`Slayback Pharma LLC et al. v.
`Eye Therapies LLC et al.
`
`Patent Owner Eye Therapies, LLC’s Demonstratives | February 27, 2023
`
`Case No. IPR2022-00142
`(’742 Patent)
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`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
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`1
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`Eye Therapies Exhibit 2216, 1 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`
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`Lumify - the #1 Eye Doctor Recommended
`Redness Reducer
`
`EX-2191, EX-2055, EX-2081
`
`Paper 30 at 2, 67-69; EX-2020, ¶313; EX-2023, ¶¶6-7
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`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
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`2
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`Eye Therapies Exhibit 2216, 2 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Attributes of the Lumify versus
`Prior Commercial Redness Relievers
`
`Lumify’s Healthcare Provider-Facing Website
`Comparison with Competitors (EX-2111.)
`
`EX-2023 at ¶¶ 8-13
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`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
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`3
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`Eye Therapies Exhibit 2216, 3 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Overview of Issues to be Addressed
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`• Petitioner failed to prove inherent anticipation
`– radial keratotomy patients do not inevitably have eye redness
`– brimonidine administered with other drugs that can prevent development of
`hyperemia
`– “about 0.025%” does not encompass 0.03%
`• Petitioner’s obviousness arguments are hindsight-driven
`– brimonidine caused redness
`– brimonidine whitening was concentration dependent
`• optimize upward, if at all
`– POSA would have increased, not decreased, the pH
`• Patented invention showed objective indicia of non-obviousness
`– unexpected superior results
`– industry praise and rapid commercial success for Lumify
`
`See generally ,Paper 30 at 39-69
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`4
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`Eye Therapies Exhibit 2216, 4 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Ground 1: Anticipation
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`’553 Patent
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`Eye Therapies Exhibit 2216, 5 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Ground 1: Petitioner Failed to Meet Its Heavy Burden on
`Inherent Anticipation
`
`“A party must ... meet a high standard in order to
`rely on inherency ….”
`
`Millennium Pharms., Inc. v. Sandoz Inc., 862 F.3d 1356, 1367 (Fed. Cir. 2017)
`
`“[T]he limitation at issue necessarily must be present
`or is the natural result of the combination of elements
`explicitly disclosed by the prior art.”
`
`“[I]nherency may not be established by probabilities or
`possibilities. The mere fact that a certain
`thing may result from a given set of circumstances is
`not sufficient.”
`
`Endo Pharms. Sol., Inc. v. Custopharm Inc., 894 F.3d 1374, 1381 (Fed. Cir. 2018) (emphasis added);
`see also Galderma Labs., L.P. Teva Pharms. USA, Inc., 799 F. App’x 838, 845 (Fed. Cir. 2020).
`
`Paper 30 at 40-43
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`Eye Therapies Exhibit 2216, 6 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Slayback’s Shifting Theories – Ground 1 (’553 Patent)
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`Petition
`
`Reply
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`Petition at 34
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`Reply at 7-8
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`Paper 59 at 2, 8
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`Eye Therapies Exhibit 2216, 7 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Petitioner’s Burden
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`• Prove that Example 1 of the ’553 patent
`necessarily and inevitably (i.e., unavoidably)
`
`– Reduces eye redness
`
`– consisting essentially of administering brimonidine
`
`– to patients having an ocular condition
`
`– brimonidine is present at a concentration between
`about 0.001% … to about 0.05% (claim 1)
`
`• about 0.001% to about 0.025% (claim 2)
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`Paper 30 at 40-43; Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 8 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Radial Keratotomy Does Not Necessarily and Inevitably
`Cause Hyperemia
`
`“cornea”
`
`• Cornea is avascular (EX-2177)
`
`• Properly done, precision cuts to the
`cornea during radial keratotomy would not
`cause conjunctival hyperemia
`– Dr. Sher agreed with Dr. Noecker, patentee’s
`expert
`• EX-2020, ¶ ¶104-105; EX-2162, 113:6-114:4
`
`Paper 30 at 27, 41; EX-2020 at ¶¶35, 104-105, 149, 189
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`Eye Therapies Exhibit 2216, 9 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Inflammation Can Develop Without Redness
`
`• Five cardinal signs of inflammation
`– Pain
`– Swelling
`– Redness
`– Heat
`– Impaired function
`• Not all signs of inflammation are manifested
`Q. Okay. So when you have an inflammatory event, all
`these signs, whether it’s four or five, they don’t all
`have to coexist or comanifest from a single
`inflammatory event; is that true?
`[Objection omitted]
`A. That’s a fair statement.
`
`EX-2162, 104:23-106:12
`
`Neal Sher
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`Paper 30 at 40-41, 53; EX-2020, ¶¶145-146, 234-235; Paper 59 at 8-9
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`10
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`EX-2162, 106:16-107:5
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`Eye Therapies Exhibit 2216, 10 of 101
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`Inflammation Can Develop Without Redness
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`• Even if inflammation develops, Dr. Sher acknowledged that a patient can have
`inflammation without redness
`
`Neal Sher
`
`Q. So you can have pain without swelling, for example, or
`pain without an impaired function, correct?
`A. Yes.
`[Objection omitted]
`THE WITNESS: Yes.
`Q. Or even pain without redness, correct?
`A. Yes.
`
`EX-2162, 107:2-11
`
`• See accord EX-2174 at 4 (explaining that “[i]n more severe [alkali] burns
`the conjunctiva and episclera are blanched”).
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`Paper 30 at 40-41, 53; EX-2020, ¶¶145-146, 234-235; Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 11 of 101
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`Pain Relief Without Redness Reduction
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`• Dr. Sher also admitted that one can treat pain without reducing
`redness.
`
`Q. But it is possible that, for example, you can relieve
`pain but not have any effect on redness, right?
`[Objection omitted]
`A. Could you relieve pain without affecting redness?
`Q. Yeah.
`A. It’s possible.
`
`EX-2162, 109:3-11
`
`Neal Sher
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`Paper 30 at 40-42, 53; EX-2020, ¶¶145-146, 234-235; Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 12 of 101
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`Dr. Sher Acknowledges That Hyperemia from Radial
`Keratotomy Is Only a Possibility
`
`• Dr. Sher relies on evidence that confirms the
`speculum/forceps (foreign materials) used in radial
`keratotomy may only possibly cause hyperemia
`– “Foreign body redness can arise when materials or irritants are
`caught on the surface of the eye and cause inflammation. The
`inflammation triggers …causing eye lid edema (puffy eye) and
`possibly hyperemia” (EX-1049, ¶¶ 47, 50; see also EX-2213,
`34:15-21)
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`Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 13 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Brimonidine Administered With Other Drugs That Can
`Prevent Development of Hyperemia
`
`• Dr. Sher and Petitioner argue that brimonidine is the only drug
`administered in radial keratotomy in Example 1
`
`• But Dr. Sher admitted that it would be malpractice not to administer other
`drugs
`
`EX-1002, ¶112
`
`A. Yes. You could not do [radial keratotomy] without
`anesthetizing the cornea. It probably would be
`malpractice
`
`Neal Sher
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`EX-2213, 22-24-23:13
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`Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 14 of 101
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`Brimonidine Administered With Other Drugs That Can
`Prevent Development of Hyperemia
`• Dr. Sher admitted that anti-inflammatories (steroids & NSAIDs) and
`antibiotics are typically administered
`Q. Okay. Well, were only anesthetics used as a way of
`addressing the pain that a patient may feel? And my
`question is presurgically.
`A. And frequently nonsteroidal drops, there are a number of
`them, including diclofenac, which I did a lot of
`research on and have the patent -- one of the patents
`for corneal pain. Would use that preop and then postop.
`And related drops -- and related drops to various NSAIDS
`can be used.
`Would ketorolac be one?
`Q.
`Yes.
`A.
`[...]
`Frequently, in almost all cataract surgery, in almost
`any of these types of surgeries that we've been
`discussing, a mixture of an antibiotic and a steroid
`would be used postoperatively to reduce postoperative
`inflammation and possibly to prevent infection.
`EX-2213, 18:10-19:20
`
`Neal Sher
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`Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 15 of 101
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`Brimonidine Administered With Other Drugs That Can
`Prevent Development of Hyperemia
`
`• Dr. Sher admitted that the anti-inflammatories and antibiotics can prevent
`redness from developing
`Q. Just so that I'm clear, it is possible that they could
`have used in RK surgery a steroid preoperatively and
`postoperatively to reduce inflammation?
`Yes.
`A.
`[...]
`Q.
`Any other symptoms that that cocktail of antibiotics
`and steroids may have been used to address?
`A. Well, the -- the steroids would address all the signs of
`inflammation. So it would reduce swelling of the
`conjunctiva. It would reduce redness. It would reduce
`inflammation, pain, and depending on the procedure and
`depending on how much -- how many drops you used
`postoperatively and what regimen.
`
`Neal Sher
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`EX-2213, 19:21-21:8
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`Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 16 of 101
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`Brimonidine Administered With Other Drugs That Can
`Prevent Development of Hyperemia
`• Dr. Sher admitted that saline drops are administered during radial keratotomy
`
`Q. So is it fair to say that the tear or wetting drops that
`may be administered during or preoperatively to RK
`surgery help to lubricate the eye?
`A. Yes.
`Q. And they could be applied before surgery as well as
`during surgery?
`A. It could be. It's generally during because patients are
`blinking before the surgery.
`
`Neal Sher
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`EX-2213, 27:19-28:3
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`• The saline drops can reduce eye redness
`
`“[I]f a patient had hyperemia due to dry eyes, Refresh Plus® lubricant could have
`reduced redness rather than brimonidine.”
`
`EX-2020, ¶173
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`Paper 59 at 8-9
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`Eye Therapies Exhibit 2216, 17 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Petitioner’s Failure of Proof
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`Petitioner Failed to Carry Its Heavy Burden of Proving Inherency because:
`
`1. Radial keratotomy patients of Example 1 would have been
`administered other drugs with brimonidine (Sher: would have been
`“malpractice” not to do so)
`
`2. Other drugs used in radial keratotomy would admittedly impact
`development of hyperemia
`
`3. Not all patients would unavoidably have hyperemia
`
`4. No proof that 0.03% brimonidine in a prophetic, incomplete radial
`keratotomy protocol would necessarily and inevitably reduce
`hyperemia
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`Paper 30 at 40-43
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`Eye Therapies Exhibit 2216, 18 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Claim Construction
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`“about 0.025%” & “ocular condition”
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`Eye Therapies Exhibit 2216, 19 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Claim Construction Principle - Phillips
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`“Ultimately, the interpretation to be given a term can only be
`determined and confirmed with a full understanding of what
`the inventors actually invented and intended to envelop with
`the claim. The construction that stays true to the claim
`language and most naturally aligns with the patent’s
`description of the invention will be, in the end, the correct
`construction.”
`
`Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005) (quoting Renishaw PLC v. Marposs Societa’ per Azioni, 158 F.3d
`1243, 1249 (Fed. Cir. 1998).
`
`Paper 30 at 29-30; Paper 59 at 3-6
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`Eye Therapies Exhibit 2216, 20 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`A Key Discovery of the ’742 Patent
`
`•
`
`Induce vasoconstriction to reduce eye redness (hyperemia) while
`minimizing rebound hyperemia
`
`EX-1001, 2:35-41
`
`• Repeated throughout ’742 patent (EX-1001)
`• 2:1-33 (set up in Background of Invention)
`• 4:25 (heading “Vasoconstriction with Reduced Hyperemia”)
`• 4:25-30, 47-56, 5:35-45, 5:65 to 6:4, 6:37-39
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`Paper 30 at 25-27; Paper 59 at 3-6
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`Eye Therapies Exhibit 2216, 21 of 101
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`Figure 6: A Graphical Representation of Inventor’s Key
`Discovery
`
`• Balancing benefit (vasoconstriction) v. Risk (rebound) for optimum concentration
`
`0.025%
`without
`rebound
`hyperemia
`
`Vasoconstriction curve
`
`Rebound hyperemia curve
`
`0.03% with
`rebound
`hyperemia
`
`EX-2161, 19:52-54, Figure 6 (annotated)
`
`EX-2020, ¶95
`Specification to POSA: stay below the 0.03% red zone to realize “key discovery” and “finding” of
`the present invention
`
`Paper 30 at 31-35; EX-2020, ¶¶93-96, 110-113; Paper 59 at 3-6
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`Eye Therapies Exhibit 2216, 22 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`“about 0.025%” Critically Lies Beneath the Red Zone
`
`• 0.025% is slightly to the right of the visual midpoint
`between 0.01% and 0.03%
`• Specification teaches 0.025% is preferred 22 times
`(e.g., EX-1001, 5:49-51, 5:59-61, 7:4-8, 7:9-19, 7:20-26, 8:4-11,
`8:12-16, 9:20-24, 9:28-34, 9:35-42, 9:53-55, 9:63-67, 10:3-8,
`10:9-17, 11:26-31, 12:60-67)
`• 0.03% is associated with rebound hyperemia
`
`EX-2161, 19:52-54, Fig. 6
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`Paper 30 at 31-35; EX-2020, ¶¶93-96, 110-113; Paper 59 at 3-6
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`Eye Therapies Exhibit 2216, 23 of 101
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`“about 0.025%” – Slayback’s Litigation Driven Position
`Dr. Williams explained that a POSA would understand “about” means no more than ± 10%
`
`Petitioner’s expert, Dr. Laskar, on the other hand, does not even know what “about” means and cannot answer questions
`regarding the scope of “about 0.025%”
`
`EX-2021 at ¶ 40
`
`Q. Within the meaning of the ’742
`patent, is it your opinion that 0.035
`percent is about 0.025 percent?
`[Objection omitted]
`THE WITNESS: Without – without having
`a definition of "about," it makes it
`difficult to respond.
`
`EX-2212 at 48:12-19
`
`Q. Well, irrespective of paragraph 14,
`let me ask it generally with respect
`to the – to the '742 patent, is it
`your opinion that 0.035 percent is
`about 0.025 percent?
`[Objection omitted]
`THE WITNESS: How are you defining
`"about"?
`
`Dr. Laskar
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`Paper 30 at 35-36; EX-2021, ¶¶39-45 ; Paper 59 at 6-7
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`EX-2212 at 46:19-25
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`Eye Therapies Exhibit 2216, 24 of 101
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`“about 0.025%” – Dr. Laskar’s Rounding Opinion
`
`Dr. Laskar argues that “about
`0.025%” encompasses 0.03%
`based on rounding
`
`But Dr. Laskar admitted that
`applying general chemistry rounding
`principles, 0.025% would round
`down to 0.02%, not up to 0.03%
`
`EX-1003 at ¶ 72
`
`Q. Under the “Rules of Rounding” expressed in
`Laskar Exhibit 8, 0.025 would round down to
`0.02 and 0.035 would round up to 0.04;
`correct?
`[Objection omitted]
`THE WITNESS: That's what those two sentences
`say.
`
`Dr. Laskar
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`Paper 59 at 6
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`Eye Therapies Exhibit 2216, 25 of 101
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`“about 0.025%” – No More than ± 10%
`
`Dr. Laskar agrees ”USP applies to the brimonidine formulations of the ’742
`patent”
`“since ’742 deals with pharmaceuticals and the USP also relates to
`drugs, that the guidances that the USP provides would seem to me to
`be a more relevant resource, and reference to use.”
`
`Dr. Laskar
`
`EX-2212, 129:14-130:3
`
`Regarding FDA acceptance criteria, Dr. Laskar agrees that
`“[i]t is important to keep the concentration of the drug in a drug product
`within what is – what is the accepted upper and lower specification for
`that drug product.
`
`26
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`EX-2198, 51:14-24
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`Paper 59 at 6-7
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`Eye Therapies Exhibit 2216, 26 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`“Ocular condition” – Limiting Preamble
`
`EX-1001 at claim 3
`
`• Purposeful statement for which the step in patented
`method is performed.
`See Jansen v. Rexall Sundown, Inc., 342 F.3d 1329, 1333 (Fed.
`Cir. 2003).
`
`Paper 30 at 25-27; EX-2020 at ¶¶99-105; Paper 59 at 1-3
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`Eye Therapies Exhibit 2216, 27 of 101
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`’742 Patent: Eye Redness = Hyperemia
`
`EX-1001, 1:4-11
`
`See also EX-1001
`14:19-22 (treating conjunctival hyperemia),
`14:23-24 (reducing redness in the eye),
`14:7-14 (achieving scleral whitening),
`12:14-15 (red eye, including chronic red eye)
`
`•
`
`’742 patent never describes “eye redness” as
`hemorrhage
`
`Paper 30 at 25-27; EX-2020 at ¶¶99-105; Paper 59 at 1-3
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`Eye Therapies Exhibit 2216, 28 of 101
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`’742 Patent: Ocular condition ≠ Hemorrhage
`
`• Read in light of the limiting preamble,
`
`• a POSA would have understood “ocular condition” to mean a condition from which
`hyperemia can arise and can be reduced
`
`• hemorrhage is not eye redness in context of ’742 patented method
`
`• subconjunctival hemorrhage cannot be reduced
`
`Q. Subconjunctival hemorrhaging -- or hemorrhage that's not
`treated. It's only in time it goes away I think you said;
`is that fair?
`A. I don't know of any treatment. It just goes away.
`EX-2162, 112:18-23
`
`Neal Sher
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`Paper 30 at 13-15, 25-27; EX-2020 at ¶¶99-105, 168; Paper 59 at 1-3
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`Eye Therapies Exhibit 2216, 29 of 101
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`Ocular condition Is Not a Surgical Procedure
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`• LASIK and radial keratotomy are surgical procedures, not ocular conditions
`
`Neal Sher
`
`EX-1002, ¶41
`
`• Even petition acknowledges that LASIK and radial keratotomy are surgical
`procedures (Paper 2 at 13)
`
`Paper 30 at 13-15, 25-27; EX-2020 at ¶¶99-105, 168; Paper 59 at 1-3
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`Eye Therapies Exhibit 2216, 30 of 101
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`Ground 2: Anticipation
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`Walters
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`Eye Therapies Exhibit 2216, 31 of 101
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`Ground 2: Walters 1991 Does Not Inherently Anticipate
`
`• Too many unknowns
`– No mention of eye redness
`– No patient information
`(inclusion/exclusion criteria)
`• Patient could have had no baseline
`redness
`• Patients could have taken redness
`relievers
`– Even if there were patients with eye
`redness, there is no information
`whether they received 0.02% or
`0.08% brimonidine or placebo
`
`EX-1005 at 4
`
`Paper 30 at 43-44; EX-2020 at ¶¶ 195-200; Paper 59 at 10
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`Eye Therapies Exhibit 2216, 32 of 101
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`Ground 3: Obviousness
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`Eye Therapies Exhibit 2216, 33 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Slayback’s Shifting Theories – Ground 3
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`Petition
`
`Reply
`
`Reply at 13
`
`Slayback abandons two of its six
`“excellent reasons”
`
`Petition at 53
`
`Paper 59 at 20-21; EX-2022 at § III.E.
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`Eye Therapies Exhibit 2216, 34 of 101
`Slayback v. Eye Therapies - IPR2022-00142
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`Ground 3: Petitioner Failed to Establish Obviousness
`
`• The ’553 patent does not disclose or suggest a method of
`reducing redness using low-concentration brimonidine
`
`• Norden uses 0.2% brimonidine with anti-inflammatories,
`antibiotics, and saline solution, which can prevent redness
`development
`
`• A POSA would not have lowered 0.2% brimonidine in the
`direction of the claims and expected to reduce redness
`
`– brimonidine’s whitening propensity was concentration dependent
`– lowering its concentration would decrease its α-1 vasoconstriction
`effects and accentuate its α-2 vasodilative effects
`
`Paper 30 at 44-59
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
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`35
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`
`
`’553 Patent Prophetic Example 1, Blocks Perception of
`Pain, Does Not Suggest Redness Reduction
`
`• Because redness reduction is alleged
`to be inherent, it cannot be used to
`assess obviousness
`
`“That which is inherent is unknown, and
`obviousness cannot be predicated on what
`is unknown.”
`
`In re Spormann, 363 F.2d 444, 448 (C.C.P.A. 1966)
`
`EX-1004 at Example 1
`
`Paper 30 at 40-43; EX-2020, ¶¶150, 188-194 ; Paper at 11-12
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`
`’553 Patent Prophetic Example 1, Blocks Perception of
`Pain, Does Not Suggest Redness Reduction
`
`• Five cardinal signs of inflammation
`– Redness is one, pain is another (EX-2162, 104:23-106:12)
`– One can have pain from inflammation without redness
`(Id. at 107:2-11)
`– One can treat pain from inflammation without reducing
`redness (Id. at 109:3-11)
`• Example 1 only “appears to suggest that brimonidine”
`“blocks the perception of pain” (EX-1004, 5:1-2)
`– This is how anesthetics work (EX-1004, 1:54-55)
`• Dr. Sher agreed (EX-2213, 23:14-22, 24:21-25:12)
`• Dr. Sher: Anesthetics cannot reduce ocular
`hyperemia (EX-2213, 25:13-26:15)
`• Norden: brimonidine is an anesthetic (EX-1006, 471)
`• Other agents: anti-inflammatories, antibiotics, saline
`drops would have been used, which could impact
`redness relief (EX-2213, 18:10-21:8, 27:19-28:3)
`
`EX-1004 at Example 1
`
`Paper 30 at 40-43; EX-2020, ¶¶150, 188-194 ; Paper at 11-12
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`
`’553 Patent, Example 4 Neither Taught Nor Suggested
`Brimonidine to Reduce Eye Redness
`
`• Like Example 1, Example 4
`assesses an anesthetic effect of
`brimonidine to block nerve traffic
`and relieve sensation of ocular
`pain
`
`EX-1004 at Example 4, Fig. 1
`
`Paper 30 at 53-55; EX-2020 at ¶¶235-238; Paper 59 at 12
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`’553 Patent, Example 4 Neither Taught Nor Suggested
`Brimonidine to Reduce Eye Redness
`
`• Example’s reference to signs of
`neurogenic inflammation to include
`redness only a general statement, not
`particular to the model
`
`• One can treat pain from inflammation
`without affecting redness, if present (EX-
`2213,109:3-11)
`
`• Uncontested that prophetic Example 4
`was not designed to measure redness
`reduction (EX-2020, ¶¶154-160)
`– extremely broad concentration range up to
`0.5%
`
`• No one would have understood Example
`4 to suggest brimonidine could reduce
`redness at, for example, 0.025% (Id.)
`
`EX-1004 at Example 4
`
`Paper 30 at 53-55; EX-2020 at ¶¶235-238; Paper 59 at 12
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`39
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`
`’553 Patent – Overarching Conclusion Does Not Include
`Redness Reduction
`
`Paper 30 at 53-55; EX-2020 at ¶¶235-238; Paper 59 at 12
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`40
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`Norden: Undisputed That Brimonidine Used With Other
`Agents That Can Reduce Redness
`
`Anti-inflammatories
`
`Antibiotics
`
`Anesthetics
`
`Lubricants
`
`EX-1006, 4-5; see also EX-2213, 18:10-21:8, 27:19-28:3
`
`Paper 30 at 55-57; EX-2020 at ¶¶173, 244
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`41
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`
`A POSA Would Not Have Lowered Brimonidine’s Concentration in
`Norden and Expected It to Reduce Redness
`
`• Norden purported to show 0.2% brimonidine reduced hyperemia
`• Brimonidine’s α-2 to α-1 affinity >1000:1
`• High concentrations (>0.2%) trigger brimonidine’s α-1 effect to
`vasoconstrict and whiten (blanch) eyes
`– but still cause redness (>30%) – Alphagan label (EX-2012 at 6, 9)
`• At low concentrations, brimonidine’s α-1 effects are minimized, and its
`α-2 effects are accentuated (vasodilation)
`– Alphagan P label (20%) (EX-2012 at 11, 14)
`• Posa would not have lowered brimonidine’s concentration to lower its
`hyperemic effect
`– highly improbable that it would have any α-1 vasoconstriction effect (EX-1018)
`
`Paper 30 at 44-51; EX-2020 at ¶¶205-249; Paper 59 at 10-21
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`
`Brimonidine’s Concentration Dependency for Whitening
`(Blanching) Eyes
`
`• Borne out by expansive clinical studies
`
`– Alphagan 0.5% → Conjunctival blanching (redness reduction) in 50% of subjects
`– Alphagan 0.35% → Conjunctival blanching in a significant number of subjects
`– Alphagan 0.2% → Blanching in 3.5% of subjects
`– Alphagan P (0.15% and 0.1%) → No blanching reported
`
`• Corroborated by Petitioner’s reference, EX-1027 at 5
`– “Not only was a dose response relation shown for the ocular hypotensive
`effects of brimonidine, but also for the effects on … conjunctival blanching…”
`
`Paper 30 at 49-51 ; EX-2020, ¶¶ 77-79, 135, 182, 219-220;
`Paper 59 at 13, 16-18
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`43
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`
`A POSA Would Not Have Lowered Brimonidine’s Concentration in
`Norden and Expected It to Reduce Redness
`
`EX-1018, 2
`
`Paper 30 at 18-19, 44-51; EX-2020 at ¶¶205-249, 282;
`Paper 59 at 10-21
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`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
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`44
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`
`
`Brimonidine: “Least Likely” to Cause Ocular Vasoconstriction
`
`EX-1035 at 2
`
`Paper 30 at 15, 19, 45-51;
`EX-2020, ¶¶43-44, 67-68, 80-86, 213-214, 282; Paper 59 at 13-16
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`45
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`
`More Reasons Why Brimonidine Was Not Expected
`to Cause Ocular Vasoconstriction
`
`• Magnitude of vasoactivity is predicted
`based on location and density of
`adrenergic receptors and affinity for
`agonist (EX-2169 at 3)
`• Ocular vasoconstriction (conjunctival
`blanching) “is an α-1 effect” (Id. at 1)
`
`EX-2169 at Table 3
`
`Paper 30 at 15;
`EX-2020, ¶¶43-44, 51, 59, 63-68, 76, 80, 255-256; Paper 59 at 13-16
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`46
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`
`
`More Reasons Why Brimonidine Was Not Expected
`to Cause Ocular Vasoconstriction
`
`• Stimulating α-2 receptors in ocular
`vasculature causes vasodilation
`(hyperemia) (EX-2020 at ¶¶ 44, 63-64, 78)
`
`EX-2169 at Table 3
`
`Paper 30 at 15;
`EX-2020, ¶¶43-44, 51, 59, 63-68, 76, 80, 255-256; Paper 59 at 13-16
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`47
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`
`
`Prior Art Teaches That Anterior Portion of the Eye Consists of
`Endothelial Cells
`
`EX-2176 at 1
`
`EX-2020 at ¶63; Paper 59 at 13-16
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`
`Prior Art Repeatedly Teaches Brimonidine Vasodilates
`Endothelial Cells
`
`EX-1019 at 3;
`
`see also EX-1035 at 5
`
`Paper 30 at 15, 19, 46-47, 49; EX-2020 at ¶¶ 43-44, 59, 63, 80, 214-215;
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`Paper 59 at 15-16
`
`49
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`
`
`Dr. Sher Has Rendered Irrelevant Petitioner’s References That α-2
`Agonists Can Vasoconstrict
`• Dr. Sher asserts that only references referring to vasoactivity in the
`eye are relevant (EX-1049 at ¶67)
`
`• None of Petitioner’s references indicate that α-2 agonists
`vasoconstrict
`– Langer (EX-1090): Evaluated constriction in vasculature of kidneys, bones,
`stomach, etc. (see Tables 3-4)
`– Duka (EX-1091): Evaluated α-2A peripheral vasoconstriction, which does not
`include the eyes
`– Phillip (EX-1092): Experimented on genetically engineered mice with no
`evaluation on vasoconstriction in the eye
`
`Paper 59 at 14-15
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`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
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`50
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`
`
`Vasodilation v. Vasoconstriction for Different α-2
`Subtype Receptors
`• Stimulating α-2 receptors pre-synaptically (α-2A subtype)
`suppresses norepinephrine and leads to dilation of blood
`vessels
`– EX-2020 at ¶44; EX-2169 at 2; EX-1092 at 2; EX-1090 at 8
`
`• Stimulating α-2 receptors post-synaptically (α-2B
`subtype) may cause vasoconstriction
`
`Paper 30 at 18-19; EX-2020 at ¶¶66-67; Paper 59 at 13-16
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`
`
`Vasodilation v. Vasoconstriction for Different α-2
`Subtype Receptors
`
`• Receptors in conjunctiva/episclera: α-
`1 receptors and α-2A receptors
`
`EX-1017 at 5
`
`– Consistent with the ’742 patent: “The a-
`2A subtype also mediates potent
`constriction of the porcine, but not
`human, ciliary artery.” (EX-1001, 1:45-47)
`
`Paper 30 at 18-19; EX-2020 at ¶¶66-67; Paper 59 at 13-16
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`
`
`Claims Must Be Considered as a Whole
`
`“In determining obviousness/nonobviousness, an
`invention must be considered ‘as a whole’ and
`claims must be considered in their entirety.”
`
`Medtronic, Inc. v. Cardiac Pacemakers, Inc., 721 F.2d 1563, 1567 (Fed. Cir. 1983) (internal citations omitted)
`
`“The determination of obviousness is made with
`respect
`to the subject matter as a whole, not
`separate pieces of the claim.”
`
`Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1086 (Fed. Cir. 2008)
`
`Paper 30 at 51-53; Paper 59 at 21-23
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`53
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`
`
`A POSA Would Need to Consider Numerous Interrelated
`Formulation Variables
`
`pH
`
`pH
`
`• Decrease solubility
`• Increase permeability
`• Increase tolerability
`
`• Increase solubility
`• Decrease permeability
`• Decrease tolerability
`
`EX-2021 at ¶¶52, 53, 113
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`A POSA Would Be Motivated to Target pH 7.4
`
`Paul Laskar
`
`Q. The physiological pH of the human eye is
`approximately 7.4, correct?
`A. The tear form of the eye has a pH of about 7.4.
`Q. Then formulating an ophthalmic formulation, a
`formulator would try to get the formulation as close
`to the pH of the eye as possible, correct?
`[Objections omitted]
`THE WITNESS: That is a goal.
`
`EX-2198 at 43:2-11
`
`EX-2021 at ¶96; EX-2020 at ¶¶ 251-252
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`
`No Formulation Considerations Necessitate Targeting
`Claimed pH
`
`– Efficacy
`
`– Permeability
`
`– Stability
`
`– Solubility
`
`Paper 30 at 51-53; EX-2021 at ¶¶40, 59, 95-106; Paper 59 at 21-23
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`As Concentration Decreased, pH Increased
`
`Alphagan® 0.5%
`
`Alphagan® 0.2%
`
`Alphagan® P 0.15%
`Alphagan® P 0.1%
`
`5.5
`
`6
`
`pH
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`6.5
`
`7
`
`7.5
`
`8
`
`8.5
`
`57
`
`0.60%
`
`0.50%
`
`0.40%
`
`0.30%
`
`0.20%
`
`0.10%
`
`Brimonidine Concentration
`
`0.00%
`
`4
`
`4.5
`
`5
`
`EX-2021, ¶¶ 98-101; EX-2012 at 1, 6; EX-2014 at 1;
`EX-1033 at 8:15-18, 13:59
`
`Eye Therapies Exhibit 2216, 57 of 101
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`
`
`Dr. Laskar’s Unsupported Opinions on Alphagan® Products
`
`Paul
`Laskar
`
`Q.
`
`You say that, "The increased pH of the Alphagan
`P products, as compared to the Alphagan
`products, was most likely motivated by the
`stability of Purite, not by any property of
`brimonidine."
`Do you see that?
`I do.
`You do not have any personal knowledge of
`Allergan's motivation concerning Alphagan
`products; correct?
`I do not have any firsthand information.
`You did not work at Allergan when Allergan
`formulated Alphagan P; correct?
`That is correct. I'm basing that statement on my
`understanding and – understanding of and
`information about the Purite preservative.
`EX-2212 at 99:4-100:15
`
`A.
`Q.
`
`A.
`Q.
`A.
`
`EX-2007 at 339-340
`
`Paper 59 at 21-23
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`
`Permeability Would Not Have Motivated a POSA to
`Target the Claimed pH
`
`Layers of the sclera
`
`Paper 30 at 5-6; EX-2020, ¶¶34, 38; EX-2178 at 3;
`EX-2179 at 1; Paper 59 at 22
`
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`59
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`Solubility Would N