1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1732
`
`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.
`
`A.
`
`Q.
`
`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
`
`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 1525
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1732
`
`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.
`
`A.
`
`Q.
`
`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
`
`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 1525
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1733
`
`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.
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1734
`
`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
`
`may be a new speech for you. Because you're midstream on your
`
`testimony, no one can speak with you in particular about your
`
`testimony. So everyone would run the other way as opposed to
`
`greeting you.
`
`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
`
`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.
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1735
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1736
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1737
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1739
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1742
`
`that could potentially be bad. But we weren't necessarily
`
`concerned that we had to be exactly isotonic with the
`
`environment. We figured we had wiggle room.
`
`Q.
`
`And you testified earlier that Example 5 of your '865
`
`patent was not an isotonic formulation; is that right?
`
`A.
`
`Q.
`
`That is correct.
`
`Did you nonetheless consider the formulation of
`
`Example 5 to be a candidate formulation for intravitreal
`
`injection?
`
`A.
`
`Q.
`
`Yes.
`
`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
`
`formulation?
`
`A.
`
`Q.
`
`No, it does not.
`
`Does it indicate anything about whether Regeneron
`
`preferred one of those formulations over another?
`
`A.
`
`Q.
`
`Not that I've seen in the document, no.
`
`Were you permitted as a Regeneron employee to
`
`publicly identify the formulation for Eylea before the Eylea
`
`product was released onto the market?
`
`A.
`
`Q.
`
`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
`
`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 1535
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1743
`
`Regeneron's commercial formulation?
`
`A.
`
`Q.
`
`Not to my knowledge, no.
`
`Now, you invented formulations of aflibercept that
`
`have greater than 98 percent native conformation following
`
`storage?
`
`A.
`
`Q.
`
`Yes.
`
`To your understanding at the time, did the FDA
`
`require some degree of stability in the products that it
`
`approves?
`
`A.
`
`Q.
`
`Yes.
`
`To your understanding at the time, did the FDA
`
`require at least 98 percent native conformation for an approved
`
`intravitreal product?
`
`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
`
`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 1536
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1744
`
`achieve at least 98 percent native conformation in order for
`
`the product to be approved?
`
`A.
`
`That would not have been an obligate requirement. We
`
`needed a stable formulation. A stable formulation is supported
`
`based on what your clinical experience is. We wanted the 98
`
`percent or -- as pure as we could possibly get it because we
`
`wanted the best possible product, you know, for the patient.
`
`That was our goal.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`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
`
`Hope, and then -- god -- since probably -- what? -- '81 at Penn
`
`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
`
`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 1537
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1745
`
`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
`
`she started complaining about her eyesight. And then we
`
`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
`
`my daughter, you know, get to see her at swim meets and get to
`
`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
`
`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
`
`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 1538
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PhD - DIRECT
`
` 1746
`
`conversations with her ophthalmologist, which she didn't like
`
`much, but I kind of was I'm not going to sit there and let you
`
`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
`
`my mother to blindness? What we're doing right now is not
`
`working. It's just getting worse. Can we just try something
`
`better or different? If it doesn't work, we're no worse off.
`
`And he agreed at that point to order the drug in.
`
`She did her three loading doses. Her vision improved. She got
`
`to the point where she was seeing 20/40. With eyeglasses, she
`
`was driving again. She got to see Kendra grow up. And it
`
`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.
`
`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 1539
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1747
`
`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
`
`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 1540
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1748
`
`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
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 1541
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1749
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1750
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1751
`
`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
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1752
`
`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
`
`meaning by page 3.
`
`Q.
`
`At the bottom you should see DTX 736.0003 of the
`
`exhibit.
`
`A.
`
`Q.
`
`Yes, I do.
`
`And under the heading "Formulation," you see this
`
`formulation contains phosphate, NaCl, polysorbate 20, and
`
`40 mg/mL VEGF Trap, correct?
`
`A.
`
`Q.
`
`Yes.
`
`And we see similar cautionary statements in this memo
`
`as well for the formulation; is that correct?
`
`A.
`
`Q.
`
`That is correct.
`
`The time that the drug product is held or stored at
`
`25 degrees C should be kept to a minimum, correct?
`
`A.
`
`Q.
`
`correct?
`
`A.
`
`Q.
`
`During the manufacturing process, yes.
`
`And temperatures above 25 degrees C must be avoided,
`
`Yes.
`
`And the drug product should be held or stored at 2 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
`
`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 1545
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1753
`
`8 degrees C, correct?
`
`A.
`
`Q.
`
`That's correct.
`
`And like the prior memo, there's no stability,
`
`turbidity, or native conformation data in this particular memo;
`
`is that right?
`
`A.
`
`Q.
`
`No. It's a recipe.
`
`Can we go to the formulation table at the second half
`
`of this page. And here again, water for injection, or WFI, is
`
`identified as the solvent; is that right?
`
`A.
`
`Q.
`
`correct?
`
`A.
`
`Q.
`
`That is correct.
`
`And polysorbate 20 is identified as the stabilizer,
`
`Yes.
`
`Now, let's look at DTX 725 and look at the lead
`
`formulation. And I want to focus in this exhibit first on the
`
`email on page 1 which is dated May 8th, 2006, from Dr. Furfine
`
`to you.
`
`A.
`
`Q.
`
`Do you see that?
`
`It's in the middle of the page.
`
`Yes, I do.
`
`And you see Dr. Furfine addresses you. He says,
`
`"Ken, can you provide to Ellen the two formulations that we are
`
`moving into the tox study." Correct?
`
`A.
`
`Q.
`
`Yes.
`
`And then you then responded in the email above this
`
`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 1546
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 1
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
` 7
`
` 8
`
` 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`KENNETH S. GRAHAM, PHD - CROSS
`
` 1754
`
`and you provided two formulations; is that right?
`
`A.
`
`Q.
`
`Yes, it is.
`
`And the formulation above is entitled the lead
`
`formulation; is that right?
`
`A.
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
