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`JAY M. STEWART, MD - REDIRECT
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` 1358
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`would find in the specification that says any one of these
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`regimens should be used or called out to be used with DME or
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`diabetic retinopathy?
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`A.
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`Q.
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`No.
`
`When it came to your testimony that you provided here
`
`in court today, did you assume that you had to find an example
`
`in order to find enablement or written description?
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`A.
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`Q.
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`No, I didn't.
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`Let's go back, then, to the press release, which was
`
`DTX 3198. And let's go to the second page of the exhibit.
`
`And let's call up the description of the VEGF
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`Trap-Eye in Phase II development paragraph.
`
`Now, I believe you indicated that what was written on
`
`the page for the first indication that involved an eight-week
`
`dosing regimen was what? 2 milligrams every eight weeks after
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`three monthly loading doses?
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`A.
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`The first one was 2 milligram monthly and then
`
`2 milligram every eight weeks after three monthly loading doses
`
`was the second option.
`
`Q.
`
`Now, even if there's no express recitation of the
`
`number five there, does the prn dosing regimen permit dosing
`
`that would include five monthly loading doses in the context of
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`this regimen?
`
`A.
`
`You could happen upon a scenario where five loading
`
`doses are given through the course of using a prn approach.
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3
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`3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1220
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`JAY M. STEWART, MD - REDIRECT
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` 1359
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`Q.
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`And would that prn regimen also permit, then, those
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`five loading doses being followed by an eight-week dosing
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`regimen?
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`A.
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`It could be if that's how circumstances played out
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`for that particular patient.
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`MS. MAZZOCHI: Nothing further, Your Honor. Thank
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`you.
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`doctor?
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`THE COURT: Recross?
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`MR. GREGORY: Nothing further, Your Honor.
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`THE COURT: Any exhibits we need to tidy up with the
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`MR. GREGORY: None from us, sir.
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`THE COURT: Are the stack that was in the binder part
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`of the record, or are you satisfied just --
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`MR. GREGORY: We are satisfied. We don't need to
`
`move them into evidence.
`
`THE COURT: All right. Understood.
`
`Any other exhibits from defense standpoint, then.
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`MS. MAZZOCHI: Your Honor, because so many of what
`
`was in the stack I've never seen before, let me -- can I just
`
`have -- to see if I need to put them in the record for this
`
`witness just to make sure that the Court has context and
`
`completeness. But, otherwise, we don't have anything further.
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`But we'll clean that up tomorrow morning if that's all right.
`
`THE COURT: Understood.
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1221
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1360
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`MS. MAZZOCHI: Thank you.
`
`THE COURT: Doctor, thank you. You can step down.
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`You can leave all the documents up there. Someone will tidy
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`those up. Thank you, sir.
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`If I could ask counsel to grab whatever's up here,
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`whomever it belongs to.
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`While we're doing that, Mylan may call its next
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`witness.
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`If everyone has finished rotating and whatnot,
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`Counsel, you may call your next witness.
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`MR. SALMEN: Thank you, Your Honor. Heinz Salmen on
`
`behalf of defendants Mylan and Biocon. We call Dr. Gregory
`
`MacMichael as our next witness.
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`THE COURT: Doctor, if you would come all the way to
`
`the front.
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`You may proceed, Counsel.
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`MR. SALMEN: Thank you, Your Honor.
`
`GREGORY MACMICHAEL, PhD, DEFENDANTS' WITNESS, SWORN
`
`DIRECT EXAMINATION
`
`BY MR. SALMEN:
`
`Q.
`
`A.
`
`Q.
`
`Good afternoon, Dr. MacMichael.
`
`Good afternoon.
`
`Would you please introduce yourself to the Court.
`
`THE WITNESS: Your Honor, my name is Greg MacMichael.
`
`THE COURT: Good afternoon, sir.
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1222
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1361
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`BY MR. SALMEN:
`
`Q.
`
`Dr. MacMichael, are you here testifying on behalf of
`
`Mylan and Biocon?
`
`A.
`
`Q.
`
`Yes, I am.
`
`And did you prepare a set of demonstrative slides to
`
`assist with your testimony today?
`
`A.
`
`Q.
`
`Yes, I did.
`
`Okay.
`
`If we could pull up DDX 8 on the screen.
`
`And I believe you've been provided a binder and a
`
`printout of these slides. Dr. MacMichael, are these the slides
`
`that you prepared?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes, they are.
`
`Dr. MacMichael, where are you from?
`
`I'm from New Jersey.
`
`And turning to your demonstrative slide, DDX 2, on
`
`the screen, will you please provide the Court with a summary of
`
`your educational background.
`
`A.
`
`Yes. I went to Penn State to get a bachelor's degree
`
`in microbiology. Subsequent to that, I went to North Carolina
`
`State University to get a master's degree in microbiology and
`
`biochemistry focusing on the use of -- I went to North Carolina
`
`State to get my master's degree in microbiology and
`
`biochemistry with a focus on the use of bacteria to break down
`
`hazardous wastes and degrade oil spills.
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1223
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1362
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`Q.
`
`A.
`
`What was your doctoral thesis in?
`
`Yes. I got my PhD in microbiology and biochemistry
`
`at Mississippi State University, again working on the use of
`
`bacteria for the cleanup of hazardous waste and oil spills.
`
`Q.
`
`After receiving your doctorate from Mississippi State
`
`University in 1984, where did you begin your career?
`
`A.
`
`Yeah. My first job after college was working at a
`
`company called Techne.
`
`Q.
`
`And will you please summarize for the Court your
`
`professional experience at Techne.
`
`A.
`
`Yes. At Techne I was working with an individual
`
`named Norman Burney, who also was a famous innovator. And
`
`together we worked on the development of bioreactors for
`
`growing up animal cells to produce therapeutic proteins.
`
`Q.
`
`A.
`
`Q.
`
`How many years were you at Techne?
`
`Six years.
`
`After your six years at Techne, where did you
`
`continue your career?
`
`A.
`
`I moved over to Centocor and was the assistant
`
`director of cell culture research and development.
`
`Q.
`
`A.
`
`What was the focus of your work at Centocor?
`
`It was focused on developing high-cell-density,
`
`high-volumetric productivity processes for making monoclonal
`
`antibodies.
`
`Q.
`
`Will you please explain to the Court what a
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1224
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1363
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`monoclonal antibody is.
`
`A.
`
`Yes. As you're developing a therapeutic, you will
`
`basically genetically modify numerous cells, and then you will
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`look to see which one was the highest level of productivity.
`
`You will then pick that specific clone that was obtained from
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`that one cell, and thus the term "monoclonal antibody."
`
`Q.
`
`Did you have any notable achievements during your
`
`time at Centocor?
`
`A.
`
`Q.
`
`A.
`
`Yes, I did.
`
`And can you describe for the Court, please.
`
`Yes. I developed the high-density upstream processes
`
`for Centoxin, the first monoclonal ever approved, Remicade, and
`
`ReoPro.
`
`Q.
`
`A.
`
`Q.
`
`A.
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`sepsis.
`
`And were those FDA-approved medications?
`
`They were all FDA-approved medications.
`
`And what type of drug product is Centoxin?
`
`Centoxin is a immunoglobulin M for the treatment of
`
`Q.
`
`What were your primary contributions to the
`
`development of Centoxin?
`
`A.
`
`Developing the high cell density processes, doing the
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`tech transfer into manufacturing, and supporting the
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`manufacturing efforts.
`
`Q.
`
`A.
`
`What type of drug product is Remicade?
`
`Remicade is an IgG monoclonal antibody for the
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1225
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
`
` 1364
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`treatment of autoimmune disorder.
`
`Q.
`
`What were your primary contributions to the
`
`development of the Remicade product?
`
`A.
`
`Again, developing high cell density, high volumetric
`
`productivity processes for the manufacturing of Remicade.
`
`Q.
`
`And turning to the ReoPro product, what type of drug
`
`product is ReoPro?
`
`A.
`
`ReoPro is a subclass of a monoclonal. It's a
`
`fragment, called Fab -- fragment of an antibody is called a
`
`Fab -- and it was actually a fusion protein. It was part
`
`human, part mouse.
`
`Q.
`
`Can you describe to the Court what your primary
`
`contributions were to the development of ReoPro?
`
`A.
`
`Again, my focus was on the upstream processes to
`
`develop high productivity to be able to meet market demand.
`
`Q.
`
`After your time at Centocor, I see you moved on to
`
`Chiron. Why did you make the move to Chiron?
`
`A.
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`Yes. My supervisor, the head of development at
`
`Centocor, moved over to Chiron to be the senior vice president
`
`of development and manufacturing. He asked if I would join him
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`at Chiron, and I became the director of production in vaccines
`
`development in St. Louis.
`
`Q.
`
`A.
`
`What was the focus of your work at Chiron?
`
`It was developing subunit vaccines in a cell line
`
`called Chinese hamster ovarian cells.
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3
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`3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1226
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
`
` 1365
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`Q.
`
`Will you please explain to the Court what a Chinese
`
`hamster ovarian, or CHO, cell is.
`
`A.
`
`Yes. In the production of various therapeutic
`
`proteins, they use animal cells. A Chinese hamster ovarian
`
`cell was proved to be a very robust cell line, reached high
`
`levels of cell density and productivity, and also had more
`
`favorable what we call glycosylation patterns.
`
`Q.
`
`Can you expand on that? What is a glycosylation
`
`pattern?
`
`A.
`
`Yes. Inside each of our cells, there's a whole set
`
`of machinery that synthesizes proteins. And after the primary
`
`protein is synthesized, the cells then can further -- what's
`
`called posttranslational modification. They can modify those
`
`cells by putting sugars on those cells to change the
`
`performance in the bloodstream.
`
`Q.
`
`Dr. MacMichael, did you invent the glycosylation
`
`pattern for the proteins you were working on?
`
`A.
`
`No. Every cell in the human body has the ability to
`
`glycosylate proteins.
`
`Q.
`
`A.
`
`And what notable achievements did you have at Chiron?
`
`At Chiron we produced -- we developed multiple
`
`vaccines, but one of most interest would be hepatitis B vaccine
`
`where I led the global team, which included a clinical,
`
`regulatory, and manufacturing and development, and basically
`
`developed a new formulation for that vaccine.
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1227
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1366
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`Q.
`
`Let me follow up on that, Dr. MacMichael. Were you
`
`overseeing the formulation activities during that development?
`
`A.
`
`Q.
`
`Yes, I was.
`
`After Chiron, I see you moved over to Eli Lilly in
`
`1997. Why did you make the move to Lilly?
`
`A.
`
`Yes. Eli Lilly was trying to develop a product
`
`called Xigris, activated protein C produced in HEK293 cell
`
`line, but they lacked the internal experience of how to grow
`
`those cells at high cell density. So they recruited me in to
`
`help them develop the process.
`
`Q.
`
`A.
`
`Q.
`
`What was your title at Lilly?
`
`Senior director of development.
`
`What type of drug products were you working on at
`
`Lilly? What was your focus?
`
`A.
`
`Q.
`
`The focus was on therapeutic proteins.
`
`Will you please describe to the Court some of your
`
`notable achievements at Lilly.
`
`A.
`
`Yes. Probably the two more notable achievements was
`
`the successful development and registration of Xigris,
`
`activated protein C for the treatment of sepsis; and
`
`additionally the development of truncated parathyroid hormone,
`
`known as Forteo, for the treatment of osteoporosis.
`
`Q.
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`Were those drugs approved by any regulatory
`
`authorities?
`
`A.
`
`They were approved by the FDA and the EMA.
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1228
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1367
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`Q.
`
`I see you continued your career at Wyeth. What was
`
`your title at Wyeth?
`
`A.
`
`At Wyeth I was vice president of vaccines
`
`development.
`
`Q.
`
`And I see you have a couple drug names listed here on
`
`Slide 3 of DDX 8. What are those drugs that you were referring
`
`to?
`
`A.
`
`They're probably two of my more notable
`
`accomplishments while at Wyeth. Prevnar 13 is a pneumococcal
`
`vaccine that vaccinates against 13 different types of
`
`pneumococcal pneumonia.
`
`Q.
`
`Let me ask a follow-up to that, Dr. MacMichael. What
`
`was your contribution to the development of the Prevnar 13
`
`formulation?
`
`A.
`
`Yes. I had responsibilities from cell line
`
`development through upstream process development, purification
`
`and final formulation and the development of the analytical --
`
`of the assays required for in process and release testing.
`
`Q.
`
`Did you contribute to the stable formulation for the
`
`Prevnar 13?
`
`A.
`
`Q.
`
`Yes.
`
`And how did you achieve a stable formulation in
`
`Prevnar 13?
`
`A.
`
`Yes. Initially, we found that, heading into Phase I
`
`clinical trials, the vials -- just vibration in the
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1229
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1368
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`refrigerators was sufficient agitation to cause some undesired
`
`aggregation. We addressed that by adding Pluronic -- by adding
`
`polysorbate 80 to prevent the aggregation.
`
`Q.
`
`The second product on your list at Wyeth is FluMist.
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`What type of drug product is FluMist?
`
`A.
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`FluMist is a more advanced version of the annual flu
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`vaccine that many of us get. The difference with FluMist is
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`it's -- actually, the virus is not inactivated; so it elicits a
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`better immune response. It's sprayed up the nose, and it
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`cannot grow in the lungs. So it gets a very good immune
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`response protecting the recipient against the flu.
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`Q.
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`Dr. MacMichael, what was the general time frame for
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`your work on the Prevnar 13 and FluMist formulation?
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`A.
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`Q.
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`2002 through 2008.
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`I see you next were the senior vice president of
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`development and manufacturing at Cook Pharmica in 2008.
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`What was the focus of your work at Cook?
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`A.
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`Cook was a contract development and manufacturing
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`organization. That is, we didn't have our own products; we
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`developed and manufactured the products for our clients.
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`Q.
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`And then in 2010 you moved on to Novartis as global
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`head of biologics. What was the focus of your work at
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`Novartis?
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`A.
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`My focus at Novartis was the development activities
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`required to bring the biologic pipeline in Novartis, which
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1230
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1369
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`included cell line development, upstream process development,
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`purification, final formulation development, and the analytics
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`required for all of those activities.
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`Q.
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`Thank you, Dr. MacMichael.
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`If we turn to Slide 4 of DDX 8, can you describe to
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`the Court what you have illustrated here on Slide 4.
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`A.
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`This is a summary of some of the products that we
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`touched on. These are eight products that I successfully
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`developed and supported the registration and the interactions
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`with the FDA and EMA.
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`Q.
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`Let me ask about that, Dr. MacMichael. In your over
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`30 years of industry experience, did you gain experience on the
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`regulatory side of product development?
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`A.
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`Q.
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`A.
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`Yes, I did.
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`Can you describe that experience briefly.
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`Yes. To bring these types of molecules successfully
`
`forward, you have numerous interactions with the FDA and the
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`EMA. It also requires an understanding of how to construct the
`
`various submissions that are required for successful
`
`registration.
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`Q.
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`Dr. MacMichael, are you still active in the
`
`pharmaceutical industry?
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`A.
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`Yes, I am. I founded my own consultancy called
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`CMC Bioservices.
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`Q.
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`And what types of companies do you generally consult
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1231
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1370
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`for?
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`A.
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`I consult in the pharmaceutical industry everything
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`from a large pharma company down to small startups.
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`Q.
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`A.
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`What technical areas do you generally consult in?
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`My focus is on therapeutic proteins, vaccines, and
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`cell and gene therapies, from development of cell lines all the
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`way down through the final drug product.
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`Q.
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`Last question on your background Dr. MacMichael.
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`Using your own words, how would you describe your areas of
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`expertise?
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`A.
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`Yeah. My expertise -- CMC stands for chemistry
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`manufacturing control is the term we used for doing process
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`development and manufacturing. My expertise starts with cell
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`line development, and the cell lines that produce therapeutic
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`proteins are put down in vials called cell banks. We do a cell
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`line selection for the highest producer.
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`Subsequent to that, we develop across the upstream
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`process, grow the cells up, and produce the desired protein.
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`We then need to purify it. And then subsequent to having it
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`purified in what we call bulk. It is then formulated into the
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`final vial.
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`So in many ways, I have responsibilities from vial to
`
`vial, is one way to put it.
`
`Q.
`
`A.
`
`Is that vial to vial illustrated on Slide 6 of DDX 8?
`
`Yes, it is.
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6
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`W h e e l i n g , W V
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`2 6 0 0 3
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`3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1232
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1371
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`Q.
`
`Dr. MacMichael, I see you've cited DTX 7087, pages 1
`
`through 6. There's a copy of it in your binder, but we could
`
`also show that on the screen for you.
`
`Is this a copy of your current CV?
`
`A.
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`Yes, it is.
`
`MR. SALMEN: Your Honor, we move to admit DTX 7087
`
`into evidence.
`
`THE COURT: Any objection?
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`MR. BERL: No objection.
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`THE COURT: Without objection, so admitted.
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`(DTX 7087 was admitted.)
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`MR. SALMEN: And at this time, Your Honor, we proffer
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`Dr. Gregory MacMichael as an expert in the formulation and
`
`development of therapeutic proteins.
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`THE COURT: Any voir dire or objection?
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`MR. BERL: No, Your Honor.
`
`THE COURT: Without objection then, motion granted.
`
`The doctor is deemed so qualified.
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`You may proceed, Counsel.
`
`MR. SALMEN: Thank you, Your Honor.
`
`BY MR. SALMEN:
`
`Q.
`
`Dr. MacMichael, if we turn to Slide 7 of your slide
`
`presentation, DDX 8, let's talk about the opinions that you
`
`plan to provide to the Court today.
`
`If I could first direct your attention to PTX 2, we
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1233
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1372
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`have the first page of PTX 2 here on Slide 8.
`
`What is PTX 2?
`
`PTX 2 is the '865 patent.
`
`And did you review and analyze the '865 patent,
`
`A.
`
`Q.
`
`PTX 2, in forming your opinions?
`
`A.
`
`Q.
`
`Yes, I did.
`
`And let's also put DTX 0030 on the screen.
`
`Dr. MacMichael, did you review and consider the
`
`document known as the prosecution history for the '865 patent
`
`in forming your opinions?
`
`A.
`
`Q.
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`Yes, I did.
`
`Turning to slide -- back to Slide 8 of DDX 8,
`
`Dr. MacMichael, before we go through your opinions, let's just
`
`set the stage a little.
`
`Did you conduct your analysis in this case from the
`
`perspective of a person of ordinary skill in the art?
`
`A.
`
`Q.
`
`Yes.
`
`And if we look at Slide 8, top callout, citing
`
`DDX 2679, pages 19 to 20, MacMichael opening report, is this
`
`the definition for the person of ordinary skill in the art that
`
`you applied in forming your opinions?
`
`A.
`
`Q.
`
`Yes, it is.
`
`And I'll read that definition into the record for
`
`you, Dr. MacMichael.
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`"A POSA during the relevant time period would have a
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1234
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1373
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`fairly high level of education and skill. Here, a POSA would
`
`have at least a PhD in chemistry, chemical engineering,
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`biochemistry, pharmacology, or a related field, along with one
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`to two years of experience in the development and manufacture
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`of formulations of therapeutic proteins or a lower degree with
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`more practical industrial experience. A POSA would have access
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`to biologists, biochemists, physicians, pharmaceutical
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`formulators, and the like with knowledge and experience in
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`fields such as drug discovery and development and the treatment
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`of ophthalmologic conditions."
`
`Dr. MacMichael, is this the definition of a person of
`
`ordinary skill in the art that you applied in forming your
`
`opinions?
`
`A.
`
`Q.
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`Yes, it is.
`
`Dr. MacMichael, did Dr. Trout also offer for a person
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`of ordinary skill in the art?
`
`A.
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`Q.
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`Yes, he did.
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`Do you have Dr. Trout's definition illustrated at the
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`bottom right-hand side of Slide 8 of DTX 8, citing DTX 2251,
`
`page 11?
`
`A.
`
`Q.
`
`A.
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`Yes, I did.
`
`How did Dr. Trout's definition compare to yours?
`
`Relatively similar. Dr. Trout just had a master's
`
`degree where I had suggested a PhD for the POSA. Other than
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`that, the two definitions were relatively similar.
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1235
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1374
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`Q.
`
`Dr. MacMichael, would your opinions regarding the
`
`'865 patent change at all if the Court were to adopt
`
`Dr. Trout's definition?
`
`A.
`
`Q.
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`No, they would not.
`
`Now, let's move on to our second foundational point,
`
`Dr. MacMichael. Turning to Slide 9 of DDX 8, are you aware
`
`that the Court issued a claim construction order regarding
`
`certain terms of the '865 patent that are relevant to your
`
`opinions?
`
`A.
`
`Q.
`
`Yes, I am.
`
`And if we look here on Slide 9, we have the Court's
`
`claim construction order marked for identification at DTX 6439
`
`here at page 20. I'll read this for you, Dr. MacMichael.
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`"The Court adopts Mylan's definition of 'cosolvent.'
`
`It is an organic substance added to the primary solvent to
`
`increase the solubility of the solute, here a VEGF antagonist."
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`Dr. MacMichael, is this the construction of the claim
`
`term "cosolvent" that you applied to your analysis regarding
`
`infringement and validity of the '865 patent?
`
`A.
`
`Q.
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`Yes, it is.
`
`If we turn to Slide 10, please.
`
`Dr. MacMichael, will you explain to the Court what
`
`you have illustrated here in the bubble at the center of
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`Slide 10, DDX 8, citing DTX 6439, page 20.
`
`A.
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`Yes. I took the Court's construction for an organic
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1236
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1375
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`cosolvent and edited Claim 1. And as you see in the
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`highlighted yellow -- excuse me -- red is the insertion of the
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`Court's construct.
`
`Q.
`
`And, Dr. MacMichael, is that the version of Claim 1
`
`that you applied in your analysis regarding the infringement
`
`inquiry?
`
`A.
`
`Q.
`
`Yes, it is.
`
`If we turn to Slide 11, please, of DDX 11.
`
`Dr. MacMichael, will you please summarize for the
`
`Court the opinions you plan to offer today regarding the
`
`alleged infringement of the '865 patent against Mylan and
`
`Biocon's Yesafili product.
`
`A.
`
`Yes. Applying the Court's claim construction order,
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`Yesafili does not infringe on the asserted Claims 4, 7, 9, 11,
`
`and 14 through 17 of the '865 patent.
`
`Q.
`
`And did you form an opinion regarding whether
`
`polysorbate 20 at 0.03 percent in Yesafili is an organic
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`cosolvent?
`
`A.
`
`Q.
`
`A.
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`Yes, I did.
`
`And what was your conclusion?
`
`My conclusion is that polysorbate 20 at 0.03 percent
`
`in Yesafili is not an organic cosolvent.
`
`Q.
`
`And did you form an opinion regarding whether
`
`polysorbate 20 at 0.03 percent in Yesafili is increasing
`
`solubility of the solute aflibercept in the Yesafili product?
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1237
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1376
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`A.
`
`Q.
`
`A.
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`Yes, I did evaluate.
`
`And what was your conclusion in that regard?
`
`My conclusion was that polysorbate 20 at 0.03 percent
`
`in Yesafili does not increase solubility of the solute
`
`aflibercept.
`
`Q.
`
`Dr. MacMichael, I understand that you were unable to
`
`attend Dr. Trout's testimony in person. Were you nonetheless
`
`able to review Dr. Trout's trial testimony as well as his
`
`associated demonstratives?
`
`A.
`
`Q.
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`Yes, I was.
`
`Was there any portion of Dr. Trout's testimony that
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`you want to respond to specifically during your testimony
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`today?
`
`A.
`
`Q.
`
`There's two points where I believe we disagree.
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`Can you explain to the Court those two points of
`
`Dr. Trout's testimony that you would like to respond to.
`
`A.
`
`Q.
`
`A.
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`Yes.
`
`First point, please.
`
`The first point, Dr. Trout defined inhibiting
`
`aggregation as equal to increasing solubility.
`
`Q.
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`A.
`
`Q.
`
`A.
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`Do you agree or disagree with that testimony?
`
`I disagree.
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`And your second point, Dr. MacMichael?
`
`The second point where I differ is reducing
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`insolubility is equivalent to increasing solubility. I
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1238
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`GREGORY MACMICHAEL, PhD - DIRECT
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` 1377
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`disagree.
`
`Q.
`
`Dr. MacMichael, I would next like to talk about some
`
`of the technology relevant to your opinions in this case. If
`
`we could turn to Slide 13. Here on Slide 13 of DDX 8 we have
`
`DTX 5172, the Bontempo reference. Dr. MacMichael, did you
`
`review and consider the Bontempo reference in forming your
`
`opinion?
`
`A.
`
`Q.
`
`Yes, I did.
`
`Will you please explain to the Court the information
`
`you have identified here in Slide 13 from Bontempo that's
`
`relevant to your opinions and testimony in this case.
`
`A.
`
`Yes. I pulled a list of potential buffers that could
`
`be used in a protein formulation.
`
`Q.
`
`And that information -- does that information come
`
`from page 7 of DTX 5172, Bontempo?
`
`A.
`
`Q.
`
`Yes, it does.
`
`If we turn to the next slide, Slide 14 -- actually,
`
`I'm sorry. I forgot to ask a question.
`
`Could we go back one.
`
`Dr. MacMichael, can you please explain the relevance
`
`of the information that you provided in the parentheticals
`
`following each of the listed buffers?
`
`A.
`
`Yeah. The parentheticals are showing the pH ranges
`
`where each of these buffers would -- each one of these moieties
`
`would be effective as a buffer.
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1239
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`GREGORY MACMICHAEL, PhD - DIRECT
`
` 1378
`
`Q.
`
`And, for example, if we look at succinate, what would
`
`be the buffering range for that buffer?
`
`A.
`
`Q.
`
`A pH of 3.2 to 6.6.
`
`And for citrate, what would be the known buffering
`
`range for a citrate buffer?
`
`A.
`
`Q.
`
`2.1 to 6.2.
`
`For histidine, what would be the known buffering
`
`range for a histidine buffer?
`
`A.
`
`Q.
`
`5.5 to 6.5.
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`If we turn to Slide 14, please, of DDX 8.
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`Here, Dr. MacMichael, we have Exhibit DTX 5196. This
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`is the Strickley reference. Dr. MacMichael, did you review and
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`rely on the Strickley reference?
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`A.
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`Q.
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`Yes, I did.
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`And please explain to the Court the teaching in
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`Strickley that you have highlighted here on Slide 14 from
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`page 2 of DTX 5196.
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`A.
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`Yes. I pulled out Strickley's definition of a
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`cosolvent.
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`Q.
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`And is that identified in the yellow highlighted
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`language there?
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`A.
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`Q.
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`Yes, it is.
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`I'll read that for you, Dr. MacMichael.
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`"Cosolvents are mixtures of miscible solvents and are
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`oft