EYE THERAPIES, LLC
`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)
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`1
`
`Eye Therapies Exhibit 2216, 1 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`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)
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`1
`
`Eye Therapies Exhibit 2216, 1 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`2
`
`Eye Therapies Exhibit 2216, 2 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`3
`
`Eye Therapies Exhibit 2216, 3 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Overview of Issues to be Addressed
`
`• 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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`4
`
`Eye Therapies Exhibit 2216, 4 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Ground 1: Anticipation
`
`’553 Patent
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`5
`
`Eye Therapies Exhibit 2216, 5 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`6
`
`Eye Therapies Exhibit 2216, 6 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Slayback’s Shifting Theories – Ground 1 (’553 Patent)
`
`Petition
`
`Reply
`
`Petition at 34
`
`Reply at 7-8
`
`Paper 59 at 2, 8
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`7
`
`Eye Therapies Exhibit 2216, 7 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Petitioner’s Burden
`
`• 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)
`
`Paper 30 at 40-43; Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`8
`
`Eye Therapies Exhibit 2216, 8 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`9
`
`Eye Therapies Exhibit 2216, 9 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`Paper 30 at 40-41, 53; EX-2020, ¶¶145-146, 234-235; Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`10
`
`EX-2162, 106:16-107:5
`
`Eye Therapies Exhibit 2216, 10 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Inflammation Can Develop Without Redness
`
`• 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”).
`
`Paper 30 at 40-41, 53; EX-2020, ¶¶145-146, 234-235; Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`11
`
`Eye Therapies Exhibit 2216, 11 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Pain Relief Without Redness Reduction
`
`• 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
`
`Paper 30 at 40-42, 53; EX-2020, ¶¶145-146, 234-235; Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`12
`
`Eye Therapies Exhibit 2216, 12 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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)
`
`Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`13
`
`Eye Therapies Exhibit 2216, 13 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`EX-2213, 22-24-23:13
`
`Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`14
`
`Eye Therapies Exhibit 2216, 14 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`15
`
`Eye Therapies Exhibit 2216, 15 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`EX-2213, 19:21-21:8
`
`Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`16
`
`Eye Therapies Exhibit 2216, 16 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`EX-2213, 27:19-28:3
`
`• 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
`
`Paper 59 at 8-9
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`17
`
`Eye Therapies Exhibit 2216, 17 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Petitioner’s Failure of Proof
`
`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
`
`Paper 30 at 40-43
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`18
`
`Eye Therapies Exhibit 2216, 18 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Claim Construction
`
`“about 0.025%” & “ocular condition”
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`19
`
`Eye Therapies Exhibit 2216, 19 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Claim Construction Principle - Phillips
`
`“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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`Eye Therapies Exhibit 2216, 20 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`Paper 30 at 25-27; Paper 59 at 3-6
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`21
`
`Eye Therapies Exhibit 2216, 21 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`22
`
`Eye Therapies Exhibit 2216, 22 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`“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
`
`Paper 30 at 31-35; EX-2020, ¶¶93-96, 110-113; Paper 59 at 3-6
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`23
`
`Eye Therapies Exhibit 2216, 23 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`“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
`
`Paper 30 at 35-36; EX-2021, ¶¶39-45 ; Paper 59 at 6-7
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`EX-2212 at 46:19-25
`
`24
`
`Eye Therapies Exhibit 2216, 24 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`“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
`
`Paper 59 at 6
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`25
`
`Eye Therapies Exhibit 2216, 25 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`“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
`
`EX-2198, 51:14-24
`
`Paper 59 at 6-7
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`Eye Therapies Exhibit 2216, 26 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`“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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`27
`
`Eye Therapies Exhibit 2216, 27 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`’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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`28
`
`Eye Therapies Exhibit 2216, 28 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`’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
`
`Paper 30 at 13-15, 25-27; EX-2020 at ¶¶99-105, 168; Paper 59 at 1-3
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`29
`
`Eye Therapies Exhibit 2216, 29 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Ocular condition Is Not a Surgical Procedure
`
`• 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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`30
`
`Eye Therapies Exhibit 2216, 30 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Ground 2: Anticipation
`
`Walters
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`31
`
`Eye Therapies Exhibit 2216, 31 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`32
`
`Eye Therapies Exhibit 2216, 32 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Ground 3: Obviousness
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`33
`
`Eye Therapies Exhibit 2216, 33 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Slayback’s Shifting Theories – Ground 3
`
`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.
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`34
`
`Eye Therapies Exhibit 2216, 34 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`35
`
`Eye Therapies Exhibit 2216, 35 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`’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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`36
`
`Eye Therapies Exhibit 2216, 36 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`’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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`37
`
`Eye Therapies Exhibit 2216, 37 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`’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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`38
`
`Eye Therapies Exhibit 2216, 38 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`’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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`39
`
`Eye Therapies Exhibit 2216, 39 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`’553 Patent – Overarching Conclusion Does Not Include
`Redness Reduction
`
`Paper 30 at 53-55; EX-2020 at ¶¶235-238; Paper 59 at 12
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`40
`
`Eye Therapies Exhibit 2216, 40 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`41
`
`Eye Therapies Exhibit 2216, 41 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`42
`
`Eye Therapies Exhibit 2216, 42 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`43
`
`Eye Therapies Exhibit 2216, 43 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`44
`
`Eye Therapies Exhibit 2216, 44 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`45
`
`Eye Therapies Exhibit 2216, 45 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`46
`
`Eye Therapies Exhibit 2216, 46 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`47
`
`Eye Therapies Exhibit 2216, 47 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`48
`
`Eye Therapies Exhibit 2216, 48 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`Eye Therapies Exhibit 2216, 49 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`50
`
`Eye Therapies Exhibit 2216, 50 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`51
`
`Eye Therapies Exhibit 2216, 51 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`52
`
`Eye Therapies Exhibit 2216, 52 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`53
`
`Eye Therapies Exhibit 2216, 53 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`54
`
`Eye Therapies Exhibit 2216, 54 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`55
`
`Eye Therapies Exhibit 2216, 55 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`56
`
`Eye Therapies Exhibit 2216, 56 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`58
`
`Eye Therapies Exhibit 2216, 58 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`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
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE
`
`59
`
`Eye Therapies Exhibit 2216, 59 of 101
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`Solubility Would N
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
