charge any additional fees required under 37 CFR 1.16 and 1.17, or
`credit overpayment to Deposit Account No. 07-0630. A duplicate copy of this sheet is enclosed.
`
`Respectfully submitted,
`GENENTECH, INC.
`
`By: p-c,~
`Ja~tHaSak
`Reg. No. 28,616
`(for Wer.dy M. Lee
`Reg. No. 40,3'78)
`
`Date: June ~3 , 1997
`
`460 Pt. San 8ruPo Blvd.
`So. San Francisco, CA 94080-4990
`Phone: (415) 225-1994
`Fax: (415) 952-9881
`
`Revised !101131961
`
`332 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`.,
`
`y<
`\
`~ () \
`'9;./
`
`Patent Docket P0709P1
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Group Art Unit: 1816
`
`Examiner: P. Nolan
`
`In re Application of
`
`Paul J. Carter et al.
`
`Serial No.: 08/146,206
`
`Filed: November 17, 1993
`
`For: METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`PETITION AND FEE FOR THREE MONTH EXTENSION OF TIME
`f37 CFR 1.136fall
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`Sir:
`
`Applicant petitions the Commissioner of Patents and Trademarks to extend the time for
`response to the OFFICIAL ACTION dated 23 December 1996 for three month(s) from 23 March 1997
`to 23 June 1997. The extended time for response does not exceed the statutory period.
`Please charge Deposit Account No. 07-0630 in the amount of $930.00 to cover the cost of
`the extension. Any deficiency or overpayment should be charged or credited to this deposit account.
`A duplicate of this sheet is enclosed.
`
`Respectfully submitted,
`GENENTECH, INC.
`
`Date: June 2 a I 1997
`
`460 Pt. San Bruno Blvd.
`So. San Francisco, CA 94080-4990
`Phone: ( 415) 225-·1994
`Fax: (415) 952-9881
`
`By: ~E~,
`i
`
`Janet Hasak
`Reg. No. 28,616
`(for Wendy M. Lee
`Reg. No. 40,378)
`
`~
`s
`
`i -~iS
`I~ f
`~~ ---.. ~te
`
`~<:;
`
`Revised 110/17/96)
`
`333 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`... -
`
`•
`
`•
`
`THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Patent Docket P0709P1
`
`Group Art Unit: 1816
`
`Examiner: P. Nolan
`
`ation of
`
`Paul J. Carter et al.
`
`Serial No.: 08/146,206
`
`Filed: 17 November 1993
`
`For: METHOD FOR MAKING
`HUMANIZED ANTIBODIES
`
`ti1~
`1 0 b fh
`#e9/~
`c ~
`
`-<// 1( 97
`
`AMENDMENT UNDER 37 C.F.R. §1.111
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`Sir:
`In response to the Office Action dated December 23, 1996, the period for response having been
`extended as a result of the enclosed Petition for a three-month Extension of Time and requisite fee,
`Applicants respectfully request reconsideration of the above-identified application in view of the
`
`following amendments and remarks.
`
`IN THE CLAIMS:
`1.
`(Twice Amended) A method for making a h
`
`anized antibody comprising amino acid
`
`sequences of a non-human, import antibod
`of:
`(a)
`
`obtaining the amino acid sequ ces of at least a portion of an import heavv chain
`
`nd a human antibody, comprising the steps
`
`(b)
`
`(c}
`
`import variable do ain and the consensus human variable domain;
`
`substituting an i port CDR amino acid sequence for the corresponding cortnsus
`~
`human CDR mino acid sequence;
`I
`!a
`
`I~ f
`·~~ --~c:;
`
`e-t"-
`
`334 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`Page2
`
`•
`
`(d)
`
`aligning the amino acid sequences of a Framework Region
`
`) of the import
`
`variable domain and a corresponding FR of the consensus hu
`
`(e)
`
`identifying import FR residues in the aligned FR s quences that are non(cid:173)
`
`homologous to the corresponding consensus FR resi es;
`
`(f)
`
`determining if the non-homologous import FR resid e is expected to have at least
`
`one of the following effects:
`
`(1)
`
`(2)
`
`(3)
`
`non-covalently binds antigen directly:[,
`
`interacts with a CDR; or
`participates in the VL - VH interface y affecting the proximity or orientation of
`the V L and V H regions with res ct to one another; and
`
`(g)
`
`for any non-homologous import FR r sidue which is expected to have at least one
`
`of these effects, substituting that r sidue for the corresponding amino acid residue
`
`in the consensus FR .
`
`6.
`
`(Twice Amended) The method
`
`f clai
`
`herein the corresponding consensus FR
`
`residues substituted in step (g) are sel
`
`ted from the group consisting of 4L, [35L,] 36L. 38L, 43L,
`
`44L, 46L, 58L, 62L [64L,] 65L, 66L, 7L, 68L, 69L, 70L, [71 L,] 73L, 85L, 87L. 98L, 2H, 4H, 24H,
`
`36H, 37H 39H, 43H, 45H, 49H, H 69H, 70H, 73H, 74H, 75H, 76H, [and] 78H and 92H.
`
`7.
`
`(Twice Amended) A
`
`thod comprising providing at least a portion of an import, non-human
`
`heavv chain variable doma· amino acid sequence having a ComplementariJy Determining Region
`
`egion (FR}, obtaining the amino acid sequence of at least a portion of
`../:. /'(__ (CDR) and a Framewor
`· a consensus human v
`V
`·able domain of a human heayy chain immunoglobulin subgrciup having a
`CDR and a FR, sub tituting the non-human CDR for the human CDR in the consensus human
`
`variable domain, a d substituting a non-human amino acid residue for the consensus amino acid
`
`residue at at lea t one of the following sites:
`
`4L, [35L,] 36L BL, 43L, 44L, 46L, 58L, 62L [64L,] 65L, 66L, 67L, 68L, 69L, 70L, [71 L,] 73L,
`
`85L, 87L. 98 I 2H, 4H, 24H, 36H, 37H 39H, 43H, 45H, 49H, 69H, 68H ?OH, 73H, 74H, 75H,
`
`76H, [and]
`
`335 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`Page3
`/
`
`Please cancel claim 9, without prejudice.
`
`•
`
`{Twice Ame ded) A humanized antibody variable domain having a non-human
`1 O.
`Complementaril.y De rmining Region (CDR) incorporated into a [consensus] human antibody
`~\variable domain, wher in an [human] amino acid residue has been substituted [by a non-] for the
`human amino acid resi ue at a site selected from the group consisting of:
`
`• ·p4L, [35L,) 36L 38L, 43L, 44L, 46L, 58L, 62L [64L,] 65L, 66L, 67L, 68L, 69L, 70L, [71 L,) 73L,
`85L, 87L 98L, 2H, 4H, 2 H, 36H, 37H 39H, 43H, 45H, 49H, 68H. 69H, 70H, 73H, 74H, 75H,
`
`76H, [and] 78H and 92H.
`
`15.
`
`{Twice Amended) A method for en · 1e1ring a humanized antibody comprising
`n-t\~~n, import heavy chain variable domain into g_
`humah heavy chain immunoglobulin subgroup.
`
`introducing amino acid residues from a
`consensus human variable domain o
`
`,--
`/
`Please cancel claims 19-21, without prejudice.
`
`{Amended) A humanized antibody omprising a consensus human variable domain of a
`22.
`human heavy chain immunoglobulin s grouft. wherein the amino acid residues forming the
`Complementarny Determining Regio s {C~s} thereof comprise non~human import antibody
`amino acid residues.
`
`In claim 25, line 1, please replace "abo~-about 5--.
`
`Please add the following claims:
`
`--26. The humanized antibody of claim 2 wherein the human heavy chain immunoglobulin
`subgroup is VH subgroup Ill.
`
`27.
`The humanized antibody o claim 26 wherein the consensus human variable domain
`comprises the amino acid seq nee of SEQ ID N0:4.
`
`0
`
`I
`
`I
`
`336 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`Serial No. 08/146,206
`Page4
`
`•
`
`The humanized antibody of claim 22 further comprising a consensus man light chain
`28.
`variable domain comprising th