Case IPR2022-00142
`U.S. Patent No. 8,293,742
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SLAYBACK PHARMA LLC
`
`Petitioner
`
`v.
`
`EYE THERAPIES LLC
`
`Patent Owner
`
`
`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
`
`
`DECLARATION OF NEAL A. SHER, MD, FACS
`IN SUPPORT OF PETITIONER’S REPLY
`
`
`
`Slayback Exhibit 1049
`Slayback v. Eye Therapies - IPR2022-00142
`
`

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`TABLE OF CONTENTS
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`Page
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`B.
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`C.
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`INTRODUCTION ........................................................................................ 1
`I.
`II. MATERIALS CONSIDERED .................................................................... 2
`III. PERSON OF ORDINARY SKILL IN THE ART ..................................... 2
`IV. CLAIM CONSTRUCTION ......................................................................... 2
`A.
`There Is No Clinical Difference Between “About 0.025%”
`and “0.03%” Brimonidine ................................................................. 2
`The ’742 Patent Defines “Ocular Condition” Broadly ................. 20
`B.
`V. ANTICIPATION OF CLAIMS 1–2 OF THE ’742 PATENT ................ 24
`A.
`The ’553 Patent Discloses Administration of Brimonidine at
`a Concentration of “about 0.025%” ............................................... 25
`The ’553 Patent Discloses Administration of Brimonidine
`“to a patient having an ocular condition” ...................................... 25
`The ’553 Patent Discloses “[a] method for reducing eye
`redness” ............................................................................................. 29
`VI. OBVIOUSNESS OF CLAIMS 1–6 OF THE ’742 PATENT ................. 33
`A. Dr. Noecker Appears Not to Dispute that Certain
`Limitations of Claims 1-6 Are Disclosed by the Prior Art ........... 33
`A POSA Would Have Been Motivated to Use Brimonidine
`as a Redness Reliever With a Reasonable Expectation of
`Success ............................................................................................... 34
`1.
`Alpha-1 and Alpha-2 Agonists Both Cause
`Vasoconstriction ..................................................................... 35
`a.
`Both alpha-1 and alpha-2 receptors mediate
`vasoconstriction............................................................ 36
`Alpha-1 and alpha-2 receptor subtypes ..................... 40
`b.
`Brimonidine Was Known to Be a Potent
`Vasoconstrictor that Reduced Eye Redness ........................ 44
`The Side Effects of Brimonidine Would Not Have
`Deterred a POSA .................................................................... 52
`
`B.
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`2.
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`3.
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`TABLE OF CONTENTS
`(continued)
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`Page
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`
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`C. A POSA Would Have Been Motivated to Use Brimonidine
`at Low Concentrations ..................................................................... 54
`D. A POSA Would Have Been Motivated to Keep Brimonidine
`At the Surface of the Eye ................................................................. 57
`A pH Range of 5.5 to 6.5 Would Have Been Tolerable to
`Patients .............................................................................................. 62
`The Additional Limitations of Claims 4–6 Do Not Render
`Those Claims Non-Obvious ............................................................. 63
`VII. SECONDARY CONSIDERATIONS ....................................................... 65
`A.
`There Is No Nexus Between the ’742 Patent Claims and Dr.
`Noecker’s Objective Evidence of Non-Obviousness ..................... 65
`Brimonidine’s Effect As a Redness Reducer Would Not
`Have Been Unexpected ..................................................................... 68
`VIII. CONCLUSION ........................................................................................... 69
`
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`E.
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`F.
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`B.
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
`
`I.
`
`INTRODUCTION
`1.
`I am the same Neal A. Sher, M.D., who submitted the Declaration of
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`Neal A. Sher, MD, FACS (EX-1002, “Opening Declaration”) dated November 4,
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`2021, in support of Petitioner’s petition for inter partes review of U.S. Patent No.
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`8,293,742 (EX-1001, “the ’742 patent”). I understand that the Board has instituted
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`inter partes review of claims 1–6 of the ’742 patent and that Patent Owner has filed
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`a Patent Owner’s Response (“POR”), together with the Declaration of Robert J.
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`Noecker, MD, MBA (EX-2020, “the Noecker Declaration”) in support of the POR.
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`I submit this reply expert declaration in support of Petitioner’s reply to the POR and
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`to respond to the Noecker Declaration.
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`2.
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`I provided in my Opening Declaration the details of my compensation
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`for my work on this matter. My compensation is not contingent upon, and in no way
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`related to, the outcome of this litigation or the testimony that I give.
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`3.
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`I also provided in my Opening Declaration a summary of my
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`qualifications and background, including my education and experience, as well as a
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`copy of my curriculum vitae.
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`4.
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`I discussed in my Opening Declaration my understanding of the
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`relevant legal standards as provided by counsel. My understanding of these legal
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`standards has not changed since I submitted my Opening Declaration.
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`II. MATERIALS CONSIDERED
`5.
`In preparing this reply declaration, I considered the Board’s Institution
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`Decision, the POR, the Noecker Declaration and materials cited therein, and the
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`materials identified in this reply declaration. I have listed the materials I considered
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`in Exhibit C to this reply declaration. I also considered my Opening Declaration
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`and the materials listed in Exhibit B to my Opening Declaration.
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`III. PERSON OF ORDINARY SKILL IN THE ART
`6.
`In paragraph 26 of my Opening Declaration, I provided my opinion
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`regarding the qualifications of the person of ordinary skill in the art (“POSA”) with
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`respect to the ’742 patent. In paragraph 31 of his declaration, Dr. Noecker provides
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`a definition the POSA, which differs from mine in that Dr. Noecker’s POSA appears
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`to be less skilled. Although I disagree with Dr. Noecker’s definition, my opinions
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`expressed in my Opening Declaration and in this reply declaration would not change
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`if Dr. Noecker’s definition were applied.
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`IV. CLAIM CONSTRUCTION
`A. There Is No Clinical Difference Between “About 0.025%” and
`“0.03%” Brimonidine
`In my Opening Declaration, I relied on Dr. Laskar’s opinion that “about
`
`7.
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`0.025%” as recited in claims 2 and 3 of the ’742 patent includes “0.03%.” Opening
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`Declaration (EX-1002) ¶ 45 (citing Laskar Declaration (EX-1003) ¶ 73). In his
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`declaration, Dr. Noecker opines that “about 0.025%” does not include “0.03%” in
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`part because, in Dr. Noecker’s view, “the specification conveys a critical difference
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`for 0.025% by clinically distinguishing it from 0.03%.” Noecker Declaration (EX-
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`2020) ¶ 108 (emphasis added). I disagree.
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`8.
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`To support his opinion that the ’742 patent specification “clinically
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`distinguish[es]” 0.025% from 0.03%, Dr. Noecker relies on Figure 2 and Figure 6 of
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`the specification. See, e.g., Noecker Declaration (EX-2020) ¶¶ 92–95.
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`9.
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`For ease of reference, a side-by-side comparison of Figure 2 and Figure
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`6 is reproduced below:
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`EX-1046.
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`10. As an initial matter, Figures 2 and 6 are highly imprecise. Although
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`both figures appear to convey some qualitative information regarding the
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`relationship between brimonidine concentration (x-axis) and biological effects (y-
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`axis), neither figure conveys any quantitative information to a POSA.
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`11.
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`In both figures, the x-axis contains some numerical information
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`regarding the brimonidine concentrations depicted in the figures (.001%, .005%,
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`0.01%, 0.03%, etc.), but there are no hash marks indicating where exactly those
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`concentrations fall on the x-axis. Further, there are no incremental hash marks
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`indicating where any non-enumerated concentrations (e.g., 0.02% or 0.025%) fall.
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`12. Moreover, in both figures, the x-axis scale appears to be non-linear. For
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`example, the enumerated concentration appearing just over halfway across the
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`length of the x-axis (0.10%) represents an increase of only 0.10% brimonidine from
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`zero, but the second half of the x-axis (i.e., 0.10% to 0.5%) spans a range of 0.40%
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`brimonidine concentrations. If the x-axis were linear, one would expect the span
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`from zero to the midpoint of the x-axis to cover the same range as the midpoint to
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`the end of the x-axis (e.g., zero to 0.10% in the first half and 0.10% to 0.20% in the
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`second half). The x-axis also does not appear to be logarithmic. For example, in
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`Figure 2, the enumerated concentration appearing just over halfway across the length
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`of the x-axis (0.10%) is one-hundred times greater than the first enumerated
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`concentration (.001%) at the very beginning of the x-axis, but the final enumerated
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`concentration (0.5%) appearing at the very end of the x-axis is only five times greater
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`than the enumerated concentration appearing around the midpoint of the x-axis. And
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`in both figures, the first two enumerated concentrations (.001% and .005%), which
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`are five-fold different from one another, appear to be closer to one another than the
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`next two enumerated concentrations (0.01% and 0.03%), which are only three-fold
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`different from one another yet appear to be spaced further apart. Thus, a POSA
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`would not be able to identify with precision where on the x-axis any given
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`concentration would fall. For at least this reason, I disagree with Dr. Noecker’s
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`opinion that a POSA would be able to pinpoint where a concentration of 0.025%
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`falls on the x-axis of Figures 2 and 6. See, e.g., Noecker Declaration (EX-2020) ¶
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`95 n.8.
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`13.
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`In both figures, the y-axis is completely devoid of quantitative
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`information. For example, in both figures, there is no scale indicated for any of the
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`five measurements listed in the legend of Figure 2 (“Vasoconstriction,” “IOP
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`Reduction (Glaucoma),” “Endo Cell Pump Inhibition,” “Rebound Hyperemia,” and
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`“Net Vasoconstriction Benefit”) that are depicted in the figures. See Noecker
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`Deposition Transcript (EX-1053) at 81:16–82:6 (Dr. Noecker admitting there are no
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`units on the y-axis). The only “scale” shown on the y-axis ranges from “0” to
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`“++++”—a “scale” that conveys no quantitative information whatsoever to a POSA.
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`For example, a POSA would not know whether the scale of the y-axis in each figure
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`U.S. Patent No. 8,293,742
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`is linear or, like the x-axis, non-linear, and this is equally true for each one of the
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`five measurements listed in the legend of Figure 2. Similarly, a POSA would not
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`know whether the scale of the y-axis in each figure covers a broad or narrow range
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`of numerical values for each of the five measurements listed in the legend of Figure
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`2. It could be that the scale covers a range that increases 500-fold from one end to
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`the other, just as the range of the x-axis in each figure does. Or, it could be that the
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`scale of the y-axis in each figure is much narrower (e.g., increasing only two-fold).
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`Further, the scales for each of the five measurements listed in the legend of Figure 2
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`could cover widely varying ranges (e.g., a broad range for vasoconstriction, a narrow
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`range for rebound hyperemia, etc.). Thus, a POSA would be unable to glean any
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`quantitative information from the y-axis of Figures 2 and 6.
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`14. Adding to the imprecision, in both figures, the underlying data appear
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`to have been plotted as smoothed line graphs rather than straight line graphs. To
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`understand the importance of this distinction, one must consider how experimental
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`data are typically measured. In a typical experiment, the independent variable (in
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`this case, the brimonidine concentration) is changed a certain number of times and
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`the dependent variable (e.g., the level of vasoconstriction) is measured after each
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`change. For example, a researcher might measure the level of vasoconstriction
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`resulting from administration of an ophthalmic solution containing either 0.01%,
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`0.03%, or 0.05% brimonidine. The researcher would obtain a datapoint for the
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`dependent variable (level of vasoconstriction) corresponding to each iteration of the
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`independent variable (0.01%, 0.03%, and 0.05% brimonidine).
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`15. To represent this data graphically, the researcher could simply plot the
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`individual datapoints on a graph. Or, the researcher could plot the individual
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`datapoints and then connect those datapoints using a straight line to more clearly
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`illustrate how the dependent variable changes as the independent variable changes.
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`The researcher could also choose to “smooth” these straight lines, a process in which
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`a computer program estimates where new datapoints would fall in between the
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`experimentally determined datapoints and plots a smooth line to connect these
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`estimated datapoints with the experimentally determined datapoints. The researcher
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`could also choose to include some indication as to which datapoints on the smoothed
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`line graph were actually experimentally determined. Or, as appears to be the case in
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`Figures 2 and 6, the researcher could omit these indications entirely.
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`16. Smoothed line graphs can give the false impression that underlying data
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`were actually experimentally determined when they in fact were not. This is
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`especially true where, as here, the smoothed line graphs retain no indication as to
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`which datapoints were experimentally determined. For example, to continue the
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`hypothetical discussed above, a researcher may have actually experimentally
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`determined the level of vasoconstriction resulting from administration of 0.01%,
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`0.03%, and 0.05% brimonidine. If the researched plotted these data using a straight
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`line graph, it would be apparent that these datapoints (0.01%, 0.03%, and 0.05%)
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`were experimentally determined because there would be a vertex at each of these
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`points on the graph. If these straight lines were smoothed, however, then it would
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`no longer be apparent which datapoints were experimentally determined because
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`there would be only a smooth line with no vertices indicating an experimentally
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`determined datapoint. In this scenario, on this smoothed line graph it would appear
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`that a datapoint at 0.025% had been experimentally determined when it in fact had
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`not—only the surrounding 0.01% and 0.03% datapoints had been experimentally
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`determined, and the “datapoint” at 0.025% was estimated by the computer program
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`that plotted the smoothed line. Thus, because the underlying data appear to have
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`been plotted as smoothed line graphs, a POSA would not make precise conclusions
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`about small differences between two concentrations (e.g., 0.025% and 0.03%).
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`17. Further, a POSA would not make conclusions regarding the clinical
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`significance of Figures 2 and 6 without knowing how precise (or imprecise) the
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`underlying data were. The datapoints depicted in a graph do not typically represent
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`data from a single experiment; rather, they typically represent an average of the data
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`collected from many experiments. For example, in the hypothetical discussed above,
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`a researcher would typically run the experiment several times at each of the 0.01%,
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`0.03%, and 0.05% concentrations. The researcher would then typically calculate the
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`average of the results (level of vasoconstriction) at each concentration, and the
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`average values would typically be plotted in the graph. The repetition of
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`experiments allows the researcher to increase the accuracy of the estimate of the
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`“true” result at each concentration. Of course, experimental results come with some
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`uncertainty and variability. Uncertainty and variability can be represented by a
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`statistical calculation called a “standard deviation,” which, in lay terms, is simply a
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`measure of how spread out the data are in relation to the average. For that reason,
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`graphs and data reporting clinical results typically include one or more measures of
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`variability, including the standard deviation. For example, line graphs typically
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`include “error bars,” which can represent one standard deviation above and below
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`the average datapoint depicted on the graph (or another measure of variability and
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`uncertainty). Without any error bars or other indication of the standard deviation of
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`the data, there is no way to ascertain the precision (or imprecision) of the data. As
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`Dr. Noecker admitted, there are no error bars in Figure 2 or Figure 6 and no
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`information regarding standard deviation of the data represented in these figures.
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`See Noecker Deposition Transcript (EX-1053) at 89:19–90:3.
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`18. All of the above reflects the high degree of imprecision of Figures 2
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`and 6. Because of this high degree of imprecision, a POSA would be unable to reach
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`any quantitative conclusions regarding these figures, let alone reach the exacting
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`conclusion Dr. Noecker makes—that the figures “clinically distinguish” between the
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`effect of brimonidine concentrations that differ by only five-thousands of a
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`percentage (0.025% compared to 0.03%).
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`19. Dr. Noecker asserts that “Figure 2 conveys to a skilled ophthalmologist
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`a critical distinction between brimonidine at a concentration of 0.03% (maximum
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`vasoconstriction with rebound hyperemia) and concentrations less than 0.03%
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`(slightly lower vasoconstriction without, importantly, rebound hyperemia).”
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`Noecker Declaration (EX-2020) ¶ 94. Dr. Noecker supports this assertion by
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`pointing to the rebound hyperemia arrow that Dr. Noecker believes “starts to lift off
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`the x-axis” at 0.03% and the net vasoconstriction benefit arrow with an apex at
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`0.03%. Id. As an initial matter, a POSA would not rely on the blurry, imprecise
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`Figure 2 to discern with certainty the exact percentages at which rebound hyperemia
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`begins and net vasoconstriction benefit reaches its maximum; rather, a POSA would
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`rely on the inventor’s representation that the maximum benefit of brimonidine is at
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`around 0.03%. ’742 Patent (EX-1001) at 19:54–56. Dr. Noecker asserts that Figure
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`2 teaches that “concentrations less than 0.03%” produce no rebound hyperemia
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`(Noecker Declaration (EX-2020) ¶ 94), but Dr. Noecker fails to acknowledge that
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`the rebound hyperemia curve remains relatively constant, and visibly above the x-
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`axis (presumably indicating at least some amount of rebound hyperemia), starting at
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`the concentration of 0.01% and perhaps even lower at 0.005%. The following
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`screenshot of a magnified Figure 2 from Dr. Noecker’s declaration shows this
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`clearly, where the rebound hyperemia curve is the dark gray, solid line:
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`Id. ¶ 93 (magnified).
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`20. Further, although I disagree that a POSA could view Figure 2 and make
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`any assessments with certainty, Dr. Noecker’s characterizations of Figure 2 actually
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`contradict his opinion that the figure clinically distinguishes between 0.025% and
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`0.03% brimonidine. For example, Dr. Noecker admits that “brimonidine’s
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`vasoconstriction benefit … effectively maximizes and plateaus at about 0.03%” and
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`that “brimonidine’s maximum vasoconstriction effect after netting out its tendency
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`to cause rebound hyperemia is at 0.03%.” Id. ¶ 94; see also Noecker Deposition
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`Transcript (EX-1053) at 83:14–20 (Dr. Noecker admitting that the “net
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`vasoconstriction benefit” accounts for rebound hyperemia); id. at 86:1–17 (Dr.
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`Noecker “stand[ing] by” the assertion in his declaration that the maximum
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`vasoconstriction benefit occurs at 0.03% brimonidine). A POSA would not read
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`Figure 2 to clinically distinguish between 0.025% (which is not indicated anywhere
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`on either of the Figures on which Dr. Noecker relies) and 0.03% when maximum
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`vasoconstriction and maximum net vasoconstriction benefit both occur at around
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`0.03% (as pointed out by Dr. Noecker).
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`21. Moreover,
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`the ’742 patent’s own prosecution history further
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`demonstrates that Figure 2 does not clinically distinguish between 0.025% and
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`0.03% brimonidine. In the ’481 provisional application—to which the ’742 patent
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`claims priority—Figure 4 contains a graph that appears to be a prior version of
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`Figure 2 of the ’742 patent, although in Figure 4 of the ’481 provisional application
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`the net vasoconstriction curve is not visible in this scanned, black-and-white copy of
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`the document:
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`’481 Provisional Application (EX-1011) at 111.
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`22. The ’481 provisional application describes its Figure 4 as teaching that
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`“[t]he net vasoconstrictive effect curve (vasoconstriction - rebound) is shown by the
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`thicker light gray curve, and peaks at ~ 0.025% ± 0.01% (intersecting dashed lines).”
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`Id. Thus, the ’481 provisional application explains in words what Figure 2 would
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`convey to a POSA—that the maximum net vasoconstriction benefit occurs in the
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`range of 0.015% to 0.035%. Id. This aligns with my interpretation that even the
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`inventors conveyed that concentrations with the range of ± 0.01% around 0.025%
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`achieved the same peak net vasoconstrictive effect, and therefore showed no
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`meaningful clinical differences.
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`23. Dr. Noecker also relies on Figure 6 of the ’742 patent to support his
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`opinions (Noecker Declaration (EX-2020) ¶ 95), but Figure 6 is even less clear than
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`Figure 2. Figure 6 of the ’742 patent contains no legend describing what any of the
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`curves on the graph are meant to depict. While it is not unreasonable for the
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`inventors to have used the same identification conventions as in Figure 2, that is not
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`clear from the patent. Dr. Noecker characterizes Figure 6 as “effectively an
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`expanded version of Figure 2.” Id. ¶ 95. Although the two figures superficially
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`share some similarities, there are notable differences. Most notably, the curve that
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`Dr. Noecker has labeled the “rebound hyperemia curve” of Figure 6 is clearly not
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`the same as the corresponding curve in Figure 2 (the curve that was actually labeled
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`by the specification as “rebound hyperemia”). In Figure 6, the curve Dr. Noecker
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`labeled “rebound hyperemia” crosses above the two curves nearest to it (the thin,
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`solid black curve and the dotted curve). In Figure 2, the curve labeled rebound
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`hyperemia by the ’742 patent never crosses the other two curves (labeled “IOP
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`Reduction (Glaucoma)” and “Endo Cell Pump Inhibition”)—it remains visibly
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`below those two curves for the entire length of the x-axis. See Noecker Deposition
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`Transcript (EX-1053) at 91:2–92:15 (Dr. Noecker admitting same). Dr. Noecker
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`provided no explanation as to how these two distinct curves in Figures 2 and 6
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`represent the same rebound hyperemia. In fact, it is mathematically impossible for
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`these curves to have been derived from the same underlying data. Thus, a POSA
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`would conclude that the two figures are not the same, and would not have viewed
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`them as “interchangeable,” as Dr. Noecker did.
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`24. Even assuming that Dr. Noecker annotated Figure 6 appropriately, Dr.
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`Noecker’s assertion that Figure 6 clinically distinguishes between 0.025% and
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`0.03% brimonidine is still incorrect. Dr. Noecker asserts that brimonidine “starts
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`causing rebound hyperemia” at 0.03% and points to his rebound hyperemia curve
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`“transitioning from dark gray to red.” Noecker Declaration (EX-2020) ¶ 95. Dr.
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`Noecker’s assertions lack support. First, Dr. Noecker points to nothing in the
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`specification (or elsewhere) indicating that the curve “transitioning from dark gray
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`to red” means that rebound hyperemia is beginning. Indeed, Dr. Noecker’s rebound
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`hyperemia curve is well above zero (presumably indicating some amount of rebound
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`hyperemia) even at the point on the x-axis where Dr. Noecker believes 0.025%
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`would fall.
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`25. Dr. Noecker also points out that the ’742 patent states “FIG. 6 depicts
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`a graphical representation of a finding of the present invention that an increased
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`rebound hyperemia begins at around 0.03% for brimonidine.” Id. (citing ’742 Patent
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`(EX-1001) at 19:52–54). But, importantly, the ’742 patent uses words of
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`approximation—“rebound hyperemia begins at around 0.03%.” Id. (emphasis
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`added). The ’742 patent does not explicitly state that Figure 6 shows no rebound
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`hyperemia at concentrations lower than exactly 0.03% brimonidine as Dr. Noecker
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`asserts. Rather, a POSA would read the ’742 patent’s words of approximation with
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`respect to Figure 6 and conclude that rebound hyperemia could begin either a little
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`less than, at, or a little more than 0.03% brimonidine. In fact, Dr. Noecker’s own
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`annotated version of Figure 6 illustrates this point—his rebound hyperemia curve is
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`above zero even at the point on the x-axis that he has labeled 0.025% brimonidine.
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`Thus, a POSA would read the ’742 patent’s description of Figure 6 and reasonably
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`conclude that “at around 0.03%” includes 0.025%. Even Dr. Noecker admits that
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`his annotated figure shows only that the 0.025% concentration “keep[s] rebound
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`hyperemia at a minimum”—the figure does not demonstrate that 0.025% eliminates
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`rebound hyperemia entirely, as he later suggests. Id. (emphasis added).
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`26. Further, contrary to Dr. Noecker’s opinions, the ’742 patent suggests
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`that rebound hyperemia does not occur even at a concentration of 0.033%.1 Indeed,
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`I agree with the Board’s conclusion in its institution decision that “Figure 4E of the
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`references cited by Patent Owner illustrates that, four hours after a third application
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`of a concentration of 0.033% brimonidine, there is no indication of rebound
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`hyperemia. … This therefore suggests that increased hyperemia may not necessarily
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`occur until the brimonidine concentration exceeds 0.03%.” Institution Decision
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`(Paper 13) at 11–12 (emphasis added).
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`27.
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`I also disagree with Dr. Noecker’s assertion that Figure 6 “is clearly
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`1 I understand that Patent Owner has asserted that the reference to 0.033%
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`brimonidine in the ’742 patent was in error, but there is nothing in the specification
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`that signaled to me that this was an error. This was not the only instance where the
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`concentration of brimonidine changed in the data presented in Example 1. See ’742
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`Patent (EX-1001) at 19:61–20:19 (explaining that in Example 1 “a patient was
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`treated with brimonidine at claimed concentrations” and noting the results shown in
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`Figure 4, with Figure 4A being baseline, Figure 4B testing 0.01% brimonidine,
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`Figure 4C testing 0.02% brimonidine, Figure 4D testing 0.02% brimonidine, and
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`Figure 4E testing 0.03% brimonidine). The 0.033% brimonidine concentration is
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`within the range of brimonidine concentrations disclosed in the specification.
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`conveying with the blue dot on the x-axis that is placed slightly to the right of the
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`visual middle point between 0.01% and 0.03% a concentration of about 0.025%.”
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`Noecker Declaration (EX-2020) ¶ 95, n.8. As discussed above, Figure 6 contains no
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`hash marks or other indications of where even the enumerated concentrations fall
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`exactly on the x-axis, let alone the non-enumerated concentrations, such as 0.025%.
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`The blue dot is not referenced anywhere in the specification, and none of the “several
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`other parts of the specification identifying about 0.025% as part [sic] top end of a
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`preferred concentration range” cited by Dr. Noecker are tied to Figure 6 in any way.
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`Id. As discussed above, the scale of the x-axis in Figure 6 appears to be non-linear.
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`Thus, a POSA would not assume that a dot that is “placed slightly to the right of the
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`visual middle point between 0.01% and 0.03%” must correspond to 0.025%. Id.
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`28. Figure 4 of the ’481 provisional application also undermines Dr.
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`Noecker’s opinion that the blue dot in Figure 6 of the ’742 patent must correspond
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`to the 0.025% concentration. As noted above, the ’481 provisional application states
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`that the “intersecting dashed lines” of its Figure 4 correspond to 0.025%. ’481
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`Provisional Application (EX-1011) at 111. As clearly shown in Figure 4, the dashed
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`line intersects the x-axis nearest to the second zero in the “0.03%” marking. Thus,
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`the demarcation of 0.025% in Figure 4 of the ’481 provisional application is not
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`located at the same point on the x-axis as the blue dot in Figure 6 of the ’742 patent,
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`which Dr. Noecker believes must correspond to 0.025%. The following side-by-
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`side comparison of magnified excerpts taken from Figure 4 of the ’481 provisional
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`application (left side, dashed line) and the annotated Figure 6 from Dr. Noecker’s
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`declaration (right side, blue dot and green line) illustrates the discrepancy:
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`
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`’481 Provisional Application (EX-1011) at 111 (magnified); Noecker Declaration
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`(EX-2020) ¶ 95 (magnified).
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`29. Dr. Noecker’s opinions are further contradicted by Figure 6 itself. Dr.
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`Noecker asserts that the 0.025% concentration’s “combination of near-maximal
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`vasoconstriction effects and minimal rebound hyperemia allowed the patented
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`invention to produce a more effective scleral whitening in the eye without the side
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`effects associated with prior art redness relievers.” Noecker Declaration (EX-2020)
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`¶ 95. But Figure 6 makes no mention of the criticality of the 0.025% concentration.
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`Quite the contrary, Figure 6 states that “the net effectiveness of brimonidine as a
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`decongestant is greatest between about 0.01% and about 0.03%.” ’742 Patent (EX-
`
`1001) at 19:55–56. Thus, a POSA would not understand Figure 6 to clinically
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`distinguish 0.025% from 0.03% because Figure 6 explicitly teaches that both
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`concentrations fall within the range in which “the net effectiveness of brimonidine
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`as a decongestant is greatest.” Id.
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`30.
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`In my experience, demonstrating a clinically significant difference
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`between the effects of a drug at concentrations differing by only five-thousands of a
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`percentage is a futile task. In my clinical experience of over forty years, I cannot
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`provide any example of any drug used for any indication that has a significant
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`therapeutic difference in the range of five-thousands of a percentage point. This is
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`especially true in ophthalmology. Ophthalmic medications that are administered by
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`eye drops are much less precise than other dosage forms due to the nature of the
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`administration. Patients frequently miss the eye entirely or may get only a small
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`amount of medication on the surface of the eye. Frequently, patients get zero, one,
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`or two drops on the eye. Furthermore, patients usually do not shake the bottle to
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`ensure homogenous distribution of the ingredients in the solution/suspension. Also,
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`patients may store the bottle with its cap off, leading to evaporation of the solution.
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`Thus, any attempt to demonstrate a clinically significant difference between 0.025%
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`and 0.03% would be marred with uncertainty due to the nature of the administration
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`of eye drops.
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`31. Finally, I note that the origin of the underlying data depicted in Figures
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`2 and 6 is completely unknown. Even Dr. Noecker admits that he does not know
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`where or how the underlying data were obtained. See Noecker Deposition Transcript
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
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`(EX-1053) at 89:2–18.
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`32. For at least these reasons, it is my opinion that the ’742 patent
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`specification does not clinically distinguish between 0.025% and 0.03%.
`
`B.
`33.
`
`The ’742 Patent Defines “Ocular Condition” Broadly
`In my Opening Declaration, I opined that a POSA would have
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`understood the term “ocular condition” to include at least a list of certain conditions,
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`and I based this opinion on the fact that the ’742 patent defines “