IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF NEW JERSEY
`
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB INCORPORATED and
`BAUSCH & LOMB PHARMA HOLDINGS
`
`CORP.,
`
`Plaintiffs,
`
`v.
`
`LUPIN, LTD. and LUPIN
`PHARMACEUTICALS, INC.,
`
`Defendants.
`
`Civil Action No. l:l4—cv—00667 (JBS)(KMW)
`Civil Action No.
`l:14—cv—04149 (JBS)(KMW)
`Civil Action No. 1:14-cv-05144 (JBS)(KMW)
`Civil Action No. 1:l5—cv—0O335 (JBS)(KMW)
`
`INNOPHARMA LICENSING, INC.,
`Civil Action No. l:14—cv—O6893 (JBS)(KMW)
`INNOPHARMA LICENSING, LLC,
`INNOPHARMA, INC. and INNOPHARMA, Civil Action No. 1:15-cv-03240 (JBS)(KMW)
`LLC,
`
`Defendants.
`
`(Consolidated Actions)
`
`REPLY EXPERT REPORT OF STEPHEN G. DAVIES, D.Phil.
`
`I.
`
`BACKGROUND AND QUALIFICATIONS
`
`l.
`
`1, Stephen G. Davies, D.Phil., submit this reply report at the request of Plaintiffs
`
`Senju Pharmaceutical, C0,, Ltd., Bausch & Lomb Incorporated, and Bausch & Lomb Pharma
`
`Holdings Corp. as an expert in the field of organic chemistry and medicinal chemistry. My
`
`qualifications in these areas, as well as other areas, are summarized in my responsive expert
`
`report dated January 29, 2016, and established by my curriculum vitae, attached as Appendix B
`
`to my responsive expert report, and list of publications, attached as Appendix C to my responsive
`
`expert report.
`
`2.
`
`I am submitting this reply report
`
`in response to the responsive report of Dr.
`
`Clayton H. Heathcock, dated February 12, 2016.
`
`Page 1 of
`
`SENJU EXHIBIT 2267
`Innopharma v Senju,
`IPR2015-00902 & IPR2015-00903
`
`Page 1 of 25
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`

`
`3.
`
`I reserve the right to further address Dr. Heathcock’s statements, opinions and
`
`conclusions at a later time. To the extent. Dr. Heathcock provides additional statements, opinions
`
`or conclusions, including any rebuttal or reply reports, I may offer further opinions.
`
`II.
`
`INFORMATION CONSIDERED
`
`4.
`
`In forming the opinions expressed in this expert report,
`
`I had available the
`
`documents cited herein,
`
`the documents cited in my responsive expert report as well as the
`
`publications listed on my curriculum vitae and publications list. I have also reviewed the
`
`responsive expert report of D1‘. Heathcock.
`
`I also base this opinion on my professional and
`
`academic experience in the areas of organic chemistry and medicinal chemistry.
`
`I reserve the
`
`right to testify about these materials and experience. To the extent I am provided additional
`
`documents or information, including any expert reports produced by Lupin or InnoPharma, I
`
`may offer further opinions.
`
`In addition to these materials, I may consider additional documents
`
`and information in forming any rebuttal opinions. Additionally, I may prepare demonstratives to
`
`illustrate any opinions I may present.
`
`III.
`
`STATEMENT OF OPINIONS EXPRESSED AND BASES AND REASONS
`THEREFOR
`
`A.
`
`5.
`
`A Person of Ordinary Skill in the Art
`
`My discussion regarding the person of ordinary skill in the art was set forth in my
`
`responsive expert report, and nothing in Dr. Heathcock’s report has changed any of my opinions
`
`stated in my responsive expert report.
`
`6.
`
`Dr. Heathcock states “I note that the patents-in-suit are directed to pharmaceutical
`
`formulations and formulation science. While Dr. Lawrence’s definition of the POSA directly
`
`addresses this field (requiring a ‘pharmaceutical scientist’), Dr. Davies’ definition misses the
`
`mark in focusing on chemistry as the relevant field. This narrow focus on chemistry in his
`
`2
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`definition of the POSA may account,
`
`to some extent, for Dr. Davies’ misplaced focus in
`
`rendering his opinions on the structural minutiae of various pharmaceutical
`
`formulation
`
`excipients or ingredients. Because Dr. Davies, focuses on the chemistry, however, Irespond to
`
`those chemistry-based arguments, ir1 this report. Nevertheless, my opinions would not change,
`
`regardless of which definition of a POSA is used.” (Heathcock Responsive Report at ‘ll 31.)
`
`I
`
`disagree with Dr. Heathcock’s statements. As set forth in my responsive report, “[a]s of January
`
`21, 2003, a person of ordinary skill in the art would have had at least a Bachelor’s degree in a
`
`field such as pharmaceutical chemistry, chemistry or a related discipline with about three to five
`
`years of work experience in this area, or a comparable level of education and training.” (Davies
`
`Responsive Report at ‘H 11.) My definition encompasses “a pharmaceutical scientist” from Dr.
`
`Lawrence’s definition, with which Dr. Heathcock agrees.
`
`(Heathcock Responsive Report at ‘ll
`
`29.) My definition is in fact broader than Dr. Lawrence’s, including “related disciplines” such as
`
`formulation science.
`
`B.
`
`7.
`
`Non-steroidal Anti-Inflammatory Drugs
`
`Dr. Heathcock describes and depicts the structures of several non-steroidal anti-
`
`inflammatory drugs (“NSAIDS”), concluding that “all of these NSAID compounds - bromfenac,
`
`flurbiprofen, diclofenac, ketorolac — have a carboxyl moiety.” (Heathcock Responsive Report at
`
`‘M 32-37.) As discussed in my responsive report, bromfenac is structurally and chemically
`
`dissimilar to diclofenac, ketorolac and flurbiprofen.
`
`(Davies Responsive Report at ‘][‘][ 16-44.)
`
`The physical, chemical and biological properties of molecules containing multiple functional
`
`groups do not depend solely on the characteristics of one of those functional groups.
`
`(Id. at ‘H
`
`16.) These properties depend on complex interactions between all the functional groups present
`
`in the molecule and their disposition relative to each other, and it is a gross oversimplification to
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`suggest that all carboxylic acids will behave similarly or will have similar properties.
`
`(Id. at ‘fl‘][
`
`16-44.)
`
`C.
`
`Surfactants
`
`8.
`
`Dr. Heathcock describes the properties of surfactants generally, recognizing that
`
`“non-ionic surfactants may have some differences in their compositions and three-dimensional
`
`structures,” and identifying Critical micelle concentration (“CMC”) as “a unique characteristic of
`
`each surfactant.” (Heathcock Responsive Report at
`
`‘][‘][ 38-41.) As discussed in my opening
`
`report, non-ionic surfactants, including polysorbate 80, tyloxapol, Octoxynol 9, and Octoxynol
`
`40, are structurally and chemically diverse and therefore possess diverse characteristics,
`
`including molecular weight and CMC.
`
`(Davies Responsive Report at ‘][‘][ 62-79.) The CMC,
`
`which Dr. Heathcock characterizes as
`
`a unique characteristic of each surfactant, varies
`
`significantly among polysorbate 80, Octoxynol 9, Octoxynol 40 and tyloxapol.
`
`(Id. at fl[‘I[ 67, 75.)
`
`As discussed in my opening report, a person of ordinary skill in the art would expect these
`
`differences in CMC to lead to significantly different functional and chemical properties,
`
`including solubilizing properties.
`
`(Id. at ‘J[ 64.)
`
`Indeed, Dr. Lawrence relies on the solubilizing
`
`properties of surfactants for her position on motivation to combine various teachings of unrelated
`
`documents in the art for allegedly improving the physical stability of an ophthalmic solution
`
`containing an acidic NSAID and BAC.
`
`(See, e. g., Lawrence Opening Report at ‘]I 69.)
`
`9.
`
`Dr. Heathcock states that “[i]n addition to being a surfactant,
`
`tyloxapol was
`
`reported to be a potent antioxidant, which means it inhibits the oxidation of other molecules,”
`
`citing U.S. Patent No. 5,474,760 (“the ’760 patent”).
`
`(Heathcock Responsive Report at ‘J[ 42.)
`
`As discussed further below, I disagree with Dr. Heathcock’s statement. The ’760 patent on
`
`which Dr. Heathcock relies is irrelevant to tyloxapol’s use in aqueous bromfenac ophthalmic
`
`solutions.
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`Page 4 of 25
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`D.
`
`Dr. Heathcock Has Not Established That a Precipitate Will Form Between an
`NSAID such as Bromfenac and BAC
`
`10.
`
`Dr. Heathcock states that “[b]ased on the teachings of the prior art, a POSA would
`
`have known that NSAIDs were known to form complexes with quaternary ammonium
`
`compounds while in solution, causing them to precipitate from solution.
`
`It is most likely that
`
`these insoluble complexes between BAC and acidic NSAIDS are salts where the anion is the
`
`NSAID carboxylate and the cation is the BAC ammonium ion.” (Heathcock Responsive Report
`
`at ‘][ 45.) Dr. Heathcock repeats this assertion throughout his report.
`
`I disagree with Dr.
`
`Heathcock’s statements. As discussed in my responsive report, Dr. Lawrence and now Dr.
`
`Heathcock fail to consider the significant structural and chemical differences among NSAIDS
`
`and the unpredictability of a system containing an NSAID and BAC. Moreover, an NSAID and
`
`a quaternary ammonium compound cannot form a complex, and can only potentially form a salt.
`
`A complex is a species formed from two or more not necessarily charged fragments held
`
`together by more than simple electrostatic charges, whereas a salt is a mixture of positive cations
`
`and negative anions held together by purely electrostatic charges where the overall charge is zero.
`
`(Davies Responsive Report at ‘H 14, n.l.)
`
`It makes no sense, therefore, to state that “NSAIDs
`
`were known to form complexes with quaternary ammonium compounds while in solution.”
`
`ll.
`
`Dr. Heathcock further states that “a POSA would have been concerned that a
`
`complex would form in a solution containing the NSAID bromfenac sodium and the quaternary
`
`ammonium compound benzalkonium chloride (“BAC”), causing the compounds to precipitate
`
`from solution.”
`
`(Heathcock Responsive Report at ‘][ 47.)
`
`I disagree with Dr. Heathcock’s
`
`statements for all the reasons discussed below and in my responsive report. Dr. Heathcock has
`
`failed to identify any evidence that a precipitate forms between bromfenac and BAC in an
`
`aqueous solution. Moreover, as discussed above, it makes no sense to state that “a complex
`
`Page 5 of 25
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`Page 5 of 25
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`would form in solution.” As discussed in my opening report, ophthalmic solutions such as those
`
`described in U.S. Patent No. 4,910,225 (“Ogawa”), U.S. Patent No. 5,891,913 (“Sallmann”) and
`
`EP 0 306 894 (“Fu”) are very dilute, with low concentrations of active ingredient and
`
`preservative.
`
`(Id. at ‘II 54.) At dilute concentrations, the anions and cations will be well-solvated
`
`and less likely to interact in any way that would lead to precipitation.
`
`(Id.) Without testing of a
`
`given system, a person of ordinary skill in the art simply could not have predicted whether the
`
`bromfenac anion would form a precipitate with BAC.
`
`12.
`
`Dr. Heathcock cites
`
`several
`
`references regarding ophthalmic solutions of
`
`6
`diclofenac' 2, ketorolac3 4, and flurbiprofen5 . Dr. Heathcock’s reliance on these references is
`
`Dr. Heathcock cites Khalil, E., Sallam, A., “Interaction of Two Diclofenac Acid Salts
`
`with Copolymers of Ammoniumethacrylate: Effect of Additives and Release Profiles, “ 25(4)
`
`Drug Development and Industrial Pharmacy 419-427 (1999) (Heathcock Responsive Report at ‘H
`
`46), but this reference does not disclose bromfenac or benzalkonium chloride, and is thus
`
`irrelevant.
`
`2
`
`Dr. Heathcock further cites US. Patent No. 5,597,560 as allegedly disclosing a
`
`“diclofenac—BAC complex.”
`
`(Heathcock Responsive Report at
`
`‘J[ 59.)
`
`I disagree with Dr.
`
`Heathcock’s statement. The ’560 patent discloses “the formation of an insoluble complex
`
`between Diclofenac and Tobramycin, which was identified by thin—layer chromatography (TLC),
`
`HPLC, infra-red spectroscopy (FIG. 1) and DSC (FIG. 2).” (’560 patent at 6:49-52.) Bromfenac
`
`is nowhere disclosed in the ’560 patent. Moreover, Dr. Heathcock cites to an example of
`
`diclofenac and BAC ophthalmic compositions where diclofenac and BAC do not form an
`
`insoluble complex.
`
`(Heathcock Responsive Report at ‘][ 61, n.9 (“Indeed, in U.S. Pat. 6,265,444,
`
`the inventors ex ressed sur rise that diclofenac and BAC were ‘unex ectedl
`P
`P
`P
`
`3’
`
`com atible .
`P
`
`.
`
`. in
`
`6
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`Page 6 of 25
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`Page 6 of 25
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`the present ophthalmic composition’ and noted that ‘[w]hile the reasons for this are not entirely
`
`clear, .
`
`.
`
`. the presence of the divalent cation is believed to prevent the BAK from complexing the
`
`diclofenac out of the system.”’).)
`
`3
`
`Dr. Heathcock cites Fu to argue that “[a] number of phenylacetic acid-derived NSAIDS
`
`were known as of 2003 to complex with BAC and precipitate from solution.”
`
`(Heathcock
`
`Responsive Report at ‘][‘][ 48, 50.) As discussed in my opening report, however, Fu discloses
`
`formulations containing the specific NSAID ketorolac tromethamine, not NSA]Ds generally or
`
`bromfenac in particular, with BAC.
`
`(Davies Responsive Report at ‘II 29.) Bromfenac is nowhere
`
`disclosed in Fu, and bromfenac and ketorolac are structurally and chemically dissimilar in
`
`numerous respects.
`
`(Id. at ‘M 29-36.) Moreover, Fu does not even establish that ketorolac and
`
`BAC form a precipitate, as Fu does not test the disclosed turbid ketorolac formulations to
`
`determine the chemical makeup of the precipitate.
`
`(Id. at ‘H 56.)
`
`4
`
`Dr. Heathcock further cites U.S. Patent No. 5,558,876 (“the ’876 patent”) to argue that
`
`“[i]t was known that the common carboxyl group shared by bromfenac, diclofenac, ketorolac and
`
`flurbiprofen was
`
`involved in the complexation interaction with benzalkonium chloride.”
`
`(Heathcock Responsive Report at
`
`‘H 48.) Dr. Heathcock further states that the ’876 patent
`
`discloses a “ketorolac—BAC complex.” (Id. at ‘l[ 59.) Idisagree with Dr. Heathcock’s statements.
`
`The ’876 patent does not establish that a precipitate forms between BAC and bromfenac or
`
`ketorolac, as it contains no disclosure of bromfenac/BAC formulations or ketorolac/BAC
`
`formulations.
`
`(See ’876 patent.)
`
`1 therefore disagree with Dr. Heathcock’s statement, citing
`
`the ’876 patent,
`
`that “[t]he prior art explicitly taught that NSAIDS generally had a stability
`
`problem in the presence of BAC, and formed an insoluble matter.”
`
`(Heathcock Responsive
`
`Report at ‘I[ 50.)
`
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`Page 7 of 25
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`misplaced, however, because diclofenac, ketorolac and flurbiprofen are structurally and
`
`chemically dissimilar from bromfenac, as discussed in my opening report.
`
`(Davies Responsive
`
`Report at ‘M 16-52.)
`
`Importantly, none of these references establishes that a precipitate forms
`
`between bromfenac and BAC in an aqueous solution.7 In any given system, there is no way to
`
`predict whether an individual NSAID anion will form an insoluble salt with a BAC cation
`
`without experimentation.
`
`(Id. at ‘I[ 58.) Indeed, the very art that Dr. Heathcock relies on provides
`
`an example in which diclofenac and BAC do not form a complex or a precipitate, confirming
`
`Dr. Heathcock states that “U.S. Patent No. 5,505,113, describes a formulation that
`
`includes an NSAID, including flurbiprofen or ketorolac tromethamine, that ‘is interactive with
`
`benzalkonium chloride’ such that combining the drug with BAC ‘remov[es] the benzalkonium
`
`chloride from solution, and consequently reduc[es]
`
`its effectiveness as a preservative.”’
`
`(Heathcock Responsive Report at ‘I[ 50.) Bromfenac is nowhere disclosed in the ’l13 patent.
`
`Moreover, the ’1l3 patent, which is directed to non-NSAID Bufrolin compositions, does not
`
`even establish that flurbiprofen and BAC form a precipitate.
`
`(’ 1 13 patent at 3: 14-15.)
`
`6
`
`Dr. Heathcock further states that WO 1994/015597 “described the mechanism for the
`
`formation of these ‘well-known’ complexes,” with “NSA]I)s generally” and that W0 ’597
`
`discloses a “f1urbiprofen—BAC complex.”
`
`(Heathcock Responsive Report at ‘J[‘][ 50, 59.)
`
`I
`
`disagree with Dr. Heathcock’s statements. WO ’597 is directed to flurbiprofen ophthalmic
`
`solutions in particular; bromfenac is nowhere disclosed.
`
`(W0 ’597 at 1:6—12.) Moreover,
`
`WO ’597 nowhere describes any “complex” as forming between flurbiprofen and BAC.
`
`7
`
`Dr. Heathcock also cites the description of Japanese Patent No. 2,954,356 in the
`
`specification of the ’813 patent.
`
`(Heathcock Responsive Report at ‘H 51.) This disclosure,
`
`however, does not indicate or establish that bromfenac and BAC form a precipitate.
`
`8
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`Page 8 of 25
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`Page 8 of 25
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`that the existence of a precipitate indeed cannot be established without testing.
`
`(Heathcock
`
`Responsive Report at ‘I[ 61, n.9 (“Indeed, in US. Pat. 6,265,444, the inventors expressed surprise
`
`that diclofenac and BAC were ‘unexpectedly compatible .
`
`.
`
`.
`
`in the present ophthalmic
`
`composition’ and noted that ‘[w]hile the reasons for this are not entirely clear, .
`
`.
`
`. the presence
`
`of the divalent cation is believed to prevent the BAK from complexing the diclofenac out of the
`
`system.”’).) The formation of a precipitate will depend in part on the solvation of the NSAID
`
`anion itself. The more solvated the NSAID anion is, the more it will tend to stay in solution and
`
`not form an insoluble salt with a BAC cation.
`
`(Id.) The formation of a precipitate will further
`
`depend on the solubility of the NSAID salt—in this case, bromfenac sodium.
`
`(Id.)
`
`Indeed, salt
`
`formation will depend on the interaction of all the ions in solution and their solvation, including
`
`those from the N SA1D salt and those from the separate and distinct BAC salt. (Id.) In particular,
`
`a person of ordinary skill in the art would expect the bromfenac anion to be better solvated in
`
`water than diclofenac or ketorolac anions because of its increased hydrogen bonding ability and
`
`greater number of strong hydrogen bonding sites. (Id. at ‘H 54.)
`
`13.
`
`I therefore disagree with Dr. Heathcock’s assertion that “all of these structural
`
`differences Dr. Davies recites do not negate the fact that these compounds all still form insoluble
`
`complexes due to complexation of the carboxyl group with BAC. Thus, differences between
`
`bromfenac and other NSAIDS would not undermine a POSA’s concern that bromfenac would
`
`complex with BAC, based on the presence of a carboxyl group in bromfenac, and based on the
`
`explicit
`
`teachings in the prior art regarding complexation of such NSAIDS with BAC.”
`
`(Heathcock Responsive Report at ‘]I 53.) Dr. Heathcock has failed to identify any evidence of a
`
`precipitate forming between bromfenac and BAC. Dr. Heathcock contends that NSAIDS “all
`
`still form insoluble complexes,” but then cites an example of diclofenac and BAC ophthalmic
`
`Page 9 of 25
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`Page 9 of 25
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`compositions in which diclofenac and BAC do not form an insoluble complex.
`
`(Heathcock
`
`Responsive Report at ‘H 61, n.9 (‘‘Indeed, in U.S. Pat. 6,265,444, the inventors expressed surprise
`
`that diclofenac and BAC were ‘unexpectedly compatible .
`
`.
`
`.
`
`in the present ophthalmic
`
`composition’ and noted that ‘[w]hile the reasons for this are not entirely clear, .
`
`.
`
`. the presence
`
`of the divalent cation is believed to prevent the BAK from complexing the diclofenac out of the
`
`system/”).) That no precipitate formed between diclofenac and BAC in the ophthalmic solution
`
`disclosed in the ’444 patent, despite that diclofenac contains a carboxylic acid group, indicates
`
`that Dr. Heathcock’s focus on the carboxylic acid moiety alone is simply wrong.
`
`(See also
`
`Heathcock Responsive Report at 91 49.)
`
`It also supports my opinion that in any given system,
`
`there is no way to predict whether an individual NSAID anion will form an insoluble salt with a
`
`BAC cation without experimentation.
`
`I therefore disagree with Dr. Heathcock’s statements that
`
`“[a] POSA would find that the more relevant inquiry in examining whether bromfenac was likely
`
`to have this problem in the presence of BAC to be whether bromfenac has a carboxylic acid
`
`moiety (and it does), because it would have been clear to a POSA that the undesirable complexes
`
`between acidic NSAIDS and BAC are salts formed from the interaction of an anionic NSAID
`
`carboxylate ion and the cationic BAC ammonium ion” and “it is my opinion that a POSA as of
`
`the time of the invention in 2003 would have known that bromfenac, diclofenac, ketorolac, and
`
`flurbiprofen were ophthalmic phenylacetic acid-derived NSAIDS. As a result, the POSA would
`
`have also expected these compounds to behave similarly in solution at least to the extent related
`
`to their common phenylacetic acid moieties. Thus, the POSA would have been concerned that
`
`the NSAID-BAC complexes described in the prior art could form in a formulation containing
`
`bromfenac and BAC.”
`
`(Heathcock Responsive Report at ‘][‘][ 54, 61.) Clearly, based on the
`
`evidence identified by Dr. Heathcock, the presence of a carboxylic acid moiety alone does not
`
`10
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`Page 10 of 25
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`Page 10 of 25
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`end the inquiry. Dr. Heathcock admits in fact that “the solubility of the complex/salt formed
`
`between an NSAID and BAC will depend not only on the nature of the NSAID anion, but also
`
`on the nature of the cation.” (Heathcock Responsive Report at ‘ll 58.) The “nature of the NSAID
`
`anion” is not limited to its carboxylic acid moiety, as discussed in detail in my responsive report.
`
`14.
`
`Indeed, Dr. Heathcock agrees that “a POSA could not have known with certainty
`
`that bromfenac would form a precipitate with BAC” and “[e]ven if the differences between
`
`bromfenac and these other NSAIDS reduce the extent of complexation for bromfenac, that
`
`certainly does not eliminate the possibility of any complexation between bromfenac and BAC.”
`
`(Heathcock Responsive Report at ‘][‘][ 64, 58.) Dr. Heathcock contends, however, that “[s]uch
`
`testing would have revealed that despite the structural differences Dr. Davies points out between
`
`bromfenac and other NSA]Ds, bromfenac does indeed form insoluble complexes with BAC, as a
`
`POSA would have suspected based on the prior art.”
`
`(Id)
`
`I disagree with Dr. Heathcock’s
`
`statement, for which he has provided no support or testing. Dr. Heathcock identified no evidence
`
`or testing in the prior art that bromfenac forms a precipitate with BAC. Tellingly, in Ogawa,
`
`there is no indication that bromfenac and BAC form a precipitate.
`
`(See, e.g., ’225 patent.)
`
`I
`
`therefore disagree with Dr. Heathcock’s statement that “a POSA would have identified that such
`
`complexes do form with the combination of bromfenac and BAC (which they do, as discussed
`
`below) and would have been motivated to remedy that problem through modifications to the
`
`formulation.” (Heathcock Responsive Report at ‘I[ 49.)
`
`15.
`
`Dr. Heathcock states that “Dr. Davies catalogs structural differences between
`
`bromfenac and several other acidic NSAlDs - diclofenac, ketorolac, flurbiprofen and pranlukast.
`
`This laundry list of differences seems intended to create the impression that a POSA would not
`
`have a reasonable expectation that bromfenac would not form an insoluble BAC salt, as do the
`
`11
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`Page 11 of 25
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`other four acidic NSAlDs.
`
`I disagree. As an initial matter, although Dr. Davies does not say so,
`
`diclofenac, ketorolae, flurbiprofen and pranlukast differ from each other in much the same way
`
`that bromfenac differs from each of these compounds.” (Heathcock Responsive Report at ‘II 52.)
`
`Dr. Heathcock further states that “these differences exist even as between diclofenac, ketorolae,
`
`and flurbiprofen, but the prior art nonetheless teaches that all of these compounds are subject to
`
`complexation with BAC,” citing W0 ’597, the ’876 patent, and the ’56O patent. (Id. at ‘H 59.)
`
`I
`
`disagree with Dr. Heathcock’s statements. As discussed above, in any given NSAID and BAC
`
`system, a person of ordinary skill in the art cannot determine whether an individual NSAID
`
`anion will form an insoluble salt with a BAC cation without experimentation. Dr. Heathcock has
`
`not established that bromfenac and BAC forms an insoluble salt, and he has not established that
`
`each of diclofenac, ketorolae, flurbiprofen and pranlukastg forms insoluble salts in solution with
`
`BAC. As discussed above, W0 ’597, the ’876 patent and the ’560 patent do not establish that
`
`“complexes” form between flurbiprofen and BAC, ketorolac and BAC, and diclofenac and BAC,
`
`respectively, contrary to Dr. Heathcock’s assertion. Moreover, Dr. Heathcock cites an example
`
`of diclofenac and BAC ophthalmic compositions in which diclofenac and BAC do not form an
`
`insoluble complex.
`
`(Heathcock Responsive Report at ‘I[ 61, 11.9 (“Indeed, in U.S. Pat. 6,265,444,
`
`the inventors expressed surprise that diclofenac and BAC were ‘unexpectedly compatible .
`
`.
`
`. in
`
`the present ophthalmic composition’ and noted that ‘[w]hile the reasons for this are not entirely
`
`clear, .
`
`.
`
`. the presence of the divalent cation is believed to prevent the BAK from complexing the
`
`diclofenac out of the system.”’).) Dr. Heathcock states that “these NSAID compounds are
`
`repeatedly discussed together in the prior art, and classified together, based on their similarities.”
`
`8
`
`Pranlukast is not an NSAID, contrary to Dr. Heathcock’s assertion.
`
`(Davies Responsive
`
`Report at ‘][ 45.)
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`Page 12 of 25
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`12
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`Page 12 of 25
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`

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`(Heathcock Responsive Report at ‘J[ 59.) That NSAlDs are classified together in the art based on
`
`their common mechanism of action as non-steroidal anti-inflammatory drugs tells a person of
`
`ordinary skill in the art nothing about whether a particular NSAID will form a precipitate with
`
`BAC in an ophthalmic solution.
`
`16.
`
`Dr. Heathcock states that “Dr. Davies notes that bromfenac is a primary amine,
`
`diclofenac is a secondary amine, ketorolac is a tertiary amine, and flurbiprofen has no amino
`
`group and suggests that these and other differences in their chemical structures result in different
`
`basicities, different hydrogen bonding abilities and therefore differences in lipophilicity and
`
`solubility. While this may be true, Dr. Davies has pointed to no evidence that these differences
`
`would render bromfenac different from the other NSAIDs with regard to formation of insoluble
`
`complexes with BAC. As noted above, despite these differences, ketorolac, diclofenac and
`
`flurbiprofen all form insoluble complexes with BAC.” (Heathcock Responsive Report at ‘H 57
`
`(citations omitted).)
`
`I disagree with Dr. Heathcock’s statements. Contrary to Dr. Heathcock’s
`
`statement and as discussed above, I provided ample evidence in my responsive report that these
`
`differences would render bromfenac different from the other NSAIDS with regard to the
`
`formation of insoluble complexes with BAC. Moreover, as discussed above, Dr. Heathcock has
`
`not established that ketorolac, diclofenac and flurbiprofen all form insoluble complexes with
`
`BAC. Tellingly, Dr. Heathcock does not dispute that significant structural and chemical
`
`differences exist among bromfenac, ketorolac, diclofenac and flurbiprofen.
`
`In fact, Dr.
`
`Heathcock admits that “bromfenac’s structure is more closely related to that of amfenac than to
`
`that of diclofenac” and that there are “differences in chemical structure between [ketorolac and
`
`flurbiprofen] and between [ketorolac and flurbiprofen] and bromfenac.” (Heathcock Responsive
`
`Report at
`
`‘]I 60.) Moreover,
`
`these acknowledged differences by Dr. Heathcock in basicity,
`
`13
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`Page 13 of 25
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`Page 13 of 25
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`

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`hydrogen bonding ability, lipophilicity and solubility between bromfenac, on the one hand, and
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`the other NSAIDS, on the other hand, support my position that a well—solvated molecule like
`
`bromfenac could not have been predicted to precipitate with BAC absent experimentation.
`
`Indeed, there is no teaching in Ogawa of the formation of any salt or any “insoluble complex”
`
`between bromfenac and BAC or any physical
`
`instability of bromfenac and BAC solutions.
`
`(Davies Responsive Report at ‘][ 14.)
`
`17.
`
`Dr. Heathcock states that “Dr. Davies repeatedly makes the claim that ‘because
`
`bromfenac is freely water-soluble .
`
`.
`
`. a person of ordinary skill in the art would have understood
`
`that bromfenac sodium does not require a solubilizer to make it dissolve in water. A person of
`
`ordinary skill in the art would thus not have needed to add a solubilizer to a bromfenac sodium
`7
`formulation,’ citing paragraph 55 of my report.
`
`(Heathcock Responsive Report at ‘][ 65.)
`
`I
`
`disagree with Dr. Heathcock’s statement, which misquotes and mischaracterizes my responsive
`
`report.
`
`In paragraph 55 of my report, I stated that “because bromfenac sodium is freely water-
`
`soluble, a person of ordinary skill in the art would have understood that bromfenac sodium does
`
`not require a solubilizer to make it dissolve in water.”
`
`(Davies Responsive Report at ‘I[ 55
`
`(citations omitted) (emphasis added).) Dr. Heathcock states that “[t]his argument ignores the
`
`plain teachings of the prior art. First, as noted above, the solubility of bromfenac, on its own, is
`
`not equivalent to the solubility of a bromfenac—BAC complex or salt, which would likely have a
`
`far lower solubility because of the hydrophobicity of the cationic BAC.” (Heathcock Responsive
`
`Report at ‘J[ 65.) I disagree with Dr. Heathcock’s statement, for which he provides no support.
`
`I
`
`further disagree with Dr. Heathcock’s statement because it mischaracterizes my report, in which
`
`I do not discuss the solubility of bromfenac “on its own,” but rather the solubility of bromfenac
`
`sodium salt.
`
`Indeed, Dr. Lawrence admits that bromfenac sodium salt is freely water-soluble.
`
`14
`
`Page 14 of 25
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`Page 14 of 25
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`

`
`(Video Deposition Transcript of M. Jayne Lawrence, Senju Pharmaceuticals v. Lupin et al., Case
`
`Nos. 1:14—cv—0O667, 1:14-cv-04149, 1:14-cv-05144, 1:15-cv-00335,
`
`1: l4—cv—06893, 1:15-cv-
`
`O3240 (September 4, 2015) (“Lawrence Transcript”) at 33:7—9.)
`
`18.
`
`Dr. Heathcock states, citing the declaration of Shirou Sawa, Exhibit 2098 to
`
`IPR2015-00903, that “I understand that the inventor of the patents—in-suit, himself, reported that
`
`bromfenac forms insoluble complexes with BAC. Thus, not only would the POSA expect that
`
`bromfenac, like other NSAIDS in the same class, would form insoluble complexes with BAC,
`
`but when the POSA tested bromfenac in the presence of BAC, s/he would find that to be the case
`
`and would be motivated to solve the problem.” (Heathcock Responsive Report at ‘ll 66; see also
`
`91 53.)
`
`I disagree with Dr. Heathcock’s statement. As an initial matter, I understand that the
`
`laboratory notebooks of the inventor of the patents-in-suit are not prior art to the patents-in-suit.
`
`As discussed above, Dr. Heathcock has identified no evidence in the prior art that bromfenac and
`
`BAC form a precipitate. Moreover, the statement in Mr. Sawa’s lab notebook identified by Dr.
`
`Heathcock does not establish that a precipitate is formed between bromfenac and BAC.
`
`(Id.) Dr,
`
`Heathcock has pointed to no testing or other evidence in Mr. Sawa’s notebook that supports the
`
`conclusion that the cloudiness results from the formation of a precipitate between bromfenac and
`
`BAC.
`
`19.
`
`Therefore, for all
`
`the reasons discussed above and in my opening report, Dr.
`
`Heathcock has failed to establish that a precipitate would form between bromfenac and BAC.
`
`In
`
`any given system, including a solution of bromfenac and BAC,
`
`there is no way to predict
`
`whether an individual NSAID anion will form an insoluble salt with a BAC cation without
`
`experimentation.
`
`Page 15 of 25
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`15
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`Page 15 of 25
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`

`
`E.
`
`Dr. Heathcock Has Not Established That a Person of Ordinary Skill in the
`Art Would Combine Ogawa, Sallmann, and Fu
`
`20.
`
`Dr. Heathcock states that “[a] POSA formulating a NSAID-containing ophthalmic
`
`solution would have been motivated to look to Ogawa, Sallmann, Fu and other references that
`
`disclose phenylacetic acid-derived ophthalmic NSAIDS. These references disclosed well-known
`
`NSA]Ds for such formulations, the challenges to formulating with phenylacetic acid-derived
`
`NSAlDs, and the solutions that had been developed.” (Heathcock Responsive Report at ‘]I 55;
`
`see also ‘]I 56.)
`
`I disagree with Dr. Heathcock’s statements. As discussed in my responsive
`
`report, Ogawa teaches the use of polyvinyl pyrrolidone (“PVP”) and sodium sulfite,
`
`_a well-
`
`known antioxidant,
`
`to chemically stabilize bromfenac from degradation and prevent
`
`the
`
`formation of red insoluble matters.
`
`(Davies Responsive Report at ‘]I 14.) There is no teaching in
`
`Ogawa of the formation of any salt or any “complex” between bromfenac and BAC or any
`
`physical stability of bromfenac and BAC solutions.
`
`(Id.) In contrast, U.S. Patent No. 5,891,913
`
`(“Sallmann”) is directed to formulations of diclofenac potassium in particular and contains no
`
`teaching that diclofenac is susceptible to chemical degradation.
`
`In fact, the very art that Dr.
`
`Heathcock relies on provides an example in which diclofenac and BAC ophthalmic compositions
`
`do not form an insoluble complex, confirming that the existence of a precipitate cannot be
`
`established without testing.
`
`(Heathcock Responsive Report at ‘]I 61, n.9 (“Indeed, in U.S. Pat.
`
`6,265,444,
`
`the inventors expressed surprise that diclofenac and BAC were ‘unexpectedly
`
`compatible .
`
`.
`
`. in the present ophthalmic composition’ and noted that ‘[w]hile the reasons for
`
`this are not entirely clear, .
`
`.
`
`. the presence of the divalent cation is believed to prevent the