UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box I450
`Alexandria, Virginia 22313-1450
`www.uspto.gov
`
`05/1 3/2005
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`90/007,542 15’
`901007 57
`02/16/2007
`759°
`47554
`~
`SIDLEY AUSTIN LLP
`ATTN: DC PATENT DOCKETING
`1501 K STREET, Nw
`WASHINGTON, DC 20005 ~
`
`6331415
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`22338-10230
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`7585
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`‘
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`-
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`-
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`DATE MAILED: 02/ I 6/2007
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`Please find below and/or attached an Office communication concerning this application or proceeding.
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`PTo.9oc (Rev, .o,o3)
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`Genzyme Ex. 1008, pg 188’
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`Genzyme Ex. 1008, pg 188
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`

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`
`
`
`
`Commissioner for Patents
`United States Patent and Trademark Ofiice
`P.0. Box145o.
`Alexandria, VA 2231 3-1450
`wwwusptagov
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`DO NOT USE IN PALM PRINTER
`
`(THIRD PARTY REQUESTER'S CORRESPONDENCE ADDRESS)
`
`LISA V. MUELLER
`
`WOOD PHILLIPS KATZ CLARK & MORTIMER
`
`3800 WEST MADISON STREET, SUITE 3800
`
`CHICAGO, IL 60661
`
`EX PARTE ‘REEXAMINATION COMMUNICATION TRAN_SMITTAL FORM
`
`
`REEXAMINATION CONTROL NO. 90/007 542.
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`‘L 6l o I 0 E2 4/ V75»
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`"PATENT NO. 6331415.
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`ART UNIT 3991.
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`Enclosed is a copy of the latest communication from the.United States Patent and Trademark
`Office in the above identified ex parte reexamination proceeding (37 CFR 1.550(f)).
`
`Where this copy is supplied after the reply by requester, ‘37 CFR 1.535, or the time for filing a
`reply has passed, no submission on behalf of-the ex parte reexamination requester will be
`acknowledged or considered (37 CFR 1.550(g)).
`
`PTOL-465 (Rev.O7-O4)
`
`'
`
`Genzyme Ex. 1008, pg 189
`
`Genzyme Ex. 1008, pg 189
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`

`
`.
`Office Action in Ex Parte Reexamination
`H
`
`' Control No.
`, 90/007,542 We I oo-rmra)
`Examiner
`Bennett Celsa
`
`.
`
`-
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`Patent Under Reexamination
`6331415
`A” Unit
`3991
`
`_
`
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address -
`
`bfi This action is made FINAL.
`a|Z Responsive to the communication(s) filed on 30 October 2006 .
`cI:] A statement under 37 CFR 1.530 has not been received from the patent owner.
`'
`
`A shortened statutory period for response to this action is set to expire g month(s) from the mailing date of this letter.
`. Failure to respond within the period for response_wi|l result in termination of the proceeding and issuance of an ex parte reexamination
`certificate in accordance with this action. 37 CFR 1.550(d). EXTENSIONS OF TIME ARE GOVERNED BY 37 CFR 1.550(c).
`If the period for response specified above is less than thirty (30) days, a response within the statutory minimum of thirty (30) days
`will be considered timely.
`
`Part I
`
`THE FOLLOWING A'ITACHMENT(S) ARE PART OF THIS ACTION:
`
`1-. E Notice of References Cited by Examiner, PTO-892.
`
`3. E]
`
`Interview Summary, PTO-474.
`
`2.
`
`IX information Disclosure Statement, PTO/SB/08.
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`‘
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`I
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`4. D
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`.
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`~
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`Part II.
`
`SUMMARY OF ACTION 7
`
`1a.
`
`Claims 1-_.36 are subject to reexamination.
`
`~ 1b.
`2.
`
`Claims __ are not subject to reexamination.
`Claims
`have been canceled in the present reexamination proceeding.
`
`Claims __ are patentable and/or confirmed.
`
`Claims 1-36 are rejected.-
`
`Claims T are objected to.
`
`3 4 5
`
`.
`
`_
`' The drawings, filed on __'are acceptable.
`6
`7. D ‘The proposed drawing correction, filed on __ has been (7a)Ij approved (7b)I:j "disapproved.
`8 .
`I:I Acknowledgment is made of the priority claim under 35 U.S.C. § 119(a)-(d) or (f).
`a)D All b)l] Some‘ c)[j None
`of the certified copies have
`
`1D been received.
`2[] not been received.
`
`3E] been filed in Application No. _:
`
`43. been filed in reexamination Control No. __
`5D been received by the International Bureau in PCT application No.
`* See the attached detailed Office action for a list of the certified copies not received.
`
`9. D Since the proceeding appears to be in condition for issuance of an ex parte reexamination certificate 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.
`
`'
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`10. D Other:
`
`cc: Reuester if third
`U.S. Patent and Traderrark Office
`
`PTOL-466 (Rev. 08-06)
`
`Office Action in Ex Parte Reexamination
`
`Genzyme EXF.‘ajf5o1§ 70123
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`Genzyme Ex. 1008, pg 190
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`Application/Control Number: 90/007,542; 90/007,859
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`Page 2.
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`Art Unit: 3991
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`Reexamination: Final Office Action
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`' Reexamination of US Patent, No.-6,331,415 (Cabil|y '2 patent).
`Status of the Claims.‘
`
`Claims 1-36 are pending and under reexamination. The.text of those sections of
`
`Title 35, U.S. Code not included in this action can be found in a prior Office action.
`Procedural Posture: .
`
`\ M
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`erger of 3”’ Pan‘/yVRequests 90/007, 542 and 90/00 7,859
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`i. 90/007542 (‘7542 Proceeding):
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`ii. 90/007859 (‘7859 Proceeding)
`
`"
`
`Reexamination request filed:
`Reexamination ordered:
`Patent Owner.Statement:-
`First Office Action mailed:
`Patent Owner Response dated
`‘7542 AND_ ‘7859 merged:
`
`'
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`12/23/05
`5/13/05
`1/23/06
`7/7/05.
`2 none
`none
`N/A
`9/13/05
`, N/A
`1/25/05 '
`'
`6/6/06
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`Following the merger of the 90/007,542 and 90/007,859 proceedings, the First
`Office Action dated September-133, 2005 in the ‘7542 proceeding was withdrawn in light
`of the l\l_on-Final Office_Action dated August 16, 2006.
`I
`I Patentee’s November 25,2005 response (with Declarations) andthe November
`30, 2006 response (with Declarations) to the September 13, 2005 and subsequent
`,
`August 16 2006 office actions, respectively in the 90/007,542 proceeding are
`
`‘
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`I
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`‘
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`considered in this office action,
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`Additionally, the submitted December 14, 2006 and January 16, 2007‘ informationw
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`‘
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`disclosure statement have~b'een considered in this office action.
`
`/nfonnuation‘ Disclosure Statement (IDS)
`
`Examiner-initialed copies of the December 14, 2006 IDS (four pages) and the '.
`
`Genzyme Ex. 1008, pg 191
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`Genzyme Ex. 1008, pg 191
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`ApplicationlControl Number: 90/007,542; 90/007,859
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`Page 3
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`Art Unit: 3991
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`‘January 16, 2007 IDS (thirty pages) -submitted under Rule 1.97(c), (requiring 1.17(p)
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`-fees), accompany this office action. The newly submitted Moore 5,840,545 Patent
`
`»- reference presented in the Dec. 14"‘ IDS necessitated the makingof the new grounds of
`
`rejection found‘ in this office action.
`
`There is a substantial new question of patentability raised» by the Moore
`
`-5,840,545 patent. The Moore patent was cited by the Examiner in an anticipation,
`
`‘ rejection in a related co—pending application (U.S.S.N. :08/422,187) but is now being
`
`viewed in a new light since the claims addressed in 08/422,187 were drawn to different
`
`subject matter (e.g. process for producing altered antibody heavy or light chain or
`
`‘fragments thereof).
`
`Priority
`
`The8,331,425 (Cabi|ly 2) patent undergoing reexamination issued on December
`51.8, 20:0_1from application 07_/205,419 (filed 6/10/88) which was a continuation of '
`06/483,457 (filled 41/87/83”) now’4,818,567. (Cabil|y 1) patent. ‘H
`V
`D
`1 Cumulative PriorArt :
`The 1982 Valle and Deacon references are,cumulative in their teaching of
`microinjection of mRNA encoding. light and heavy‘ immunoglobulin chains into _Xenopus-
`oocyte cells toproduce secreted active antibody. Accordingly, only the Deacon .
`_
`V
`.
`reference was utilized in the obviousness double patenting rejection(s) recited below.
`
`‘Additionally, the Oi and Ochi references are cumulative in their teaching of ,
`restoring hybridoma cell antibody expression by vector transformation with a light chain
`
`‘ Genzyme Ex. 1008, pg'192
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`Genzyme Ex. 1008, pg 192
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`Page 4
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`Art Unit: 3991
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`gene. Accordingly, only the Ochi reference was utilized in the obviousness double
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`patenting rejection(s) recited below.
`
`Further, the Moore et al. 4,642,334 patent (claiming functional single chain
`
`antibodies) is deemed cumulative to the child Moore et al. 5,840,545 patent reference
`
`cited below (drawn to the methods and vectors used in making single chain antibodies).
`
`Withdrawn Objection (s) and/or Rejection (s):
`
`The following obviousness double patenting rejections raised in the August 16, 2006
`
`office action are hereby withdrawn for the following reasons:
`
`1. Claims 1-4, 11, 13, 15-18, 21, 23-25 and 33 of U.S. Pat. No. 6,331,415
`(Cabilly 2) rejected on the ground of nonstatutory obviousness-type double patenting as
`being unpatentable over claims 1-7 of U.S. Patent No. 4,816,567 (3/89: Cabilly 1)
`(wherein "or" is being interpreted as "and" in light of the Cabilly 1 patent prosecution
`history).
`
`2. Claims 1-36 of U.S. Pat. No. 6,331,415 (Cabilly 2) are rejected on the
`ground of nonstatutory obviousness-type double patenting as being unpatentable over
`claims 1-7 of U.S. Patent No. 4,816,567 (Cabilly 1) as applied to claims 1-4, 11, 13, 15-
`18, 21, 23-25 and 33 (wherein "or" is being interpreted as "and" in light of the Cabilly 1
`patent prosecution history) and further in view of Axel et al U.S. Pat. No. 4,399,216
`(8183), Rice et al. PNAS USA 79(12182):7862-7865, Kaplan et al. EP 004722 (1182),
`Builder et aL U.S. Pat. No. 4,511,502 (issued 4/85), Accolla et al. PNAS USA 77(1):
`563-566 Dallas (WO 82/03088), Deacon (Biochemical. Society Transactions, 4
`(1976):818-820), 1981 Valle (Nature, 291 (May '81) pages 338-340; and Ochi(Nature,
`302(3124183) pages 340-342).
`4
`
`To the extent the above obviousness double patenting rejections were predicated
`on claim interpretation that “or” is equivalent to "all", patentee’s arguments and
`evidence regarding claim interpretation of “or” (as meaning “or”) in the parent Cabilly 1
`patent application was found persuasive.
`
`In response to the above double patenting rejections, patentee argued (See
`
`October 30, 2006 patentee response particularly at pages 4-5 top and pages 10-20),
`
`that the prosecution history of the parent application (Cabilly 1) supports an
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`Genzyme Ex. 1008, pg 193
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`Genzyme Ex. 1008, pg 193
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`Application/Control Number: 90l007,542; 90/007,859
`Art_ Unit: 3991
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`interpretation that “or” has its ordinary meaning (“or” is “or”) and not “and/or”. Relevant
`
`in this regardwas the prosecution history of the parent Cabilly 1 application described
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`'
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`.on pages 11-14 of the owner's response -to an Examiner indefinite rejection which
`
`demonstrated that “or” was being defined by the patentee and the Examiner as having
`
`its conventional alternative meaning. Accordingly, the above obviousness double
`
`patenting rejections, to the extent that they were predicated on "of; as being interpreted
`
`to include “and”, have been overcome.
`
`-
`
`3. Claims 1-36 of U.S. Pat. No._6,331,415 (Cabilly 2) arerejected on the
`ground of nonstatutory obviousness-type double patenting as being unpatentable over
`claims 1-7 of U.S. Patent No. 4,816,567 (Cabilly 1)as applied to claims 1-4, 11, 13, 15-
`' 18, 21, 23-25 and 33 (wherein "or" "is being interpreted as "and" in light of the Cabilly ~1
`patent prosecution history) and further inview of Axel et al U.S. Pat. No. 4,399,216 L
`(8183), Rice et al. PNAS USA 79(12182):7862—7865, Kaplan et al. EP 004722 (1182),
`Builder et aL U.S. Pat. No. 4,511,502 (issued 4/85), Accolla et al. PNAS USA 77(1):
`0563-566 Dallas (WO 82/03088), Deacon (Biochemical. Society Transactions, 4
`(1976):818—820), 1981 Valle (Nature, 291 (May '81) pages 338-340; and Ochi('Nature,
`302(3124183) pages 340-342).
`.
`V
`‘
`'
`
`The obviousness double patenting rejection cited above (predicatedon “or” as .
`having its ordinary meaning) in‘ which the Cabilly 1 patentwas combined with the Axel, '
`Rice et al., Kaplan et al., Builder et al., Aco/la et al., Dallas, Deacon, Valle (1981) and .
`Ochi references iswithdrawn in light of a. new/ypresented modified rejection which
`further includes the newly submitted Moore et al. US. Pat. No. 5,840,545.-
`
`The Instant 8,331,41 (CabiIIyA2) Patented Invention Undergoing Reexamination
`
`The following patent. claim methods and compositions are representative:
`1. M_ETHoos;«
`
`I 1. A process for producing an immunoglobulin molecule or an immunologically
`functional immunoglobulin" fragment comprising at least the variable domains of the
`immunoglobulin heavy and light chains, in a single host cell comprising:
`
`iGenzyme Ex. 1008, pg 194
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`Genzyme Ex. 1008, pg 194
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`(i) transforming said single host cell with"a first DNA sequence encoding at least the '
`variable domain of the immunoglobulin heavy chain and a second DNA sequence
`encoding at least the variable domain of the immunoglobulin light chain, and
`
`.
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`(ii) independently expressing said first DNA sequence and said second DNA sequence
`so that said immunoglobulin heavy and light chains are produced as separate‘
`molecules in said transformed single host cell. See Claim_1.
`
`33. A process for producing an immunoglobulin molecule or an immunologically
`functional immunoglobulin fragment comprising at least the variable domains of the
`immunoglobulin heavy and light chains, in a single host cell comprising:
`independently expressing a first DNA sequence encoding at least the variable
`domainof the immunoglobulin heavy chain and a. second DNA sequence encoding at
`least the variable domain of the immunoglobulin light chain so that said immunoglobulin
`heavy and light chains are produced as separate molecules in said single host cell
`transformed with said first'*and~second DNA sequences.
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`_
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`21. A method comprising:
`
`a) preparing a DNA sequence consisting essentially of DNA encoding an ‘
`immunoglobulin consisting of an immunoglobulin heavy chain and light chain or Fab
`region, said immunoglobulin having specificity for a particular known antigen;
`
`b) inserting the DNA sequence of step a) into a replicable expression vector operably —
`linked to a suitable promoter;
`'
`‘
`'
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`V c) transforming a prokaryotic or eukaryotic microbial host cell culture with the vector of
`A step b);
`A
`-
`‘
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`v
`A
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`A d) culturing the host cell; and
`t e) recovering the immunoglobulin from the host cell culture, said immunoglobulin being
`capable of binding to a knownantigen.
`
`ii. ‘COMPOSITIONS:
`
`15. A vector comprising a DNA encoding at least a (first) variable immunoglobulin heavy
`chain domain and a second DNA sequence encoding at least a variable immunoglobulin
`light chain domain wherein the 15‘ and 2”“ DNA sequences are located at different
`insertion sites in the vector.
`v
`'
`~
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`18. A transformed host cell comprising at least two vectors in which one vector
`comprises a variable immunoglobulin heavy chain domain and a second vector
`comprises a variable immunoglobulin light chain domain.
`'
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`’ Genzyme Ex. 1008, pg 195
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`Genzyme Ex. 1008, pg 195
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`32. The insoluble particles of‘heavy and light chains or Fab region produced by‘ the
`method of claim 21 in which theheavy and light chains or Fab regions are deposited
`.within the cells (e.g. claim 27).
`‘
`‘
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`.
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`The Reference US Pat. No. 4,816,567 Cabilly 1 Patent Claims:
`
`1 a. The Cabilly l ('567 Patent) Claims
`
`.
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`-Independent claims 1, 3, -5, and 7 of the ‘567 patent. read as follows;
`_
`1. A method comprising .
`-
`_
`_
`_
`9
`a) -preparing a DNA sequence encoding a chimeric immununoglobulin heavy or light
`chain having specificity for a particular known antigen wherein a constant region is
`' homologous to the corresponding constant region of an antibody of a first
`mnmmalian species and a variable region thereof is homologous to the variable- region
`of an antibody derived from a second, different mammalian species;
`b) inserting -the sequence into a replicable expression" vector operably linked to a
`suitable promoter co_mpatible with a host cell;
`-
`c) transforming the host cell with the vector of (b);.
`’d) culturing the host cell; and
`.
`e), recovering the chimeric heavy or light chain from the host cell culture."
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`'
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`A
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`3. A composition comprising a chimeric immunoglobulin heavy orlight chain having.
`specificity for a particular knownantigen having a constant [egion homologous to a
`”-c‘oriré§p6fiding constant _régi6rT6f anTafitiboJdy7E5ffé’f;first mammalian species andfa
`. variable region homologous to a variable region of an antibody derived from a -
`second, different mammalian species.
`
`‘
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`A 5. HA replicable expression vector comprising DNA operably linked to a promoter
`compatiblewith a suitable host cell, said DNA»encoding a chimeric immunoglobulin
`‘heavy or light chain having specificity for a particular known antigen and having a
`' constant. region homologous to a corresponding region of) an antibody of a first
`mammalian species and a variable region homologousto a variable region of an
`' antibody derived from a second, different mammalian species.
`
`7. ‘Recombinant host cells transformed with the vector of claim 5.
`
`Claims 2, 4 and 6 (dependent on ‘claims 1, 3 and 5, respectively) recite that the first
`mammalian species (i.e. the source of the constant region) is human.
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`Genzyme Ex. 1008, pg 196
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`Genzyme Ex. 1008, pg 196
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`Cabilly.1 (‘567 Patent) and Cabilly 2 (‘-41.5 Patent) Claim Interpretation
`' Antibodies are proteins which generally refer to tetramers or aggregates thereof
`having specific immunoreactive activity comprising light and heavy chains in a “Y”
`configuration (having variable branch and constant stem regions),4with or without
`
`covalent linkage. ‘567 patent col. 6,'|ines 14-18.
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`_
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`c
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`9
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`Similarly, an “immunog|obulin” generally comprises two heavy and two light
`
`"chains “but may have specific immunoreactive activity (i.e. an “antibody”) or lack such
`specific immunoreactive activity (i.e. “non-specific immunoglobulin”. or “NS|”). See
`Cabilly l patent col. 6,»|ines 18-20; and Cabilly 2 patent'Fig. 1.
`c The phrase “chimeric immunoglobulin heavy or light» chain” refers to a species of
`immunoglobulin heavy or light-chain in which the constant region is homologous to the
`constant region of an antibody of a firstwmammalian species and the variable regionis
`
`homologous to the -variable region of an antibody derived from a second,’ different
`— mammalian species. See claim 1 and 3 definitiori;‘567 patent col. 6, lines 48-59.
`
`_ The phrase “replicable expressionvector (comprising ‘DNA) operably linked to a _
`. suitable promoter compatible with a «host cell" of Cabilly 1 claims 1 and 5 is discussed in
`
`the ‘567 patent specification An “expression vector" includes:
`
`.
`.._. vectors which are capable of expressing DNA sequences
`contained therein, i.~e., the coding sequences are operably linked to
`other sequences capable of effecting their expression. It is implied,
`although not always explicitly stated, that these expression vectors
`_must be replicable in the host organisms .
`.
`t
`.
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`‘567 patent, col. 8, 11. 21427.
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`1 Genzyme Ex. 1008, pg 197
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`Genzyme Ex. 1008, pg 197
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`I ‘_‘Host cells," as recited in Cabilly 1. claims 1_and 7, include prokaryotic or
`eukaryotic cells, including eukaryotic microbes, and ‘cells derived from multicellular
`
`organisms, such as mammalian cells. See ‘567 patent, col. 8, line 46 to col. 10, 1ines
`13-30, 57
`1
`1
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`The final step of the Cabilly '1 claim1‘process calls for “recovering the chimeric ‘
`heavy or light chain from the host cell culture”_: “[t]he protein thus. produced is then -.
`recovered from the cell culture by methods known in the art, but the choice of which is
`necessarily dependent on the form in which the protein is expressed. “ 1567 patent, col.
`13," lines 33
`
`i The recombinant procedures used to obtain the DNA sequences, prepare
`vectors, ‘transform cells, culture cells, and recover the immunoglobulins are -the same,
`whether for recombinant immunoglobulins that_mimic naturally occurring ones or for
`altered recombinant immunoglobulins, such as chimeric antibodies. See eg, ‘567
`patent, col. 15, lines 59 to col. 16, line 15; and col; 28, lines 44-47.
`
`-
`
`New Reiectionisl
`y
`Claim Rejections - 35 use § 102:
`y
`Claims 1-7, 9-10, 14-18 and 21, 23-36 "are rejected under 35 0.8.0. 102(e) as
`1.
`being anticipated by Moore et al. U.S. l‘-"at. No. .5,840,545 (Nov. 24, 1998: effective
`filing date of March 15, 1982 of date of_ 06/358,414). ~
`
`Moore et al. disclose and claim a hybrid DNA strategy for the preparation of
`specific binding polypeptides comprised of two different polypeptide chains, which
`together assume a conformation, having _high binding affinity to a predetermined ligand
`
`Genzyme Ex. 1008, pg 198,
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`Genzyme Ex. 1008, pg 198
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`H or haptenic site thereof l(see e.g. Moore ‘545, col. 2, lines 39452). One or both of the
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`different polypeptide chains derived from the variable region of the light and heavy
`chains of an immunogiobulin may be usedto provide specific binding analogous to the
`bindingvsite of an immunoglobulin,~with the composition being referred to as an "rFv”
`and with the portions corresponding to L-rFv (variable light region of an antibody) and I
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`l-l-rFv_(variab|e heavy region _of an antibody), thus forming a functioning single chain
`
`antibody (compare to instant patent “Fab proteins” or “univalent antibodies”: Cabilly ‘415 H
`' patent col. 5, lines 17-28).
`
`.
`
`For example the Moore Patent claims: ,
`
`1. A hostcellwhich expresses a recombinant double—chain antibody fragment
`(rFv) comprising two polypeptide. chains having substantially the same amino A
`. acid sequence of at least-a portion of the variable region, without constant region
`amino acids, of a mammalian immunogiobulin, the immunoglobulin having,
`binding specificity toa predetermined ligand, wherein-the polypeptide chains are
`prepared-by expression of a DNA sequence coding for the variable region, said ‘
`’ expression occurring in the absence of expression of a DNA sequencecodjng for
`aénatively associated constant region, and wherein the_two polypeptide chains
`.
`combine to form the rFv which has a high affinityand specificity for the
`predetermined ligand.
`‘
`'-
`.
`‘
`
`and
`
`' 2. A method of synthesizing an rFv fragment comprising:
`
`(1) cloning first and second DNA molecules respectively encoding heavy and
`light chains from a hybridoma producing _an antibody to 'a_ predetermined ligand;-
`
`(2) tailoring the cloned DNA molecules to express fragments comprising 95-125
`amino acids of the heavy and light chain variable regions, without constant
`regions, in a host cell;
`‘
`‘
`‘
`-
`
`~(3) inserting the tailored DNA molecules into an expression vector in proper
`relationshipwith transcriptional and translational regulatory signals in the vector; -
`
`Genzyme Ex. 1008, pg 199
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`Genzyme Ex. 1008, pg 199
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`(4) transforming the" host cell with the" expression vector and growing the host
`cell, whereby the light and heavy variable region polypeptides are expressed and .
`' associate. to form an rFv having substantially the same binding specificity for the"
`predetermined ligand as the antibody from the hybridoma.
`'
`
`Accordingly, the Moore patent discloses and claims a method ofimaking an
`
`“immunologically functional immunoglobulin fragment” (as in instant claims 1, 21 and 33
`_ and dependent claims thereon) ‘comprising independently“expressing in a-host variable
`9 heavyiand light chain domains4(e.g. rFV including heavy chain gamma and light chain
`I kappa as in instant claims 23-25: see col.‘ 1, lines 33-42, col. 3, lines 59-63; col. 17,
`lines 4-8) lacking constant regions, and a “host cell” transformed with a single genetic _
`,-construct (e.g. a vector or plasmid, including pBR322; see e.g. Moore at col. 5, lines 32- 5
`‘ 35: wide. variety of vectors may be employed for amplification or expression; and col._ 7,
`lines 39-50 exemplifying vectors including pBR322) or two separate constructs
`
`I
`
`comprising DNA (e.g. ds cDNA derived from a monoclonal produced, by a hybridoma as ’
`
`in instant claim 14_: see Moore patentclaim 2) encoding variable light and heavy chains
`.~ (e.g. see Moore, patent claim 1; col. 10, lines 1-5; col. 23, |ines.35-45 (pBR322); and col.
`V 24, lines 50-60 (pGM1L and pGM1l-I); col. 11, lines 5-12), thus anticipating instant-_‘
`: claims 1-5, 14-18, 21, 23-25 and 33.
`The Moore patent further teaches, “appropriate host cells” including non-secreting
`gram negative bacteria (e.g. E. Coll: which formintracellular rFV precipitates requiring
`- lyses, denaturant solubilization and refolding as in instant_c|aims 6-7, 10,26-28, 30 and
`32: see'Moore at col. 10; bottom of col. 24-col. 25,. line 27) as well as secreting hosts
`
`_.
`
`(e.g. S. cerevisiae or yeast as in instant claims 6-7, 9, 29: see e.g. Moore col. 5, lines
`
`Genzyme Ex. 1008, pg 200
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`Genzyme Ex. 1008, pg 200
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`47-52) from which functioning rFV is recovered (as in instant claim 31). See also Moore
`
`patent claims; col. 3; col. .10, lines 8-30 and 39-55; col. 11 and examples). Moore
`
`additionally teaches the diagnostic and therapeutic use of their isolate rFV antibodies by
`
`labeling the variable light and/or heavy chains with diagnostic labels (e.g. fluorescers as
`
`a ‘‘label’’) or “hazardous labels” (e.g. radioisotopes and toxins as a “drug") for
`
`therapeutic use in mammalian subjects (as in instant claims 34-36). See Moore
`
`Abstract; col. 3; and columns 25-26. Thus Moore further anticipates instant claims 6-7,
`
`9-10, 26-32 and 34-36.
`
`2.
`
`Claims 1-7, 9-10, 14-21 and 23-36 rejected under 35 U.S.C. 103(a) as being
`
`unpatentable over Moore et al. U.S. Pat. No. 5,840,545 as applied above against
`
`claims 1-7, 9-10, 14-18, 21 and 23-36 alone, or if necessary further in view of Axel
`
`et al. U. S. Pat. No. 4,399,216 (Aug. 1983: filed Feb. 25, 1980) as applied against
`
`instant claims 19-20 (mammalian host cell).
`
`H
`
`A
`
`The Moore patent anticipating teaching discussed supra against instant claims 1-
`
`7, 9-10, 14-18, 21 and 23-36 is herein incorporated in its entirety.
`
`The Moore patent reference differs from instant claims 19-20 by failing to
`
`specifically teach expressing their single chain antibody (comprising variable chain light
`
`and heavy fragments) in a mammalian host cell.
`
`However, it is noted that the Moore patented invention is broadly applicable to
`
`the use of any “host cell”, including secreting eukaryotic (e.g. yeast) and non-secreting
`
`bacterial (e.g. E.co|i) host cells for making single-chain antibodies. Additionally, the
`
`Moore patent specifically teaches utilizing mammalian derived gene sequences from
`
`Genzyme Ex. 1008, pg 201
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`Genzyme Ex. 1008, pg 201
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`Art Unit: 3991
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`~
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`"
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`'
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`V
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`hybridomas for obtaining single chain antibody mammalian mimics-forstherapeutic use
`in mammals. See Moore at col. 3,lines-5.9-col.4,'|ines 30; col. 25-26'.
`Thus, the Moore patent reference would render the selection of amammalian
`host cell from a ‘small number of alternative host cells (e.g. yeastor bacteria) for
`antibody expression prima fascie obvious to one of ordinary. skill in the art at the time of
`the instant invention, especially in view of the Moore teaching toward the making of
`
`mammalian antibody mimics for use in mammalian therapy.
`
`Additionally, in this regard,the Axel reference teaches the advantageous use of
`eukaryotic (e.g. mammalian) host cells, compared to bacterial host ce||s,.for the
`expression of proteinaceous materials, including antibodies. The advantages of using a
`mammalian host cells includehthe ability to -use unaltered genes coding for protein
`precursors which areconverted by the eukaryotic cell to the desired protein (Axel at col.
`36-41), the ability to produce glycosylated eukaryotic pro:teins,(‘Axel at- col; 3, lines 3-7).
`and the absence of bacterial endotoxins (Axel, col. 3, lines 8-12). The Axel patent
`
`further teaches a process for inserting DNA into eukaryotic cells, particularly DNA which
`includes a gene or genes (i.e. DNA 1) coding for desiredproteinaceious materials for
`
`which no selective criteriorexists, by including in the genetic construct DNA encoding a_ t
`
`-
`
`reporter protein (i.e. DNA.||). See Axel Abstract; and patent clairris, especially claims
`1,2,7, 22-24, 26-32, 37, 51-55 and 60,
`.
`
`A Accordingly, the Axel reference provides further motivation to oneof ordinary skill
`
`in the art to utilize mammalian host cells as the “appropriate host cell” in the‘Moore
`
`method of ‘producing single chain antibodies.
`
`Genzyme Ex. 1ooe, pg 202
`
`Genzyme Ex. 1008, pg 202
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`pi
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`A
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`Page 14
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`Art" Unit: 3991
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`A Thus, it would have been pn'ma facie obvious to one of ordinary skill in the art at
`the time of the instant invention to utilize a mammalian host cell (as in instant claims 19-
`20) in the Moore method in light of the Axel reference teaching of the advantageous use
`thereof in methods of making proteins, including antibodies.
`'
`_
`_
`3.
`Claims" 1-7, 9-10, 14-18, and 21-36 rejected under 35 U.S.C. 103(a) asnbeing
`unpatentable over Moore et al. US. Pat. No. 5,640,545 as applied above against
`claims 1-7," 9-10, 1.4-18.and 21,. 23-36 and in view of Accollaet al. PNAS_ USA 77(1)
`
`_ 563-566 (January 1980) as applied against instant claim 22 (anti-CEA antibody).
`
`. The Moore patent anticipating teaching‘ discussed supra against instantclaims 1-
`
`«-
`
`l '7, 9-10, 14-18, 21 and 23-36 is herein incorporated in its entirety.
`
`The Moore patent reference differs from instant claim 22 by failing to specifically
`-teach making a single—chain4antibody to CEA (i.e. carcinoembryonic antigen).
`'
`,
`However, the Moore patented method is broadly useful for making (using
`hybridoma technology) single-chain antibodies “for any |igan'd”—,' with exemplification of_
`ndinitrophenyl (example 1), K.-chain (light chain) of MOPC41 and the heavy chain of
`
`~ myelomaS107 which represents a tumor ligand (see col. 11, lines 30-37; Example 1;
`
`col. 17, lines 1-10 et seq; and patent claims 1-2). Moore additionally teaches the
`
`diagnostic and therapeutic use of their rF\( antibodies by labeling the variable light
`and/or heavy chains with diagnostic labels (e.g. fluorescent ‘flabelt’_) or “hazardous
`labels” (e.g[ radioisotopes and toxins as a“drug”) for-therapeutic use in mammalian
`subjects (as in instant claims 34-36). See Moore Abstract; col. 3 and columns 25-26.
`
`Moore's use of single-chain antibodies lacking an immunogenic immunoglobulin
`
`iGenzyme Ex. 1008, pg‘ 203
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`Genzyme Ex. 1008, pg 203
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`Art Unit: 3991
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`Page 15
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`constant region makes Moore's single-chain antibodies more advantageous for in vivo
`
`- diagnosis or therapeutic use. See Moore at col. 1, lines 64—co|. 2, lines 8.
`
`Carcinoembryonic antigen (CEA) is a glycoprotein antigen present exclusively in
`adenocarcinoma of the.human digestive tract and in digestive fetuses of 2-6 month
`gestation (see Acco/a at page 563, left column). Accol/a et al. describe making (using
`hybridoma_technology) labeled-monoclonal antibodies to ‘CEA for in vitro and in vivo
`diagnostic use (e.g. antigen identification in human tissues and body fluids)L See
`Abstract.
`1
`
`It would have been prima facie obvious to one of ordinary skill in the art at the
`
`.
`
`time of the instant invention to utilize the Moore method to make less immunogenic
`single chain antibodies to CEA for their recognized use in in vivo diagnostics or
`therapeutics against human adenocarcinoma as taughtby Accola.
`
`oBvIousNEss DiC.g);glJBLEgl3A'l'gIEflNTlNG
`V Claims 1-7, 9-11, 13-18, 21 and 23-36 of U.S. Pat. No. 6,331,415 (Cabilly 2)
`4. 1
`are’ rejected on the ground of nonstatutory obviousness-type double patenting as
`
`being unpatentable over claims 1-7 of U.S. Patent No. 4,816,567 lcabilly 1) and
`
`1 Moore et al. U.S. Pat. No.‘5,840,545 (Nov. 24, 1998: effectively filed March 15,
`
`1932;
`
`A The Reference Cabi//K 1 Patent Claims:
`The .Cabi||y'1 patented invention is drawn to:
`
`Claim 1: A method comprising
`
`Genzyme Ex. 1008, pg 204 V
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`Genzyme Ex. 1008, pg 204
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`a) preparing a DNA sequence encoding a chimeric immununoglobulin heavy or light
`chain having specificity for a particular known antigen wherein a constant region is
`homologous to the corresponding constant region of an antibody of a first
`mammalian species and a variable region thereof is homologous to the variable region
`of an antibody derived from a second, different mammalian species;
`
`b) inserting the sequence into a replicable expression vector operably linked to a
`suitable promoter compatible with a host cell;
`
`c) transforming the host cell with the vector of (b);
`
`d)