UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States 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 rNVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`90/007,542
`
`05/13/2005
`
`6331415
`
`22338-10230
`
`7585
`
`02/2512008
`
`47554
`7590
`SIDLEY AUSTIN LLP
`ATTN: DC PATENT DOCKETING
`1501 K STREET, NW
`WASHINGTON, DC 20005
`
`EXAMrNER
`
`ART UNIT
`
`PAPER NUMBER
`
`DATE MAILED: 02/25/2008
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`PT0-90C (Rev. 10/03)
`
`Sanofi/Regeneron Ex. 1 017, pg 498
`
`Merck Ex. 1017, pg 524
`
`

`
`,
`
`Commissioner for Patents
`United States Patent and Trademark Office
`P.O. Box1450
`Alexandria, VA 22313-1450
`WWNJJs:pi'O.QOI/
`
`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.
`
`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.0?-04)
`
`Sanofi/Regeneron Ex. 1017, pg 499
`
`Merck Ex. 1017, pg 525
`
`

`
`Office Action in Ex Parte Reexamination
`
`Control No.
`90/007,542
`
`Examiner
`Bennett Celsa
`
`Patent Under Reexamination
`~331415
`
`Art Unit
`3991
`
`•• The MAILING DATE of this communication appears on the cover sheet with the correspondence address •·
`
`b[gj This action is made FINAL.
`a[gj Responsive to the communication(s) filed on 21 May 2007.
`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.£ 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 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.
`
`[gl Notice of References Cited by Examiner, PT0-892.
`[gl Information Disclosure Statement, PTO/SB/08.
`
`3.
`
`4.
`
`0
`0
`
`Interview Summary, PT0-474.
`
`Part II SUMMARY OF ACTION
`1a. [gl 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.
`[gl Claims 1-36 are rejected.
`
`4.
`
`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 None
`
`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. __
`
`sO been received by the International Bureau in PCT application No. __ .
`
`9. 0
`
`* See the attached detailed Office action for a list of the certified copies not received.
`Since the proceeding appears to be in condition for issuance of an ex parte reexamination certificate e;~<cept 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: Requester (if third party reauester)
`U.S. Patent and Traderrarl< Office
`PTOL-466 (Rev. 0~6)
`
`Office Action in Ex Parte Reexamination
`
`Part of Paper No. 11/19/07
`
`Sanofi/Regeneron Ex. 1017, pg 500
`
`Merck Ex. 1017, pg 526
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 2
`
`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 3rd Partly Requests 90/007,542 and 90/007,859
`
`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:
`
`5/13/05
`7/7/05.
`none
`9/13/05
`1/25/05
`6/6/06
`
`12/23/05
`1/23/06
`none
`N/A
`N/A
`
`Following 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.
`
`Patent owner's November 25, 2005 response (with Declarations) and October
`
`30, 2006 response (with Declarations) to the September 13, 2005 and subsequent
`
`August 16, 2006 office actions, respectively in the 90/007,542 proceeding were filed.
`
`Final rejection of claims 1-36 was mailed February 16, 2007 including raising a
`
`new ground of rejection over the Moore 5,840,545 patent included in the IDS submitted
`
`December 14, 2006 and January 16, 2007 information disclosure statements.
`
`A Patent Owner Response After-Final rejection (dated 5/21/07) that included:
`
`a. 132 Declarations by Michael Botchan, Steven Lanier McNight, Mathhew P. Scott, and
`·
`Sidney Altman;
`· b. An Information Disclosure Statement (IDS);
`c. A Confidential Information Disclosure Statement (Artifact Sheet);
`d. Exhibit B (54 pages) Moore 06/358,414 application with original claims 1-25; and
`e. 181/182 Petition and Renewed Petition to Reopen Prosecution To Withdraw Finality
`or alternatively for the Filing of a Request for Continued Reexamination (RCR) is
`acknowledged.
`
`Sanofi/Regeneron Ex. 1 017, pg 501
`
`Merck Ex. 1017, pg 527
`
`

`
`Application/Control Number: 90/007 ,542; 90/007,859
`Art Unit: 3991
`
`Page 3
`
`The Petition decision of June 1, 2007 resulted in the granting of this RCR. The
`
`finality of the February 16, 2007 Office Action is hereby withdrawn, and the prosecution
`
`is reopened for consideration of the patent owner May 21, 2007 response and
`
`Declaration submissions.
`
`Information Disclosure Statement (IDS)
`
`The 9/6/07 IDS submitted listing references on a PT0-1449 has been considered
`
`as indicated by the enclosed Examiner-initaled copy. It is to be noted, however, that
`
`consideration by the examiner of the information submitted in an IDS means nothing
`
`more than considering the documents in the same manner as other documents in Office
`
`search files are considered by the examiner while conducting a search of the prior art in
`
`a proper field of search. See MPEP 609, at page 600-125, Revision 2, May 2004.
`
`Information Submitted Under MPEP § 724.02 in Petition Under 37 CFR 1.59 (b) and
`1.182 (expunge) and 1.183 (3rd Party service):
`
`The owner has submitted papers on 5/21/07 and 1 0/24/07 deemed confidential
`
`and/or proprietary along with a petition for expungement of this material and director
`
`Waiver of the 37 CFR § 1.550(f) 3rd party service requirement.
`On October 9, 2007, the petition under 37 CFR 1.183 to waive the 3rd party
`
`I
`
`service requirement was granted and the submitted documents provisionally sealed
`
`pending a materiality determination regarding the expungement of these documents.
`Pursuant to MPEP § 724.04 the submitted information is found immaterial to the
`patentability and/or confirmation of the instant reexamination claims.
`
`Priority
`
`The 6,331,425 (Cabilly 2) patent undergoing reexamination issued on December
`
`18, 2001 from application 07/205,419 (filed 6/1 0/88) which was a continuation of
`
`06/483,457 (filed 4/8/83) now the 4,816,567 (Cabilly 1) patent.
`
`Sanofi/Regeneron Ex. 1 017, pg 502
`
`Merck Ex. 1017, pg 528
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 4
`
`Withdrawn Objection (s) and/or Rejection (s):
`
`The following rejections raised in the February 16, 2007 office action are hereby
`withdrawn for the following reasons:
`
`Claims 1-7, 9-10, 14-18 and 21,23-36 are rejected under 35 U.S. C. 102(e) as
`1.
`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 ).
`
`Claims 1-7, 9-10, 14-21 and 23-36 rejected under 35 U.S.C. 103(a) as being
`2.
`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 claims 19-20.
`
`Claims 1-7, 9-10, 14-18 and 21-36 rejected under 35 U.S.C. 103(a) as being
`3.
`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 Accolla et al. PNAS USA 77(1) 563-566
`(January 1980) as applied against instant claim 22 (anti-CEA antibody).
`
`Claims 1-7, 9-11, 13-18,21 and 23-36 of U.S. Pat. No. 6,331,415 (Cabilly 2) are
`4.
`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).
`
`Claims 1-7, 9-1.1, 13-21 and 23-36 rejected on the ground of nonstatutory
`5.
`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 as applied
`above against claims 1-7, 9-11, 13-18, 21 and 23-36 and 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).
`
`Claims 1-7, 9-11, 13-18 and 21-36 rejected on the ground of nonstatutory
`6.
`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 as applied
`above against claims 1-7, 9-11, 13-18, 21 and 23-36 and in view of Accolla et al. PNAS
`USA 77(1) 563-566 (January 1980) applied against instant claim 22.
`
`The above six rejections relying upon the Moore'545 patent claim teaching of single
`host expression of antibody variable chains is withdrawn for reasons discussed infra.
`Additionally, the vector constructs and corresponding host of instant claims 15-17 that
`require "different insertion sites" for the variable antibody heavy and light chains are not
`anticipated by the Moore vector construct that inserts its variable regions at the same
`pstl restriction site (see Moore col. 23, lines 35-45).
`
`Sanofi/Regeneron Ex. 1 017, pg 503
`
`Merck Ex. 1017, pg 529
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 5
`
`Teachings of the Moore 5,840,545 disclosure and patent claims 1-2 with respect
`.
`to the 06/358, 414 application (filed March 15, 1982)
`
`Patent Owner Evidence: includes:
`
`a. Arguments in 5/21/07 owner response pages 7-20:
`
`b. Submitted Declarations of: Drs. Altman, Botchan McKnight and Scott:
`
`c. Copy of Dr. Yarranton Declaration submitted as paper no. 27, dated April 3, 1996
`
`from 08/165,530 application (issued as Moore 5,965,405 patent).
`
`Examiner Holding:
`
`Upon review of the 5,840,545 patented claims and file patent history along with
`
`the patent owner submitted 132 declarations, the Examiner finds that the '545 patented
`
`invention and accompanying disclosure describes and enables expression, using two
`
`vectors, of light and heavy antibody chains comprising variable regions in separate
`
`prokaryotic (E. Coli) or eukaryotic (yeast) host cells for producing an assembled
`
`functional single-chain antibody (Fab or Fv) as of March 15. 1982.
`
`However, the Moore '545 patent claims encompassing single host expression of
`
`variable light and heavy chain for producing single-chain antibody are only entitled to
`
`the June 5. 1995 date since the original 06/358,414 specification and claims 1-25 only
`
`disclose the separate expression of the heavy and light chain antibody fragment in
`
`different host cells as pointed out by the patent owner on pages 13-14 of the 5/21/07
`
`response.
`
`In this regard, the Moore '545 patent claims 1-2 were first presented as new
`
`claims 32, 34 and 35 in the June 5, 1995 preliminary amendment (copy enclosed) in the
`
`Moore 08/461,071 application, which later issued as the Moore '545 patent.
`
`Newly presented Moore application claims 32 (A recombinant double-chain
`
`antibody fragment) and 34 (host) correspond to Moore issued patent claim 1, whereas
`
`claim 35 corresponds to Moore issued claim 2.
`
`Support for the preliminary amendment, and new claims 32, 34 and 35 was
`
`asserted by Moore (through his attorney) to be:
`
`Sanofi/Regeneron Ex. 1017, pg 504
`
`Merck Ex. 1017, pg 530
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page6
`
`a. "generally based on the claim set of ancestor (sic) application, 06/358,414, filed
`March 15, 1982";
`b. "Support for the recital of host cells is provided at, e.g., p. 8, last paragraph of the
`specification"; and
`c. "The process for 'tailoring' a cloned DNA to remove the part encoding the constant
`region is described at, e.g., pp. 10-15 of the application".
`
`However, no support for single host expression of variable light and heavy chains was
`
`found for new claims 32, 34 and 35 in the 06/358,414 application filed March 25, 1982.
`
`Patent Owner Arguments wlr to Moore '545 Patent and Examiner Rebuttal:
`
`1. Patent Owner: Moore fails to disclose eukaryotic yeast host cell expression stating:
`Moreover, the Moore '545 patent contains no description of a non-bacterial host
`cell being used to produce light or heavy chain variable region polypeptides. The
`passage cited by the Office (i.e., col. 5, lines 47-52 of '545 patent) at best
`suggests that a yeast cell could be a host cell that could be used to amplify eDNA
`obtained from a eDNA library. There is no discussion there or anywhere else in
`the description, however, of yeast cells being used for expression of
`polypeptides. The only type of host cells identified as being used for expression
`in the written description of the '545 patent are bacterial host cells. Altman
`Declaration,~ 12; McKnight Declaration,~ 12. As such, the Office is incorrect in
`stating that the Moore '545 written description describes eukaryotic cells, such as
`yeast, which produce and secrete functioning rFv. 5/21/07 response: pp.19-20.
`Examiner Response: The Examiner respectfully disagrees.
`
`The Moore document, taken as a whole, clearly discloses and enables the
`
`concept of using both non-secreting prokaryotes, such as bacteria, as well as secreting
`
`eukaryotes, such as yeast, for expression of antibody chains. Although, Moore defines
`
`an "appropriate host" for expression in the context of the amplification step (at col. 5,
`
`lines 47-52) to include both E. Coli. and yeast it is equally clear that Moore
`
`encompasses yeast as an "appropriate host", by the nature of its ability to express and
`
`secrete antibody chains. This is clearly supported by the Moore patent disclosure at
`
`columns 8-10 which details two expression host strategies, in which one expression
`
`host secretes polypeptide e.g, yeast, while another expression host is a non-secretor
`
`e.g. E. Coli that requires lysing the host in order to recover the expressed antibody
`
`polypeptide for reconstituting rFv. See especially col. 8, lines 1-11; col. 10, lines 22-60.
`
`Sanofi/Regeneron Ex. 1 017, pg 505
`
`Merck Ex. 1017, pg 531
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page?
`
`The Cabil/y Patented Inventions:
`
`i. The Instant 6,331,415 (Cabil/y 2) Patented Invention Undergoing Reexamination
`
`The following patent claim methods and compositions are representative:
`
`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:
`
`(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 transfonried 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.
`
`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 1st and 2"d DNA sequences are located at different insertion sites in the
`vector.
`
`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.
`
`Sanofi/Regeneron Ex. 1 017, pg 506
`
`Merck Ex. 1017, pg 532
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`PageS
`
`32. The insoluble particles of heavy and light chains or Fab region produced by the method of
`clai·m 21 in which the heavy and light chains or Fab regions are deposited within the cells (e.g.
`claim 27).
`
`ii. The Reference US Pat. No. 4,816,567 Cabillv 1 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 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.
`
`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.
`
`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 daims 1, 3 and 5, respectively) recite that the first mammalian species
`o.e. the source of the constant region) is human.
`
`Cabilly 1 ('567 Patent) and Cabilly 2 ('415 Patent) Claim Interpretation
`
`Antibodies are proteins that 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
`
`Sanofi/Regeneron Ex. 1 017, pg 507
`
`Merck Ex. 1017, pg 533
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 9
`
`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, different
`
`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.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 .... '567 patent, col. 8, 11. 21-27.
`
`"Host cells," in Cabilly 1 claims 1 and 7, include prokaryotic or eukaryotic cells,
`
`such as eukaryotic microbes, and cells derived from multicellular organisms, like
`
`mammalian cells. See '567 patent, col. 8, line 46 to col. 10, 1ines 13-30, 57.
`
`The light or heavy chain Cabilly 1 claim 1 recovery step encompasses "
`
`... methods known in the art, but the choice of which is necessarily dependent on the
`
`form in which the pro~ein 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 coi. 28, lines 44-4 7.
`
`Sanofi/Regeneron Ex. 1 017, pg 508
`
`Merck Ex. 1017, pg 534
`
`

`
`Application/Control Number: 90/007 ,542; 90/007,859
`Art Unit: 3991
`
`Page 10
`
`OUTSTANDING DOUBLE PATENTING REJECTION:
`
`Claims 1-36 of U.S. Pat. No. 6,331,415 (Cabilly 2) are rejected on the ground
`7.
`of nonstatutory obviousness-type double patenting as being unpatentable over
`claims 1-7 of u~s. Patent No. 4,816,567 (Cab illy 1) in view of Axel et al. U.S. Pat.
`No. 4,399,216 (8/83), Rice and Baltimore, PNASUSA 79 (12/82):7862-7865, Kaplan
`et al. EP 004722 (1/82), Builder et al. U.S. Pat. No. 4,511,502 (issued 4/85), Accolla
`et al. PNAS USA 77(1 ): 563~566 (1980), Dallas (WO 82/03088), Deacon
`(Biochemical. Society Transactions, 4 (1976):818-820), 1981 Valle (Nature, 291
`(May '81) pages 338-340; Ochi (Nature, 302 (3/24/83) pages 340-342 alone, or
`further in view of Moore et al. U.S. Pat. No. 5,840,545 (Nov. 24, 1998: effectively
`filed March 15, 1982).
`
`The Reference Cabilly 1 Patent Claims:
`
`It is noted that this double patenting rejection utilizes the Moore '545 patent for its
`
`teaching of single chain antibody expression in separate hosts along with the
`
`reconstitution of assembled active antibody.
`
`The Cabilly 1 invention is drawn to:
`
`Claim 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
`mammalian species and a variable region thereof is homologous to the variable region of an antibody
`derived from a second, different mar:nmalian 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 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.
`·
`·
`
`Claim 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. 1 017, pg 509
`
`Merck Ex. 1017, pg 535
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 11
`
`In the reference Cabilly 1 disclosure, "immunoglobulins" are defined as being
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`comprised of light (kappa or lambda) and heavy chains (gamma, mu, alpha, delta or
`
`epsilon), which when assembled, possess "specific immunoreactive activity" and are
`
`labeled "antibodies". See Cabilly 1 at col. 3, lines 15-42; col. 6, lines 14-24.
`
`The reference Cabilly 1 defines the phrase "chimeric immunoglobulin heavy or
`
`light chain" as referring 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, different mammalian species. See Cabilly 1 patent: col.
`
`6, lines 48-59.
`
`The reference Cabil/y I patent includes mammalian chimeric immunoglobulin light
`
`and heavy chains which are derived from humans (dependent claims 2 and 4).
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`Mammalian antibody sources are derived in situ from mammalian B lymphocytes or
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`from cell culture hybridomas. See Cabilly 1 patent col. 1, lines 38-42.
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`The reference Cabil/y 1 claimed "(replicable ) expression vector'' is defined as
`
`vectors capable of expressing DNA sequences contained therein which are frequently in
`
`the form of plasmids, thus 'plasmid' and 'expression vector' are often used
`
`interchangeably. See Cabil/y 1 patent col. 8, lines 21-45.
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`The reference Cabil/y 1 claimed "host cells" include prokaryotic (most preferably
`
`the gram(-) bacteria E. Coli. Strains ATCC: 31446 and 31537) or eukaryotic cells,
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`including eukaryotic microbes, and cells derived from multicellular organisms, such as
`
`mammalian cells. See Cab illy 1 patent , col. 8, 1 ine 46 to col. 10, lines 13-30, 57.
`
`The reference Cabil/y 1 claimed means of successfully "recovering the chimeric
`
`heavy or light chain from the host cell culture" (above claim 1 step e) is determined by
`
`the type of protein and host organism but utilizes art known techniques including cell
`
`lysis of insolubilized particles present in the host (e.g. gram-negative~- Coli) followed
`
`by denaturant solubilization unless the host organism normally secretes the protein out
`
`of the cell (e.g. some yeast and gram positive bacteria). See Cabilly 1 patent col. 4,
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`lines 27-35; col. 12, line 66-col. 13, line 18.
`
`Sanofi/Regeneron Ex. 1 017, pg 51 0
`
`Merck Ex. 1017, pg 536
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 12
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`Both the Cabilly 1 and the instant Cabilly 2 patented inventions include claims
`
`directed to the same statutory subject matter: recombinant processes, vectors and host
`
`cells for making immunoglobulins (particularly chimeric immunoglobulins) and immuno(cid:173)
`
`globulin products. 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 44-4 7.
`
`The reference Cabilly 1 patent specification discloses expressing heavy and light
`
`chains preferably for immunoglobulin assembly, a utility which is supported by the
`
`reference Cabilly 1 claimed antigen specificity of its chains; and thus it is appropriate to
`
`construe the reference Cabilly 1 patent claims to suggest production of chimeric
`
`immunoglobuins (e.g. antibodies) using recombinant technology, and vectors and host
`
`cells for doing so. Geneva Pharmaceuticals, Inc., 349 F.3d at 1385, 68 USPQ 2d at
`
`1875.
`
`The instant Cabilly 2 patented generic invention drawn to producing an
`
`immunoglobulin (or immunologically active fragment) clearly encompasses the chimeric
`
`immunoglobulin species (or immunologically active fragment) as evidenced by instant
`
`patent claim13 encompassing a chimeric immunoglobulin.
`
`The reference Cabilly 1 patented invention differs from the instant patent since it
`
`fails to teach the co-expression of light and heavy antibody chains in a host cell.
`
`i. One of ordinary skill in the art would have been motivated to express, in a
`single host, light and heavy immunoglobulin chains (using one or two vectors)
`when viewing the reference Cabilly 1 patented invention in light of the prior art
`
`Axel teaches a process for inserting foreign DNA into eukaryotic cells by co(cid:173)
`
`transforming the cells with the disclosed foreign DNA and an unlinked DNA that codes
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`for a se.lectable phenotype not otherwise expressed by the cell (see col. 3, lines 21-27).
`
`Axel describes the process as particularly suited for the transformation of DNA into
`
`eukaryotic cells for making antibodies (see col. 3, lines 31-36). Axel discloses and
`
`claims the expression of antibodies in mammalian host cells as intact (assembled)
`
`Sanofi/Regeneron Ex. 1 017, pg 511
`
`Merck Ex. 1017, pg 537
`
`

`
`Application/Control Number: 90/007,542; 90/007,859
`Art Unit: 3991
`
`Page 13
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`proteins. See Axel: abstract; col. 5, lines 3-7 and 24-28; patent claims 1, 7, 22-24, 28
`
`and 29.
`
`Rice introduced a recombinant rearranged murine kappa light chain gene
`
`construct into an Abelson murine leukemia virus (A-Mulv)-transformed lymphoid cell
`
`line which already synthesized y2b heavy chain protein (see page 7862). Rice inserted
`
`the light chain gene into a plasmid, transfected the cells, and then examined the
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`polypeptides as well as the RNA produced by the cells (see pages 7863-7864 and
`
`F