UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`MICRO LABS LIMITED AND MICRO LABS USA INC.
`Petitioners,
`
`v.
`
`SANTEN PHARMACEUTICAL CO., LTD. AND ASAHI GLASS CO., LTD.
`Patent Owners.
`_____________
`
`Inter Partes Review No. IPR2017-01434
`U.S. Patent No. 5,886,035
`
`_____________
`
`SUPPLEMENTAL DECLARATION OF MITCHELL A. DELONG, PH.D.
`
`Micro Labs Exhibit 1031
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`TABLE OF CONTENTS
`
`I. BACKGROUND AND QUALIFICATIONS ...................................................... 2 
`A. Education and Experience ............................................................................... 2 
`B. Materials Reviewed ......................................................................................... 2 
`II. PERSON OF ORDINARY SKILL IN THE ART (POSA) ................................. 2 
`III. A POSA WOULD HAVE BEEN MOTIVATED TO SELECT COMPOUND C
`AS A LEAD COMPOUND BASED ON KLIMKO’S DATA ............................ 6 
`IV. A POSA WOULD NOT HAVE VIEWED KLIMKO TO TEACH AWAY
`FROM SELECTION OF COMPOUND C AS A LEAD COMPOUND ........... 12 
`A. A POSA Would Not Have Been Discouraged by the Moderate Hyperemia
`Side Effect Reported with Compound C ....................................................... 12 
`B. No Initial Increase in IOP Is Observed Following Klimko’s Administration
`of Compound C .............................................................................................. 19 
`C. A POSA Would Not Consider An Initial Increase in IOP As A Cause for
`Concern For Compound C ............................................................................. 27 
`D. Moderate Hyperemia and Potential Initial Increase in IOP Would Not
`Dissuade A POSA From Selecting Compound C As A Lead Compound, But
`Rather Provide Strong Motivation for Modifying Compound C In Light of
`Kishi’s Teachings .......................................................................................... 30 
`1. An Initial Increase in IOP Would Not Dissuade A POSA from Selecting
`Compound C As A Lead Compound ....................................................... 30 
`2. Moderate Hyperemia and Potential Initial Increase in IOP Would Have
`Motivated A POSA to Modify Compound Based on Kishi’s Teachings 33
`V. THE PRIOR ART AS A WHOLE WOULD HAVE MOTIVATED A POSA
`TO MODIFY COMPOUND C WITH DIFLURORINATION AT C-15
`POSITION WITH A REASONABLE EXPECTATION OF SUCCESS .......... 40 
`A. Substituting the C-15 Hydroxyl Group With Fluorine Atoms Would Have
`Been A Natural And Obvious Choice For A POSA ..................................... 41 
`B. A POSA Would Have Been Motivated to Modify Compound C With C-15
`Difluorination In Light of Ueno Japan With A Reasonable Expectation of
`Success ........................................................................................................... 45 
`VII. MY OPINIONS IN THIS MATTER ARE CONSISTENT WITH MY PRIOR
`OPINIONS IN THE CANADIAN PROCEEDING ........................................... 51 
`
`i
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`Micro Labs Exhibit 1031-2
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`

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`VIII.  ALLEGED OBJECTIVE INDICIA OF NON-OBVIOUSNESS ................. 55 
`A. Tafluoprost Is Not A Commercial Success ................................................... 55 
`B.  No Unexpected Results Exist ........................................................................ 62 
`C.  Purported Long-felt Need Is Unfounded ....................................................... 63 
`D. There Is No Evidence of Failure of Others ................................................... 63 
`E.  Any Alleged Evidence of Secondary Considerations Is Not Commensurate
`with the Claims of the ’035 Patent ................................................................ 65 
`IX. CONCLUSION .................................................................................................. 68 
`
`ii
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`Micro Labs Exhibit 1031-3
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`

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`
`
`I, Mitchell A. deLong, Ph.D., declare as follows:
`
`1.
`
`I have been retained by the law firm Pillsbury Winthrop Shaw
`
`Pittman LLP (“Pillsbury”) on behalf of Petitioners Micro Labs Limited and Micro
`
`Labs USA Inc. (“Micro Labs” or “Petitioners”). I previously submitted a
`
`declaration in support of Petitioners’ Petition for Inter Partes Review of U.S.
`
`Patent No. 5,886,035 Under 35 U.S.C. § 311 and C.F.R. § 42.108 in the above-
`
`referenced matter that was executed on May 12, 2017. (Ex. 1027, deLong Decl.)
`
`2.
`
`I submit my present declaration in support of Petitioners’ Reply and
`
`also in response to the Patent Owner Response (Paper 22), including the two
`
`declarations submitted by Dr. Timothy L. Macdonald in support of Patent Owner’s
`
`arguments that are dated September 6, 2017 (Ex. 2001) and March 4, 2018 (Ex.
`
`2028). Dr. Macdonald’s declarations do not change my previous opinions and, as I
`
`also explain in further detail below, I disagree with the opinions offered by Dr.
`
`Macdonald in many respects.
`
`3.
`
`For this matter, the compensation that I receive is not dependent on
`
`the substance of any of my testimony or opinions nor is it dependent on the
`
`outcome of this matter. However, I want to clarify how I am being compensated. I
`
`am being billed at a rate of $420 per hour in connection with my work on this
`
`declaration, $670 per hour for any deposition testimony and $225 per hour for
`
`travel time but do not receiving all of my billings as compensation because a
`
`1
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`Micro Labs Exhibit 1031-4
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`

`

`
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`portion goes to an expert retention service. For instance, I am only receiving $250
`
`per hour as I reported in my original declaration of the $420 per hour billed rate in
`
`connection with my work on this declaration.
`
`I.
`
`BACKGROUND AND QUALIFICATIONS
`A. Education and Experience
`4. My educational background and relevant experience is summarized in
`
`my prior declaration (Ex. 1027). A copy of my curriculum vitae is also attached to
`
`my prior declaration as Appendix B.
`
`B. Materials Reviewed
`In forming my opinions for this matter including my declarations, I
`5.
`
`rely on my educational background and relevant experience including the training
`
`and skills that I have accumulated during the course of my career. I have also
`
`reviewed Patent Owner Preliminary Response (Paper 10) and Patent Owner
`
`Response (Paper 22) including declarations submitted by both Drs. Macdonald and
`
`Fechtner in support of these papers inclusive of the exhibits and articles appended
`
`thereto. I have also reviewed the Supplemental Declaration of Aron Rose, M.D.
`
`(Ex. 1032) that I understand is also being submitted in support of Petitioner’s
`
`Reply. An updated list of documents that I have considered while preparing this
`
`reply declaration is attached as Appendix A.
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART (POSA)
`I understand that Dr. Macdonald has proposed that a POSA “would
`
`6.
`
`2
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`Micro Labs Exhibit 1031-5
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`

`

`
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`have been an individual or a team with a Ph.D. degree in medicinal or organic
`
`chemistry, 3 years of work experience in medicinal chemistry, and 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.” (Ex. 2001, Macdonald Decl. ¶ 51.) However,
`
`to the extent that his definition of the POSA would not have “at least several years
`
`of experience researching and developing preventative or therapeutic medicines for
`
`treatment of eye diseases,” I disagree with Dr. Macdonald. Since the claims of
`
`U.S. Patent No. 5,866,035 (“the ’035 patent”) are directed to preventative or
`
`therapeutic medicines for treatment of eye diseases, including but not limited to
`
`diseases such as glaucoma and ocular hypertension (’035 patent, claims 4-14), the
`
`POSA with respect to the ’035 patent must have some relevant academic or
`
`industry experience in researching and developing preventative or therapeutic
`
`medicines for treatment of eye diseases.
`
`7. While Dr. Macdonald agrees with me that the POSA with respect to
`
`the ’035 patent would 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,” he
`
`disagrees that such a POSA would include a chemist with this specific expertise,
`
`because, according to Dr. Macdonald, “[c]hemists working on such projects often
`
`3
`
`Micro Labs Exhibit 1031-6
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`

`

`
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`do not have specific prior experience with eye diseases or animal studies.” (Ex.
`
`2001, Macdonald Decl. ¶¶ 51–52.) Dr. Macdonald’s opinion is contrary to what I
`
`have seen and experienced from my many years of experience working in the
`
`development of medicines to treat eye diseases/conditions, including having
`
`successfully brought to the commercial drug market bimatoprost (Latisse®) for the
`
`treatment of hypotrichosis of the eyelashes via licensing and netarsudil
`
`(Rhopressa®) for the treatment of elevated intraocular pressure in patients with
`
`glaucoma or ocular hypertension via Aerie Pharmaceuticals.1 Dr. Macdonald’s
`
`opinions seem to be based on a misunderstanding of the definition of a POSA.
`
`Having worked in the relevant area that is directly related to the ’035 patent, it is
`
`my opinion that Dr. Macdonald’s misguided definition of the POSA speaks to his
`
`lack of relevant experience and runs contrary to what people in the field knew and
`
`
`1 My research and development work has also led to five Investigational New Drug
`
`(“IND”) applications. All five of those drugs are either prostaglandin analogs, rho-
`
`kinase inhibitors, or combinations thereof, and they are all used to treat elevated
`
`IOP. Four of my five INDs proceeded to and completed phase 2 clinical trials,
`
`including a novel prostaglandin prodrug termed AR-102. I also have a pending
`
`New Drug Application for a combination drug for treatment of glaucoma and
`
`elevated intraocular pressure.
`
`4
`
`Micro Labs Exhibit 1031-7
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`

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`
`
`were actually doing at the time of the alleged invention. As I stated in my prior
`
`declaration, I understand that a POSA is a hypothetical person who is presumed to
`
`be aware of all the pertinent prior art at the time the alleged invention was made,
`
`thinks along conventional wisdom in the art, and is a person of ordinary creativity.
`
`(Ex. 1027, Macdonald Decl. ¶¶ 26–27 (emphases added).)
`
`8.
`
`I also disagree with Dr. Macdonald’s opinion that the POSA would
`
`not have “familiarity designing, formulating and evaluating ophthalmic
`
`compositions for treatment of eye conditions that include glaucoma or ocular
`
`hypertension.” (Ex. 2001, Macdonald Decl. ¶ 53.) While the claims of the ’035
`
`patent are generally directed to medicines containing at least one of the claimed
`
`compounds as an active ingredient and do not recite any particular formulation
`
`details, the specification of the ’035 patent discloses “[t]ypical formulations” of an
`
`ophthalmic solution and an ophthalmic ointment that are encompassed by the
`
`claimed medicines of the alleged invention in the ’035 patent. (’035 patent, at col.
`
`27, ll. 6–67, Example 22). Because development of the claims of the ’035 patent
`
`requires designing, formulating and evaluating ophthalmic compositions for
`
`treatment of eye conditions that include glaucoma or ocular hypertension, the
`
`POSA must have a complete understanding of such skill. Accordingly, it is my
`
`opinion that Dr. Macdonald’s definition of the POSA lacks specificity. Dr.
`
`Macdonald’s overly broad definition of a POSA misguided his opinions on the
`
`5
`
`Micro Labs Exhibit 1031-8
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`

`
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`state of the art of the ’035 patent and a POSA’s understanding of the art as of
`
`December 1996. Dr. Macdonald’s misunderstanding of what type of knowledge
`
`and experience the POSA should possess could be due to his lack of actual
`
`experience in industry and in the development of medicines to treat eye diseases
`
`such as glaucoma.
`
`9.
`
`Based on my definition of the POSA, it is my opinion that Dr.
`
`Macdonald is not qualified to speak on the understanding of a POSA in “some of
`
`relevant aspects in relation to the issues in this proceeding,” specifically the
`
`development of potential prostaglandin analogues that could be used for treatment
`
`and/or management of elevated intraocular pressure (IOP)/ocular hypertension and
`
`glaucoma. (Ex. 2001, Macdonald Decl. ¶ 4.) None of Dr. Macdonald’s published
`
`works are specifically in the area of prostaglandin analogues, or in the areas of
`
`treating glaucoma or ocular hypertension, let alone any works in the area of using
`
`prostaglandin analogues in the treatment of glaucoma or ocular hypertension. (Id.
`
`at ¶ 8; Ex. A.)
`
`III. A POSA WOULD HAVE BEEN MOTIVATED TO SELECT
`COMPOUND C AS A LEAD COMPOUND BASED ON KLIMKO’S
`DATA
`I note that Dr. Macdonald does not dispute that long-lasting IOP-
`
`10.
`
`reducing efficacy is an important factor for a POSA when it comes to selection of a
`
`lead compound. Instead, Dr. Macdonald offers an opinion in his declaration that
`
`6
`
`Micro Labs Exhibit 1031-9
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`

`

`
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`neither Table 4 nor Figure 2 of Klimko that measures percent IOP reduction in
`
`laser-treated cynomolgus monkey eyes at various time points contain any data that
`
`would establish that compound C has a longer-lasting efficacy than the other
`
`compounds in the table or figure. I disagree with Dr. Macdonald’s erroneous
`
`opinion. For the reasons discussed below, a POSA would easily recognize
`
`compound C as exhibiting a longer-lasting IOP-reducing efficacy than the other
`
`compounds disclosed in Klimko.
`
`11. Dr. Macdonald’s opinion is based on a flawed analysis of the data
`
`because he incorrectly focuses only on the “last measured time point” (the last time
`
`point measured after administration of the fifth dose) in the data of the table and
`
`figure to contend that Klimko does not establish that any of Compounds A–D have
`
`a longer-lasting efficacy than the others. (Ex. 2001, Macdonald Decl. ¶¶ 90–91;
`
`PO Resp. at 43–44).
`
`12. A POSA when considering which of the compounds has the longest-
`
`lasting efficacy would immediately consider the significance of the percent IOP
`
`reduction measured at the time point that follows the greatest elapsed time between
`
`doses.2 In Klimko’s data this is 16 hours after the fourth dose (i.e., 16/4). In other
`
`
`2 The 5 dose-treatment regimen of Klimko of each of compounds A, B, C, D and E
`
`were at time = 0 for dose 1, time = hour 8 for dose 2, time = hour 24 for dose 3,
`
`7
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`Micro Labs Exhibit 1031-10
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`

`
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`words, the percent IOP reduction measured at the time point that is 16 hours after
`
`the fourth dose is the furthest time point out following any administration of a
`
`dose of the compounds and therefore has the most significance to the POSA when
`
`determining which compounds have the potential for the longest-lasting IOP
`
`reducing efficacy. That is precisely why that particular data point is taken in the
`
`first place. That POSA would not focus on the percent IOP reduction at the “last
`
`measured time point” that occurs only 6 hours after administration of a dose that is
`
`the fifth dose (i.e., 6/5). There is some overlap in the percent IOP reduction error
`
`bars as between compound C and compounds D and A at this time point (16/4), but
`
`this would not dissuade a POSA from recognizing that compound C has the
`
`greatest and longest-lasting IOP-reducing potential (30.2±4.4 percent IOP
`
`reduction) compared to the other compounds.
`
`
`time = hour 32 for dose 4 and then at around time = hour 48 for dose 5 (i.e., shortly
`
`after the percent IOP-reduction measurement is taken at 16 hours after the fourth
`
`dose (16/4). The timing mimics the activity of people working in a research lab
`
`that would conduct the testing as easily recognized by the POSA: administration in
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`the morning of dose 1, 8 hours later at the end of the day for dose 2, 16 hours later
`
`the next morning for dose 3, 8 hours later for dose 4 at the end of the day and then
`
`16 hours+ the next day for dose 5.
`
`8
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`Micro Labs Exhibit 1031-11
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`

`

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`13. Dr. Macdonald and I are in agreement that a POSA would not just
`
`want to rely on one isolated time point, 16 hours after the fourth dose, but would
`
`want to consider other available data, if any are available, before reaching a
`
`decision on selection of compound C as the lead compound. That POSA would
`
`not only consider in my opinion the percent IOP reduction at 16 hours after the
`
`fourth dose but also the entirety of the graph in Figure 2 of Klimko. Klimko’s data
`
`show the trend of the IOP-reducing effect at 2, 4, and 6 hours after administration
`
`of the fifth dose. This exhibited trend would be recognized by a POSA in my
`
`opinion as most closely evidencing what would have also been seen with respect to
`
`the corresponding previous time points that are before the 16 hours following
`
`administration of the fourth dose that were not measured or reported by Klimko.
`
`14. As shown in Figure 2, compounds D, A and B all reach their
`
`respective peak percent IOP-reduction early, at only 2 or 4 hours following
`
`administration of a dose (i.e., in this case the fifth dose), whereas the peak effect in
`
`percent IOP reduction for compound C does not begin taking effect until 6 hours
`
`after administration of the dose (as reflected by the upward curve before the 4
`
`hours after the preceding dose and then downward curve between hour 4 and 6
`
`after administration of the preceding dose). In other words, a POSA would
`
`understand that compounds D, A and B have a shorter time to peak IOP-reduction
`
`and therefore a shorter duration of IOP reduction efficacy when compared to
`
`9
`
`Micro Labs Exhibit 1031-12
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`

`

`compound C as discussed further below.
`
`
`
`This is supported by Stjernschantz’s data that confirms that compound D has a
`
`shorter time to peak effect (~ 4 hours) compared to compound C (6 hours or
`
`longer). (See Ex. 2017 at pp. 16-17, Table V (showing that compound (2)
`
`(compound D in Klimko) reaches its peak effect at 3-4 hours after administration
`
`while compound (4) (compound C in Klimko) reaches its peak at 6 hours (or even
`
`longer) after administration).)
`
`15. An earlier peak IOP-reduction effect (2-4 hours for compounds A, B
`
`and D) was known to correlate with a shorter duration of IOP reduction as also
`
`shown in Figure 2, while a longer time to peak effect correlates with a prolonged
`
`duration of IOP reduction. A POSA considering Klimko’s data as a whole would
`
`recognize that compound C has a longer duration (i.e., longer-lasting) of IOP-
`
`10
`
`Micro Labs Exhibit 1031-13
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`

`

`
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`reduction effect as compared to compound D, A and B. This is further confirmed
`
`by Klimko’s data wherein compounds D, A and B start to show reduced
`
`effectiveness 4 to 6 hours after administration of the fifth dose, in contrast to
`
`compound C, which does not exhibit diminished IOP-reducing effectiveness. (Ex.
`
`1003, p. 18, Table 4, p. 30, Figure 2.) Based on the percent IOP reduction at the
`
`furthest time point following administration of a dose (i.e., 16 hours after the
`
`fourth dose) and also the trend for the percent IOP reduction for all the time points
`
`following administration of the fifth dose, a POSA would have the reasonable
`
`expectation that compound C, when compared to the other compounds, would have
`
`the longest lasting efficacy and also less diminishment in IOP-reducing
`
`effectiveness 6 hours after administration of a dose.
`
`16. A POSA selecting a potential lead compound for treatment of
`
`glaucoma and ocular hypertension would also find compound C attractive as a lead
`
`compound for selection for further development because of its later peak time for
`
`IOP-reduction (6 hours or longer). This is in addition to the longer-lasting efficacy
`
`advantage that a POSA would expect for compound C as compared to the other
`
`compounds. This is because as of December 1996 it was commonly known in the
`
`field that intraocular pressure is highest in the early morning between 6 a.m. and 8
`
`a.m., therefore it would be ideal to align the peak time for IOP-reduction of a
`
`potential once-daily drug with the highest IOP time of the patients. (See, e.g., Ex.
`
`11
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`Micro Labs Exhibit 1031-14
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`

`

`
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`1040, Camras C.B. et al., “Comparison of latanoprost and timolol in patients with
`
`ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the
`
`United States,” Ophthalmology, 103(1):138–47 (January 1996), at 8 (administering
`
`latanoprost in the evening rather than in the morning to “block an early morning
`
`diurnal spike of IOP.”). Therefore, a POSA would recognize that the later peak
`
`time for the IOP-reduction (6 hours or longer) of compound C has the greatest
`
`potential for achieving this goal through administration of compound C once-daily
`
`in the evening before the patient goes to sleep.
`
`IV. A POSA WOULD NOT HAVE VIEWED KLIMKO TO TEACH AWAY
`FROM SELECTION OF COMPOUND C AS A LEAD COMPOUND
`A. A POSA Would Not Have Been Discouraged by the Moderate
`Hyperemia Side Effect Reported with Compound C
`17. Dr. Macdonald misapprehends Klimko when he makes the conclusory
`
`judgment, without analyzing the scientific data presented in Klimko, that in his
`
`opinion a POSA would not have considered compound C to be a lead compound
`
`because of its “unacceptable therapeutic profile,” and that Klimko teaches away
`
`from selection of compound C as a lead compound. To the contrary, based on the
`
`data available in Klimko, and as already explained in my previous declaration, a
`
`POSA would have viewed compound C as having an acceptable therapeutic profile
`
`and would have selected compound C as a lead compound. A POSA would not
`
`have viewed Klimko as somehow teaching away from compound C.
`
`12
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`Micro Labs Exhibit 1031-15
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`

`

`
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`18. As an initial matter, unlike other forms of scientific publications, the
`
`primary goal in drafting a patent application is to obtain a patent; this would be
`
`understood by all researchers and thus the POSA. Klimko is a European Patent
`
`Application that relates to the use of cloprostenol, fluprostenol, their analogues and
`
`their pharmaceutically acceptable salts and esters to treat glaucoma and ocular
`
`hypertension. (Ex. 1003, p. 2, ll. 4–5.) Specifically, the claims in Klimko are
`
`directed to the use of a therapeutically effective amount of a class of compounds
`
`that encompass cloprostenol, fluprostenol, their analogues and their
`
`pharmaceutically acceptable salts. (Id., pp. 24–28, Claims 1–31.)
`
`19.
`
`In the “Background of the Invention,” Klimko acknowledges that
`
`both cloprostenol and fluprostenol are “generically included” although not
`
`“specifically mentioned” in the compounds already disclosed in European Patent
`
`Application EP364417 A1 to Stjernschantz et al. (“Stjernschantz” (Ex. 2017)).
`
`(Id., p. 3 (“Because they contain heteroatom (O) interruption of the omega chain,
`
`both cloprostenol and fluprostenol are generically included in the subclass defined
`
`in formula 2 by Stjernschantz et al.”).) Klimko further acknowledges that “[t]he
`
`only example of a heteroatom-interrupted omega chain disclosed by Stjernschantz
`
`et al. is 16-phenoxy-17, 18, 19, 20 tetranor-PGF2α isopropyl ester,” which is
`
`referred as compound C in Klimko. (Id. at p.15).
`
`20.
`
`Since compound C was disclosed in the prior art reference
`
`13
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`Micro Labs Exhibit 1031-16
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`

`

`
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`Stjernschantz, a POSA would have understood that the inventors of Klimko knew
`
`that, to be able to obtain a patent on the compounds cloprostenol and fluprostenol,
`
`they must assert or claim that these compounds somehow had certain advantages
`
`over the already disclosed compound C. The POSA in reviewing Klimko and the
`
`data therein would easily recognize the intent behind the obviously self-serving
`
`remarks in Klimko as specifically drafted to distinguish over and/or specifically
`
`exclude/carve out compound C.
`
`21. A POSA in December 1996 reviewing the conjunctival hyperemia test
`
`data disclosed in Table IV of Stjernschantz, which is specifically cited to in
`
`Klimko (Ex. 1003, p. 3, l. 42), would not conclude that compound C displays
`
`“unacceptable hyperemia” as reported by Klimko in the “Background of the
`
`Invention.” (Id. at l. 42.)
`
`22.
`
`In Stjernschantz, compound C (Klimko’s designation) and PGF2α-IE,
`
`along with other PGF2α derivatives, were tested for conjunctival hyperemia after
`
`topical application in rabbits. (Ex. 2017, p. 10, ll. 16–19). Conjunctival hyperemia
`
`was scored on a scale from 0 to 4 indicating degree of hyperemia with a score of 0
`
`indicating a complete absence of any hyperemia and a score of 4 indicating marked
`
`hyperemia with conjunctival chemosis (i.e., the worst). (Id. at ll. 19–20). Table IV
`
`in Stjernschantz presents the degree of conjunctival hyperemia as tested for a
`
`number of compounds including compound C (i.e., compound (4)):
`
`14
`
`Micro Labs Exhibit 1031-17
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`

`

`
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`
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`(Ex. 2017 at p. 15, Table IV, ll. 1–11 & 40–41.) The score for conjunctival
`
`hyperemia for compound C is only 2.3 ± 0.3. The score of 2.3 representing the
`
`degree of hyperemia is not a 4 representing the worst degree of hyperemia nor is it
`
`even a 3. A POSA would not consider a modest score of 2.3 to be “unacceptable”
`
`conjunctival hyperemia side effect. In addition, Dr. Stjernschantz, “an expert in
`
`the field who developed latanoprost” according to Dr. Macdonald, similarly
`
`characterizes a likewise close score of “2.0 ± 0.3” for 17-phenyl-18, 19, 20-trinor-
`
`PGF2α derivatives (i.e., compound (2) in Stjernschantz, referred as compound D in
`
`Klimko) as showing “only modest conjunctival/episcleral hyperemia.” (Id. at p.
`
`15
`
`Micro Labs Exhibit 1031-18
`
`

`

`
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`10, ll. 57–58) (emphasis added). Thus, in my opinion, a POSA reading Klimko’s
`
`references to Stjernschantz’s IOP reducing effect data, who reviewed those data,
`
`would not conclude, as Klimko self-servingly did, that compound C “displays
`
`unacceptable hyperemia.”
`
`23. Moreover, there are additional reasons in my opinion for a POSA to
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`select compound C of Klimko if a POSA were to review Stjernschantz that Klimko
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`references and the PO seeks to rely on. As of December 1996, one of the frequent
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`and clinically unacceptable side effects known for prostaglandin derivatives that a
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`POSA would consider in selecting a lead compound was ocular irritation
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`(discomfort). Stjernschantz, however, reports in Table III that compound C
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`(compound (4) in Stjernschantz) has very little irritating effect (with a degree
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`ocular irritation of only 0.3±0.2 on a scale from 0 to 3) even at a high dose of 5 µg.
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`(Id. at p. 14, Table III, l. 25). The characterization that compound C has an
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`unacceptable therapeutic profile is belied by the data in Stjernschantz. Compound
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`C is a lead compound that would have been considered by a POSA in view of the
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`significantly potent IOP-reducing efficacy of compound C as also presented in
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`Table V of Stjernschantz. (Id. at Table V; p. 11, ll. 8–9.)
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`24. Dr. Macdonald is misguided when he attempts to interpret Klimko’s
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`screening results for hyperemia for compounds A–E using a guinea pig animal
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`model as a “confirm[ation] that compound C exhibits the unacceptable therapeutic
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`16
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`profile” described by Klimko. (Ex. 2001, Macdonald Decl. ¶¶ 79–83.) The results
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`reported in Table 3 of Klimko do not suggest that compound C exhibits an
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`unacceptable therapeutic profile, as I explain in further detail below.
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`25. As I previously noted in my first declaration, Example 5 in Klimko
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`uses a scale from 0 to 4 to score the guinea pig conjunctival hyperemia, 0
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`indicating “[n]ormal appearance of vessels at limb us and on superior rectus
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`muscle,” +1 indicating “[e]nlargement of vessels normally visible at limbus and on
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`superior rectus muscle,” +2 indicating “[b]ranch of vessels at limbus, new vessels
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`visible,” +3 indicating “[n]ew vessels visible in open bulbar conjunctival areas,”
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`and +4 being the worst and indicating “[d]iffuse redness in open bulbar
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`conjunctival areas.” (Ex. 1003, p. 16, ll. 6–15; Ex. 1027, deLong Decl. ¶ 66.) It is
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`noteworthy that none of the tested guinea pigs had a score of 4 (which is the most
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`severe score) in Table 3 of Klimko.3 This informs a POSA that compound C only
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`caused at most moderate conjunctival hyperemia in the tested guinea pigs. (Ex.
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`1003, p. 17, Table 3). A POSA would certainly not have considered compound C
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`3 The numbers in Table 3 of Klimko indicate the “percent incidence for [each]
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`score.” (Ex. 1003, p. 17, Table 3). All the numbers for each dose when added up
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`equal 100 (percent incidence) confirming that the percent incidence for a score 4
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`for each of the doses must be 0 and the reason not reported.
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`17
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`based on Table 3 in Klimko to have an unacceptable therapeutic profile,
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`particularly given that there was no reported score of 4 even when guinea pigs
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`were dosed at a higher dose of 1.0 µg of compound C.
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`26. Moderate conjunctival hyperemia is not the same as “severe
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`hyperemia” and would not have discouraged a POSA from selecting compound C
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`as a lead compound. Dr. Macdonald’s claim that, to a POSA, the data presented in
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`both Stjernschantz and Klimko show that compound C is associated with severe
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`hyperemia is incorrect. Also unsupported and erroneous is Dr. Macdonald’s claim
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`that a POSA would not have selected compound C as a lead compound. This is
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`further confirmed in view of what is known about later developed prostaglandin
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`analogs such as bimatoprost and travoprost (i.e., fluprostenol isopropyl ester) that
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`are used for the treatment of glaucoma and ocular hypertension. Prostaglandin
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`analogs that are used as topical IOP-lowering medications were generally known to
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`be associated with a high incidence of conjunctival hyperemia. (See, e.g., Ex. 1011
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`at p. 2.) Even so, both bimatoprost and travoprost―which exhibit more observed
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`incidence rates of conjunctival hyperemia compared to latanoprost―were still both
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`developed to commercially-available prostaglandin analogs after latanoprost. (Id.)
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`27.
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`Further, a POSA would also recognize that the majority (62 percent)
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`of tested guinea pigs had a score of only 2 (which indicates only mild/modest
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`hyperemia) at a dose of 0.3 µg for compound C (Ex. 1003 at p. 17, Table 3), which
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`18
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`is the same dose that shows the largest reduction in intraocular pressure at the first
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`tabulated measurement in Table 4 and Figure 2 of Klimko, which corresponds to
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`the percent IOP reduction measurement taken at 16 hours after administration of
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`the fourth dose (16/4). (Id., p. 18, Table 4; p. 30, Figure 2; Ex. 1027, deLong Decl.
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`¶ 70). A POSA would recognize compound C as a lead compound because of its
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`superior IOP-reducing efficacy and its exhibition of only mild/moderate levels of
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`hyperemia. The POSA would have been further motivated to select compound C
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`as a lead compound for further development of a PGF2α analogue for treatment of
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`glaucoma and ocular hypertension because of the teaching in Kishi, which teaches
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`how to reduce the side effect of hyperemia through removal of the hydroxyl group
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`at the C-15 position of a compound such as compound C.
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`28. Accordingly, in my opinion, a POSA would not have viewed
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`Klimko’s hyperemia data as somehow teaching away from the selection of
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`compound C as a lead compound.
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`B. No Initial Increase in IOP Is Observed Following Klimko’s
`Administration of Compound C
`29. Dr. Macdonald suggests that there is an initial increase in IOP shown
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`in Klimko following administration of compound C but this suggestion is
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`erroneous because it relies on Dr. Macdonald’s misunderstanding of what is meant
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`by an “initial increase in IOP” by a POSA. (Ex. 2028, Macdonald Suppl. Decl. ¶
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`7). As explained in greater detail below, Dr. Macdonald incorrectly concludes that
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`19
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`there is an initial increase in IOP because he does not understand what is actually
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`meant in the field when there is an “initial increase in IOP” despite having
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`referenced an article explaining what is meant by the phrase.
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`30. As of December 1996 it had been well-established in the art that high
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`doses of