SENJU EXHIBIT 2138
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 20
`
`

`
`2006 U.S. Dist. LEXIS 36039, *
`
`Page 2
`
`parties have filed Opening Briefs (Doc. ft 469 (Plaintiffs'
`Corrected Opening Brief “POB"), Doc. # 464 (Defend-
`ants' Opening Brief "DOB"), and Responsive Briefs
`(Doc. ii 470 (Plaintiffs Responsive Brief "PRB"), Doc. it
`47] (I)efendants' Responsive Brief "DRB"). The Court
`has carefully considered the parties‘ arguments as set
`forth in their briefs and at oral argument, and has thor-
`oughly reviewed and considered the evidentiary record in
`light ofthe controlling law and the directives set forth in
`the Federal Circuit's decision. The Court now rules as
`follows.
`
`I. Background
`
`Syntex owns US. Patent No. 5,.-'I0,493 ("the 493
`patent"), entitled "Ophthalmic NSAID Formulations
`Containing a Quaternary Ammonium P1'eservative and a
`Non-ionic Surfactant.“ Allergen is the exclusive distrib-
`utor and manufacturer of formulations [*3] of the 493
`patent, including the product ACULAR(R), an ophthal-
`mic solution used for treating eye inflammation. On
`April 25, 2001, Defendants notified Plaintiffs pursuant to
`2! US. C. § 355(;)(2)(B), that they had filed Abbreviated
`New Drug Application ("ANDA") 76-109 with the Food
`and D1'ug Administration, wherein Defendants sought
`approval
`to market a generic drug version of ACU-
`LAR(R). In their notice, Defendants stated that they be-
`lieved the 493 patent to be invalid on the grounds of ob-
`viousness and inequitable conduct, and not infringed by
`Defendants‘ proposed generic version of ACULAR(R).
`
`In response, on June 6, 2001, Plaintiffs filed this
`lawsuit against Defendants for patent infringement under
`21 U.S.C. § 355 and 35 U.S.C. § 27}(e). Plaintiffs there-
`afler moved for summary judgment ofinfringement. The
`Court granted partial summary judgment for Plaintiffs,
`finding that the submission of ANDA 76-109 literally
`infringed each claim ofthe 493 patent.
`
`Pursuant to 2.’ U.S.C. § 355(;)(5)(B)(iii), approval of
`AN DA 76-109 was stayed for 30 months from receipt of
`Defendants’ notification of the [*4] ANDA filing. The
`stay was set to expire at the end of October, 2003, and,
`absent a preliminary injunction from this Court, the FDA
`was then free to approve ANDA 76-I09 while the
`Court's decision on the issue of the 493 parent's validity
`was pending. As a result, on October 1?, 2003, Plaintiffs
`filed a Motion for a Temporary Restraining Order and
`Preliminary Injunction, requesting that the Court enjoin
`Defendants from engaging in the commercial manufac-
`ture, use, or sale of any product, the approval of which is
`sought
`through ANDA '.r'6—l09, until
`the Court deter-
`mined the validity and enforceability ofthe 493 patent.
`
`In ruling on Plaintiffs‘ Motion, the Court noted that
`because Plaintiffs had already prevailed on their in-
`fringement claim, to prevail on the merits, Plaintiffs only
`
`PAGE 2 OF 20
`
`needed to withstand Defendants‘ invalidity challenges,
`which included unenforceability due to obviousness, lack
`of utility, lack of enablement, indefiniteness, and inequi-
`table conduet. Based upon its review of the record, the
`Court held that Plaintiffs had sufficiently established a
`substantial likelihood that they would prevail on the is-
`sues of patent validity, and that the balance of harms
`weighed in favor [*5] of granting injunctive relief. The
`Court therefore granted the preliminary injunction.
`
`In June 2003, in the interim between the Court's rul-
`ing on the Motion for Summary Judgment and its Order
`granting a preliminary injunction, the Court heid a bench
`trial on Defendants‘ claims of invalidity and unenforcea-
`bility of the 493 patent. Subsequently, on December 29,
`2003, the Court issued its Findings of Fact and Conclu-
`sions of Law ("the December 29 Order"), wherein it con-
`cluded that Defendants‘ proposed generic version of
`ACUL/\R(R) directly infringed all of the claims of the
`493 parent and that the 493 patent was not invalid.
`In
`particular,
`the Court rejected Defendants‘ invalidity ar-
`guments based on obviousness. The Court also affirmed
`the preliminary injunction by permanently enjoining De-
`fendants
`from selling products described in ANDA
`76-109. Defendants thereafter appealed this Court's de-
`termination of non-obviousness to the Court of Appeals
`for the Federal Circuit.
`
`On May 18, 2005, the Federal Circuit issued its Or-
`der reversing this Court's ruling on non-obviousness and
`outlining criteria that the Court is to consider on remand.
`Defendants subsequently moved to vacate the permanent
`[*6]
`injunction pursuant to Federal Rule of (,‘r‘vi‘f Pro-
`eedtrre 60(b)(5). The Court denied Defendants‘ request;
`however, on December 15, 2005,
`the Federal Circuit
`vacated the permanent injunction. (Doc. ii 437.)
`
`Thereafter, on December I6, 2005, Plaintiff filed an
`Application for a Temporary Restraining Order, seeking
`to prevent Defendants fi'om commercially manufactur-
`ing, using, offering to sell, or selling within the United
`States or
`importing into the United States any drug
`product the approval for which is sought through ANDA
`76-109. On December 29, 2005, the Court granted Plain-
`tiffs’ Motion for a Temporary Restraining Order (Doc. #
`447). The parties subsequently stipulated that the Tem-
`porary Restraining Order would remain in effect until the
`Court's hearing on the Plaintiffs‘ Motion for a Prelimi-
`nary Injunction and concurrent hearing on the issue of
`obviousness. (Docs. # 463, 473.) On February 23, 2006,
`the Court held a hearing on Plaintiffs‘ Motion for Pre-
`liminary injunction and on Defendants‘ obviousness
`challenge to the claims of the 493 patent pursuant to the
`Federal Circuit's remand. The Court now makes the fol-
`
`conclusions on
`lowing factual findings and legal [*7]
`the issue of obviousness and Plaintiffs‘ request for in-
`junetive relief. '
`
`PAGE 2 OF 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 3
`
`As an initial matter, also pending before the
`1
`Court is Plaintiffs’ Motion to Remove from the
`
`Record Evidence Inadvettently Placed in the
`Record at Trial (Doc.
`it 427).
`In their Motion,
`Plaintiffs argue that, although the Court only ad-
`mitted specific pages from Dr. Mitra's expert re-
`port dut'ing trial, the entire report was placed in
`
`the record. (Mot. at 2.) Defendants oppose Plain-
`tiffs‘ Motion, arguing that granting the Motion
`would contravene the Federal Circuit's mandate,
`and that even ifthe Couit only admitted selected
`pages from the report
`into evidence, Plaintiffs
`failed to coniect this error. In support oftheir Mo-
`tion, Plaintiffs cite the following exchange from
`trial:
`
`Mr. And then, your honor, Dr. Mitra testified about some of
`Sil-
`ver:
`
`the charts within and rahs ou saw toda . He testified
`about figures 3 and 4 on surface tension when Mr. Weed
`asked him uestions; there was testimony on other pages
`as well, and those pages ofthe actual report are: 20, 22,
`23, 24, 25, 31, and 36. And then at the end, 74 throuh
`78, are just one of two sentences about each of the tables
`that he also testified about. So I would offer those
`
`_u articular pages so that the record will be clear,
`because his testimon relied upon it.
`Ms. We would object to pages out ofthe actual report as being
`Hasic
`ett:
`
`I'll admit them as evidence ofthe opinion that he has
`
`The
`Cour
`t:
`
`given here. I'll admit them.
`
`l39l:l2-l892:I9) (emphasis added).
`(R.T.
`Based on the foregoing except, Defendants only
`offered, and the Court only admitted (over Plain-
`tiffs' objection), certain pages of Dr. Mitra's re-
`port. Accordingly, only pages 20, 22, 23, 24, 25,
`31, 36, 74, 75, 76, Tr‘, 78, and exhibits A-N are
`part of the trial
`record. The Court
`therefore
`GRANTS Plaintiffs‘ Motion to strike all other
`
`potions of Dr. Mitra's report from the trial record.
`
`inventors of the 493 patent are Dr. Roger Fu and Debo-
`rah Lidgate.
`
`2. There are three types of claims in the 493 patent:
`claims to formulations (Claims I-7), claims to methods
`of treating disease by using the formulations of Claims
`1-’? (Claims 8-14), and claims to a preservative system
`(Claims 15 and 16). Claims 1, 8, and 15 a1'e the only in-
`dependent claims in the 493 parent.
`
`3. Independent Claim 1 claims:
`
`[*8] II. Obviousness
`
`A. Findings of Fact
`
`1. Preiirninary Factual Findings
`
`1. The 493 patent‘ issued on May 5, I992 from Ap—
`plication No. 07f624,027, which was filed on December
`7, 1990, and which was a continuation of Application
`No. 07;"096,I73, filed on September ll, I937. The joint
`
`acceptable
`ophthalmologically
`An
`non-steroidal
`anti-inflammatory
`drug
`formulation, comprising:
`
`ophthalmologically
`an
`acceptable
`non-steroidal
`anti-inflammatory carboxyl
`group—containing drug in
`an effective
`amount
`for
`
`ophthalmic treatment he-
`
`PAGE 3 OF 20
`
`PAGE 3 OF 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 4
`
`tween 0.001% and 10.0%
`
`wtfvol;
`
`a quaternary ammo-
`nium preservative in an an-
`timierobially
`effective
`amount between 0.001 %
`
`and 1.0% wtfvol;
`
`an ethoxylated alicyl
`phenol that conforms gen-
`erally to the formula:
`[*9]
`
`C3H 1 7C6H4(OCI~l2C
`H2)nOH where n has an
`average value of 40 in a
`stabilizing amount between
`0.001% and 1.0% wtfvol;
`and an aqueous vehicle q.s.
`[quantity
`sufficient]
`to
`100%.
`
`(Trial Ex.
`42-55.)
`
`1 at SYN0000204, 493 parent at col. 8,
`
`11
`
`4. Dependent Claim 2 claims the formulation of
`Claim 1 wherein the quaternary ammonium preservative
`is benzalkonium chloride ("BAC"); dependent Claim 3
`claims the formulation of Claim 2 wherein the ophthal-
`mologically acceptable non-steroidal anti-inflammatory
`carboxyl group-containing drug is selected from the
`group selected from ketorolac,
`indomethacin,
`flurbi-
`profen, and suprofen; dependent Claim 4 claims the for-
`mulation of Claim 3 wherein the ophthalmologically
`acceptable non-steroidal
`anti-inflammatory carboxyl
`group-containing drug is ketorolac tromethamine; and
`dependent Claim 5 claims the formulation of Claim 1,
`Fulther comprising a chelating agent in an amount be-
`tween 0.0l% and 1.0% wtfvol; a tonieifier q.s. to achieve
`isotonicity with lacrimal fluid; and IN NaOH or IN HCI
`q.s. to adjust pH to 7.40.4. (Trial Ex.
`I at SYN0000204,
`493 parent at col 8, ll 56-68—col. 9, 11 1-10.)
`
`5. Dependent Claims 6 and 7 claim specific compo-
`sitions [*l0]
`included within Claim 1, wherein the
`ophthalmologically
`acceptable
`non-steroidal
`an-
`ti-inflammatory carboxy! group-containing drug (Claim
`6) or ketorolac tromethamine (Claim 7)
`is present at
`0.50% wtfvol; BAC is present at 0.02% wtfvol (ofa 50%
`aqueous solution); Octoxynol 40 is present at 0.01%
`wtfvol (ofa 70% aqueous solution); Na2EDTA is present
`at 0.10%; NaCl
`is present either at q.s. for isotonicity
`with lacrimal fluid (Claim 6) or at 0.79% wtfvol (Claim
`7); the pH is adjusted to 7.4"0.4; and purified water is
`present at q.s. to 100%. Thus, Claims 6 and 7 are more
`
`PAGE 4 OF 20
`
`specific than Claims §—S, requiring formulations of spe-
`cific ingredients in specific amounts.
`(Trial Ex.
`I at
`SYN0000205, 4'93 ]J(l'.i"(.’.i'.-‘i' at col. 9 at I 1-47.)
`
`6. The method of treatment claims of the 493 patent
`begin with independent Claim 8. Claim 8 claims "[a]
`method of treating an ophthalmic disease caused by, as-
`sociated with, or accompanied by inflammatory process-
`es, comprising administering to a mammal suffering
`therefrom a l'ormulation comprising" the formulation of
`Claim 1. (Trial Ex. 1, at SYN0000205, -793 parent at col.
`9, 11 49-64.) Dependent Claims 9-14 claim the method of
`Claim 8 using the formulations [*1 1] of Claims 2-7,
`respectively. (Trial Ex.
`I at SYN0000205, 4'93 parent at
`col. 9, ll65-col. 10,
`ll 50.) Thus, Claims 13 and 14 claim
`methods oftreating ophthalmic disease by administering
`the very specifically claimed formulations of Claims 6
`and 7.
`
`7. Claims I5 and 16 are the preservative system
`claims. Independent Claim 15 claims "[a]n antimicrobi-
`ally effective preservative system for an ophthalmologi-
`cally acceptable non-steroidal anti-in flammatory ca1'box—
`yl group-containing drug formulation, comprising: a
`quaternary ammonium preservative in an antimicrobially
`effective amount between 0.001% and 1.0% wtfvol of
`
`in a stabilizing
`the formulation; and {Octoxynol 40]
`amount between 0.001% and 1.0% wtlvol of the formu-
`
`1ation." Dependent Claim 16 claims the preservative
`system of Claim 15 wherein the preservative is BAC.
`(Trial Ex. 1, at SYN0000205, 493 pater.-‘t at col. 10,
`II
`52-65.)
`
`8. An Information Disclosure Statement ("IDS") was
`filed along with both applications,
`identifying the fol-
`lowing prior art: 4,087,539 (1978) Muchowski er mt;
`4,089,969 (1978) Muchowski er 01; 4,097,579 (I978)
`Muchowski et ai'.; 4,232,038 (1980) Kluge et aI.;
`4,336,151 (1982) Like {*l2]
`er a1.; 4,336,152 (1982)
`Like et all; 4,545,151 (i984) Waterbury; "Influence of
`(Ethoxy)5 Octyl Phenol on the Antibacterial Propenies
`of Preservatives," M.T. Nadir, er a7., Jonmaf of Phar-
`macy and Plmrmacology, Volume 29, Supplement, De-
`cember I977, page 67P; and "Ocufen (flurhiprofen so-
`dium) 0.03% Liquifilm sterile ophthalmic solution, Al-
`lergan, product description sheet.
`
`9. In addition, the examiner cited the following ref-
`erences in initially rejecting certain claims of the 493
`patent under 35 US‘. C. 35 1'03: 4,087,538 (1973) Portnoff;
`4,230,724 (E980) Cooper e! m’.; 4,474,751 (1984) Has-
`lam er all; 4,474,811 (1984) Masucla er‘ oi; 4,500,538
`(1985) Woltersdorf; 4,559,343 (1985) Han et at;
`4,607,038 (1986) Ogata er cn".; Japanese Ref. No. 23,318
`(1935); 4,349,563 (1982) Gilbert ea‘ cn".,' The Condensed
`Cheinical Dictionary,
`Seventh Ed.; M’cCzn'cheon's
`”E;mu's:'fiers and Dete:‘gen!3" (I932) ("McCtrtc‘I3e()n's");
`
`PAGE 4 OF 20
`
`

`
`2006 US. Dist. LEXIS 36089, *
`
`Pagc 5
`
`"The Synergistic Effects of Nonionic Surfactants Upon
`Cationic Gerrnicidal Agents," Schmolka (I973). (Trial
`Exs. 024 at SYNO000245-48, 035 at SYNUOOOU34-44,
`SYN0000050-52.)
`
`sorbate 80 as a member in a list of stabilizers -- not sur-
`
`l3:44-48, 56-57.) The only
`factants. (Trial Ex. 004 at
`other stabilizer disclosed in that list is glycerin, which is
`not a surfactant. (R.T. l709:5-10.)
`
`at the
`10. A person of ordinary skill in the art [*l3]
`time of the invention is a person having a Bachelor's or
`Master's degree in the pharmaceutical sciences and hav-
`ing three to five years of experience working in the field
`under the supervision of a person having a Plr.D.
`in the
`pharmaceutical sciences. (R.T. 1707211-24; DOB at 5
`11.3.)
`
`2. The Prior Art References
`
`1 l. Plaintiffs assert that at trial, Defendants only as-
`serted that the combination of U.S. Patent‘ No. 4.545.l5I
`to Waterbury, U.S. Patent No. 4,349,563 to Gilbert 9! at'.,
`and US. Patent No. 4,559,343 to I-Ian er al'., rendered
`obvious the claims of the 493 patent. Defendants, how-
`ever, contend that in addition to these references, they
`also relied on: (1) McCatcl2eon's; (2) the Pharmaceutical
`Expert Report; (3) Gram‘ and Hacklfs Chemical Dic-
`tionary; (4) the GAP product sheet; (5) the Cosmetic
`Dictionary; (6) the Nadir reference (Trial Ex. YK); (7)
`the Schmolka reference; and (8) the Condensed Chemi-
`cal Dictionary. Plaintiff does not dispute that each of the
`references that Defendants cited are in the trial record.
`Because the inclusion of the additional references cited
`
`by Defendants does not affect the Court's ultimate de-
`termination on the issue [* M] of obviousness, the Court
`will consider all the references that Defendants have cit-
`
`ed. However, based on its review of the trial record, the
`Court finds that Defendants‘ obviousness challenge relied
`primarily on the Waterbury patent, the Gilbert patent, the
`Han patent, and McCurc}1eon's.
`
`I2. U.S. Patent No. 4,454,154 to Waterbury (the
`"I5! patent" andfor the "Waterbury patent") defines a
`number of non-steroidal anti-inflammatory dr'ugs that
`were found to be efficacious in the treatment of inflam-
`
`matory diseases.
`
`13. The Waterbury patent does not discuss the con-
`cepts of long—term stability or anti-microbial effective-
`ness and does not discuss any problem of interaction or
`complexation between BAC and ketorolac trometham-
`ine. It also does not discuss the use of EDTA or any oth-
`er chelating agent.
`(Trial Ex. 004; R.T.
`llSS:l-16,
`I l59:25l 1 60:3, l7'0?:25—l7l0:6.)
`
`I4. Although the only example formulation in the
`Waterbury patent, Example 1
`("Composition of Oph-
`thalmic Solutions
`for Topical Administration to the
`Eye"), does not include a surfactant in its composition,
`the Waterbury patent does disclose the use of the surfac-
`tant Polysorbate 80 (also referred to as "Tween 80").
`[*l5] The Waterbury patent, however, discloses Poly-
`
`PAGE 5 OF 20
`
`15. U..S'. Patent No. 4,349,563 to Gilbert (the ‘"563
`pcrterrt" andlor the "Gilbert patent") teaches the topical
`administration
`to
`the
`eye
`of
`non-steroidal
`an-
`ti-intlarnmatory agents, which as a class previously were
`thought to be ineffective in treating ocular inflammation.
`The Gilbert patent teaches that NSAIDs for ocular ad-
`ministration should include various ingredients other
`than the non-steroidal anti-inflammatory agent
`itself,
`such as antimicrobial agents, antioxidants, and metal ion
`sequestering agents. The Gilbert patent does not, howev-
`er, mention ketorolac trometharnine. (Trial Ex. WJ.)
`
`I6. Although the Gilbert patent states that "the
`presence of a stabilizer is not preferred," the patent does
`teach the optional
`inclusion of Tween or Pluronic sur-
`factants, and specifies Polysorbate 80. The Gilbert patent
`does not mention Octoxynol 40, and does not discuss the
`concepts of long-term stability or anti-microbial effec-
`tiveness [*l6]
`or any problem of interaction or com-
`plexation
`between
`BAC
`and
`NSAIDs_
`(R.T.
`l'J'll:20-|'7l2:7.) It also does not discuss the use of
`EDTA or any other chelating agent. (Trial Ex. W3.)
`
`1?. U.S. Patent No. 4,559,343 to Han, et at’. (the
`‘"343 patent" andlor the "Han patent") discloses that the
`addition of xanthines, such as caffeine,
`to ophthalmic
`solutions of acidic NSAIDs helps to reduce the irritation
`associated with the NSAIDs. (Trait Ex. AK.) Specifical-
`ly, the Han patent claims an aqueous, nonirritating, non-
`steroiclal ophthalmic composition comprising the NSAID
`suprofen, a xanthine, a preservative, and a buffer, as well
`as methods for using this composition. (In!) Two of the
`examples of the Han patent disclose the use of NSAIDs
`with either BAC or thimerosal and either Pluronic F 127
`
`or tyloxapol, but do not indicate whether Pluronic F12’?
`or tyloxapol are being used as stabilizers, or indicate
`what role these surfactants play in the example composi-
`tions at all. (lot) The Han patent does not discuss the
`concepts of long-term stability or anti-microbial effec-
`tiveness and does not discuss any problem of interaction
`or conrpiexation between BAC and ketorolac tro-
`methamine.
`lt [*l7]
`also does not discuss the use of
`EDTA or any other chelating agent. (lal)
`
`l8. McCutc}1eon’s is a compendium ofa large num-
`ber of emulsifiers and detergents. (Trial Ex. AL.) It de-
`scribes lgepal CA—89'? (Octoxynol 40) as an "Emulsifier,
`stabilizer. " I-lowever, McC'zttcheon’s does not disclose the
`use of Octoxynol 40 in a pharmaceutical. (id) There is
`nothing in McCtrrcheon’s that suggests that Octoxynol 40
`could successfully be used to solve the interaction be-
`tween a carboxyl-group-containing NSAID and a qua-
`
`PAGE 5 OF 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 6
`
`ternary ammonium preservative. There is nothing in
`McCtttc!'ierm’s that suggests that Octoxynol 40 could
`safely be used in a pharmaceutical product or in an oph-
`thalmic formulation. There is nothing in Mc‘C'tttche0n’s
`that suggests that the use of Octoxynol 40 would pre-
`serve the anti-microbial effectiveness ofa preservative.
`
`19. None of the prior an references cited by De-
`fendants disclose any functional equivalence between
`Octoxynoi 40 and any of the surfactants disclosed by the
`Waterbury, Gilbert or Han patents.
`
`20. Apart from the September 1987 Pharmaceutical
`Report authored by Dr. Fu and Ms. Lidgate ("the Syntex
`Report"), none of the prior art references 1* 1 8]
`cited by
`Defendants mention Octoxynol 40, except for McCmch-
`erm'.r. Defendants‘ expert, Dr. Mitra, provided no testi-
`mony at all regarding McCutcheon’s.
`
`21. Plaintiffs‘ expert, Dr. Stella, testified that alt-
`hough McCntcheon's refers to Octoxynol 40 as an emul-
`sifierlstabilizer,
`it uses those words in the context of
`mixing and stabilizing a non-water-miscible substance
`and water. This is an entirely different context from the
`use ofthose words in the 493 patent, which discloses the
`use of Octoxynol 40 as a stabilizer in a solution consist-
`ing of an NSAID and a quaternary ammonium preserva-
`tive. (R.T. I714:1 1-19; Trial Ex. 1, claim 1.)
`
`22. Dr. Stella also testified that there was nothing in
`McCntcheon’s that would have motivated one of ordinary
`skill in the art to combine it with the other prior art ref-
`erences
`to arrive at
`the patented inventions.
`(R.T.
`l7l5:17-22.)
`
`23. Significantly, Defendants have not identified any
`prior art reference that either discloses or suggests: (a)
`that Octoxynol 40 be used in an ophthalmic formulation;
`(b) that it be used in a preservative system with a qua-
`ternary ammonium preservative; (c) that it be used in a
`formulation with [*19]
`a quaternary ammonium pre-
`servative, such as BAC; (cl) that it be used in a formula-
`tion with a carboxyl group-containing NSAID, such as
`ketorolac tromethamine; (e) that it be used to prevent the
`formation
`of
`a
`complex
`between
`a
`carboxyl
`group—containing NSAID and a quaternary ammonium
`preservative; or (t) that it would act to maintain the anti-
`microbial effectiveness of a quaternary ammonium pre-
`servative, such as BAC, in an ophthalmic formulation.
`
`3. The Prosecution History of the 493 Patent
`
`24. As previously indicated, an IDS was filed along
`with both Application No. 07t‘096,173 and Application
`No. 07:’624,027, which led to the issuance of the 493
`patent,
`identifying the following prior art: 4,087,539
`(1978) Muchowski er at'.; 4,089,969 (l978) Muchowski
`at m’.; 4,097,579 (1978) Muchowski er .54.; 4,232,038
`
`PAGE 6 OF 20
`
`a.-'.; 4,336,151 (1982) Like er at;
`(1980) Kluge er
`4,336,152 (1982) Like at at; 4,545,151 (1984) Water-
`bury; "lnfluence of (Ethoxy)5 Octyl Phenol on the Anti-
`bacterial Properties of Preservatives," M.T. Nadir, et at,
`Jom‘mrl' of Pf1ai‘niciL'_1* and P!'iciriii(i::'(Jl(Jgy, Volume 29,
`Suppiement, December 1977, page 671’; and "Ocufcn
`(tlurbiprofen sodium) 0.03% [*20]
`Liquitihn sterile
`ophthalmic solution, Allcrgan, product description sheet.
`
`the examiner cited the following
`In addition,
`25.
`references in initially rejecting certain claims of the 493
`patent under 35 U.S.C. 55‘ 1103: 4,087,538 (1978) Poitnoff;
`4,230,724 (1980) Cooper er at; 4,474,751 (1984) Has-
`lam er (M; 4,474,811 (1984) Masuda at at; 4,500,538
`(1985) Woltersdorf; 4,559,343 (1985) Han et of;
`4,607,038 (1986) Ogata er a{_; Japanese Ref. No. 23,318
`(1985); 4,349,563 (1982) Gilbert er ml; The Comlensed
`Cheriifcat Dictionary,
`Seventh Ed.; McCtt!c.lre0n’.s
`”Etti1rI.si)‘iet's and De!er'gems" (1982); "The Synergistic
`Effects of Nonionic Surfactants Upon Cationic Germi-
`cidal Agents," Schmoika (1973).
`(Trial Exs. 024 at
`SYN0000245-48,035
`at
`S‘{N0000034—44,
`SYN0000050-52.)
`
`26. The results of Ms. Lidgate's study of formula-
`tions containing ketorolac tromethamine, BAC, and three
`different surfactants—Octoxynol 40, Tween 80, and Myrj
`52-were also disclosed to the Examiner during the ex-
`amination of the parent Application No. 07!096,l73.
`These results showed that
`solutions containing Oc-
`toxynol 40 remained clear under a variety of storage
`conditions [*21] while solutions containing Tween 80
`and Myrj 52 became turbid. (Trial Exs. 204, 205, 009,
`024 at SYN0000280, 035 at SYN0000057-64; RT.
`695:1-701 : 14, 76] 22-76219, 769: 1 I-770:25.)
`
`27. The examiner of Application No. 07.-’096,l73
`criticized the data comparing Octoxynol 40, Tween 80,
`and Myrj S2 for four reasons: (1) the data did not com-
`pare Octoxynoi 40 to the surfactants of the primary ref-
`erences;
`(2)
`the concentration of Octoxynol 40 was
`greater than the concentrations of the other surfactants;
`(3) the data was not commensurate with the then-pending
`ciaims, which did not set propoltions for the components
`of the formulations; and (4) the data was not in declara-
`tion form. (Trial Ex. 24 at SYN0000288.)
`
`that the
`28. The examiner's criticism number (1),
`surfactants of the primary references were overlooked, is
`no longer relevant at this stage in the proceedings. The
`data before the examiner compared Ocloxynol 40 to the
`surfactant most mentioned
`in
`the
`primary refer-
`ences-Tween 80. Furthermore,
`the Court-unlike the ex-
`aminer-also has before it evidence that Ms. Pulsipher
`tried to use the Pluronie F127 of Han, as well as Pluronic
`F168, to solve the ketorolac tromethaminei'BAC turbidity
`[*22]
`problem, and found that these surfactants were
`
`PAGE 6 OF 20
`
`

`
`2006 US. Dist. LEXIS 36089, *
`
`Page Tr‘
`
`unable to do what Octoxynol 40 later was discovered to
`do-namely, keep a solution of ketorolac trornethamine
`and BAC stable under variable
`conditions.
`(R.T.
`350:5-3’}’5:l5.)
`
`29. The examiner's criticism number (2), regarding
`the relative concentrations of the surfactants used in the
`
`experiments was that, whereas the concentrations of Oc-
`toxynol 40 are listed as 0.004% and 0.02%, the concen-
`trations of the other surfactants are listed as 0.0035% and
`
`0.0l% for Tween 80 and 0.00l5% and 0.01% for Myrj
`52. Therefore,
`the "high" and "low" concentrations of
`Octoxynol 40 are higher, respectively,
`than the "high"
`and "low" concentrations of the other surfactants. How-
`
`ever, comparing the results for the "low" concentration
`of Octoxynol 40 (the 0.004% column) with the "high"
`concentrations of Tween 80 and Myrj 52 (the two col-
`umns labeled 0.01%), indicates that Octoxynol 40 still
`outperforms the other surfactants. In other words, taking,
`for example, the observations made afier one month at
`40 [degree] C, a concentration of 0.004% of Octoxynol
`40 was able to keep the solution clear, whereas 0.01%
`concentrations of Tween 80 and Myrj 52-that is, concen-
`trations [*23]
`two and a half times higher than the Oc-
`toxynol 40 concentration-resulted in solutions that were
`"very turbid" and "turbid," respectively. (Trial Ex. 24 at
`SYN0000280.)
`
`30. The examiner's criticism number (3), regarding
`the then-pending claims, is irrelevant at this stage in the
`proceedings. Unlike the claims that were pending at the
`time of the examiner's comments, the claims of the 493
`patent, as finally issued and as asserted in this lawsuit,
`do set forth proportions of the formulation components.
`(See Trial Ex. 00! .)
`
`the examiner's criticism number (4),
`31. Similarly,
`that the data from Ms. Lidgate's tests was not in declara-
`tion form was specific to the prosecution context. The
`results of Ms. Lidgate's tests, supported by sworn trial
`testimony from Ms. Lidgate, are in the trial record. Ms.
`Lidgate‘s test data compares the performance of Oc-
`toxynol
`40 with
`the
`performance of other mi-
`celle-forming, non-ionic surfactants, which Dr. Mitra
`says should all perform "equally well" and which De-
`fendants have asserted to be the closest prior art to the
`493 patent._
`
`32. Defendants have argued that the data comparing
`Octoxynol 40, Tween 80, and Myrj 52 should be disre-
`garded [*24]
`because it contains inconsistencies. De-
`fendants base this argument on the fact
`that
`the data
`shows that all solutions were clear at 60 [degree] C, both
`at l month and at 5 months, thus showing that the turbid-
`ity of those particular solutions did not
`increase with
`time. Defendants have also pointed to the fact that the
`Tween 80 solutions at 40 [degree] C were described as
`
`PAGE 7 OF 20
`
`1 month, but only "turbid" at 5 months,
`"very turbid" at
`indicating that turbidity may have decreased over time.
`However, Defendants fail to take into account that all of
`the solutions containing Octoxynol 40 remained clear, at
`all temperatures and over all time periods, while the so-
`lutions containing Tween 80 and Myrj 52 became turbid
`under several different time and temperature conditions.
`(Trial Ex. 24 at SYN0000280.) This demonstrates that
`the solutions containing Octoxynol 40 had better "ro-
`bust" stability under a variety of conditions than did the
`solutions containing Tween 80 and Myrj 52.
`
`33. Defendants have also argued that because the
`original claims of Application No. 07t096,l73 claimed
`"a stabilizing amount of a nonionic surfactant," Trial Ex.
`24 at SYN0000235, the applicants admitted to the PTO
`[*25]
`that all nonionic surfactants are the same. The
`applicants, however, made no such admission and in fact
`subsequently narrowed the claims to just the use of Oc-
`toxynol 40. The prosecution history in its entirety, there-
`fore, supports a conclusion that the applicants did not
`believe all nonionic surfactants to be the same.
`
`34. Defendants also point to the applicants‘ state-
`ment
`in the prosecution history that "such compounds
`[non-ionic polyoxyethylated octylphenol surfactants] are
`generally known to those skilled in the art as useful sur-
`factant compounds." (Trial Ex. 24 at SYN0000259.)
`However, the fact that such compounds may have been
`known to be "usefiil surfactant compounds," does not
`support the inference that they were known, prior to the
`inventions of the 493 patent, to be useful in ophthalmic
`formulations or in solubilizing NSAIDHBAC complexes.
`In fact, several other types of known surfactant com-
`pounds were specificalty found by the Syntex scientists
`not to be usefill in ketorolac tromethaminei’BAC formu-
`lations.
`
`35. On March 5, 199], the PTO issued a rejection of
`all ofthe claims of Application No. 0'l'i’624,027 as obvi-
`ous over the prior art. The Examiner noted that the [*26]
`Gilbert and Han patents both taught the use of "nonionic
`surfactants" as stabilizing agents and stated that any
`non-ionic surfactant would lead to "better solubilization
`
`ofsaid quaternary ammonium compound." (Trial Ex. 35
`at SYN0000043.) 36. The examiner of Application No.
`0?a’624,027 also specifically rejected claims 37 and 33 as
`obvious over the Nadir and Schmolka references. The
`
`Nadir reference suggested the use of Octoxynoi 5 in
`conjunction with antibacterial preservatives. (Trial Ex.
`035 at SYN0000048, SYN0000O90; RT. 766:3-76822,
`771:]-772:4.)
`
`3?. In response to the March 5, 1991 rejection, on
`September 5, I99], Dr. Derek Freyberg, in-house coun-
`sel for Syntex submitted an Amendment of the claims.
`Specifically,
`in response to the Examiner's rejection of
`
`PAGE 7 OF 20
`
`

`
`2006 US. Dist. LEXIS 36089, *
`
`Page 3
`
`claims 3? and 38 over the Nadir reference, Dr. Freyberg
`submitted a declaration of Ms. Lidgate (the "Lidgate
`Declaration"). The Lidgate Declaration included the re-
`sults of a test performed by Ms. Lidgate that compared
`for'mulations containing Octoxynol 40, Octoxynol 5, and
`Octoxynol 3. (Trial Ex. 035 at SYN0000057—64; Rfl‘.
`769:l1~T"0:25.)
`
`38. The September 5, 1991 Amendment also stated
`as follows:
`
`have shown in the
`Applicants [*2?]
`prosecution of the parent to this applica-
`tion that other nonionic surfactants, such
`as Tween and Myrj, fail to act as stabi-
`lizers in the claimed formulations; and the
`enclosed Declaration of Deborah M.
`
`that
`Lidgate demonstrates
`toxynols are unsatisfactory.
`
`certain oc-
`
`Thus, the Amendment attempted to convince the Exam-
`iner that he was wrong in treating all nonionic surfactants
`alike because at least some surfactants, including certain
`octoxynols, would not work to stabilize the claimed for-
`mulations. (Trial Ex: 035 at SYN0000062.)
`
`39. When Ms. Lidgate turned her data from the ex-
`periment in question over to Syntex's patent department,
`the data included the results of experiments on formula-
`tions containing Octoxynol 40, Octoxynol 5, Octoxynol
`3, and Octoxynol 12.5. Included in those results was Ms.
`Lidgate's observation that, after three months of stability
`testing,
`the formulations containing Octoxynol 40 and
`Octoxynol 12.5 looked equivalent. (R.'I‘. 658:1-66023.)
`
`40. Although Ms. Lidgate noted that the formula-
`tions containing Octoxynol 40 and Octoxynol
`12.5
`looked equivalent, she did not conclude that they were
`equivalent
`in any other respect.
`In particular,
`[*28]
`Ms. Lidgate had no evidence that the formulation con-
`taining Octoxyrrol 12.5 would pass the "USP challenge"
`test for antibacterial effectiveness. (R.'l‘. 651:l3-652:l2,
`660: 16-661 :8.)
`
`41. While Ms. Lidgate did not make the decision as
`to which of the octoxynols would be included in the
`Lidgate Declaration, she believed the Declaration to be
`accurate and truthful at the time that she signed it. Ms.
`Lidgate testified that she had no reservations about the
`fact that the Declaration did not mention Octoxynol 12.5
`because the purpose of the Declaration was to show that
`not all octoxynols would be suitable for use in the