UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`SLAYBACK PHARMA LLC,
`
`Petitioner,
`
`v.
`
`EYE THERAPIES, LLC,
`
`Patent Owner.
`
`__________________
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`__________________
`
`DECLARATION OF ROBERT J. NOECKER, MD, MBA
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`Table of Contents
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`Page
`Introduction ...................................................................................................... 4
`I.
`Qualifications and Professional Experience .................................................... 4
`II.
`Information Considered ................................................................................... 8
`III.
`IV. Summary of Opinions ...................................................................................... 9
`V.
`Level of Ordinary Skill in the Art .................................................................11
`VI. Technical Background ...................................................................................13
` Anatomy of the Eye .............................................................................13
`Adrenergic Receptors ..........................................................................17
`Ocular Conditions................................................................................20
`1.
`Eye redness ...............................................................................20
`2.
`Glaucoma ..................................................................................23
`State-of-the-art redness relievers: “an α1 mediated effect” .................24
`Not all α-adrenergic agonists characterized as “vasoconstrictors”
`work similarly ......................................................................................27
`1.
`Vasoconstriction (α1 effect) versus vasodilation (α2 effect)
` ...................................................................................................27
`Adrenergic receptor location and effect of agonist
`selectivity on reduction of eye redness .....................................28
`Brimonidine—a highly selective α2 agonist ........................................30
`1.
`Brimonidine’s known adverse side effects ...............................30
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`2.
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`1
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`2.
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`3.
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`The prior art established that brimonidine’s blanching
`effects were concentration dependent, rapidly diminishing
`as the concentration decreased ..................................................34
`A POSA would not have chosen brimonidine as an α2
`agonist redness reliever absent hindsight knowledge ...............37
`VII. The ’742 Patent ..............................................................................................40
`VIII. Claim Construction ........................................................................................48
`Relevant Legal Principles ....................................................................48
`“ocular condition” ...............................................................................48
`“about 0.025%” ...................................................................................52
`1.
`“about 0.025%” does not include 0.03% ..................................52
`2.
`Responses to Dr. Laskar’s Opinions .........................................56
`IX. The ’742 patented methods would not have been obvious ...........................59
`Relevant Legal Principles ....................................................................60
`Discussion of References Relied on by Dr. Sher ................................61
`1.
`Alphagan® Label 1998 and Alphagan® NDA ...........................61
`2.
`Federal Register 1988 ...............................................................66
`3.
`U.S. Patent No. 6,294,553 .........................................................67
`4. Walters 1991 .............................................................................75
`5.
`Norden 2002 ..............................................................................77
`6.
`U.S. Patent No. 6,242,442 .........................................................81
`7.
`Scruggs 2000 .............................................................................84
`8.
`U.S. Patent No. 6,562,873 .........................................................85
`Response to the Petitioner’s Grounds of Purported Invalidity ...........85
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`2
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`1.
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`2.
`
`Ground No. 1 – The ’553 patent does not expressly or
`inherently anticipate claims 1 and 2 .........................................85
`Ground No. 2 – Walters 1991 does not expressly or
`inherently anticipate claims 1 and 2 .........................................89
`Ground No. 3 – Claims 1-6 are not obvious .............................91
`3.
` Objective, real-world evidence of nonobviousness ..........................118
`1.
`Lumify® Product .....................................................................119
`2.
`Unexpected superiority of the ’742 patent’s invention over
`prior art ophthalmic redness reducers .....................................121
`Lumify®—the commercial embodiment of the patented
`invention—enjoyed significant industry praise ......................141
`
`3.
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`3
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`I.
`
`Introduction
`I, Robert J. Noecker, submit this declaration to state my opinion on the
`1.
`
`matters described below.
`
`2.
`
`I have been retained by Eye Therapies, LLC, as an independent expert
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`in this proceeding before the United States Patent and Trademark Office.
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`3.
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`I understand that this proceeding involves U.S. Patent No. 8,293,742
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`(“the ’742 patent”), and that I have been asked to provide my opinions of whether
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`the subject matter of the claims of the ’742 patent is patentable.
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`4.
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`This declaration sets forth my opinions from the perspective of a person
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`ordinarily skilled person in the art, which I have formed in this proceeding based on
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`my education, training, clinical research, knowledge, personal and professional
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`experience, my understanding as an expert in the field, and my study of the evidence.
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`5.
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`I am being compensated for my time at the rate of $750 per hour. This
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`compensation is not contingent upon the nature of my findings, the presentation of
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`my findings in testimony, or the outcome of this proceeding.
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`II. Qualifications and Professional Experience
`6. My curriculum vitae is submitted with this declaration as Appendix A.
`
`I have summarized my educational and professional background below.
`
`7.
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`I received a Bachelor of Science in Biology from the Massachusetts
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`Institute of Technology in 1985. I also received a Bachelor of Science in Materials
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`4
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`Science and Engineering, as well as a Bachelor of Science in Humanities and
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`Engineering (Literature) from the Massachusetts Institute of Technology in 1986.
`
`8.
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`After completing my undergraduate studies, I went on to obtain an
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`M.D. degree from the University of North Carolina School of Medicine in 1990.
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`After completing medical school, I undertook an internship in internal medicine at
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`the Moses H. Cone Memorial Hospital in Greensboro, North Carolina from July of
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`1990 until June of 1991. In July of 1991, I began my residency in ophthalmology at
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`the University of Arizona. I completed that residency in June of 1994. I then went
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`on to complete a clinical fellowship in ophthalmology at the New England Eye
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`Center at Tufts University School of Medicine in Boston, Massachusetts from July
`
`of 1994 to June of 1995.
`
`9.
`
`Since completing my residency and fellowship, I have held a number
`
`of academic positions at universities across the country. Starting in June of 1994, I
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`held the position of Assistant Professor of Ophthalmology at Tufts University
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`School of Medicine. In June of 1996, I returned to the Department of Ophthalmology
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`at the University of Arizona, first as an Assistant Professor of Ophthalmology (1996-
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`2002), and then as an Associate Professor of Ophthalmology (2002-2003). During
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`my time at the University of Arizona, I also served as Residency Director from July
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`of 1998 until June of 2003, as a Faculty Member in the Biomedical Engineering
`
`Interdisciplinary Program in the Graduate College of the University of Arizona from
`
`5
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`July of 1998 until December of 2003, and as the Associate Chair for Clinical
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`Activities for the Department of Ophthalmology from July of 2002 until December
`
`of 2003.
`
`10.
`
`In January of 2004, I became a member of the faculty of the Department
`
`of Ophthalmology at the University of Pittsburgh School of Medicine, first as a
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`Visiting Associate Professor of Ophthalmology (2004-2007), then as an Associate
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`Professor of Ophthalmology (2007-2009), and finally as a Professor of
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`Ophthalmology (2009-2011). I also served as the Vice Chair of the UPMC Eye
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`Center at the University of Pittsburgh School of Medicine from January 2004
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`through June 2011.
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`11. Since 2011, I have worked as an ophthalmologist and director of
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`glaucoma at the Ophthalmic Consultants of Connecticut. I am on the staff of St.
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`Vincent’s Hospital, Hartford Hospital, and the West Haven Veteran’s Hospital. I am
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`a Clinical Professor at the Frank Netter School of Medicine at Quinnipiac
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`University, and I am an Assistant Clinical Professor at Yale School of Medicine in
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`the Department of Ophthalmology. I lecture, teach, and train ophthalmology
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`residents, optometry residents, students, and medical students.
`
`12.
`
`I have received a number of honors and awards throughout my career.
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`Those awards include, among other things, being selected to the Best Doctors in
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`America every year since 2004, as well as a Top Doctor by a number of other
`
`6
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`services. Additionally, I have been selected as the Clinical Instructor of the Year by
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`the ophthalmology residents three times during my tenure at the University of
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`Pittsburgh and have received teaching awards at each institution where I have been
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`a faculty member. I am currently the Acting President of Connecticut Glaucoma
`
`Society.
`
`13.
`
`I have conducted research in the field of ophthalmology for nearly 30
`
`years and have been an investigator on numerous clinical trials for ophthalmic
`
`products, a full list of which can be found in my curriculum vitae. See Appendix A
`
`at 33-35
`
`14. Over the course of my career, I have authored or co-authored over 100
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`peer-reviewed publications and have had several hundred abstracts published. I also
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`serve as a contributing editor for seven different publications and as a peer-reviewer
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`for twelve additional publications. I frequently lecture on the subjects of diagnosis
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`and treatment of ophthalmic disorders. My other qualifications are set forth in my
`
`curriculum vitae.
`
`15.
`
`I have participated in multiple clinical trials for brimonidine and related
`
`ophthalmic medications and have published peer review papers on its use. I prescribe
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`brimonidine on a daily basis (and have done so for over twenty years) for the
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`treatment of multiple ocular conditions. I also treat patients on a daily basis with eye
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`redness and the associated underlying conditions.
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`7
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`16.
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`I have consulted for numerous pharmaceutical companies over the
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`years. I also have served as an expert witness in the field of ophthalmology, and my
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`testimony has been credited in court.
`
`17.
`
`I have been a member of several professional associations for many
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`years. I have been a member of the Association for Research in Vision and
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`Ophthalmology since 1989, and a fellow of American Academy of Ophthalmology
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`since 1991. I have also been a member of American Society for Cataract and
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`Refractive Surgery since 1992, and an associate member of Association of
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`University Professors in Ophthalmology since 1998. I have been and still am an
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`active member of American Glaucoma Society since 2000. I have been a member of
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`Connecticut Glaucoma Society and Connecticut Society for Eye Physicians since
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`2011. In 2020, I have been elected as a co-chair of Connecticut Glaucoma Society.
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`And since 2021, I have been elected as the acting president of Connecticut Glaucoma
`
`Society.
`
`18. On the basis of my education and experience, I believe I am qualified
`
`to express the opinions provided below.
`
`III.
`
`Information Considered
`In forming my opinions, I had available the documents cited herein and
`19.
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`in Appendix B, as well as the publications listed in my curriculum vitae at Appendix
`
`A. I additionally have based my opinions on my professional and academic
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`8
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`experience in the area of pharmaceutical formulation. I reserve the right to testify
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`about these materials and experience. For the reasons discussed below, I disagree
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`with Dr. Sher’s and Dr. Laskar’s conclusions that the claims of the patents are invalid
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`based on anticipation and obviousness.
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`IV. Summary of Opinions
`I have been asked to provide my opinion as to whether the methods of
`20.
`
`reducing redness recited in claims 1-6 of the ’742 patent are patentable over certain
`
`prior art references. It is my opinion that the methods of claims 1-6 are patentable.
`
`21. Dr. Sher has failed to establish that the ’553 patent or Walters 1991
`
`destroys the novelty of the methods of claims 1 and 2, expressly or inherently.
`
`Neither the ’553 patent nor Walters 1991 discloses or even suggests using low
`
`concentration brimonidine to reduce eye redness. And there is no data indicating that
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`any of the patients administered with low concentration brimonidine necessarily and
`
`inevitably experienced redness reduction in the eye.
`
`22. Dr. Sher has failed to establish that any of the cited prior art references
`
`render any of claims 1-6 obvious.
`
`23. First, brimonidine was known to cause high incidences of ocular
`
`allergic reactions, clinically reaching rates of 13%. While this may have been a
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`tolerable property for treating the serious disease of glaucoma, it would have been
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`yet another property that would have discouraged skilled artisans from considering
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`9
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`it in an OTC redness reliever, where the potential for misuse exists and a heightened
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`need for safety arises.
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`24. Second, there is no evidence that a POSA would have been motivated
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`to use low-concentration brimonidine—a highly selective α2 agonist with very little
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`α1 effect—to reduce eye redness when the art at the time clearly indicated that eye
`
`whitening is an α1-mediated effect and brimonidine’s whitening effect was
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`concentration dependent, sharply decreasing as its concentration decreased.
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`25. Third, even if a POSA would have pursued an α2 agonist as a redness
`
`reliever—which Dr. Sher failed to prove—the POSA would have looked toward α2
`
`receptor agonists other than brimonidine that still had a relatively high selectivity
`
`for α1 adrenergic receptors, such as apraclonidine and oxymetazoline.
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`26. Further illustrating the patentability of the ’742 patent claims, there is
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`substantial evidence supporting the ’742 patent’s objective indicia of non-
`
`obviousness, including unexpectedly superior redness reducing efficacy, coupled
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`with rapid onset, long duration of action, and little or no rebound hyperemia and
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`tachyphylaxis. This superior efficacy and safety profile have garnered significant
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`industry praise that is reflected in the ’742 patented invention’s commercial success
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`and the current copying by competitors.
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`10
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`V. Level of Ordinary Skill in the Art
`I understand that the Petitioner contends that “[a] POSA was a
`27.
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`composite person (or team) that included a medical doctor and a pharmaceutical
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`formulator.” Pet. at 15. I understand that the Petitioner further contends that “[t]he
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`medical doctor was an ophthalmologist with at least three to four years of experience
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`in LASIK surgery, clinical trials and U.S. FDA regulation of eye products, and had
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`experience in the use of topical brimonidine and apraclonidine and topical
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`vasoconstrictors such as naphazoline and tetrahydrozoline” and that “[t]he
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`pharmaceutical formulator had a doctorate in pharmaceutics or a related degree and
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`at least three to five years of experience developing eye drop formulations for
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`clinical trial and regulatory approval.” Id.
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`28.
`
`In my opinion, the qualifications that the Petitioner attributes to a POSA
`
`go far beyond those of a person of ordinary skill. In any event, my opinions
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`expressed herein would not change regardless of which definition is applied.
`
`29. The field to which the ’742 patent pertains is interdisciplinary. I agree
`
`that a person of ordinary skill in the relevant art may be represented by a team of
`
`individuals with experience and various skills relating to eye care, including, inter
`
`alia, the medical and pharmaceutical formulation arts. Furthermore, a person of
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`ordinary skill in the relevant art may also have been part of or have access to a team
`
`of individuals with experience in chemistry, in designing and evaluating ophthalmic
`
`11
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`formulations, and/or in administering ophthalmic formulations to treat ocular
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`conditions obtained by some combination of education and work experience.
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`30. The medical doctor is a specialist in treating diseases of the eye, such
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`as an optometrist or ophthalmologist, with three to four years of experience, who
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`also has experience designing and running clinical trials on ophthalmic formulations.
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`In my opinion, the pharmaceutical formulator had a Bachelor’s degree in
`
`pharmaceutics or a related discipline with about three to five years of work
`
`experience in this area, or a comparable level of education and training, such as a
`
`Ph.D. with one to two years of experience in this area.
`
`31.
`
`In light of the above, I believe the POSA should be defined as follows:
`
`The POSA is a composite person engaged in developing pharmaceutical
`
`formulations and treatment methods for the eye, and includes a medical doctor and
`
`pharmaceutical formulator with the qualifications outlined above. This person may
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`also work in collaboration with other scientists and/or clinicians who have
`
`experience with chemistry; developing, designing, and/or evaluating ophthalmic
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`formulations; administering ophthalmic formulations; running clinical trials related
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`to such formulations; and/or treating patients using such formulations.
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`12
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`VI. Technical Background
` Anatomy of the Eye
`32. The eye is a complex, multi-layered organ. Even today, the exact
`
`mechanisms of action involved in certain ocular physiological processes are not
`
`completely understood. Thus, there are still significant uncertainties surrounding
`
`many eye treatments. See EX-2030 (Agarwal) at 13.
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`33.
`
`I provide the following images of the eye and its anatomy to guide the
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`discussion in the succeeding paragraphs:
`
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`Anatomy of the Eye.
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`34. This image shows a cross-section of the eye. Ophthalmic products
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`aimed at reducing redness—sometimes referred to as ophthalmic decongestants or
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`redness relievers—target the “white” of the eye, which consists of the conjunctiva,
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`the episclera, and the sclera. EX-1001 (’742 patent) at 14:7-14; EX-1002, ¶71
`
`(“scleral whitening makes the eye look less red.”).
`
`35. The cornea is a transparent surface of the eyeball in front of the lens
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`and acts as the major refractive element in the optical pathway. The cornea lacks
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`blood vessels (i.e., avascular) so that light may pass through it easily and be focused
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`onto the retina. EX-2177 at 1. Any abnormal growth of blood vessels onto the cornea
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`can significantly impair vision. See id.
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`36. The conjunctiva is a clear, thin tissue that covers the sclera and lines
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`the inside of the eyelids. EX-2172 at 4. Some of its roles are to lubricate the ocular
`
`surface, transport substances to and from the surface, and provide a line of defense
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`against external insults. The sclera, also commonly referred to as the white of the
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`eye, is a semi-rigid structure of connective tissue that provides a protective covering
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`of the eyeball. EX-2178 at 2. It acts as the supporting wall for the eyeball,
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`maintaining the eyeball’s shape and protecting delicate interior parts from injury. Id.
`
`at 3.
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`37. As shown in the image below, the sclera consists of four layers. The
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`outermost layer is the episclera, which is a clear, thin tissue resting on top of the
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`eyeball. Id. at 3. The second layer (stroma) and the third layer (lamina fusca) are
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`fibrous connective tissue layers. See id. The bottom layer is endothelium, which is a
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`thin inner cellular lining of the choroid. See id.
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`
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`Layers of the sclera.
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`38. Each of the conjunctiva, episclera, and sclera has blood vessels. The
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`conjunctiva and the episclera have blood vessels known as superficial and deep
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`conjunctival capillary and episcleral plexuses. EX-2179 at 1. Dilation of these blood
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`vessels makes them more visible, triggering eye redness. The surface of the sclera,
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`deep into the episclera, also contains blood vessels. When dilated, these blood
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`vessels at the sclera interface with the episclera, which can make the eye appear red.
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`Id.
`
`39. The ciliary body is located inside of the eye and performs multiple
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`functions. EX-2171 at 1. The ciliary body changes the shape of the lens when the
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`eye focuses. Id. It also produces clear fluid (aqueous humor) that fills the space
`
`located between the cornea and the lens, providing nutrients to these parts of the eye.
`
`Id. As further explained below, an increased amount of the aqueous humor increases
`
`the intraocular pressure, which can cause glaucoma. Glaucoma is a serious disease
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`that, if not properly treated, can lead to blindness.
`
`40. The eyes have a natural defense mechanism to protect them from the
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`external environment. When a foreign substance is introduced, the eye produces
`
`tears or secretes mucus to eliminate that substance.
`
` Adrenergic Receptors
`41. Adrenergic receptors are receptors on the surface of the cells in the
`
`sympathetic nervous system (“SNS”), which is a network of nerve cells found in
`
`organs, including the eyes. EX-2169 (Derick 1995) at 1. There are two types of
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`adrenergic receptors: alpha and beta. Id. at 2. The alpha-adrenergic receptors are
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`further categorized into two subtypes, known as alpha 1 (α1 receptors) and alpha 2
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`(α2 receptors), both of which are found in the eye. Id. The α1 receptors are located in
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`the post-synaptic effector cells, frequently in smooth muscle. Id. The α2 receptors
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`are located presynaptically and postsynaptically. Id.
`
`42. The adrenergic
`
`receptors
`
`interact with a specific
`
`type of
`
`neurotransmitters known as catecholamines (e.g., epinephrine and norepinephrine)
`
`to send messages across the SNS and elicit bodily responses. Id. at 1. Importantly,
`
`the two types of α-adrenergic receptors work in different ways to mediate different
`
`systemic responses, excitatory versus relaxation responses. See id. at 4.
`
`43. When activated, α1 receptors release norepinephrine and produce an
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`excitatory response (i.e., a fight-or-flight response), vasoconstricting blood vessels
`
`or causing smooth-muscle contraction. Id. at 2, 4; EX-2162 (Sher Dep. Tr.) at 74:9-
`
`24, 75:11-17. This is known as an α1 mediated effect. EX-1016 (Griffith 2003) at
`
`12-13; EX-1035 at 2 (Burke). As discussed further below, the α1 effect was widely
`
`accepted as responsible for the ocular vasoconstriction that reduced eye redness. See
`
`EX-1016 (Griffith 2003) at 12-13; EX-1035 (Burke) at 2; see also EX-1023 (Scruggs
`
`2000) at 5; EX-1019 (Lachkar 1998) at 3 (“[v]asoconstriction is mediated mainly
`
`via α-1 adrenergic receptors”).
`
`44. The α2 receptors, however, can work in opposition to the α1 effect
`
`mediated by the α1 receptors. They can mediate an inhibitory effect that decreases
`
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`the release of the neurotransmitters, like norepinephrine.1 EX-2169 (Derick 1995) at
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`2-3. Importantly, these effects can cause blood vessels to dilate, triggering relaxation
`
`that can clinically manifest as sedation, depression, hypotension, and eye redness.
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`Id. at 4; Ex. 1001 at 1:38-55; see also EX-2169 (Derick 1995) at 5 (describing the
`
`sedative effect clonidine, an α2 agonist). EX-1019 (Lachkar 1998) at 3
`
`(“[B]rimonidine tartrate may also produce vasodilatation via the α2-adrenergic
`
`receptors on endothelial cells, which release endothelial-derived relaxing factor.”);
`
`EX-2012 (Alphagan® Label 2001) at 3, 8, 9, 12; EX-2014 (Alphagan P® Label 2005)
`
`at 2, 4 (noting that fatigue and drowsiness are common side effects of the Alphagan®
`
`products, which contain 0.2% brimonidine, a highly selective α2 receptor agonist);
`
`EX-1035 (Burke) at 2 (because of brimonidine’s high affinity for the α2 receptor,
`
`“brimonidine would be the least likely to produce α1-adrenoceptor mediated side
`
`effects, such as mydriasis and ocular vasoconstriction”).
`
`
`1 At the cellular level, when α2 receptors are triggered pre-synaptically by an
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`α2 agonist, a cascade of cellular activity results that decreases norepinephrine
`
`release. EX-2169 (Derick 1995) at 2. Post-synaptically, α2 receptor agonists can
`
`also exert an inhibitory effect on the SNS by inhibiting release of adenyl cyclase.
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`Id. at 3.
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`45. Needless to say, the mechanism of action of the adrenergic receptors
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`involves “complicated chemical reactions” and has been the subject of “hundreds, if
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`not thousands, of papers on receptors.” EX-2162 (Sher Dep. Tr.) at 76:12-77:3. In
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`my opinion, any efforts to develop a treatment involving the adrenergic receptors is
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`an unpredictable endeavor that requires a careful balancing of clinical efficacy and
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`unintended side effects. This is particularly true, as explained below, for over-the-
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`counter (OTC) redness relievers, which are subject to potential misuse that leads to
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`serious ocular side effects.
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` Ocular Conditions
`46. There are many ocular conditions. The signs and symptoms of ocular
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`conditions differ, as do the methods of treating them. Below, I discuss the ocular
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`conditions of eye redness and glaucoma, which are relevant to the subject matter of
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`the ’742 patent.
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`Eye redness
`1.
`47. Red eye, also known as ocular hyperemia, refers to a common
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`ophthalmic condition caused by vasodilation—an increase in the diameter of blood
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`vessels on the eye and the influx of blood that “congests” the vessel. EX-2162 (Sher
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`Dep. Tr.) at 112:18-113:5 (testifying that hyperemia involves “dilated but unbroken
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`blood vessels”). It can occur in any of the visible layers of the eye that have
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`vasculature, such as the conjunctiva, the episclera, or the sclera. See id. at 82:17-
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`83:7 (testifying that eye whitening occurs through the vasoconstriction of “blood
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`vessels in the ocular surface”).
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`48. There is a social stigma linked to red eyes, as they are often associated
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`with drinking, drug abuse, and lack of sleep. EX-2011 at 1-2; EX-2211.
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`Additionally, it is a common side effect of glaucoma medication use is eye redness,
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`which can lead to decreased adherence with glaucoma therapy. See id. at 1. This is
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`particularly dangerous because glaucoma patients who do not use their medication
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`as prescribed could be on a slippery slope towards blindness. See id.
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`49. Because of the social stigma associated with red eyes, affected
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`individuals are often eager to efficiently manage the redness. See id. at 1-2. But to
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`determine how to treat the red eye, the physician must first determine the underlying
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`cause and the location of redness. Common causes of red eye include conjunctivitis
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`(infectious and noninfectious), foreign body, environmental eye irritation, and dry
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`eye. The manner in which red eye should be managed will differ depending on the
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`underlying cause.
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`50. Conjunctivitis occurs when blood vessels in the conjunctiva dilate due
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`to allergens (noninfectious), or virus or bacteria (infectious). Conjunctivitis typically
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`only affects the blood vessels in the conjunctiva.
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`51. Foreign body redness can arise when materials or irritants are caught
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`on the surface of the eye and cause inflammation. The inflammation triggers an
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`immune response involving conjunctival leukocytes, causing eye lid edema (puffy
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`eye) and possibly hyperemia. Contact lenses can also trigger eye redness, primarily
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`near the limbus, which is the border between the cornea and the sclera.
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`52. Dry eye can arise due to a variety of reasons, including exposure to a
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`dry environment, dehydration, nutrition, medication, etc. Regardless of the root
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`cause, dry eye redness presents as a consistent pattern of ocular hyperemia—fine
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`horizontal vessel dilation mainly in the intrapalpebral fissure of the conjunctiva.
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`53. Rebound hyperemia is a type of eye redness that occurs when a patient
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`stops using a
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`redness
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`reliever
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`(ophthalmic decongestant). The
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`initial
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`vasoconstriction resulting from the use of the ophthalmic decongestant causes
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`oxygen deficiency (i.e., ischemia) in the blood vessels. EX-1001 (’742 patent) at
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`4:40-46 (explaining that the art at the time “considered the complication of rebound
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`hyperemia to be intrinsic to vasoconstriction, wherein blood flow is reduced, causing
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`attendant ischemia with some inflammatory cascade, precipitating rebound
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`hyperemia in many cases and often leading to medicamentosa”). When the drug
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`wears off, compensatory vasodilation occurs to flood/engorge the vessels with blood
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`and bring in the needed oxygen. Id. The user thus experiences more eye redness than
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`before. Id.
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`54. Distinct from rebound hyperemia—and even tolerance, which occurs
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`with chronic use of a drug—tachyphylaxis is a rapidly decreasing response to an
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`ocular decongestant following its initial administration. EX-2185 (Abelson 2006) at
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`1. It occurs due to a reduction in the availability of α1 receptors (downregulation) in
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`an attempt to maintain homeostasis within the affected cells. Id. Because
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`tachyphylaxis leads to a rapid reduction in the efficacy of ocular decongestants, it
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`could prompt the patient to instill more drops more frequently to obtain the same
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`level of whitening, leading to misuse and overuse of the drug. See id. This could
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`cause toxic conjunctivitis and medicamentosa of the eye—which could manifest as
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`a chronic red eye that persists even after discontinuation of the offending eye drop.
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`EX-2183 (Spector) at 1.
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`2. Glaucoma
`55. Glaucoma is an eye disease that gradually damages the optic nerve,
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`which can ultimately lead to blindness. EX-2011 at 1. While the pathology of all
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`types of glaucoma are not completely understood, a fluid buildup in the anterior
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`chamber—the area between the cornea and the lens—is thought to be a major risk
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`