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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1048
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`prior art makes the invention obvious is also required, neither
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`of which have been disclosed.
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`So I'll sustain the objection. Again, we can proceed
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`and leave the unconnected bodies of testimony out there. The
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`Court will not draw that connection. And so I'll just say that
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`now. But objection sustained.
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`You may proceed, Counsel.
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`MR. HUNT: Just to be clear, Your Honor, we're free
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`to proceed and discuss the disclosure of the Liu reference and
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`then we can tie it together appropriately in a few minutes,
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`correct?
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`THE COURT: "Appropriately" being the key word, but
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`otherwise, yes. But, again, I just want to make sure that I'm
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`quite clear. The Court will not take up the invitation to put
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`a bow on something that should have been wrapped and presented
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`in opening disclosures.
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`MR. HUNT: Understood, Your Honor.
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`BY MR. HUNT:
`
`Q.
`
`If we could please turn to Slide 55. And we're
`
`looking on the right-hand side at another disclosure from the
`
`Liu reference, Dr. Rabinow.
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`If you could please describe for the Court what is
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`disclosed at DTX 730, page 35.
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`A.
`
`Liu is describing high-concentration antibody
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`formulations. He is describing a particular formulation that
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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 910
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1048
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`prior art makes the invention obvious is also required, neither
`
`of which have been disclosed.
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`So I'll sustain the objection. Again, we can proceed
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`and leave the unconnected bodies of testimony out there. The
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`Court will not draw that connection. And so I'll just say that
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`now. But objection sustained.
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`You may proceed, Counsel.
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`MR. HUNT: Just to be clear, Your Honor, we're free
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`to proceed and discuss the disclosure of the Liu reference and
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`then we can tie it together appropriately in a few minutes,
`
`correct?
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`THE COURT: "Appropriately" being the key word, but
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`otherwise, yes. But, again, I just want to make sure that I'm
`
`quite clear. The Court will not take up the invitation to put
`
`a bow on something that should have been wrapped and presented
`
`in opening disclosures.
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`MR. HUNT: Understood, Your Honor.
`
`BY MR. HUNT:
`
`Q.
`
`If we could please turn to Slide 55. And we're
`
`looking on the right-hand side at another disclosure from the
`
`Liu reference, Dr. Rabinow.
`
`If you could please describe for the Court what is
`
`disclosed at DTX 730, page 35.
`
`A.
`
`Liu is describing high-concentration antibody
`
`formulations. He is describing a particular formulation that
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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 910
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1049
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`contains a histidine buffer, a trehalose stabilizer, a
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`polysorbate 20 component, at pH of 6. He discloses that
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`protein concentrations of 40 to 150 mg/mL have been studied and
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`are stable and that formulations also containing trehalose or
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`sucrose stabilizers in a concentration range of 20 to
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`350 millimolar are also stable as well as a polysorbate
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`concentration range of .01 percent to .1 percent.
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`In specific, he is directing attention to a table
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`where he is describing an 80 mg/mL antibody formulation
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`comprising histidine and trehalose and showing that, over a
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`period of 24 months, the -- well, at three months and beyond,
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`that -- at 5 degrees, the -- by size-exclusion chromatography,
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`the percent monomer exceeds 98 percent to meet the claim
`
`limitation of the '865.
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`Q.
`
`If we could please move to Slide 56.
`
`Dr. Rabinow, on Slide 56 have you set forth the
`
`combinations of prior art references that you contend render
`
`Claim 1 of the '865 patent obvious?
`
`A.
`
`Q.
`
`Yes.
`
`And is there intended to be any relation on this
`
`slide between the claims on the left and the references on the
`
`right?
`
`A.
`
`Q.
`
`Yes.
`
`Okay. So let's just briefly summarize your opinions.
`
`Could you please summarize your opinion regarding 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
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 911
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1050
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`obviousness of Claim 1 in view of Lucentis in combination with
`
`Fraser?
`
`A.
`
`Yes. Claim 1 of the '865 would be obvious in view of
`
`Lucentis plus Fraser.
`
`Q.
`
`And separately, can you summarize your opinion
`
`regarding obviousness of Claim 1 in view of Fraser in
`
`combination with Liu?
`
`A.
`
`Yes. Claim 1 of the '865 would be obvious in view of
`
`Fraser plus Liu.
`
`Q.
`
`Now, would the person of ordinary skill in the art
`
`have a reasonable expectation of success in combining the
`
`disclosures that we've discussed today of the Lucentis prior
`
`art -- that is, Shams and Gaudreault -- with the disclosures of
`
`Fraser?
`
`A.
`
`Q.
`
`Yes.
`
`And similarly, would the person of ordinary skill in
`
`the art have a reasonable expectation of success when combining
`
`the disclosures that we have discussed today of Fraser in
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`combination with Liu?
`
`A.
`
`Q.
`
`Yes.
`
`Turning to Slide 57, do you have an opinion as to
`
`whether the person of ordinary skill in the art would have been
`
`motivated to combine her knowledge of Lucentis with Fraser?
`
`A.
`
`Yes. It would be provided by Saishin, DTX 2751,
`
`page 1, where it is disclosed that VEGF Trap R1R2 is a fusion
`
`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 912
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1051
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`protein and, further, that it -- subcutaneous or a single
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`intravitreous injection of Vermont VEGF Trap R1R2 strongly
`
`suppressed choroidal neovascularization in mice with
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`laser-induced rupture of Bruch's membrane.
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`And that, therefore, it is concluded that VEGF Trap
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`R1R2 may provide a new agent for consideration for treatment of
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`patients with choroidal neovascularization and diabetic macular
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`edema. And this is back in 2003.
`
`Q.
`
`And this disclosure from Saishin, Dr. Rabinow, is at
`
`DTX 2751, page 1?
`
`A.
`
`Q.
`
`Correct.
`
`And did you rely on DTX 2751, the Saishin reference,
`
`for purposes of your analysis?
`
`A.
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`Q.
`
`Yes.
`
`If we could please turn to Slide 58.
`
`Is there anything else that supports your opinion
`
`regarding the person of ordinary skill in the art's motivation
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`to combine her knowledge of Lucentis with Fraser?
`
`A.
`
`Saishin at DTX 2751, page 7, discloses further that
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`VEGF Trap R1R2 deserves consideration as a potential treatment
`
`for two complications of diabetic retinopathy: retinal
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`neovascularization and macular edema. It emphasizes again that
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`a single intravitreous injection of VEGF Trap R1R2 markedly
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`suppressed the development of choroidal neovascularization over
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`the course of two weeks. And, concurrently, additional
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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 913
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1052
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`preclinical studies should explore modes of local delivery to
`
`the eye that can be used adjunctively or as an alternative to
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`systemic administration. This is DTX 2751 at page 7.
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`Q.
`
`Thank you, Dr. Rabinow.
`
`Now, we just discussed your opinions regarding the
`
`motivation to combine Lucentis with Fraser. Is it also your
`
`opinion that Saishin, DTX 2751, provides a motivation to
`
`combine Fraser and Liu?
`
`A.
`
`Q.
`
`It does.
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`Is there any additional disclosure in Saishin besides
`
`what you've already described that is relevant to the
`
`motivation to combine Fraser with Liu?
`
`A.
`
`Well, it's clear -- I'm sorry. Could you repeat
`
`that.
`
`Q.
`
`Yeah.
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`I'm just looking for confirmation that your opinion
`
`with regard to motivation to combine Lucentis and Fraser is the
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`same for Fraser and Liu; is that correct?
`
`A.
`
`It is. It also provides a reasonable expectation of
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`success to do so as well.
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`Q.
`
`A.
`
`Q.
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`And that's the Saishin reference, correct?
`
`That is correct.
`
`Is there anything else about the knowledge of the
`
`person of ordinary skill in the art that would provide the
`
`person of ordinary skill in the art a reasonable expectation of
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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 914
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1053
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`success in combining Lucentis and Fraser?
`
`A.
`
`There is knowledge that Lucentis at the time that we
`
`were discussing had been used in humans. And, therefore,
`
`safety studies would have been conducted as well as stability
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`studies.
`
`Q.
`
`Thank you, Doctor.
`
`I would like to now discuss your anticipation
`
`opinions with regard to the Dix '226 patent. Have you prepared
`
`some slides to assist in your presentation of anticipation to
`
`the Court?
`
`A.
`
`Q.
`
`Yes.
`
`Okay.
`
`Mr. Gibson, next slide, please, Slide 60.
`
`Dr. Rabinow, what have you included on this slide to
`
`assist in your anticipation analysis?
`
`A.
`
`So as before, I list out the individual claim
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`limitations of Claim 1 of the '865. And on the right side is
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`displayed Dix '226, the cover page to page 2.
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`Q.
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`This one is a little less wieldy because we're only
`
`talking about one reference, correct?
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`A.
`
`Q.
`
`A.
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`Q.
`
`Yes.
`
`Shall we march through it?
`
`Please do.
`
`All right.
`
`If we could turn to Slide 61, please.
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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 915
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1054
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`How does Dix '226, DTX 13, disclose the initial
`
`limitations of Claim 1?
`
`A.
`
`Dix discloses a formulation inhibiting vascular
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`endothelial growth factor, VEGF, on page 4. And the -- it
`
`states that it is suitable for injection. He discloses a
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`lyophilized formulation is reconstituted with sterile water
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`suitable for injection; so that implies that there is a vial
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`involved, which meets one of the claim limitations of Claim 1.
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`And the POSA would understand as of the date of Dix that
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`ophthalmic formulations as well as cancer formulations were
`
`being considered for VEGF medicaments.
`
`Q.
`
`Would the person of ordinary skill in the art also
`
`understand from the disclosures of Dix that intravitreal
`
`administration is a possibility?
`
`A.
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`Yes, certainly, because that was being done already
`
`for other VEGF antagonists.
`
`Q.
`
`If we could please move to Slide 62.
`
`How does the Dix '226 patent relate to the VEGF
`
`antagonist limitations of Claim 1?
`
`A.
`
`So Dix discloses a VEGF antagonist fusion protein in
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`a Chinese hamster ovary, or CHO, cell, comprising a
`
`polynucleotide of amino acids 27 to 457 of sequence ID
`
`Number 4, wherein said fusion protein binds vascular
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`endothelial growth factor.
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`So this directly discloses the claim limitation of
`
`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 916
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1055
`
`essentially the essential wording of Claim 1 on the left-hand
`
`side of the screen, and it certainly discloses a vascular
`
`endothelial growth factor antagonist. And it confirms it on --
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`so that was -- I read that on DTX 13, page 13. And on page 6
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`it confirms this by stating that, again, VEGF antagonist is
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`expressed in a CHO cell line. And it comprises, again, amino
`
`acids 27 to 457 of sequence ID Number 4 and is glycosylated at
`
`asparagine residues 62, 94, 149, 222, and 308. This is at
`
`DTX 13, page 6.
`
`Q.
`
`If we could turn, please, to Slide 63.
`
`Which Claim 1 elements have you highlighted from
`
`Dix '226, DTX 13, on this slide, Doctor?
`
`A.
`
`Q.
`
`These are formulation claim elements.
`
`And could you please describe the formulation
`
`elements that are disclosed in DTX 13 --
`
`A.
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`Q.
`
`A.
`
`Yes.
`
`-- as they relate to Claim 1 of the '865 patent?
`
`Right.
`
`So it states at DTX 13, page 4, a polysorbate may be
`
`present. And this meets the organic cosolvent limitation using
`
`Regeneron's infringement contention definition.
`
`It also -- on that same page of Dix, for a buffer he
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`divulges -- discloses 1- to 10-millimolar phosphate buffer, 1-
`
`to 10-millimolar citrate buffer. And few lines down, he
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`further discusses a 5-millimolar phosphate buffer and
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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 917
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1056
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`5-millimolar citrate buffer. And, furthermore, on DTX 13,
`
`page 7, he also discloses 10-millimolar phosphate.
`
`And a stabilizing agent as a claim element of Claim 1
`
`is disclosed by 20 percent by sucrose on page 7 of Dix. It's
`
`mentioned multiple times on pages 4 and 7, sucrose.
`
`Q.
`
`If we could turn to Slide 64.
`
`Dr. Rabinow, how does DTX 13, the Dix '226 patent,
`
`relate to the stability elements of Claim 1?
`
`A.
`
`So DTX 13 at page 7 displays Table 1, which shows the
`
`percent VEGF Trap native conformation values of a 50 mg/mL
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`protein formulation stored at 5 degrees at three months where
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`the value is 98.8 percent, which exceeds the claim limitation
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`of at least 98 percent VEGF in native conformation following
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`storage at 5 degrees for two months as measured by
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`size-exclusion chromatography.
`
`Q.
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`I just want to make sure that I'm clear. The Table 1
`
`in DTX 13, page 7, that you display here, Doctor, indicates
`
`that the data is reflecting percent VEGF Trap native
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`configuration.
`
`Do you see that?
`
`I do.
`
`Would a person of ordinary skill in the art have an
`
`A.
`
`Q.
`
`understanding of whether there's a difference between native
`
`configuration and native conformation as reflected in Claim 1?
`
`A.
`
`They're essentially equivalent.
`
`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 918
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`BARRETT E. RABINOW, PhD - DIRECT
`
` 1057
`
`Q.
`
`And does DTX 13, the Dix '226 patent, also disclose
`
`that the stability data reflected in Table 1 was measured by a
`
`particular analytical method?
`
`A.
`
`Q.
`
`It was size-exclusion chromatography.
`
`Turning to Slide 65, can you summarize your opinion
`
`regarding the Dix '226 reference as it relates to your
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`anticipation analysis of Claim 1 of the '865 patent?
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`A.
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`Yes. Dix '226 anticipates all of the claim
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`limitations of Claim 1 of the '865 and therefore anticipates
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`Claim 1.
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`Q.
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`And your testimony, just so that it's clear, is that
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`the Dix '226 patent discloses each and every limitation of
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`Claim 1, correct?
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`A.
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`Q.
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`That's correct.
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`Now I'd like to move to your anticipation opinions
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`with regard to the dependent claims.
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`If we could go to Slide 66, please.
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`Do you have opinions regarding the dependent claims
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`as it relates to the Dix '226 patent --
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`A.
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`Q.
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`A.
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`Yes.
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`-- DTX 13?
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`Yes. The Dix '226 anticipates Claims 4, 7, 9, 11,
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`and 14 through 17.
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`Q.
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`Let's go to Slide 67 and first look at Claim 2 of the
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`'865 patent.
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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 919
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1058
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`What have you highlighted on Slide 67 relating to the
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`concentration limitations of Claim 2 of the '865 patent?
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`A.
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`Dix --
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`THE COURT: One second, Doctor.
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`Yes, Counsel?
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`MR. TRASK: Your Honor, I object to the passage at
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`the bottom of this slide. It's outside the scope of his expert
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`reports. The 40 mg/mL prelyophilized solution is discussed
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`nowhere in either of the doctor's reports.
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`THE COURT: Understood.
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`Counsel?
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`MR. HUNT: Your Honor, I'd need a minute to take a
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`look through the report, but the Dix '226 patent is very clear
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`from day one that there has been anticipation argument that Dix
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`'226 patent, DTX 13, is prior art for all that it discloses.
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`And there is and can be no argument that plaintiff has not been
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`put on notice of this anticipation theory that the Dix '226
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`patent anticipates the claims of the '865 patent.
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`So, with that, Your Honor, if you'll permit me a
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`moment, I'll take a look through the expert report.
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`THE COURT: Understood. Okay, Counsel.
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`MR. TRASK: If I may while he's looking.
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`So to be clear, the top box discloses a range of 10
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`to 50 mg/mL of fusion protein. That's disclosed in the
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`doctor's report, and we don't object to that.
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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 920
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1059
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`There's several paragraphs in the report which I can
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`point counsel to -- paragraph 124 of the opening report,
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`paragraph 8 of the reply report -- where that passage is
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`disclosed, the 10 to 50 range. We disagree that's a disclosure
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`of 40, but it's disclosed and they can rely on it. The 40
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`mg/mL prelyophilized solution is nowhere in the report.
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`Counsel is free to look, of course.
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`THE COURT: But that's from the Dix reference,
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`correct?
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`MR. TRASK: It's in the Dix reference, but it was
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`never discussed. And there are sections in the report
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`purporting to state where Dix discloses 40 mg/mL. That passage
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`is discussed nowhere in the report.
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`THE COURT: Understood.
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`At this point, objection will be overruled. Counsel
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`of course will be free to probe that particular issue on cross
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`and likewise address it in posttrial submissions.
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`But for now, objection overruled.
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`MR. HUNT: Thank you, Your Honor.
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`BY MR. HUNT:
`
`Q.
`
`If we could go to Slide 68, please. How does DTX 13,
`
`the Dix '226 patent, disclose the polysorbate limitations of
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`Claims 2, 4, and 5 of the '865 patent, Dr. Rabinow?
`
`A.
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`On page 4 it discloses polysorbate may be present.
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`That addresses that claim element of Claim 2 where it
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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 921
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1060
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`discloses -- comprises polysorbate. The range in Dix is .05
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`to .15 percent polysorbate 20, which overlaps the claim
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`limitation of .03 percent to .1 percent polysorbate 20 of
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`Claim 4 as well as the limitation of Claim 5 of .1, .01, to
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`3 percent polysorbate 20.
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`So Dix discloses the presence of polysorbate 20 as
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`well as its ranges, which address Claims 2, 4, and 5.
`
`Q.
`
`If we could turn to Slide 69.
`
`How does DTX 13, the Dix '226 patent, relate to the
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`buffer limitation of dependent Claim 7?
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`A.
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`The buffer limitation is 5- to 25-millimolar buffer.
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`Dix discloses 1- to 10-millimolar phosphate buffer, 1- to
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`10-millimolar citrate; and a few lines down, 5-millimolar
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`phosphate buffer, 5-millimolar citrate buffer on page 4 of
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`DTX 13.
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`Q.
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`And with respect to the added limitation of Claim 9
`
`of the '865 patent, Dr. Rabinow, on the next slide, what is
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`expressly disclosed in Dix '226, DTX 13?
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`A.
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`On pages 4 and -- well, on page 4 it discloses pH
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`6.25, which lies in the interval of the Claim 9 limitation of
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`pH about 6.2 to 6.3. And, furthermore, on page 7 of Dix it
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`discloses pH of about 6 to 6.5, which similarly overlaps the
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`range of 6.2 to 6.3, the claim limitation of Claim 9.
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`Q.
`
`If we could go to DDX 4, Slide 71, what does
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`Dix '226, DTX 13, disclose regarding the additional stabilizing
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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 922
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1061
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`agent limitations of Claims 10 and 11?
`
`A.
`
`On page 4 of Dix, it is stated that the formulation
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`contains sucrose, which addresses the claim element of -- the
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`stabilizing agent comprises a sugar of Claim 10.
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`Claim 11 goes beyond that and specifies that the
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`sugar is selected from the group consisting of sucrose, et
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`cetera. And sucrose is specifically disclosed on page 4. So
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`that addresses claim -- the Claim 11 limitation as well.
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`Q.
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`And, Dr. Rabinow, are these the same two passages of
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`Dix that we looked at on the prior slide?
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`A.
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`Q.
`
`Yes.
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`And I just -- I want to make the record clear. You
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`referred to page -- DTX 13, page 4. And I think that that same
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`page number was reflected here, but on the prior slide the
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`second callout was referred to as DTX 13, page 7. Do you
`
`understand that the second callout on this page is also at
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`DTX 13, page 7?
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`A.
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`Q.
`
`Yes.
`
`If we could please move to Slide 72.
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`Now, Dr. Rabinow, you may have mentioned this earlier
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`in connection with the VEGF antagonist elements of Claim 1, but
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`what does Dix '226, DTX 13, disclose regarding the
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`glycosylation characteristics of Claim 14 of the '865 patent?
`
`A.
`
`Dix discloses the fusion protein comprises amino
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`acids 27 to 457 of sequence ID Number 4 and is glycosylated at
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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 923
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1062
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`asparagine residues at 62, 94, 149, 222, and 308. So it fully
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`discloses the claim element of Claim 14.
`
`Q.
`
`A.
`
`Q.
`
`And that is at DTX 13, page 6, correct, Doctor?
`
`That is correct.
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`Finally, let's discuss the stability limitations in
`
`the dependent claims of the '865 patent. On DDX 4, Slide 73,
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`what have you highlighted here from DTX 13, the Dix '226
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`patent?
`
`A.
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`Dix discloses in Example 1 on page 7 that turbidity
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`was measured at OD405 and furthermore provides data at three
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`months of a formulation stored at 5 degrees. And the turbidity
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`value is zero, thus meeting the claim limitation of a turbidity
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`of .01 or lower at OD405 after two months storage at 5 degrees.
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`Q.
`
`Now, turning to Slide 74, what does DTX 13, the
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`Dix '226 patent, disclose regarding formulation stability over
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`time?
`
`A.
`
`In Table 9 on page 9 is listed the percent native
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`configuration, equivalent as we said before to conformation, at
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`two months' storage of 5 degrees, a value of 99.6 percent, thus
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`meeting the claim limitation of at least 99 percent after two
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`months at 5 degrees.
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`Q.
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`And, Dr. Rabinow, does Dix tell us what analytical
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`method is used to generate the data reflected in Table 9?
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`A.
`
`Q.
`
`Yes. Size-exclusion chromatography.
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`And Table 9 is at DTX 13, page 9, correct?
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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 924
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1063
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`A.
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`Q.
`
`Yes.
`
`Turning to Slide 75, what does Dix '226, DTX 13,
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`disclose regarding the further stability limitations of
`
`Claim 17?
`
`A.
`
`Dix on page 7, Table 1, provides a value for percent
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`VEGF Trap native configuration -- equivalent, as we said, to
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`conformation -- at 24 months, 5 degrees storage, of
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`98.3 percent, which meets therefore the limitation of at least
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`98 percent of VEGF antagonist following storage at 5 degrees
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`for 24 months as measured by size-exclusion chromatography.
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`The same technique was used in Dix.
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`Q.
`
`Now, looking at Table 1 of the Dix '226 patent at
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`DTX 13, page 7, there's a reference here to VEGF Trap.
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`Do you see that?
`
`Yes.
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`And would the person of ordinary skill in the art
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`A.
`
`Q.
`
`understand, or does the Dix '226 patent tell them, that VEGF
`
`Trap is in fact a VEGF antagonist fusion protein?
`
`A.
`
`Q.
`
`Yes.
`
`Dr. Rabinow, if we look at DDX 4, Slide 75, is it
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`your opinion that Dix '226, DTX 13, discloses each and every
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`limitation of the asserted claims of the '865 patent?
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`A.
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`Q.
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`They are. It is.
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`And, therefore, is it your opinion that the Dix '225
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`[sic] patent, DTX 13, anticipates the asserted claims of the
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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 925
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1064
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`'865 patent?
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`A.
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`Q.
`
`That is correct. I agree with that.
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`Dr. Rabinow, I'd like to now return to your
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`obviousness analysis and specifically focus on the asserted
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`dependent claims.
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`Could we please display Slide 77, Mr. Gibson.
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`Now, Dr. Rabinow, have you prepared a summary chart
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`to assist you in comparing the prior art disclosures, and
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`specifically your asserted combination of Lucentis and Fraser,
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`and separately Fraser and Liu, to Claims 4, 7, 9, 11, and 14
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`through 17 of the '865 patent?
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`A.
`
`Q.
`
`Yes.
`
`Is it your opinion that Claims 4, 7, 9, 11, and 14
`
`through 17 of the '865 patent would have been obvious to one of
`
`ordinary skill in the art after consideration of Fraser in
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`combination with Liu?
`
`A.
`
`Q.
`
`Yes.
`
`Is it also your opinion that Claims 4, 7, 9, 11, and
`
`14 through 17 of the '865 patent would have been obvious to one
`
`of ordinary skill in the art after consideration of the
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`Lucentis disclosures in Shams and Gaudreault in combination
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`with Fraser?
`
`A.
`
`Q.
`
`Yes.
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`With that in mind, Doctor, I would like to proceed to
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`discuss some of the disclosures in the prior art. And then
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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 926
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1065
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`after that discussion, we can further revisit your obviousness
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`combinations. Okay?
`
`A.
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`Q.
`
`Fine.
`
`Turning to the next slide, Slide 78, how does Fraser,
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`DTX 729, apply to the dependent claims of the '865 patent?
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`A.
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`Fraser discloses 2-mL aliquots that were used to dose
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`the monkeys in his study. And it is clear that, individually,
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`solutions had to be withdrawn from 2 mL because, in certain
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`cases, multiple vials were drawn. So that addresses the claim
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`limitation of the vial of Claim 1 in Claim 2.
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`Furthermore, Fraser discloses VEGF Trap R1R2 as
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`provided by Regeneron Pharmaceuticals, Inc., Tarrytown,
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`New York, which addresses the claim element of Claim 2, said
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`VEGF antagonist fusion protein.
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`40 mg/mL is the claim element. Fraser has 24.3
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`mg/mL, which, by routine experimentation in light of what the
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`prior art was that is known by the POSA, could have been so
`
`optimized. Fraser also discloses a buffer -- I'm sorry. Let
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`me back up.
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`The final claim element of Claim 2 is polysorbate,
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`which is addressed in -- on page 2 of Fraser by the term
`
`"Tween 20." So that addresses fully Claim 2.
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`The disclosure of .1 percent weight-per-volume
`
`Tween 20 similarly addresses Claims 4 and Claims 5 because
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`the .1 percent weight per volume clearly addresses Claim 4 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 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 927
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1066
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`well as Claim 5. It's in the interval denoted by the extremes
`
`of values. So that addresses Claims 4 and 5.
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`The claim element of 5- to 25-millimolar buffer of
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`Claim 7 is disclosed by Fraser's use of the term "5-millimolar
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`phosphate, 5-millimolar citrate." So that addresses Claim 7.
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`Claim 9 has a limitation of pH about 6.2 to 6.3. And
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`Fraser discloses pH 6.0, which is about 6.2 to 6.3.
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`Claim 10 has a limitation of comprising a sugar, and
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`the term "20 percent sucrose" is expressly disclosed in Fraser.
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`So that addresses Claim 10 as well as Claim 11, which specifies
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`the group consisting of sucrose, et cetera.
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`Finally, Claim 14, the claim limitation of said VEGF
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`antagonist fusion protein is glycosylated at asparagine
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`residues corresponding to asparagine residue 62, 94, 149, 222,
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`and 308 of sequence ID Number 4 is addressed by the term that
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`Fraser uses, "VEGF Trap R1R2 (Regeneron Pharmaceuticals),"
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`which a POSA would know by that point referred unambiguously to
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`a protein molecule fusion protein glycosylation pattern, amino
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`acid sequence of that descriptor in the claim limitations of
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`Claim 14.
`
`Q.
`
`Thank you, Dr. Rabinow.
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`And if I may, especially when you're reading from a
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`technical document, if you could please make a point to try and
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`talk just a bit slower for the court reporter's benefit. I
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`think everyone would appreciate it.
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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 928
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`BARRETT E. RABINOW, PhD - DIRECT
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` 1067
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`A.
`
`Q.
`
`I apologize.
`
`Thank you.
`
`Now, I want to revisit your discussion of the
`
`24.3 mg/mL concentration that's disclosed in the Fraser
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`reference DTX 729, page 2, that we've been discussing.
`
`How does the 24.3 mg/mL dose in Fraser compare to the
`
`40 mg/mL limitation in Claim 2 in light of what is disclosed in
`
`Fraser?
`
`A.
`
`Fraser discloses a 24.3 mg/mL formulation. He uses
`
`that to dose monkeys of various sizes, and he has various doses
`
`that are given to each monkey.
`
`The smallest dose that was administered
`
`is .1 milliliters. That was administered to his animals.
`
`.1 mL times 24.3 mg/mL would give a dose of
`
`2.43 milligrams to the monkeys, which is the -- conservatively
`
`the lowest dose of the series. Okay?
`
`The POSA would know as well, for intravitreal
`
`administration for humans, that values of .05 milliliters were
`
`administered from both bevacizumab as well as ranibizumab.
`
`So 2.43 milligrams divided by .05 mL, or say -- just
`
`because we want to be generous here, .06 mL, because we're
`
`expecting some wastage, would give you a value of 40 mg/mL.
`
`Q.
`
`And when you indicated a moment ago, Dr. Rabinow,
`
`that I believe the person of ordinary skill in the art would
`
`want to be generous, that's with regard to the 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
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