CONTROL NOS. 90/007,542 AND 90/007,859
`Control No. 90/007,542
`
`DOCKET NOS. 22338-10230 AND -10231
`Attorney Docket No. 22338-10230
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Group Art Unit:
`
`3991
`
`Examiner:
`
`Bennett M. Celsa
`
`Confirmation No.1
`
`7585
`
`) ) ) ) ) ) ) ) ) 3
`
`)
`
`Reexamination of Patent No. 6,331,415
`
`Shmuel CABILLY et al.
`
`Control No. 90/007,542
`
`Filed: May 13, 2005
`
`For: METHODS OF PRODUCING
`
`IMMUNOGLOBULINS, VECTORS
`AND TRANSFORMED HOST CELLS
`
`FOR USE THEREIN
`
`DECLARATION OF DR. DOUGLAS A. RICE UNDER 37 C.F.R. § 1.132
`
`1, Douglas A. Rice, declare as follows:
`
`1.
`
`2.
`
`3.
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`4.
`
`I am a citizen and resident of the United States of America. A copy of my curriculum
`vitae is attached as Exhibit A to this declaration.
`
`I am the same Douglas Rice listed as the first author on the paper entitled “Regulated
`expression of an immunoglobulin K gene introduced into a mouse lymphoid cell line,”
`published at Proc. Nat ’l Acad. Sci. USA 79: 7962-65 (1982).
`‘
`
`I have reviewed the Office Action mailed September 13, 2005, in the reexamination of
`U.S. Patent No. 6,331,415, and the references cited in that communication.
`
`I have been retained by the owners of the ’4l5 patent, City of Hope and Genentech, Inc.,
`to comment on the Examiner’s characterization of my 1982 PNAS paper and its relevance
`to the claims of the ’415 patent.
`
`5.
`
`At page 6 of the Office action, the Examiner states:
`
`Rice et al successfully introduced a recombinant rearranged murine kappa
`light chain gene construct into an Abelson murine leukemia virus (A-
`MuLV)- transformed lymphoid cell line, which is a cell line that already
`synthesized y2b heavy chain protein (see page 7862). Rice inserted the
`light chain gene into a plasmid, used this plasmid to transfect the cells, and
`then examined the polypeptides as well as the RNA produced by the cells
`(see pages 7863-7864, and Figures 2 and 3). Lastly, since the cells were
`producing both immunoglobulin chains, the cells were examined for the
`ability to assemble the chains into IgG molecules, leading to the
`
`
`
`Mylan v. Genentech
`Mylan v. Genentech
`IPR2016-00710
`IPR2016-00710 PAGE B339
`Genentech Exhibit 2080
`
`Genentech Exhibit 2080
`
`EVIDENCE APPENDIX
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`

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`CONTROL NOS. 90/007,542 AND 90/007,859
`Control No. 90/007,542
`
`DOCKET NOS. 22338-10230 AND -10231
`Attorney Docket No. 22338-10230
`
`observation that “[e]ssentially all of the K chain produced in the K-2 cells
`appears to be assembled into lgG2b.” (see page 7864). Thus, at the time
`of filing the application for the ’567 [sic] and ’415 patent it was known in
`the art that host cells could express “heavy or light chains,” and that
`expression of both chains was routine, resulting in assembly into
`immunoglobulins.
`
`6.
`
`7.
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`8.
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`9.
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`For the following reasons, I do not agree with the Examiner’s conclusions concerning my
`paper.
`
`The focus of my research in David Baltimore’s laboratory was immunoglobulin (lg) gene
`regulation in lymphoid cells. Our objective was to develop an experimental platform for
`understanding the molecular mechanisms associated with the regulation of Ig gene
`expression. We were not attempting to develop a system for recombinantly producing
`immungolobulins.
`
`In our 1982 PNAS paper, we reported that a rearranged kappa (K) light chain gene could
`be introduced into a lymphoid cell line and expressed. As we stated in the paper (page
`7864), “[t]his opens the possibility of examining control and rearrangement mechanisms
`[for lg genes] in lymphoid cells by using inserted genetic elements.”
`
`We chose the 81A-2 cell line for use in our experiments because it exhibited a relatively
`mature B cell phenotype and expressed a heavy chain gene but not a light chain gene. As
`we explained in the introduction to our paper:
`‘
`
`B cell differentiation proceeds from the “pre-B” lymphocyte, which
`synthesizes u immunoglobulin (Ig) heavy chains but no light chains, to the
`mature B lymphocyte, which synthesizes both heavy and light chains and
`expresses surface 1g, and finally to the lg-secreting plasma cell. The
`availability of transformed cell analogs has allowed biochemical
`characterization of these stages of cellular differentiation.
`
`10.
`
`The degree of maturation of the B cells in the 81A-2 cell line was an important factor in
`our decision to use this cell line. The 81A-2 line is a subclone of the 18-8 cell line.
`
`Because the parental 18-8 cell line is capable of expressing its endogenous K light chain
`gene, we hoped that the 81A-2 subclone would be poised to express an exogenous
`functionally rearranged light chain gene. We thus designed our experiments to
`investigate whether a virus-transformed cellular analog of a lymphoid cell at the proper
`stage of development, exemplified in our work by the 81A-2 subclone, would be a good
`model system for studying the regulation of light chain gene expression.
`
`11.
`
`The transformant we describe in the paper was not designed to produce a functional
`immunoglobulin that would bind antigen. The K chain transformant described in the
`paper is only capable of producing the gamma-2b (y2b) heavy chain protein encoded by
`81A-2 genomic DNA and the exogenous K light chain protein encoded by the murine
`MOPC41 K light chain gene that we introduced into the cell. Because the antigen binding
`specificities of the heavy chain and light chain polypeptides were different, there was no
`
`EVIDENCE APPENDIX
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`PAGE B390
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`

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`CONTROL NOS. 90/007,542 AND 90/007,859
`Control No. 90/007,542
`
`DOCKET NOS. 22338-10230 AND -10231
`Attorney Docket No. 22338-10230
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`12.
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`13.
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`14.
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`15.
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`16.
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`17.
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`expectation and it is unlikely that expression products of this cell line would exhibit
`selective antigen binding activity.
`
`My paper did not discuss expression of exogenous Ig heavy chain genes in lymphoid
`cells. In our experiments, we did not attempt to insert an exogenous heavy chain gene
`along with the exogenous light chain gene we inserted into the 81A-2 subclone. In fact,
`the 81A-2 host cell would have been an inappropriate host cell for this purpose because it
`already expressed an endogenous heavy chain.
`
`It never occurred to us, as part of our work leading to the results published in the PNAS
`paper, to attempt to express exogenous heavy and light chain genes in the 81A-2 cell line.
`
`The Examiner is incorrect, and I disagree with the suggestion, that by early April 1983,
`my PNAS paper had made routine or predictable the task of expressing exogenous
`immunoglobulin light and heavy chain genes in the same cell. In later experiments, I
`attempted to use the techniques described in the PNAS paper to introduce and express
`single Ig genes into other lymphoid cell lines. Most of these experiments failed to
`produce stable transfectants. Thus, my experience was that using the same transfection
`and selection conditions described in the PNAS paper with other cell lines or other Ig
`genes did not routinely yield stable transformants containing even a single exogenous Ig
`gene.
`
`I also was not aware of any published reports by early April 1983 describing the
`introduction and expression of both immunoglobulin heavy and light chain genes into a
`single host cell. As of that date, I also was not aware of any groups attempting to
`introduce and express both immunoglobulin heavy and light chain genes into a single
`host cell.
`
`Finally, my paper did not establish that the exogenous Ig light chain and the endogenous
`heavy chain polypeptides were properly assembled in the 81A-2 transformant into an Ig
`tetramer with antigen-binding activity. While the paper reports the presence of a higher
`molecular weight product that is approximately the size of an H2L2 tetramer, as shown in
`Figure 4 of the paper, we did not in any way prove these were antigen-binding HZL2
`tetramers. On the contrary, we had no way to predict what the antigen-binding properties
`of such a product would be because, as discussed above, the antigen-binding specificities
`of the component heavy and light chain polypeptides were different.
`
`In view of these observations, 1 do not agree with the Examiner’s suggestion that my
`paper explains how to produce a lymphoid cell line that expresses exogenous heavy chain
`and light chain immunoglobulin genes.
`I did not demonstrate in my paper that one could
`transfect a host cell with both heavy and light chain genes. My paper also does not
`establish that the transfected cell line forms properly assembled immunoglobulin
`tetramers out of the endogenous heavy chain and exogenous light chain. My paper does
`not explain how one might make transfected host cells that produce immunoglobulins
`formed from the products of independently expressed exogenous heavy and light chain
`genes. In view of the inherent limitations of the experimental system described in my
`paper and the uncertainties we describe in our conclusions, I simply do not agree with the
`
`EVIDENCE APPENDIX
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`- 3 -
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`PAGE B391
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`

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`CONTROL NOS. 90/007 542 AND 90/007,859
`Control No. 90/007,542
`
`DOCKET NOS. 22338-10230 AND 40231
`Attorney Docket No. 22333-10230
`
`Examiner that my paper made it routine to transfect lymphoid cell lines with exogenous
`immunoglobulin heavy and light chain genes.
`
`I declare that all statements made herein of my own knowledge are true and that all statements
`made on information and belief are believed to be true, and further that these statements were
`made with the knowledge that Willfill false statements and the like so made are punishable by
`fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code, and that
`such willful false statements may jeopardize the validity of the patent subject to this
`reexamination proceeding.
`
`
`
`EVIDENCE APPENDIX
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`- 4 —
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`PAGE 3392