`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Officc
`Address: COMMISSIONER FOR PATENTS
`P.O. Box I450
`Alexandria, Virginia 223 I 3-I450
`www.usplo.gov
`
`APPLICATION NO.
`90/007,542 if
`‘Moo? 35‘!
`7590
`
`475 S4
`
`05/13/2005
`
`FIRST NAMED INVENTOR
`633 I415
`
`ATTORNEY DOCKET N04
`22338-10230
`
`CONFIRMATION N0.
`7585
`'
`
`02/16/2007
`
`-
`
`_
`
`‘
`
`EXAMINER
`
`‘
`‘
`SIDLEY AUSTIN LLP
`ATTN: DC PATENT DOCKETING
`1501 K STREET, NW
`WASHINGTON, DC 20005
`
`I
`
`DATE MAILED: 02/16/2007
`
`Please fincl below and/or attached an Office communication concerning this application or proceeding.
`
`PTO—90C (Rev. 10/03)
`
`Genzyme Ex. 1019, pg 500
`
`
`
`0v,‘ UNITED STATES PATENT AND TRADEMARK OFFICE
`5
`
`Commissioner for Patents
`United States Patent and Trademark 0ITce
`P.0. Box145oI
`Alexandria. VA 223111450
`ww:w:PfO.I:w
`
`DO NOT USE IN PALM PRINTER
`
`(THIRD PARTY REQUESTER'S CORRESPONDENCE ADDRESS)
`
`.
`
`LISAV. MUELLER
`WOOD PHILLIPS KAT2 CLARK & MORTIMER
`
`I 3800 WEST MADISON STREET, SUITE 3800
`CHICAGO, IL 60661
`
`EX PARTE ‘REEXAMINATION COMMUNICATION TRAN_SMITTAL FORM
`
`REEXAMINATION CONTROL NO. 90/007 542. L at 0 I 0 a ’z, swab
`
`‘PATENT NO. 6331415.
`
`ART UNIT 3991.
`
`Enclosed is a copy of the latest communication from the.United States Patent and Trademark
`Ofiice 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.07-04)
`
`Genzyme Ex. 1019, pg 501
`
`
`
`—
`Office Action In Ex Parte Reexamination
`_
`
`‘Control No.
`A 90/007,542 We I no-tmrra)
`Examiner
`Bennett Celsa
`
`-
`
`_
`
`Patent Under Reexamination
`6331415
`A“ Unit
`3991
`
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address -
`
`DE 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 _will 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 CFR1.550(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 ATTACHMENT(S) ARE PART OF THIS ACTION:
`
`1-. X Notice of References Cited by Examiner. PTO-892.
`
`3. E]
`
`Interview Summary, PTO-474.
`
`2. E information Disclosure Statement, PTO/SB/O8.
`
`'
`
`‘
`
`4. D
`
`.
`
`Part II.
`
`SUMMARY OF ACTION 1
`
`1a.
`
`Claims 1-36 are subject to reexamination.
`
`.
`
`b 2 3
`
`4..
`
`'
`
`1
`
`5 6 7 8
`
`Claims
`
`Claims
`
`are not subject to reexamination.
`
`have been canceled in the present reexamination proceeding.
`
`Claims __ are patentable and/or confirmed.
`
`Claims L36 are rejected.-
`
`Claims T are objected to.
`
`' The drawings, filed on y are acceptable.
`
`[:1 ‘The proposed drawing correction, filed on __ has been (7a)Ij approved (7b)I:I "disapproved.
`.
`. E] Acknowledgment is made of the priority claim under 35 U.S.C. § 119(a)-(d) or (f).
`a)D All b)l] Some* c)D None
`of the certified copies have
`ilj been received.
`2D not been received.
`
`3[:] been filed in Application No. __
`
`4D. been filed in reexamination Control No. _
`
`5|: 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. [I 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.
`»
`
`'
`
`10. D Other:
`
`I
`
`u.s. Patent and Traderrerk Office I
`PTOL-466 (Rev. 08-06)
`
`Office Action in Ex Parte Reexamination
`
`.
`
`»
`Part of Paper No. 20070123
`
`Genzyme Ex. 1019, pg 502
`
`
`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Reexamination: Final Office Action
`
`Reexamination of US Patent, No.-6,331,415 (Cabilly *2 patent).
`Status of the Claims 1
`
`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:
`-.
`
`Merger of 3"’ Part/yvRequests 90/007, 542 and 90/00 7, 859
`
`ii. 90/007859. (‘7859 Proceeding):
`i. 90/007542 (7542 Proceeding):
`12/23/05
`Reexamination request filed:
`5/13/05
`1/23/06
`Reexamination ordered:
`7/7/05.
`2 none
`Patent Owner.Statement:-
`none
`N/A
`First Office Action mailed:
`9/13/05
`, N/A
`Patent Owner Response dated
`1/25/05 '
`‘7542 AND_ ‘7859 merged:
`'
`6/6/06
`
`'
`
`-
`
`Following the merger of the 90/007,542 and 90/007,859 proceedings, the irst
`
`Office Action dated Se‘ptemberI13‘, 2005 ‘in the ‘7542 proceeding was withdrawn in light
`of the l\l_on-l-7ina| Office_Action dated August 16, 2006.
`Patentee’s hlovember 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
`
`I
`
`I
`
`considered in this office action,
`
`Additionally, the submitted December 14, 2006 and January 16, 2007 informatiorr
`
`disclosure statement have been considered in this office action.
`
`Information‘ Disclosure Statement (IDS)
`
`Examiner-initialed copies of the December 14, 2006 IDS (four pages) and the ‘I
`
`Genzyme Ex. 1019, pg 503
`
`
`
`Applicationlcontrol Number: 90/007,542; 90/007,859
`
`_
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`V
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`..
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`Page 3
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`Art Unit: 3991
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`'
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`January 16, 2007 IDS (thirty pages) submitted under Rule 1.97(c), (requiring 1.17(p)
`
`-fees), accompany this office action. The newly submitted Moore 5,840,545 Patent
`
`reference presented in the Dec. 14"‘ IDS necessitated the making of 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. O8/422,187) but is now being
`
`viewed in a new light since the claims addressed in 08/422,‘l87 were drawn to different
`
`subject matter (e.g. process for producing altered antibody heavy or light chain or
`
`-fragments thereof).
`
`Priority
`
`The_6,331,425 (Cabi|ly 2) patent undergoing reexamination issued on December
`518, 2'001‘from application 07_/205,419 (filed 6/10/88) which was a continuation of '
`06/483,457 (filed 41/87/83”) now'4,818,567_ (Cabil|y 1) patent.
`
`' Cumulative Prior Art :
`
`The 1982 Valle and Deacon references are,cumulative in their teaching of
`microinjection of mRNA encoding" light and heavy‘ immunoglobulin chains into Xuenopus
`oocyte cells to produce secreted active antibody. Accordingly, only the Deacon .
`
`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. 1019, pg 504
`
`
`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 4
`
`gene. Accordingly, only the Ochi reference was utilized in the obviousness double
`
`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) andlor Rejection (s):
`
`The following obviousness double gatenting 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).
`—
`
`To the extent the above obviousness double patenting rejections were predicated
`on claim interpretation that “or” is equivalent to
`patentee's arguments and
`evidence regarding claim interpretation of “or” (as meaning “of’) 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
`
`Genzyme Ex. 1019, pg 505
`
`
`
`Application/Control Number: 90/007,542; 90/007,859
`Art_ Unit: 3991
`'
`1
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`=
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`Page 5
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`_
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`‘
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`I
`
`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
`
`.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 "or; as being interpreted
`
`to include "and”, have been overcome.
`
`-
`
`_
`
`3. Claims 1-36 of U.S. Pat. No._6,331,415 (Cabilly 2) arelrejected 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 Cabil|y1
`patent prosecution history) and further inview 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 (W0 82I03088), 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 (predicated "on "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., Acolla et al., Da//as, Deacon, Valle _(1981) and .
`Ochi references isrwithdrawn in light of a. newly ‘presented modified rejection which
`further includes the newly submitted Moore et al. U. ‘S. Pat. No. 5, 840, 545.-
`
`The Instant 6,331,415 (CabiIIy_2) Patented Invention Undergoing Reexamination
`
`The following patent claim methods and compositions are representative:
`g. ME7HODS:«
`
`A 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:
`
`Genzyme Ex. 1019, pg 506
`
`
`
`Applicationlcontrol Number: 90/007,542; 90/007,859
`Art Unit: 3991
`»
`
`'
`
`4
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`0
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`Page 6
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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
`
`.
`
`(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_‘l.
`
`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.
`
`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;
`’
`4
`'
`
`.
`
`V c) transforming a prokaryotic or eukaryotic microbial host cell culture with the vector of
`- step b);
`
`V
`A
`.
`A d) culturing the host cell; and
`e e) recovering the immunoglobulin from the host cell culture, said immunoglobulin being
`capable of binding to a known antigen.
`»
`
`ii. 'coM_Po'smoNs:
`
`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
`'
`-
`
`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.
`'
`
`Genzyme Ex. 1019, pg 507
`
`
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`’ Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
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`.
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`Page 7 '
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`32. The insoluble particles ofheavy and light chains or Fab region produced by’ the
`method of claim 21 in which thegheavy and light chains or Fab regions are deposited
`.within the cells (e.g. claim 27).
`'
`
`.
`
`The Reference US Pat. No. 4,816,567 Cabilly 1 Patent Claims:
`
`’ a. The Cabilly l ('567 Patent) Claims
`{
`.
`.
`Independent claims 1, 3, 5, and 7 of the ‘567 patentreadb as follows;'
`1. A method comprising i
`_
`,
`g
`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_rnpatib|e with a host cell;
`-
`c) transforming the host cell with the vector of (b);.
`‘d) culturing the host cell; and
`V
`e)_ recovering the chimeric heavy or light chain from the host cell culture.
`
`,
`
`'
`
`A
`
`3. A composition comprising a chimeric immunoglobulin heavy orlight chain having.
`specificity for a particular known_antigen having a constant region homglogggus tg gar‘
`icrorréspafidmg constant régi6rT6f ah’a"fitib6Ey36fiéi;first m*a‘rmnéiiaa species andia
`. variable region homologous to a variable region of an antibody derived from a -
`second, different mammalian species.
`
`_ 5. IA 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 homologous to 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, V4 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.
`
`Genzyme Ex. 1019, pg 508
`
`
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`' Application/Control Number: 90/007,542; 90/007,859
`
`Art Unit: 3991
`
`Cabilly.1 ('56? Patent) and Cabilly 2 (‘.415 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),‘with or without
`
`covalent linkage. ‘567 patent col. 6, lines 14-18.
`
`Similarly, an “immunoglobulin” 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 “NSl”). See
`Cabilly l patent col. 6,»|ines 18-20; and Cabilly 2 patentFlg. 1.
`1 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 firstumammalian species and the variable regionis
`homologous to the “variable region of an antibody iderivedgfrom a second,’ different
`I
`mammalian species. See claim 1 and 3 definitiori;‘567 patent col. 6, lines 48-59.
`
`_ The phrase “replicable expressionvector (comprisingDNA) 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
`.
`
`567 patent, col. 8, 11. 21-27.
`
`Genzyme Ex. 1019, pg 509
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`
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`Application‘/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
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`A
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`'-
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`Page9
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`I ‘fHost 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
`4
`V
`
`The final step of the Cabi||y"l claimlprocess calls for “recovering the chimeric I
`
`heavy or light chain from the host cell culture”; “[t]he protein thusproduced is then -4
`recovered from the cell culture by methods known in the art, but the choice ofwhich is
`necessarily dependent on the form in which the protein is expressed. “ i567 patent, col.
`13, lines 3-6.
`
`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 thatmimic naturally occurring ones or for
`
`-
`
`altered recombinant immunog’lobu|ins,such as chimeric antibodies. See eg, ‘567
`patent, col. 15, lines .59 to col. 16, line 15; and col; 28, lines 44-47.
`
`New Reiection(s)
`
`Claim Rejections - 35 usc § 102
`
`1.
`Claims 1-7, 9-1 0, 14-13 and 21, 23-35 are rejected under 35 u.s.c. 102(e) as
`being anticipated by Moore et al. U.S. Pat. No. '5,840,545 (Nov. 24, 1998: effective
`filing date of March 15, 1982 of date of_ O6/358,414). t
`
`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. 1019, pg 510
`
`
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`‘Application/Control-Number: 90/007,542; 90/007,859 ‘
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`' Art Unit: 3991
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`’
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`4
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`Page 10
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`~
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`I or haptenic site thereof (see e.g. Moore ‘545, col. 2, lines 39452). One or bothof the
`
`different polypeptide chains derived from the variable region of the light and heavy
`chains of an immunoglobulin may be used to provide specific binding analogous to the
`bindingsite of an immunoglobulin, with the composition being referred to as an "rF\/‘
`and with the portions corresponding to L-rFv (variable light region of an antibody) and I
`
`l-l—rFv_(variab|e heavy region of an antibody), thus forming a functioning single chain
`
`antibody (compare to instant patent “Fab proteins” or “u_niva|ent antibodies”: Cabilly '415‘
`. ‘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 .
`. acid sequence of at least-a portion of the variable region, without constant region
`amino acids, of a mammalian immunoglobulin, the immunoglobulin having,
`binding specificity toa predetermined ligand, wherein -the polypeptide chains are
`preparedby expression of a DNA sequence coding for the variable region, said ‘
`’ expression occurring in the absence of expression of a DNA sequencefcodjng for
`aénatively associated constant region, and wherein thetwo polypeptide chains
`_combine to form the rFv which has a high affinity_and specificity for the
`predetermined ligand.
`9
`'-
`V
`‘
`
`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. 1019, pg 511
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`
`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
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`'
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`._
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`Page 11
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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 independentlyexpressing in a-host variable
`iheavyand light chain domains(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- 1
`
`‘ 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
`
`comprising DNA (e.g. ds cDNA derived from ‘a monoclonal produced, by a hybridoma as '
`
`V
`
`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.
`_24, lines 50-60 (pGM1L and pGM1 H); col. 11, lines 5-12), ‘thus anticipating instant-
`: claims 1-5, 14-18, 21, 23-25 andv33.
`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_claims 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 eg Moore col. 5, lines
`
`Genzyme Ex. 1019, pg 512
`
`
`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
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`Page 12
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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).
`
`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. 1019, pg 513
`
`
`
`Application/Control Number: 90/007,542; 9&0/0(vJ7',859
`Art Unit: 3991
`_
`_
`'
`'
`
`V’
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`'
`
`A
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`'Page13
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`hybridomas for obtaining single chain antibody mammalian mimics foritherapeutic 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 aimammalian
`host cell from a small number of altemative host cells (e.g. yeastor bacteria) for
`antibody expression prima fascie obvious to one of ordinaryskill 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 cells,.for the
`expression of proteinaceous materials, including antibodies. The advantages of using a
`mammalian host cells includethe ability to -use unaltered genes coding for protein
`precursors which are converted by the eukaryotic cell to the desired. protein (Axel at col.
`36-41), the ability to produce glycosylated eukaryotic proteins(Axel at- col. 3,. lines 3-7).
`and the absence of bacterial eneotoxihs -(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,
`
`h
`
`-
`
`reporter protein (i.e. DNA.ll). See Axel Abstract; and patent claims, especially claims
`1,2,7, 22-24, 26-32, 37, 51 -55 and 60.
`.
`
`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. 1019, pg 514
`
`
`
`Application/Control ‘Number:-90/007,542; 90/007,859 ‘
`Art" Unit: 3991
`
`‘
`
`_
`
`.
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`.
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`Page 14
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`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) asbeing
`
`unpatentable over Moore etaal. U.S. Pat. No. 5,840,545 as applied above against
`
`claims 1-7,’ 9-10, 1.4-18.and 21,- 23-36 and in view of Accollaeet 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 instanteclaims 1-
`
`«-
`
`7, 9-10, 14-1 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-chainantibody to CEA (i.e. carcinoembryonic antigen).
`l-lowever, the Moore patented method is broadly useful for making (using
`hybridoma technology) single-chain antibodies "for any ligand”-,' with exemplification of
`ldinitrophenyl (example 1), K-chain (light chain) of MOPC41 and the heavy chain of .
`
`~ mye|oma'S107 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 “|abel’.’) 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
`
`Genzyme Ex. 1019, pg 515
`
`
`
`Application/Control ‘Numbers 90/007,542; 90/007,859 0
`Art Unit: 3991
`_
`‘
`
`.
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`‘
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`A
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`Page 15
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`constant region makes Moore’s single-chain antibodies more advantageous for in vivo
`
`a diagnosis or therapeutic use. See Moore at col. 1, lines 64-col. 2, lines 8.
`
`Carcinoembryonic antigen (CEA) is a glycoprotein antigen present exclusively in
`adenocarcinoma of thehuman digestive tract and in digestive fetuses of 2-6 month
`
`gestation (see Accola at page 563, left column). Accola et al. describe making (using
`hybridomatechnology) labeled-monoclonal antibodies to ‘CEA for in vitro and in vivo
`
`diagnostic use (e.g. antigen identification in human tissues and body fluids)". See
`Abstract.
`2
`4
`
`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.
`
`_
`bBVlQUSNE$S D7O%UBLEg i’ATENTlNG A
`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 (Cabilly 1) and
`
`V Moore et al. U.S. Pat. No.‘5,340,545 (Nov. 24, 1998: effectively filed March 15,
`
`1982).
`
`The Reference Cabilly 1 Patent Claims:
`
`The 'Cabi|lyv1 patented invention is drawn to:
`
`Claim 12- A method comprising
`
`Genzyme Ex. 1019, pg 516
`
`
`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 16
`
`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) culturing the host cell; and
`
`e) recovering the chimeric heavy or light chain from the host cell culture.
`
`Claim 3: A composition comprising a chimeric immunoglobulin heavy or light chain
`having specificity for a particular known antigen having a constant region homologous to
`a corresponding constant region of an antibody of a first mammalian species and a
`variable region homologous to a variable region of an antibody derived from a
`second. different mammalian species.
`
`Claim 5: A replicable expression vector co