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`
`DANIEL E. ALBERTI, ESQ., SB# 68620
`ROPERS, MAJESKI, KOHN,
`BENTLEY, WAGNER & KANE
`1001 Marshall Street
`
`Redwood City, CA
`(415) 364~a2oo
`
`94063
`
`JOHN G. HARKINS, JR., ESQ.
`LLOYD R. ZIFF, ESQ.
`ELEANOR MORRIS ILLOWAY,
`HARKINS CUNNINGHAM
`
`ESQ.
`
`1800 One Commerce Square
`2005 Market Street
`
`Philadelphia, PA
`(215)
`a51—57oo
`
`19103-7042
`
`Attorneys for Defendant,
`CENTOCOR,
`INC.
`
`IN THE UNITED STATES DISTRICT COURT
`
`NORTHERN DISTRICT OF CALIFORNIA
`
`GENENTECH,
`
`INC.,
`
`Plaintiff,
`
`ICENTOCOR,
`
`INC.,
`
`Defendant.
`
`\..&\._r\.a\._aI...vI..u-._d\_u-..’
`
`Case Number C 94-01379 BAC
`
`AFFIDAVIT OF
`
`JOHN GHRAYEB, Ph.D.
`
`Date: August 26, 1994
`Time:
`9:00 a.m.
`
`Dept: Courtroom 5, 17th Floor
`
`COMMONWEALTH OF PENNSYLVANIA
`
`COUNTY OF CHESTER
`
`SS
`
`onnoonno
`
`DR.
`
`JOHN GHRAYEB, being duly sworn, deposes and
`
`says:
`
`1.
`
`I am the Vice President of Pharmaceutical
`
`Research of Centocor, Inc.
`
`I make this affidavit in support
`
`of Centocor’s motion for summary judgment.
`
`While my job
`
`title has changed over the years,
`
`I have been personally
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Genzyme Ex. 1045, pg 1103
`
`Genzyme Ex. 1045, pg 1103
`
`
`
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`
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`
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`
`26
`
`27
`
`28
`
`
`
`DANIEL E. ALBERTI, ESQ., SB# 68620
`ROPERS, MAJESKI, KOHN,
`BENTLEY, WAGNER & KANE
`1001 Marshall Street
`
`Redwood City, CA
`(415) 364~a2oo
`
`94063
`
`JOHN G. HARKINS, JR., ESQ.
`LLOYD R. ZIFF, ESQ.
`ELEANOR MORRIS ILLOWAY,
`HARKINS CUNNINGHAM
`
`ESQ.
`
`1800 One Commerce Square
`2005 Market Street
`
`Philadelphia, PA
`(215)
`a51—57oo
`
`19103-7042
`
`Attorneys for Defendant,
`CENTOCOR,
`INC.
`
`IN THE UNITED STATES DISTRICT COURT
`
`NORTHERN DISTRICT OF CALIFORNIA
`
`GENENTECH,
`
`INC.,
`
`Plaintiff,
`
`ICENTOCOR,
`
`INC.,
`
`Defendant.
`
`\..&\._r\.a\._aI...vI..u-._d\_u-..’
`
`Case Number C 94-01379 BAC
`
`AFFIDAVIT OF
`
`JOHN GHRAYEB, Ph.D.
`
`Date: August 26, 1994
`Time:
`9:00 a.m.
`
`Dept: Courtroom 5, 17th Floor
`
`COMMONWEALTH OF PENNSYLVANIA
`
`COUNTY OF CHESTER
`
`SS
`
`onnoonno
`
`DR.
`
`JOHN GHRAYEB, being duly sworn, deposes and
`
`says:
`
`1.
`
`I am the Vice President of Pharmaceutical
`
`Research of Centocor, Inc.
`
`I make this affidavit in support
`
`of Centocor’s motion for summary judgment.
`
`While my job
`
`title has changed over the years,
`
`I have been personally
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Genzyme Ex. 1045, pg 1103
`
`Genzyme Ex. 1045, pg 1103
`
`
`
`involved with Centocor's research and development efforts in
`
`the monoclonal antibody field since 1984.
`
`2.
`
`The c7E3 product is a fragment of a chimeric
`
`antibody which is intended to inhibit the formation of blood
`
`clots in the cardiovascular system.
`
`A chimeric antibody is
`
`a protein molecule which derives certain portions of its
`
`structure from one mammalian species (here a mouse) and
`
`other portions from a second species (here a human).
`
`3.
`
`Centocor first began work on the anti-
`
`clotting drug ultimately known as c7E3 in 1986.
`
`In March of
`
`that year, it received a live culture of the murine (or
`
`mouse) hybridoma cell, 7E3,
`
`from Dr. Barry 8. Coller of the
`
`State University of New York at Stony Brook ("SUNY"). This
`
`hybridoma cell resulted from a fusion of a mouse antibody-
`
`producing cell and a mouse myeloma cell, a cell capable of
`
`immortalizing the resulting fusion, that is, making it
`
`capable of continued cell division under culture.
`
`The
`
`antibody secreted by 7E3 binds specifically to a
`
`glycoprotein found on human blood platelets and thereby
`
`inhibits a step involved in the formation of blood clots.
`
`Centocor licensed 7E3 from SUNY to pursue research in the
`
`area of anti-clotting agents of potential benefit to
`
`patients at risk of the injurious consequences of blood
`
`clots. More generally, Centocor's focus has been on various
`
`antibody—derived diagnostic and therapeutic products since
`
`its founding.
`
`..2._
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`1 2 3 4 5 6 7 8 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`Genzyme Ex. 1045, pg 1104
`
`Genzyme Ex. 1045, pg 1104
`
`
`
`4.
`
`In 1987, Centocor isolated and cloned the DNA
`
`sequences from the so-called variable region genes in 7E3.
`
`These sequences are those which contain the genetic code for
`
`the portion of the 7E3 antibody responsible for its specific
`
`binding properties —— the variable regions of the so—called
`
`heavy and light chains making up the complete antibody.
`
`5.
`
`A mouse or human antibody is composed of four
`
`chains,
`
`two heavy and two light, each with a variable region
`
`and a constant region. Different genes within an antibodyw
`
`producing cell "express" different segments of the various
`
`chains, which are then assembled within the cell into
`
`complete antibodies.
`
`6.
`
`The cloned variable region DNA sequences were
`
`then inserted into expression vectors constructed by Dr.
`
`Vernon T. Oi and Dr. Sherie L. Morrison and licensed by
`
`Centocor from Stanford and Columbia Universities. These
`
`vectors —- means of inserting DNA from one source into
`
`another cellular context —— contained human antibody
`
`constant regions and related expression sequences. Thus,
`
`when the variable region DNA sequences were added,
`
`the
`
`vectors ended up containing the DNA coding for complete
`
`heavy and light chains.
`
`7.
`
`Centocor succeeded by the end of 1987 in
`
`"transfecting" (or inserting) each of these vectors into a
`
`single non—antibody secreting cell of murine myeloma origin.
`
`The cell thus transfected, called a "transfectoma", was
`
`-.3-
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Q300~JCDCfifitCdb3F4
`
`10
`
`II
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`Genzyme Ex. 1045, pg 1105
`
`Genzyme Ex. 1045, pg 1105
`
`
`
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`demonstrated to have the capability of secreting an intact
`
`and biologically active (or functional) four chain antibody.
`
`The antibody was chimeric; that is,
`
`the variable regions
`
`were derived from the mouse 7E3 and the constant regions
`
`were of human antibody derivation.
`
`8.
`
`The transfectoma from which c7E3 is derived
`
`was created on September 19, 1988. This represented a
`
`continuation of the work begun at the end of 1987; and the
`
`same vectors were used.
`
`The September 19, 1988 transfectoma
`
`cell was subsequently subcloned to select a cell line
`
`capable of high level production of c7E3 to be used in
`
`clinical trials.
`
`The actual clinical product used by
`
`Centocor is an antibody fragment which retains the binding
`
`characteristics of the whole antibody.
`
`It is produced by
`
`cleaving the whole antibody with an enzyme which correctly
`
`selects the desired fragment. All of this research and
`
`development activity occurred prior to the issuance of the
`
`Genentech '56? patent.
`
`9.
`
`Shortly after receiving the 7E3 cell line,
`
`Centocor commenced toxicologic, pharmokinetic and
`
`pharmacologic testing of the 7E3 antibody and fragments
`
`thereof,
`
`including testing in animal models. Upon creation
`
`of transfectoma cell lines, similar testing began with c7E3
`
`and fragments thereof.
`
`such testing is required by the FDA
`
`_4_.
`
`AFFIDAVIT OF JOHN GHRAYEB: Ph-D-
`
`Genzyme Ex. 1045, pg 1106
`
`Genzyme Ex. 1045, pg 1106
`
`
`
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`
`subjects.
`
`
`
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`before
`this /3‘ ‘~
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`/1145
`, 1994.
`
`
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`‘NOTARY P ‘LIé'
`
`Mm-zem I3§rr:3?;:2§’:$‘ggufit$UIc
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`My Commission Expires Jury 21 199-;
`
`
`
`
`..5...
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Genzyme Ex. 1045, pg 1107
`
`Genzyme Ex. 1045, pg 1107
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