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`BERNHARDT TROUT, PHD - DIRECT
`
` 2043
`
`based on Gaudreault of the aflibercept, much less than the
`
`10 mg/mL.
`
`Q.
`
`Now, let's take a look at Ferrara 2004.
`
`Just for the record, this is a different Ferrara
`
`article. It's PTX 1838.
`
`Did you review this article as well?
`
`Yes, I did.
`
`Okay. And if we look to page 7 of the article, can
`
`A.
`
`Q.
`
`you explain what Ferrara is disclosing here and how it's
`
`relevant to the consideration of an appropriate concentration
`
`to use.
`
`A.
`
`Certainly.
`
`So Ferrara -- and, again, different from the Ferrara
`
`that we just talked about a little while ago, it's referring to
`
`the VEGF Trap again and is basically just relating what I said
`
`earlier and what the POSA would know. Because of the fact that
`
`this not a natural molecule, it's completely constructed, the
`
`junctions between the various structural elements in such
`
`multicomponent molecules can generate an immune response,
`
`which, again, I think I talked about this last week too, is
`
`something that the formulator is very concerned about.
`
`Q.
`
`What would the relevance of this discussion in
`
`Ferrara 2004, Exhibit 1838, have had on the concentration that
`
`the POSA would have wanted to use for an intravitreal
`
`injection?
`
`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 1836
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2043
`
`based on Gaudreault of the aflibercept, much less than the
`
`10 mg/mL.
`
`Q.
`
`Now, let's take a look at Ferrara 2004.
`
`Just for the record, this is a different Ferrara
`
`article. It's PTX 1838.
`
`Did you review this article as well?
`
`Yes, I did.
`
`Okay. And if we look to page 7 of the article, can
`
`A.
`
`Q.
`
`you explain what Ferrara is disclosing here and how it's
`
`relevant to the consideration of an appropriate concentration
`
`to use.
`
`A.
`
`Certainly.
`
`So Ferrara -- and, again, different from the Ferrara
`
`that we just talked about a little while ago, it's referring to
`
`the VEGF Trap again and is basically just relating what I said
`
`earlier and what the POSA would know. Because of the fact that
`
`this not a natural molecule, it's completely constructed, the
`
`junctions between the various structural elements in such
`
`multicomponent molecules can generate an immune response,
`
`which, again, I think I talked about this last week too, is
`
`something that the formulator is very concerned about.
`
`Q.
`
`What would the relevance of this discussion in
`
`Ferrara 2004, Exhibit 1838, have had on the concentration that
`
`the POSA would have wanted to use for an intravitreal
`
`injection?
`
`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 1836
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2044
`
`A.
`
`Well, it would teach the POSA to use a low
`
`concentration. Again, it's going to be much lower than the
`
`10 mg/mL to try to minimize the risk of such an immune
`
`response.
`
`Q.
`
`Let's take a look at the Wang reference. That's
`
`PTX 1556.
`
`And we'll blow up part of page 1.
`
`What is Wang teaching here, and how does it relate to
`
`the protein concentration that the person of ordinary skill
`
`would have wanted to use?
`
`A.
`
`Well, Wang here -- again, this is a review article.
`
`It says, "Increasing protein concentration generally increases
`
`protein aggregation."
`
`Q.
`
`And so how would that be relevant to the POSA who's
`
`trying to choose a concentration to use for intravitreal
`
`injection?
`
`A.
`
`Well, it would teach the POSA to use as low a
`
`concentration as possible, again teach away from these higher
`
`concentrations like 40 mg/mL. Again, aggregation can cause
`
`serious problems, as the formulator would understand, not only
`
`in -- you don't want to inject aggregates as such into the eye,
`
`but also the possibility of these immune responses.
`
`Q.
`
`Okay.
`
`And for the record, this is page 9 of PTX 1556, the
`
`Wang reference.
`
`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 1837
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2045
`
`Doctor, in view of the -- all of the prior art that
`
`you reviewed, what would the POSA have thought in terms of an
`
`appropriate concentration of aflibercept for intravitreal
`
`injection if the POSA had wanted to use aflibercept for
`
`intravitreal injection?
`
`A.
`
`Well, the POSA would choose a concentration probably
`
`lower than that of ranibizumab, so lower than 10 mg/mL.
`
`Q.
`
`What would the POSA have thought about the idea of
`
`using 40 mg/mL?
`
`A.
`
`Well, the POSA would be taught away from using
`
`40 mg/mL. In other words, it wouldn't be a good idea.
`
`Q.
`
`Now, I'd like to turn to a new topic, which is
`
`polysorbate 20.
`
`Doctor, if we pull up the claims again, do all of the
`
`asserted claims require polysorbate 20?
`
`A.
`
`Q.
`
`Yes, they do.
`
`And do you understand Dr. Rabinow in his combination
`
`to have relied on Gaudreault and Shams for this limitation?
`
`A.
`
`Q.
`
`Yes.
`
`And what do the references -- well, let's first look
`
`at Gaudreault.
`
`And, again, this is page 2 of Gaudreault. What does
`
`Gaudreault teach with respect to its formulation and
`
`polysorbate 20?
`
`A.
`
`Well, Gaudreault teaches, as we have here -- this is
`
`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 1838
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2046
`
`the formulation in the first -- or the top excerpt and the
`
`highlighted one -- highlighted sentence for polysorbate, which,
`
`again, I think Your Honor noted correctly that Tween 20 is a
`
`synonym for polysorbate. It teaches 0.05 percent.
`
`THE COURT: I've been right about this for the last
`
`couple weeks, Doctor, if you ask all them out there.
`
`Oh, come on. That was funnier.
`
`MR. BERL: No comment. Too tired to laugh, Your
`
`Honor.
`
`THE COURT: Limping to the finish line, but I thought
`
`that was better than that.
`
`THE WITNESS: That was funny from up here.
`
`THE COURT: Thank you.
`
`BY MR. BERL:
`
`Q.
`
`Doctor, did Genentech proceed with this formulation
`
`that has .05 percent polysorbate?
`
`A.
`
`Q.
`
`No, Genentech did not.
`
`Let's take a look at the Shams reference. And,
`
`actually, we'll look at Dr. Rabinow's discussion of the Shams
`
`reference in regards to this limitation. What does Shams teach
`
`with respect to its formulation and polysorbate 20?
`
`A.
`
`Okay. So this is a cutout or excerpt on the bottom
`
`right, again, from Dr. Rabinow from Shams. And you can see
`
`highlighted here 0.01 percent polysorbate 20.
`
`Q.
`
`And what is the concentration, Doctor, required by
`
`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 1839
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2047
`
`Claim 4 of the '865 patent?
`
`A.
`
`Claim 4 is about 0.03 percent to about 0.1 percent
`
`polysorbate 20.
`
`Q.
`
`And Dr. Rabinow put the .01 percent polysorbate 20
`
`from Shams in green and colored also in green the
`
`about .03 percent to about .1 percent in Claim 4.
`
`Do you agree with his analysis that Shams teaches
`
`that concentration required by Claim 4 of polysorbate 20?
`
`A.
`
`No, because Shams teaches 0.01 percent, which doesn't
`
`fall in the range of polysorbate from Claim 4.
`
`Q.
`
`What concentration did Genentech ultimately use for
`
`Lucentis?
`
`A.
`
`Q.
`
`0.01 percent.
`
`Now, let's discuss Fraser, the last reference in this
`
`combination. Again, that's DTX 729.
`
`Does Fraser say anything about intravitreal
`
`administration?
`
`A.
`
`Q.
`
`No.
`
`What concentration of Tween 20 or polysorbate 20 does
`
`Fraser disclose, looking at page 2 of the reference?
`
`A.
`
`Q.
`
`A.
`
`0.01 percent.
`
`Now, reading --
`
`I apologize. Sorry to interrupt.
`
`0.1 percent -- added an extra zero.
`
`0.1 percent, for the record.
`
`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 1840
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2048
`
`Q.
`
`My last case in West Virginia was all about something
`
`0.001 percent, and everyone throughout the trial kept adding
`
`and subtracting zeros throughout the entire time. So the
`
`record was a mess. Thank you for correcting yourself.
`
`Now, Doctor, reading Dr. Rabinow's combination as a
`
`whole, the Lucentis plus Fraser, and assuming the POSA combined
`
`those references contrary to your opinion, what concentration
`
`of polysorbate would the POSA have preferred to use?
`
`A.
`
`Well, if one were going to do that, it would be
`
`0.01 percent.
`
`Q.
`
`A.
`
`Why?
`
`Well, that's what the Shams teaches, and that's what
`
`it recommended for the clinical trials. And, in fact, that's
`
`what finally Genentech used.
`
`Q.
`
`And the clinical trial that Shams is discussing, is
`
`that a systemically administered drug as in 729, Fraser, or is
`
`that an intravitreal trial?
`
`A.
`
`Q.
`
`No. Shams teaches intravitreal clinical trials.
`
`And would that have been more relevant to the POSA
`
`than formulations like Fraser?
`
`A.
`
`Q.
`
`Yes. Of course.
`
`Now, let's turn to the next limitation of the claim,
`
`the 98 percent native conformation as measured by
`
`size-exclusion chromatography limitation.
`
`Do any of Fraser, Gaudreault, or Shams teach 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 1841
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
`
` 2049
`
`98 percent native conformation limitation?
`
`A.
`
`Q.
`
`No, they do not.
`
`Did Dr. Rabinow present any evidence that any of the
`
`formulations in Fraser, Gaudreault, or Shams achieved the
`
`98 percent native conformation limitation?
`
`A.
`
`Q.
`
`No, he did not.
`
`Now, did either of the Gaudreault formulations go
`
`into clinical trials?
`
`A.
`
`Q.
`
`No, they did not.
`
`You mentioned before that Shams went into clinical
`
`trials. Does that mean that it met the 98 percent native
`
`conformation requirement?
`
`A.
`
`Q.
`
`A.
`
`No, it does not.
`
`Why not?
`
`Well, there's no indication -- it might be stable
`
`enough for clinical trials, but there's no indication that it
`
`met the 98 percent limitation here.
`
`Q.
`
`Did either Gaudreault or Shams teach that the
`
`ranibizumab formulations had 98 percent native conformation?
`
`A.
`
`Q.
`
`No, they did not.
`
`Now, even if one somehow believed that the Shams
`
`formulation or the Gaudreault formulation had 98 percent native
`
`conformation of ranibizumab, would the POSA have expected that
`
`the same formulation with aflibercept would have 98 percent
`
`native conformation?
`
`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 1842
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
`
` 2050
`
`A.
`
`Q.
`
`A.
`
`Based on that of ranibizumab, no.
`
`Why not?
`
`They're different molecules. They're going to behave
`
`differently. And as I mentioned, aflibercept is this fusion
`
`protein. It's not a natural molecule. So, if anything, if one
`
`were -- had that information and were to do the comparison, one
`
`would expect it to be less stable.
`
`Q.
`
`Let's take a look at Wang again. That's Exhibit
`
`1556. And we'll look at page 7 of the article.
`
`What -- in this Section 2.3.1 in the sentence
`
`beginning "mutation of one amino acid," what is Wang teaching
`
`here?
`
`A.
`
`Well, maybe just to read the whole sentence,
`
`"Mutation of one amino acid in a peptide or protein can
`
`dramatically increase the aggregation propensity."
`
`That's just one. If we're talking about completely
`
`different molecules, that can make them substantially different
`
`in terms of --
`
`Q.
`
`Was there one amino acid difference between
`
`ranibizumab and aflibercept or a lot more than one difference?
`
`A.
`
`Q.
`
`A lot more than one.
`
`Now, let's move on to discuss the pH limitation and
`
`in particular the pH limitation found in Claim 9 of the '865
`
`patent.
`
`And that says about 6.2 to 6.3; is that right?
`
`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 1843
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
`
` 2051
`
`A.
`
`Q.
`
`Yes. Correct.
`
`Does the Fraser plus Lucentis prior art, even if
`
`combined, teach using the required pH range of Claim 9?
`
`A.
`
`Q.
`
`No, they do not.
`
`Now, if we look at Shams and Gaudreault again now
`
`side by side -- Gaudreault, 1839, and Shams, 726 -- what are
`
`the pHs used in those formulations that Dr. Rabinow relies on?
`
`A.
`
`Well, the Gaudreault is in the upper left here. That
`
`pH is 5.0. The Shams is kind of the bottom right, and that pH
`
`is 5.5.
`
`Q.
`
`A.
`
`Q.
`
`Does that meet the limitation of about 6.2 to 6.3?
`
`No. Neither do.
`
`Now, the third reference here, Fraser, if we -- we
`
`looked at that a moment ago. That had a pH of 6.0; is that
`
`right?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Correct.
`
`Would the POSA have just used that pH?
`
`No.
`
`Why not?
`
`Well, because, first of all, the POSA, in
`
`investigating a formulation for the '865 patent, would
`
`investigate that for aflibercept with intravitreal
`
`administration in mind, whereas Fraser doesn't teach
`
`intravitreal administration.
`
`Q.
`
`Did Dr. Rabinow ever identify which precise
`
`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 1844
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2052
`
`formulation in his combination the POSA would have used if
`
`combining Fraser, Gaudreault, and Shams?
`
`A.
`
`Q.
`
`No, he did not.
`
`If you assume Dr. Rabinow's hypothesis that the POSA
`
`would have substituted aflibercept into the ranibizumab
`
`formulation, what pH would the POSA have used?
`
`A.
`
`Well, the ranibizumab is at 5.5. So if one were
`
`going to do that, it would be 5.5.
`
`Q.
`
`What if you performed experimentation to find a
`
`different pH, as Dr. Rabinow suggests?
`
`A.
`
`Well, then, that would be a whole formulation study,
`
`a whole investigation.
`
`Q.
`
`Would you end up with the same formulation, or at
`
`that point do you have a different formulation than the one
`
`you'd have if you combined the references?
`
`A.
`
`Well, then, you have likely a different formulation.
`
`You're doing a whole research project at that point.
`
`Q.
`
`Now, let's turn to the turbidity limitation. And we
`
`can look at that in Claim 15.
`
`Does that require a turbidity of 0.01 or lower at
`
`OD405 after two months' storage at 5 degrees?
`
`A.
`
`Q.
`
`Yes. That's correct.
`
`Did Dr. Rabinow present any evidence that a
`
`40-milligram formulation of aflibercept would achieve the
`
`claimed level of turbidity in view of Fraser, Gaudreault, 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 1845
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PHD - DIRECT
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` 2053
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`Shams?
`
`A.
`
`Q.
`
`No, he did not.
`
`Have you seen any such disclosure or teaching in
`
`those references?
`
`A.
`
`Q.
`
`No.
`
`Can you conclude that the Shams formulation meets the
`
`turbidity limitation of Claim 15 on the basis of a disclosure
`
`for use in a clinical trial?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`No.
`
`Is the turbidity limitation synonymous with stable?
`
`No.
`
`Is the 98 percent native conformation limitation
`
`synonymous with stable?
`
`A.
`
`Q.
`
`A.
`
`No.
`
`Why do you say no to those questions? Why not?
`
`Well, because stable doesn't mean it has to be
`
`98 percent or meet this particular turbidity requirement. It
`
`could be stable and not be at 90 percent and not meet this
`
`turbidity requirement.
`
`Q.
`
`Based on the prior art on which Dr. Rabinow relied
`
`for obviousness, even if combined, would the POSA have had any
`
`expectation that the formulations Regeneron claimed of the '865
`
`patent would meet the turbidity limitations of the claims?
`
`A.
`
`Q.
`
`No.
`
`Same question for the 98 percent native conformation,
`
`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 1846
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BERNHARDT TROUT, PHD - DIRECT
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` 2054
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`would the POSA have had any expectation of success?
`
`A.
`
`Q.
`
`Same answer. No.
`
`Would the prior art formulations on which Dr. Rabinow
`
`relied, even if combined, necessarily and always have the
`
`turbidity required by the asserted claims?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`No. There's no reason to think that.
`
`And how about for 98 percent native conformation?
`
`Again, no reason to think that either.
`
`Is the claimed protein concentration relevant to
`
`turbidity?
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`How so?
`
`Well, again, generally, the higher concentration
`
`leads to a higher aggregation propensity, hence higher
`
`insoluble aggregates and hence higher turbidity.
`
`Q.
`
`Did Dr. Rabinow point to any prior art turbidity data
`
`on 40 mg/mL of aflibercept?
`
`A.
`
`Q.
`
`No.
`
`Did Dr. Rabinow point to any turbidity data on
`
`40 mg/mL of ranibizumab?
`
`A.
`
`Q.
`
`No.
`
`In your view, Dr. Trout, are the asserted claims
`
`obvious over the combination of Fraser and Lucentis?
`
`A.
`
`Q.
`
`No.
`
`Now, we're done with Fraser and Lucentis.
`
`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 1847
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
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` 2055
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`MR. BERL: I can keep going, Your Honor. I'm at your
`
`pleasure.
`
`THE COURT: Let's call it a day. Let's do that.
`
`Is that all right with you, Doctor?
`
`THE WITNESS: Yes, as long as you give the order that
`
`the attorneys can't talk with me.
`
`THE COURT: Motion granted.
`
`Yes, Doctor, because you remain midstream on your
`
`testimony, even though you've come and gone once but you're
`
`considered midstream again by our rules, you are prohibited
`
`from contact with other humanoids about your testimony here.
`
`So you're welcome. You can go ahead and step down,
`
`sir. Have a lovely evening in quiet solitude.
`
`THE WITNESS: Thank you.
`
`Thank you, Your Honor.
`
`THE COURT: You're welcome.
`
`Everybody okay with starting at 8:30 tomorrow?
`
`MR. BERL: Absolutely.
`
`THE COURT: Let's do that. And we'll sprint through
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`the tape at that point, as they say.
`
`Anything we need to take up from Regeneron's
`
`standpoint at this juncture?
`
`MR. BERL: Not from Regeneron, Your Honor.
`
`THE COURT: Mr. Rakoczy, anything from Mylan?
`
`MR. RAKOCZY: Nothing from Mylan.
`
`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 1848
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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` 2056
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`THE COURT: Okay. And we anticipate at this point
`
`that Dr. Trout will be the last witness; is that correct?
`
`Anybody being called by Mylan on the back end?
`
`MR. RAKOCZY: Not as far as we know. He'll be the
`
`last one.
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`THE COURT: Okay. Al right. Well, let's do that.
`
`We'll see everyone at 8:30 tomorrow morning. And, again, my
`
`promise to be prompt with notifications about any change in the
`
`lunch run schedule tomorrow. Apologies for any heart
`
`palpitations I gave everybody.
`
`With that, everybody have a pleasant evening, and
`
`we'll see you all tomorrow morning.
`
`Thank you very much.
`
`(Proceedings concluded at 5:07 p.m.)
`
`
`
`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 1849
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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` 2057
`
`CERTIFICATE
`
`I, Cindy L. Knecht, Registered Professional Reporter and
`
`Official Reporter of the United States District Court for the
`
`Northern District of West Virginia, do hereby certify that the
`
`foregoing is a true and correct transcript of the proceedings
`
`had in the above-styled action on June 22, 2023, as reported by
`
`me in stenotypy.
`
`I certify that the transcript fees and format comply with
`
`those prescribed by the Court and the Judicial Conference of
`
`the United States.
`
`Given under my hand this 22nd day of June 2023.
`
`/s/Cindy L. Knecht
`____________________________
`Cindy L. Knecht, RMR/CRR
`Official reporter, United States
`District Court for the Northern
`District of West Virginia
`
`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 1850
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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` 2058
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`UNITED STATES DISTRICT COURT
`
`NORTHERN DISTRICT OF WEST VIRGINIA
`
`Regeneron Pharmaceuticals, Inc.
`
` Plaintiff,
`
` VS. CIVIL ACTION NO.
`
` 1:22-cv-61
`
`Mylan Pharmaceuticals, Inc., and Volume 9
`
`Biocon Biologics,
`
` Defendants.
`
`- - -
`
`Proceedings had in the bench trial of the above-styled
`action on June 23, 2023, before Honorable Thomas S. Kleeh
`District Judge, at Clarksburg, West Virginia.
`
`- - -
`
` APPEARANCES:
`
` On behalf of the Plaintiff:
`
`David I. Berl
`Ellen E. Oberwetter
`Arthur J. Argall, III
`Kathryn S. Kayali
`Haylee Bernal Anderson
`Andrew V. Trask
`Williams & Connolly, LLP
`680 Maine Avenue, SW
`Washington, D.C. 20024
`202.434.5000
`
`
`
`
`
`Andrew E. Goldsmith
`Kellogg, Hansen, Todd, Figel & Frederick, PLLC
`1615 M. Street NW, Suite 400
`Washington, DC 20036
`202.326.7945
`
`APPEARANCES CONTINUED ON NEXT PAGE
`
`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 1851
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
`
` 2059
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`On behalf of the Plaintiff, continued:
`
`
`
`Steven Robert Ruby
`Carey, Douglas, Kessler & Ruby, PLLC
`797 Virginia Street, East, Suite 901
`Charleston, WV 25301
`304.345.1234
`
`
`Petra Scamborova
`Regeneron Pharmaceuticals, Inc.
`777 Old Saw Mill River Road
`Tarrytown, NY 10591-6717
`914.847.7611
`
`On behalf of the Defendants:
`
`Deanne M. Mazzochi
`William A. Rakoczy
`Heinz J. Salmen
`Eric R. Hunt
`Lauren M. Lesko
`Neil B. McLaughlin
`Lawrence Scott Beall
`Katie A. Boda
`Rakoczy, Molino, Mazzochi & Siwik, LLP
`6 W. Hubbard Street, Suite 500
`Chicago, IL 60654
`312.527.2157
`
`Gordon H. Copland
`William J. O'Brien
`Steptoe & Johnson
`400 White Oaks Blvd.
`Bridgeport, WV 26330
`304.933.8162
`
`
`
`
`
`
`
`
`
`
`
` Proceedings recorded utilizing realtime translation.
` Transcript produced by computer-aided transcription.
`
`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 1852
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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` 2060
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`Friday Morning Session,
`
`June 23, 2023, 8:30 a.m.
`
`- - -
`
`THE COURT: I've gotten my coffee mishap out of the
`
`way back there; so it should be smooth sailing from here.
`
`Good morning, Doctor. You remain under oath.
`
`Mr. Berl, you may proceed.
`
`MR. BERL: Thank you, Your Honor.
`
`DIRECT EXAMINATION (CONTINUED)
`
`BY MR. BERL:
`
`Q.
`
`A.
`
`Q.
`
`Good morning, Dr. Trout.
`
`Good morning, Mr. Berl.
`
`I'd like to shift now to Dr. Rabinow's second
`
`combination, Fraser plus Liu.
`
`Do you agree with Dr. Rabinow that Fraser and Liu
`
`combined render the asserted claims obvious?
`
`A.
`
`Q.
`
`No, I do not.
`
`Now, before we get into the various limitations of
`
`the claims and details of the references, do you think that
`
`there's any reason that the POSA would have chosen those two
`
`references, Fraser and Liu, from amongst all of the prior art?
`
`A.
`
`Q.
`
`No, no reason.
`
`And, Doctor, do you believe that there's any reason
`
`that the POSA would have sought to combine Fraser plus Liu?
`
`A.
`
`No. And, again -- or I guess I'll say a little more
`
`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 1853
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PhD - DIRECT
`
` 2061
`
`about this, but Liu doesn't have anything to do with
`
`aflibercept or anything related.
`
`Q.
`
`Now, I understand that opinion, Dr. Trout, but unless
`
`I specifically say otherwise, for this portion of the testimony
`
`I'd like you to assume that the POSA would have combined Fraser
`
`with Liu as Dr. Rabinow asserts.
`
`Can you do that?
`
`Okay.
`
`With that, let's look at the first limitations of
`
`A.
`
`Q.
`
`Claim 1 --
`
`If we can put that on the screen.
`
`-- relating to ophthalmic formulations and
`
`intravitreal injection. Do either Fraser or Liu disclose
`
`ophthalmic formulations?
`
`No.
`
`Let's look at Fraser. It's DTX 729 again, and this
`
`A.
`
`Q.
`
`is page 1.
`
`What is Fraser discussing?
`
`A.
`
`Well, as highlighted here in this excerpt in the
`
`lower right side, the aim of the present study was to evaluate
`
`the effects of transient inhibition of VEGF on pituitary
`
`ovarian function in the macaque, so nothing to do with
`
`ophthalmics.
`
`Q.
`
`Is there any disclosure in Fraser of intravitreal
`
`administration?
`
`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 1854
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PhD - DIRECT
`
` 2062
`
`A.
`
`Q.
`
`No.
`
`What kind of administration is Fraser using -- local
`
`intravitreal administration or systemic administration?
`
`A.
`
`Q.
`
`Systemic intravenous, so not intravitreal.
`
`Would the POSA interested in making an ophthalmic
`
`formulation for intravitreal administration have looked to
`
`Fraser either alone or in combination with Liu?
`
`A.
`
`Q.
`
`No.
`
`And why does this distinction matter between an IV
`
`formulation and an intravitreal formulation? What, if
`
`anything, is different about these ophthalmic intravitreal
`
`formulations?
`
`A.
`
`Well, the current concerns are quite different. I
`
`think I testified last week to some of those differences. One
`
`major difference, of course, is having to go through this very
`
`narrow-bore needle -- which I think Your Honor saw earlier this
`
`week -- a very thin needle, which is going to encompass shear.
`
`The other things, issue with particulates and other
`
`aspects of -- can be very different for intravitreal.
`
`Q.
`
`Would Liu cause the POSA to want to use Fraser or a
`
`modified version thereof intravitreally?
`
`A.
`
`Q.
`
`No.
`
`Does Liu teach anything about intravitreal injections
`
`or formulations?
`
`A.
`
`No.
`
`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 1855
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BERNHARDT TROUT, PhD - DIRECT
`
` 2063
`
`Q.
`
`Now, I'd like to move to the next limitations of the
`
`claim relating to aflibercept.
`
`You already discussed that with respect to Fraser
`
`yesterday. Do those same opinions apply to the combination of
`
`Fraser with Liu?
`
`A.
`
`Q.
`
`Yes. That's correct.
`
`And do the opinions you expressed yesterday regarding
`
`glycosylation of aflibercept with Fraser, do those apply to the
`
`combination of Fraser and Liu?
`
`A.
`
`Q.
`
`Yes.
`
`Now, the new reference in this combination is Liu.
`
`That's DTX 730. Does Liu teach the aflibercept amino acid
`
`sequence?
`
`A.
`
`Q.
`
`No.
`
`Does Liu teach the glycosylation of aflibercept or
`
`the sites of glycosylation?
`
`A.
`
`No. Of course, it doesn't teach aflibercept; so it
`
`doesn't teach the glycosylation of it.
`
`Q.
`
`Okay. Let's go to the next limitation of the claim,
`
`40 mg/mL. Dr. Rabinow again cites to Fraser for the 40 mg/mL
`
`limitation.
`
`Do the opinions you discussed yesterday about that
`
`apply here?
`
`A.
`
`Q.
`
`Yes.
`
`Now, do you agree with Dr. Rabinow that the POSA
`
`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 1856
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
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`BERNHARDT TROUT, PhD - DIRECT
`
` 2064
`
`would select an appropriate intravitreal dose based on the
`
`amount of a VEGF Trap used to inhibit ovarian function in
`
`monkeys in Fraser?
`
`A.
`
`Q.
`
`A.
`
`No.
`
`Why not?
`
`Because they're different types of approaches,
`
`different indications, different organs, different parts of the
`
`body.
`
`Q.
`
`What about Dr. Rabinow's suggestion that the POSA
`
`would use a 60-microliter injection rather than a 50-microliter
`
`injection for intravitreal administration, if one were applying
`
`the prior art, in order to be generous?
`
`A.
`
`Q.
`
`I didn't see any basis for that.
`
`If one used a higher dose volume than 50 microliters,
`
`would one change the concentration of the drug product?
`
`A.
`
`Well, it depends; but, generally, one would increase
`
`the dosage.
`
`Q.
`
`And so you'd use the same concentration if you had an
`
`overage?
`
`A.
`
`Yes. Well, I think the overage, frankly, would have
`
`been in the vial, not in the syringe, but it was a little
`
`unclear. But the point is the concentration would be whatever
`
`the concentration is in the vial.
`
`Q.
`
`Now, let's take a look at Liu with respect to the
`
`concentration. And we'll take a look -- again, this is
`
`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 1857
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`
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`BERNHARDT TROUT, PhD - DIRECT
`
` 2065
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`DTX 730. And we've put on the screen part of page 35 of Liu.
`
`Does Liu teach concentration ranges for formulations
`
`of other proteins other than aflibercept?
`
`A.
`
`Yes. And I've highlighted a range here in
`
`paragraph 13 of Liu. It says -- a little hard to read maybe on
`
`the screen, but it does say antibody 40 to 150 mg/mL.
`
`Q.
`
`What does Liu teach about the concentration of
`
`aflibercept?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Nothing.
`
`What about VEGF antagonists?
`
`Nothing.
`
`What about an appropriate concentration for
`
`intravitreal administration?
`
`A.
`
`Q.
`
`Nothing.
`
`Would Liu alone or in comb
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