UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United Scates Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.gov
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`05/13/2005
`
`90/007,542..;-
`qo(OO/g-S~
`47554
`7590
`SIDLEY AUSTIN LLP
`ATTN: DC PATENT DOCKETING
`1501 K STREET, NW
`WASHINGTON, DC 20005
`
`02/16/2007
`
`6331415
`
`22338-10230
`
`7585
`
`EXAMINER
`
`ART UNIT
`
`PAPER NUMBER
`
`DATE MAILED: 02/16/2007
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`PT0-90C (Rev. 10/03)
`
`Sanofi/Regeneron Ex. 1 008, pg 185
`
`Merck Ex. 1008, pg 211
`
`

`
`r
`
`ffl.!
`
`~-~-.. ~~ UNITED STATES PATENT AND TRADEMARK 0FF1CE
`.
`\·
`'~ ......... 'J.!i~
`
`Commissioner for Patents
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`vwwwus:pto.gov
`
`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 TRANSMITTAL FORM
`
`REEXAMINATION CONTROL NO. 90/007,542. L "1 o I o v -"11 ~"~
`
`PATENT NO. 6331415.
`
`ART UNIT 3991.
`
`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.07.Q4)
`
`Sanofi/Regeneron Ex. 1 008, pg 186
`
`Merck Ex. 1008, pg 212
`
`

`
`Office Action in Ex Parte Reexamination
`
`· Control No.
`90/007,542
`
`Examiner
`Bennett Celsa
`
`Patent Under Reexamination
`\."iblool,~'r""lJ 6331415
`Art Unit
`3991
`
`•• The MAILING DATE of this communication appears on the cover sheet with the correspondence address ••
`
`b[8J This action is made FINAL.
`a[8J Responsive to the communication(s) filed on 30 October 2006.
`cO 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 2. month(s) from the mailing date of this letter.
`Failure to respond within the period for response will result iri 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 ATTACHMENT(S) ARE PART OF THIS ACTION:
`
`1.
`
`2.
`
`[8J Notice of References Cited by Examiner, PT0-892.
`
`[8J Information Disclosure Statement, PTO/SB/08.
`
`3. 0
`4. 0
`
`Interview Summary, PT0-474.
`
`Part II. SUMMARY OF ACTION
`
`1a.
`
`[8J Claims 1-36 are subject to reexamination.
`
`1 b. 0 Claims __ are not subject to reexamination.
`
`2. 0 Claims __ have been canceled in the present reexamination proceeding.
`
`3. 0 Claims __ are patentable and/or confirmed.
`
`4 .. [8J Claims 1-36 are rejected.·
`
`5. 0 Claims __ are objected to.
`
`6. 0 · The drawings, filed on __ are acceptable.
`
`7. 0 The proposed drawing correction, filed on __ has been (7a)0 approved (7b)0 disapproved.
`
`8. 0 Acknowledgment is made of the priority claim under 35 U.S.C. § 119(a)-(d) or (f).
`
`a)D All b)D Some* c)D No11e
`
`of the certified copies have
`
`10 been received.
`
`20 not been received.
`
`30 been filed in Application No. __ .
`
`40. been filed in reexamination Control No. __
`
`50 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. 0
`
`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. 0 Other: __
`
`cc: R~uester (if third party. requester)
`U.S. Palen! and Tradeorer1< Office
`PTOL-466 (Rev. 08-06)
`
`Office Action in Ex Parte Reexamination
`
`Part of Paper No. 20070123
`
`Sanofi/Regeneron Ex. 1 008, pg 187
`
`Merck Ex. 1008, pg 213
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 2.
`
`Reexamination: Final Office Action
`
`Reexamination of US Patent No. 6,331,415 (Cabilly 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:
`
`Merger of Yd Parlly Requests 90/007,542 and 901007,859
`
`i. 90/007542 ('7542 Proceeding):
`
`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:
`
`12/23/05
`5/13/05
`1/23/06
`7/7/05.
`none
`none
`N/A
`9/13/05
`N/A
`1/25/05
`6/6/06
`
`Following the merger of the 90/007,542 and 90/007,859 proceedings, the First
`
`Office Action dated September 13, 2005 in the '7542 proceeding was withdrawn in light
`
`of the Non-Final Office Action dated August 16, 2006.
`
`Patentee's November 25, 2005 response (with Declarations) and the 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
`
`considered in this office action.
`
`Additionally, the submitted December 14, 2006 and January 16, 2007 informatiOFr
`
`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
`
`Sanofi/Regeneron Ex. 1 008, pg 188
`
`Merck Ex. 1008, pg 214
`
`

`
`,
`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 3
`
`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. 141h IDS necessitated t.he 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. 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
`
`The 6,331,425 (Cabilly 2) patent undergoing reexamination issued on December
`
`18, 2001 from application 07/205,419 (filed 6/10/88) which was a continuation of·
`
`06/483,457 (filed 4/8/83) now 4,816,567 (Cabilly 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 Xenopus·
`.
`
`.
`
`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
`
`Sanofi/Regeneron Ex. 1 008, pg 189
`
`Merck Ex. 1008, pg 215
`
`

`
`,
`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page4
`
`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) 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).
`
`To the extent the above obviousness double patenting rejections were predicated
`on claim interpretation that "or" is equivalent to "and", 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
`
`Sanofi/Regeneron Ex. 1 008, pg 190
`
`Merck Ex. 1008, pg 216
`
`

`
`Application/Control Number: 90/007,542; 901007,859
`Art Unit: 3991
`
`Page 5
`
`interpretation that "or'' has its ordinary meE,~ning ("or'' is "or'') and not "and/or''. Relevant
`
`in this regard was 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) 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).
`
`The obviousness double patenting rejection cited above (predicated on "or" as
`having its ordinary meaning) in·which the Cabilly 1 patent was combined with the Axel,·
`Rice et al., Kaplan et al., Builder et al., Acolla et al., Dallas, Deacon, Valle (1981) and .
`Ochi references is· withdrawn 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 (Cabilly 2) Patented Invention Undergoing Reexamination
`
`The following patent claim methods and compositions are representative:
`
`i. METHODS:
`
`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:
`
`Sanofi/Regeneron Ex. 1 008, pg 191
`
`Merck Ex. 1008, pg 217
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 6
`
`(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 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
`domain of 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;
`
`· · c) transforming a prokaryotic or eukaryotic microbial host cell culture with the vector of
`· step b);
`
`d) culturing the host cell; and
`e) recovering the immunoglobulin from the host cell culture, said immunoglobulin being
`capable of binding to a known antigen .
`
`. ii. COMPOSITIONS:
`
`15. A vector comprisin·g 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 1st and 2nd DNA sequences are located at different
`insertion sites in the vector. ·
`
`18. A transformed host cell comprising at least two vectors iri which one vector
`comprises a variable immunoglobulin heavy chain domain and a second vector
`comprises a variable immunoglobulin light chain domain.
`
`Sanofi/Regeneron Ex. 1 008, pg 192
`
`Merck Ex. 1008, pg 218
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit 3991
`
`Page 7 ·
`
`32. The insoluble particles of heavy and light chains or Fab region produced by the
`method of claim 21 in which the heavy 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 I ('567 Patent) Claims
`
`Independent claims 1, 3, 5, and 7 of the '567 patent read as follows;
`
`1. A method comprising
`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 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.
`
`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
`c~orresponaing constant regiori.-of an~ antib·a·ay afi:dlrsl n,·ain~maHan spe.cies.ar1CI a .-.
`variable region homologous to a variable region of an antibody derived from a
`second, different mammalian species.
`
`5. A replicable expression vector comprising DNA operably linked to a promoter
`compatible with 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, 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.
`
`Sanofi/Regeneron Ex. 1 008, pg 193
`
`Merck Ex. 1008, pg 219
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 8
`
`Cabilly.1 ('567 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 "NSI"). See
`
`Cabilly I patent col. 6, -lines 18-20; and Cabilly 2 patent Fig. 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 first mammalian species and the variable region is
`
`homologous to the variable region of an antibody derived from a second, differ~nt
`
`"
`mammalian species. See claim 1 and 3 definition;'567 patent coL 6, lines 48-59.
`
`The phrase "replicable expression vector (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.~ .• 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 .. : .
`
`'567 patent, col. 8, 11. 21-27.
`
`Sanofi/Regeneron Ex. 1 008, pg 194
`
`Merck Ex. 1008, pg 220
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 9
`
`''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, lin~ 46 to col. 10, 1 ines
`
`13-30, 57
`
`The final step of the Cabilly 1 claim 1 ·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. " '567 patent, col.
`
`13, lines 3-6.
`
`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 e.g., '567
`
`patent, col. 15, lines .59 to col. 16, line 15; and coL 28, lines 44-47.
`
`New Rejection(s)
`
`Claim Rejections- 35 USC § 102
`
`1.
`
`Claims 1~7, 9-10, 14-18 and 21,23-36 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 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
`
`Sanofi/Regeneron Ex. 1 008, pg 195
`
`Merck Ex. 1008, pg 221
`
`

`
`Application/Contra~ Number: 90/007,542; 90/007,859 ·
`· Art Unit: 3991
`
`Page 10
`
`or haptenic site thereof (see e.g. Moore '545, col. 2, lines 39.:.52). One or botti of 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
`
`binding site 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
`
`H-rFv.(variable heavy region of an antibody), thus forming a functioning single chain
`
`antibody (compare to instant patent "Fab proteins" or "univalent antibodies": Cabilly '415
`
`· patent col. 5, lines 17 -28).
`
`For example the Moore Patent claims: .
`
`1. A host cell which 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 to a predetermined ligand, wherein the polypeptide chains are
`prepared by expression of a DNA sequence c6ding for the variable region; said
`expression occurring in the absence of expression of a DNA sequence codjng for
`a"natively associated constant region, and wherein the two polypeptide chains
`combine to form the rFv which has a high affinity and 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
`relationship with transcriptional and translational regulatory signals in the vector; ·
`
`Sanofi/Regeneron Ex. 1 008, pg 196
`
`Merck Ex. 1008, pg 222
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 11
`
`(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 of making an
`
`"immunologically functional immunoglobulin fragment" (as in instant claims 1, 21 and 33
`
`. and dependent claims thereon) comprising independently expressing in a host variable
`
`heavy and light chain domains (e.g. rFV including heavy chain gamma and light chain
`
`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-
`
`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 eDNA 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, lines 35-45 (pBR322); and col. .
`
`24, lines 50-60 (pGM1 Land pGM1 H); 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. Coli: which form-intracellular 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 e.g. Moore coL 5, lines
`
`Sanofi/Regeneron Ex. 1 008, pg 197
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`Merck Ex. 1008, pg 223
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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. coli) host cells for making single-chain antibodies. Additionally, the
`
`Moore patent specifically teaches utilizing mammalian derived gene sequences from
`
`Sanofi/Regeneron Ex. 1 008, pg 198
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`Merck Ex. 1008, pg 224
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`hybridomas for obtaining single chain antibody mammalian mimics for therapeutic use
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`in mammals. See Moore at col. 3, lines 59-col.4, lines 30; col. 25-26.
`
`Thus; the Moore patent reference would render the selection of a·mammalian
`
`host cell from a small number of alternative host cells (e.g. yeast or 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 cells, for the
`
`expression of proteinaceous materials, including antibodies. The advantages of using a
`
`mammalian host cells include the 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 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 desired proteinaceious materials for
`
`which no selective criterior exists by including in the genetic construct DNA encoding a
`
`reporter protein (i.e. DNA II). See Axel Abstract; and patent claims, especially claims
`
`1,2,7, 22-24,26-32,37,51-55 and 60.
`
`i
`Accordingly, the Axel reference provides further motivation to one of ordinary skill
`
`in the art to utilize mammalian host cells as the "appropriate host cell" in the Moore
`
`method of producing single chain antibodies.
`
`Sanofi/Regeneron Ex. 1 008, pg 199
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`Merck Ex. 1008, pg 225
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`

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`. r
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`Thus, it would have been prima 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) 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 and 21, 23-36 and in view of Accol/a eta/. 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 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 claim 22 by failing to specifically
`.
`.
`teach making a single-chain antibody to CEA (i.e. carcinoembryonic antigen).
`
`.
`
`However, the Moore patented method is broadly useful for making (using
`
`hybridoma technology) single-chain antibodies "for any ligand", with exemplification of
`
`dinitrophenyl (example 1 ), K-chain (light chain) of MOPC41 and the heavy chain of
`
`myeloma S1 07 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 rFV antibodies by labeling the variable light
`
`and/or heavy chains with diagnostic labels (e.g. fluoreseent "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.
`
`Moore's use of single-chain antibodies lacking an immunogenic immunoglobulin
`
`Sanofi/Regeneron Ex. 1 008, pg 200
`
`Merck Ex. 1008, pg 226
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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-col. 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 Accola at page 563, left column). Accola 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): See
`
`Abstract.
`
`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 DOUBLE PATENTING
`
`4.
`
`Claims 1-7, 9-:-11, 13-18, 21 and 23-36 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) and
`
`Moore et al. U.S. Pat. No. 5,840,545 (Nov. 24, 1998: effectively filed March 15,
`
`1982).
`
`The Reference Cabilly 1 Patent Claims:
`
`The Cabilly 1 patented invention is drawn to:
`
`Claim 1: A method comprising
`
`Sanofi/Regeneron Ex. 1 008, pg 201
`
`Merck Ex. 1008, pg 227
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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 th