UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`ALCON RESEARCH LIMITED
`Patent Owner
`
`Patent No. 8,268,299
`
`Inter Partes Review Case No. IPR2017-01053
`
`SECOND DECLARATION OF DR. YVONNE M. BUYS, M.D.
`
`1
`
`Exhibit 1092
`ARGENTUM
`IPR2017-01053
`
`000001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`ALCON RESEARCH LIMITED
`Patent Owner
`
`Patent No. 8,268,299
`
`Inter Partes Review Case No. IPR2017-01053
`
`SECOND DECLARATION OF DR. YVONNE M. BUYS, M.D.
`
`1
`
`Exhibit 1092
`ARGENTUM
`IPR2017-01053
`
`000001
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION .......................................................................................... 3
`
`TRAVATAN Z DID NOT SATISFY ANY LONG-FELT BUT UNMET
`NEED ............................................................................................................. 3
`
`A. Alcon Misidentifies The Alleged “Need,” To The Extent It Even
`Existed .................................................................................................. 4
`
`B. Whether Or Not Alcon’s Characterization Of The Alleged “Need” Is
`Adopted, Any Such Need Was Not “Unmet” ...................................... 7
`
`C.
`
`TRAVATAN Z Does Not Satisfy The “Need” Alleged By Alcon ... 13
`
`1.
`
`2.
`
`3.
`4.
`
`The actual data in the references relied upon by Dr. Parrish do
`not support Dr. Parrish’s testimony ......................................... 13
`The data shows that, if anything, TRAVATAN Z makes OSD
`symptoms worse, not better ..................................................... 24
`TRAVATAN Z fails to control IOP in many patients ............ 27
`There are numerous options for treating elevated IOP in
`patients who present with OSD ............................................... 30
`
`
`
`
`
`I.
`
`II.
`
`
`
`
`2
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`000002
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`
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`I, Yvonne Buys, do declare as follows:
`
`INTRODUCTION
`
`
`I.
`
`1.
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`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
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`I have been retained as an expert witness on behalf of Argentum
`
`Pharmaceuticals LLC for a inter partes review (IPR) for U.S. Patent No. 8,268,299
`
`(“the ’299 patent”). I am being compensated for my time by the hour in preparing
`
`this declaration, but my compensation is not tied to the outcome of this matter. I
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`understand that this, my second declaration, will accompany a reply filing in the
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`inter partes review proceeding involving the above-mentioned U.S. Patent.
`
`3.
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`In formulating my opinions expressed in this declaration, the
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`documents I considered include Alcon’s Patent Owner Response (Paper 22;
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`“POR”), Dr. Parrish’s Declaration (ALCON2027) and the documents cited therein,
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`as well as the other documents I cite in this declaration. I also rely on my
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`background knowledge, education, and expertise in this field generally, which I
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`have described previously. See EX1021, ¶¶ 3-9; EX1023.
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`II. TRAVATAN Z DID NOT SATISFY ANY LONG-FELT BUT UNMET
`NEED
`
`4.
`
`Alcon argues that TRAVATAN Z “has met a long-felt need for a
`
`highly effective antiglaucoma medication that is free of BAK.” POR, pp. 56-58.
`
`In support of its arguments, Alcon relies exclusively on the Declaration of Richard
`3
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`000003
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`
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`K. Parrish, II, PhD (EX2027). Alcon and Dr. Parrish make various misstatements
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`and/or mischaracterize the references they rely on, and I wish to address those
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`issues in this declaration. I will note, however, that if this declaration fails to
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`address something argued by Alcon or Dr. Parrish, that should not be taken as an
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`admission that I agree with any such arguments raised by Alcon and its experts.
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`Instead, I am simply pointing out in this declaration the arguments and statements
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`made by Alcon and Dr. Parrish that I believe to be the most in need of correction.
`
`A. Alcon Misidentifies The Alleged “Need,” To The Extent It Even
`Existed
`
`5.
`
`Alcon argues that “there has been a long-felt need for a highly
`
`effective BAK-free antiglaucoma drug that can be provided once per day and that
`
`would be less likely to give rise to OSD over an extended period of use.” POR, pp.
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`57-58. Likewise, Dr. Parrish claims that “as of 2006, there was a long-felt need
`
`among those treating glaucoma for a highly-effective, BAK-free antiglaucoma
`
`drug that would not lead to an increased risk of the exacerbation of OSD symptoms
`
`with chronic use.” ALCON2027, ¶ 26. However, to the extent that there was a
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`need at all, Alcon mischaracterizes what that need was. First of all, it is not clear
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`why Alcon and Dr. Parrish focus only on glaucoma treatments, since many of the
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`claims of the ’299 patent do not seem to be so limited (e.g., claim 1). Alcon
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`suggests that this is appropriate because “glaucoma is one of only two conditions
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`that requires chronic, daily dosing with an ophthalmic composition.” POR, 57.
`4
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`000004
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`
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`While glaucoma and dry eye may be the most common ocular conditions that
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`require chronic drops, there are many other conditions that may also require
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`chronic daily topical steroids, such as patients who have had corneal transplants,
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`cases of interstitial keratits (herpetic infection of the cornea), and cases of chronic
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`uveitis. Thus, claim 1 does not suggest a pure focus only on glaucoma.
`
`6.
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`The medical problem focused on by Alcon and Dr. Parrish traces back
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`to patients with primary open-angle glaucoma (“POAG”) who require intraocular
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`pressure (“IOP”) lowering as a result. Id., ¶ 17. Alcon and Dr. Parrish then
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`identify ocular surface disease (“OSD”) as a potential problem in such patients.
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`Id., ¶¶ 24-25. Even if one is limited to just focusing on this medical issue, while
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`those propositions may be true, the weakness with Alcon’s and Dr. Parrish’s
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`argument is that they then jump straight to the conclusion that these patients need a
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`“highly effective, BAK-free antiglaucoma drug” that will not exacerbate OSD. Id.,
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`¶ 26.
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`7.
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`The problem with this analysis is that Alcon and Dr. Parrish provide
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`no basis or explanation for why this alleged need was focused solely on an
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`antiglaucoma “drug.” To the contrary, by 2006 there were other treatment options
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`for patients with primary open-angle glaucoma who exhibited elevated IOP, either
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`with or without OSD symptoms. Thus, to the extent there was a “need” in 2006 at
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`all, it would be more correctly characterized as a need for an antiglaucoma
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`5
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`000005
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`
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`treatment that would not exacerbate OSD symptoms. In other words, there is no
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`reason why a practitioner in the field would have focused on a need solely directed
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`to an antiglaucoma drug, as opposed to an antiglaucoma treatment in general.
`
`Support for my position can be found in Dr. Parrish’s own Exhibit 2129, which
`
`explains that the goal in treating patients with POAG is to control IOP while
`
`stabilizing the optic nerve and visual field. ALCON2019, P63. (This same exhibit
`
`also lists numerous treatment options, two out of three of which involve non-
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`pharmaceutical options. Id.)
`
`8.
`
`I believe this distinction is important because, as I discuss in the next
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`section below, as of 2006 there already were known solutions for treating patients
`
`with elevated IOP who exhibited OSD symptoms. By narrowly defining the
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`“need” as one specifically for an antiglaucoma drug, as opposed to an
`
`antiglaucoma treatment in general, Alcon and Dr. Parrish conveniently attempt to
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`sidestep and ignore the other antiglaucoma treatments already known as of 2006
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`that would not have exacerbated or led to an increased risk of OSD symptoms.
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`9.
`
`Lastly, I will stand by my original testimony that the percentage of
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`patients who suffer from a BAK allergy at all is quite low, estimated at around 8%.
`
`See EX1021, ¶ 12. While Dr. Parrish claims that this figure is unreliable
`
`(ALCON2027, ¶ 39), I will note that the paper he turns to, Hong et al. (EX2139),
`
`reports results consistent with my estimate. Specifically, Hong says that 4-11% of
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`6
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`000006
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`
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`patients show a skin-test-positive (allergy) rate to salts of benzalkonium chloride
`
`(i.e., BAK) (EX2139, p. 447 (second column)). This range clearly brackets my
`
`estimate of 8% based on the teachings of Bagnis (EX1026, p. 391).
`
`10.
`
`In any event, the point is not to try to determine the BAK-allergy rate
`
`to multiple significant digits. Instead, the relevant point here is that the percentage
`
`of patients exhibiting any kind of allergic reaction to BAK is quite low, likely in
`
`the single digits, thus showing that any “need” for a BAK-free medication is either
`
`nonexistent or, at best, quite modest. I am not aware of any patient populations
`
`who could not be adequately treated as of 2006, without resorting to using
`
`TRAVATAN Z.
`
`B. Whether Or Not Alcon’s Characterization Of The Alleged “Need”
`Is Adopted, Any Such Need Was Not “Unmet”
`
`11. When the problem is properly viewed as patients who need an
`
`antiglaucoma treatment that does not exacerbate OSD symptoms, then neither
`
`Alcon nor Dr. Parrish can disagree that there were numerous such treatment
`
`options available as of 2006. The options as of 2006 included both surgical
`
`procedures, as well as laser treatments.1 The surgical options include
`
`
`1 Dr. Parrish relies on Exhibit 2129 to support his contention that PGAs are the
`
`mostly commonly prescribed medications for lowering IOP in glaucoma patients
`
`(ALCON2027, ¶ 19 n.6), despite the fact that this reference is dated 2016. To the
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`7
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`000007
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`
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`trabeculectomy, glaucoma drainage devices, combined surgeries with cataract
`
`surgery such as combined cataract surgery and trabeculectomy, cataract surgery
`
`and glaucoma drainage device, cataract surgery and endocylophotocoagulation,
`
`and a variety of other glaucoma surgical procedures such as nonpenetrating
`
`glaucoma surgery, canaloplasty, Trabectome, trabecular meshwork bypass stent
`
`and Ex-PRESS mini glaucoma shunt, all of which achieve the dual goals of both
`
`lowering IOP and avoiding the exacerbation of OSD symptoms. See
`
`ALCON2011, pp. 24-27. Surgical treatment options would not typically be
`
`expected to cause or exacerbate OSD symptoms because successful procedures do
`
`not require ongoing medical management.
`
`12. With respect to laser treatments, there were two such treatment
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`options available in 2006, known as argon laser trabeculoplasty (“ALT”) and
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`selective laser trabeculoplasty (“SLT”). See ALCON2011, pp. 22-23. Similar to
`
`the surgical procedures described above, both SLT and ALT were known to
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`alleviate elevated IOP in patients with glaucoma, and worked by improving
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`outflow of aqueous humor. Nor would these procedures typically cause or
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`exacerbate OSD symptoms because these treatments are non-medical. These laser
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`extent this reference is considered relevant, I will point out that it also confirms my
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`testimony in teaching that “eye care providers can lower IOP with medications,
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`laser therapy, or incisional glaucoma surgery.” ALCON2129, P63.
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`8
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`procedures have been identified in the art as suitable for first-line treatment in at
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`least some patients. Id., p. 22 (“Laser trabeculoplasty can be considered as initial
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`therapy in selected patients.”).
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`13. Dr. Parrish himself acknowledges that such procedures were known as
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`of 2006, and Dr. Parrish’s claim that such procedures were “less advanced” than
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`they are today does nothing to negate the fact that these treatments were indeed
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`available options at that time. ALCON 2027, ¶ 18 n.5. An advantage not
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`mentioned by Dr. Parrish is that these treatments were useful not only for lowering
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`IOP while avoiding preservatives such as BAK, but they also avoided the
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`inconvenience of and difficulty adhering to long-term eye drop therapy altogether.
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`See ALCON2011, p. 21 (noting the poor level of patient adherence to eye drop
`
`therapy, with one study reporting nearly 45% of patients taking fewer than 75% of
`
`their prescribed doses). For these reasons, at least some patients in 2006 would opt
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`for a surgical or laser procedure as a first treatment option, without even trying
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`antiglaucoma medications available via eye drops, and irrespective of any fear of
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`or potential for OSD symptoms.
`
`14. Finally, even if I were to accept Alcon and Dr. Parrish’s
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`characterization of the “need” as being directed specifically to a BAK-free
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`antiglaucoma drug, even this need was met as of 2006. In particular, by 2006 there
`
`were several BAK-free antiglaucoma drugs available that were used to treat
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`9
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`
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`elevated IOP due to glaucoma. One example is preservative-free TIMOLOL
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`(available in two different concentrations of either 0.25% or 0.5%), which was
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`prescribed to treat patients with elevated IOP while avoiding potential problems
`
`attributed to BAK. EX1049, p. 339 (second column) (“A new product ('timolol-
`
`BAC') has been developed in order to avoid some of the side effects of
`
`timolol+BAC. Timolol-BAC is identical in all respects to timolol+BAC except
`
`that it lacks a preservative.”). Indeed, Dr. Parrish admits that many other classes of
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`drugs were also available in 2006 to lower IOP, including beta blockers, alpha-2
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`agonists, topical carbonic anhydrase inhibitors and combination drugs.
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`ALCON2027, ¶ 20. In addition, oral drugs were also available at that time,
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`including oral carbonic anhydrase inhibitors like acetazolamide and
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`methazolamide, which also would not have included BAK.
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`15. Further calling into question Alcon’s and Dr. Parrish’s claim that
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`there was an “unmet” need for a “highly effective BAK-free antiglaucoma drug
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`that can be provided once per day,” is the fact that any given PGA drug could
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`easily have been formulated as preservative-free simply by packaging it in single-
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`dose form. Alcon’s expert, Dr. Majumdar, expressly admits this point.
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`ALCON2023, ¶ 45 (“Of course, unit-dose formulations could be made without any
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`preservative at all.”); see also EX1045 (Deposition Transcript of Dr. Majumdar),
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`pp. 107-08. Indeed, this was the case with the TIMOLOL product I mentioned
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`10
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`000010
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`
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`above. EX1049, p. 339 (“To guarantee sterility each package consists of a
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`hermetically sealed single dose unit.”).
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`16. Dr. Parrish admits that ZIOPTAN is one such single-dose,
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`preservative-free product, but dismisses it as “not comparable to other PGAs.”
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`EX2027, ¶ 33. Dr. Parrish does not explain the reasons for his position, which
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`begs the question why this product was introduced to begin with if it were so
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`inferior to PGAs (including TRAVATAN Z). Dr. Parrish also fails to mention that
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`other single-dose products have also been developed, including MONOPOST,
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`which is a preservative-free unit-dose form of latanoprost, as shown by the
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`package label. See EX1046, p.2 (sixth column) (showing that it is a single-dose
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`form of the active ingredient latanprost, without BAK).
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`17. These points are relevant to the arguments raised by Alcon and Dr.
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`Parrish because, if there really were an unmet need for a “highly effective BAK-
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`free antiglaucoma drug that can be provided once per day” as they claim, drug
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`manufacturers could readily have developed any of the then-known PGAs in unit-
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`dose form, thereby completely avoiding BAK or any preservative at all. While Dr.
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`Parrish claims that ZIOPTAN is considerably more expensive that XALATAN
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`(ALCON2027, ¶ 33), he is purposely making this comparison to the name-brand
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`version instead of the generic version of latanoprost (see, e.g., ALCON2027, ¶ 19).
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`Furthermore, Dr. Parrish is silent regarding the cost of ZIOPTAN as compared to
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`11
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`TRAVATAN Z, which is the relevant consideration in terms of whether
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`TRAVATAN Z truly satisfies a need (presumably lower cost) not met by
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`ZIOPTAN. His claims are therefore unsupported.
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`18. The claim by Alcon and Dr. Parrish that TRAVATAN Z satisfied a
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`long-felt but unmet need for a BAK-free antiglaucoma drug is contradicted by the
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`fact that BAK-free drugs could have been introduced into the market any time
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`before 2006, at least some were (e.g., TIMOLOL), and additional preservative-free
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`options continue to be introduced to the market since TRAVATAN Z (e.g.,
`
`MONOPOST). The fact that preservative-free products continue to be introduced
`
`suggests that TRAVATAN Z did not actually satisfy the need alleged by Alcon
`
`and Dr. Parrish, which is a point I discuss in more detail below.
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`19.
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`In sum, the “need” alleged by Alcon and Dr. Parrish was either
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`nonexistent or, at best, exceedingly modest, such that it is not surprising that a
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`company did not develop a preservative-free version of travoprost prior to 2006—
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`there simply was not significant demand for such a product given all the other
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`treatment options available, and the fact that BAK sensitivity was, at most, a
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`relatively minor concern. Dr. Parrish acknowledges this very point when he
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`testifies that “in my experience, the side effects of acute use of BAK usually are
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`minor and infrequent, such as ocular irritation and scratchiness, foreign body
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`sensation, or blurring vision.” To the extent that any need did exist, it was easily
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`12
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`000012
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`
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`satisfied as of 2006 by non-drug options such as surgery or laser treatment, or by
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`other preservative-free ophthalmic compositions such as TIMOLOL.
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`C. TRAVATAN Z Does Not Satisfy The “Need” Alleged By Alcon
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`20. Dr. Parrish claims that “[b]ecause of its unique preservative system,
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`TRAVATAN Z® satisfied the long-felt, unmet need for a highly-effective, BAK-
`
`free antiglaucoma drug, and has been particularly beneficial in patients that had
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`worsening of the OSD symptoms as a result of chronic exposure to BAK.”
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`ALCON2027, ¶27. While Dr. Parrish cites papers that contain seemingly
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`supportive “sound-bite” quotations, a closer analysis of these papers show that the
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`actual data does not support the conclusory statements apparently relied upon by
`
`Dr. Parrish. To the contrary, numerous references actually establish the opposite
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`of Dr. Parrish’s claims, namely that TRAVATAN Z makes OSD symptoms no
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`better and, if anything, worse. As a result, TRAVATAN Z fails to satisfy the
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`alleged need for an antiglaucoma drug that does exacerbate OSD symptoms.
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`These points are discussed in more detail below.
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`1.
`
`The actual data in the references relied upon by Dr. Parrish
`do not support Dr. Parrish’s testimony
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`21. An unfortunate but widely noted trend in the scientific literature
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`involves spurious conclusory claims included in papers that are funded or
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`otherwise supported by industry sponsors—claims which are not actually
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`supported by the data reported in the very same paper. This is a phenomenon that I
`13
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`000013
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`
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`have personally investigated in the past, specifically in regards to studies
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`comparing PGAs, which includes the drug at issue here, travoprost. The results of
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`my investigation were detailed in a publication in the American Journal of
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`Ophthalmology in 2009, which concluded that while 90% of the industry-funded
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`studies contained “pro-industry” conclusions, only 24% of the industry-funded
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`studies actually demonstrated a statistically significant main outcome measure.
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`See EX1047, 33 (Results and Conclusions). Furthermore, my study found that the
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`published conclusions were not consistent with the results of the main outcome
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`measure in 62% of the industry-funded studies examined, compared with 0% of the
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`non-industry-funded studies. Id. These findings are relevant here because most if
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`not all of the papers relied upon by Dr. Parrish suffer from this very shortcoming.
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`22. Dr. Parrish claims that TRAVATAN Z satisfies his alleged long-felt
`
`unmet need because of its BAK-free preservative system which, according to Dr.
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`Parrish, leads to a decreased incidence of OSD symptoms. ALCON2027, ¶ 27. In
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`support of this proposition, Dr. Parrish cites three references (although he fails to
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`provide specific citations within any of the references). Id., ¶ 27 n.12. I note that
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`all three references are funded by Alcon, and I address the discrepancies in each
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`below.
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`14
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`a)
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`Exhibit 2132 – Katz et al.
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`23. First, starting with Dr. Parrish’s Exhibit 2132, this is a paper by Katz
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`et al., where one of the coauthors is from Alcon, and the research was funded by
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`Alcon. EX2132, p. 1253 (author #4), p. 1260 (“Disclosures”). Although I cannot
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`say for certain since Dr. Parrish did not provide any pinpoint cites for this
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`reference, I presume Dr. Parrish was relying on the “Conclusions” section of the
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`abstract of this paper, which claims that switching from BAK-preserved
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`latanoprost to BAK-free travoprost yielded “significant improvements” in OSD
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`symptoms. Id., p. 1253. The “Discussion” section of this paper contains similar
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`conclusory remarks. Unfortunately, these statements are not borne out by the
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`actual study data reported therein. This can be easily seen by looking at the
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`“Results” section of the paper, which provides a statistical analysis of the actual
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`data resulting from the study. I highlight key conclusions from each result section
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`below, with all underlines added to highlight the relevant findings:
`
`• Mean change in OSDI scores
`
`For the overall cohort of patients with all baseline OSDI scores, mean
`OSDI scores at the 12-week time point were not statistically different
`between the groups. (Id., pp. 1256-57.)
`
`When normalized to baseline values, the mean change in OSDI score
`from the entry visit to the 12-week follow-up visit was not significantly
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`15
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`000015
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`
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`larger (P = 0.10) for the patients with mild OSD at baseline who were
`randomized to BAK-free travoprost 0.004% (−5.0 ± 10.8 units, n =
`140) than for patients with mild OSD at baseline who continued on
`BAK-preserved latanoprost 0.005% (−2.7 ± 12.1 units, n = 132). (Id.,
`p. 1257.)
`
`Mean change from baseline OSDI scores in the “baseline–moderate”
`and “baseline-severe” groups were not statistically different between
`the treatment groups. (Id.)
`
`For the overall cohort of patients with all baseline OSDI scores, mean
`changes in OSDI scores at the 12-week time point were not
`statistically different between groups. (Id.)
`
`• Patients improving to normal OSDI scores
`
`For the overall cohort of patients with all baseline OSDI scores, the
`percentage of patients who improved to normal OSDI scores after 12
`weeks was not significantly different between groups. (Id., pp. 1257-
`58.)
`
`• Outcomes stratified by duration of pretreatment
`
`The percentage of patients improving to a normal OSDI score was not
`significantly different between the treatment groups for patients who
`were exposed to BAK-preserved latanoprost 0.005% for 1-6 months
`or for 6-24 months prior to entry into the study. (Id., p. 1258.)
`
`
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`16
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`000016
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`
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`• Patients with ≥10 point improvement in OSDI scores
`
`The percentage of patients who improved ≥10 points in OSDI scores
`from baseline to week 12 was not statistically different between the
`treatment groups for the overall cohort, or for the subgroups of
`patients with mild, moderate, or severe baseline OSDI scores. (Id., p.
`1258.)
`
`• Absence of corneal staining
`
`The percentage of patients without corneal staining at week 12 was
`not statistically different between treatment groups for the overall
`cohort, or for the subgroups of patients with mild, moderate, or severe
`baseline OSDI scores. (Id., pp. 1258-59.)
`
`• Safety assessments
`
`No statistical differences in safety parameters were observed between
`treatment groups. (Id., p. 1259.)
`
`24. For every category reported in the “Results” section, the Katz study
`
`again and again concludes that there were no statistically significant differences
`
`between the treatment containing BAK versus the BAK-free treatment.2 These
`
`
`2 When a study is done to compare outcomes between groups, a statistical test is
`
`performed to determine if the differences between the groups are real versus
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`simply due to chance. While publications sometimes report numerical differences,
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`these are difficult to interpret because these are the average values for a group and
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`17
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`statistical results stand in stark contrast to the conclusory statements apparently
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`relied upon by Dr. Parrish. In recognition of its lack of statistically meaningful
`
`results, the Katz paper concludes that at most, “these results may indicate some
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`cumulative, long-term adverse effect of BAK on ocular surface health.” Id., p.
`
`1259, second column (underline added). Thus, not only were the authors unwilling
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`to conclude with any level of certainty that BAK does in fact reduce ocular surface
`
`health, they also stopped short of concluding with any degree of statistical
`
`relevance that the BAK-free composition improved patient OSD symptoms, their
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`conclusory statements unsupported by the data notwithstanding.
`
`25.
`
`In sum, the Katz paper, Exhibit 2132, fails to show that BAK-free
`
`travoprost (i.e., TRAVATAN Z) actually satisfies the alleged need identified by
`
`Dr. Parrish for a treatment that reduces OSD symptoms.
`
`b)
`
`Exhibit 2133 – Henry
`
`26. Dr. Parrish next cites Exhibit 2133, a paper by Henry et al., where the
`
`research was again funded by Alcon. EX2133, p. 620 (“Acknowledgements”). I
`
`do not consider the variability of the individual results. Thus, statistical
`
`significance takes the variability of the results into account and provides an
`
`estimate of the likelihood that the difference is real, as opposed to a random
`
`chance. The lack of a statistical difference here means that the data in Katz cannot
`
`differentiate between any real differences versus only random chance.
`
`18
`
`000018
`
`
`
`can only surmise what portions of this paper Dr. Parrish may have been relying
`
`upon, since once again he did not provide any pinpoint cites for this reference. See
`
`ALCON2027, ¶ 27 n.12. In any event, it is apparent that this study also contains
`
`significant flaws, calling into serious question any conclusions stated therein.
`
`27. To begin with, I will note that this study only looks at a subset of
`
`patients, those believed to be already having issues with BAK-preserved PGAs.
`
`See EX2133, 613 (“Methods”). While this in and of itself is not problematic, it
`
`serves as a backdrop for the more problematic aspect of this study. First, looking
`
`at the “Results” section, it is reported that while 813 such patients were originally
`
`enrolled, 17 of these patients were excluded due to protocol violations. Id., p. 615
`
`(second column). However, the study does not say what “protocol violations” it is
`
`referring to, and this is problematic because, for example, the enrolled patients may
`
`have stopped following the “protocol” due to discomfort or other problems caused
`
`by the BAK-free PGA therapy—which of course would be contrary to the end-
`
`result being assessed by this study. The failure of the authors to describe the
`
`details of these “protocol failures” immediately leads one to question the veracity
`
`of this study. Things then get worse.
`
`28. The Results section next reports that 105 patients—13% of the total
`
`enrolled—did not complete the study. Id. Critically, the main reason given for
`
`these dropouts was due to adverse events (“AE”), which occurred in 45 patients or
`
`19
`
`000019
`
`
`
`6% of the 813 patients. The paper only states that “[t]he most common reasons for
`
`early discontinuation were related and unrelated adverse events....” Id. This
`
`statement suggests that not all of these reasons were deemed to be secondary to
`
`TRAVATAN Z, which indicates that at least some of the reasons for dropout were
`
`in fact treatment-related (i.e., related to the TRAVATAN Z treatment that the
`
`patients were switched to). This conclusion is bolstered by the next sentence that
`
`specifically lists 49 drug-related adverse events, many of which are related to or
`
`associated with OSD.3 Later, the study lists some other AE in 3 patients that likely
`
`were not drug-related (e.g., non-specific infection, vomiting and shortness of
`
`breath, aortic dissection, metastatic cancer of the liver and abdominal rash) (id., p.
`
`617, second column), which to me suggests that the other 42 of the 45 patients (5%
`
`of the 813 patients enrolled) were not included in the analysis because of drug-
`
`related AE. Such exclusions due to “protocol violations” and drug-related adverse
`
`events are extremely relevant because the endpoint of the study was measuring
`
`improvements allegedly seen by switching patients to the BAK-free TRAVATAN
`
`Z treatment. The authors’ decision to simply exclude patients who had adverse
`
`events too significant that they could not follow the protocol or continue with the
`
`3 The AE that lead to discontinuation and being excluded from the analysis were:
`
`conjunctival hyperemia n=20 or 3%; ocular irritation n=12 or 2%; burning n=7 or
`
`1%; decreased vision n=5 or 1%; itching n=5 or 1%. Id.
`
`20
`
`000020
`
`
`
`study significantly biases the study in favor of TRAVATAN Z and the outcome
`
`that Alcon was obviously hoping to see.
`
`29. A related interesting observation is the comment made in the
`
`Discussion section that, overall, 6% of patients using the BAK-free treatment still
`
`complained of conjunctival hyperemia, and that for half of these it was severe
`
`enough to cause discontinuation of the treatment (3% of the initial 813 patients
`
`discontinued due to conjunctival hyperemia - and these are excluded from the
`
`analysis as mentioned above). Id., p. 620 (first column). However, this compares
`
`to only 4% of patients having hyperemia at the original baseline. So comparing the
`
`results seen during treatment to those seen before treatment began indicates that in
`
`a group of patients who had tolerability issues with BAK-preserved PGAs, the
`
`most common symptom was conjunctival hyperemia, and even after changing to
`
`the BAK-free treatment, the incidence of conjunctival hyperemia was actually
`
`higher by 2%.
`
`30. A final problem with the Henry study is that it was an open label
`
`study, i.e. no blinding/masking and no randomization. This is mentioned in the
`
`very last paragraph, where the authors reveal that:
`
`21
`
`000021
`
`
`
`The study did not evaluate differences in efficacy and safety between
`BAK-free travoprost and other prostaglandin therapy in a parallel,
`randomized, masked fashion. The change in therapeutic regimen may
`have fostered the expectation in some patients of a superior therapy,
`possibly resulting in more favorable subjective outcomes than may
`have been observed in a randomized, double-masked study.
`
`Thus, as the authors acknowledge, patient expectations likely influenced their own
`
`subjective assessments of the treatment. Since the entire study was based on
`
`patients’ self-reporting as to their OSD scores (id., p. 615 (first column)), this bias
`
`even further calls into question the significance of the reported results.
`
`31.
`
`In sum, the Henry paper, Exhibit 2133, likewise fails to show that
`
`BAK-free travoprost (i.e., TRAVATAN Z) actually satisfies the alleged need
`
`identified by Dr. Parrish for a treatment that reduces OSD symptoms.
`
`c)
`
`Exhibit 2136 – Kahook
`
`32. Lastly, Dr. Parrish cites Exhibit 2136, a paper by Kahook and Ammar
`
`discussing additional research funded by Alcon. See EX2136, p. 262 (first
`
`column). However, this paper deals exclusively with an in vitro study of various
`
`PGA on human corneal epithelial cells. Thus, Kahook did not look at OSD
`
`symptoms in actual patients at all, and is therefore irrelevant to the conclusion for
`
`which Dr. Parrish cites it (ALCON2027, ¶ 27 n.12). It is also noteworthy that
`
`Kahook, in the third-to-last sentence of the discussion section states that “[s]till,
`
`22
`
`000022
`
`
`
`the majority of clinical studies [i.e., in vivo studies] fail to show a direct dose-
`
`related effect of BAK on ocular surface health matching the plethora of available
`
`in vitro data.” The authors are thus recognizing the same point I am making
`
`here—that in vivo studies regarding negative effects of BAK were not confirming
`
`the results that might have been expected based on the in vitro data showing
`
`BAK’s cytotoxic properties.
`
`d)
`
`Other references
`
`33. Additional references f
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