IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`In the Inter Partes Review (IPR) of U.S. Patent No. 5,886,035
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`DECLARATION OF ARON D. ROSE, M.D.
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`I, Aron D. Rose, M.D., declare as follows:
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`I.
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`INTRODUCTION AND BACKGROUND QUALIFICATIONS
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`A. Qualifications
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`1.
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`I am a practicing ophthalmologist and member of The Eye Care
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`Group specializing in complex cataract surgery and glaucoma. I have privileges
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`as an attending physician and surgeon at Yale New Haven Hospital and Saint
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`Mary’s Hospital in Connecticut.
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`2.
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`In addition to my ophthalmology practice, I teach at Yale University
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`as Associate Clinical Professor in the Department of Ophthalmology and Visual
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`Sciences at the School of Medicine and as Associate Clinical Professor in the
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`Graduate Entry Program in Nursing at the School of Nursing. I was also the
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`previous Director of Residency Training in the Department of Ophthalmology
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`and Visual Sciences at the Yale School of Medicine. I am also an Associate
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`Micro Labs Exhibit 1028
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`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`In the Inter Partes Review (IPR) of U.S. Patent No. 5,886,035
`
`DECLARATION OF ARON D. ROSE, M.D.
`
`I, Aron D. Rose, M.D., declare as follows:
`
`I.
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`INTRODUCTION AND BACKGROUND QUALIFICATIONS
`
`A. Qualifications
`
`1.
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`I am a practicing ophthalmologist and member of The Eye Care
`
`Group specializing in complex cataract surgery and glaucoma. I have privileges
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`as an attending physician and surgeon at Yale New Haven Hospital and Saint
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`Mary’s Hospital in Connecticut.
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`2.
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`In addition to my ophthalmology practice, I teach at Yale University
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`as Associate Clinical Professor in the Department of Ophthalmology and Visual
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`Sciences at the School of Medicine and as Associate Clinical Professor in the
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`Graduate Entry Program in Nursing at the School of Nursing. I was also the
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`previous Director of Residency Training in the Department of Ophthalmology
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`and Visual Sciences at the Yale School of Medicine. I am also an Associate
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`Micro Labs Exhibit 1028
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`Clinical Professor in the Department of Medical Sciences at the Frank H. Netter
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`MD School of Medicine at Quinnipiac University. I am also a member of the
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`Connecticut Glaucoma Society.
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`3.
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`I earned my M.D. from New York Medical College in 1985
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`following a B.A. from Brown University in 1980.
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`4.
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`I have authored or co-authored 17 peer-reviewed publications, have
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`served as an investigator in 20 studies dealing with the treatment of glaucoma
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`and ocular hypertension, and have presented numerous lectures on these topics.
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`5. My curriculum vitae, provided in Appendix B, contains more details
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`on my background, experience, publications, and prior expert testimony.
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`B. Scope of Work
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`6.
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`I have been retained by the law firm Pillsbury Winthrop Shaw
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`Pittman LLP (“Pillsbury Winthrop”) on behalf of Petitioners Micro Labs Limited
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`and Micro Labs USA Inc. (together "Micro") in connection with this matter. I
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`am being compensated at a rate of $500 per hour for my work in connection with
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`my consultation for this declaration. My compensation is neither dependent on
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`the substance of my testimony and opinions in this matter nor is it dependent on
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`the outcome of this matter.
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`7.
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`For purposes of preparing my declaration, I have examined U.S.
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`Patent No. 5,886,035 (“the ’035 patent,” Ex. 1001) and the other prior art
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`2
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`Micro Labs Exhibit 1028-2
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`materials identified below. I understand that the contents of declaration will be
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`relied on in collaboration with a medicinal chemist to evaluate whether the
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`subject matter claimed in the ’035 patent would have been obvious to a person of
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`ordinary skill in the art as defined below. My understanding is that my expertise
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`will be relied on insofar as it relates to the development of prostaglandin
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`analogues for the treatment and/or management of elevated intraocular pressure
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`(IOP) and glaucoma for all relevant time periods including the period that is just
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`prior to the time of the alleged invention that is the subject of the ’035 patent.
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`8.
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`This declaration summarizes only my current opinions, which are
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`subject to change depending upon additional information and/or analysis. I and
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`others either working with me or under my direction prepared the exhibits of the
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`materials that I reviewed and relied upon in my declaration. The entirety of my
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`declaration, including the exhibits and referenced materials, supplies the basis for
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`my analysis and conclusions. The organizational structure of the declaration is
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`for convenience. I reserve the right to supplement my opinions or respond as
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`needed to opinions and assertions made by others in this matter.
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`9.
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`To the extent that facts and other considerations overlap, I generally
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`discuss such issues only once for the sake of brevity. Neither the specific order
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`in which each issue is addressed nor the organization of my declaration or
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`exhibits affects the ultimate outcome of my opinions.
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`3
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`Micro Labs Exhibit 1028-3
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`C. U.S. Patent No. 5,886,035 (Ex. 1001)
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`10.
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`I have read the ’035 patent, which I have been informed allegedly
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`covers the commercially-available product ZIOPTAN.® I am aware that
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`ZIOPTAN® is an ophthalmic solution containing tafluprost marketed by Oak
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`Pharmaceuticals, Inc. (“Oak”).
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`11.
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`I have been informed and understand that Oak is the holder of the
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`New Drug Application for ZIOPTAN® and the ’035 patent is listed in the FDA’s
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`Electronic Orange Book in connection with this product. I understand that the
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`’035 patent is assigned to patent owners Santen Pharmaceuticals Co., Ltd.
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`(“Santen”) and Asahi Glass Co., Ltd. (“Asahi”).
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`12.
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`I have been informed and understand that the claims of the ’035
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`patent are directed to fluorine-containing prostaglandin derivatives, specifically
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`derivatives having two fluorine (F) atoms at the C-15 position, their alkyl esters,
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`or their salts, and to medicines containing one of these compounds as an active
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`ingredient. I also understand that the compounds covered by the ’035 patent are
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`alleged to be useful in medicine to treat an eye disease such as glaucoma and
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`ocular hypertension.
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`13.
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`I understand that Oak, Santen and Asahi have filed a lawsuit for
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`patent infringement against Micro in connection with Micro’s filing of
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`Abbreviated New Drug Application No. 209051 that seeks FDA approval to
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`4
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`Micro Labs Exhibit 1028-4
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`commercially market a generic tafluprost product. I understand that this lawsuit
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`has been stylized Santen Pharmaceutical Co., Ltd., Asahi Glass Co., Ltd. and
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`Oak Pharmaceuticals, Inc. v. Micro Labs limited and Micro Labs USA Inc., Case
`
`No. 16-cv-00353 (D. Del. 2016).
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`II. BACKGROUND
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`A. Legal Understanding
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`14. My opinions as stated herein are predicated on my knowledge and
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`expertise.
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`15.
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`It is my understanding that each of the claims of the ’035 patent
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`define the scope of the invention that is entitled to protection. I understand that
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`in assessing the claims of the ’035 patent for purposes of this declaration, they
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`are to be construed with the broadest reasonable interpretation. It is also my
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`understanding that such interpretation includes giving the plain and ordinary
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`meaning to the claim language and as informed by what I understand to be the
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`patent specification. It is my opinion in reviewing the claims that there are no
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`claim terms that require special interpretation beyond their plain and ordinary
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`meaning.
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`16.
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`I understand that a patent claim is unpatentable as obvious if the
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`subject matter of the claim as a whole would have been obvious to a person of
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`ordinary skill in the art at the time of the invention.
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`5
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`Micro Labs Exhibit 1028-5
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`17.
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`I understand that prior art references can be combined to find that a
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`claim is obvious under 35 U.S.C. § 103 when there was an objective reason for a
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`person of ordinary skill in the art, at the time of the invention, to combine the
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`references or make obvious modifications in view of them based on but not
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`limited to (A) identifying a teaching, suggestion, or motivation to combine prior
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`art references; (B) combining prior art methods according to known methods to
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`yield predictable results; (C) substituting one known element for another to
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`obtain predictable results; (D) using a known technique to improve a similar
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`device in the same way; (E) applying a known technique to a known device
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`ready for improvement to yield predictable results; (F) trying a finite number of
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`identified, predictable potential solutions, with a reasonable expectation of
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`success; or (G) identifying that known work in one field of endeavor may prompt
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`variations of it for use in either the same field or a different one based on design
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`incentives or other market forces if the variations are predictable to a person of
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`ordinary skill in the art.
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`18.
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`I further understand that in the chemical arts the structural similarity
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`between the claimed compound or molecule and the prior art subject matter
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`creates what is known as a prima facie case of obviousness when the prior art
`
`provides reason to combine or modify the prior art structures to arrive at the
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`claimed compound. I understand that this prima facie case of obviousness is
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`6
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`Micro Labs Exhibit 1028-6
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`
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`established where the structural relationships indicate a motivation to combine or
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`modify the prior art. I also understand that important to the establishment of a
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`prima facie case of obviousness is the proper selection of a so-called lead
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`compound where the prior art available to the person of ordinary skill in the art
`
`would have led that person to modify a known compound in a particular manner.
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`19. My understanding is that to qualify as a starting point in the lead
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`compound selection, a prior art compound must have sufficiently attractive
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`properties to motivate a person of ordinary skill in the art to select that particular
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`compound over others identified in the prior art. In stepping into the shoes of a
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`person of ordinary skill in the art, I understand that the selection of a so-called
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`lead compound cannot be made simply because of structural similarity. I
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`understand that in determining and describing a prima facie case of obviousness I
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`am to avoid using hindsight. That means I must avoid using the patent of the
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`claimed subject matter as a “roadmap” to arrive at selecting a structurally similar
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`compound and subsequently subjecting it to modification. Accordingly, it is my
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`understanding that selecting a prior art compound requires that I look beyond
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`simply structural similarity and take into consideration the known functional
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`properties and limitations of the prior art compounds in the relevant field.
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`20. Based on the above understanding, I have also been asked to
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`consider the question of what compound a person of ordinary skill in the art
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`7
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`Micro Labs Exhibit 1028-7
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`would have selected as a starting point in view of the prior art materials that I
`
`have reviewed.
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`B.
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`Person of Ordinary Skill in the Art
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`21. My understanding is that the inquiry into the obviousness of the
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`claims of the ’035 patent is based on the perspective of a person of ordinary skill
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`in the art at the time of the claimed invention. I am informed that this person of
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`ordinary skill in the art is a hypothetical person who is presumed to be aware of
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`all pertinent art, thinks along conventional wisdom in the art, and is a person of
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`ordinary creativity. I understand that the time period relevant to the inquiry of
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`obviousness is the time period prior to December 26, 1996, which I understand is
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`the earliest priority date claimed by the owners of the ’035 patent.
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`22. Based on my education, experience and training, I am familiar with
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`the level of skill in the art just prior to the December 26, 1996 time frame as it
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`pertains to the subject matter of the ’035 patent. It is my opinion that this person
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`of ordinary skill in the art would be a person with a Ph.D. in medicinal and/or
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`organic chemistry having at least several years of experience researching and
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`developing preventative or therapeutic medicines for treatment of eye diseases.
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`It is my further opinion that this person would have familiarity designing,
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`formulating and evaluating ophthalmic compositions for treatment of eye
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`conditions that include glaucoma or ocular hypertension. I believe that this
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`8
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`Micro Labs Exhibit 1028-8
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`person would also have sufficient familiarity interpreting or evaluating studies
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`that use animal models to test for IOP activity and side effects of compounds
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`having the potential to treat glaucoma or ocular hypertension. This person also
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`would draw upon the specialized experiences and skills of others on his team
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`with these skills since it would be reasonable that the person of ordinary skill in
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`the art would be working as part of a multi-disciplinary team with respect to the
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`subject research.
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`23.
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`Insofar as the person of ordinary skill in the art defined above, I can
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`offer the perspective of the knowledge and experience of a person that is either
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`(1) a person of ordinary skill in the art or (2) working with a person of ordinary
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`skill in the art in reviewing and evaluating efficacy screens of candidate
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`compounds for the treatment of elevated intraocular pressure or glaucoma. I
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`believe that such screening would include review and consideration of efficacy
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`measurements and an understanding of undesirable side-effects including, but not
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`limited to hyperemia and other forms of eye irritation.
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`III. Materials Considered
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`24.
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`I have formulated my opinions based on my understanding of the
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`scope of the tasks I have been given as referenced above, as well as my review of
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`the ’035 patent and the prior art cited in Appendix A.
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`25.
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`The materials that I have reviewed including prior art and relied on
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`9
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`Micro Labs Exhibit 1028-9
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`for this Declaration is tabulated in Appendix A.
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`IV. BACKGROUND AND STATE OF THE ART
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`26.
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`I set forth below in my insight and opinion as to what the person of
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`ordinary skill in the art that is conducting research in the area of developing
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`PGF2α analogues (the field encompassed by the claims of the ’035 patent) to treat
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`ocular hypertension and glaucoma would have been aware of regarding the
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`following topics: (1) glaucoma and ocular hypertension; (2) prostaglandin-based
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`medicines for treating glaucoma and ocular hypertension; (3) animal models use
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`to evaluate IOP-reducing activity and hyperemia; (4) hyperemia or redness in the
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`eye caused by prostaglandin-based medicines; and (5) PGF2α analogue receptors
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`in the eye and their proposed effect on uveoslceral outflow.
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`27. Unless otherwise specifically noted, my discussion of the
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`background and state of the prior art is based on the perspective of what was
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`known at the time of the alleged invention of the ’035 patent. Again, I
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`understand from counsel that the relevant time period is just prior to December
`
`26, 1996.
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`A. Ocular Hypertension and Glaucoma
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`28. Ocular hypertension usually refers to any situation in which the
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`pressure inside the eye (intraocular pressure or IOP) is higher than normal. With
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`ocular hypertension, the front of the eye does not drain fluid properly, causing
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`10
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`Micro Labs Exhibit 1028-10
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`eye pressure to increase because fluid builds up in the front part of the eye.
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`Elevated intraocular pressure is a concern because people with ocular
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`hypertension can develop glaucoma, which is a disease where eye pressure
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`damages the optic nerve, causing vision loss. The pathophysiology of ocular
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`hypertension and glaucoma was highly researched as of December 26, 1996.
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`29. Ocular hypertension is not the same as glaucoma. With ocular
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`hypertension, the optic nerve looks normal and there are no signs of vision loss.
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`People with ocular hypertension, however, should be observed more closely
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`because the existence of ocular hypertension creates an increased risk for the
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`onset of glaucoma. Patients with ocular hypertension are often considered
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`“glaucoma suspects” meaning that they may develop glaucoma because of their
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`elevated intraocular pressure. Glaucoma is a disease that is one of the leading
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`causes of blindness for many people over 60 years old, as intraocular pressure
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`slowly rises with increasing age.
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`30.
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`Eye pressure is measured in millimeters of mercury (mm Hg).
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`Normal eye pressure ranges from 12-22 mm Hg. Ocular hypertension is any
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`pressure greater than 22mm Hg. Elevated intraocular pressure is caused by the
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`imbalance in the relationship between production and drainage of fluid in the
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`eye. Elevated intraocular pressure can be caused by improperly functioning
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`drainage channels or more fluid being produced in the eye than normal.
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`11
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`Micro Labs Exhibit 1028-11
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`31.
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`The most common type of glaucoma is known as primary open-
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`angle glaucoma, where the drainage structures of the eye appears normal but the
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`pressure inside the eye is too high and a characteristic pattern of progressive
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`damage to the optic nerve results.
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`
`Treatment of Ocular Hypertension or Glaucoma with
`Prostaglandins
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`B.
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`32. Ocular hypertension and glaucoma treatments include surgical
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`procedures, laser treatments, implantation of drainage devices and application of
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`pharmacological drugs (i.e., medicine).
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`33.
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`In terms of medicine, ocular hypertension and glaucoma are often
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`controlled with eye drop medication that reduces IOP. Eye drop medication
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`helps to drain excessive eye fluid and/or decreases the amount of fluid made by
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`the eye. Medicines are classified by their active ingredient and include:
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`prostaglandin analogues, beta blockers, alpha agonists and carbonic anhydrase
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`inhibitors. Prostaglandins and their analogues reduce IOP primarily by
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`increasing the outflow of intraocular fluid from the eye.
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`34.
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`Prior to December 26, 1996, naturally-occurring prostaglandin F2α
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`known in short form as PGF2α had long been known to effect reduction of
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`intraocular pressure. Many research groups were investigating PGF2α analogues
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`for use in treating ocular hypertension and glaucoma.
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`12
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`Micro Labs Exhibit 1028-12
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`35.
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`The characterization of the distribution of prostaglandin receptors in
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`the eye, specifically those that might be involved in modulating intraocular
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`pressure was well-known prior to December 26, 1996.1 2 3
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`36.
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`The PGF2α analogue latanoprost emerged as an early success in the
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`treatment of ocular hypertension and glaucoma. Latanoprost was introduced in
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`1996 in the United States and Europe. In June 1996, the United States FDA
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`approved an ophthalmic solution containing latanoprost that is marketed as
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`XALATAN®. (Ex. 1016).
`
`37.
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`I am aware from my review of EP 0 639 563 to Klimko et al.
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`1 Lee, P.Y. et al., “The effect of prostaglandin F2 alpha on intraocular pressure in
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`normotensive human subjects,” Invest. Ophthalmol. Vis. Sci. Oct. 29(10):1474–
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`1477 (1988) (Ex. 1018).
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`2 Camras, C.B. et al., “Maintained reduction of intraocular pressure by
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`prostaglandin F2 alpha-1-isopropyl ester applied in multiple doses in ocular
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`hypertensive and glaucoma patients,” Ophthalmology Sep. 96(9):1329–1337
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`(1989) (Ex. 1019).
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`3 Nilsson, S.F. et al., “Increased uveoscleral outflow as a possible mechanism of
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`ocular hypotension caused by prostaglandin F2 alpha-1-isopropylester in the
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`cynomolgus monkey,” Exp. Eye Res. May 48(5):707–716 (1989) (Ex.1020).
`
`13
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`
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`Micro Labs Exhibit 1028-13
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`(“Klimko,” Ex. 1003), that is discussed in detail further below, compounds that
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`were under investigation prior to December 26, 1996 included PGF2α analogues
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`structurally similar to latanoprost that exhibited greater IOP-reducing activity
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`than latanoprost when tested in the eyes of cynolmogous monkeys. These
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`compounds also exhibited some potential for inducing hyperemia when tested in
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`guinea pigs.
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`38. Many researchers studying the IOP-reducing activity of these PGF2α
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`analogues also noted their potential for inducing hyperemia. Other undesirable
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`side-effects resulting from the administration of these analogues include eye
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`irritation, changes in eye color and eyelid skin.
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`C. Hyperemia Side Effect of Prostaglandin-Based Medicines
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`39. At the time of the claimed invention of the ’035 patent
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`prostaglandin-based medicines used to treat ocular hypertension or glaucoma,
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`such as latanoprost, were known to produce certain negative side effects, most
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`commonly hyperemia.
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`40. Hyperemia is a condition in which redness is observed on the
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`surface of the eye due to vasodilation (i.e., increased diameter of blood vessels).
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`Prior to December 26, 1996, hyperemia was already a well-characterized side
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`effect of certain drug products for the eye, including prostaglandin-based drugs.
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`As hyperemia is associated with both discomfort and cosmetic concerns among
`
`14
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`Micro Labs Exhibit 1028-14
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`patients, it is commonly associated with reduced compliance, and thus highly
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`undesirable.
`D. Animal Models for Testing IOP-Reducing Activity and
`Hyperemia Resulting from the Use of Prostaglandins and their
`Analogues
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`41.
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`Prior to December 26, 1996, animal models were regularly used in
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`order to study glaucoma, evaluate the potential of candidate compounds to treat
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`elevated intraocular pressure, and study the side effects of administering such
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`compounds.4 5
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`42.
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`The cynomolgus monkey model is one such standard model
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`employed to assess drug candidates for treatment of elevated intraocular pressure
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`and glaucoma. The benefit and advantage of using a cynomolgus monkey animal
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`model are twofold: retinal and optic nerve anatomy are very similar to humans,
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`and the physiological characteristics of the cynomolgus monkey are very close to
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`the human eye. This animal model is a model with which I have great
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`
`4 Pederson, J.E. et al., “Laser-induced primate glaucoma. I. Progression of
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`cupping,” Arch. Ophthalmol. Nov. 102(11):1689-92 (1984) (Ex. 1021).
`
` 5
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` Radius, R.L. et al., “Laser-induced primate glaucoma. II. Histopathology,” Arch.
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`Ophthalmol. Nov. 102(11):1693-8 (1984) (Ex. 1022).
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`
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`15
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`
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`Micro Labs Exhibit 1028-15
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`
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`familiarity, as I co-authored one of the original articles describing its usefulness.6
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`This cynomolgus monkey model was also used in the Klimko (Ex. 1003) prior
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`art reference detailed below in my declaration.
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`43. Another animal model regularly used prior to December 26, 1996
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`when studying PGF2α side-effects such as hyperemia was the guinea pig model.7
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`It is chosen as it exhibits primate-like characteristics, felt especially useful in
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`assessing similar side effects as humans.
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`44. A drug compound candidate that displays hyperemia would not be
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`abandoned but suggests that structural modification would be needed to alleviate
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`this side effect.
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`V.
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`SELECTION OF A LEAD COMPOUND IN VIEW OF PRIOR ART
`
`EP 0 639 563 A2 (“Klimko,” Ex. 1003)
`
`A.
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`45.
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`I have reviewed EP 0 639 563 A2 to Klimko et al. (“Klimko”),
`
`
`6 Lee, P.Y. et al., “Pharmacological testing in the laser-induced monkey glaucoma
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`model,” Curr. Eye Res. Jul. 4(7):775-81 (1985) (Ex. 1023).
`
` 7
`
` Bito, L.Z. “Species differences in the responses of the eye to irritation and
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`trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice
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`of experimental animals for eye research,” Exp. Eye Res. Dec. 39(6):807-29 (1984)
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`(Ex. 1024).
`
`16
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`Micro Labs Exhibit 1028-16
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`
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`which was published on February 22, 1995. Klimko is generally directed to the
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`use of prostaglandin analogues, and their pharmaceutically acceptable salts and
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`esters, to reduce elevated IOP. (Id., p. 2, ll. 3-8).
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`46. Klimko discloses four compounds designated as compounds A-D
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`that are compared to the reference standard compound latanoprost, which is
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`identified as compound E. (Id., p. 15, l. 47 – p. 15, l. 50). As discussed
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`previously in paragraph 36, latanoprost was approved as a treatment for
`
`glaucoma and ocular hypertension in 1996 in the United States. (Ex. 1016).
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`47. Klimko discloses 15-hydroxy prostaglandin analogues A, B, C and
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`D (below) in Table 2. (Ex. 1003, p. 15, Table 2). Each of these prostaglandin
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`analogues retains the 15-postion hydroxyl (—OH) group of naturally occurring
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`PGF2α.
`
`48. Compound A is the isopropyl ester of cloprostenol.
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`17
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`Micro Labs Exhibit 1028-17
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`
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`Compound A
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`49. Compound B is the isopropyl ester of fluprostenol that differs from
`
`compound A by replacement of the chlorine (Cl) atom with a trifluoromethyl
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`(CF3) group.
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`
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`Compound B
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`50. Compound C, shown below, differs from Compound A by
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`replacement of the chlorine (Cl) atom with a hydrogen (H) atom.
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`
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`Compound C
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`51. Compound D,shown below, differs from compound C by
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`replacement of the omega side-chain oxygen atom of a phenoxy group with a
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`18
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`Micro Labs Exhibit 1028-18
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`
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`methylene (-CH2-) group.
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`Compound D
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`(See id., p. 15, Table 2).
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`52. Klimko describes in Example 6 a study of the IOP-reducing effect
`
`of compounds A through E in cynomolgus monkeys trained to sit in restraint
`
`chairs and conditioned to accept experimental procedures without the need for
`
`chemical restraint. (Id., p. 18, ll. 10-17). The right eyes of the cynomolgus
`
`monkeys were first lasered to induce ocular hypertension, and then administered
`
`a five-dose treatment of formulations of compounds A through E to the lasered
`
`right eyes of the cynomolgus monkeys. (Id.). Klimko states that the test protocol
`
`included a five dose treatment regimen because of the typical delayed response to
`
`prostaglandins. (Id.). Klimko describes measuring the level of IOP by using a
`
`pneumatonometer after light corneal anesthesia with dilute proparacaine. (Id.).
`
`53. Klimko describes how baseline IOP values were initially measured
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`prior to treatment with the test formulation. (Id., p. 18, ll. 18-20). IOP values
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`19
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`Micro Labs Exhibit 1028-19
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`
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`were then measured at 1 to 7 hours after the first dose, 16 hours after the fourth
`
`dose, and 1to 4 hours after the fifth dose. (Id.). The same amount (0.3 µg per
`
`dose) of each of compounds A through E were compared for IOP reduction. (Id.,
`
`p. 18, ll. 22-23). Table 4 in Klimko (reproduced below, along with graphical
`
`depiction in Figure 2) tabulates the results of “Percent IOP Reduction” for each
`
`of compounds A through E at 16 hours after the fourth dose (16/4), at 2 hours
`
`after the fifth dose (2/5), at 4 hours after the fifth dose (4/5) and at six hours after
`
`the fifth dose (6/5). (Id., p. 18, Table 4 and P. 30, Figure 2).
`
`
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`20
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`
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`Micro Labs Exhibit 1028-20
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`54. Although I no longer perform animal model studies, I am very
`
`familiar with such studies, particularly those involving cynomolgus monkeys as
`
`they fall within the scope of my prior research experience. I am therefore
`
`accustomed to evaluating the resulting data of studies like those in Table 4 of
`
`Klimko (reproduced above) that screen for IOP-reducing effect. (Id.).
`
`55.
`
`Table 4 and Figure 2 above indicate significant IOP-reducing
`
`activity for compounds A through D, relative to the latanoprost reference
`
`compound E that was already on the market prior to December 26, 1996. The
`
`data presented in Klimko show that all four candidates A through D perform
`
`better at reducing IOP than latanoprost reference compound E.
`
`21
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`Micro Labs Exhibit 1028-21
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`56.
`
`In my opinion, the person of ordinary skill in the art at the time of
`
`the claimed invention would have believed that compound C had the greatest
`
`IOP-reducing potential because it appears to have a more prolonged effect when
`
`compared to the other compounds following administration of the fifth dose at
`
`which time the IOP is measured every two hours. (See id., p. 18, Table 4 and p.
`
`30, Figure 2). Of the candidate compounds A through D, compound C is the
`
`only compound that does not begin to experience diminished IOP-reducing
`
`potential between hours 4 and 6. (Id.).
`
`57.
`
`In addition, compounds A and B show about a greater than one hour
`
`delay in reaching the IOP-reducing efficacy of Compound C at the time of the
`
`fifth dosing. (Id.). Moreover, between hours 4 and 6, their IOP-reducing activity
`
`of compounds A and B already begins to diminish. (Id.). Compound C shows a
`
`relatively steady efficacy following the fifth dosing, and the percentage of IOP
`
`reduction drops down between hour 4 and 6 to nominally the same level as that
`
`following the fourth dose. (Id.). Although compound D shows the highest IOP-
`
`reducing potential at hours 2 and 4, compound D demonstrates a substantial
`
`reduction in IOP-reducing effect from 4 to 6 hours following the fifth dose. (Id.).
`
`58.
`
`In my opinion, a person of ordinary skill in the art prior in view of
`
`Klimko would also have assessed compound C as having one of the greatest IOP-
`
`reducing potential because it shows the greatest percent IOP reduction following
`
`22
`
`
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`Micro Labs Exhibit 1028-22
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`
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`administration of 4 of the 5 doses. (Id.). Specifically, a person of ordinary skill
`
`in the art reviewing the data in Table 4 would have noted that compound C had
`
`the greatest percent IOP reduction with 30.2% measured 16 hours after
`
`administration of the fourth dose. (Id.). Compound C also possessed superior
`
`IOP-reducing effect when compared to latanoprost (compound E) that was
`
`already available in the market prior to December 26, 1996. (Id.).
`
`59.
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`In my opinion, compound C would be a strong lead compound
`
`candidate for further investigation based on its initial percent IOP reduction at
`
`16/4 as well as its prolonged effect evidenced by the increase in Percent IOP
`
`Reduction from 4/5 to 6/5. (See id.). It is clear to a person of ordinary skill in
`
`the art from Figure 2 that compound C performs differently from the other
`
`compounds in that it exhibits a longer-lasting effect than the other compounds.
`
`(Id., p. 30, Figure 2).
`
`60. Klimko also presents data from hyperemia studies in Example 5 for
`
`compounds A through E. (Id., pp. 16-18). Compounds A through E all exhibit
`
`hyperemia, in the guinea pig model. (Id.). Klimko describes that the objective of
`
`the guinea pig conjunctival hyperemia model is to provide a primary screening
`
`indication for the potential for inducing conjunctival hyperemia in humans.
`
`61. Klimko describes that the guinea pigs were maintained in their
`
`cages during the study and removed only for scoring and dosing. (Id., p. 16, l. 6).
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`23
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`Micro Labs Exhibit 1028-23
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`Klimko further describes that the guinea pig eyes were evaluated using a
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`magnifying lens with fluorescent illumination and scores for conjunctival
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`hyperemia were recorded for upper bulbar conjunctiva according to the following
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`criteria:
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`
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`(Id., p. 16, ll. 6-20).
`
`62.
`
`I am familiar with analyzing the data from guinea pigs that are used
`
`to test for hyperemia, such as that shown below in Table 3 of Klimko. I agree
`
`with the findings in Klimko that compound C produces more hyperemia than
`
`compound D and compound D in turn produces more hyperemia than compound
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`E. (Id., p. 18, ll. 1-6). I also agree that the hyperemia produced by compound A
`
`and compound B appears to be intermediate between that of compounds D and E.
`
`(Id.).
`
`
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`24
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`Micro Labs Exhibit 1028-24
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`63.
`
`In my opinion, although compound C produces more hyperemia in
`
`guinea pigs, a person of ordinary skill in the art would still look to it as a
`
`potential lead compound because a) it demonstrates lasting effectiveness at 6
`
`hours after the fifth dose in contrast to compounds A, B, and D, which
`
`demonstrate reduced effectiveness from 4 to 6 hours after the fifth dose and b) it
`
`demonstrates one of the largest reductions in intraocular pressure after four doses
`
`in the monkey model. In addition, compound C also possessed superior IOP-
`
`reducing effect when compared to a commercially available compound that was
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`latanoprost (compound E).
`
`
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`25
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`Micro Labs Exhibit 1028-25
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`B.
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`United States Patent No. 5,292,754 (“Kishi,” Ex. 1005)
`
`64. United States Patent No. 5,292,754, entitled “Treatment for
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`Hypertension or Glaucoma in Eyes” with first named inventor Morio Kishi
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`issued on March 8, 1994 (“Kishi”).
`
`65. Kishi discloses 15-deoxyprostaglandin derivatives as agents for
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`reducing IOP and pharmaceutical formulations containing such derivatives. (Ex.
`
`1005, col. 41, l. 60-col. 43, l. 36).
`
`66. Kishi teaches that removing the C-15 hydroxyl group from the
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`compounds taught by Klimko leads to compounds that do not produce side
`
`effects such as conjunctival hyperemia:
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`
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`[D]erivatives of conventional prostaglandins which are
`derived
`from said conventional prostaglandins by
`deleting the hydroxy group at 15-position are more
`stable, particularly in liquid phase, than the conventional
`prostaglandins, and that they show the intraocular
`pressure-reducing activity. . . In particular, the
`compounds of the invention as described above have a
`signifi
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