Control No. 90/007,542
`
`Attorney Docket No. 22338-10230
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Group Art Unit:
`
`3991
`
`Examiner:
`
`Bennett Celsa
`
`) ) ) ) ) )
`
`Reexamination of Patent No. 6,331,415
`
`Shmuel CABILLY et al.
`
`Control No. 90/007,542
`
`) Confirmation No.2
`
`7585
`
`) ) ) )
`
`)
`
`Filed: May 13, 2005
`'
`For: METHODS OF PRODUCING
`
`IMMUNOGLOBULINS, VECTORS
`AND TRANSFORMED HOST CELLS
`
`FOR USE THEREIN
`
`DECLARATION OF DR. TIMOTHY JOHN ROY HARRIS UNDER 37 C.F.R. § 1.132
`
`1, Timothy John Roy Harris, do hereby declare and state:
`
`1.
`
`2.
`
`3.
`
`4.
`
`I am a citizen of the United Kingdom, and reside in San Diego, California. My c.v. is
`attached as Exhibit A.
`
`I am presently Chief Executive Officer of Novasite Pharmaceuticals. Prior to this
`position, I served in a variety of research and management positions in the biotechnology
`industry.
`
`In early 1983, I was head of Molecular Biology at Celltech, Ltd., now part of UCB
`Pharma. Recombinant antibody production was a key research focus for the company,
`and its scientific advisors were experts in that field. Celltech is the same corporate entity
`that was involved in a protracted interference contest in the'Patent and Trademark Office
`(PTO) with Genentech and City of Hope concerning recombinant antibody production.
`
`I have been retained by Genentech and City of Hope to provide my views on certain
`issues that have arisen in connection with the reexamination proceeding of U.S. Patent
`No. 6,331,415 (the ’415 patent)
`
`5.
`
`I have reviewed the following patents and publications:
`
`-
`-
`
`-
`
`-
`
`-
`
`Cabilly, U.S. Patent No. 4,816,567 (the ’567 patent)
`Cabilly, U.S. Patent No. 6,331,415;
`'
`
`Axel, U.S. Patent No. 4,399,216 (Axel).
`
`Rice, PNAS 79: 7862, 1982 (Rice)
`
`Kaplan, European Patent No. 0 044 722 (Kaplan)
`
`- _1_Page 1
`
`GENENTECH 2004
`GENZYME V. GENENTECH
`IPR2016-00383
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`GENENTECH 2004
`GENZYME V. GENENTECH
`IPR2016-00383
`
`

`
`Control No. 90/007,542
`
`Attorney Docket No. 22338-10230
`
`-
`
`-
`
`._
`
`Accolla, PNAS 77: 536, 1980 (Accolla)
`
`Builder, U.S. Patent No. 4,511,502 (Builder)
`
`6.
`
`I have also reviewed certain documents associated with the reexamination proceeding of
`the ‘4l5 patent, including:
`
`-
`
`—
`
`-
`
`A PTO Office Action in reexamination no. 90/007,542 dated September
`13, 2005 (“Office Action”);
`
`A PTO Order granting ex parte reexamination of the ’4l5 patent, dated
`July 7, 2005 (“Reexamination Order”); and
`
`A Request for Ex Pane Reexamination dated May 13, 2005 (“Request for
`Reexamination”).
`
`In addition, in preparing this declaration, I reviewed literature I found relevant fiom the
`same general time period as the ’567 and ’4l5 patents.
`
`In this declaration, I provide my opinions on the scientific observations found in the PTO
`Office Action concerning Axel, Rice, Kaplan, Accolla and Builder from the perspective
`of a person of ordinary skill in this art on or before the filing date of the ’4l5 patent (i.e.,
`April 8, 1983).
`
`’
`
`I understand that the ’567 patent claims are directed to processes, vectors and host cells
`for producing chimeric immunoglobulin heavy or light chain polypeptides, and to a
`composition containing a chimeric immunoglobulin heavy or light chain polypeptide.
`The ’567 patent method claims cover situations where only one chimeric
`immunoglobulin heavy or light chain polypeptide is produced in a single host cell.
`
`The ’415 patent claims differ from the ’567 patent claims. One difference is that the
`method claims in the ’41 5 patent require that DNA sequences encoding the heavy an_d the
`light immunoglobulin chain polypeptides be independently expressed by a single host
`cell. Another difference is that the method claims in the ’4l5 patent require assembly of
`the heavy and light chain polypeptides into an immunoglobulin molecule or an
`_
`immunologically functional fragment that comprises at least the variable domains of the
`heavy and light chain polypeptides.
`
`Meaning of “Having Specificityfor a Particular Known Antigen” in the ‘567 Patent Claims
`
`11.
`
`The ’567 patent claims use the phrase “having specificity for a particular known
`antigen... .” I have been asked to explain what that phrase would have meant to a person
`of ordinary skill in the art in view of the ’567 patent disclosure in early April of 1983.
`
`By this time, the physical structure and biological functions of immunoglobulins were
`fairly well known. The description of immunoglobulin structure in the ’567 and ’4l5
`patents (e.g., ’4l5 patent, col. 3, line 17 to col. 4, line 5) is consistent with what was
`generally understood about immunoglobulin structure and function. By this time, it also
`
`_2_Page 2
`
`

`
`Control No. 90/007,542
`
`Attorney Docket No. 22338-10230
`
`13.
`
`14.
`
`was accepted that the antigen binding function of immunoglobulins was associated with
`the variable domains of the heavy and light chain polypeptides, and that an individual
`heavy or light chain polypeptide ordinarily would not bind to antigen very well, if at all.
`
`I would rely on this general understanding of immunoglobulin structure and function to
`answer the question of what the phrase “having specificity for a particular known
`antigen” means as it is used in the claims of the ’567 patent.
`I view that phrase as it is
`used in the claims of the ’567 patent as referring to amino acid sequences within the
`variable domain of the individual chimeric heavy chain or light chain polypeptide that
`confer antigen binding specificity. In such a chimeric polypeptide, these sequences
`would be derived from the variable domains of an antibody or an antibody fragment
`exhibiting an antigen binding function.
`
`I do not read this phrase as it is used in the ’567 patent claims as requiring that the
`individual chimeric heavy chain or light chain polypeptide be assembled into a molecule
`that actually exhibits antigen-binding function, such as an immunoglobulin molecule or
`an immunologically functional fragment that includes the variable domains of the heavy
`and light chain polypeptides.
`
`General Observations on State ofthe Art in 1983
`
`15.
`
`16.
`
`17.
`
`I understand that the PTO has suggested that the inventions claimed in the ’4l5 patent
`would have been considered obvious to a scientist working in this field in April of 1983.
`-I also understand that this is based on their opinion of what the claims of the ’567 patent
`would have suggested to a scientist at the time in view of Axel, Rice, Kaplan, Builder and
`Accolla.
`I do not agree with the conclusions or rationale offered by the PTO.
`
`I
`
`By early April of 1983, I was aware that a number of groups had successfully expressed
`polypeptides using recombinant techniques. These experiments generally involved
`expression of genes encoding relatively small polypeptides with simple tertiary structures
`(e. g., monomeric or dimeric proteins). The state of the art in this time frame is reflected
`in a review paper I authored (Harris, “Expression of Eukaryotic Genes in E. coli,”
`Genetic Engineering 4: 127-85 (1983), attached as Exhibit B). In early April of 1983, I
`was not aware of any publications reporting the production of an active multimeric
`protein with a complexity comparable to an immunoglobulin by independent expression
`of the genes encoding the distinct constituent polypeptides of the protein in a single host
`cell.
`
`Immunoglobulin molecules are large (approx. 150 kD) and complex tetrameric proteins.
`By early April of 1983, it was believed that the functional properties of immunoglobulins
`— particularly antigen binding — were dependent on specific covalent and non-covalent‘
`interactions within and between the heavy and light chains. For example, each pair of
`heavy and light chain polypeptides in an immunoglobulin is joined by several inter- and
`intra-chain cystine bonds. The immunoglobulin tetramer also has several inter-chain
`cystine linkages. These interactions between the heavy and light chain polypeptides were
`known to be important to antigen binding and other functions associated with
`
`_3l°age 3
`
`

`
`C0fltr01 N0. 90/007.542
`
`Attorney Docket No. 22338-10230
`
`immunoglobulins. See, e.g., Edelman, G. M., Ann. N. Y. Acad. Sci. 190: 5-25 (1971),
`referenced in col. 3, lines 18-19 of the ‘415 patent and provided as Exhibit C.
`
`18.
`
`19.
`
`Scientists working in this field at the time understood that mature B cells are able to
`assemble immunoglobulin tetramers out of the endogenous light and heavy immuno-
`globulin chain polypeptides naturally produced by those cells. However, I do not believe
`a scientist in this field, in early April of 1983, would equate this general understanding of
`B cell function as providing any particular insights into the challenge of recombinant
`production of an immunoglobulin molecule or immunologically functional fragment
`through expression of exogenous heavy and light chain genes in a single host cell.
`
`I therefore do not agree with the suggestion of the PTO that, by early April of 1983, the
`patents and publications they identify demonstrate that the expression using recombinant
`DNA techniques of genes encoding complex multimeric proteins such as
`immunoglobulins had become routine.
`
`The Axel Patent
`
`20.
`
`The first publication the PTO identifies is U.S. Patent No. 4,399,216, to Axel, Wigler,
`and Silverstein (“Axel patent”). The PTO describes the relevance of the Axel patent as
`follows:
`
`Axel et al teaches a process for inserting foreign DNA into eukaryotic cells
`by co-transforming the cells with this foreign DNA and an unlinked DNA
`that codes for a selectable phenotype not otherwise expressed by the cell
`(see column 3, lines 21-27). Axel describes the process as particularly
`suited for the transformation of DNA into eukaryotic cells for making
`immunoglobulins (see column 3, lines 31 to 36). Axel thus demonstrates
`the predictability of expression of multiple heterologous proteins in a single
`host cell. Axel also suggests the desirability of expressing immunoglobulins
`in mammalian host cells, and as intact (assembled) proteins. Office Action,
`page 5.
`
`21.
`
`22.
`
`The Axel patent describes a process for inserting a single heterologous gene (“DNA 1”)
`into a host cell co-transfonned with a “selectable marker” gene (“DNA II”). Figure 1 in
`the patent provides an overview of the Axel process. In the Axel patent terminology,
`“DNA 1” encodes a desired “proteinaceous material not associated with a selectable
`phenotype” that is to be isolated from the transformed host cell. See, col. 3, lines 31 to
`36. The selectable marker is introduced by DNA II.
`»
`.
`
`Two elements are essential to the process described in the Axel patent. First, the host cell A
`.must be co-transformed to contain DNA I and DNA II. Second, DNA II must impart into
`the transformed host cell a selectable marker associated with expression of DNA II by the
`_cell. This enables a scientist to select transformed cells that are expressing DNA II from
`cells that are not expressing DNA II. This is done, according to the Axel patent, by
`introducing into the mediumin which the cells are growing an agent that facilitates the
`selective removal of those cells that are not expressing DNA II.
`-\
`
`_4_Page 4
`
`

`
`Control No. 90/007,542
`
`Attorney Docket No. 22338-10230
`
`23.
`
`The choices in Axel for DNA II are limited to genes that introduce selectable markers.
`As Axel explains at col. 5, lines 58-67:
`
`Although any DNA II coding for a selectable phenotype would be usefuliin
`the cotransformation process of the present invention, the experimental
`details set forthparticularly concern the use of a gene for thymidine kinase
`obtained from herpes simplex virus and the use of a gene for adenine
`phosphoribosyl transferase.
`In addition, a DNA II which includes a gene
`coding for a selectable phenotype associated with drug resistance, e. g., a
`mutant dihydrofolate reductase gene which renders cells resistant to
`methotrexate, greatly extends the applicability of the process.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`For the process described in the Axel patent to work, DNA H must encode a polypeptide
`that introduces a selectable phenotype not normally exhibited by the cell. A gene
`encoding an immunoglobulin heavy or light chain polypeptide cannot function in the role
`described in the Axellpatent for DNA II, because its expression in a cell would not have
`introduced a “selectable marker” into the cell.
`
`I do not find a description in the Axel patent for procedures where cells are transformed
`to express more than two distinct DNA sequences. Instead, the patent consistently states
`that one DNA (DNA_I) encodes the polypeptide to be expressed by and isolated from the
`cell, and a second DNA (DNA II) encodes an introduced selectable marker.
`I, also see
`nothing in the Axel patent describing or suggesting procedures where host cells are
`transfonned with an additional, different DNA (a “DNA III”) which would be necessary
`to use the Axel patent method to express genes encoding immunoglobulin heavy and
`light chain polypeptides in a single transformed host cell.
`
`I also do not read the brief references to “antibodies” in the Axel patent as suggesting that
`genes encoding both heavy and light chain polypeptides can or should be expressed in a
`single host cell. These references are simply suggesting that antibody polypeptides might
`be a type of “proteinaceous material” that could be produced using the method described
`in the Axel patent.
`
`I also do not find in the Axel patent any description of methods for producing a complex
`multimeric protein, such as an immunoglobulin, by independently expressing the genes
`encoding the individual polypeptide constituents of the multimeric protein in a single host
`cell. I note that the only examples in Axel concern small monomeric polypeptides (eg,
`the rabbit B—globin polypeptide). In addition, none of the experiments described in the
`Axel patent actually show isolation of the polypeptides that were produced by the
`transformed host cells.
`.
`.
`
`I do not agree with the Examiner that the Axel patent suggests the desirability of
`producing immunoglobulins as “intact (assembled) proteins.” I am unable to find any
`mention in Axel of the desirability of producing “intact (assembled)” immunoglobulins,
`and nothing in the Axel patent provides any guidance on how to assemble “intact”
`immunoglobulins.
`
`_5_Page 5
`
`

`
`Control No. 90/007,542
`
`Attorney Docket No. 22338-10230
`
`29.
`
`The Axel patent does theorize that eukaryotic cells might process proteinaceous materials
`encoded by a DNA I to form complete, biologically active material (col. 7, lines 57 to
`67). However, what the Axel patent is discussing at this point is the idea that eukaryotic
`cells will add non-protein elements (particularly carbohydrate side chains) to the
`produced polypeptide. Since the Axel patent does not envision that two distinct
`polypeptides will be produced by and isolated from the transformed host cell or that the
`expression products of DNA I and DNA 11 will form a protein complex, this passage
`cannot be read as addressing the idea that an immunoglobulin molecule might be
`produced by the transformed cell and assembled into an intact tetramer.
`
`I do not disagree with the Examiner’s observation that Axel describes a process where a
`host cell is co-transformed to contain two foreign genes (a foreign DNA of interest and
`an unlinked foreign DNA that codes for a selectable marker). However, I do not agree
`that Axel can be read as establishing, to a scientist working in this field in early April of
`1983, that producing two or more complex polypeptides, in addition to the required
`selectable marker, in ,a single host cell would be predictable.
`I also do not agree with the
`Examiner’s statement that Axel suggests the desirability of producing immunoglobulins
`as “intact (assembled) proteins,” or that doing so would be predictable based on the
`contents of the Axel patent in early April of 1983. As I explain above, there is simply no
`discussion in the Axel patent regarding production of intact immunoglobulins.
`
`The Rice Publication
`
`31.
`
`The PTO cites a paper by Rice and Baltimore (Rice) as showing that “it was known in the
`art that host cells could express ‘heavy and light chains,’ and that expression of both
`chains was routine, resulting in assembly into immunoglobulins.” Office Action, page 6.
`I do not agree that this is what the Rice paper actually describes or suggests.
`
`While it was known by early April of 1983 that B cells express endogenous DNA
`corresponding to heavy and light immunoglobulin chain polypeptides and assemble these
`chains into immunoglobulin tetramers, the Rice paper does not address whether
`exogenous recombinant DNA sequences corresponding to heavy and light chain
`‘polypeptides could be independently expressed in a single host cell or whether those
`polypeptides could be assembled into immunoglobulin molecules or immunologically
`functional fragments.
`
`The Rice paper reports on experiments designed to explore the mechanisms that regulate
`immunoglobulin gene expression in immunoglobulin-producing cells. As Rice
`acknowledges at page 7862, col. 1, “although much is now known about Ig gene
`structure, relatively little is known about the molecular mechanisms that control lg gene
`expression.”
`
`The experiments described in Rice involved insertion of a rearranged kappa (K) light
`chain gene into an Abelson murine leukemia virus-transformed lymphoid cell line
`designated 81A-2. Rice reports that the 81A-2 subclone expresses an endogenous
`immunoglobulin heavy chain gene, but does not express an endogenous K light chain
`gene.
`
`_6_Page 6
`
`

`
`Control No. 90/007,542
`
`Attomey Docket No. 22338-10230
`
`35.
`
`Rice indicates that the transfected cells expressed the introduced murine K light chain
`gene based on their detection of mRNA corresponding to the introduced gene. Rice
`reports that they detected three classes of mRNA, two of which were “aberrant" and
`appeared to contain an intervening sequence that is not present in correctly processed
`mRNA for the murine K light chain gene, which suggests that the transfected cells may
`not have been consistently or correctly transcribing the exogenous immunoglobulin light
`chain gene.
`
`I do not believe a scientist, in early April of 1983, would view the Rice publication as
`establishing that expression of recombinant DNAs encoding exogenous heavy and light
`immunoglobulin chain polypeptides in one host cell was a routine matter. In my view,
`the Rice paper does not address the question of whether exogenous light @ heavy chain
`polypeptides, if expressed by a transformed host cell, will be assembled into an “intact”
`immunoglobulin molecule. Instead, what Rice shows is that it is possible to express an
`exogenous light chain polypeptide in a particular mature B cell subclone that was already
`expressing an endogenous heavy chain and had lost its previous ability to produce
`endogenous light chain.
`"
`
`I also note that the particular lymphoid subclone used in Rice would not be suitable for
`processes that are the focus of the ’4l5 patent. This is because that subclone was already
`expressing an endogenous heavy chain.
`
`Rice does not explain how to selectively deactivate or control immunoglobulin chain
`expression in the 81A-2 cell line used in their experiments. The paper only reports that
`the line has lost functional K constant region genes and that the line continued to express
`its endogenous heavy chain gene. Rice does not describe any other transformed host
`cells in the paper.
`
`I therefore disagree with the suggestions of the PTO that Rice shows that “it was known
`in the art that host cells could express ‘heavy and light chains, and that expression of both
`chains was routine, resulting in assembly into immunoglobulins.”
`
`Kaplan, Accolla and Builder
`
`40.
`
`In the Office Action,.the PTO also addresses a number of other publications, including a
`published European Patent application filed by Kaplan, a paper published by Accolla, and
`a U.S. patent issued to Builder.
`I do not believe any of these publications suggests the
`idea of producing bothheavy and light immunoglobulin chain polypeptides in a single
`host cell.
`
`Kaplan, in my opinion, does nothing more than illustrate a general hypothetical approach
`that one might try to express an individual immunoglobulin light chain or heavy chain
`polypeptide. There are no examples provided in Kaplan of successful expression of
`immunoglobulin heavy or light chain polypeptides. Most significantly, nothing in
`Kaplan suggests that a heavy chain polypeptide and a light chain polypeptide should be
`produced in a single cell. Instead, as I read Kaplan, it suggests that a scientist could
`attempt to produce individual immunoglobulin chain polypeptides in separate host cell
`
`_7|?age 7
`
`

`
`Control No. 90/007,542
`
`Attorney Docket No. 22338-10230
`
`42.
`
`43.
`
`cultures. As such, I do not believe a scientist working in this field in early April of 1983
`would have viewed Kaplan as suggesting the production of heavy and light
`immunoglobulin chain polypeptides in a single transformed host cell.
`
`Accolla describes a source for antibodies that bind to carcinoembryonic antigen (CEA).
`It does not describe or suggest any manipulations of the genes encoding the antibodies. It
`provides no suggestion that one should produce both heavy and light immunoglobulin
`chains in a single host cell.
`
`The Builder patent describes methods for refolding proteins produced by bacterial
`expression systems in which the proteins have formed insoluble “refractile” bodies. It
`does not describe any approaches for modulating or selecting the conditions for
`'
`expression of genes encoding immtmoglobulin chains. In my view, the Builder patent
`does not suggest the idea of expressing multiple polypeptides, particularly
`immunoglobulin heavy and light chain polypeptides, in a single host cell.
`
`.
`
`'
`
`*#####¢¢##¢
`
`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 willful false statements and the like so made are ptmishable 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 ofthe patent subject to this
`reexamination proceeding.
`
`Timo
`
`hn Roy Harris
`
`Date
`
`Mvealod Wk °w>s/
`
`_g_Page 8
`
`

`
`Curriculum Vitae
`
`TIMOTHY JOHN ROY HARRIS, PH.D.
`
`
`
`Work Address
`
`Novasite Pharmaceuticals
`11025, Roselle St,
`San Diego, CA 92121
`Tel: (858) 875 - 8524
`
`Home Address
`
`8076 Paseo Arrayan
`Carlsbad, CA 92009
`Tel: 760-635-0139
`Cell: 6l9~788~7l00
`PDA : 619-278-8661
`
`
`
`PERSONAL
`
`Date of Birth: May I 1, 1950
`Married with four children
`
`EDUCATION
`
`10/72 - 10/74
`9/71 - 10/72
`l0/68 - 9/7]
`
`Ph.D., Molecular Virology, University of Birmingham, UK
`M.Sc., General Virology, University of Birmingham, UK
`B.Sc., Biochemistry, University of Birmingham, UK
`
`EXPERIENCE AND ACCOMPLISHMENTS
`
`3/05 — Present
`
`8 President & CEO
`Novasite Pharmaceuticals, San Diego CA
`
`Novasite is a drug discovery and development company that is identifying new therapeutics for
`common diseases through modulation of membrane receptors
`
`6/03 - 12/04
`
`President & ChiefEcecutive Oflicer
`Structural Genomix, Inc., San Diego, CA
`
`Structural GenomiX is a drug discovery and development company focused on innovative cancer
`therapeutics
`
`- Successfully in-.1icensed Troxatyl® from Shire in July 2004
`o Over $18M in revenue received in 2003 and over $20M in 2004
`- Negotiated a Bridge Loan of c.$13M from existing investors in July 2004
`- Maintained relationships with key stakeholders
`- Continued to drive our drug discovery programs to the clinic
`. Initiated and fostered relationships with key analysts, investors, partners and media
`- Managed the company's
`research and development, operations,
`infrastructure,
`technology platform, and strategic partnerships
`
`Page 9
`
`

`
`Page 2 of 6
`
`rounds of financing amounting to $85M in private equity
`
`- Directed 3 successful
`financing in 1999/2000
`. Initiated and successfully negotiated the acquisition and integration of Prospect
`Genomics, Inc. in 2001
`- Responsible for the scientific and business direction, programs, and objectives for over
`110 employees
`_
`- Hired one of the best management teams in the Biotechnology Industry
`. Member of Board of Directors
`
`12/97-2/99
`
`Senior Vice President ofResearch
`Axys Pharmaceuticals, "La Jolla, CA
`[Axys was the merged company of Sequana Therapeutics and Arris
`Pharmaceutical]
`- Member of Executive committee
`
`- Member of Clinical Development committee
`- Oversaw all Research at Axys (South) and at Nemapharm (c 200 people in total)
`
`12/93-12/97
`
`Senior Vice President ofR & D and Chief Technicdl Officer
`Sequana Therapeutics, La Jolla, CA.
`
`0 Member of Board of Directors
`
`- Built research team from 5 people to over 160 in four years
`- Directed the research of approximately 160 scientists
`- Member of team that took the company through the IPO (6/95) and the secondary
`offering (7/96)
`- Initiated and executed the acquisition of the C. elegans company Nemaphann (10/96)
`-
`Initiated and successfully negotiated several
`strategic
`alliances with major
`pharmaceutical companies (Asthma - Boehringer lngelheim; Osteoporosis — Boehringer
`Mannheim; Type 2 Diabetes and obesity - Glaxo Wellcome; Schizophrenia and Bipolar
`Disease -Parke-Davis)
`'
`- Member ofteam that negotiated the merger of Sequana with Arris Pharmaceutical
`
`3/89 - 12/93
`
`_
`Director of Biotechnology
`Glaxo Group Research Limited, Greenford, UK
`
`- Responsible for three departments as a line management function (Natural Products
`Discovery, Protein Biochemistry and Biochemical Targets) reporting to the Research
`Director
`
`- Proselytized the importance of biotechnology and molecular biology in drug discovery
`company-wide
`
`7.'IR Hnrric
`
`Page
`
`

`
`V Page 3 0:6
`
`- Member of the Research Executive Committee which exercised control over resources,
`priorities and defined research direction in the Research Directorate (UK) as a whole
`(c.750 people)
`- Deputy chairman of the Research Management Committee, overseeing GI research
`~ Responsible
`for
`identifying several potential
`strategic
`alliances with small
`Biotechnology companies (e.g. with Gilead Sciences, Ligand Pharmaceuticals and
`ICOS)
`- Initiated the Glaxo deal with MegaBios for CF gene therapy
`- Member of the International Research Strategy group, which oversaw research strategy
`worldwide
`
`0 Initiated the formation of the Glaxo Centre for Natural Products Research in Singapore
`in 1991
`
`0 Implemented the Glaxo Genetics Initiative to maximize opportunities to capitalize from
`the human genome project
`identifying the genes concerned with the molecular
`pathology of common diseases
`.
`- Attended Senior management training course at the London Business School
`
`4/87 - 3/89
`
`Head ofSub-Division ofMolecular Biology
`Celltech Ltd., Slough, UK
`
`- Responsible for all Molecular Biology at Celltech (34 people)
`- Attended a "Strategic Management" course at Ashridge College
`- Directed and was responsible for the significant progress made in the “Connective
`Tissue Diseases” project, such that a deal was subsequently made with Merck (USA)
`- Directed a group designing and making recombinant antibodies for therapeutic use
`- Consistently used as technical back up in interactions with Japanese and American
`companies
`
`11/82 - 4/87
`
`Head ofMolecular Biology
`Celltech Ltd., Slough, "UK
`
`- Directed a division consisting of four departments (Chemistry, Molecular Genetics,
`Molecular Biology. and Microbial Genetics)
`lipase, collagenase,
`including lingual
`- Oversaw the cloning of several cDNAs
`stromelysin, tissue inhibitor of metalloproteinase (TIMP), glutamine synthetase and
`complement factors I&H
`- Personally made a library of 600,000 clones in Professor R A Lamb's laboratory at
`Northwestern University, Chicago (7/83) which resulted in two papers being
`subsequently published
`’
`- Took overall responsibility for a MicroVax running DNA and protein sequence
`handling programs (UWGCG) and a molecular modeling facility.
`
`T”? ""'"“
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`Page 11
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`

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`Page 4 oz 6
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`3/8] - ll/82
`
`Group Leader, Molecular Biology
`Cellteeh Ltd., Slough UK
`
`- Set-up the molecular biology laboratory
`- Primarily responsible for cloning cDNA copies of calf chymosin mRNA and for
`obtaining the nucleotide sequence, so that the cDNA could be tailored into suitable
`expression vectors for synthesis of prochymosin in E.coli and yeast
`- Cloned full—length cDNA copies of the mRNA for tissue plasminogen activator (t-PA)
`
`11/78 - 3/81
`
`‘
`Senior Scientific Ojflcer, Biochemistry Department
`The Animal Virus Research Institute (AVRI), Pirbright, Surrey, UK
`
`- Applied novel techniques to examine the structure and function of the 5'end of FMDV-
`RNA. The sequence of 120 nucleotides was obtained at the 5' end of the RNA and
`additional sequences obtained around the poly (C) tract
`- The advent of recombinant DNA techniques led to the cloning of a DNA copy of
`FMDV- RNA with scientists from Wellcome, Beckenham leading to attempts to
`produce FMDV capsid proteins in E.coli using defined expression vectors for use as
`potential vaccines
`
`10/77 - 11/78
`
`Postdoctoral Fellow, Department ofMicrobiology
`State University of New York, Stony Brook, NY
`
`° Aspects of poliovirus RNA structure in Dr. Eckard Wimmer’s laboratory. Three
`publications came from this work
`
`9/74 - .10/77
`
`Higher Scientific Ojficer, The Animal Virus Research Institute
`Pirbright, Surrey, UK
`
`- Worked with Dr. Fred Brown on molecular aspects of antigen variation of the
`enterovirus, swine vesicular disease virus and its relationship to the human pathogen
`Coxsackie B5 virus
`
`- Studies were also done on the biochemical differences between a virulent and an
`attenuated foot and mouth disease virus (FMDV)
`
`DIRECTORSHIPS/SCIENTIFIC ADVISORY BOARD MEMBERSHIPS
`- Member of Board of Directors ofDendreon Corporation, Seattle (1999 — 2004)
`- Member of Board of Directors and Scientific Advisory Board of Cerylid Biosciences, Australia
`(2001 — 2003)
`- Member of Scientific Advisory Board ofBionomics Limited, Australia (2003 - present)
`
`

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`Page 5 016
`
`OTHER POSITIONS AND ACCOMPLISHMENTS
`' Fellow of the Institute of Biology (FI Biol)
`- Visiting Professor, Birkbeck College London (4/87 - 1/94)
`- Member of Molecular Biology and Genetics Subcommittee of the SERC Biological Sciences
`Committee (1985-1989)
`0 Chairman of SERC Protein Engineering Underpinning’ Programme (1986-87)
`- Chairman ABPI Biotechnology Committee (1990 - 1994)
`- Chainnan LINK Protein Engineering Management Committee (1989 - 1993)
`- Member ofMRC Molecular and Cellular Biology Board (1992 -1994)
`- Member of Genetics and Human Health Subcommittee of the MRC (1993-94)
`- Editor, Current Opinion in Biotechnology (1989-present)
`- Member of expert subcommittee on human genome research reporting to the UK Office of
`Science and Technology (1993)
`- Member of UK DOH committee on 'Exploitation of Molecular Genetics in the NHS' (1993)
`- Supervised three graduate students and examined 2 D.Phil theses for University of Oxford
`- Attended Senior Executive Program at London Business School (1999)
`
`SOCIETIES
`
`- Society for General Microbiology
`0 Biochemical Society
`. Institute of Biology
`
`OTHER INTERESTS
`Swimming, Squash, Running, SCUBA diving, watching sports car racing, Flying (Private Pilot),
`Driving (Porsche 911)
`
`REFERENCES
`
`Available upon request.
`
`PUBLICATIONS & PATENTS
`Over 85 publications and 5 issued patents. List available upon request.
`
`T”? Harris
`
`Page 13