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 STEPHEN G. DAVIES, D.PHIL.
`
`Eye Therapies Exhibit 2022, 1 of 73
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`__________________
`
`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 STEPHEN G. DAVIES, D.PHIL.
`
`Eye Therapies Exhibit 2022, 1 of 73
`Slayback v. Eye Therapies - IPR2022-00142
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`
`
`Table of Contents
`
`I.
`
`II.
`III.
`
`QUALIFICATIONS AND BACKGROUND ................................................. 1
`Education and Experience ..................................................................... 1
`Documents and Information Considered in Forming Opinions ............ 4
`Scope of Work, Compensation.............................................................. 4
`Testimony as Expert in Last Four Years ............................................... 5
`LEGAL STANDARDS ................................................................................... 5
`STATEMENTS OF OPINIONS EXPRESSED AND BASES AND
`REASONS THEREFOR ................................................................................. 6
`U.S. Patent No. 8,293,742 ..................................................................... 6
`A Person of Ordinary Skill in the Art ................................................... 7
`Claim Construction................................................................................ 9
`Technical Tutorial ...............................................................................10
`1.
`Different Chemical Compounds Have Different
`Characteristics ...........................................................................10
`Chemistry of Brimonidine ........................................................11
`Chemistry of Naphazoline and Tetrahydrozoline .....................13
`Three Dimensional
`Structures
`of Brimonidine,
`Naphazoline, and Tetrahydrozoline ..........................................14
`Additional Selected Compounds ..............................................16
`5.
`Response to Dr. Laskar’s Section Entitled “2-Imidazoline
`Derivatives Were Known as Vasoconstrictors for Reducing Eye
`Redness” ..............................................................................................18
`
`2.
`3.
`4.
`
`Eye Therapies Exhibit 2022, 2 of 73
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`
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`I.
`
`QUALIFICATIONS AND BACKGROUND
`Education and Experience
`I, Stephen G. Davies, D.Phil., submit this declaration at the request of
`
`1.
`
`Eye Therapies, LLC (“Eye Therapies” or “Patent Owner”) as an expert in the fields
`
`of organic chemistry and medicinal chemistry. I understand this is being submitted
`
`in support of the Patent Owner’s Response in connection with IPR2022-00142. My
`
`qualifications in these areas, as well as other areas, are established below and by my
`
`curriculum vitae, which is attached as Appendix A, and list of publications, which
`
`is attached as Appendix B.
`
`2.
`
`I am the Waynflete Professor of Chemistry Emeritus at the University
`
`of Oxford, and Extraordinary Lecturer in Chemistry at New College, Oxford,
`
`England. I have been employed teaching chemistry at Oxford since 1980. From
`
`2006 to 2011, I was Chairman of the Department of Chemistry. In this position, I
`
`had full responsibility for all teaching, research, financial and managerial matters in
`
`one of the largest chemistry departments in the world. I have also supervised more
`
`than 100 graduate students and 100 post-doctoral fellows in the areas of organic,
`
`organometallic and medicinal chemistry.
`
`3.
`
`In 1973, I earned a B.A. in Chemistry from the University of Oxford. In
`
`1975, I earned a D. Phil. in Chemistry from the University of Oxford. In 1980, I
`
`received a D. Sc. in Chemistry from the University of Paris.
`
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`4.
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`Over the course of my career, I have been a committee member of many
`
`professional organizations, a list of which can be found in my curriculum vitae.
`
`5.
`
`I have authored over 600 publications and have given scores of research
`
`lectures. My research interests include synthetic organic and medicinal chemistry,
`
`and in particular, the preparation of chemically and stereochemically pure organic
`
`compounds,
`
`including
`
`the asymmetric and stereoselective synthesis of
`
`enantiomerically pure organic compounds for potential therapeutic use. A list of my
`
`publications may be found attached as Appendix B.
`
`6.
`
`I have also held several editorial appointments. I was the Founding
`
`Editor and Editor of Organic Series of “Oxford Chemistry Primers” and “Oxford
`
`Chemistry Masters.” I was also the Founding Editor and currently Editor-in-chief
`
`of “Tetrahedron: Asymmetry” (1990-2017). I am also the Editor of the “On
`
`Chemistry” Books, and for many years (1989-2017), I was an Executive Editorial
`
`Board Member of the “Tetrahedron” family of Journals.
`
`7.
`
`Over the course of my career, I have received several awards, including
`
`the Hickinbottom Fellowship (1984); Pfizer Award for Chemistry (1985); 1984
`
`Corday Morgan Medal, Royal Society of Chemistry (1986); Royal Society of
`
`Chemistry Award for Organometallic Chemistry (1987); Pfizer Award for
`
`Chemistry (1988); Royal Society of Chemistry Bader Award (1989); Tilden Lecture
`
`Award, Royal Society of Chemistry (1996); Royal Society of Chemistry Award in
`
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`Stereochemistry (1997); Prize Lectureship of the Society of Synthetic Organic
`
`Chemistry, Japan (1998); Distinguished Technopreneur Award, Singapore (2008);
`
`Royal Society of Chemistry Perkin Prize for Organic Chemistry (2011); and Doctor
`
`Honoris Causa, University of Salamanca, Spain.
`
`8.
`
`I am also the founder of numerous companies including ones focused
`
`on the preparation of compounds for potential pharmaceutical use. Along with
`
`several others, I founded Oxford Asymmetry, Ltd. in 1992, which became a division
`
`of Oxford Asymmetry International plc, with a mission to provide pharmaceutical
`
`companies with enantiomerically pure compounds of interest on any desired scale,
`
`from small amounts for biological evaluation and research, to commercial
`
`quantities. Currently, I am the Founder and Non-executive Chairman of SciInk
`
`Ltd. I was also a Non-executive Director of Oxford University Innovation Ltd. I
`
`was also the Founder and Non-executive Director of OxStem Ltd., OxStem Neuro
`
`Ltd., OxStem Cardio Ltd., OxStem Oncology Ltd., OxStem Ocular Ltd, OxStem
`
`Beta Ltd, and OxStem Immuno Ltd. I am also the Founder of Summit Therapeutics
`
`plc and Summit Therapeutics Inc., which develops pharmaceutical compounds and
`
`has one such compound currently undergoing evaluation after a Phase III clinical
`
`trial. I am also the Founder and Non-executive Director of Raphael Laboratories
`
`Limited, which is developing prophylactics against airborne respiratory viruses
`
`Eye Therapies Exhibit 2022, 5 of 73
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`including COVID-19 and all of its variants, one of which successfully completed a
`
`Phase II clinical trial.
`
`Documents and Information Considered in Forming
`Opinions
`In forming my opinions, I had available the documents cited herein and
`
`9.
`
`in Appendix C as well as the publications listed in Appendix B. I additionally have
`
`based my opinions on my professional and academic experience in the area of
`
`organic chemistry and medicinal chemistry. I reserve the right to testify about these
`
`materials and experience.
`
`Scope of Work, Compensation
`I have been retained by counsel for Eye Therapies in this matter. I will
`
`10.
`
`be compensated for my time preparing for and testifying in this matter at the rate of
`
`£450 per hour. No part of my compensation is contingent upon the outcome of this
`
`matter or any issue in it.
`
`11.
`
`To the extent I am provided additional documents or information,
`
`including any expert declarations produced by Slayback Pharma LLC (“Petitioner”
`
`or “Slayback”) or additional documents produced by the Petitioner, I may offer
`
`further opinions. In addition to these materials, I may consider additional documents
`
`and information in forming any rebuttal opinions. Additionally, I reserve the right to
`
`prepare one or more visual aids or demonstratives to illustrate my opinions,
`
`Eye Therapies Exhibit 2022, 6 of 73
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`including at trial. I also reserve the right to provide a technical tutorial to provide
`
`additional background information on my opinions.
`
`Testimony as Expert in Last Four Years
`12. Appendix D to this Declaration is a list of the cases where I have
`
`testified at deposition and/or trial in the last four years.
`
`II.
`
`LEGAL STANDARDS
`13.
`I have no formal legal training, but I have been informed by Patent
`
`Owner’s counsel about the appropriate legal standards as set forth below and I have
`
`applied these standards in rendering my opinions. I reserve the right to supplement
`
`my report to take into account any modifications to these standards, if I am informed
`
`of such.
`
`14.
`
`I have been informed that the U.S. patent statute provides that issued
`
`patents are presumed valid over the prior art.
`
`15.
`
`I have been informed and understand that to find a patent claim invalid
`
`for obviousness, the claimed invention, as a whole, when considered against the
`
`prior art taken as a whole would have had to have been obvious to a person having
`
`ordinary skill in the art at the time the invention was made. I understand that, in
`
`making an obviousness determination, it is improper to consider the prior art with a
`
`hindsight bias based on the teachings of the patent. One must not use the patent as a
`
`template to suggest how the elements of the prior art could have been combined.
`
`Eye Therapies Exhibit 2022, 7 of 73
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`16.
`
`I have also been informed and understand that the claimed invention
`
`and the prior art must each be looked at “as a whole.” One must also consider those
`
`portions of the prior art that “teach away” from the claimed invention. It is not
`
`sufficient to consider an isolated portion of one reference that is similar to what the
`
`patent discloses and claims, if either the reference as a whole or another reference or
`
`the prior art as a whole teaches or suggests something different from that isolated
`
`portion. I also understand that, in resolving whether an invention is obvious based
`
`on the teachings of multiple references, one must consider whether the combination
`
`yields no more than predictable results or achieves an unexpected result.
`
`17.
`
`I have also been informed and understand that, in determining whether
`
`or not a patented invention would have been obvious, the following factors must be
`
`considered: the scope and content of the prior art, the differences between the prior
`
`art and the claims at issue, the level of ordinary skill in the art, and whatever
`
`objective indicia of non-obviousness may be present.
`
`III.
`
`STATEMENTS OF OPINIONS EXPRESSED AND BASES AND
`REASONS THEREFOR
`U.S. Patent No. 8,293,742
`18. Although I have not been asked to opine on validity in this matter, I
`
`have reviewed U.S. Patent No. 8,293,742 (“the ’742 patent”). Generally speaking,
`
`the ’742 patent claims, inter alia, methods for reducing eye redness. I understand
`
`Eye Therapies Exhibit 2022, 8 of 73
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`that other experts will describe the state of the art relevant to their expertise and
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`opine on the validity of the patent. I understand that the relevant priority date is
`
`August 1, 2008.
`
`A Person of Ordinary Skill in the Art
`I understand that Dr. Noecker will explain that the field to which the
`
`19.
`
`’742 patent pertains is interdisciplinary. Thus, I understand that Dr. Noecker will
`
`explain 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. I further understand that
`
`Dr. Noecker will explain that a person of 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 formulations, and/or in
`
`administering ophthalmic formulations to treat ocular conditions obtained by some
`
`combination of education and work experience. As an example, the person of
`
`ordinary skill would have had access to a chemist.
`
`20.
`
`I understand that Dr. Noecker will explain that the medical doctor is a
`
`specialist in treating diseases of the eye, such as an optometrist or ophthalmologist,
`
`with three to four years of experience, who also has experience designing and
`
`running clinical trials on ophthalmic formulations. I understand that Dr. Williams
`
`will explain that the pharmaceutical formulator had a Bachelor’s degree in
`
`Eye Therapies Exhibit 2022, 9 of 73
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`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.
`
`21.
`
`In light of the above, I understand that Dr. Noecker will explain that 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 also work in collaboration with other scientists
`
`and/or clinicians who have experience with chemistry; developing, designing, and/or
`
`evaluating ophthalmic formulations; administering ophthalmic formulations;
`
`running clinical trials related to such formulations; and/or treating patients using
`
`such formulations.
`
`22.
`
`I understand that the Petitioner contends that “[a] POSA was a
`
`composite person (or team) that included a medical doctor and a pharmaceutical
`
`formulator.” (Petition at § I.C.) I understand that the Petitioner further contends that
`
`“[t]he medical doctor was an ophthalmologist with at least three to four years of
`
`experience in LASIK surgery, clinical trials and U.S. FDA regulation of eye
`
`products, and had experience in the use of topical brimonidine and apraclonidine and
`
`topical vasoconstrictors such as naphazoline and tetrahydrozoline” and that “[t]he
`
`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
`
`clinical trial and regulatory approval.” (Id.)
`
`23. Regardless of which definition applies, the theoretical POSA would
`
`have had access to a team with relevant experience, which includes medicinal
`
`chemistry and organic chemistry. My opinions expressed herein would not change
`
`regardless of which definition is applied.
`
`Claim Construction
`I understand that the Petitioner contends that the following phrases
`
`24.
`
`require construction:
`
`Claim Term/Phrase Claims
`“about 0.025%”
`2, 3
`“ocular condition”
`1, 3
`
`(See Petition at §§ III.B, III.C.)
`
`25.
`
`I understand that the Petitioner contends that the phrase “about 0.025%”
`
`includes 0.03%. (See Petition at § III.B.) I understand that Patent Owner’s other
`
`experts will explain that “about” means “plus or minus 10%,” and that “about
`
`0.025%” would not encompass 0.03%.
`
`26.
`
`I understand that the Petitioner contends that the term “ocular
`
`condition” would be understood “to include, without limitation: eye redness;
`
`glaucoma (including open-angle glaucoma); elevated intraocular pressure, also
`
`known as ocular hypertension; postoperative reduction of subconjunctival
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`hemorrhage and hyperemia after refractive surgery such as LASIK and radial
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`keratotomy; subconjunctival hemorrhage and hyperemia prophylaxis prior to
`
`refractive surgery such as LASIK and radial keratotomy; and redness in the eye
`
`following LASIK or radial keratotomy.” (Petition at § III.C; EX-1002 (Sher Decl.)
`
`at ¶ 47.) I understand that Dr. Noecker will respond to this position.
`
`Technical Tutorial
`1.
`Different Chemical Compounds Have Different
`Characteristics
`27. As of the August 1, 2008, priority date for the ’742 patent, and still
`
`today, one basic scientific premise remains: Different chemical compounds have
`
`different physical, chemical, and biological properties, and they must be tested to
`
`determine how they behave in vivo. This is a concept I have taught in my
`
`undergraduate chemistry courses for decades and still teach in tutorials today, and a
`
`concept that would have been well understood by a POSA.
`
`28. Many factors affect a compound’s biological activity, for example
`
`lipophilicity/hydrophobicity, lipophobicity/hydrophilicity, three-dimensional shape,
`
`hydrogen-bonding capability (including number and sites of hydrogen-bond donors
`
`and receptors), electronic structure, and the number (and type) of heteroatoms.
`
`29. Although many have tried to predict a priori how a particular
`
`compound will act in vivo, the reality is that as of August 2008 and even today,
`
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`testing is required. That is precisely why preclinical and clinical studies are done.
`
`If chemists were able to perfectly design a molecule for an intended purpose with
`
`any sort of certainty, we would not exist in the world we do: Agencies like FDA
`
`would not need to mandate clinical trial testing; diseases would not be left uncured;
`
`preclinical and clinical trials would not fail. But the reality is, even today, to
`
`determine a molecule’s activity in vivo, you must run the test.
`
`Chemistry of Brimonidine
`2.
`The two-dimensional chemical structure of brimonidine is provided
`
`30.
`
`below:
`
`Figure 1. Two-dimensional structure of brimonidine (depicted as free base).
`
`31. Chemically, brimonidine includes various defined chemical elements:
`
`It is a 2-imidazoline derivative, with the imidazoline substituent depicted in red
`
`above. But, importantly, it contains a secondary amine (NH) component highlighted
`
`in blue above, linked at the “2” position of the imidazoline substituent, putting it in
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`Eye Therapies Exhibit 2022, 13 of 73
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`a class of compounds known as aminoimidazolines.1 From a chemical perspective,
`
`it is more correct to call brimonidine an aminoimidazoline derivative than a 2-
`
`imidazoline derivative, and this distinction has implications for the biological
`
`activity of the drug.
`
`32.
`
`Importantly, the secondary amine component makes the imidazoline
`
`ring part of a guanidinium functional group. From a chemical perspective, this
`
`means the uncharged form of brimonidine exists as a pair of tautomers. This is
`
`particularly relevant, as it is a functional group known to be versatile and unique in
`
`terms of hydrogen bonding and electrostatic interactions in biological systems. (See
`
`EX-2040 (de Mendoza 2007) at 198.)
`
`33. Moreover, brimonidine contains a heterocyclic fused bicyclic ring—
`
`specifically, a quinoxaline substituent, circled in black above, with a bromine located
`
`on the ortho position of the structure, and the aminoimidazoline group located at the
`
`meta position. This substituent is also known to be particularly susceptible to N-
`
`oxidation on either or both quinoxaline nitrogens, resulting in degradation.
`
`1 This is specifically acknowledged by Dr. Laskar’s own reference, Griffith 2003 at
`
`page 3, Table 1.1, which describes brimonidine as an aminoimidazoline, but
`
`describes naphazoline and tetrahydrozoline (among others) as imidazolines. (See
`
`EX-1016 (Griffith 2003) at 3, Table 1.1.)
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`3.
`The
`
`Chemistry of Naphazoline and Tetrahydrozoline
`two-dimensional chemical structures of naphazoline and
`
`34.
`
`tetrahydrozoline are provided below:
`
`Figure 2. Two-dimensional structures of naphazoline (left) and tetrahydrozoline
`(right) (depicted as free bases).
`
`35. Chemically, these two compounds share a number of characteristics:
`
`They are both 2-imidazoline derivatives, with the imidazoline substituent
`
`highlighted in red above. But naphazoline and tetrahydrozoline differ from
`
`brimonidine in a number of respects. For example, neither is an aminoimidazoline
`
`and neither contains a guanidinium functional group.
`
`36. Both naphazoline and tetrahydrozoline also contain bicyclic, carbocylic
`
`substituents shown in black above. Naphazoline, however, contains a 1-naphthyl-
`
`methylene group, while tetrahydrozoline contains a 1-tetralinyl group. On both of
`
`these molecules, the imidazoline group is located on the 1-position of the carbocylic
`
`ring (corresponding to the ortho position on brimonidine’s ring structure), and there
`
`is no corresponding 2-position substitution (which would correspond to the meta
`
`position on brimonidine’s ring structure).
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`37.
`
`In terms of binding affinity, in hindsight, it is not surprising that
`
`naphazoline and tetrahydrozoline behave somewhat similarly: both have the 2-
`
`imidazoline substituent (i.e., one hydrogen-bond donor and one hydrogen-bond
`
`acceptor), and both have a carbocylic ring.
`
`4.
`
`Three Dimensional Structures of Brimonidine,
`Naphazoline, and Tetrahydrozoline
`Looking at the two-dimensional structure of a compound provides
`
`38.
`
`some information about a given molecule—but it generally ignores the three-
`
`dimensional shape of the molecule and its flexibility (or lack thereof). Below are
`
`three-dimensional depictions of brimonidine, naphazoline, and tetrahydrozoline,
`
`both in the plane of the page, as well as at about 90° to the plane of the page.
`
`Eye Therapies Exhibit 2022, 16 of 73
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`Figure 3. Three-dimensional depictions of brimonidine, naphazoline, and
`tetrahydrozoline, using Chem3D minimized structure.
`
`39. Here, the three-dimensional structures show that naphazoline and
`
`tetrahydrozoline have similar structures, with their imidazoline rings freely rotating,
`
`more or less perpendicular to their carbocylic rings. By contrast, brimonidine is
`
`relatively flat—it has a nitrogen lone pair that is conjugated to both the imidazoline
`
`ring and the quinoxaline ring, giving it a relatively high barrier for rotation (meaning
`
`Eye Therapies Exhibit 2022, 17 of 73
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`that
`
`its
`
`imidazoline ring
`
`is not freely rotating, as
`
`in naphazoline and
`
`tetrahydrozoline).
`
`Additional Selected Compounds
`5.
`I understand that in addition to naphazoline and tetrahydrozoline, the
`
`40.
`
`compounds oxymetazoline, clonidine, and apraclonidine are relevant to this matter.
`
`I provide the structure of each, as well as the three-dimensional depictions of each,
`
`both in the plane of the page, as well as at about 90° to the plane of the page, below:
`
`HN
`
`N
`CH3
`
`H3C
`
`HO
`
`H3C
`
`CH3
`CH3
`
`Oxymetazoline
`
`HN
`
`HN
`
`N
`Cl
`
`Cl
`
`HN
`
`HN
`
`N
`Cl
`
`Cl
`
`NH2
`
`Apraclonidine
`
`Clonidine
`
`Figure 4. Two-dimensional structures (depicted as free bases).
`
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`Figure 5. Three-dimensional depictures of oxymetazoline, apraclonidine, and
`clonidine, using Chem3D minimized structure.
`
`41.
`
`Similar
`
`to
`
`brimonidine,
`
`apraclonidine
`
`and
`
`clonidine
`
`are
`
`aminoimidazoline compounds, with both containing a guanidinium moiety. By
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`Eye Therapies Exhibit 2022, 19 of 73
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`contrast, like tetrahydrozoline and naphazoline, oxymetazoline is an imidazoline—
`
`not an aminoimidazoline—and has no guanidinium moiety.
`
`Response to Dr. Laskar’s Section Entitled “2-Imidazoline
`Derivatives Were Known as Vasoconstrictors for Reducing
`Eye Redness”
`42. Dr. Laskar’s declaration includes a section entitled “2-Imidazoline
`
`Derivatives Were Known as Vasoconstrictors for Reducing Eye Redness,” wherein
`
`he provides chemical structures of brimonidine, naphazoline, and tetrahydrozoline,
`
`and broadly alleges that because they are each “2-imidazoline derivatives with a
`
`bicyclic substituent,” “a POSA had a reasonable expectation that brimonidine was a
`
`vasoconstrictor compound that could be used to reduce redness in the eye.” (See
`
`EX-1003 (Laskar Decl.) at ¶ 36.) Dr. Laskar’s chemical assumptions are wrong, and
`
`a POSA with access to a chemist would know this.
`
`43. As an initial matter, there are nearly infinite permutations of “2-
`
`imidazoline derivatives with a bicyclic substituent.” Assuming, as Dr. Laskar
`
`contends, that naphazoline and tetrahydrozoline were known to reduce eye redness
`
`and that a POSA was interested in finding a structurally similar compound as an
`
`alternative redness reliever, he would not look to brimonidine. Rather, if a POSA
`
`were interested in using “2-imidazoline derivatives with a bicyclic substituent,”
`
`based on his experience with naphazoline and tetrahydrozoline, he would likely aim
`
`to find a molecule that retained a simple hydrogen bond donor-acceptor group (i.e.,
`
`Eye Therapies Exhibit 2022, 20 of 73
`Slayback v. Eye Therapies - IPR2022-00142
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`
`
`one hydrogen-bond donor and one hydrogen-bond acceptor) and a
`
`lipophilic/hydrophobic hydrocarbon moiety.2 In addition, from a three-dimensional
`
`shape perspective, he would likely seek to retain a similar conformation—i.e., a flat
`
`moiety attached to a freely rotating substituent.3 Put simply, if, as Dr. Laskar
`
`contends, a POSA would believe that the key to producing a vasoconstrictor that
`
`could be used to treat eye redness was to follow the chemistry of naphazoline or
`
`tetrahydrozoline, there are a multitude of chemical modifications that he would be
`
`interested in making that would not land him at brimonidine. Indeed, Dr. Laskar’s
`
`2 In contrast, as explained above, brimonidine has two hydrogen-bond donors and
`
`three hydrogen-bond
`
`acceptors; moreover,
`
`there
`
`is no particularly
`
`lipophilic/hydrophobic moiety in brimonidine, as the bicyclic ring structure includes
`
`heteroatoms (nitrogen), and a bromide substituent, making it less lipophilic, as
`
`compared to the carbocylic ring structure of naphazoline and tetrahydrozoline.
`
`3 In contrast, brimonidine is relatively flat—as explained above, given that it is an
`
`aminoimidazoline, its exocyclic nitrogen lone pair is conjugated to both of its ring
`
`structures, which means it has a relatively high barrier for rotation. If brimonidine
`
`were modified to be a true 2-imidazoline (rather than an aminoimidazoline), it would
`
`have a freely rotating moiety, more in line with the three-dimensional structures of
`
`naphazoline and tetrahydrozoline.
`
`Eye Therapies Exhibit 2022, 21 of 73
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`own reference supports this, as Griffith 2003 highlights the one-carbon bridge
`
`between C-2 of the imidazoline ring and a phenyl substituent as a common feature
`
`of the various vasoconstrictors identified therein. (See EX-1016 (Griffith 2003) at
`
`31.)
`
`44.
`
`In any event, Dr. Laskar’s broad statement—effectively that all “2-
`
`imidazoline derivatives with a bicyclic substituent” would be vasoconstrictors that
`
`could be used to treat eye redness, on the basis that two members of the class may
`
`do so—is unsupportable. To start, Dr. Laskar selectively focuses on the structural
`
`commonality among these molecules as the premise for his argument. (See, e.g.,
`
`EX-1003 (Laskar Decl.) at ¶¶ 36-37.) But Dr. Laskar’s science is a flawed
`
`oversimplification—it is not one moiety that controls the behavior of a compound in
`
`vivo, rather, it is the whole compound that matters—its shape, its electron density
`
`profile, its hydrophobicity/lipophilicity, and hydrogen bonding capability, among
`
`other things. (See § III.D.1, supra.)
`
`45. Additionally, Dr. Laskar’s own reference undercuts the basis for his
`
`opinions. For example, he entirely ignores that certain similarly substituted “2-
`
`imidazoline derivatives” are alpha-antagonists (e.g., which would block the given
`
`receptor, without activation), rather than alpha-agonists (e.g., which would activate
`
`the given receptor, like brimonidine). For example, Griffith 2003 identifies
`
`phentolamine as another example of a similarly substituted 2-imidazaoline
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`Eye Therapies Exhibit 2022, 22 of 73
`Slayback v. Eye Therapies - IPR2022-00142
`
`
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`derivative, but phentolamine is an alpha-antagonist. (EX-1016 (Griffith 2003) at
`
`9.) By Dr. Laskar’s argumentation, a POSA should have had a reasonable
`
`expectation that phentolamine (a 2-imidazoline derivative) was a vasoconstrictor
`
`compound that could be used to reduce redness in the eye. (See EX-1003 (Laskar
`
`Decl.) at ¶ 37 (“The fact that brimonidine was a 2-imidazoline derivative gave a
`
`POSA a reasonable expectation that brimonidine was a vasoconstrictor that could be
`
`used to treat redness in the eye.”).) But in reality, phentolamine is a similarly
`
`substituted 2-imidazoline derivative that blocks the receptor (as an antagonist) rather
`
`than activating it (as an agonist). Dr. Laskar has not addressed this at all.
`
`46. Moreover, Dr. Laskar’s selective focus on “2-imidazoline derivatives”
`
`and specifically “2-imidazoline derivatives with a bicyclic substituent” ignores the
`
`overarching teachings of Griffith 2003, his own reference. For example, Griffith
`
`2003 explicitly states that “alpha-adrenoceptors accommodate a far more diverse
`
`assortment of structures [than beta-agonists][,]” and goes on to describe a variety of
`
`compounds accommodated by the receptors, which are not limited to “2-imidazoline
`
`derivatives with bicyclic substituents,” fused or not. (See EX-1016 (Griffith 2003)
`
`at 30-31.)
`
` Indeed, Griffith 2003 describes naphazoline, tetrahydrozoline,
`
`oxymetazoline (a 2-imidazoline with a single aromatic ring), xylometazoline (a 2-
`
`imidazoline with a single aromatic ring) as imidazolines and vasoconstrictors (See
`
`id. at 31.) It explicitly states that these compounds “are selective alpha-1-agonists
`
`Eye Therapies Exhibit 2022, 23 of 73
`Slayback v. Eye Therapies - IPR2022-00142
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`
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`and thus are vasoconstrictors,” and goes on to emphasize the fact that they “all
`
`contain a one-carbon bridge between C-2 of the imidazoline ring and a phenyl
`
`substituent; thus the general skeleton of a phenylethylamine is contained within the
`
`structures.” (See id.) But Dr. Laskar fails to take into account Griffith 2003’s own
`
`teaching about the structural features of a vasoconstrictor and fails to mention
`
`oxymetazoline or xylometazoline (or structures related thereto) as potential options
`
`for a POSA.
`
`47. Dr. Laskar also states that Griffith 2003 “describe[s] brimonidine as
`
`‘[c]losely related to the imidazoline α1-agonists” to support his obviousness
`
`argument. (EX-1003 (Laskar Decl.) at ¶ 35.) This is taken out of context. Griffith
`
`2003 does, in fact, describe aminoimidazolines as being closely related to
`
`imidazolines—which, chemically, they are—but that does not mean that
`
`aminoimidazolines would behave the same way as an imidazoline, in vivo, which
`
`Griffith 2003 itself acknowledges. In fact, Griffith 2003 describes alpha-1 agonists
`
`as generally being vasoconstrictors, but states that brimonidine has “properties
`
`similar to those of alpha-2 agonists.” (See EX-1016 (Griffith 2003) at 31 (emphasis
`
`added).) And Griffith 2003 does not selectively focus on brimonidine; rather, it
`
`describes a number of compounds within the aminoimidazoline class as being
`
`“closely related” to the imidazolines, stating “[c]losely related to the imidazoline α1-
`
`agonists are the aminoimidazolines, clonidine (35), apraclonidine (33), brimonidine
`
`Eye Therapies Exhibit 2022, 24 of 73
`Slayback v. Eye Therapies - IPR2022-00142
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`
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`(34); and the structurally similar guanidines, guanabenz (36) and guanfacine (37).”
`
`(Id.)
`
`48. Griffith 2003 also makes clear that these molecules have notable
`
`differences in activity. For example, it states that “[t]he other imidazolines,
`
`[apraclonidine] (33) and [brimonidine] (34), were synthesized as analogues of
`
`[clonidine] (35) and were discovered to hav
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