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`THOMAS A. ALBINI, MD - DIRECT
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`ordinary skill in the art that is different from your
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`definition?
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`A.
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`Q.
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`He did.
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`Would your analysis change under Dr. Csaky's
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`definition of a person of ordinary skill in the art?
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`A.
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`Q.
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`No.
`
`Let's turn to a little bit of a background about this
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`case, just starting with Slide 9.
`
`Have you assessed in this matter the issue of
`
`invalidity with respect to U.S. Patent Numbers 10,888,601 and
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`11,253,572?
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`A.
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`Q.
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`I have.
`
`Is it okay if I refer to those as the '601 and the
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`'572 patents going forward?
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`A.
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`Q.
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`Yes.
`
`Would it also be okay if I refer to those as the
`
`dosing patents in some instances today?
`
`A.
`
`Q.
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`patents?
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`A.
`
`Q.
`
`Yes.
`
`You'll understand I'm referring to the '601 and '572
`
`I will.
`
`So let's talk about the asserted claims. Do you
`
`understand that the claims shown here on Slide 10 are the
`
`claims that are being asserted in this matter by Regeneron?
`
`A.
`
`That's 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
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`W h e e l i n g , W V
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`2 6 0 0 3
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`3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 618
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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`Q.
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`Those include Claims 11 and 19 of the '601 patent and
`
`Claims 6 and 25 of the '572 patent?
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`A.
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`Q.
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`That's right.
`
`Are you rendering opinions on the anticipation and
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`obviousness of each of those patents?
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`A.
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`Q.
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`Yes.
`
`Do you understand that other experts will be opining
`
`on certain elements of one or more of those patent claims?
`
`A.
`
`Q.
`
`Yes.
`
`And one of those, you understand, will be
`
`Dr. Rabinow --
`
`That's correct.
`
`-- writing opinions with respect to Claim 6?
`
`That's correct.
`
`Did you rely on Dr. Rabinow for opinions regarding
`
`A.
`
`Q.
`
`A.
`
`Q.
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`Claim 6?
`
`A.
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`Yes, I did. I do not see myself as an expert in
`
`formulation, just in vitreoretinal disorders and their
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`treatment. So I did rely on him in that regard.
`
`Q.
`
`If we flip ahead to Slide 11 here, can you briefly
`
`provide a description to the Court of the opinions that you're
`
`going to be presenting today?
`
`A.
`
`The basic arguments are going to be that these
`
`claims, as you outlined -- the DME, DR claims -- are
`
`anticipated by the September 14th, 2009 Regeneron press release
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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 619
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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`and the 1999 '747 patent; that they are also obvious through
`
`those prior art pieces in combination with others; and that the
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`patent Claim 6 of the '572 patent as regards formulation is
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`anticipated and obvious.
`
`Q.
`
`Dr. Albini, I would like to start by talking about a
`
`little bit of scientific background before we delve into your
`
`opinions and the ways of treating various angiogenic eye
`
`disorders before 2011.
`
`Let's start with the anatomy of the eye. Can you --
`
`and the Court has heard a lot of this already, but can you
`
`briefly describe what you've shown here on Slide 13?
`
`A.
`
`Sure. This is a cartoon cross section of the eye,
`
`showing the front parts of the eye, the cornea -- the clear
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`part that you see when you look into somebody's eyes -- and the
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`lens.
`
`And the -- shows deeper into the eye. You have the
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`vitreous gel, which occupies most of the volume of the eye,
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`especially that back component. And then that orange-colored
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`tissue that you see there is sort of the wallpaper lining of
`
`the inside of the eye called the retina. This is neurologic
`
`tissue that connects to the optic nerve and sends visual
`
`impulse information back to the brain for you to be able to
`
`see.
`
`And if you want to progress the slides, this cartoon
`
`starts to move.
`
`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 620
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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` 759
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`When light comes into the eye, it goes -- it's
`
`focused by the cornea and the lens onto the fovea. The fovea
`
`is a specific part of the macula, the center part of the
`
`macula, and the macula is a part of a retina in general.
`
`And that's the part where you have your highest
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`definition vision. That is the part that's affected by the
`
`diseases at issue here, both diabetic macular edema and
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`exudative, or wet, macular degeneration.
`
`In those disease states, either because the blood
`
`vessels are leaky, as they are in diabetic macular edema, or
`
`because they're leaky because of abnormal growth of vessels
`
`that develops in macular degeneration, the retina becomes
`
`distorted which, in turn, distorts your vision.
`
`And the miraculous discovery over the last two or
`
`three decades is that a lot of that disease process is driven
`
`by a molecule called vascular endothelial growth factor and
`
`that blocking this vascular endothelial growth factor not only
`
`causes some of these immature blood vessels to disappear, but
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`it decreases the fluid buildup and consequent distortion of the
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`retina; and, even more miraculously, it improves patient's
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`vision. And this blockage has been responsible for greatly
`
`reducing cases of blindness due to macular degeneration and
`
`diabetic macular edema over the last few decades.
`
`Q.
`
`Thank you, Dr. Albini.
`
`Now, I'd like to shift to a discussion of state 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
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 621
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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` 760
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`the art and the background with regard to what was known prior
`
`to 2011, including with respect to some of these VEGF
`
`inhibitors that you just made reference to.
`
`Do you understand first -- we'll be filling in this
`
`timeline as we go along, but do you understand that 2011 to be
`
`the year the patents-in-suit were filed?
`
`A.
`
`Q.
`
`That's my understanding.
`
`Let's start by talking about the VEGF drugs that were
`
`being administered in trials -- or the clinic prior to 2011.
`
`Would that have included ranibizumab?
`
`A.
`
`Ranibizumab and bevacizumab -- a very similar
`
`molecule to ranibizumab but different in many ways -- were the
`
`two main agents that were in use prior to the 2011 date.
`
`Q.
`
`And was aflibercept also being tested in clinical
`
`trials prior to 2011?
`
`A.
`
`It was available for clinical trial use only, that's
`
`correct.
`
`Q.
`
`So if we flip to Slide 21, can you describe what's
`
`shown here on this slide, Dr. Albini.
`
`A.
`
`This is a review article that was published in 2009
`
`by Dixon and coauthors, and it describes the -- what became
`
`known as the aflibercept molecule. It's VEGF Trap-Eye, which
`
`was a scientific name, as Dr. Yancopoulos testified the other
`
`day, that was used for this molecule prior to the aflibercept
`
`name and the Eylea names being given to it. But it 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
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 622
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
`
` 761
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`protein with key binding receptors of the VEGF receptor 1 and
`
`receptor 2 fused with the FC portion of an antibody.
`
`Q.
`
`And here on the slide you're referring to DTX 0204,
`
`pages 1 and 3 from the Dixon reference?
`
`A.
`
`That's correct. Also here there is another reference
`
`from Adis in 2008 which makes reference to the same protein.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`And Adis, that's DTX 4008 that you're referring to?
`
`That's correct.
`
`What's the year of the Dixon reference?
`
`2008.
`
`And was VEGF Trap-Eye also known as aflibercept in
`
`the prior art?
`
`A.
`
`Q.
`
`That's correct.
`
`And is that shown here on Slide 22 in excerpts from
`
`DTX 0204 and DTX 4008?
`
`A.
`
`Especially in the Adis 2008 article. The title of
`
`the article itself is "Aflibercept."
`
`Q.
`
`In the abstract of Adis, the reference is
`
`aflibercept, and it says that Regeneron and Bayer are
`
`developing the agent for eye disorders?
`
`A.
`
`Q.
`
`That is correct.
`
`And turning to the next slide, Slide 23, you've shown
`
`the '747 patent on the left hand. Is that one of the patents
`
`and references you've relied on in forming your opinions in
`
`this case?
`
`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 623
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`THOMAS A. ALBINI, MD - DIRECT
`
` 762
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`A.
`
`Q.
`
`That is correct.
`
`And did the '747 patent recite a molecule called
`
`VEGFR1R2-Fc delta C1(a)?
`
`A.
`
`That is correct. That is the name given to the
`
`fusion protein of the VEGF receptor 1 and 2 bound with the Fc
`
`receptor that was in clinical use.
`
`Q.
`
`A.
`
`Q.
`
`Is that molecule also known as aflibercept?
`
`That is correct.
`
`Flipping ahead to Slide 24, this is another
`
`disclosure from the '747 patent that you provided here.
`
`Does the '747 patent disclose a method of treatment
`
`for an angiogenic eye disorder?
`
`A.
`
`It does. In the specification there are outlined
`
`patient visits that should occur when the patients are being
`
`treated with this molecule, and it says that after the first
`
`30 days, the patient should return for periodic examinations on
`
`a monthly basis thereafter.
`
`It also describes that the patient needs to be
`
`continuously monitored through periodic examinations for fluid
`
`in the retina. And at the time fluorescein angiography is
`
`mentioned as an imaging modality to do that with. And it also
`
`mentions that, in a preferred embodiment of what's taught in
`
`this patent, the initial treatment is followed by subsequent
`
`treatments that are given at dosing intervals ranging from one-
`
`to six-month dosing intervals.
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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 624
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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` 763
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`Q.
`
`And looking at the face of the '747 patent, do you
`
`see the date of the '747 patent's priority application?
`
`A.
`
`I'm not so clear on all of the legal terms; so
`
`maybe -- but I see the date there, December 4th, 2007, although
`
`my recollection is that this patent was first filed in 1999.
`
`Q.
`
`Thank you.
`
`And flipping to the next slide, Slide 25, is that
`
`'747 patent now reflected on this timeline that you've
`
`provided?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`And that '747 patent, that's DTX 2730?
`
`That's correct.
`
`Now, moving on to Slide 26, let's talk about some of
`
`the other VEGF inhibitors that were known and being used by
`
`ophthalmologists before the '601 and '572 patents were filed.
`
`What was the first anti-VEGF antibody approved by the
`
`FDA for treating an angiogenic eye disorder?
`
`A.
`
`The first antibody molecule that was approved was
`
`ranibizumab. There was a prior medicine called Macugen, which
`
`was an aptamer. It's a slightly different type of technology.
`
`It is a binding molecule much like these others all targeting
`
`various subtypes of vascular endothelial growth factor.
`
`Ranibizumab became FDA approved for use in wet
`
`macular degeneration in 2006. And what we have here is a
`
`picture of the label of the drug with an excerpt describing
`
`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 625
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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` 764
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`dosing frequencies of intravitreal injection once a month and
`
`another approved dosing regimen of one injection every three
`
`months for the first four injections and quarterly injections
`
`thereafter.
`
`The other main drug in use was bevacizumab.
`
`Bevacizumab is quite an interesting story. It's another
`
`molecule that also targets vascular endothelial growth factor.
`
`It was also developed by the Genentech. Both these drugs were
`
`developed by Genentech.
`
`Ranibizumab was developed specifically for use in the
`
`eye while bevacizumab was developed for intravenous use in
`
`cancer patients. Bevacizumab was available prior to the
`
`availability of ranibizumab. And in 2005 a number of
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`physicians began to inject bevacizumab off-label intravitreally
`
`to treat angiogenic eye disorders. There was already good data
`
`coming from Phase II studies and other studies showing that
`
`there was great efficacy with ranibizumab.
`
`And there was a desire to have this efficacy
`
`available to patients before the molecule was actually approved
`
`by the FDA; so bevacizumab was used. And that quickly in 2005
`
`spread throughout the world, where this became the major drug
`
`that was used in this sphere. And it remains to this day
`
`probably used just as often as the name-brand drugs in the
`
`United States.
`
`One of the main driving factors for the use 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 626
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`THOMAS A. ALBINI, MD - DIRECT
`
` 765
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`bevacizumab, even though it's not specifically FDA-approved for
`
`this indication, is a huge differential in cost. The
`
`ranibizumab was approximately $2,000 per injection whereas
`
`bevacizumab, when you bought a bag of drug for intravenous use
`
`and you aliquoted it out to inject it into the eye, the cost of
`
`a single ocular injection came out to about $50. So it was a
`
`great drug to have especially for patients of limited means.
`
`Q.
`
`In your discussion of the ranibizumab label that we
`
`just had prior to your discussion of bevacizumab, were you
`
`referring to DTX 4056?
`
`A.
`
`Q.
`
`That is correct.
`
`Thank you.
`
`If we flip ahead, can you briefly tell the Court what
`
`you've shown here on Slide 27 with respect to ranibizumab and
`
`how it was being used in clinical trials?
`
`A.
`
`These are three outcomes from trials with ranibizumab
`
`that were available in the 2006 to 2008 time frame. And I
`
`think these are really important graphs of top-line data from
`
`these drugs.
`
`The first to the left is the top-line visual acuity
`
`results from the ANCHOR trial of monthly ranibizumab for the
`
`treatment of wet macular degeneration.
`
`The line that you see there going down on the bottom
`
`is the control arm. And that was treatment with standard of
`
`care at the time, which was a type of laser and photodynamic
`
`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 627
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
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`THOMAS A. ALBINI, MD - DIRECT
`
` 766
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`intravenous treatment called photodynamic therapy. That was
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`the best treatment that we had when I was a resident. And as
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`seen there, patients continued to lose vision. Although they
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`lost vision less quickly than they might have without this
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`therapy, it just retarded the rate of vision loss, but patients
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`still continued to lose vision.
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`The really earth-shattering result that was seen in
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`ANCHOR study and other studies, the MARINA study which we'll be
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`talking about later, was this quick rise in visual acuity that
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`was then maintained over time as you see in the other two lines
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`that go up to where patients are gaining about ten letters,
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`what we call ETDRS letters of visual acuity. That translates
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`into being able to read two lines further down on the eye
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`chart, roughly, in that area. So that was really a very
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`welcome and amazing improvement in the treatment of macular
`
`degeneration.
`
`In the center box you see the top-line data from a
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`smaller prospective study called the PrONTO study, which just
`
`to have institutional pride, was performed at Bascom Palmer Eye
`
`Institute. And this study tested the concept whether we could
`
`reduce injections, not necessarily inject patients every month
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`as was done in the original ranibizumab study, but make
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`decisions on a monthly basis whether or not a patient needed an
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`injection by considering certain clinical factors and
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`considering the state of the retina, especially as evidenced by
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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 628
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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`imaging technologies, newer technologies that were available at
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`the time, especially something called optical coherence
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`tomography, or OCT, examinations, which are now pretty
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`ubiquitous in the retinal world as a way of evaluating the
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`health of the macula.
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`So this study showed, as you can see there, that you
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`could get very profound benefit and visual acuity results,
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`really very nicely mirroring the benefits that you see in
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`ANCHOR with this as-needed treatment strategy. This is the
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`so-called prn treatment strategy which became very poplar very
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`quickly in that 2007 and beyond range.
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`And, finally, you have the results of a quarterly
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`dosing study with ranibizumab, the EXCITE study, which showed
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`that monthly dosing, which is the triangle line up on top,
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`outperformed quarterly dosing. So these were initial monthly
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`loading doses and then followed by quarterly dosing. And that
`
`although that treatment strategy resulted in a success compared
`
`to photodynamic therapy, certainly compared to observation
`
`alone and no treatment, it was not as good as monthly dosing.
`
`Q.
`
`And when you were referring to these charts here,
`
`you're referring to excerpts from DTX 4061?
`
`A.
`
`Q.
`
`That's correct.
`
`With respect to the PrONTO study, did you also rely
`
`in the process of formulating your opinions on DTX 3115, the
`
`Fung 2007 reference?
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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 629
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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`A.
`
`Q.
`
`I did.
`
`Now, turning to the next slide, could you tell the
`
`Court a little bit about how bevacizumab was being used in the
`
`clinic and how it was being evaluated in clinical trials?
`
`A.
`
`This is a clinical trial of bevacizumab for exudative
`
`macular degeneration, a one-year prospective study, showing
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`that this drug could be used to obtain similar results with
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`that seven- to eight-letter gain by 12 months. And this was
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`also done with initial loading doses and then reinjection of
`
`the drug on an as-needed basis going forward.
`
`Q.
`
`So flipping back to the timeline now, so just to
`
`summarize, by 2006 there was an anti-VEGF agent, ranibizumab,
`
`that had been approved for monthly dosing and for every-12-week
`
`dosing?
`
`A.
`
`Q.
`
`That's correct.
`
`And by 2007 the results of the PrONTO study using
`
`as-needed maintenance dosing, had that been reported?
`
`A.
`
`Q.
`
`That's correct.
`
`And by 2008 had data been reported with respect to
`
`the use of bevacizumab in the treatment of AMD and is that
`
`reflected here --
`
`A.
`
`Q.
`
`Yes.
`
`-- on the timeline?
`
`I would like to shift focus a little bit. And can
`
`you tell the Court how ranibizumab was being used in the
`
`C i n d y L . K n e c h t , R M R / C R R / C B C / C C P
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`P O B o x 3 2 6 W h e e l i n g , W V 2 6 0 0 3 3 0 4 . 2 3 4 . 3 9 6 8
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`Regeneron Pharmaceuticals, Inc. Exhibit 2003 Page 630
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`THOMAS A. ALBINI, MD - DIRECT
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`context of treating DME in that time frame.
`
`A.
`
`This is a review article by Dr. Lalwani from 2009
`
`that reviews the results of a early study with ten patients who
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`received injections of ranibizumab at baseline, month one and
`
`month two, so essentially three loading doses, and then
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`received q8-week dosing for the month four and six. And it
`
`showed that there was good visual acuity gains from this
`
`treatment strategy in this small number of patients with
`
`diabetic macular edema.
`
`Q.
`
`Is that Lalwani reference now referenced on this
`
`timeline here at Slide 31?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`That is correct.
`
`And that's from DTX 2733?
`
`That's correct.
`
`Now, turning to the next slide and turning back to
`
`that Dixon reference which you've referenced earlier, was
`
`aflibercept being used in a Phase II AMD trial prior to 2011?
`
`A.
`
`The Dixon article from 2009 describes both --
`
`describes a Phase II study, the CLEAR-IT 2 study, of
`
`2 milligrams for 12 weeks of the -- of aflibercept being used
`
`followed by a prn treatment regimen after the loading dose
`
`phase of the study.
`
`And it also describes a Phase III study for wet
`
`macular degeneration using the 2-milligram dose administered
`
`either every four weeks or every eight weeks and compared 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 631
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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`ranibizumab.
`
`Q.
`
`A.
`
`Q.
`
`And these are selections from DTX 0204?
`
`That's correct.
`
`And flipping to the next slide, Slide 33, can you
`
`tell the Court how else aflibercept was being used prior to
`
`2011?
`
`A.
`
`This is a Regeneron press release dated
`
`September 14th, 2009. And it describes a Phase III study in
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`retinal vein occlusion. That's another angiogenic eye disorder
`
`treated -- VEGF-driven and treated with these same agents. And
`
`this describes a protocol with six monthly doses and then prn
`
`dosing thereafter.
`
`And it also describes a Phase II study in diabetic
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`macular edema with a monthly arm, also an arm where there were
`
`three monthly loading doses and then every-eight-week
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`injections and another arm where there were three monthly doses
`
`and prn injections going forward.
`
`Q.
`
`A.
`
`Q.
`
`And those selections are from DTX 3198?
`
`That's correct.
`
`Can you tell the Court how aflibercept was being used
`
`in the treatment of DME prior to 2011?
`
`A.
`
`This is a manuscript from Do in 2009. And it
`
`describes a small study of a single injection of 4 milligrams
`
`of aflibercept in a small number of patients, and it describes
`
`a visual acuity benefit from that single injection.
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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 632
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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`Q.
`
`And that visual acuity benefit, again, that was nine
`
`letters at one month?
`
`A.
`
`Q.
`
`That's correct, which is an impressive benefit.
`
`And are those Dixon disclosures and the Do
`
`disclosures referenced here on the timeline at Slide 35?
`
`A.
`
`Q.
`
`Yes.
`
`So now we've reviewed what was being done in clinical
`
`trials up to now. Let's shift focus and discuss what
`
`physicians were doing in actual clinical practice before 2011.
`
`So on this next slide, Slide 36, can you explain
`
`what's shown here?
`
`A.
`
`These are excerpts from a roundtable discussion that
`
`was published in a professional journal called Retinal
`
`Physician in 2007. And I think this is a great way to get a
`
`snapshot of what the POSA was thinking at that time.
`
`These are three prominent retina specialists in the
`
`United States, and they're describing their treatment
`
`protocols. The first one there is Dr. Rosenfeld from Miami.
`
`He was the lead investigator and designer of the PrONTO study.
`
`And he describes his treatment regimen trying to minimize the
`
`number of injections but treat the patients until there's no
`
`fluid in the retina. And once they're dry, then having the
`
`ability to skip those injections.
`
`Dr. Reichel from Boston also says that he's a big
`
`believer in prn dosing. He gives only one injection on 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 633
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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`routine basis, sees the patient four weeks later, and already
`
`makes a decision whether or not to re-treat. So this would be
`
`a regimen that would be essentially one loading dose, or just a
`
`single primary dose, followed by immediate prn protocol
`
`injections.
`
`And Dr. Hariprasad from Chicago also gives his
`
`opinion that he doesn't necessarily give three full loading
`
`doses, but he gives monthly injections until the patient's
`
`retina is dry and then presumably stops injecting until there's
`
`reaccumulation of fluid.
`
`THE COURT: Counsel, if I could interrupt.
`
`Doctor, when you reference dry, you're referring to
`
`the elimination of any leakage or bleeding from the
`
`VEGF-spurred blood vessels and the rest; is that correct?
`
`THE WITNESS: Yes. I'm so sorry that I didn't
`
`explain that.
`
`So we often use that as a colloquial term for seeing
`
`that there's been resolution of fluid. And you're right on
`
`point there with what that means. That's right.
`
`THE COURT: When you say fluid, would there be any
`
`other fluids that are offshoots of these various diseases of
`
`the eye other than blood?
`
`THE WITNESS: So most of the fluid is clear. It
`
`doesn't have red blood cells in it. It's a serous fluid that's
`
`in there that extrapolates from the vessels. But the red blood
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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 634
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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` 773
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`cells are usually contained within the vessels. You can have
`
`blood also. So it can be either blood, but the majority of the
`
`time it's actually not full blood.
`
`THE COURT: But it's fluid that's coming from the
`
`blood vessels?
`
`THE WITNESS: That's exactly right.
`
`THE COURT: Understood. Thank you.
`
`Sorry, Counsel. Go right ahead.
`
`THE WITNESS: Sorry I didn't explain that better.
`
`THE COURT: Oh, no. That's good.
`
`Go ahead, Counsel.
`
`BY MR. McLAUGHLIN:
`
`Q.
`
`The excerpts that you've been referring to, those are
`
`coming from DTX 2035?
`
`A.
`
`Q.
`
`That's correct.
`
`Turning to the next slide, Slide 37, can you describe
`
`what's shown here?
`
`A.
`
`This is a quote from the same roundtable discussion.
`
`This is Dr. Brown from Houston, Texas, another prominent retina
`
`specialist. And he says that he uses treat and extend from the
`
`start. I'd just like to point out to everybody that this is
`
`back in 2007 that he's describing this treatment strategy.
`
`The treat-and-extend strategy is another strategy
`
`that came into vogue slightly after the prn strategy, but the
`
`concept here was to not only reduce the number of injections
`
`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 635
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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` 774
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`but to reduce the number of visits that patients needed to come
`
`back. And so that if a patient established themselves as
`
`someone who was -- who could maintain the retina free of fluid
`
`for a longer period of time, then the physicians became
`
`comfortable with having those patients come in at longer
`
`periods to minimize the burden of visits over time.
`
`And so this is just a nice historical document
`
`showing that already in 2007 this type of treatment strategy
`
`was indeed being employed.
`
`Q.
`
`Is that something that you employed in your own
`
`practice prior to 2011?
`
`A.
`
`Q.
`
`Yes.
`
`Was Dr. Brown's description of treat and extend
`
`consistent with the general understanding of the
`
`treat-and-extend regimen in that time frame?
`
`A.
`
`Q.
`
`Yes.
`
`And turning to the next slide, Slide 38, can you
`
`describe what you've shown here?
`
`A.
`
`This is a survey result from a survey that's
`
`performed by the American Society of Retina Specialists every
`
`year. And it basically serves as a way to communicate amongst
`
`the profession what the treatment modalities are, treatment
`
`trends are within the community of retina specialists.
`
`So this -- for example, this question is asking
`
`physicians to identify what their treatment strategy is for
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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 636
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`THOMAS A. ALBINI, MD - DIRECT
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` 775
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`exudative macular degeneration or wet macular degeneration.
`
`And in 2010, out of 337 respondents to this survey, 43 percent
`
`said they were using a prn strategy and 34 percent were already
`
`using a treat-and-extend strategy.
`
`Q.
`
`Turning to the next -- sorry. Flipping back just to
`
`confirm, you're referring to DTX 2040?
`
`A.
`
`Q.
`
`Yes.
`
`Flipping to the next slide, Slide 39, can you explain
`
`what's shown here?
`
`A.
`
`This is an article showing a study result for
`
`intravitreal bevacizumab -- that's Avastin -- for myopic
`
`choroidal neovascularization, a short-term and one-year result.
`
`And the interesting thing to me was that this is already making
`
`reference to the treat-and-extend approach, just to document
`
`that this was already something that was seen as a treatment
`
`strategy that was well known within the field in 2009 by the
`
`time this was published.
`
`Q.
`
`A.
`
`Q.
`
`And this is from DTX 4113?
`
`That is correct.
`
`So are all these refe