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`DANIEL E. ALBERTI, ESQ., SB# 68620
`ROPERS, MAJESKI, KOHN,
`BENTLEY, WAGNER & KANE
`1001 Marshall Street
`Redwood City, CA
`94063
`(415) 364-8200
`
`JOHN G. HARKINS, JR., ESQ.
`LLOYD R. ZIFF, ESQ.
`ELEANOR MORRIS ILLOWAY, ESQ.
`HARKINS CUNNINGHAM
`1800 One commerce Square
`2005 Market Street
`Philadelphia, PA 19103-7042
`(215) 851-6700
`
`Attorneys for Defendant,
`CENTOCOR, INC.
`
`IN THE UNITED STATES DISTRICT COURT
`
`NORTHERN DISTRICT OF CALIFORNIA
`
`GENENTECH,
`
`INC. I
`
`Plaintiff,
`
`/CENTOCOR,
`
`INC.,
`
`Defendant.
`
`)
`)
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`)
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`)
`)
`)
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`Case Number C 94-01379
`
`BAC
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`AFFIDAVIT OF
`JOHN GHRAYEB, Ph.D.
`
`Date: August 26, 1994
`Time: 9:00 a.m.
`Dept: Courtroom 5, 17th Floor
`
`COMMONWEALTH OF PENNSYLVANIA
`
`ss
`
`COUNTY OF CHESTER
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`DR. JOHN GHRAYEB, being duly sworn, deposes and
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`says:
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`1.
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`I am the Vice President of Pharmaceutical
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`Research of centocor, Inc.
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`I make this affidavit in support
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`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.
`
`Sanofi/Regeneron Ex. 1 045, pg 11 00
`
`Merck Ex. 1045, pg 1126
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`involved with centocor's research and development efforts in
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`the monoclonal antibody field since 1984.
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`2.
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`The c7E3 product is a fragment of a chimeric
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`antibody which is intended to inhibit the formation of blood
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`clots in the cardiovascular system. A chimeric antibody is
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`a protein molecule which derives certain portions of its
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`structure from one mammalian species (here a mouse) and
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`other portions from a second species (here a human) .
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`3.
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`Centocor first began work on the anti(cid:173)
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`clotting drug ultimately known as c7E3 in 1986.
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`In March of
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`that year, it received a live culture of the murine (or
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`mouse) hybridoma cell, 7E3, from Dr. Barry S. Coller of the
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`State University of New York at stony Brook ( 11 SUNY 11 ) . This
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`hybridoma cell resulted from a fusion of a mouse antibody-
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`producing cell and a mouse myeloma cell, a cell capable of
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`immortalizing the resulting fusion, that is, making it
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`capable of continued cell division under culture. The
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`antibody secreted by 7E3 binds specifically to a
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`glycoprotein found on human blood platelets and thereby
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`inhibits a step involved in the formation of blood clots.
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`Centocor licensed 7E3 from SUNY to pursue research in the
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`area of anti-clotting agents of potential benefit to
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`patients at risk of the injurious consequences of blood
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`clots. More generally, Centocor's focus has been on various
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`antibody-derived diagnostic and therapeutic products since
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`its founding.
`
`-2-
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Sanofi/Regeneron Ex. 1045, pg 11 01
`
`Merck Ex. 1045, pg 1127
`
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`4.
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`In 1987 1 Centocor isolated and cloned the DNA
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`sequences from the so-called variable region genes in 7E3.
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`These sequences are those which contain the genetic code for
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`the portion of the 7E3 antibody responsible for its specific
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`binding properties -- the variable regions of the so-called
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`heavy and light chains making up the complete antibody.
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`5.
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`A mouse or human antibody is composed of four
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`chains, two heavy and two light, each with a variable region
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`and a constant region. Different genes within an antibody(cid:173)
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`producing cell "express 11 different segments of the various
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`chains, which are then assembled within the cell into
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`complete antibodies.
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`6.
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`The cloned variable region DNA sequences were
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`then inserted into expression vectors constructed by Dr.
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`Vernon T. Oi and Dr. Sherie L. Morrison and licensed by
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`Centocor from Stanford and Columbia Universities. These
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`vectors -- means of inserting DNA from one source into
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`another cellular context -- contained human antibody
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`constant regions and related expression sequences. Thus,
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`when the variable region DNA sequences were added, the
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`vectors ended up containing the DNA coding for complete
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`heavy and light chains.
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`7.
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`Centocor succeeded by the end of 1987 in
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`11 transfecting 11
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`(or inserting) each of these vectors into a
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`single non-antibody secreting cell of murine myeloma origin.
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`The cell thus transfected, called a "transfectoma", was
`
`-3-
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Sanofi/Regeneron Ex. 1 045, pg 11 02
`
`Merck Ex. 1045, pg 1128
`
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`demonstrated to have the capability of secreting an intact
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`and biologically active (or functional) four chain antibody.
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`The antibody was chimeric; that is, the variable regions
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`were derived from the mouse 7E3 and the constant regions
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`were of human antibody derivation.
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`8.
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`The transfectoma from which c7E3 is derived
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`was created on September 19, 1988. This represented a
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`continuation of the work begun at the end of 1987; and the
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`same vectors were used. The September 19, 1988 transfectoma
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`cell was subsequently subcloned to select a cell line
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`capable of high level production of c7E3 to be used in
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`clinical trials. The actual clinical product used by
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`Centocor is an antibody fragment which retains the binding
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`characteristics of the whole antibody. It is produced by
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`cleaving the whole antibody with an enzyme which correctly
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`selects the desired fragment. All of this research and
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`development activity occurred prior to the issuance of the
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`Genentech '567 patent.
`
`9.
`
`Shortly after receiving the 7E3 cell line,
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`Centocor commenced toxicologic, pharmokinetic and
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`pharmacologic testing of the 7E3 antibody and fragments
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`thereof, including testing in animal models. Upon creation
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`of transfectoma cell lines, similar testing began with c7E3
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`and fragments thereof. Such testing is required by the FDA
`
`-4-
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Sanofi/Regeneron Ex. 1 045, pg 11 03
`
`Merck Ex. 1045, pg 1129
`
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`prior to the commencement of any clinical trials with human
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`subjects.
`
`Sworn to and subsc~bed
`before PT..~ ;:_his /'3 t ~_
`~ ,1994.
`c~~
`
`' NOTARY P
`
`. LIC
`
`-
`
`Notarial Seal
`Beverly C. Haivorsen Nota p br
`My c~~;:• Boro, CrreSter c6un~ 10
`'
`
`Jssron Expires July 21, 1997 -
`
`-5-
`
`AFFIDAVIT OF JOHN GHRAYEB, Ph.D.
`
`Sanofi/Regeneron Ex. 1 045, pg 11 04
`
`Merck Ex. 1045, pg 1130