`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`In the Inter Partes Review (IPR) of U.S. Patent No. 5,886,035
`
`DECLARATION OF MITCHELL A. DELONG, PH.D.
`
`I, Mitchell A. deLong, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION AND BACKGROUND
`A. Qualifications
`I am Vice President (Chemistry R&D) of Aerie Pharmaceuticals and
`
`1.
`
`an Adjunct Professor in the Department of Chemistry at Duke University. I am an
`
`expert in synthetic organic and medicinal chemistry with more than 25 years of
`
`experience in the chemical arts.
`
`2.
`
`I earned my Ph.D. in Synthetic Organic and Medicinal Chemistry
`
`with a concentration in Cancer Biology from Stanford University in 1991.
`
`3.
`
`I also earned in 1982 a multidisciplinary Bachelor of Science degree
`
`in Biology and Chemistry from Michigan State University-Lyman Briggs College
`
`during which I was a 4-year National Merit Scholar.
`
`4.
`
`I have led research and development teams including a team at the
`
`1
`
`
`
`Micro Labs Exhibit 1027
`
`
`
`Duke Eye Center at Duke University that has resulted in three spinoff companies.
`
`In 2006, one of the companies filed an Investigational New Drug Application
`
`(IND) to advance a novel prostaglandin prodrug named AR-102 that subsequently
`
`completed Phase 2 clinical trials.
`
`5. My expertise and experience in organic synthetic and medicinal
`
`chemistry include research and development of analogues of naturally occurring
`
`prostaglandins. I have synthesized prostaglandin analogues and tested them in
`
`various animal models to study their potential for use in treating glaucoma and
`
`ocular hypertension.
`
`6.
`
`I am named as inventor on 45 issued patents and 85 published patent
`
`applications in the United States. A number of these patents and published
`
`applications relate to the subject matter of prostaglandin analogues, their
`
`preparation and their use in the treatment of glaucoma and ocular hypertension.
`
`7.
`
`I have published research in several peer-reviewed academic journals
`
`and also given numerous invited talks and scientific presentations on a variety of
`
`subjects including prostaglandins and glaucoma treatments.
`
`8. My curriculum vitae provided as Appendix B contains additional
`
`details relating to my background including experience and publications.
`
`B.
`
`9.
`
`Scope of Work
`
`I have been retained by the law firm Pillsbury Winthrop Shaw Pittman
`
`2
`
`
`
`Micro Labs Exhibit 1027-2
`
`
`
`LLP (“Pillsbury”) on behalf of Petitioners Micro Labs Limited and Micro Labs
`
`USA Inc. ("Micro") to consult in connection with this matter. My compensation
`
`on this matter is $250 per hour and it is neither dependent on the substance of my
`
`testimony nor the outcome of this matter.
`
`10.
`
`For purposes this declaration, I have been asked to assess whether a
`
`person of ordinary skill in the art (“POSA”), which I define later in my declaration,
`
`would have found the subject matter claimed in the claims of U.S. Patent No.
`
`5,886,035 (“the ’035 patent,” Ex. 1001) obvious in view of the prior art and the
`
`general knowledge of the POSA.
`
`11.
`
`In relation to the above, I was asked to review and discuss in my
`
`declaration the problems to be solved by and also the understandings and
`
`motivations of the POSA researching and developing prostaglandin analogues that
`
`could be used for treatment and/or management of elevated intraocular pressure
`
`(IOP)/ocular hypertension and glaucoma. I was asked to discuss the preceding in
`
`view of the prior art that I reviewed and to assess what would have been the
`
`POSA’s starting point for a lead compound and what modifications in view of the
`
`prior art teachings the POSA would have made to the lead compound.
`
`12.
`
`This declaration summarizes only my current opinions, which are
`
`subject to change depending upon additional information and/or analysis. I reserve
`
`the right to respond as needed to any additional information or any response to my
`
`3
`
`
`
`Micro Labs Exhibit 1027-3
`
`
`
`declaration.
`
`13.
`
`I and others working under my direction prepared and referenced the
`
`exhibits I reviewed and relied upon for my declaration. The entirety of my
`
`declaration, including exhibits and referenced materials, supplies the basis for my
`
`analysis and conclusions. The organizational structure of the declaration is for
`
`convenience.
`
`14.
`
`To the extent that facts and other considerations overlap, I generally
`
`discuss such information and issues related to them only once for the sake of
`
`brevity and those reviewing my declaration should refer to my earlier discussions
`
`in the declaration as needed. Neither the specific order in which each issue is
`
`addressed nor the organization of my declaration or exhibits affects the ultimate
`
`outcome of my analysis and conclusion.
`
`C. U.S. Patent No. 5,886,035 (Ex. 1001)
`
`15.
`
`I have reviewed the ’035 patent in that I have read and familiarized
`
`myself with it.
`
`16.
`
`I understand based on my review that the ’035 patent has 14 claims
`
`and is directed to fluorine-containing prostaglandin derivatives, specifically
`
`derivatives having two fluorine atoms at the C-15 position, their alkyl esters, or
`
`their salts, and to medicines containing one of these compounds as an active
`
`ingredient. These compounds are intended for use in medicine to treat eye diseases
`
`4
`
`
`
`Micro Labs Exhibit 1027-4
`
`
`
`or conditions, such as glaucoma and ocular hypertension.
`
`17.
`
`I understand that the ’035 patent is assigned to Patent Owners Santen
`
`Pharmaceuticals Co., Ltd. (“Santen”) and Asahi Glass Co., Ltd. (“Asahi”) and is
`
`alleged to cover the commercially-available drug product ZIOPTAN®, which is an
`
`ophthalmic solution containing the active compound tafluprost. I further
`
`understand that the ’035 patent is listed in the FDA’s Electronic Orange Book:
`
`Approved Drug Products with Therapeutic Equivalence Evaluations in connection
`
`with Oak Pharmaceuticals, Inc.’s (“Oak”) New Drug Application (NDA) for
`
`ZIOPTAN®. (Patent and Exclusivity for N202514, Ex. 1017). I understand that
`
`the claims of the ’035 patent is alleged to cover tafluprost and medicines that
`
`contains tafluprost.
`
`18.
`
`I understand that Micro is being sued for patent infringement by Oak,
`
`Santen and Asahi on claims 1-14 of the ’035 patent in the United States District
`
`Court for the District of Delaware. I am aware that the basis for this lawsuit is a
`
`technical act of infringement based on Micro’s filing of an Abbreviated New Drug
`
`Application seeking FDA approval to commercially market Micro’s proposed
`
`generic tafluprost product prior to the expiration of the ’035 patent. I understand
`
`that this case has been docketed as Santen Pharmaceutical Co., Ltd., Asahi Glass
`
`Co., Ltd. and Oak Pharmaceuticals, Inc. v. Micro Labs limited and Micro Labs
`
`USA Inc., Case No. 16-cv-00353 (D. Del. 2016).
`
`5
`
`
`
`Micro Labs Exhibit 1027-5
`
`
`
`II. BACKGROUND
`A. Legal Understanding of the Law of Obviousness
`1.
`Interpreting the Claims
`
`19.
`
`I am aware that each of the claims of a patent define the scope of the
`
`subject matter claimed by the patent. I understand that for purposes of determining
`
`the question of whether the claims of the ’035 patent would be obvious to a POSA
`
`they are to be construed as understood by a POSA using the broadest reasonable
`
`interpretation in view of the patent specification. I understand that unless given a
`
`specific meaning in the patent specification, the claim terms are to be given their
`
`plain and ordinary meaning as informed by how the POSA would understand
`
`them.
`
`20.
`
`It is my opinion in reviewing the claims of the ’035 patent that there
`
`are no claim terms that require special interpretation as given by the inventors
`
`beyond that of the plain and ordinary meaning that would be given by a POSA.
`
`
`2.
`
`
`Understanding Invalidity of Claims Based on
`Obviousness under 35 U.S.C. § 103
`
`21.
`
`I understand that a patent claim is invalid as obvious if the subject
`
`matter of the claim would have been obvious to a POSA at the time of the
`
`invention. I understand that the following factors must be evaluated to determine
`
`whether claimed subject matter is obvious: (1) the scope and content of the prior
`
`art; (2) the difference or differences, if any, between the scope of the claim of the
`
`6
`
`
`
`Micro Labs Exhibit 1027-6
`
`
`
`patent under consideration and the scope of the prior art; and (3) the level of
`
`ordinary skill in the art at the time of the alleged invention.
`
`22.
`
`I understand that prior art references can be combined to find that a
`
`claim is obvious under 35 U.S.C. § 103 when there was a reason for a POSA, at
`
`the time of the invention, to combine the references or make obvious modifications
`
`in view of them based on but not limited to: (1) identifying a teaching, suggestion,
`
`or motivation to combine prior art references; (2) combining prior art methods
`
`according to known methods to yield predictable results; (3) substituting one
`
`known element for another to obtain predictable results; (4) using a known
`
`technique to improve a similar device in the same way; (5) applying a known
`
`technique to a known device ready for improvement to yield predictable results;
`
`(6) trying a finite number of identified, predictable potential solutions, with a
`
`reasonable expectation of success; or (7) identifying that known work in one field
`
`of endeavor may prompt variations of it for use in either the same field or a
`
`different one based on design incentives or other market forces if the variations are
`
`predictable to a POSA.
`
`23.
`
`I further understand that in the chemical arts the structural similarity
`
`between the claimed compound or molecule and the prior art subject matter creates
`
`what is known as a prima facie case of obviousness when the prior art gives a
`
`reason to combine or modify the prior art structures to arrive at the claimed
`
`7
`
`
`
`Micro Labs Exhibit 1027-7
`
`
`
`compound. I understand that this prima facie case of obviousness is established
`
`where the structural relationships indicate a motivation to combine or modify the
`
`prior art. I also understand that important to the establishment of a prima facie
`
`case of obviousness is the proper selection of a so-called lead compound where the
`
`prior art available to a POSA would have led that person to modify a known
`
`compound in a particular manner.
`
`24. My understanding is that to qualify as a starting point in the lead
`
`compound selection, a prior art compound must have sufficiently attractive
`
`properties to motivate a POSA to select that particular compound over others
`
`identified in the prior art. I understand that the selection of a so-called lead
`
`compound by a POSA cannot be made simply because of structural similarity. I
`
`understand that in determining and describing a prima facie case of obviousness I
`
`am to avoid using hindsight. That means that stepping into the role of a POSA, I
`
`must avoid using the patent of the claimed subject matter as a “roadmap” to arrive
`
`at selecting a structurally similar compound and subsequently subjecting it to
`
`modification. Accordingly, it is my understanding that selecting a prior art
`
`compound requires that I look beyond simply structural similarity and take into
`
`consideration the known functional properties and limitations of the prior art
`
`compounds in the relevant field.
`
`25.
`
`Finally, I have been informed that there are so-called objective indicia
`
`8
`
`
`
`Micro Labs Exhibit 1027-8
`
`
`
`of non-obviousness, also known as “secondary considerations,” that are to be
`
`considered when assessing the strength of the prima facie case of obviousness.
`
`These secondary considerations include: (1) commercial success; (2) long-felt but
`
`unresolved needs; (3) copying of the invention by others in the field; (4) initial
`
`expressions of disbelief by experts in the field; (5) failure of others to solve the
`
`problem that the inventor solved; and (6) unexpected results. I also understand
`
`that evidence of objective indicia of non-obviousness must be commensurate in
`
`scope with the claimed subject matter.
`3.
`Person of Ordinary Skill in the Art
`
`26.
`
`I understand that in order to assess whether a claim in a patent would
`
`have been obvious in light of the prior art, I must step backward in time and into
`
`the shoes worn by the hypothetical POSA when the invention was unknown and
`
`just before it was made, which I understand is December 26, 1996 for the present
`
`matter.
`
`27.
`
`I am informed that this POSA is presumed to have known the relevant
`
`art at the time including the prior art and thinks along conventional wisdom in the
`
`art. I am informed that this means a POSA is a person of ordinary creativity and
`
`he or she is not simply a pair of hands following directives but presumed to have
`
`an understanding of the prior art and its technical implications, as well as the
`
`problems faced by those working in the field, and is able to apply common
`
`9
`
`
`
`Micro Labs Exhibit 1027-9
`
`
`
`knowledge to attempt to solve a given problem.
`
`28. Based on my knowledge and experience, it is my opinion in
`
`reviewing the ’035 patent that the POSA with respect to the subject matter of
`
`the ’035 patent is a person with a Ph.D. in medicinal and/or organic chemistry
`
`having at least several years of experience researching and developing preventative
`
`or therapeutic medicines for treatment of eye diseases. It is my further opinion that
`
`this person would have familiarity designing, formulating and evaluating
`
`ophthalmic compositions for treatment of eye conditions that include glaucoma or
`
`ocular hypertension. It is my opinion that this person would also have sufficient
`
`familiarity interpreting or evaluating studies that use animal models to test for
`
`IOP-reducing activity and side effects of compounds having the potential to treat
`
`glaucoma or ocular hypertension or could draw upon the specialized experiences
`
`and skills of others on his team with these skills since it would be reasonable that
`
`the POSA would be working as part of a multi-disciplinary team with respect to
`
`the subject research.
`B. Materials/References
`I have formulated my opinions herein based in part upon my review
`
`29.
`
`of the materials tabulated in Appendix A of this declaration, which includes
`
`the ’035 patent and the prior art discussed in my declaration further below.
`
`10
`
`
`
`Micro Labs Exhibit 1027-10
`
`
`
`III. BACKGROUND AND STATE OF THE PRIOR ART
`
`30. Unless I specifically note otherwise, my discussion here of the
`
`background and state of the prior art is based on what was known or being done at
`
`the time of the alleged invention of the ’035 patent.
`
`31. Naturally occurring prostaglandins (PGA, PGB, PGE, PGF and PGI)
`
`are C-20 unsaturated fatty acids. They are known to possess a wide range of
`
`pharmacological activities that include relaxation of smooth muscle, induction of
`
`labor and reduction of intraocular pressure. Although naturally occurring
`
`prostaglandins are characterized by their activity against a particular receptor, they
`
`generally are not specific for any one prostaglandin receptor. Therefore, naturally
`
`occurring prostaglandins are known to cause side effects such as inflammation as
`
`well as irritation when administered systemically. It is generally believed that the
`
`rapid metabolism of naturally occurring prostaglandins following their release in
`
`the body limits the effects of the prostaglandin to a local area.
`
`32.
`
`Prior to December 26, 1996, the naturally occurring the Prostaglandin
`
`F in humans PGF2α had been known since the early 1980’s to effect reduction of
`
`intraocular pressure. (Camras et al. “Reduction of intraocular pressure in normal
`
`and glaucomatous primate (Aotus trivirgatus) eyes by topically applied PGF2α,”
`
`Curr. Eye Res. 1:205-209 (1981) (Ex. 1009)). PGF2α is characterized by hydroxyl
`
`groups at the C9 and C11 positions on the alicyclic ring, a cis-double bond between
`
`11
`
`
`
`Micro Labs Exhibit 1027-11
`
`
`
`C5 and C6, and a trans-double bond between C13 and C14.1 Thus, PGF2α has the
`
`following formula:
`
`
`
`33.
`
`Prompted by the IOP-reducing activity of PGF2α, many researchers
`
`prepared PGF2α analogues and studied these in an effort to find compounds
`
`suitable for the treatment of ocular hypertension (i.e., elevated IOP) and glaucoma.
`
`34. Ocular hypertension refers to a situation when pressure inside the eye
`
`is higher than normal (i.e., elevated IOP). Ocular hypertension is a concern
`
`because it can lead to glaucoma, which is a disease of the eye that causes vision
`
`loss or blindness when, among other causes, it is thought that high pressure in the
`
`eye damages the optic nerve.
`
`PGF2α analogues that could be used to treat ocular hypertension and
`35.
`
`1 The subscripted “2” in the PGF2α refers to the number of double bonds in the
`
`prostaglandin, which in the case of PGF2α is two, and the subscripted “α” refers to
`
`the orientation of the hydroxyl group at C-9 on its ring. (See Nelson, N.A.
`
`“Prostaglandin Nomenclature,” J. Med. Chem., 1974, 17 (9), pp. 911–918, Ex.
`
`1026, p. 911-912).
`
`12
`
`
`
`Micro Labs Exhibit 1027-12
`
`
`
`glaucoma have been disclosed in the prior art. In order to determine and assess
`
`their pharmacological activities, these analogues are tested in animals using animal
`
`models to test for IOP-reducing activity and potential side effects. These animal
`
`models include cynomolgus monkey models to test for IOP-reducing activity and
`
`guinea pigs to test for potential to induce the negative side effect of hyperemia.
`
`36. Hyperemia is a condition that presents as redness in the eye.
`
`Hyperemia can affect patient compliance with taking a medicine for treating
`
`glaucoma or ocular hypertension. This is because patients experiencing redness in
`
`the eye depending on its severity may decide to not take the medicine as regularly
`
`as required or may discontinue the use of the medicine entirely.
`
`37.
`
`Therefore, prior to December 26, 1996, a further consideration for
`
`researchers that were seeking to develop a PGF2α analogue useful for treating
`
`ocular hypertension and glaucoma was the potential of the analogue to induce
`
`hyperemia. During this time, researchers were investigating reducing side-effects
`
`and improving bioavailability through preparation of isopropyl esters of PGF2α as a
`
`prodrug (Alm A 1989 Progress in Clin and Biological Research pp. 447-458, Ex.
`
`1014) in addition to the use of a phenyl ring at the distal end of the PGF system
`
`(Stjernschantz J 1992 Drugs of the Future, pp. 691-704, Ex. 1015).
`
`38.
`
`The isopropyl ester was well-known to be the preferred ester prodrug
`
`form of choice for PGF2a analogues for ophthalmic administration. (Ex. 1010).
`
`13
`
`
`
`Micro Labs Exhibit 1027-13
`
`
`
`This optimized form was realized in the development of latanoprost, which is an
`
`isopropyl ester PGF2α analogue that emerged in 1996 as an early success for
`
`treating ocular hypertension and glaucoma. (Ex. 1001, col. 1, ll. 31-37; Ex. 1015).
`
`The isopropyl ester was the preferred prodrug over the free acid and was adopted
`
`by others in discovery of similar IOP reducing drugs isopropyl unoprostone and
`
`travoprost. (Ex. 1013, at 1134).
`
`39.
`
`Latanoprost was used in both the United States and Europe. In the
`
`United States, latanoprost obtained FDA approval in June of 1996 as the active
`
`ingredient contained in the ophthalmic solution marketed as XALATAN® (Ex.
`
`1016).
`
`40. Other compounds under consideration to treat glaucoma and elevated
`
`IOP tested against latanoprost, prior to December 26, 1996, included PGF2α
`
`analogues: 16-phenoxy-17,18,19,20-tetranorprostaglandin F2α, isopropyl ester
`
`(hereinafter referred to also as “compound C”), cloprostenol isopropyl ester and
`
`fluprostenol isopropyl ester. (EP 0639563A2 to Klimko et al. (“Klimko”), Ex.
`
`1003, p. 15, Table 2). These compounds are structurally close to latanoprost.
`
`41. Compound C is structurally very similar to tafluprost, which is a
`
`compound covered by the ’035 patent and the active ingredient in ZIOPTAN®.
`
`Compound C differs in its chemical structure from tafluprost only slightly in that at
`
`the C-15 position of Compound C, where there is a hydroxyl substituent (i.e., —
`
`14
`
`
`
`Micro Labs Exhibit 1027-14
`
`
`
`OH), tafluprost is substituted with two fluorine (F) atoms.
`
`
`
`42. Compound C, cloprostenol isopropyl ester and fluprostenol isopropyl
`
`ester, along with similar analogues bearing a 16-phenoxy functionality,
`
`demonstrated superior IOP-reducing activity over latanoprost while presenting
`
`slightly elevated occurrence of the undesired side effect of hyperemia when
`
`compared to latanoprost. (Ex. 1003, pp. 15-19).
`
`43. However, prior to December 26, 1996, it was also known in the prior
`
`art that the 15-hydroxyl group on the prostaglandin omega side chain at C-15 was
`
`responsible, in part, for the negative side effect of hyperemia. (U.S. Patent No.
`
`5,292,754 to Kishi et al. (“Kishi”), Ex. 1005 col. 1, l. 65-col. 2, l. 11). The prior
`
`art in a reference referred to later as Kishi in my declaration demonstrated that
`
`hyperemia could be eliminated by removing the 15-hydroxyl group. (Id.). A
`
`compound that has the potential for inducing unwanted hyperemia would suggest
`
`to a POSA that structural modifications would be needed to alleviate these effects.
`
`44. On November 12, 1996, prior to the earliest filing date of the ’035
`
`patent, a group at Alcon unrelated to the inventors of the ’035 patent filed a
`
`15
`
`
`
`Micro Labs Exhibit 1027-15
`
`
`
`provisional application disclosing a series of 15-fluoro-15-deoxy analogues as
`
`effective ocular hypotensives. (PCT/US97/20671 (the “’671 application, Ex.
`
`1012), claiming priority to Provisional U.S. Application No. 60/030,519 (“’519
`
`provisional, Ex. 1013”))2.
`
`
`
`
`
`
`
`
`
`
`
`
`
`5
`
`7
`
`
`
`
`
`
`
`
`
`6
`
`8
`
`
`
`
`
`45.
`
`The ’671 application recognized the problem with side effects of
`
`existing prostaglandin analogues, including hyperemia, as well as the
`
`prostaglandins’ instability in vivo, and prepared the 15-deoxy-15-fluoro analogues
`
`as a response. (Ex. 1012 p. 3, ll. 1-17; Ex. 1013 p. 2, l. 27-p.3, l. 15). The ’671
`
`application also cites numerous prior art references for the proposition of
`
`substituting the 15-hydroxy group at the C-15 position of a prostaglandin with
`
`
`2 The ’671 publication disclosed compounds 5-8 but only compounds 6-8 were
`
`disclosed in the ’519 provisional.
`
`16
`
`
`
`Micro Labs Exhibit 1027-16
`
`
`
`fluorine. (Ex. 1012, p. 3, ll. 16-23). I understand that this ’671 application is not
`
`statutory prior art but it does reflect in my opinion and provides evidence of the
`
`state of the art just prior to December 26, 1996, as the provisional for this
`
`application was filed by others conducting research in the same area at the named
`
`inventors of the ’035 patent just prior to the December 26, 1996 date.
`
`46. Compounds 6-8 of the ’671 application represents the state of the art
`
`and also the general thinking of the POSA prior to December 26, 1996, which was
`
`to make PGF2α analogues with fluorine substitutions at the C-15 position. The
`
`preparation of a PGF2α analogue substituted at the C-15 carbon with a fluorine was
`
`also already known in the prior art as acknowledged by the ’035 patent as it stated
`
`that the prior art disclosed a prostaglandin, 15-fluoro-15-deoxy PGF2α, analogue.
`
`(Ex. 1001, col. 1, ll. 48-51.)
`
`47. As such, given the state of the art and what was known in the prior
`
`art, there is nothing “inventive” or non-obvious with respect to tafluprost, as the
`
`introduction of a fluorine (F) atom at the C-15 position was already being done by
`
`others and the introduction of two fluorine (F) atoms as this same position was also
`
`taught by the prior art as I discuss further below.
`
`IV. PRIOR ART REFERENCES
`
`1.
`
`European Patent Application EP 0 639 563 A2 (“Klimko”
`Ex. 1003)
`I have reviewed European Patent Application EP 0 639 563 A2 to
`
`48.
`
`17
`
`
`
`Micro Labs Exhibit 1027-17
`
`
`
`Klimko et al. (“Klimko”), which published on February 22, 1995. Klimko
`
`describes the use of prostaglandin analogues, and their pharmaceutically
`
`acceptable salts and esters, for treatment of glaucoma and ocular hypertension.
`
`49. Klimko discloses four PGF2α analogues designated as compounds A
`
`through D that are compared with respect to their IOP-reducing capabilities and
`
`potential to induce hyperemia to the reference standard compound latanoprost (Ex.
`
`1003, p. 14, l. 47-p. 19, l. 36 and p. 30, Figure 2). Latanoprost is identified as
`
`compound E.
`
`50.
`
`Each of compounds A through D retains the 15-postion hydroxyl (—
`
`OH) group of naturally occurring PGF2α and is reported by Klimko to exhibit
`
`greater IOP-reducing activity than latanoprost. (Id.). Compound A and B are the
`
`compounds that are the subject of the invention by Klimko whereas compounds C,
`
`D and E (latanoprost) are compounds previously known in the prior art prior to the
`
`disclosure of compounds A and B. (Id., p. 3, ll. 46-50 and p. 14, l. 47-p. 15, l. 50).
`
`51.
`
`The structure and name of compounds A through E appear in Table 2
`
`in Klimko. (Id., p. 15, Table 2).
`
`52. Compound A is the isopropyl ester of cloprostenol.
`
`18
`
`
`
`Micro Labs Exhibit 1027-18
`
`
`
`OH
`
`O
`
`O
`
`HO
`
`O
`
`H OH
`
`
`
`
`
`
`
`Compound A
`
`
`
`Cl
`
`
`
`53. Compound B is the isopropyl ester of fluprostenol. Compound B
`
`differs from compound A by replacement of the chlorine atom (Cl) with a
`
`trifluoromethyl (CF3) group.
`
`OH
`
`O
`
`O
`
`HO
`
`O
`
`H OH
`
`
`
`
`
`
`
`Compound B
`
`CF3
`
`
`
`54. Compound C is shown below. It differs from Compound A by
`
`replacement of the chlorine atom (Cl) with a hydrogen (H) atom.
`
`
`
`
`
`
`
`
`
`55. Compound D is shown below. Compound D differs from compound
`
`19
`
`
`
`Micro Labs Exhibit 1027-19
`
`
`
`C by replacement of the omega side-chain oxygen atom of a phenoxy group with a
`
`methylene (-CH2-) group.
`
`OH
`
`O
`
`O
`
`HO
`
`H OH
`
`
`
`
`
`Compound D
`
`
`
`
`
`
`
`56.
`
`The compounds in Table 2 were studied using animal models to test
`
`their IOP-reducing potential and potential for inducing hyperemia. (Id., p. 14, l.
`
`47-p. 19, l. 35 and p. 30, Figure 2). I have examined and relied on data derived
`
`from testing using animal models in my own research. I am therefore very familiar
`
`with such tests even though I do not directly perform such studies myself in the
`
`laboratory. More specifically, I am very familiar with the animal model studies
`
`that are described in Klimko including how a POSA would interpret the data
`
`resulting from these studies.
`
`57.
`
`In the study in Example 6 of Klimko, cynomolgus monkeys were
`
`used as an animal model to test the IOP-reducing capabilities of compounds A
`
`through E. (Id., p. 18, l. 8-p. 19, l. 35 and p. 30, Figure 2). Klimko describes that
`
`in this study the right eyes of the cynomolgus monkeys were first treated with a
`
`laser to induce ocular hypertension. (Id., p. 18, l. 12-23). The monkeys were then
`
`20
`
`
`
`Micro Labs Exhibit 1027-20
`
`
`
`subjected to a five-dose treatment administered to the lasered right eyes of the
`
`cynomolgus monkeys using test formulations of compounds A-E. (Id.).
`
`58. Klimko describes how baseline IOP values were initially determined
`
`prior to treatment with the test formulation. (Id.). IOP values were then
`
`determined from 1 to 7 hours after the first dose, 16 hours after the fourth dose,
`
`and 1 to 6 hours after the fifth dose. (Id.). The same amount (0.3 µg per dose) of
`
`each of compounds A-E were compared in Table 4 for their IOP reduction activity.
`
`(Id.). Klimko states that the study’s test protocol included a five dose treatment
`
`regimen because of the typical delayed response to prostaglandins. (Id.).
`
`59.
`
`Table 4 in Klimko (reproduced below) tabulates the results of the
`
`study in Example 6. (Id., p. 18, Table 4). Table 4 shows “Percent IOP Reduction”
`
`for each of compounds A to E 16 hours after the fourth dose (16/4), 2 hours after
`
`the fifth dose (2/5), 4 hours after the fifth dose (4/5) and six hours after the sixth
`
`dose (6/5).
`
`
`
`21
`
`
`
`Micro Labs Exhibit 1027-21
`
`
`
`60.
`
`Figure 2 in Klimko (reproduced below) depicts a graphical
`
`representation of the data in Table 4 where “Mean % Change in IOP from
`
`Baseline” for each of compounds A-E is plotted relative to the time in “Hours
`
`After Preceding Dose” from 16 hours after the fourth dose (16/4), 2 hours after the
`
`fifth dose (2/5), 4 hours after the fifth dose (4/5) and 6 hours after the fifth dose
`
`(6/5). (Id., p. 30, Figure 2).
`
`
`
`
`
`
`
`
`
`61.
`
`It is my opinion that the data tabulated in Table 4 and depicted
`
`graphically in Figure 2 indicate to a POSA that there is significant IOP-reducing
`
`activity for compounds A, B, C and D relative to compound E (latanoprost) with
`
`22
`
`
`
`Micro Labs Exhibit 1027-22
`
`
`
`compound C showing longer-lasting efficacy than the other compounds up through
`
`6 hours after administration of the fifth dose (6/5). (See id., p. 18, Table 4 and p.
`
`30, Figure 2).
`
`62.
`
`Specifically, following the administration of the fifth dose, IOP is
`
`measured at two hour intervals and efficacy of compound C after the
`
`administration of the fifth dose lasts longer than the other compounds. This is
`
`evident from the data in Table 4 where in contrast to the other compounds,
`
`compound C’s IOP Percent Reduction is increasing from the 4/5 mark to the 6/5
`
`mark from 23.6% to 28.9%. (See id., p. 18, Table 4).
`
`63. Compounds A, B, D and E begin to show reduced effectiveness 4 to 6
`
`hours after administration of the fifth dose (i.e., from 4/5 to 6/5). (See id., p. 18,
`
`Table 4, p. 30, Figure 2). Compounds A and B show about a two hour delay to
`
`reach the IOP-reducing effectiveness of Compound C and then between hours 4
`
`and 6 after administration of the fifth dose, IOP-reducing effectiveness begins to
`
`diminish. (Id.). Compound D shows the most dramatic IOP-reducing effect in
`
`hours 2 and 4, but then experiences a substantial drop off in IOP-reducing
`
`effectiveness from 4 to 6 hours following the fifth dose. (Id.).
`
`64. A POSA would realize that of the candidate compounds A through D
`
`that could be selected as a lead compound, compound C is the only compound that
`
`does not begin to experience diminished IOP-reducing effectiveness based on the
`
`23
`
`
`
`Micro Labs Exhibit 1027-23
`
`
`
`available data in Example 6 and that if the data is extrapolated past 6 hours after
`
`the fifth dose it is only compound C that would be reasonably expected to exhibit
`
`less diminishment in IOP-reducing effectiveness. (See id.). Therefore, compound
`
`C would be the compound of choice as lead compound due to its apparent long-
`
`lasting efficacy relative to the other compounds. This attribute of compound C is
`
`clearly reflected in Figure 2, which shows that compound C is the only line on the
`
`graph having a downward curve from 16/4 through to 6/5 reflecting whereas all of
`
`the other compounds have lines that are upward curves reflecting that IOP-
`
`reducing efficacy is diminishing. (Id., p. 30, Figure 2).
`
`65. A POSA would also find compound C a compelling lead compound
`
`candidate because it exhibits superior IOP-reducing activity relative to latanoprost
`
`and of the candidate compounds is the only one that does not exhibit diminished
`
`IOP-reducing effectiveness through the 6/5 mark. A POSA would understand this
`
`to mean that compound C has the potential to be more long-lasting in IOP-
`
`reducing effectiveness and would thus POSA would be interested in selecting
`
`compound C as a lead compound. Moreover, a POSA would also recognize from
`
`Figure 2 that IOP-reducing effectiveness could potentially be increasing beyond
`
`the 6/5 mark as compared to the other compounds. In addition, a POSA would
`
`have also selected compound C as a lead compound because this compound has
`
`the greatest mean % change in IOP from baseline 16 hours after administration of
`
`24
`
`
`
`Micro Labs Exhibit 1027-24
`
`
`
`the fourth dose (16/4) compared to all other compounds. (Id., p. 18, Table 4:
`
`Compare Percent IOP reduction of 32.2% to percentages of other compounds.).
`
`66.
`
`In Example 5 in Klimko screening for hyperemia was conducted for
`
`compounds A-E using a guinea pig animal model. (Id., pp. 16-18). Klimko
`
`describes that the objective of the guinea pig conjunctival hyper