Inter Partes Review
`United States Patent No. 8,293,742
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SLAYBACK PHARMA LLC
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`Petitioner
`v.
`EYE THERAPIES, LLC
`
`Patent Owner
`
`Patent No. 8,293,742
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`
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`Case No. IPR2021-Unassigned
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`
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`DECLARATION OF PAUL A. LASKAR, PH.D.
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`SLAYBACK EXHIBIT 1003
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`Inter Partes Review
`United States Patent No. 8,293,742
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`TABLE OF CONTENTS
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`Page
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`I. 
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`QUALIFICATIONS AND BACKGROUND ................................................. 4 
`A. 
`Education and Experience ..................................................................... 4 
`B.  Materials Considered ............................................................................. 6 
`C. 
`Scope of Work, Compensation .............................................................. 7 
`D. 
`Testimony as Expert in Last Four Years ............................................... 7 
`LEGAL STANDARDS ................................................................................... 8 
`II. 
`PERSON OF ORDINARY SKILL IN THE ART (POSA) .......................... 10 
`III. 
`IV.  BACKGROUND TO THE ‘742 PATENT ................................................... 11 
`A. 
`The Use of Vasoconstrictor Eye Drops to Reduce Eye Redness Was
`a Well Established Field ...................................................................... 11 
`2-Imidazoline Derivatives Were Known as Vasoconstrictors for
`Reducing Eye Redness ........................................................................ 12 
`Brimonidine Was Known to Be a Potent Vasoconstrictor With
`Favorable Properties for an Eye Redness Reducer ............................. 13 
`Brimonidine Was Approved in 1996 for Use in Eye Drops ............... 14 
`Prior Art Discloses “Low Concentrations” of Brimonidine ............... 16 
`The Prior Art Disclosed Brimonidine Eye Drops With a pH of 6.3 to
`6.5 ........................................................................................................ 17 
`V.  U.S. PATENT 8,293,742 ............................................................................... 18 
`A. 
`Excerpts from the Specification of the ‘742 Patent ............................ 18 
`Summary of the Present Invention ............................................ 18 
` 
`Background of the Invention .................................................... 18 
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`B. 
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`C. 
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`D. 
`E. 
`F. 
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`“Brimonidine” Is Defined Broadly ........................................... 19 
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`VI.  CLAIM CONSTRUCTION .......................................................................... 20 
`A. 
`“0.03%” Is Included in “about 0.025%” ............................................. 20 
`VII.  OPINIONS FROM THE PERSPECTIVE OF A FORMULATOR .............. 26 
`A. 
`Certain Publications Relied on by Dr. Sher ........................................ 26 
`The ‘553 Patent ......................................................................... 26 
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`  Walters 1991 ............................................................................. 28
`3.
`Pasquali 2013 ……………………………………………… 33
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`B. 
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`C. 
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`Alphagan® Label 1998 ............................................................. 33 
`Scruggs 2000 ............................................................................. 33 
`Federal Register 1988 ............................................................... 34 
`Derick 1997 ............................................................................... 34 
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`A POSA Was Motivated to Formulate at a pH between about 5.5 and
`about 6.5 .............................................................................................. 35 
`It Was Routine for a POSA to Formulate Brimonidine Ocular Drops
`at Any Concentration Between 0.001% and 0.05% and at Any pH
`between about 5.5 and about 6.5 ......................................................... 36 
`D.  Dose Ranging ...................................................................................... 37 
`E. 
`A Proper Comparison to the Prior Art Would Be to the “0.03%”
`Brimonidine in Example 1 of the ‘553 Patent or to the 0.02%
`Brimonidine in Walters 1991 .............................................................. 38 
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`Inter Partes Review
`United States Patent No. 8,293,742
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`1.
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`I, Paul A. Laskar, Ph.D., have been retained by counsel for Petitioner
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`Slayback Pharma LLC (Petitioner or Slayback). I understand that Petitioner seeks
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`inter partes review (“IPR”) of U.S. Patent 8,293,742 (EX-1001, ‘742 patent),
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`assigned to Eye Therapies, LLC (Patent Owner), to request that the United States
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`Patent and Trademark Office cancel claims 1-6 of the ‘742 patent as unpatentable. I
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`submit this expert declaration in support of Petitioner’s IPR Petition for the ‘742
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`patent.
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`I.
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`QUALIFICATIONS AND BACKGROUND
`A. Education and Experience
`2.
`I am currently President and Principal Consultant with Paul Laskar
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`Associates, Inc.
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`3.
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`In 1965 I received a B.A. in General Science (Chemistry, Biology) from
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`University of Rochester.
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`4.
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`In 1968 I received a B.S. in Pharmacy from University of Illinois –
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`Medical Center.
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`5.
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`In 1971 I received an M.S. in Pharmacy from University of Illinois –
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`Medical Center.
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`United States Patent No. 8,293,742
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`6.
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`In 1974 I completed my Ph.D. in Pharmaceutical Sciences at Oregon
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`State University with a minor in Biostatistics.
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`7.
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`In 1988 I received an MBA from University of California at Irvine,
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`(General Management, International Management, Marketing).
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`8.
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`Following completion of my graduate work, I taught for about nine
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`years at two colleges of pharmacy, University of Illinois-Chicago Campuses and
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`Creighton University. In late 1982, I joined Allergan as a formulation scientist
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`where I advanced ultimately to Director of Product Development in Allergan’s
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`dermatology business group, Herbert Laboratories. In this capacity, I was involved
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`in CMC (chemistry, manufacturing, and controls) activities for Allergan’s beta-
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`blocker ophthalmic as well as other ophthalmic products as well as their first topical
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`retinoid.
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`9.
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`I then joined CoCensys where I led the CMC efforts for two successful
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`INDs, one for a parenteral and the other for an oral liquid. In 1994, I joined Santen
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`Inc, the U.S. subsidiary of a leading Japanese specialty company, Santen LTD.
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`There I led the pharmaceutical development department which during my tenure
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`resulted in four successful NDAs and formulation of Santen’s first prostanoid
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`product for glaucoma.
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`United States Patent No. 8,293,742
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`10. After leaving Santen, I joined Dey LP, a nebulization and nasal
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`specialty company where I led their pharmaceutical development department for
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`about three years during which time I led the CMC activities to a successful NDA
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`filing.
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`11.
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`I then established a consulting business. During the course of the
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`approximately fifteen years I have been consulting, I have aided clients in a number
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`of dermatology, ophthalmology, oral, inhalation, and other projects beginning at
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`proof of concept to NDA/ANDA filing and approval. I have assisted clients in
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`identifying development strategies, both from scientific and regulatory perspectives;
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`identified and monitored CROs and CMOs; written, contributed to, and edited CMC
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`sections of regulatory submissions from INDs to NDAs; and served as CMC
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`representative in various FDA meetings ranging from PIND to pre-NDA.
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`12.
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`[not used]
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`13. A copy of my curriculum vitae, which further details my qualifications
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`and experience, is attached as Exhibit A to this Report.
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`B. Materials Considered
`14.
`In forming my opinions set forth in this Declaration, I considered and
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`relied upon my education, background, and years of experience in the practice of
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`Pharmaceutics, as well as the materials identified in this Declaration. The materials
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`considered are listed in Exhibit C. One of the listed materials that I considered is
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`the Declaration of Neal A. Sher, M.D. (EX-1002, Sher), an expert in ophthalmology
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`and refractive surgery.
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`C. Scope of Work, Compensation
`15.
`I have been retained by counsel for Petitioner in connection with this
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`matter. I am being compensated for my consulting work at the rate of $300 per hour,
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`except deposition preparation and deposition at $375/hour. My compensation in this
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`case is in no way dependent on the outcome of this matter.
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`16.
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`I reserve the right to supplement or modify my opinions and to offer
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`additional testimony rebutting any evidence or arguments advanced by Patent
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`Owner, its experts, or any other witness, and to comment on any declarations and/or
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`other evidence submitted in connection with this matter.
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`D. Testimony as Expert in Last Four Years
`17. Exhibit B to this Declaration is a list of the case where I have testified
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`at deposition and/or trial since October 2017.
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`II. LEGAL STANDARDS
`18.
`I have been informed by counsel for Petitioner of certain legal standards
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`and I have applied these standards in rendering my opinions.
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`19. When I say in this Declaration “I understand,” I mean that “I understand
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`from counsel for Petitioner in this IPR.”
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`20.
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`I understand that to prove anticipation or obviousness, it is a
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`Petitioner’s ultimate burden to prove anticipation or obviousness by a preponderance
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`of the evidence, which means more probable than not.
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`21.
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`I understand that the question of whether the claims of a patent are
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`anticipated or obvious is considered from the perspective of a person of ordinary
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`skill in the art (POSA).
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`22.
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`I understand that whether a patent claim is anticipated or obvious is
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`ascertained at the relevant time period, which in this IPR I understand to mean before
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`August 1, 2007.
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`23.
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`I understand that an obviousness analysis involves ascertaining the
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`scope and content of the prior art, the background and experience of a POSA, the
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`differences between the claimed invention and the prior art and whether there are
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`additional factors present that may nevertheless weigh against obviousness such as
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`unexpected results attributable to the invention actually claimed.
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`24.
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`I understand that under the existing law, in assessing obviousness when
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`there is a design need or market pressure to solve a problem, a POSA has good reason
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`to pursue the known options within his or her technical grasp. If this would lead to
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`the claimed invention with a reasonable expectation of success, it is likely the
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`product not of innovation but of ordinary skill and common sense. The fact that a
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`combination of elements was obvious to try can show that it was obvious.
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`25.
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`I understand that a prior art reference anticipates a patent claim if the
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`prior art reference discloses subject matter within the scope of the claim, with all of
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`the claim limitations.
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`26.
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`I understand that claim elements can be disclosed in the prior art either
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`expressly or inherently. In assessing anticipation, a claim element is inherent in a
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`reference if that element, or characteristic, is the natural result that flows from the
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`reference’s disclosure.
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`27.
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`In assessing obviousness, a claim element is inherent when it is the
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`natural result that flows from what is otherwise obvious.
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`III. PERSON OF ORDINARY SKILL IN THE ART (POSA)
`28.
`I understand that a person of ordinary skill (POSA) is a hypothetical
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`person possessing the education, training, experience, skill and knowledge of the
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`ordinary practitioner in the field of an alleged invention, is presumed to know the
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`relevant art at the relevant time (in this IPR before August 1, 2007), and can rely on
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`the knowledge and skill of others if it was ordinary to do so. A POSA is not an
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`automaton and would employ the inferences and creative steps of a person in the
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`relevant field.
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`29.
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`In my opinion, with respect to claims 1-6 of the ‘742 patent, a POSA
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`was a composite person (or a team) that included a pharmaceutical formulator and a
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`medical doctor. The pharmaceutical formulator had a doctorate in pharmaceutics or
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`a related degree and at least three to five years of experience developing ocular drop
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`formulations (commonly referred to as eye drops) for clinical trial and regulatory
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`approval. I rely on Dr. Sher’s opinion that the medical doctor was an
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`ophthalmologist with at least three to four years of experience in LASIK surgery and
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`at least three to four years of experience in clinical trials and U.S. FDA regulation
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`of products for the eye and that the medical doctor was an ophthalmologist with
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`experience in the use of topical bromonidine and apraclonidine and topical
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`vasoconstrictors such as naphazoline tetrahydrozoline. EX-1002, Sher, ¶26
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`IV. BACKGROUND TO THE ‘742 PATENT
`30. The ‘742 patent relates to the field of using vasoconstrictor ocular drops
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`to reduce redness in the eye. Ocular drops are commonly referred to as eye drops.
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`Claims 1-6 of the ‘742 patent relate to using brimonidine as the vasoconstrictor
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`compound in a method to reduce eye redness.
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`A. The Use of Vasoconstrictor Eye Drops to Reduce
`Eye Redness Was a Well Established Field
`31. The use of vasoconstrictor-based eye drops to reduce eye redness was
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`a well-established field. For example, in 1988 the U.S. FDA required the label for
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`over-the-counter (OTC) vasoconstrictor eye drops to identify the product as a
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`“redness reliever.” EX-1009, Federal Register 1988, p. 7092.
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`B. 2-Imidazoline Derivatives Were Known as
`Vasoconstrictors for Reducing Eye Redness
`32. Compounds known as “2-imadazoline derivatives” take their name
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`from an imidazoline moiety (shown in red) that is substituted at the 2- position:
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`2-Imidazoline
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`33. Going back to at least the 1980’s, naphazoline and tetrahydrozoline
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`
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`were well-known 2-imidazoline derivatives used as vasoconstrictor compounds in
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`over the counter redness reducing eye drops. Federal Register 1988 (EX-1009, p.
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`7089). Like naphazoline and tetrahydrozoline, brimonidine is a 2-imidazoline
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`derivative:
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` Naphazoline Brimonidine Tetrahydrozoline
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`34. Timmermans 1980 (EX-1015) shows the structure of naphazoline and
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`tetrahydroziline (“tetryzoline”) in Fig. 34 at p. 30. Timmermans 1980 shows the
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`structure of brimonidine (“UK-14,304-18”) in Fig. 31 at p. 28. Timmermans 1980
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`(p. 1) discusses the use of imidazoline derivatives “in practical pharmacotherapy” as
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`vasoconstrictors that “can temporarily relieve the unpleasant symptoms of rhinitis
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`or conjunctivitis, as a result of vasoconstriction within the congested tissues.” I rely
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`on Dr. Sher’s opinion that the classic symptom of conjunctivitis is a red eye. EX-
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`1002, Sher, ¶28
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`35. Griffith 2003
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`(EX-1016, p. 13) describes naphazoline and
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`tetrahydrozoline as imidazoline α1-agonists “widely employed as vasoconstrictors
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`for treating [] bloodshot eyes.” Griffith 2003 (p. 31) goes on to describe brimonidine
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`as “Closely related to the imidazoline α1-agonists.”
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`36. Because brimonidine is a 2-imidazoline derivative with a bicyclic
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`substituent similar to the bicyclic substituents in naphazoline and tetrahydrozoline,
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`a POSA had a reasonable expectation that brimonidine was a vasoconstrictor
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`compound that could be used to reduce redness in the eye.
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`C. Brimonidine Was Known to Be a Potent Vasoconstrictor
`With Favorable Properties for an Eye Redness Reducer
`37. The fact that brimonidine was a 2-imidazoline derivative gave a POSA
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`a reasonable expectation that brimonidine was a vasoconstrictor that could be used
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`to treat redness in the eye. I rely on Dr. Sher’s opinion that the prior art described
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`brimonidine as a “potent” vasoconstrictor compound. EX-1002, Sher, ¶31.
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`38.
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`I also rely on Dr. Sher’s opinion that in addition to teaching brimonidine
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`was a vasoconstrictor, the prior art taught that brimonidine caused vasoconstriction
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`primarily in the front (anterior) part of the eye but not the posterior. EX-1002, Sher,
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`¶32.
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`39. A POSA considered brimonidine’s site specific vasoconstrictor activity
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`an important property for an eye redness reducer because, to reduce eye redness,
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`vasoconstriction is only needed in the front part of the eye and not desirable in the
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`posterior portion of the eye. EX-1002, Sher, ¶33.
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`D. Brimonidine Was Approved in 1996 for Use in Eye Drops
`40. Because the eye is delicate and sensitive, and eyesight is so important
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`to quality of life, not all chemical compounds are suitable for the eye. For this
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`reason, at all relevant times the U.S. FDA has been especially careful about the
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`chemicals it would approve for use in topical eye drops. Brimonidine was approved
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`by the U.S. FDA as Alphagan® for use in topical eye drops in 1996, with 30 million
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`units dispensed in the four years following its introduction in 1996. David 2001
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`(EX-1021, p. S72).
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`41.
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`I rely on Dr. Sher’s opinion that brimonidine was considered to be safe,
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`well-tolerated, and with a low rate of allergic response. EX-1002, Sher, ¶35.
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`42. Even though the prior art approval of brimonidine eye drops (i.e.
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`Alphagan®) was to lower intraocular pressure in open angle glaucoma or ocular
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`hypertension and not to reduce eye redness (EX-1008, Alphagan® Label 1998), U.S.
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`FDA approval of brimonidine for use in the eye, and more than a decade of use from
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`1996 to August 2007, gave a POSA confidence that brimonidine could be used safely
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`in a topical eye drop.
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`43. Therefore, before August 1, 2007 there were excellent reasons why a
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`POSA had a reasonable expectation that brimonidine could be used as the redness
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`relieving vasoconstrictor in a topical eye drop:
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`a) 2-imidazoline derivatives had been in commercial use for decades
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`as vasoconstrictor compounds in redness reducing topical eye drops;
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`b) brimonidine was a 2-imidazoline derivative and was known to be a
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`potent vasoconstrictor;
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`c) brimonidine was known to exert its vasoconstrictor activity on the
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`front but not the back portion of the eye;
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`d) brimonidine was approved by the U.S. FDA for use in a topical eye
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`drop for over ten years;
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`e) brimonidine was considered to be safe, well tolerated and with a low
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`rate of allergic response; and
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`f) it had been reported that brimonidine drops dripping from the eye
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`caused “blanching,” i.e. whitening, of the skin on the cheeks
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`(Scruggs 2000 (EX-1023, p. 671)), further suggesting to a POSA
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`that brimonidine could be used to reduce redness in the eye.
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`E. Prior Art Discloses “Low Concentrations” of Brimonidine
`44. According to the ‘742 patent, the “invention generally relates” to using
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`vasoconstrictor compounds at “low concentrations.” ‘742 patent (EX-1001,
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`Abstract).
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`45. The Abstract of the ‘742 patent, indicates that “low concentrations”
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`includes “below 0.05% weight by volume.”
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`46. Under the heading “Definitions,” the ‘742 patent (3:58-65) defines
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`“low concentrations” as follows:
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`The term ‘low concentrations’ refers to concentrations
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`from between about 0.0001% to about 0.05% . . .weight by
`volume.
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`47. Therefore, “low concentrations”
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`in
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`the ‘742 patent
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`includes
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`concentrations from between about 0.0001% to about 0.05% weight by volume.
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`48. Example 1 of the ‘553 patent (EX-1004), discussed infra, discloses
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`administering brimonidine drops at a concentration of 0.03% weight by volume to
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`patients undergoing radial keratotomy.
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`49. Walters 1991 (EX-1005), discussed infra, discloses administering
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`brimonidine drops at a concentration of 0.02% weight by volume to patients with
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`open-angle glaucoma or ocular hypertension.
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`50. Thus, the ‘553 patent (EX-1004) and Walters 1991 (EX-1004) both
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`disclose the administration of brimonidine that meets the ‘742 patent’s definition of
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`“low concentration.”
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`F. The Prior Art Disclosed Brimonidine
`Eye Drops With a pH of 6.3 to 6.5
`pH is a consideration in eye drops. Claims 3, 4 and 6 of the ‘742 patent
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`51.
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`require the brimonidine to be formulated as an ocular drop with a pH of “between
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`about 5.5 and about 6.5.” Brimonidine eye drops with pH 6.3 to 6.5 were published
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`in Alphagan Label® 1998 (EX-1008), discussed infra.
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`V. U.S. PATENT 8,293,742
`A. Excerpts from the Specification of the ‘742 Patent
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`Summary of the Present Invention
`51.b The ‘742 patent states: “The present invention is generally related to
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`compositions and methods for inducing vasoconstriction.” ‘742 patent (EX-1001,
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`Summary of the Present Invention, 2:37-38).
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`Background of the Invention
`In the first paragraph under “Background of the Invention,” the ‘742
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`52.
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`patent (Id. at 1:6-10) states: “Dilation of small blood vessels . . . causes many
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`clinically undesirable events including surface hemorrhage and hyperemia following
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`Lasik surgery, eye redness (conjunctival hyperemia), and nasal congestion. . . .”
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`53. The second paragraph of the Background section (id. 1:12-30) is a brief
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`discussion of “adrenergic receptors.” This paragraph states these receptors “are
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`divided pharmacologically into a-1, a-2 and β-adrenergic receptor types” (id. at 1:15-
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`17). The “a-adrenergic receptors” are stated to include the “a-1 adrenergic
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`receptors” and the “a-2 adrenergic receptors.” Id. at 1:19-24. This paragraph
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`concludes with the statement that: “Vascular constriction is known to be mediated
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`by a-adrenergic receptors.” Id. at 1:29-30.
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`54. The fourth paragraph of the Background states “brimonidine” is
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`“known” to have “selective a-2 agonist activity.” Id. at 1:48-50. I note that the ‘742
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`patent uses the terms “selective alpha-2 (a-2) adrenergic receptor agonists” and “a-2
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`agonists” interchangeably. Id. at 4:48-50.
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`55. The sixth paragraph of the Background section states that brimonidine
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`was known to be a vasoconstrictor. Id. at 1:61-63 (“It is a known property of all
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`a adrenergic receptor agonists, including brimonidine, to cause vasoconstriction.”)
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`“Brimonidine” Is Defined Broadly
` The claims of the ‘742 patent are directed to using “brimonidine.” The
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`56.
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`specification defines “brimonidine” to broadly encompass, without limitation,
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`“brimonidine salts and other derivatives, and specifically includes, but is not limited
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`to, brimonidine
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`tartrate, 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-
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`tartrate, Alphagan™, and UK14304.” Id. at 4:7-11.
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`VI. CLAIM CONSTRUCTION
`A. “0.03%” Is Included in “about 0.025%”
`57.
`I have been asked by counsel to opine on whether about “0.025%,” as
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`recited in claims 2 and 3 the ‘742 patent includes “0.03%.” I understand that in
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`construing patent claims reviewing courts use the following general rule: “The claim
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`construction that stays true to the claim language and most naturally aligns with the
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`patent’s description of the invention will be, in the end, the correct construction.”
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`For the following reasons it is my opinion that “0.03%” is included in “about
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`0.025%” as recited in claims 2 and 3 the ‘742 patent.
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`58.
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`I understand that I am to give my claim construction opinion from the
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`perspective of what a POSA would understand a claim to mean at the relevant time.
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`My opinions remain the same for the entire period August 1, 2008 to July 27, 2009.
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`59. The recited upper limit of the claimed range in claims 2 and 3 of the
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`‘742 patent is “about 0.025%.” EX-1001, ‘742 patent claims 2 and 3 (emphasis
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`added).
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`60.
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`I understand that when “about” is used as part of a numeric range, the
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`use of the word “about” avoids a strict numerical boundary to the specified
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`parameter. I understand that when “about” is used to define the limit of a numerical
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`range, the extension beyond the stated number depends on what a POSA would
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`reasonably consider “about” to encompass.
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`61.
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`I understand that patent claims are to be construed based on the intrinsic
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`evidence, which includes the claims of the patent, the specification of the patent, and
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`the prosecution history. I understand that the patent claims have primary
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`importance, the specification is typically the best evidence to interpret the claims,
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`and although often less precise, the prosecution history can shed light on the proper
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`construction. I also understand that evidence that is not intrinsic evidence, i.e.
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`“extrinsic evidence,” may also be considered in claim construction. I am not aware
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`of extrinsic evidence that excludes “about 0.025%” from including “0.03%” in the
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`context of the ‘742 patent.
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`62.
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`In this IPR I understand the intrinsic evidence to be: a) the claims of
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`the ‘742 patent (EX-1001); b) the specification of the ‘742 patent (EX-1001),
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`including its original claims (EX-1010); and c) the prosecution history of the ‘742
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`patent, which I understand to include the file wrapper of the U.S. Application
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`12/460,941 (EX-1024), U.S. Provisional Application 61/207,481 (EX-1011, ‘481
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`Provisional) U.S. Provisional Application 61/203,120 (EX-1012, ‘120 Provisional),
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`U.S. Provisional Application 61/192,777 (EX-1013, ‘777 Provisional), and U.S.
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`Provisional Application 61/137,714 (EX-1014, ‘714 Provisional). I have not been
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`asked to opine on whether any of the foregoing applications support any of the
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`challenged claims.
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`63.
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`In my opinion the foregoing intrinsic evidence does not provide explicit
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`instruction as to whether “about 0.025%” is meant to include or exclude “0.03%.”
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`Therefore, I understand that whether “about 0.025%” includes “0.03%” must be
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`interpreted in its technologic and stylistic context, that claim construction of “about
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`0.025%” must focus on the criticality of this numerical limitation to the invention,
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`and the relevant inquiry is the purpose of the limitation in the claimed invention.
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`64.
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`In my opinion, the specification of the ‘742 patent discloses that a
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`brimonidine concentration of 0.03% does accomplish the purpose of the claimed
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`invention.
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`65. First, the alleged invention is stated to reside in “low concentrations”
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`of brimonidine.‘742 patent, EX-1001, Abstract. The ‘742 patent (3:58-65) defines
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`“low concentrations” as follows:
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`The term ‘low concentrations’ refers to concentrations
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`from between about 0.0001% to about 0.05% . . .weight by
`volume.
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`Because the specification describes up to “about 0.05%” as a “low concentration
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`suitable for the purpose of the invention, “0.03%” is a “low concentration” with
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`respect to the context and purpose of the claimed invention.
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`66. Second, the specification identifies concentration ranges that include up
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`to about 0.05% brimonidine as a “preferred” embodiment.
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`When the methods and compositions of the present
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`invention are used in conjunction with Lasik surgery, the
`preferred a-2 agonist is brimonidine at a concentration
`of from about 0.015% to about 0.05%. [12:60-63
`(emphasis added)]
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`For the methods of scleral whitening, the preferred
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`a-2 agonist is brimonidine at a concentration of from
`about 0.01% to about 0.05% [13:14-16 (emphasis
`added)]. . .
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`67. Also, brimonidine is identified by the specification as a “selective a-2
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`agonist” (5:52-54) and the specification discloses that in a “preferred embodiment”
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`the concentration of the “the selective a-2 adrenergic receptor agonist” is in a range
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`up to “about 0.035%” (9:11-16).
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`68. These preferred embodiments from the specification, that plainly
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`include “0.03%,” inform the POSA that “about 0.025%” includes “0.03%.”
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`69. Third, the specification describes Figure 4E as depicting the left eye of
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`a patient “after being treated with a composition of the present invention
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`comprising brimonidine at 0.033%.” 3:30-33 (emphasis added). According to the
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`specification, the application of “0.033%” brimonidine did not result in “rebound
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`hyperemia.” 20:17-19. The specification’s positive statement regarding 0.033%
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`brimonidine further informs the POSA that “about 0.025%” is not meant to exclude
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`“0.03%.”
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`70. Fourth, according to the specification (2:2-8), brimonidine is “a known
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`selective alpha 2 agonist [] associated with significant rebound hyperemia (primary
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`or delayed onset vasodilation) in its current concentration range for treating
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`glaucoma of about 0.1% to 0.2%.” A POSA understood, that compared to the
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`foregoing concentration range of “about 0.1% to 0.2%,” a concentration of “0.03%”
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`brimonidine accomplishes a significant reduction in brimonidine concentration that
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`is the purpose of the concentration limitation recited in claims 2 and 3 of the ‘742
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`patent.
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`71. Fifth, the ‘742 patent does not indicate that keeping the brimonidine
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`concentration below 0.03% is critical. In addition, Figure 2 of the ‘742 patent
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`illustrates that 0.03% is included in the range where “Net Vasoconstriction Benefits”
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`are the highest.
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`72. Sixth, from the perspective of a pharmaceutical formulator, “about
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`0.025%” includes “0.03%” because, as the upper limit of a range, a concentration of
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`“about 0.025%” rounded up to two decimal points is “0.03%.” Moreover, a POSA
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`expected that in the context of the ‘742 patent it would be difficult to distinguish
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`between the clinical effect of “about 0.025%” and “0.03%” brimonidine.
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`73. For all of these reasons, it is my opinion that “about 0.025%,” as recited
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`in claims 2 and 3 of the ‘742 patent, includes “0.03%.” Therefore, “between about
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`0.001% to about 0.025% weight by volume,” as recited in claim 2 of the ‘742 patent
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`(Limitation 2.1), includes “0.03%” and “wherein said brimonidine concentration is
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`between about 0.001% and about 0.025% weight by volume” (Limitation 3.6) also
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`includes 0.03%.
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`74. Also, it is my opinion that there is no ascertainable difference in the
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`upper bound of the concentration ranges in claims 2 a