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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1732
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`months in a glass vial?
`
`A.
`
`It shows that it was unchanged from the initial
`
`measurement; so it's good stability.
`
`Q.
`
`Now, in the course of your stability study work on
`
`aflibercept formulations, did you also vary the amounts of
`
`polysorbate 20?
`
`A.
`
`Q.
`
`A.
`
`Q.
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`A.
`
`Q.
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`We did.
`
`Let's look at PTX 2265, page 1.
`
`What is this document, Dr. Graham?
`
`This is the 205th stability study protocol.
`
`And what amount of polysorbate did you test here?
`
`0.06 percent.
`
`And if we look at page 2, Table 1, of PTX 2265, was a
`
`glass vial tested in this study as well?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes, it was.
`
`Was that Device 7?
`
`Yes, it is.
`
`Let's compare the formulation of the SS205 protocol
`
`that we just looked at with the formulation of Example 5 of the
`
`'865 patent, PTX 2, page 8, Column 10. How do these two
`
`formulations compare, Dr. Graham?
`
`A.
`
`So they have the same components. The difference is
`
`that there is .03 percent polysorbate in Example 5
`
`and .06 percent polysorbate in Study 205.
`
`Q.
`
`Did you look at these -- this .06 percent
`
`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 1525
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1733
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`polysorbate 20 formulation by size-exclusion chromatography?
`
`A.
`
`Q.
`
`Yes, we did.
`
`Let's look at PTX 2266, page 15. Is this the SEC
`
`data for the glass vial at 5 degrees C?
`
`A.
`
`Q.
`
`Yes, it is.
`
`And what was the percent native conformation as
`
`measured by SEC following storage in a glass vial for two
`
`months at 5C for this formulation?
`
`A.
`
`Q.
`
`A.
`
`Q.
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`99.0 percent.
`
`Did you run turbidity analysis here as well?
`
`Yes, we did.
`
`Let's look at PTX 2267, page 17.
`
`THE COURT: Counsel, once we go through this table,
`
`if we're at a spot to take our afternoon break.
`
`MR. TRASK: Absolutely, Your Honor.
`
`BY MR. TRASK:
`
`Q.
`
`A.
`
`Q.
`
`Is this the turbidity data for the SS205 study?
`
`Yes, it is.
`
`And what was the turbidity at 5 degrees Celsius for
`
`two months in a glass vial?
`
`A.
`
`Q.
`
`A.
`
`It was unchanged from the initial measurement.
`
`Is that a good result?
`
`Yes.
`
`MR. TRASK: Okay. Happy to break at this point, Your
`
`Honor, if you'd like.
`
`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 1526
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1734
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`THE COURT: Why don't we go ahead and do that, then.
`
`We're going to take ten minutes. We'll resume at 3:00, a
`
`couple minutes after that.
`
`Doctor, you haven't been in the courtroom; so this
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`may be a new speech for you. Because you're midstream on your
`
`testimony, no one can speak with you in particular about your
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`testimony. So everyone would run the other way as opposed to
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`greeting you.
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`THE WITNESS: Sounds good.
`
`THE COURT: You're welcome.
`
`I just didn't want you to think that anyone was being
`
`rude or discourteous to you. But you can go ahead and step
`
`down, sir. But you're a man without a country for the next ten
`
`minutes or so.
`
`We'll see everyone in a few. Thank you.
`
`(A recess was taken from 2:54 p.m. to
`
`3:15 p.m.)
`
`THE COURT: Apologies. That break ran over. We had
`
`a cataclysmic user error with the Keurig coffee machine. That
`
`was my user error. Don't worry. We're getting new carpet as
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`part of the great asbestos project. That's what we're telling
`
`ourselves.
`
`Counsel, you may proceed.
`
`MR. TRASK: It doesn't show on the black robe.
`
`THE COURT: That's the beauty of the black robe.
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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
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1527
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1735
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`Thank you, sir. Go right ahead.
`
`MR. TRASK: Thank you.
`
`BY MR. TRASK:
`
`Q.
`
`If we could turn back to Stability Study 207 briefly,
`
`Dr. Graham.
`
`A.
`
`Q.
`
`Sure.
`
`And if we look at PTX 2275. And, actually, this one
`
`is not in your binder; so I'm going to hand up copies of this.
`
`MR. TRASK: With the Court's permission?
`
`THE COURT: You may.
`
`BY MR. TRASK:
`
`Q.
`
`A.
`
`Q.
`
`Doctor, do you have PTX 2275 in front of you?
`
`Yes.
`
`Okay.
`
`And for the record, this is Bates-stamped
`
`RGN-EYLEA-MYLAN-00475679. And it's a native Excel file printed
`
`as a PDF.
`
`Doctor, we previously discussed the two-month
`
`5C-degree pull date in exhibit -- in Stability Study SS207.
`
`Does this exhibit, PTX 2275, show the same pull date at two
`
`months, 5 degrees C, that we discussed in connection with
`
`PTX 1825 for Stability Study 207?
`
`A.
`
`Q.
`
`Yes, I believe it does.
`
`And for the record, what is the pull date at two
`
`months, 5C, in Stability Study SS207?
`
`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 1528
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1736
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`21 March 2006.
`
`Okay. I'd also -- we can put that aside for the
`
`A.
`
`Q.
`
`moment.
`
`I'd also like to discuss or revisit briefly in
`
`connection with SS207, PTX 2277, page 15. And this --
`
`actually, this is -- if we could look at the bottom of this
`
`Excel spreadsheet.
`
`So, Doctor, I think you testified about the date at
`
`the bottom of this Excel spreadsheet, SS207, indicating when
`
`the two months' SEC data was run?
`
`A.
`
`Q.
`
`Yes.
`
`Can you explain the date it was run and the
`
`connection to the date shown at the bottom of this spreadsheet.
`
`A.
`
`Okay. So this is a sequence number. What we do is
`
`we start the sequence and we assign a date code to it. So 06
`
`is 2006, 03 is March, 20 is the 20th of March. The F is the
`
`system number or system identifier that we used.
`
`So this sequence actually was started the day before
`
`the samples were pulled. And we did that because we were
`
`running standards and systems suitability, and we wanted to
`
`ensure that we got all the standard system suitability, all
`
`that done, and then allowed -- had a system that's all set,
`
`ready to go, you walk in in the morning, you pull out your
`
`samples, you put them on, and you run them that day. We didn't
`
`want things drifting later and later. We just wanted to be set
`
`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 1529
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1737
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`and primed and ready to go.
`
`Q.
`
`Okay. So what was the date that you were getting the
`
`size-exclusion chromatography analysis machine ready?
`
`A.
`
`So the date we were getting it ready was the 20th,
`
`which was the date before the pull.
`
`Q.
`
`A.
`
`Q.
`
`And that's March 20th, 2006?
`
`Yes.
`
`And then what's the date on which you actually ran
`
`the sample for 5 degrees C, two months?
`
`A.
`
`They would have gone up on the 21st, the day they
`
`were pulled.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`And that's March 21, 2006?
`
`Yes.
`
`Okay.
`
`We can take that down.
`
`Thank you, Doctor.
`
`Doctor, did you sit for a deposition in this case?
`
`Yes, I did.
`
`Do you recall during your deposition counsel for
`
`defendants showed you some internal Regeneron documents where
`
`polysorbate was referred to as a stabilizing agent?
`
`A.
`
`Q.
`
`Yes, I did.
`
`During your work involving formulations of
`
`aflibercept, did you sometimes call polysorbate 20 a stabilizer
`
`or a stabilizing agent?
`
`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 1530
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1738
`
`A.
`
`Q.
`
`Yes, I did.
`
`Did you also refer to polysorbate 20 as an organic
`
`cosolvent in connection with that work?
`
`A.
`
`Q.
`
`Yes, I did.
`
`And did you also call polysorbate 20 at times a
`
`surfactant?
`
`Yes.
`
`Can you explain why you were using these different
`
`A.
`
`Q.
`
`labels?
`
`A.
`
`So surfactant is kind of self-explanatory. It's the
`
`chemical structure of the polysorbate.
`
`Cosolvent is, you know, what we were using it for
`
`within the formulation. And a cosolvent stabilizes the
`
`formulation; so hence stabilizer or stabilizing agent.
`
`Q.
`
`So would I be mistaken if I called polysorbate 20 a
`
`stabilizing agent?
`
`A.
`
`No, you would not be.
`
`MR. RAKOCZY: Your Honor, I'm going to object.
`
`Again, expert testimony. Also, he's offering opinions on
`
`construction of claims. He didn't offer any of that before.
`
`We're hearing this for the first time.
`
`THE COURT: Counsel?
`
`MR. TRASK: This is not in connection with the claim,
`
`Your Honor. I'm referring to the documents that he prepared in
`
`the course of his development of the invention.
`
`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 1531
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1739
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`THE COURT: Well, let's stick to those actual
`
`documents as opposed to what's his interpretation thereof.
`
`Otherwise, sustained.
`
`MR. TRASK: Thank you, Your Honor.
`
`BY MR. TRASK:
`
`Q.
`
`Let's look at PTX 672.
`
`What is this document, Doctor?
`
`A.
`
`So this is the pharmaceutical development section
`
`that I wrote for Eylea.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Section of what?
`
`The BLA.
`
`Is this the Eylea BLA?
`
`Yes.
`
`Okay. And you're familiar with this document?
`
`Yes.
`
`It's a long document, 483 pages. What was your
`
`specific involvement with this document?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`I wrote it.
`
`The whole thing?
`
`Yes.
`
`Okay. If we turn to page --
`
`Sorry.
`
`THE COURT: Understood, Doctor.
`
`BY MR. TRASK:
`
`Q.
`
`If we turn to page 26 of this document, Dr. Graham,
`
`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 1532
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1740
`
`did you write this section of the document as well?
`
`A.
`
`Q.
`
`A.
`
`I did.
`
`And what is this section of the document?
`
`It is describing the choice of organic cosolvent and
`
`the selection of the concentration for the formulation.
`
`Q.
`
`If we look at the last paragraph on page 26 of
`
`Exhibit PTX 672, do you see where it says polysorbate 20 was
`
`selected as the organic cosolvent?
`
`A.
`
`Yes. It says polysorbate 20 was selected as the
`
`organic cosolvent because a lower concentration was required to
`
`stabilize the VEGF Trap when subjected to agitation stress.
`
`Q.
`
`Why did you call polysorbate 20 an organic cosolvent
`
`in this document?
`
`A.
`
`Because that's what I was using it for in the
`
`formulation.
`
`Q.
`
`And you understood, when you wrote this document,
`
`that it would be submitted to the FDA?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`And was it, in fact, submitted to the FDA?
`
`Yes, it was.
`
`And this is an accurate statement?
`
`Yes, it is.
`
`Okay.
`
`We can take that down.
`
`Now, when you were working to develop more stable
`
`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 1533
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1741
`
`intravitreal formulations of aflibercept, were you aware of
`
`public information about other existing protein formulations?
`
`A.
`
`Q.
`
`Some, yes.
`
`And in the course of your work, did you ever consider
`
`taking the aflibercept and just plugging it into a formulation
`
`that had been used to stabilize a different protein?
`
`A.
`
`Q.
`
`A.
`
`No.
`
`Why not?
`
`All right. So proteins are individuals. No two
`
`proteins really behave exactly the same. They have different
`
`likes and dislikes. So a formulation that works well for one
`
`protein may not work well for another one. Things like pH
`
`are critical. Choice of stabilizer can be critical.
`
`MR. RAKOCZY: Again, objection, Your Honor. Again,
`
`that's expert opinion testimony. He can testify about his
`
`personal experience with aflibercept, but now he's venturing
`
`into other proteins and what would and would not work.
`
`THE COURT: That's sustained.
`
`BY MR. TRASK:
`
`Q.
`
`Moving on, when developing your invention, was
`
`tonicity a consideration for you, Doctor?
`
`A.
`
`Q.
`
`A.
`
`To a degree.
`
`Okay. Can you explain that?
`
`So we knew that we -- or thought that we did not want
`
`to inject something that was 1,000 milliosmoles. We thought
`
`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 1534
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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`that could potentially be bad. But we weren't necessarily
`
`concerned that we had to be exactly isotonic with the
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`environment. We figured we had wiggle room.
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`Q.
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`And you testified earlier that Example 5 of your '865
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`patent was not an isotonic formulation; is that right?
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`A.
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`Q.
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`That is correct.
`
`Did you nonetheless consider the formulation of
`
`Example 5 to be a candidate formulation for intravitreal
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`injection?
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`A.
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`Q.
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`Yes.
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`Now, does -- the '865 patent on which you're named as
`
`an inventor, does that identify which of the formulations it
`
`discloses is the one that corresponds to Regeneron's Eylea
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`formulation?
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`A.
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`Q.
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`No, it does not.
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`Does it indicate anything about whether Regeneron
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`preferred one of those formulations over another?
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`A.
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`Q.
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`Not that I've seen in the document, no.
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`Were you permitted as a Regeneron employee to
`
`publicly identify the formulation for Eylea before the Eylea
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`product was released onto the market?
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`A.
`
`Q.
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`I was not.
`
`And to your knowledge, prior to Eylea's launch, was
`
`the formulation that you invented that eventually became the
`
`commercial Eylea formulation ever publicly identified as
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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
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`3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1535
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1743
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`Regeneron's commercial formulation?
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`A.
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`Q.
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`Not to my knowledge, no.
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`Now, you invented formulations of aflibercept that
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`have greater than 98 percent native conformation following
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`storage?
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`A.
`
`Q.
`
`Yes.
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`To your understanding at the time, did the FDA
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`require some degree of stability in the products that it
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`approves?
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`A.
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`Q.
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`Yes.
`
`To your understanding at the time, did the FDA
`
`require at least 98 percent native conformation for an approved
`
`intravitreal product?
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`MR. RAKOCZY: Your Honor, I'm going to object to the
`
`extent he's asking what the FDA did or didn't think, did or
`
`didn't require.
`
`MR. TRASK: He just testified that he wrote part of
`
`the BLA --
`
`THE COURT: Understood, but let's focus on his
`
`understanding as to why or why not certain things might or
`
`might not be included in there.
`
`Overruled with that caveat.
`
`BY MR. TRASK:
`
`Q.
`
`Okay. Dr. Graham, when you were developing your
`
`aflibercept formulations, did you understand that you needed to
`
`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 1536
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1744
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`achieve at least 98 percent native conformation in order for
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`the product to be approved?
`
`A.
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`That would not have been an obligate requirement. We
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`needed a stable formulation. A stable formulation is supported
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`based on what your clinical experience is. We wanted the 98
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`percent or -- as pure as we could possibly get it because we
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`wanted the best possible product, you know, for the patient.
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`That was our goal.
`
`Q.
`
`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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`Now, is aflibercept a fusion protein, Doctor?
`
`Yes, it is.
`
`Is aflibercept an antibody?
`
`No.
`
`Are fusion proteins and antibodies the same thing?
`
`No, they are not.
`
`MR. RAKOCZY: Objection, Your Honor. Again, expert
`
`testimony.
`
`THE COURT: Sustained.
`
`BY MR. TRASK:
`
`Q.
`
`Okay. So one brief point to wrap up, Doctor.
`
`You've been working as a scientific researcher for
`
`about how long?
`
`A.
`
`Well, 22 years at Regeneron, ten years at the City of
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`Hope, and then -- god -- since probably -- what? -- '81 at Penn
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`State. So what? 42 years, give or take.
`
`Q.
`
`And of all the scientific work you've done over 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
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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 1537
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1745
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`course of your career, where did the inventions of the '865
`
`patent rank?
`
`A.
`
`Q.
`
`A.
`
`Well, that's probably at the top of the heap.
`
`Why is that?
`
`Well, I have a very personal story with respect to
`
`Eylea. My mother suffered from wet AMD. I knew that my
`
`grandmother, her mom, had gone blind. I didn't know why. Now,
`
`my mom was a very, very private person. She never revealed
`
`what was going on with her. She had basically gone blind in
`
`one eye from the disease, and we didn't know this. And then
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`she started complaining about her eyesight. And then we
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`realized or learned, she finally fessed up, that she had the
`
`disease in the other eye.
`
`You know, she was getting regular doses of Lucentis
`
`every month, but her vision was getting worse. My wife and I
`
`were, like, trying to find every opportunity so she could see
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`my daughter, you know, get to see her at swim meets and get to
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`see her and spend time with her while she still could see her.
`
`And by the time or before -- shortly before Eylea was
`
`approved, her vision had gotten to 21/20, 21/40. She wasn't
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`driving anymore. You know, she was somebody that always liked
`
`to do crossword puzzles and word things, couldn't see to do
`
`those. So it was kind of very dire.
`
`Eylea got approved. I had seen the clinical data and
`
`thought, well, this looks better. I started having
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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 1538
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PhD - DIRECT
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` 1746
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`conversations with her ophthalmologist, which she didn't like
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`much, but I kind of was I'm not going to sit there and let you
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`go blind; I want to see if there's something we can do. I
`
`suggested Eylea. I got back oh, these things are all the same.
`
`I finally, in March of 2011, got to the point where I
`
`stood and looked at him and said, okay, why are you sentencing
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`my mother to blindness? What we're doing right now is not
`
`working. It's just getting worse. Can we just try something
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`better or different? If it doesn't work, we're no worse off.
`
`And he agreed at that point to order the drug in.
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`She did her three loading doses. Her vision improved. She got
`
`to the point where she was seeing 20/40. With eyeglasses, she
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`was driving again. She got to see Kendra grow up. And it
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`maintained her vision up until the last few months of her life.
`
`You know, what can you do better than save your
`
`mother's sight?
`
`MR. TRASK: Thanks so much, Doctor.
`
`Nothing further at this time.
`
`THE COURT: Understood.
`
`Cross?
`
`MR. RAKOCZY: May we approach with some binders, Your
`
`Honor.
`
`THE COURT: You may.
`
`MR. RAKOCZY: Good afternoon, Your Honor. William
`
`Rakoczy for Mylan and Biocon.
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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 1539
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PHD - CROSS
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` 1747
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`THE COURT: You may proceed, sir.
`
`CROSS-EXAMINATION
`
`BY MR. RAKOCZY:
`
`Q.
`
`A.
`
`Q.
`
`Good afternoon, Dr. Graham.
`
`Good afternoon.
`
`Nice to meet you.
`
`Dr. Graham, I'd like to start with DTX 722. And
`
`we'll pull it up on screen, and it's also in your binder that
`
`hopefully you were just handed.
`
`A.
`
`Q.
`
`Yes.
`
`I'd like you to look at page 1. You see this is an
`
`email dated March 21st, 2006, correct?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes, I do.
`
`And it's from Kathleen DeWald to you?
`
`Yes.
`
`Is that right?
`
`And I'd like to go to the attachment at page 2. And
`
`here you see a product composition, correct?
`
`A.
`
`Q.
`
`I do.
`
`It contains phosphate -- strike that.
`
`And the formulation, under the "Product Composition"
`
`heading, contains phosphate, NaCl, polysorbate 20, sucrose, and
`
`40 mg/mL VEGF Trap, correct?
`
`A.
`
`Q.
`
`I do.
`
`And I'd like to focus on the first sentence of 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
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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 1540
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PHD - CROSS
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` 1748
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`paragraph above it. It states, "This is an unstable
`
`formulation for VEGF Trap since there are minimal excipients
`
`for intravitreal delivery and the formulation contains a high
`
`concentration of VEGF Trap."
`
`Is that right?
`
`That is correct.
`
`Now, below that it actually goes on to caution that
`
`A.
`
`Q.
`
`the drug product should -- being held or stored at 25 degrees C
`
`should be kept to a minimum during the manufacturing process,
`
`correct?
`
`that.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes. I see those words on the page.
`
`And at temperatures above 25 degrees C -- strike
`
`Temperatures above 25C must be avoided, correct?
`
`That's correct.
`
`And that this drug product should be held or stored
`
`at less than minus 20 degrees C, correct?
`
`A.
`
`Q.
`
`I see that, yes.
`
`Now, I'd like to look at the table just below that.
`
`And in this table we see polysorbate 20 identified as a
`
`stabilizer as its function, correct?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`It's not identified as a solvent, correct?
`
`The description on the page says stabilizer.
`
`And the solvent in this formulation is the water or
`
`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 1541
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PHD - CROSS
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` 1749
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`the water for injection, correct?
`
`A.
`
`That is the description for water for injection on
`
`the page.
`
`Q.
`
`Now, let's take a look at one of your signed memos on
`
`your ITV formulation.
`
`Let's pull up DTX 737.
`
`And here we see a signed memo from you dated
`
`April 6th, 2006, correct?
`
`A.
`
`Q.
`
`Hang on. I'm trying to follow you.
`
`DTX 737. And I have it on the screen as well. We'll
`
`go to page 2.
`
`A.
`
`Q.
`
`Yes, I see page 2.
`
`And you see your signature dated April 6th, 2006, at
`
`the very top, correct?
`
`A.
`
`Q.
`
`Yes, I do.
`
`And this is entitled "40 mg/mL VEGF Trap for ITV in a
`
`sucrose- and polysorbate-containing formulation," correct?
`
`A.
`
`Q.
`
`That is correct.
`
`Now, we see just below that the same cautionary
`
`statements on storing the drug product.
`
`Do you see that?
`
`A.
`
`There are cautionary statements. They're not exactly
`
`the same, though, no.
`
`Q.
`
`It says the drug substance, formulated drug
`
`substance, or drug product, the time it's held or stored at 25
`
`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 1542
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PHD - CROSS
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` 1750
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`degrees C should be kept to a minimum during the manufacturing
`
`process, correct?
`
`A.
`
`Q.
`
`That's the words on the page, that's correct.
`
`And, again, it cautions that temperatures above 25
`
`degrees C must be avoided for this formulation, correct?
`
`A.
`
`Q.
`
`That is correct.
`
`And it says that this drug product formulation should
`
`be held or stored at 2 to 8 degrees C, correct?
`
`A.
`
`Well, yes, it says 2 to 8 degrees C on this page,
`
`correct.
`
`Q.
`
`Now, let's go down to the table below this as well.
`
`And here again, we see that water is identified as the function
`
`in the formulation -- or as the solvent in the formulation,
`
`correct?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Well, WFI is identified as the solvent, yes.
`
`And that's water for injection; is that right?
`
`That is correct.
`
`And the polysorbate 20, its function is identified as
`
`stabilizer, correct?
`
`Yes, it is.
`
`It's not the solvent, correct?
`
`It's identified as stabilizer.
`
`And it's not the solvent in this formulation,
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`correct?
`
`A.
`
`It's identified as a stabilizer.
`
`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 1543
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PHD - CROSS
`
` 1751
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`Q.
`
`My question is it is not the solvent in this
`
`formulation? Is that right or is that not right?
`
`A.
`
`Water is identified as the solvent in the
`
`formulation.
`
`Q.
`
`And water is the only solvent in this formulation; is
`
`that right?
`
`A.
`
`Water is what is identified as the solvent in the
`
`formulation.
`
`Q.
`
`Let's take a look at another one of your memos, DTX--
`
`I believe the next one would be -- let me back up. I want to
`
`stay on this one.
`
`This particular memo does not have any stability data
`
`for the formulation in it, correct?
`
`If -- can you show me the whole screenshot of this.
`
`Yes. Can we pull up that whole page, DTX 737,
`
`A.
`
`Q.
`
`page 2.
`
`A.
`
`Okay. So this document does not have stability data
`
`associated with it. It's a recipe that was provided to the
`
`manufacturing group so that they could formulate the material.
`
`It's not -- it's not our common practice and has never been our
`
`common practice to include stability data with a recipe.
`
`Q.
`
`My question is simple. In this document there's no
`
`stability data, no turbidity data, no native conformation data;
`
`is that right?
`
`A.
`
`That's correct.
`
`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 1544
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`KENNETH S. GRAHAM, PHD - CROSS
`
` 1752
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`Q.
`
`Let's go to DTX 736. And we have another one of your
`
`memos. Can you confirm for me on page 3 that you, in fact,
`
`signed and dated this document April 21st, 2006; is that right?
`
`Well, I see that on page 1 of 2 I signed it.
`
`And that is on page 3 of the exhibit; is that
`
`A.
`
`Q.
`
`correct?
`
`A.
`
`Oh. I'm sorry. I didn't understand what you were
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`meaning by page 3.
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`Q.
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`At the bottom you should see DTX 736.0003 of the
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`exhibit.
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`A.
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`Q.
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`Yes, I do.
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`And under the heading "Formulation," you see this
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`formulation contains phosphate, NaCl, polysorbate 20, and
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`40 mg/mL VEGF Trap, correct?
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`A.
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`Q.
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`Yes.
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`And we see similar cautionary statements in this memo
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`as well for the formulation; is that correct?
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`A.
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`Q.
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`That is correct.
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`The time that the drug product is held or stored at
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`25 degrees C should be kept to a minimum, correct?
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`A.
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`Q.
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`correct?
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`A.
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`Q.
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`During the manufacturing process, yes.
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`And temperatures above 25 degrees C must be avoided,
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`Yes.
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`And the drug product should be held or stored at 2 to
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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 1545
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`KENNETH S. GRAHAM, PHD - CROSS
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` 1753
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`8 degrees C, correct?
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`A.
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`Q.
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`That's correct.
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`And like the prior memo, there's no stability,
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`turbidity, or native conformation data in this particular memo;
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`is that right?
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`A.
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`Q.
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`No. It's a recipe.
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`Can we go to the formulation table at the second half
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`of this page. And here again, water for injection, or WFI, is
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`identified as the solvent; is that right?
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`A.
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`Q.
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`correct?
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`A.
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`Q.
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`That is correct.
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`And polysorbate 20 is identified as the stabilizer,
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`Yes.
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`Now, let's look at DTX 725 and look at the lead
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`formulation. And I want to focus in this exhibit first on the
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`email on page 1 which is dated May 8th, 2006, from Dr. Furfine
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`to you.
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`A.
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`Q.
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`Do you see that?
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`It's in the middle of the page.
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`Yes, I do.
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`And you see Dr. Furfine addresses you. He says,
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`"Ken, can you provide to Ellen the two formulations that we are
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`moving into the tox study." Correct?
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`A.
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`Q.
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`Yes.
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`And then you then responded in the email above this
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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 1546
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`KENNETH S. GRAHAM, PHD - CROSS
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` 1754
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`and you provided two formulations; is that right?
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`A.
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`Q.
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`Yes, it is.
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`And the formulation above is entitled the lead
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`formulation; is that right?
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`A.
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