IN THE COURT OF CHANCERY OF THE STATE OF DELAWARE
`
` 257
`
` Plaintiffs,
`
` vs.
`
`IMMUNOMEDICS, INC.,
`
`:
`SINOMAB BIOSCIENCE LIMITED, SKYTECH
`TECHNOLOGY LIMITED, and SHUI-ON LEUNG, :
` :
`:
` :
` : Civil Action
` : No. 2417-VCS
`:
` :
`:
`
` Defendant.
`
`- - -
`
` Chancery Courtroom No. 12A
` New Castle County Courthouse
` Wilmington, Delaware
` Thursday, November 13, 2008
` 9:35 a.m.
`
`BEFORE: HON. LEO E. STRINE, JR., Vice Chancellor.
`
`- - -
`
`TRIAL TRANSCRIPT - VOLUME II
`
`- - -
`
`------------------------------------------------------
`
`CHANCERY COURT REPORTERS
`500 North King Street - Suite 11400
`Wilmington, Delaware 19801-3759
`(302) 255-0525
`
`EFiled: Dec 11 2008 4:15PM EST
`Transaction ID 22874830
`Case No. 2471-VCS
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2052
`
`Page 001
`
`
`
` 257
`
` Plaintiffs,
`
` vs.
`
`IMMUNOMEDICS, INC.,
`
`:
`SINOMAB BIOSCIENCE LIMITED, SKYTECH
`TECHNOLOGY LIMITED, and SHUI-ON LEUNG, :
` :
`:
` :
` : Civil Action
` : No. 2417-VCS
`:
` :
`:
`
` Defendant.
`
`- - -
`
` Chancery Courtroom No. 12A
` New Castle County Courthouse
` Wilmington, Delaware
` Thursday, November 13, 2008
` 9:35 a.m.
`
`BEFORE: HON. LEO E. STRINE, JR., Vice Chancellor.
`
`- - -
`
`TRIAL TRANSCRIPT - VOLUME II
`
`- - -
`
`------------------------------------------------------
`
`CHANCERY COURT REPORTERS
`500 North King Street - Suite 11400
`Wilmington, Delaware 19801-3759
`(302) 255-0525
`
`EFiled: Dec 11 2008 4:15PM EST
`Transaction ID 22874830
`Case No. 2471-VCS
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2052
`
`Page 001
`
`
`
` 258
`
`APPEARANCES:
`
`
`
`THOMAS C. GRIMM, ESQ.
`Morris, Nichols, Arsht & Tunnell LLP
` -and-
`JAMES L. QUARLES, III, ESQ.
`JODY MANIER KRIS, ESQ.
`JAMIE T. WISZ, ESQ.
`GREGORY H. LANTIER, ESQ.
`of the District of Columbia Bar
`Wilmer Hale
` For Plaintiffs
`
`
`
`P. CLARKSON COLLINS, JR., ESQ.
`Morris James LLP
` -and-
`BRYAN J. WILSON, ESQ.
`DANIEL WAN, ESQ.
`of the California Bar
`Morrison & Foerster LLP
` For Defendant
`
`- - -
`
`CHANCERY COURT REPORTERS
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`S. Leung, Ph.D. - Redirect
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` AFTERNOON SESSION
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` (Reconvened at 1:25 p.m.)
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`THE COURT: You may proceed.
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`MR. QUARLES: Your Honor, just as a
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`matter of housekeeping. I have the documents that
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`were used in Dr. Leung's examination. I'm prepared to
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`either move them in now, move them in at whatever time
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`appropriate for the Court.
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`MR. WILSON: I don't think we have any
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`objection to any of them.
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`THE COURT: Why don't you put in a
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`list and submit it to the register.
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`MR. QUARLES: I'll do that. Thank
`
`you, Your Honor.
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`Miss Kris will do the next witness.
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`MS. KRIS: Plaintiffs call
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`Dr. Jefferson Foote.
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`JEFFERSON FOOTE, Ph.D., having been
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`first duly sworn, was examined and testified as
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`follows:
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`BY MS. KRIS:
`
`DIRECT EXAMINATION
`
`Q.
`
`A.
`
`Please state your name.
`
`Jefferson Foote.
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`J. Foote, Ph.D. - Direct
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`Q.
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`Could you describe your educational
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`background after high school?
`
`A.
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`After high school, I was an
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`undergraduate at Harvard College from 1973 until 1977.
`
`Q.
`
`A.
`
`Did you earn a degree there?
`
`Yes. I received a bachelor's degree
`
`in biochemical sciences.
`
`Q.
`
`Did you do any research projects while
`
`you were at Harvard?
`
`A.
`
`Q.
`
`that project?
`
`Yes.
`
`Who did you work with at Harvard on
`
`A.
`
`I worked with William N. Lipscomb who
`
`was a professor in the chemistry department.
`
`Q.
`
`A.
`
`What is Dr. Lipscomb known for?
`
`He's quite a distinguished chemist
`
`known for his studies on molecular structure and on
`
`quantum mechanics. He received the Nobel Prize in
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`1976 for that work.
`
`Q.
`
`What sort of work did you do with him
`
`in his lab?
`
`A.
`
`I worked on the molecular structure
`
`site studying the three-dimensional structures of
`
`proteins.
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`CHANCERY COURT REPORTERS
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`Q.
`
`What did you do after you graduated
`
`from Harvard?
`
`A.
`
`After I graduated, I worked as a lab
`
`technician at Harvard and then also at Boston College.
`
`Q.
`
`What projects did you do in the
`
`Harvard laboratory?
`
`A.
`
`At Harvard I worked with a junior
`
`faculty member named David Dressler, who worked kind
`
`of in the context of a larger group directed by a
`
`senior faculty member named Walter Gilbert.
`
`Q.
`
`And what sort of projects did you do
`
`in that lab?
`
`A.
`
`My first project there was an attempt
`
`to clone a gene for an antibody. That would have been
`
`the first instance if it had been successful.
`
`Q.
`
`In what field is Walter Gilbert known,
`
`the head of that lab?
`
`A.
`
`Walter Gilbert is a distinguished
`
`molecular biologist. He won the Nobel Prize in 1980.
`
`Q.
`
`What was the subject of his work that
`
`caused him to earn the Nobel Prize?
`
`A.
`
`Principally for developing a method of
`
`DNA sequencing.
`
`Q.
`
`And what kind of DNA sequence work did
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`CHANCERY COURT REPORTERS
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`he perform specifically?
`
`A.
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`There were various, but that included
`
`the first antibody gene which was brought there by a
`
`collaborator from outside.
`
`Q.
`
`How long were you a lab tech at
`
`Harvard?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`year.
`
`About two years.
`
`What did you do after that?
`
`I worked at Boston College for another
`
`And what was the subject of your work
`
`at Boston College?
`
`A.
`
`That was on biophysical chemistry,
`
`study of a protein.
`
`Q.
`
`After your time at Boston College,
`
`what did you do after that?
`
`A.
`
`Then I was in graduate school at the
`
`University of California at Berkeley from 1980 until
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`1985.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Did you earn a degree from Berkeley?
`
`Yes, I received a Ph.D. in 1985.
`
`In what subject matter?
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`It was in biochemistry. My particular
`
`work was in biophysical chemistry of proteins.
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`Q.
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`What did you do after receiving your
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`doctoral degree?
`
`A.
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`After I received a Ph.D., I went to
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`England, to the Medical Research Council Laboratory of
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`Molecular Biology in Cambridge, where I worked with
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`Greg Winter and Cesar Milstein.
`
`Q.
`
`Is that the same Greg Winter we heard
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`testimony about from Dr. Leung?
`
`A.
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`Q.
`
`A.
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`for?
`
`Yes.
`
`What in general is Greg Winter known
`
`Greg Winter is known for his work on
`
`developing antibody technologies, especially antibody
`
`humanization.
`
`Q.
`
`In your words, how do you define
`
`antibody humanization?
`
`A.
`
`Antibody humanization is a genetic
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`method of converting typically a mouse antibody into
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`one that looks sufficiently like a human antibody that
`
`can be used for therapy.
`
`Q.
`
`What did you do with Greg Winter at
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`the medical research council?
`
`A.
`
`My project, when I first arrived, was
`
`analysis of the first humanized antibody that he made.
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`Q.
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`A.
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`What was your role in that project?
`
`I analyzed the binding -- I analyzed
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`the binding of that antibody to its target. And I was
`
`the one who found that the humanization method had
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`actually worked.
`
`Q.
`
`Did you conduct any design work at the
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`medical research council?
`
`A.
`
`Yes. That first antibody had been
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`humanized in the heavy chain only -- I'm sorry -- and
`
`once we knew that worked, I designed the first light
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`chain.
`
`Q.
`
`You made reference back when you said
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`you had gone to England to work at the medical
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`research council that Dr. Milstein, Dr. Cesar Milstein
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`was also part of that lab?
`
`A.
`
`Q.
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`He was the director, yes.
`
`He was the director. Did you do work
`
`with him as well?
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`What did you study with Dr. Milstein?
`
`With Milstein, I studied aspects of
`
`the changes in antibodies over the course of an immune
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`response.
`
`Q.
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`Is Dr. Milstein known for something in
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`particular?
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`A.
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`Yes. No longer alive, but he was very
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`well-known, in particular, for development of
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`hybridomic technology for which he received the Nobel
`
`Prize in 1984.
`
`Q.
`
`So the time you were in the medical
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`research council, about how old were you at that
`
`point?
`
`A.
`
`Q.
`
`I turned 30 when I arrived there.
`
`About the age of 30, you had already
`
`had the privilege of working with three Nobel Prize
`
`winners?
`
`A.
`
`Q.
`
`Yes. I was very privileged.
`
`What lab techniques did you use at the
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`medical research council laboratory as they pertain to
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`antibody work?
`
`A.
`
`Pertaining to antibody work, I did
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`humanized antibody design. I did gene synthesis. I
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`did design of vectors for production of antibodies.
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`And I produced antibodies both in bacteria and in
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`mammalian cells, hybridomic technology. I did some
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`structural studies of antibodies and some biophysical
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`chemistry. There may be more things.
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`Generally, analysis of antibody
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`antigen interactions through what we call immuno
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`assays.
`
`Q.
`
`Did you personally hands-on design an
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`antibody protein sequence?
`
`A.
`
`Q.
`
`Yes.
`
`Have you personally yourself designed
`
`a CDNA sequence to encode for amino acid sequence in
`
`an antibody protein?
`
`A.
`
`Q.
`
`Yes.
`
`Have you personally constructed
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`antibodies from a sequence design?
`
`A.
`
`Q.
`
`Yes.
`
`How long did you work at the medical
`
`research council laboratory in Cambridge?
`
`A.
`
`I was there seven years, from '85
`
`until 1992.
`
`Q.
`
`A.
`
`In 1992, what did you do then?
`
`In that year I moved to the Fred
`
`Hutchinson Cancer Research Center in Seattle where I
`
`had a faculty position.
`
`Q.
`
`Why did you go to the Fred Hutchinson
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`Cancer Research Center?
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`A.
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`My wife wanted to live in Seattle and
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`I had an offer from them. It's a very prestigious
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`place and it's hard to turn down.
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`Q.
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`What was the general subject matter of
`
`your research at the Hutchinson Center?
`
`A.
`
`That was a direct continuation of what
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`I had been doing in Britain. So I worked on humanized
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`antibodies. I did structural analysis of humanized
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`antibodies. I developed a new humanization method. I
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`also developed a drug delivery method that works based
`
`on antibodies.
`
`Q.
`
`Okay. How long were you at the Fred
`
`Hutchinson cancer research center?
`
`A.
`
`I was there for 12 years, until the
`
`end of 2004.
`
`Q.
`
`For the entire duration of that time,
`
`were you engaged in the laboratory doing laboratory
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`work?
`
`A.
`
`Q.
`
`Yes.
`
`What types of techniques, rather
`
`than -- I'm sorry. I think you probably already
`
`covered that.
`
`Hutchinson?
`
`What did you do after you left Fred
`
`A.
`
`After I left Fred Hutchinson, I became
`
`self-employed and I developed several business
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`activities.
`
`Q.
`
`Okay. Can you identify the business
`
`that -- businesses you founded at that point?
`
`A.
`
`Yeah. The first one was called
`
`Arrowsmith Technology Licensing. And I developed that
`
`as a vehicle for commercializing that humanization
`
`method I mentioned inventing.
`
`Q.
`
`A.
`
`Q.
`
`And when did you form that business?
`
`I believe it was incorporated in 2003.
`
`Did you receive a patent on the method
`
`of antibody humanization?
`
`name?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes, I have an issued U.S. patent.
`
`Did your method of humanization have a
`
`We called it superhumanization.
`
`Have you commercialized your
`
`humanization technology?
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`With whom?
`
`The rights to patent were licensed to
`
`a firm that's now probably the largest biotech in
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`Australia called Arana Therapeutics.
`
`Q.
`
`Are there other business activities
`
`that you're involved with in the antibody field?
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`A.
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`Yes. I started a second company to
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`commercialize that drug delivery technology that I
`
`mentioned.
`
`Q.
`
`A.
`
`And what's the name of that company?
`
`That's called -- sorry -- but it's
`
`also called Arrowsmith. Arrowsmith Technologies
`
`Corporation this time.
`
`Q.
`
`Did you do any consulting work in the
`
`antibody field?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`Currently?
`
`Yes.
`
`What sorts of clients do you serve?
`
`I do legal consulting and I do
`
`scientific consulting.
`
`Q.
`
`What types of customers do you serve
`
`on the scientific side?
`
`A.
`
`On the scientific side, these are --
`
`in each case it's a small firm in Seattle that is
`
`working on some antibody technology.
`
`Q.
`
`And before we retained you to be a
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`testifying expert for the plaintiffs in this case, had
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`you ever previously been hired to be a testifying
`
`expert?
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`A.
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`Q.
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`A.
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`Q.
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`A.
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`Q.
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`Never been a testifying expert.
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`Have you published anything?
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`Published --
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`Any of your work?
`
`Yes. I have about 30 publications.
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`What subject matter do the articles
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`address?
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`A.
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`Well, all those after 1985 are in the
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`antibody area. They're basically research papers,
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`occasional reviews.
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`I have a section in a series called
`
`the Encyclopedia of Molecular Biology, where I wrote a
`
`series of entries on antibody-antigen interactions the
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`field is called.
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`Q.
`
`How would you describe your area of
`
`expertise?
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`A.
`
`I'd say my expertise is in antibodies.
`
`I have particular strength in antibody
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`humanization structure, behavior of antibodies as
`
`proteins.
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`Q.
`
`Could you take a look -- do you have a
`
`witness binder in front of you?
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`A.
`
`Q.
`
`I do.
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`Please take a look at Tab 1, Joint
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`Exhibit 227. Tell me what that is?
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`A.
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`Q.
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`Tab 1 is my CV.
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`Is this an accurate summary of your
`
`educational background and work experience?
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`A.
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`Yes.
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`MS. KRIS: Your Honor, Dr. Foote -- we
`
`don't want to rehash old ground that Dr. Leung has
`
`plowed, but we'd be happy to make him available before
`
`he gets into the opinions that he's going to offer in
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`this case. If you had any specific questions about
`
`the particular scientific concepts.
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`THE COURT: I don't.
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`MS. KRIS: It really would only be at
`
`your direction.
`
`BY MS. KRIS:
`
`Q.
`
`If you could turn to Tab 2 in your
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`binder, Dr. Foote. It's JX 22.
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`A.
`
`Q.
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`A.
`
`please?
`
`Yes.
`
`Could you identify that document,
`
`It's the United States patent
`
`describing the framework patching method.
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`Q.
`
`Have you reviewed this patent in
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`connection with your work in this case?
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`A.
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`I've reviewed the patent, but I mostly
`
`referred to the application as published, or as filed,
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`I mean. Yes, I reviewed it.
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`Q.
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`Were you familiar with the framework
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`patching method before you were asked to serve as an
`
`expert witness in this case?
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`A.
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`Q.
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`No.
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`Have you reviewed any other documents
`
`that describe the use of the framework patching
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`method?
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`A.
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`Other than these patent materials?
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`There's the patent -- the patent application, some
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`correspondence with the U.S. patent office. Then
`
`there were materials in the case. Sorry. Let me get
`
`back to your question.
`
`Q.
`
`Have you reviewed other documents that
`
`describe use of the framework patching method?
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`A.
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`The patent materials I discussed, and
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`then other documents in the case that were sent to me
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`to review.
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`Q.
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`Have you reviewed documents regarding
`
`the methods that Immunomedics used from 1991 through
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`2000 to humanize antibodies?
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`A.
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`Yes.
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`Q.
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`A.
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`What sorts of documents were those?
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`Quite a few. The ones that were most
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`helpful to me were papers published in 1995 about
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`humanizing a mouse antibody called LL2, and another
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`paper in 1999 about humanizing a mouse antibody called
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`Immu31. Beyond that, there were other publications.
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`There were internal Immunomedics documents. There was
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`deposition testimony. And I relied on my own
`
`experience in that field.
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`Q.
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`Was the information you reviewed, in
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`your mind, sufficient to acquaint you with the methods
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`of humanization that Immunomedics used in that period?
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`A.
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`Q.
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`Yes.
`
`Have you compared the method described
`
`in the '026 patent that was issued on framework patch
`
`to Dr. Leung, as inventor, with the methods of
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`humanization as you understand them to be from your
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`review and used in approximately the years 1991
`
`through 2000?
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`A.
`
`Q.
`
`I have.
`
`Before I get into the details about
`
`how you compared those methods, I'd like to just ask
`
`about your ultimate conclusion. What did you conclude
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`from comparing those two methods?
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`A.
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`I concluded that the two methods were
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`different. The Immunomedics' method in those papers
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`and documents was -- seemed like a rather conventional
`
`approach. The framework patching method seemed like
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`something new.
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`Q.
`
`Are you aware that Immunomedics'
`
`expert has opined that the framework patching
`
`invention is virtually identical to the humanization
`
`method practiced at Immunomedics?
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`A.
`
`Q.
`
`opinion?
`
`I am.
`
`Do you agree or disagree with that
`
`A.
`
`I disagree with that. I was very
`
`surprised when I read that.
`
`Q.
`
`And what, if anything, did you rely in
`
`forming your opinions that you're about to offer, or
`
`that you have offered and are about to explain,
`
`concerning the comparison between the '026 patent and
`
`the Immunomedics' method?
`
`A.
`
`Let me understand again. Could you
`
`ask again?
`
`Q.
`
`What information, if any, did you rely
`
`on in coming to your conclusions?
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`A.
`
`Well, I relied on all those documents.
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`Well, I have a list of all the documents I reviewed
`
`attached to my expert report. But, again, the most
`
`useful ones were the '95 and '99 papers, which spelled
`
`out the methods in use at Immunomedics.
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`Q.
`
`Can you describe for us your
`
`understanding of Immunomedics' humanization technique
`
`during the time that Dr. Leung was employed there?
`
`A.
`
`All right.
`
`The Immunomedics' humanization
`
`technique is really the same as what was developed by
`
`Greg Winter and then modified by Cary Queen, in that
`
`one takes the sequence of the antibody to be
`
`humanized -- the mouse antibody to be humanized -- one
`
`compares that sequence and the framework regions to a
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`panel of human sequences. And based on homology --
`
`that is, chemical similarity between the mouse
`
`sequence and human sequences -- one chooses a human
`
`sequence to use as the source of the human material in
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`the humanized antibody.
`
`Q.
`
`I'm just asking you to describe. I
`
`think you just went into Queen's method. Why do you
`
`think that Immunomedics' method is essentially similar
`
`to what Dr. Queen --
`
`A.
`
`Well, the description in the '95,
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`and '90 papers is like that.
`
`There's a special case we've been
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`discussing in court about framework. Maybe we can get
`
`into that at some point.
`
`Q.
`
`Yes. We absolutely will.
`
`Now, in addition, can you explain in a
`
`little bit more detail what exactly it is that you're
`
`comparing in the Queen method when you say you're
`
`trying to undertake a homology match or homology
`
`search?
`
`A.
`
`In the Queen method, you do your
`
`homology comparison over the entire length of the
`
`antibody sequence or the antibody variable region
`
`sequence. So frameworks 1, 2, 3, and 4. So over that
`
`entire length.
`
`Yes, so you evaluate your homology
`
`over that length and, in general, you pick the most
`
`homologous human sequence to use for your humanizing.
`
`But one of the -- but in addition to
`
`that, Queen especially articulated that homology
`
`itself may not be enough. You may -- in addition to
`
`ensure that your humanized antibody is still
`
`functional, you might have to bring additional mouse
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`amino acids in some positions in the framework.
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`Q.
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`A.
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`Q.
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`Is there a common term for that?
`
`That's called back mutation.
`
`Does Immunomedics use the practice of
`
`back mutations in the materials that you reviewed?
`
`A.
`
`Q.
`
`Yes.
`
`Now, you spoke earlier about an
`
`exception, I think is the word that you used, at
`
`Immunomedics about framework 4.
`
`Could you please describe your
`
`understanding of what that exception is.
`
`A.
`
`Yes. In -- well, let's take the '95
`
`paper, to begin with.
`
`The search was done over the entire
`
`length of the mouse frameworks comparing to entire
`
`human molecules. But when they -- what the
`
`Immunomedics group found was that they had a good
`
`match to a human antibody called EU, except for
`
`framework 4. EU just had a lot of mismatches in it.
`
`They thought, if we use this framework
`
`4, we might get into trouble. So we're going to take
`
`a framework 4 from some other molecule, and they did.
`
`They took one from a different human antibody called
`
`NEWM -- N-E-W-M -- capital letters.
`
`Q.
`
`Was the use of a framework 4 from a
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`different human antibody than the one selected for the
`
`framework region comprised of frameworks 1, 2 and 3 a
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`technique that was unique to Immunomedics?
`
`A.
`
`No. That had been used before.
`
`In fact, when I designed that first
`
`humanized light chain back in early 1986, it would
`
`have been, I used a framework 4 for that from a
`
`different source than frameworks 1, 2 and 3. I
`
`understand other groups have done the same since then.
`
`Q.
`
`A.
`
`Q.
`
`Were your results published?
`
`Yes.
`
`Could you take a look at Tab 3 in your
`
`binder and call up JX 297.
`
`A.
`
`Q.
`
`A.
`
`I'm at Tab 3, yes.
`
`What is that document?
`
`That's a paper I published with
`
`Greg Winter on humanizing an antibody.
`
`Q.
`
`Is that -- does that discuss anything
`
`in particular? I mean, which antibody?
`
`A.
`
`Q.
`
`This is an anti-lysozyme design.
`
`And how was the light chain of that
`
`antibody constructed?
`
`A.
`
`That was the light chain I referred
`
`to, the one I designed and constructed.
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`Q.
`
`And can you identify where in the
`
`articles it discusses the use of a different -- or a
`
`framework 4 from a different human antibody than the
`
`one selected from frameworks 1, 2, 3?
`
`A.
`
`If you go to page 68, you'll see the
`
`sequence. But in English, if you go to page 67, in
`
`the last paragraph it says, "However, the sequence
`
`encoding residues beyond number 96 of the mature
`
`protein was taken directly from the human J1 segment."
`
`The rest of that molecule had come
`
`from a human antibody called REI.
`
`Q.
`
`And you mentioned that you had since
`
`learned, or I guess since learned, since you may have
`
`been the first person to do that, being one of the
`
`first people to humanize an antibody, you since
`
`learned about others that have practiced that
`
`technique as well?
`
`A.
`
`Yes. These were mentioned earlier
`
`today in a paper by Sherman and a paper by Ohtomo.
`
`Q.
`
`Do you view the use of a different
`
`framework 4 from the framework selected in the
`
`framework 1 to 3 regions as a major departure over the
`
`Queen and Winter methods?
`
`A.
`
`No, I don't. We didn't think of this
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`as a breakthrough. We had no -- we never made any
`
`effort to patent use of a separate framework at all.
`
`Q.
`
`A.
`
`And why not?
`
`Because that's how antibodies are
`
`assembled in nature. Just in nature. In all of us in
`
`this room, we make antibodies with framework 4 from a
`
`separate gene than frameworks 1, 2 and 3.
`
`Q.
`
`We had some discussion of that. Is
`
`the natural recombination process the process that is
`
`essentially described or depicted in this slide?
`
`A.
`
`Q.
`
`Yes.
`
`How many V genes are there from which
`
`the framework 1 through framework 3 region can be
`
`selected?
`
`A.
`
`Q.
`
`About 40 or 50.
`
`Were you in the courtroom yesterday
`
`when Dr. Leung described framework patching?
`
`A.
`
`Q.
`
`Yes.
`
`Just for record purposes, the slide
`
`that Dr. Foote was referring to was PDX4. I did not
`
`call that up.
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`Based on your review of the patent
`
`applications, do you agree with his description of the
`
`framework patching method?
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`A.
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`Q.
`
`Yes.
`
`Can you describe your understanding of
`
`what framework patching entails?
`
`A.
`
`Framework patching is a method of
`
`deciding what framework sequences to use in a
`
`humanization project.
`
`Shall I discuss this in some depth?
`
`Please.
`
`Okay. And there are few steps to it.
`
`Q.
`
`A.
`
`First, you would start with your mouse sequence and
`
`then conceptually break that sequence into CDRs and
`
`frameworks.
`
`And then you, let's say, focus on
`
`framework 1. You compare that for homology against a
`
`panel of human framework 1 sequences. But you pay --
`
`you collect -- you score overall homology. But in
`
`particular you -- there's an emphasis on getting --
`
`Q.
`
`Let me stop you right there. What do
`
`you mean by "scoring overall homology"?
`
`A.
`
`What are you scoring? What's usually
`
`scored is identity. If you have a sequence ABC, and
`
`then you have another sequence ABC, those are
`
`identical.
`
`If you have ABC and then ABE, then you
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`have one mismatch at that position.
`
`Q.
`
`And so, to be even more precise,
`
`walking through the framework patching method, what
`
`constitutes the ABC sequence and what constitutes the
`
`ABE sequence in your --
`
`A.
`
`Sorry. I wasn't clear. The ABC
`
`sequence refers to the protein sequence of the
`
`framework. And ABC corresponds to amino acid
`
`residues.
`
`Q.
`
`When you say "the framework," tell us
`
`what you mean by "the framework." We've heard
`
`framework, we've heard framework regions, framework
`
`segments. Using framework patching, you start with
`
`framework 1, what exactly are you comparing for
`
`purposes of arriving, as you described, at an overall
`
`homology?
`
`A.
`
`Right.
`
`Well, framework 1, let's see. There
`
`are classical studies of antibody sequences done by
`
`Kabat and Wu that classify residues as even being part
`
`of framework, or complimentary determining region,
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`which I'll call CDR. And these are specified by
`
`position in the sequence.
`
`So the first 30 amino acids are part
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`of framework 1, and the next five amino acids -- this
`
`is in the heavy chain -- are called CDR1. So when I
`
`say framework 1, I'm referring to that first block of
`
`30 amino acids.
`
`Q.
`
`So for the homology match purpose,
`
`just so that the record is clear, what are you
`
`comparing to what?
`
`A.
`
`For the homology matching process,
`
`I'll take that first block of 30 amino acids from a
`
`mouse antibody, and I'll take a human sequence from my
`
`panel of human sequences and I'll ask, position by
`
`position, is there a match or mismatch or are these
`
`the same or identical. And if they're not identical,
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`if they're different, I'll say that's one mismatch,
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`and I'll count the number of mismatches in that bank
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`of 30 amino acids.
`
`Q.
`
`So after you've done that, what does
`
`framework patching teach you should do next?
`
`A.
`
`Let me get back to the method. I was
`
`saying the things that are particularly important in
`
`framework patching are the residues closest to the
`
`CDR.
`
`The idea there is that when you're
`
`humanized, your framework -- your human framework has
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`to provide the same chemical environment that the
`
`mouse CDRs would see in the mouse antibody. Suddenly
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`these mouse CDRs find themselves in some different
`
`chemical environment. They might not fold upright and
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`they might not bind the target antigen. So the
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`residues that are closest to the CDRs are considered
`
`very important in quite a few humanizing methods.
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`There's a strong idea in the
`
`humanizing field that framework residues close to the
`
`CDRs should be identical, or at least chemically very
`
`similar in the humanized antibody as compared to the
`
`mouse.
`
`Q.
`
`How does that concept affect the test
`
`of doing a homology search in the framework patching
`
`method?
`
`A.
`
`Right. Well, what that does is,
`
`there's a strong priority for getting -- for choosing
`
`a human framework segment. I'm calling -- the
`
`different parts of the framework segments -- so I'm
`
`calling framework 1 a framework segment. If I
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`mistakenly say frameworks or something like that, I
`
`might be talking about the whole collection: framework
`
`1, framework 2, framework 3, framework 4.
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`So I might have lost the thread of
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`your question.
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`Q.
`
`I was saying, how does the concept of
`
`paying particular attention to the amino acids
`
`residues that blank the CDRs affect how the homology
`
`search is done using the framework patching method?
`
`A.
`
`Right. When you look through those
`
`human sequences, what one would look for first are the
`
`residues that are closest to the CDR.
`
`So if the mouse -- if the four mouse
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`residues closest to a CDR go A, B, C, D, you would
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`look for human framework sequences that also go A, B,
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`C, D and say, ah, here's one that goes A, B, C, D.
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`The CDRs will think they're still in the mouse
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`antibody and fold up fine and the antibody will work
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`like gangbusters.
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`If you find human antibodies that
`
`don't go A, B, C, D, they go A, B, E, X, you might set
`
`those aside and not work with them.
`
`Q.
`
`So, for framework patching purposes,
`
`would that complete your homology search at the
`
`framework 1?
`
`A.
`
`Oh, no. There are quite a few steps
`
`in framework patching. So I've said you focus on
`
`those residues closest to the CDR. But you also look
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`at overall homology. So besides, you know, a few
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`closest to the CDRs, you look at the rest of the 30,
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`let's say, in framework 1. And you ask how many
`
`mismatches are there. And you take note when you find
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`sequences that are matched well at the CDRs -- at the
`
`CDR junction -- and also have very few mismatches to
`
`the mouse antibody over the rest of that framework
`
`segment.
`
`Q.
`
`So you're finished with framework 1?
`
`What do you do next?
`
`A.
`
`We haven't finished with framework 1.
`
`No. There's still more.
`
`Because, in addition to that -- I
`
`mentioned that in the Queen method there was a feeling
`
`that, besides homology, you might have to back mutate
`
`certain positions. And in the framework patching
`
`method, you try not to do that. A big thrust of that
`
`method is to avoid having to put in back mutations.
`
`But you may find for some reason that you need to, for
`
`one reason or another. So that is also a
`
`consideration. But now we're ready to move on to
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`framework 2.
`
`Q.
`
`Okay. And in framework 2, do you do
`
`anything different?
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`A.
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`Framework 2 you do pretty much the
`
`same. Framewo
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