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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
`Biocon Biologics,
` Defendants.
`
`- - -
`
`Proceedings had in the bench trial of the above-styled
`action on June 12, 2023, before Honorable Thomas S. Kleeh
`District Judge, at Clarksburg, West Virginia.
`
`- - -
`
` APPEARANCES:
`
` On behalf of the Plaintiff:
`
`David I. Berl
`Ellen E. Oberwetter
`Kathryn S. Kayali
`Williams & Connolly, LLP
`680 Maine Avenue, SW
`Washington, D.C. 20024
`202.434.5000
`
`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
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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 1
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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` 1
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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
`Biocon Biologics,
` Defendants.
`
`- - -
`
`Proceedings had in the bench trial of the above-styled
`action on June 12, 2023, before Honorable Thomas S. Kleeh
`District Judge, at Clarksburg, West Virginia.
`
`- - -
`
` APPEARANCES:
`
` On behalf of the Plaintiff:
`
`David I. Berl
`Ellen E. Oberwetter
`Kathryn S. Kayali
`Williams & Connolly, LLP
`680 Maine Avenue, SW
`Washington, D.C. 20024
`202.434.5000
`
`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 1
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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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 Defendant:
`
`Deanne M. Mazzochi
`William A. Rakoczy
`Neil B. McLaughlin
`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
`
`
`
`
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`
`
`
` 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
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 2
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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` 3
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`Monday Morning Session,
`
`June 12, 2023, 9:30 a.m.
`
`- - -
`
`THE COURT: Thank you. Please be seated.
`
`Madam Clerk, would you be kind enough to call our
`
`next case, please.
`
`THE CLERK: Regeneron Pharmaceuticals, Inc., v. Mylan
`
`Pharmaceuticals, Inc., Civil Action Number 1:22-cv-161.
`
`Will counsel please note your appearance for the
`
`record.
`
`MR. RUBY: Good morning, Your Honor. Steve Ruby of
`
`Carey, Douglas, Kessler & Ruby for plaintiff Regeneron
`
`Pharmaceuticals, Inc. With me I have David Berl, Ellen
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`Oberwetter, and Kathryn Kayali from Williams & Connolly in
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`Washington, D.C. And also from Regeneron I have with me Joe
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`LaRosa, who is executive vice president and general counsel;
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`Larry Coury, who is vice president and associate general
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`counsel. I'll note that Mr. Coury is a native of Mercer
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`County.
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`THE COURT: Welcome home, sir.
`
`MR. RUBY: His father is a WVU alum and his mother
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`Marshall alum. So we're glad to have him back in West Virginia
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`for a little while.
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`Also Petra Scamborova, James Evans, Andrew Deciare,
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`and Arun Bhoumik, all from Regeneron.
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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 3
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`THE COURT: Good morning, everyone.
`
`Good morning, Counsel.
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`MR. COPLAND: Good morning, Your Honor. This is
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`Gordon Copland, Steptoe & Johnson, appearing on behalf of the
`
`defendants Mylan Pharmaceuticals, Inc., and Biocon Biologics,
`
`Inc. Also appearing this morning is William O'Brien of
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`Steptoe & Johnson; William Rakoczy and Deanne Mazzochi, both
`
`with the Rakoczy Molino Mazzochi & Siwik firm.
`
`THE COURT: Good morning, everyone.
`
`All right. Here for day one for trial slated to
`
`start opening statements, but word was there was a request to
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`seal the courtroom during a portion of plaintiff's opening. Is
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`that correct?
`
`MR. COPLAND: That's correct, Your Honor. The
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`motion's not opposed by the plaintiff. We did prepare a brief
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`just in case, which I'll hand up if I may, Your Honor.
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`THE COURT: Sure. Which slides are we talking about?
`
`MR. COPLAND: It's 14 through, I believe, 45, but may
`
`I double-check that, Your Honor, when I get back to my seat?
`
`And there are about 142 slides, maybe a little more. So only
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`the portion between the first slide, which is 14, and the last
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`one that has an issue, 41, would we request sealing. And, of
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`course, that would not apply to anyone already under the
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`protective order, only to third parties present in the
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`courtroom.
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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 4
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`We do have an agreement that certain counsel for
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`Regeneron may attend even though outside-counsel-eyes-only
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`material will be some of the material, and we just ask that
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`their counsel confirm that they're agreed to be under the
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`protective order pursuant to the parties' prior agreement.
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`THE COURT: Understood.
`
`Counsel?
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`MR. RUBY: We agree to that, Your Honor, yes.
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`THE COURT: Understood. And note that we have a
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`spectator or two today. I'll leave it to counsel to police who
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`is permitted to attend -- remain in the courtroom under the
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`Court's protective order and who is not.
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`MR. COPLAND: If Mr. Berl will just give us notice
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`before he hits Slide 14, and we can pause.
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`THE COURT: Understood.
`
`A couple housekeeping matters for everyone. There
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`are additional restrooms. Since we've got a bigger crowd than
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`we had for naturalization on Friday, the line will back up
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`quickly here. There are additional restrooms up on the third
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`floor and either the elevator or stairs at the end of the hall
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`will get you there.
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`As folks may have noticed, in addition to our looming
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`asbestos abatement project, some preliminary work is ongoing on
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`the roof of the building. So please continue to refrain from
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`trying to park immediately adjacent to the courthouse, those
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 5
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`spots abutting the building. One, it'll save your cars or
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`rental cars some damage -- potential damage, I should say --
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`and we need whatever slots they randomly let us have on any
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`given day for the court personnel.
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`With that, Mr. Berl, sir, the floor is yours.
`
`MR. BERL: Good morning, Your Honor. David Berl for
`
`Regeneron. This case is about Eylea, a product that made
`
`Regeneron what it is today. More specifically, this case is
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`about the discoveries that made Eylea what it is.
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`Before the discoveries at issue in this trial,
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`Regeneron was a small fledgling company with virtually no
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`products or revenues. The discoveries of the patents-in-suit
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`led to Eylea's groundbreaking treatments for diseases that are
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`the leading causes of blindness.
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`Eylea is responsible for a majority of Regeneron's
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`revenues. It funds Regeneron's research and development into
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`the hardest diseases to treat, from cancer to Alzheimer's.
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`Regeneron had and has a culture of innovation.
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`To take just one example, when COVID struck and most
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`of the world shut down, its scientists, led by George
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`Yancopoulos, its cofounder, sprung into action immediately and
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`quickly developed a treatment that saved many lives, including
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`possibly the then-president of the United States.
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`That's who the plaintiff is.
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`The defendants in this case are Mylan and Biocon.
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
`
`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 6
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`Mylan filed an abbreviated biologic application to FDA to sell
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`a biosimilar version of Eylea. Mylan then transferred that
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`application to its successor in interest, Biocon, in Bangalore,
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`India. Biocon will be selling this product if the defendants
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`succeed in this case.
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`In order to understand the issues a little better,
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`some background on the anatomy of the eye will be helpful.
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`This is a diagram of a healthy eye. It's not drawn to scale.
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`It's intended to show in two dimensions what's obviously three
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`dimensions in real life.
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`The important components here are the retina, shown
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`in pale yellow, which is supplied by blood vessels, that are
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`shown in red; and the vitreous, which is a gelatinous area of
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`the area that abuts the retina. In between the vitreous and
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`the retina is a barrier called the ILM, the inner or internal
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`limiting membrane.
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`There's also a protein in the retina, shown in green
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`here in the little dots, called VEGF. And when VEGF is present
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`in the right amounts, it supplies the healthy blood vessels of
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`the retina and everything is fine.
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`But when there's too much VEGF in the eye, things go
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`wrong. The blood vessels increase, and the blood vessels get
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`too thick, and blood and fluid starts to leak. That creates
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`significant problems and diseases, including macular edema,
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`shown here, and other diseases that cause blindness.
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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 7
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`Regeneron developed Eylea to try to solve that
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`problem. The active ingredient in Eylea, aflibercept, shown in
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`purple here, blocks VEGF -- two hands on the football -- and
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`thereby inactivates it.
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`Now, Eylea is administered into the eye through a
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`needle, so-called intravitreal injection. When it's
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`administered into the vitreous, however, it must get into the
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`retina to do its job. It must pass through that barrier, get
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`into the retina, and inactivate the VEGF there, where there's a
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`disease state. And when it does that and inactivates much of
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`the VEGF in the retina, the VEGF essentially goes away and the
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`disease recedes. You can see the blood vessels come back to
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`their healthy state and vision is restored.
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`Now, Eylea has a VEGF inhibitor called aflibercept,
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`but there were lots of VEGF inhibitors out there, not just one,
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`for many different companies. This is the story of why a
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`product with one of those inhibitors, from a sea of potential
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`inhibitors, won out. This is the story of the two inventions
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`that made that happen.
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`There are two inventions here. One on the left is
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`directed to the product that is administered. Because of
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`witness schedules, we'll start with that one this week. And it
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`came first in time. The second invention is treating using
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`aflibercept, the VEGF inhibitors in a particular way that has
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`been proven to be very successful.
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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 8
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`Now, starting with the product patent, the '865
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`patent, you will hear from two of the inventors of the product
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`patent, Dr. Furfine and Graham, about their invention and the
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`research that led to it.
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`The products they invented, one example of which was
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`Eylea, were transformative. They bucked the conventional
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`wisdom to invent a stable formulation with a high concentration
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`of aflibercept, 40 milligrams per milliliter, required by all
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`the asserted claims through incorporation of the independent
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`claims. And that high dose and formulation of Eylea
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`facilitated the product's eventual success.
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`Now, in order to market a biosimilar version of Eylea
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`that copies from the patent the 40 milligrams per milliliter of
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`aflibercept as well as the organic cosolvent it uses of
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`polysorbate, Mylan and Biocon advanced various defenses of
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`noninfringement and invalidity. I don't think you'll hear in
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`detail about many of these defenses given how many there are,
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`but Mylan has not narrowed what it proposes to present at
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`trial; so I'll try to cover them all this morning.
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`The first dispute is whether Mylan infringes the
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`organic cosolvent limitations of the claims. And they do.
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`And this is the point where I'm going to hit material
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`that I think they want the courtroom sealed for.
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`THE COURT: Understood.
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`The Court would then seal our proceedings. Those not
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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 9
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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` 10
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`specifically permitted to be here in the Court's protective
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`order, if I could ask you to depart, please.
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`(The following proceedings (10/3 to 20/7) were sealed
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`and are filed under separate cover.)
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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 10
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`THE COURT: Thank you.
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`If I could ask court security to unseal our courtroom
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`and extend an invitation to those out there to rejoin us if
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`they'd like. Thank you.
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`Welcome back, everyone.
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`Mr. Berl, go right ahead, sir.
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`MR. BERL: Next are Mylan's invalidity defenses, and
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`we'll start with anticipation.
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`The patents at issue in this case were issued after
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`substantial examination by the US Patent and Trademark Office,
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`and they were duly issued and entitled to the presumption of
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`validity.
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`Mylan bears a heavy burden -- clear and convincing
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`evidence -- to prove the facts necessary to show invalidity.
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`It can't do so. Anticipation requires that a single record,
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`just one, disclose each and every limitation of the claims
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`expressly or inherently arranged as in the claim.
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`The first of Mylan's two anticipation references
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`called Fraser doesn't even come close to meeting 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 11
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`requirement. It's mincing lots of limitations from the claim.
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`This argument of theirs reminds me of the old Coffee Talk Joan
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`Rivers skit on Saturday Night Live. The Holy Roman Empire is
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`neither Holy nor Roman nor an empire. You may remember that.
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`That's what this is.
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`Fraser discloses neither an ophthalmic formulation
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`nor intravitreal administration nor glycosylated nor
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`aflibercept nor 98 percent native conformation nor 40
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`milligrams per milliliter. It's got none of it. And it has to
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`have everything.
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`Mylan tries to plug at least some of the holes in the
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`dam by suggesting that anything written in an article that
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`Fraser cites or, in fact, anything written in an article cited
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`by an article that Fraser cites somehow magically becomes part
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`of Fraser because anticipation, they have to have only one
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`reference.
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`First of all, that's implausible; but second, it's
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`contrary to consistent federal circuit precedent, that the host
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`document -- here Fraser -- must identify with detailed
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`particularity what specific material it incorporates. Simply
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`adding the footnote and citing a reference isn't close to
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`enough. You've gone from Joan Rivers to Six Degrees of Kevin
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`Bacon in one article.
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`Now, the second anticipation argument that they
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`advance is this, and the assertion of Dix requires the Court to
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 12
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`address a subsidiary question, which is whether Regeneron is
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`entitled to a priority date of March 21, 2006, or earlier
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`because that's before the time that Dix was filed.
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`Now, the answer to that question is yes. In fact,
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`the invention here was made far earlier in the fall of 2005,
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`but for present purposes, because Mylan has only asserted Dix,
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`we only need to show priority back to March 21, 2006, or
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`earlier.
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`If Regeneron is entitled to that date -- and we think
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`it's clear that it is -- then Dix simply is not prior art.
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`Everything you hear about Dix the next two weeks -- and I
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`suspect you'll hear quite a bit -- is totally and blessedly
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`irrelevant to this case because it's not prior art.
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`But even if Dix were prior art, then it would still
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`not anticipate the claims because it too, like Fraser, is
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`missing at least one limitation, in fact, several, including
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`intravitreal administration and an ophthalmic formulation. It
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`has none of that.
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`Now, for the 40 milligrams per milliliter
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`formulation, which is a very important limitation in the claim,
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`what they rely on is a disclosure of 10 to 50 milligrams per
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`milliliter in Dix.
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`First of all, that disclosure is not about
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`aflibercept in particular; so it's not arranged as in the
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`claim. But more importantly, the federal circuit repeatedly
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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 13
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`has been clear, including earlier this year, that the
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`disclosure of a range, like 10 to 50, is not a disclosure of
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`discrete points within that range like 50, like 40. 10 to 50
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`does not anticipate 40. It can't do that under controlling
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`law.
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`Now, with that, I'll move to obviousness, which is
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`their backup prior art argument. And the first problem with
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`Mylan's obviousness argument is their selection of references.
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`They pluck out of prior art various references, most of which
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`have nothing whatsoever to do with the issue here, which is
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`intravitreal injection that can treat diseases in the retina.
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`But that's not allowed under the law.
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`The question is not whether the so-called person of
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`ordinary skill, or the POSA, with the two prior art references
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`in front of him could combine them and arrive at the
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`patent-in-suit, which, by the way, it couldn't even if they had
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`them in front of them.
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`Mylan and Biocon don't even get to that question
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`because the question, as the federal circuit said in the WBIP
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`case, is whether the skilled artisan would have plucked one or
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`more of those references out of the sea of prior art in the
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`first place. And Mylan's experts skip over that analysis and
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`choose their references without any contemporaneous
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`justification or basis.
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`There were many VEGF inhibitors in the prior art. 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 14
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`was a sea of VEGF inhibitors. And Mylan just assumes without
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`basis that the POSA would have chosen one of them, aflibercept.
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`Not so.
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`As I mentioned earlier, there's a barrier between the
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`vitreous, where the drug is injected, and the retina and other
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`associated tissues where it needs to go. And whether the
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`molecule would get from the vitreous to the retina was
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`understood to depend on its size. And aflibercept at the time
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`was considered too big.
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`Now, the prior art taught -- and this is the
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`Gaudreault reference from Genentech in 2005. And we'll hear a
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`lot about this reference. It taught that penetration of
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`ranibizumab -- that was Genentech's product at the time. They
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`were developing a different product called ranibizumab that
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`later became Lucentis, which is a product on the market. They
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`were ahead of Regeneron; so they were publishing already.
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`And what they said was penetration of their molecule,
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`ranibizumab, into the retina is critical for its credible use.
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`You've got to get to the retina. Or as people in the field
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`often say, the tissue is the issue. So you've got to get to
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`the right tissue. And why do they say their product gets to
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`the retina? Because of its small molecule size,
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`48 kilodaltons. Kilodaltons is just a measure of weight like
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`pounds or kilograms.
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`And they contrasted it with what they called a
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`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 15
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`full-length antibody, something that was 148 kilodaltons that
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`they said was not able to penetrate the retinal layers of the
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`monkeys. So 148 was too big; 48 was good enough. And what the
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`art said -- not just Genentech but others -- is that things
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`that are over about 70 kilodaltons or about 76 kilodaltons were
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`too big.
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`Now, we all know that aflibercept, in fact, did end
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`up penetrating the eye into the retina. If it didn't, none of
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`us would be here today. Okay? We'd all be somewhere else.
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`But that's not what matters for obviousness. What matters is
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`what everyone thought and knew at the time of the invention
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`about 16, 17 years ago. And at that time aflibercept was
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`simply considered too big.
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`This is ranibizumab, what we just saw, 48
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`kilodaltons. Aflibercept was 115. And it actually behaved
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`like it's even bigger because of its unusual size. The idea of
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`using aflibercept via intravitreal injection straight into the
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`eye was actually tried in mice in the prior art, and it didn't
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`work very well.
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`The figure on the left is subcutaneous injection.
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`That's systemic injection that Your Honor is used to, less
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`scary than intravitreal injection. And what you want to look
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`for here is does the problem go down. You want the numbers to
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`go down. This is golf, not bowling.
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`And when you did this systemic administration, what
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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 16
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`we see is the bar goes way down. That works well. But when
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`you do intravitreal administration straight into the eye, the
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`bar doesn't go down very much. And what people at the time
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`said -- and not just people. This on the right is an article
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`by Genentech and in particular someone called Napoleone
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`Ferrara. He's the godfather of VEGF. He actually discovered
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`VEGF. And he, while at Genentech, developed the first two
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`anti-VEGF therapies: Avastin and then Lucentis. And what he
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`said is he looked at these data and he said there's limited
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`efficacy, despite the high binding of the molecule. And it may
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`be due at least in part to the existence of a barrier to
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`penetration of large molecules such as the VEGF Trap.
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`That's what people were thinking and saying at the
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`time. It's too big. And without showing that you want to do
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`intravitreal administration of aflibercept, that claim can't be
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`obvious because all of the claims require it.
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`But the claims actually require more. Mylan has to
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`show much more than that. They have to show that the person of
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`skill would have wanted to use 40 milligrams per milliliter of
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`aflibercept, this high concentration of aflibercept. They have
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`to show that by clear and convincing evidence.
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`And the presentation from them that you'll see in a
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`moment has all sorts of prior art showing all sorts of buffers
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`and organic cosolvents and stabilizing agents, almost nothing
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`about 40 milligrams per milliliter. That was never done in 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 17
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`prior art for aflibercept. And they can't meet that burden,
`
`including because people thought that increasing concentration
`
`increases aggregation. That's the problem I discussed earlier.
`
`In fact, Genentech in this same Gaudreault article
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`tried 40 milligrams per milliliter, and it went poorly. What
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`happened when they did 40 milligrams per milliliter was that
`
`they got ocular inflammation that was moderate to severe. Bad
`
`news. You don't want inflammation. It resolved after
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`eight days, but keep in mind this is a product that's
`
`administered every month. No one wants their eye to be
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`inflamed for one week out of every month, let alone inflamed
`
`potentially with particles that can hurt your vision and cause
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`real problems.
`
`So Genentech, the leader in the field, ditched the
`
`40 milligrams per milliliter idea and instead pursued lower
`
`doses, 6 milligrams per milliliter or 10 milligrams per
`
`milliliter, which is what they ultimately used in Lucentis.
`
`The argument based on Fraser of obviousness fails for
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`this reason alone. Not only does it fail to disclose
`
`aflibercept or intravitreal injection, it has only
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`24.3 milligrams per milliliter, and the claim requires 40. The
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`skilled artisan would have used less than 24, not more, and
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`certainly wouldn't have gone all the way up to 40 when
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`Genentech, the prior art, was teaching away from it.
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`Now, the second prior art reference for obviousness
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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 18
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`that Mylan advances is Dix. And the assertion of Dix would
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`require the Court to answer a second question in the event that
`
`the Court does not believe that Regeneron is entitled to an
`
`earlier priority date.
`
`If we are entitled to an earlier priority date, as I
`
`said, Dix goes out the window completely. But if you answer
`
`that question no, Your Honor, then you have to answer a second
`
`question. Is Dix subject to the safe harbor of 103(c) in the
`
`statute so that it cannot be used for obviousness?
`
`And the answer to that question is that Dix is
`
`subject to the safe harbor. The statute is very clear. You
`
`can't use as an obviousness reference a reference owned by the
`
`same person as the patent or subject to an assignment of -- to
`
`an obligation of assignment to the same person. Your own prior
`
`art can't be used against you for obviousness under 103(c).
`
`There is no question but that Dix shown here on the
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`right and other such references and the product patent at issue
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`were owned by the same person, Regeneron Pharmaceuticals. And
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`all of the scientists working at Regeneron at the time, of
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`course, had an obligation to assign their inventions. That's
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`how pharmaceutical companies work. If you work for them and
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`use their labs, you don't get to keep your invention. It
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`belongs to the company, of course.
`
`Now, even if Dix could be used for obviousness, it
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`doesn't really help Mylan and Biocon. It does not disclose
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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 19
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`40 milligrams per milliliter. And based on the prior art that
`
`we've seen, the skilled artisan never would have used that high
`
`a concentration. It would have used a much lower concentration
`
`for the intravitreal injection, just as the prior art
`
`repeatedly taught.
`
`In any event, even if Mylan could show motivation to
`
`make the claimed invention, it cannot show expectation of
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`success, an independent requirement of the obviousness inquiry.
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`And moreover, the objective indicia of nonobviousness,
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`including commercial success, demonstrate clearly that the
`
`invention was not obvious, as you'll hear from Dr. Richard
`
`Manning, our expert economist.
`
`Now, Regeneron did not succeed because it had a
`
`molecule that inhibited VEGF. Lots of companies had that. But
`
`consider what happened with Genentech. They were the big
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`800-pound gorilla in the field, the leaders in the field of
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`biotechnology in general and VEGF in particular. They had a
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`big first mover advantage with their product, ranibizumab.
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`And there were lots of companies out there trying to
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`compete with Genentech, who had the leader in the field,
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`Dr. Ferrara, leading their program. None of the other
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`competitors succeeded, none of them. Only Regeneron succeeded.
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`And Regeneron succeeded wildly with a product Eylea that ended
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`up being the market leader and, in fact, overtaking Genentech's
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`ranibizumab.
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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 20
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`Now, because the prior art does not invalidate the
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`patent, Mylan next turns to Section 112 defenses. Now, these
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`defenses, as I pointed out at the pretrial conference, are so
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`blatantly inconsistent with their prior art references that
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`Mylan actually has to bring two separate experts in order to
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`advance these arguments -- prior art on the one hand and
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`Section 112 on the other -- because one person couldn't
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`possibly keep them straight, let alone testify lucidly as to
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`both.
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`They start with enablement, but their theory on
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`enablement suffers from a repeated fatal flaw. Mylan r
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