UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`____________________
`
`Inter Partes Review Nos. IPR2015-01097 (U.S. Patent No. 8,751,131)
`IPR2015-01099 (U.S. Patent No. 8,669,290)
`IPR2015-01100 (U.S. Patent No. 8,927,606)
`IPR2015-01105 (U.S. Patent No. 8,871,813)1
`
`____________________
`
`REPLY DECLARATION OF M. JAYNE LAWRENCE, PH.D.
`
`
`
`
`
`1 The word-for-word identical paper is filed in each proceeding identified in the
`heading. IPR2016-00089 has been joined with IPR2015-01097; IPR2016-00091
`has been joined with IPR2015-01100; and IPR2016-00090 has been joined with
`IPR2015-01105. Each of these joined proceedings includes Petitioners
`InnoPharma Licensing, Inc., InnoPharma Licensing LLC, InnoPharma Inc.,
`Mylan Pharmaceuticals Inc., and Mylan Inc. (collectively, “InnoPharma”) in
`addition to the parties identified above.
`
`1
`
`IPR2015-01099
`IPR2015-01097
`IPR2015-01100
`IPR2015-01105
`
`Lupin EX1094
`Page 1
`
`

`
`Contents
`
`I. 
`
`II. 
`
`Introduction ...................................................................................................... 4 
`
`Qualifications ................................................................................................... 4 
`
`III.  Materials Reviewed ......................................................................................... 6 
`
`IV.  Legal Standards ............................................................................................... 7 
`
`V.  A Person of Ordinary Skill in the Art Would Have Combined
`Ogawa and Sallmann to Arrive at the Claimed Inventions ............................. 7 
`
`A. 
`
`B. 
`
`C. 
`
`Bromfenac was an NSAID with superior efficacy ................................ 9 
`
`A POSA would have considered Ogawa Example 6 .......................... 12 
`
`A POSA would have considered Sallmann Example 2 ...................... 18 
`
`D.  A POSA would have been motivated to substitute
`tyloxapol for polysorbate 80, and that substitution would
`have resulted in an improved formulation .......................................... 19 
`
`VI.  The Patent Owner Fails To Consider the Full Scope of the Prior
`Art .................................................................................................................. 28 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`E. 
`
`Complexation of acidic NSAIDs and BAC was known ..................... 28 
`
`NSAIDS are chemically and structurally similar ................................ 31 
`
`Ethoxylated octylphenols were known to solve the
`complexation problem ......................................................................... 36 
`
`BAC was commonly used for ophthalmic products ........................... 41 
`
`Tyloxapol is an octylphenol within the class disclosed in
`Fu, and tyloxapol and polysorbate 80 were among the
`few approved for ophthalmic formulations ......................................... 43 
`
`VII.  The patent owner’s Evidence of Alleged Objective Indicia Is
`Not Probative of Patentability ....................................................................... 47 
`
`2
`
`Page 2
`
`

`
`A. 
`
`B. 
`
`The Patent Owner’s purported unexpected results relating
`to tyloxapol were known in the art ...................................................... 47 
`
`The data relied upon by the patent owner do not
`demonstrate that the claimed preparations are more
`chemically stable than the closest prior art ......................................... 49 
`
`C. 
`
`Tyloxapol is not the reason for the ability to reduce pH ..................... 53 
`
`VIII.  The Dependent Claims Are Not Separately Patentable ................................. 55 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Stability ............................................................................................... 55 
`
`pH ........................................................................................................ 56 
`
`Concentration of tyloxapol .................................................................. 57 
`
`Preservative efficacy standard ............................................................. 58 
`
`IX.  Conclusions .................................................................................................... 59 
`
`
`
`3
`
`Page 3
`
`

`
`I, Jayne Lawrence, Ph.D., declare and state as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Lupin Ltd. and
`
`Lupin Pharmaceuticals Inc. for the above captioned inter partes review (“IPR”). I
`
`am being compensated for my time in connection with these IPRs at my standard
`
`consulting rate, which is GBP300 per hour. My compensation is not contingent on
`
`the conclusions I reach herein or on the specifics of my testimony. I have no
`
`financial stake in the outcome of this proceeding.
`
`3.
`
`I am the same expert who provided a declaration in these IPRs dated
`
`21 April 2015 (“opening declaration”). (EX 1005).
`
`II. QUALIFICATIONS
`
`4.
`
`I am an expert in the field of formulation and drug delivery,
`
`specifically pharmaceutical formulation for oral and parenteral use (i.e., non-oral,
`
`including intravenous intramuscular, nasal, respiratory and ophthalmic), including
`
`aqueous liquid preparations. I have been an expert in this field since prior to 2003.
`
`In formulating my opinions, I have relied upon my training, knowledge, and
`
`experience in the relevant art. A copy of my curriculum vitae was previously
`
`4
`
`Page 4
`
`

`
`provided as Exhibit 1054, and it provides a comprehensive description of my
`
`academic and employment history. (EX 1054).
`
`5.
`
`I incorporate by reference herein my qualifications, as provided in
`
`paragraphs 3-15 of my opening declaration. (EX 1005, ¶¶ 3-15).
`
`6.
`
`I have been retained by counsel for Lupin to provide a reply expert
`
`declaration to respond to opinions provided by the patent owner’s experts Dr.
`
`Williams2 and Dr. Davies3 in the declarations that each has submitted in IPR2015-
`
`01097, IPR2015-01099, IPR2015-01100, and IPR2015-01105.
`
`
`2 Dr. Williams submitted a total of four declarations, one in each IPR, each
`identified as “EX 2082,” and I respond to each of Dr. Williams’s declarations
`here. While Dr. Williams’s declarations are specific to each patent, the content of
`the declarations is largely the same. In citing to Dr. Williams’s declarations here,
`I have indicated each declaration by referencing the IPR number in which the
`declaration was filed, i.e., “1097-EX 2082” refers to Dr. Williams’s declaration
`concerning the ‘131 patent in IPR2015-01097; “1099-EX 2082” refers to Dr.
`Williams’s declaration concerning the ‘290 patent in IPR2015-01099; “1100-EX
`2082” refers to Dr. Williams’s declaration concerning the ‘606 patent in
`IPR2015-01100; and “1105-EX 2082” refers to Dr. Williams’s declaration
`concerning the ‘813 patent in IPR2015-1105. Additionally, I note that Dr.
`Williams’s declarations are repetitive. To the extent I cite to any specific
`paragraph in Dr. Williams’s declarations, it should be understood that I intend to
`refer to that paragraph, and all substantially identical paragraphs.
`3 Dr. Davies submitted a total of four declarations, one in each IPR, each identified
`as “EX 2105,” and I respond to each of Dr. Davies’s declarations here. While Dr.
`Davies’s declarations are specific to each patent, the content of the declarations is
`largely the same. In citing to Dr. Davies’s declarations here, I have indicated each
`declaration by referencing the IPR number in which the declaration was filed, i.e.,
`“1097-EX 2105,” “1099-EX 2105,” “1100-EX 2105,” and “1105-EX 2105.”
`
`5
`
`Page 5
`
`

`
`7.
`
`The opinions and conclusions I expressed in my opening declaration,
`
`and the further opinions and conclusions that I express here in this reply
`
`declaration are based on my education, my extensive experience in this field, and
`
`my review of the materials related to this matter.
`
`III. MATERIALS REVIEWED
`
`8.
`
`In forming my opinions for my opening declaration and this reply
`
`declaration, I have reviewed, among other things, U.S. Patent 8,669,290 (“the ‘290
`
`patent”), U.S. Patent 8,754,131 (“the ‘131 patent”), U.S. Patent 8,871,813 (“the
`
`‘813 patent”), U.S. Patent 8,927,606 (“the ‘606 patent”) (collectively, the “subject
`
`patents”), and papers filed in the Patent Office in connection with prosecution of
`
`each of these patents, which I understand to constitute the prosecution histories of
`
`the patents. Additionally, for this reply declaration, I have reviewed the
`
`Declarations of Robert O. Williams, III, Ph.D. submitted in IPR2015-01097,
`
`IPR2015-01099, IPR2015-01100, IPR2015-01105, including the exhibits and
`
`references cited by Dr. Williams in those declarations, and the Declarations of
`
`Stephen G. Davies, D. Phil. submitted in IPR2015-01097, IPR2015-01099,
`
`IPR2015-01100, IPR2015-01105, including the exhibits and references cited by
`
`Dr. Davies in those declarations. A full list of materials I have considered can be
`
`found in Appendix A.
`
`6
`
`Page 6
`
`

`
`IV. LEGAL STANDARDS
`
`9.
`
`I incorporate by reference herein my understanding of legal standards
`
`that I provided in paragraphs 17-40 of my opening declaration. (EX 1005, ¶¶ 17-
`
`40). As I stated in my opening declaration: (1) I have been informed of these legal
`
`standards by Petitioner’s attorneys, (2) I am not an attorney, and (3) I am relying
`
`only on instructions from Petitioner’s attorneys for these legal standards. (EX
`
`1005, ¶ 17).
`
`V. A PERSON OF ORDINARY SKILL IN THE ART WOULD
`HAVE COMBINED OGAWA AND SALLMANN TO ARRIVE
`AT THE CLAIMED INVENTIONS
`
`10.
`
`
`
`
`
`
`
`
`
` (1099-EX
`
`2082, ¶ 62; 1097-EX 2082, ¶ 67; 1100-EX 2082, ¶ 64; 1105-EX 2082, ¶ 63). I
`
`disagree with Dr. Williams’s opinions. A person of ordinary skill in the art
`
`(“POSA”) would look to the prior art in selecting excipients and amounts of those
`
`excipients, employing an approach that is consistent with routine optimization.
`
`That formulation development is typically a matter of routine optimization does
`
`7
`
`Page 7
`
`

`
`not suggest that the ingredients and amounts are arbitrarily selected. Rather, the
`
`prior art guides the POSA.
`
`11. Similarly, while a POSA may not always have 100% certainty that
`
`any given formulation would actually be suitable for its intended purpose before
`
`testing it, by following the teachings of the prior art he would often have a
`
`reasonable expectation of success. For the claims of the subject patents, that
`
`expectation of success would have been particularly strong, as the prior art
`
`presented a road map that a POSA would have followed. Given the express
`
`teachings of the prior art, Dr. Williams’s opinion fails to take into account the
`
`logical steps a POSA would take in optimizing an ophthalmic formulation, where
`
`the prior art disclosed all a POSA would need to know to make a stable aqueous
`
`preparation comprising bromfenac and tyloxapol as recited in the ʼ290 and ʼ131
`
`patent claims (EX 1005, ¶¶ 111, 272), methods of treating an inflammatory disease
`
`of the eye comprising administering a stable aqueous preparation comprising
`
`bromfenac and tyloxapol as recited in the ʼ606 patent claims (EX 1005, ¶ 495), and
`
`stable aqueous preparations consisting essentially of bromfenac, tyloxapol, boric
`
`acid, sodium tetraborate, and water as recited in the ʼ813 patent claims (EX 1005,
`
`¶ 381). In my opinion, the claims of the subject patents represent merely the
`
`routine formulation and optimization work that a POSA would carry out on a daily
`
`basis based on what was known in the prior art as of 2003.
`
`8
`
`Page 8
`
`

`
`A. Bromfenac was an NSAID with superior efficacy
`
`12.
`
`
`
` (See 1099-EX
`
`2082, ¶ 53; 1097-EX 2082, ¶ 58; 1100-EX 2082, ¶ 55; 1105-EX 2082, ¶ 54). I
`
`disagree, as a POSA would know that the prior art recognized that diclofenac is
`
`“somewhat less effective both in vitro and in vivo” than bromfenac. (EX 1007,
`
`14:15-15:33). Regardless, however, a POSA in 2003 would have been motivated to
`
`formulate an ophthalmic preparation containing bromfenac, because bromfenac
`
`had been shown both in clinical trials and through commercial experience to be
`
`safe and effective. (EX 2248 at 27).4
`
`13. Dr. Williams says that, rather than applying the simple and express
`
`teachings of the prior art, a POSA would have looked to other solutions to the
`
`bromfenac-BAC complex problem. For example, Dr. Williams opines:
`
`if a person of ordinary skill in the art would have wanted
`to maintain the use of BAC, and not have it decrease
`pharmaceutical activity or have a reduced preservative
`
`
`4
`
`
`(1099-EX 2082, ¶ 69; 1097-
`EX 2082, ¶ 74; 1100-EX 2082, ¶ 71; 1105-EX 2082, ¶ 70). I disagree that a safety
`issue with an oral formulation of a drug would dissuade a POSA from
`formulating an ophthalmic bromfenac formulation that is applied locally and only
`for a short period of time (i.e., on the order of weeks).
`
`9
`
`Page 9
`
`

`
`effect . . . he/she would have more likely used an ester or
`a prodrug without a carboxylic acid moiety, if anything,
`to avoid the alleged formulation of a precipitate.
`
`(1099-EX 2082, ¶ 85; 1097-EX 2082, ¶ 90; 1100-EX 2082, ¶ 87; 1105-EX 2082,
`
`¶ 86). I disagree with this because bromfenac had already been shown by clinical
`
`trials and through commercial use to be effective and safe. Formulating, testing,
`
`and manufacturing an “ester or a prodrug of bromfenac without a carboxylic acid
`
`moiety” as suggested by Dr. Williams would necessitate lengthy and costly clinical
`
`trials. (See 1099-EX 2082, ¶ 85; 1097-EX 2082, ¶ 90; 1100-EX 2082, ¶ 87; 1105-
`
`EX 2082, ¶ 86). A POSA would therefore have rejected this possibility outright
`
`and instead applied the teachings of the prior art with a reasonable expectation of
`
`success.
`
`14.
`
`
`
` (1099-EX 2082, ¶ 71; 1097-EX
`
`2082, ¶ 76; 1100-EX 2082, ¶ 73; 1105-EX 2082, ¶ 72). I disagree. Yanni discusses
`
`bromfenac and “other acids like it,” and states that they are effective in treating
`
`ocular inflammation, suggests that they might need to be used in high
`
`concentrations, and then proceeds to discuss other “additional” NSAIDs. (EX
`
`1007, 2:2-20). Yanni also states that “[w]hat is needed are additional non-steroidal,
`
`topically administrable anti-inflammatory agents . . . at least as potent as
`
`10
`
`Page 10
`
`

`
`benzoylphenylacetic acids in suppressing ocular inflammation.” (EX 1007, 2:15-20
`
`(emphasis added)). In other words, Yanni uses bromfenac and other acidic
`
`NSAIDs as a jumping off point to develop other drugs—
`
`
`
`
`
`15.
`
`I also disagree with Dr. Williams’s opinion as to Yanni because of the
`
`clear statement in Yanni, when referring to the comparative test results of Table 1,
`
`that “diclofenac . . . was somewhat less effective both in vitro and in vivo than the
`
`chloro- or bromo- substituted 2-amino-3-benzoylbenzeneacetic acids.” (EX 1007,
`
`14:25-29). Dr. Williams disregards this clear statement, asserting that this passage
`
`may not actually be referring to bromfenac. This is plainly incorrect. Bromfenac is,
`
`in fact, the only bromo-substituted 2-amino3-benzoylbenzeneacetic acid in Table
`
`1. (EX 1007, Table 1). The remaining bromo-substituted compounds in Table 1 are
`
`characterized by Yanni as amides and/or esters, and are discussed separately by
`
`Yanni. (EX 1007, 14:30-61). Further, even if bromfenac were not expected to be
`
`superior to diclofenac, the exhibited success of a diclofenac would only encourage
`
`a POSA to formulate solutions with similar active ingredients, such as bromfenac.
`
`16.
`
`In any event, a POSA in 2003 would have been motivated to
`
`formulate an ophthalmic preparation containing bromfenac, because bromfenac
`
`had been shown both in clinical trials and through commercial experience to be
`
`safe and effective. (EX 2248 at 27).
`
`11
`
`Page 11
`
`

`
`17. Therefore, it is my opinion that a POSA prior to 2003 would have
`
`known from the prior art that bromfenac was not an inferior NSAID, and a POSA
`
`would have been motivated to formulate an ophthalmic preparation containing
`
`bromfenac.
`
`B. A POSA would have considered Ogawa Example 6
`
`18.
`
`In my opinion, Ogawa is the closest prior art,
`
`
`
` (See,
`
`e.g., 1099-EX 2082, ¶¶ 82, 117; 1097-EX 2082, ¶¶ 86-87, 122; 1100-EX 2082,
`
`¶¶ 83-84, 120; 1105-EX 2082, ¶¶ 82-83, 120). I disagree with Dr. Williams’s
`
`opinion.
`
`19. Ogawa discloses ophthalmic formulations containing bromfenac
`
`sodium. Ogawa discloses that such formulations are subject to instability,
`
`specifically, the formation of red insoluble matters, and that this instability had
`
`been overcome by incorporating polyvinyl pyrrolidone and sodium sulfite into the
`
`formulation. (EX 1010, Experimental Examples 4-6).
`
`20. Ogawa offered no explanation for how the “red insoluble matters”
`
`formed and also offered no explanation as to how the PVP and sodium sulfite
`
`prevented the formation of these “matters.” Ogawa exemplified a few formulations
`
`(i.e., Example 6, Example 7, and Example 8) that did not form the red “matters”
`
`and described them as “stable, excellent for a long period of time.” (EX 1010,
`
`12
`
`Page 12
`
`

`
`10:5-56). Of these three formulations, the formulation described in Example 6 was
`
`reported to have the highest remaining amount of bromfenac after storage at 60°C
`
`for four weeks. For that reason, a POSA would have focused on Example 6.
`
`21. Furthermore, unlike Examples 7 and 8, the ingredients included in
`
`Ogawa’s Example 6 formulation were known to be the same as those in a
`
`commercially viable product, Bronuck. (See EX 1005, ¶¶ 79-80). As evidenced by
`
`its approval and commercialization, Bronuck had been shown to meet at least the
`
`Japanese standards of safety, efficacy, and quality, and had also been shown to
`
`have a shelf life sufficiently long to allow commercialization in Japan. Also,
`
`Example 8 is the least stable, not a commercial product, and does not include
`
`sodium edetate, which a POSA would have known helps with formulation stability.
`
`For these additional reasons, a POSA would have focused on Example 6 of Ogawa.
`
`
`
`22.
`
` (E.g., 1099-EX 2082, ¶ 67; 1097-EX 2082, ¶ 72; 1100-EX
`
`2082, ¶ 69; 1105-EX 2082, ¶ 68). I disagree. Dr. Williams appears to conflate
`
`different measurements of stability. The stability testing reported in Ogawa was
`
`carried out at 60°C. Fu likewise conducted stability testing at 60°C, but also at
`
`lower temperatures, like room temperature. (EX 1014, Example 5). As
`
`demonstrated by the testing disclosed in Fu, an ophthalmic preparation may appear
`
`13
`
`Page 13
`
`

`
`stable at 60°C, yet reveal the formation of insoluble complexes at lower
`
`temperatures. (EX 1014, Example 5). Therefore, despite Ogawa characterizing the
`
`Example 6 preparation as “stable,” a POSA would have recognized that the
`
`Example 6 preparation was nevertheless subject to the formation of insoluble
`
`complexes between bromfenac and BAC. (EX 1014 at 2). Such complexation
`
`would have been expected to have a detrimental effect on both the available
`
`amount of bromfenac and preservative efficacy, and therefore the POSA would
`
`have been motivated to solve this problem. (EX 1014 at 2).
`
`23. Dr. Williams also does not agree that a POSA would be motivated to
`
`ensure that the product could simultaneously satisfy both USP and EP preservative
`
`efficacy criteria. (See 1099-EX 2082, ¶ 228; 1097-EX 2082, ¶ 233; 1100-EX 2082,
`
`¶ 231). But a POSA is always motivated to produce new, improved products, even
`
`if they only represent an incremental benefit over an existing product, and that is
`
`particularly true where a commercial advantage exists when a product can be
`
`marketed in different parts of the world.
`
`24.
`
`14
`
`
`
`
`
`
`
`
`
`
`
`Page 14
`
`

`
` (1099-EX 2082, ¶ 117; 1097-EX 2082, ¶ 122;
`
`1100-EX 2082, ¶ 120; 1105-EX 2082, ¶ 120). A POSA, however, would know that
`
`parabens are undesirable for use as a preservative in an ophthalmic formulation at
`
`least because it was known that parabens are not stable and degrade at pH values
`
`around 8, which is a common pH for ophthalmic formulations. (EX 1167 at 206;
`
`EX 1168 at 341). Further, parabens are not as effective preservatives as BAC. (EX
`
`1113 at 831 (“[T]he FDA expert panel found the parabens unacceptable as
`
`ophthalmic solution preservatives.”)). Further, only the Example 6 formulation had
`
`been shown to be commercially viable, in the Bronuck product, which the POSA
`
`would have known contained the same ingredients as Example 6.
`
`25.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`15
`
`Page 15
`
`

`
`
`
`
`
`
`
`
`
` are “admissions” on my part that a
`
`POSA would have lacked any motivation to formulate a new bromfenac
`
`ophthalmic formulation.
`
`26.
`
`In these assertions, Dr. Williams ignores the realities of the
`
`marketplace. Formulators, and the companies for which they work, must
`
`continually develop and introduce new products to stay relevant, even if those new
`
`products are only incrementally different from existing products, and formulators
`
`would always be motivated to improve upon existing formulations. This is
`
`particularly true when existing products are marketed by other companies. Further,
`
`while other NSAIDs were available in the U.S. in 2003, different patients respond
`
`well to different drugs, which would bolster the business motivation to develop
`
`additional NSAID formulations. And, as for motivation to adjust the Example 6
`
`formulation, as I explained above, the POSA would have been concerned that the
`
`Example 6 formulation would be subject to complexation, thereby reducing the
`
`amount of bromfenac and preservative efficacy of the formulation. This would
`
`have motivated a POSA to modify the Example 6 formulation to improve its
`
`16
`
`Page 16
`
`

`
`stability and preservative efficacy. Moreover, Fu found that a solution containing
`
`ketorolac and BAC turned turbid when using polysorbate 80, but remained clear
`
`when using octoxynol 40, concluding that ethoxylated octylphenols solved the
`
`complexation issue. (EX 1014, 9:1-40). There are only four components in
`
`Example 5 of Fu: water; ketorolac; BAC; and one of three surfactants, thus, in my
`
`opinion the BAC-NSAID complex is the only logical conclusion. (EX 1014, 3:50-
`
`54, 9:1-15). Additionally, Example 5 of Fu states:
`
`At the 5 month time period it was apparent that the
`Octoxynol 40 surfactant was superior to the other two
`surfactants. At 5 months, Tween 80 and Myrj 52
`displayed turbidity when stored at RT. The presence of
`turbidity suggested the inability to solubilize a precipitate
`formed between the Ketorolac moiety and benzalkonium
`chloride.
`
`(EX 1014, 9:33-36).
`
`27. Therefore, in my opinion, a POSA prior to 2003 would have known
`
`from the prior art that the bromfenac and BAC in the Ogawa Example 6
`
`formulation may form insoluble complexes, and accordingly a POSA would have
`
`been motivated to improve upon that formulation to address the complexation
`
`problems.
`
`17
`
`Page 17
`
`

`
`C. A POSA would have considered Sallmann Example 2
`
`28. Given the expectation that insoluble complexes would form between
`
`bromfenac and BAC, based on the prior art that reported such complexes for
`
`preparations containing an NSAID and BAC, a POSA would have applied the
`
`teachings of the prior art regarding disrupting the formation of those complexes.
`
`For example, Fu taught that the addition of an ethoxylated octylphenol compound
`
`would increase the stability of a formulation so that it would exhibit no cloudiness
`
`or turbidity by disrupting the formation of complexes between bromfenac and
`
`BAC. (See, e.g., EX 1014, 3:1-3).
`
`29. The prior art Sallmann reference described and exemplified the
`
`successful use of tyloxapol with the NSAID diclofenac, further reinforcing the
`
`suitability of tyloxapol. Also, since tyloxapol has a higher molecular weight than
`
`octoxynol 40, while otherwise having similar properties, it would be expected that
`
`tyloxapol would be less toxic to the ocular membranes. (EX 1169 at 1504-1505).
`
`In any event, of all the ethoxylated octylphenol compounds, only two—octoxynol
`
`40 and tyloxapol—had been approved for ophthalmic use in the U.S. by 2003. (See
`
`EX 1113 at 830 (“The use of various additives in ophthalmic solutions is
`
`permissible; however the choices are few . . . . The use of surfactants in ophthalmic
`
`preparations is restricted similarly.”)). So, with only two surfactant choices, a
`
`18
`
`Page 18
`
`

`
`POSA would have tried both, and via routine optimization, decided upon the one
`
`that was more suitable.
`
`30. Therefore, in my opinion, a POSA prior to 2003 would have known
`
`from the prior art that adding an ethoxylated octylphenol to an ophthalmic
`
`formulation containing an NSAID and BAC would disrupt the formulation of
`
`complexes, and a POSA also would have known that tyloxapol, an ethoxylated
`
`octylphenol, could be used for this purpose.
`
`D. A POSA would have been motivated to substitute tyloxapol for
`polysorbate 80, and that substitution would have resulted in an
`improved formulation
`
`31. As an initial matter, it is my view that a POSA would consider both
`
`physical (including turbidity) and chemical stability (including seeking to prevent
`
`the degradation of the bromfenac) when seeking to improve a formulation such as
`
`that of Ogawa Example 6. It is my view that a function of polysorbate 80 in the
`
`Ogawa formulation is to stabilize the formulation against precipitation of a
`
`bromfenac-BAC complex. As I explained in my original Declaration, it was known
`
`in the art prior to 2003 that NSAIDs may form insoluble complexes in the presence
`
`of BAC, including in aqueous preparations. (EX 1005, ¶ 83; EX 1013, 1:10-17). It
`
`is also my opinion that it was understood that non-ionic surfactants, including
`
`polysorbate 80, could stabilize aqueous preparations containing both NSAIDs and
`
`BAC. (EX 1005, ¶ 84). It is my view that a POSA, upon reviewing the formulation
`
`19
`
`Page 19
`
`

`
`of Ogawa Example 6, would conclude that the polysorbate 80 is serving this
`
`function. While polysorbate 80 may be used as a wetting agent, it is my opinion
`
`that a POSA would understand that is not its function in Ogawa Example 6,
`
`because the amount of polysorbate 80 used is not consistent with a wetting agent
`
`function, and besides, BAC would also function as a wetting agent. Other
`
`requirements of a formulation such as the one in Ogawa Example 6 are served by
`
`the other excipients. In my view, a POSA would come to the conclusion that
`
`polysorbate 80 is only present in order to stabilize the formulation, including
`
`disruption of the BAC-NSAID complexes that were known to occur. However, it is
`
`also my opinion, as discussed herein, that while both are non-ionic surfactants,
`
`tyloxapol would be understood in the art to be more effective at stabilizing
`
`bromfenac, and thus a POSA would be motivated to substitute tyloxapol for
`
`
`
`
`
`
`
`
`
`
`
`polysorbate 80 to obtain an improved formulation.
`
`20
`
`Page 20
`
`

`
`
`
`
`
`
`
` (1099-EX 2105, ¶ 42;
`
`1097-EX 2105, ¶ 42; 1100-EX 2105, ¶ 33; 1105-EX 2105, ¶ 32; 1099-EX 2082,
`
`¶¶ 55-57; 1097-EX 2082, ¶¶ 60-62; 1100-EX 2082, ¶¶ 57-59; 1105-EX 2082,
`
`¶¶ 56-58). However, both diclofenac and ketorolac had been shown in the prior art
`
`to be subject to oxidative degradation. (EX 1170 at 451-453; EX 1171 at 105-113).
`
`
`
`
`
`
`
` a POSA
`
`would have been even more motivated to use tyloxapol in a bromfenac formulation
`
`as a POSA would have been aware of the studies suggesting that tyloxapol is an
`
`antioxidant.5 (See, e.g., EX 1172, 4:46-61 (discussing tyloxapol as the “best known
`
`
`5 The prior art discloses tyloxapol’s antioxidant property. (See e.g., EX 1096 at
`9902 (explaining that tyloxapol is an ophthalmic excipient and is “oxidized by
`metals”); EX 1051 at 1415). The prior art also teaches that tyloxapol is a
`surfactant and an antioxidant. (EX 1097, ¶ [0032]; EX 1098, 6:25-28). The ’290
`patent and Ogawa similarly involve nasal formulations and
`
` (EX 1001, 4:10-13, 11:51-54;
`
`(Continued...)
`
`21
`
`Page 21
`
`

`
`of this class” of alkylaryl polyether alcohol polymers that “are potent
`
`antioxidants”); EX 1173 at 783). Through routine experimentation, in my view, a
`
`POSA would have determined the optimal antioxidant combination of tyloxapol
`
`and sodium sulfite to address the oxidative degradation problem explained by the
`
`patent owner’s experts. (EX 2030, 2:1-4 (showing that there can be more than one
`
`antioxidant used), 5:12 (disclosing PVP). Thus, by the patent owner’s own
`
`reasoning, a POSA would have expected tyloxapol, a known antioxidant, to
`
`stabilize bromfenac and would have been motivated to replace polysorbate 80 with
`
`tyloxapol for that reason.
`
`32. Even Dr. Williams, has provided a reference (Doi, EX 2030) that
`
`teaches that the class of compounds to which tyloxapol belongs to not only have
`
`antioxidant properties, and Dr. Williams opines that he would look to Doi “to even
`
`further improve bromfenac’s chemical stability” of Ogawa. (1099-EX 2082, ¶ 138;
`
`1097-EX 2082, ¶ 143; 1100-EX 2082, ¶ 141; 1105-EX 2082, ¶ 141). Specifically,
`
`Doi teaches NSAIDs in ophthalmic preparation (“eye drops”) can be stabilized
`
`with the inclusion of alkylphenols. (EX 2030, 3:7-9, 3:36-39).
`________________________
`EX 1010, 4:60-62, Example 10; EX 1099, 20:13-21). Other prior art references
`investigating tyloxapol’s antioxidant property characterize tyloxapol as a
`surfactant that is a “potent antioxidant” and best-known in its class. (EX 1100,
`4:46-61; see also EX 1101, 2:38-48; EX 1102 at 1219, 1221-1222). While not all
`of these formulations are ophthalmic, in my view once in formulation tyloxapol
`will act as an antioxidant, regardless of where the formulation is ophthalmic,
`nasal, or lung.
`
`22
`
`Page 22
`
`

`
`33. The structure of tyloxapol is depicted below and the structural
`
`similarities to 2,2’-methylenebis(4-methyl-6-tert-butylphenol) would have been
`
`clear to a POSA.
`
`
`
`(EX 1051 at 1415). Moreover, in reference to tyloxapol’s p-(1,1,3,3-
`
`tetramethybutyl) phenol component (e.g., alkylphenol), the prior art explains that
`
`tyloxapol “retains functional groups to the original alcohol monomer, and these
`
`may confer its antioxidant capacity.” (EX 1102 at 1221-22). Therefore, to a POSA,
`
`tyloxapol is within the alkylphenols disclosed by Doi for use in ophthalmic
`
`preparations. Dr. Davies—who has never worked with tyloxapol (EX 1103, 48:19-
`
`21)—asserts that tyloxapol, much like polysorbate 80, is an oxidizing agent. (EX
`
`1126, ¶¶ 71-72). Dr. Davies points to two references in support, EX 2097 and EX
`
`2120, neither of which makes any reference to tyloxapol. In my view, Dr. Davies’s
`
`assertion conflicts with the experimental data presented in Yasueda, and the
`
`statements in the prior art which describe tyloxapol’s antioxidant properties.
`
`34.
`
`
`
`
`
`23
`
`Page 23
`
`

`
`
`
` (1099-EX 2105, ¶ 42; 1097-EX 2105, ¶ 42; 1100-EX
`
`2105, ¶ 33; 1105-EX 2105, ¶ 32; see also 1099-EX 2082, ¶¶ 53-57; 1097-EX 2082,
`
`¶¶ 58-62; 1100-EX 2082, ¶¶ 55-59; 1105-EX 2082, ¶¶ 54-58). I disagree.
`
`35. Dr. Davies and Dr. Williams appear to have misunderstood my
`
`opinions regarding the prior art. To clarify, I have not stated nor suggested that
`
`Ogawa teaches the formation of a complex between bromfenac and BAC. Ogawa,
`
`instead, teaches a bromfenac-containing preparation that is “stable,” to the extent
`
`stable is defined as the amount of bromfenac remaining after storage at 60°C for
`
`four weeks. However, a POSA would understand from the teachings of Fu that
`
`despite its apparent stability, the Ogawa preparation, which contains an NSAID
`
`and BAC, may nevertheless be subject to the formation of insoluble complexes at,
`
`for example, room temperature. (EX 1014, Example 5). Fu also teaches that such
`
`complexation can be disrupted by including an ethoxylated octylphenol compound
`
`in the preparation, (EX 1014, 3:1-3), and Sallmann teaches that tyloxapol, which is
`
`an ethoxylated octylphenol compound, can be used in NSAID-containing
`
`ophthalmic preparations, (e.g., EX 1012, 4:64). Each of these references is directed
`
`to the preparation of NSAID-containing ophthalmic solutions.
`
`36.
`
`In support of his opinion that a POSA would not have substituted
`
`tyloxapol for polysorbate 80, Dr. Davies presents illustrated models of the 3-
`
`2