Page I
`
`LexisNexis®
`
`'<> Positive
`
`As of: Nov 02, 2015
`
`SYNTEX (U.S.A.) LLC, a Delaware corporation; ALLERGAN, INC., a Delaware
`corporation, Plaintiffs, v. APOTEX INC., a Canadian corporation; APOTEX
`CORP., a Delaware corporation; and NOVEX PHARMA, a Canadian corporation.
`Defendants.
`
`No. C 01-02214 MJJ
`
`UNITED STATES DISTRICT COURT FOR THE NORTHERN DISTRICT OF
`CALIFORNIA
`
`2006 U.S. Dist. LEXIS 36089
`
`June 2, 2006, Decided
`June 2, 2006, Filed
`
`SUBSEQUENT HISTORY: Affirmed by Syntex
`(U.S.A.) LLC v. Apotex, Inc., 22I Fed. Appx. I 002, 2007
`U.S. App. LEXIS 9276 (Fed. Cir., 2007)
`Related proceeding at Roche Palo Alto LLC v. Apotex,
`Inc., 2007 U.S. Dist. LEXIS 67058 (N.D. Cal., Sept. I1,
`2007)
`
`PRIOR HISTORY: Syntex (USA) LLC v. Apotex Inc.,
`2006 U.S. Dist. LEXIS 34608 (N.D. Cal., May I8, 2006)
`
`For Allergan Inc., a Delaware corporation, Syntex USA
`LLC, a Delaware corporation, Counter-defendants: Al(cid:173)
`exander L. Brainerd, Christine Saunders Haskett, Keith
`R. Weed, Nathan Shafi·oth, Heller Ehrman LLP, San
`Francisco, CA.
`
`JUDGES: MARTIN J. JENKINS, UNITED STATES
`DISTRICT JUDGE.
`
`[*I] For Syntex USA LLC, a Delaware
`COUNSEL:
`corporation, Allergan Inc., a Delaware corporation,
`Plaintiffs: Alexander L. Brainerd, Christine Saunders
`Haskett, Keith R. Weed, Nathan Shafroth, Heller Ehrman
`LLP, San Francisco, CA.
`
`For Apotex Inc., a Canada corporation, Apotex Corp., a
`Delaware corporation, Novex Pharma,
`
`For Defendants: Alan H. Bernstein, Robert S. Silver,
`William J. Castillo, Caesar Rivise Bernstein Cohen &
`Pokotilo, Philadelphia, PA; Cameron Kerrigan, Daniel B.
`Pollack, Squire Sanders & Dempsey LLP, Palo Alto,
`CA; Ronald S. Lemieux, Paul Hastings Janofsky &
`Walker LLP, Palo Alto, CA.
`
`OPINION BY: MARTIN J. JENKINS
`
`OPINION
`
`FINDINGS OF FACTS AND CONCLUSIONS OF
`LAW ON RE-HEARING ON ISSUE OF OBVI(cid:173)
`OUSNESS OF THE 493 PATENT AND PLAIN(cid:173)
`TIFFS' REQUEST FOR PRELIMINARY INJUNC(cid:173)
`TIVE RELIEF
`
`is Plaintiffs Syntex
`the Court
`Pending before
`(U.S.A.) LLC and Allergan, Inc.'s Request for Prelimi(cid:173)
`nary Injunctive Relief. Concunent [*2] with Plaintiffs'
`Request, and pursuant to the Federal Circuit's decision in
`Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F. 3d 1371 (Fed.
`Cir. 2005), is the Court's re-hearing on Defendants Apo(cid:173)
`tex Inc., Apotex Corp., and No vex Pharma's (collective(cid:173)
`ly, "Defendants") obviousness challenge to Plaintiffs'
`patents-in-suit. In accordance with this Court's Order, the
`
`Page 1 of 20
`
`SENJU EXHIBIT 2138
`LUPIN v. SENJU
`IPR2015-01099
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 2
`
`parties have filed Opening Briefs (Doc. # 469 (Plaintiffs'
`Con-ected Opening Brief "POB"), Doc. # 464 (Defend(cid:173)
`ants' Opening Brief "DOB"), and Responsive Briefs
`(Doc.# 470 (Plaintiffs' Responsive Brief "PRB"), Doc.#
`471 (Defendants' Responsive Brief "DRB"). The Court
`has carefully considered the pm1ies' arguments as set
`fm1h in their briefs and at oral argument, and has thor(cid:173)
`oughly reviewed and considered the evidentiary record in
`light of the controlling law and the directives set forth in
`the Federal Circuit's decision. The Com1 now rules as
`follows.
`
`I. Bacl{ground
`
`Syntex owns U.S. Patent No. 5,110,493 ("the 493
`patent"), entitled "Ophthalmic NSAID Formulations
`Containing a Quaternary Ammonium Preservative and a
`Non-ionic Surfactant." Allergen is the exclusive distrib(cid:173)
`utor and manufacturer of formulations [*3] of the 493
`patent, including the product ACULAR(R), an ophthal(cid:173)
`mic solution used for treating eye inflammation. On
`April 25, 2001, Defendants notified Plaintiffs pursuant to
`21 U.S. C. § 3550)(2)(B), that they had filed Abbreviated
`New Drug Application ("ANDA'') 76-109 with the Food
`and Drug Administration, wherein Defendants sought
`approval to market a generic drug version of ACU(cid:173)
`LAR(R). In their notice, Defendants stated that they be(cid:173)
`lieved the 493 patent to be invalid on the grounds of ob(cid:173)
`viousness and inequitable conduct, and not infringed by
`Defendants' proposed generic version of ACULAR(R).
`
`In response, on June 6, 200 I, Plaintiffs filed this
`lawsuit against Defendants for patent infhngement under
`21 U.S.C. § 355 and 35 U.S.C. § 27l(e). Plaintiffs there(cid:173)
`after moved for summary judgment of infringement. The
`Court granted pm1ial summary judgment for Plaintiffs,
`finding that the submission of ANDA 76-l 09 literally
`infringed each claim of the 493 patent.
`
`Pursuant to 21 U.S. C. § 3550)(5)(B)(iii), approval of
`ANDA 76-l 09 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 fi·om this Court, the FDA
`was then free to approve ANDA 76-109 while the
`Com1's decision on the issue of the 493 patent's validity
`was pending. As a result, on October 17, 2003, Plaintiffs
`filed a Motion for a Temporary Restraining Order and
`Preliminary Injunction, requesting that the Court enjoin
`Defendants fi·om engaging in the commercial manufac(cid:173)
`ture, use, or sale of any product, the approval of which is
`sought through ANDA 76-l 09, until the Com1 deter(cid:173)
`mined the validity and enforceability of the 493 patent.
`
`In ruling on Plaintiffs' Motion, the Com1 noted that
`because Plaintiffs had already prevailed on their in(cid:173)
`fi·ingement claim, to prevail on the merits, Plaintiffs only
`
`needed to withstand Defendants' invalidity challenges,
`which included unenforceability due to obviousness, lack
`of utility, lack of enablement, indefiniteness, and inequi(cid:173)
`table conduct. Based upon its review of the record, the
`Com1 held that Plaintiffs had sufficiently established a
`substantial likelihood that they would prevail on the is(cid:173)
`sues of patent validity, and that the balance of harms
`weighed in favor [*5] of granting injunctive relief. The
`Cow1 therefore granted the preliminary injunction.
`
`In June 2003, in the interim between the Court's rul(cid:173)
`ing on the Motion for Summary Judgment and its Order
`granting a preliminary injunction, the Court held a bench
`trial on Defendants' claims of invalidity and unenforcea(cid:173)
`bility of the 493 patent. Subsequently, on December 29,
`2003, the Com1 issued its Findings of Fact and Conclu(cid:173)
`sions of Law ("the December 29 Order"), wherein it con(cid:173)
`cluded that Defendants' proposed generic version of
`ACULAR(R) directly infi·inged all of the claims of the
`493 patent and that the 493 patent was not invalid. In
`pm1icular, the Com1 rejected Defendants' invalidity ar(cid:173)
`guments based on obviousness. The Com1 also affirmed
`the preliminary injunction by permanently enjoining De(cid:173)
`in ANDA
`fendants fi·om selling products described
`76-109. Defendants thereafter appealed this Court's de(cid:173)
`termination of non-obviousness to the Com1 of Appeals
`for the Federal Circuit.
`
`On May 18, 2005, the Federal Circuit issued its Or(cid:173)
`der reversing this Com1's ruling on non-obviousness and
`outlining criteria that the Court is to consider on remand.
`Defendants subsequently moved to vacate the pe1manent
`injunction pursuant to Federal Rule of Civil Pro(cid:173)
`[*6]
`cedure 60(b)(5). The Court denied Defendants' request;
`however, on December 15, 2005, the Federal Circuit
`vacated the permanent injunction. (Doc.# 437.)
`
`Thereafter, on December 16, 2005, Plaintiff filed an
`Application for a Temporary Restraining Order, seeking
`to prevent Defendants from commercially manufactur(cid:173)
`ing, using, offering to sell, or selling within the United
`States or impm1ing into the United States any drug
`product the approval for which is sought through ANDA
`76-l 09. On December 29, 2005, the Com1 granted Plain(cid:173)
`tiffs' Motion for a Temporary Restraining Order (Doc. #
`447). The parties subsequently stipulated that the Tem(cid:173)
`porary Restraining Order would remain in effect until the
`Com1's hearing on the Plaintiffs' Motion for a Prelimi(cid:173)
`nary Injunction and concurrent hearing on the issue of
`obviousness. (Docs. # 463, 473.) On February 23, 2006,
`the Com1 held a hearing on Plaintiffs' Motion for Pre(cid:173)
`liminary Injunction and on Defendants' obviousness
`challenge to the claims of the 49 3 patent pursuant to the
`Federal Circuit's remand. The Com1 now makes the fol(cid:173)
`lowing factual findings and legal [*7] conclusions on
`the issue of obviousness and Plaintiffs' request for in(cid:173)
`junctive relief. 1
`
`Page 2 of 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 3
`
`As an initial matter, also pending before the
`Comt is Plaintiffs' Motion to Remove from the
`the
`Record Evidence Inadve1tently Placed in
`Record at Trial (Doc. # 427). In their Motion,
`Plaintiffs argue that, although the Comt only ad(cid:173)
`mitted specific pages fi·om Dr. Mitra's expert re(cid:173)
`pmt during trial, the entire report was placed in
`
`the record. (Mot. at 2.) Defendants oppose Plain(cid:173)
`tiffs' Motion, arguing that granting the Motion
`would contravene the Federal Circuit's mandate,
`and that even if the Court only admitted selected
`pages from the repmt into evidence, Plaintiffs
`failed to conect this error. In suppmt of their Mo(cid:173)
`tion, Plaintiffs cite the following exchange from
`trial:
`
`And then, your honor, Dr. Mitra testified about some of
`
`Mr.
`Sil-
`ver:
`
`the charts within and graphs you saw today. He testified
`about figures 3 and 4 on surface tension when Mr. Weed
`asked him questions; there was testimony on other pages
`as well, and those pages of the actual report are: 20, 22,
`23, 24, 25, 31, and 36. And then at the end, 74 through
`78, are just one of two sentences about each of the tables
`that he also testified about. So 1 would offer those
`particular pages so that the record will be clear,
`because his testimony relied upon it.
`Ms. We would object to pages out of the actual repmt as being
`Hask
`ett:
`
`hearsay.
`I'll admit them as evidence of the opinion that he has
`
`The
`Cour
`t:
`
`given here. I'll admit them.
`
`(R.T. 1891:12-1892:19) (emphasis added).
`Based on the foregoing except, Defendants only
`offered, and the Court only admitted (over Plain(cid:173)
`tiffs' objection), certain pages of Dr. Mitra's re(cid:173)
`pmt. Accordingly, only pages 20, 22, 23, 24, 25,
`31, 36, 74, 75, 76, 77, 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 repmt fi·om the trial record.
`
`inventors of the 493 patent are Dr. Roger Fu and Debo(cid:173)
`rah Lidgate.
`
`2. There are three types of claims in the 493 patent:
`claims to formulations (Claims 1-7), claims to methods
`of treating disease by using the formulations of Claims
`1-7 (Claims 8-14), and claims to a preservative system
`(Claims 15 and 16). Claims 1, 8, and 15 are the only in(cid:173)
`dependent claims in the 493 patent.
`
`3. Independent Claim 1 claims:
`
`[*8] II. Obviousness
`
`A. Findings of Fact
`
`I. Preliminary Factual Findings
`
`1. The 493 patent issued on May 5, 1992 fi·om Ap(cid:173)
`plication No. 07/624,027, which was filed on December
`7, 1990, and which was a continuation of Application
`No. 07/096,173, filed on September 11, 1987. The joint
`
`acceptable
`ophthalmo1ogically
`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 be-
`
`Page 3 of 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 4
`
`tween 0.001% and 10.0%
`wt/vol;
`
`a quatemary ammo(cid:173)
`nium preservative in an an(cid:173)
`timicrobially
`effective
`amount between 0.00 I %
`and 1.0% wt/vol;
`
`an ethoxylated alkyl
`phenol that conforms gen(cid:173)
`erally to the formula:
`(*9]
`
`C3H 17C6H4(0CH2C
`H2)nOH where n has an
`average value of 40 in a
`stabilizing amount between
`0.00 I% and 1.0% wt/vol;
`and an aqueous vehicle q.s.
`[quantity
`sufficient]
`to
`100%.
`
`(Trial Ex. I at SYN0000204, 493 patent at col. 8, II
`42-55.)
`
`4. Dependent Claim 2 claims the formulation of
`Claim I wherein the quaternary ammonium preservative
`is benzalkonium chloride ("BAC"); dependent Claim 3
`claims the formulation of Claim 2 wherein the ophthal(cid:173)
`mologically acceptable non-steroidal anti-inflammatory
`carboxyl group-containing drug is selected from the
`group selected fi·om ketorolac, indomethacin, flurbi(cid:173)
`profen, and suprofen; dependent Claim 4 claims th~ for(cid:173)
`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 I,
`further comprising a chelating agent in an amount be(cid:173)
`tween 0.0 I% and 1.0% wt/vol; a tonicifier 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 patent at col 8, II 56-68-col. 9, II 1-10.)
`
`5. Dependent Claims 6 and 7 claim specific compo(cid:173)
`included within Claim I, wherein the
`sitions (*I 0]
`ophthalmologically
`acceptable
`non-steroidal
`an(cid:173)
`ti-inflammatory carboxyl group-containing drug (Claim
`6) or ketorolac tromethamine (Claim 7) is present at
`0.50% wt/vol; BAC is present at 0.02% wt/vol (of a 50%
`aqueous solution); Octoxynol 40 is present at 0.0 I%
`wt/vol (of a 70% aqueous solution); Na2EDT A is present
`at 0.1 0%; NaCI is present either at q.s. for isotonicity
`with lacrimal fluid (Claim 6) or at 0.79% wt/vol (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
`
`specific than Claims 1-5, requiring formulations of spe(cid:173)
`cific ingredients in specific amounts. (Trial Ex. I at
`SYN0000205, 493 patent at col. 9 at 11-47.)
`
`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(cid:173)
`sociated with, or accompanied by inflammatory process(cid:173)
`es, comprising administering to a mammal suffering
`therefi·om a formulation comprising" the formulation of
`Claim I. (Trial Ex. I, at SYN0000205, 493 patent at col.
`9, 1149-64.) Dependent Claims 9-14 claim the method of
`Claim 8 using the formulations [*I I] of Claims 2-7,
`respectively. (Trial Ex. I at SYN0000205, 493 patent at
`col. 9, 1165-col. 10, II 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 15 and 16 are the preservative system
`claims. Independent Claim 15 claims "[a]n antimicrobi(cid:173)
`ally effective preservative system for an ophthalmologi(cid:173)
`cally acceptable non-steroidal anti-inflammatory cm·box(cid:173)
`yl group-containing drug fonnulation, comprising: a
`quaternary ammonium preservative in an antimicrobially
`effective amount between 0.001% and 1.0% wt/vol of
`the formulation; and (Octoxynol 40] in a stabilizing
`amount between 0.00 I% and 1.0% wt/vol of the formu(cid:173)
`lation." Dependent Claim 16 claims the preservative
`system of Claim 15 wherein the preservative is BAC.
`(Trial Ex. I, at SYN0000205, 493 patent at col. 10, 11
`52-65.)
`
`8. An Information Disclosure Statement ("IDS") was
`filed along with both applications, identifying the fol(cid:173)
`lowing prior art: 4,087,539 (1978) Muchowski et a!.;
`4,089,969 (1978) Muchowski et a!.; 4,097,579 (1978)
`Muchowski et a!.; 4,232,038 (1980) Kluge et a!.;
`4,336,151 (1982) Like (*12] et al.; 4,336,152 (1982)
`Like eta!.; 4,545,151 (1984) Waterbury; "Influence of
`(Ethoxy)5 Octyl Phenol on the Antibacterial Properties
`of Preservatives," M.T. Nadir, et a!., Journal of Phar(cid:173)
`macy and Pharmacology, Volume 29, Supplement, De(cid:173)
`cember I 977, page 67P; and "Ocufen (flurbiprofen so(cid:173)
`dium) 0.03% Liquifilm sterile ophthalmic solution, Al(cid:173)
`lergan, product description sheet.
`
`9. In addition, the examiner cited the following ref(cid:173)
`erences in initially rejecting certain claims of the 493
`patent under 35 U.S. C.§ 103: 4,087,538 (1978) Portnoff;
`4,230,724 (1980) Cooper eta!.; 4,474,751 (1984) Has(cid:173)
`lam eta!.; 4,474,811 (1984) Masuda eta!.; 4,500,538
`(1985) Woltersdorf; 4,559,343
`(1985) Han et a!.;
`4,607,038 (1986) Ogata eta!.; Japanese Ref. No. 23,318
`(1985); 4,349,563 (1982) Gilbert et a!.; The Condensed
`Chemical Dictionmy, Seventh Ed.; McCutcheon's
`"Emulsifiers and Detergents" ( 1982) ("McCutcheon's");
`
`Page 4 of 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 5
`
`"The Synergistic Effects of Nonionic Surfactants Upon
`Cationic Germicidal Agents," Schmolka ( 1973). (Trial
`Exs. 024 at SYN0000245-48, 035 at SYN0000034-44,
`SYN0000050-52.)
`
`sorbate 80 as a member in a list of stabilizers -- not sur(cid:173)
`factants. (Trial Ex. 004 at 13:44-48, 56-57.) The only
`other stabilizer disclosed in that list is glycerin, which is
`not a surfactant. (R.T. 1709:5-1 0.)
`
`10. A person of ordinary skill in the art [*13] at the
`time of the invention is a person having a Bachelor's or
`Master's degree in the pharmaceutical sciences and hav(cid:173)
`ing three to five years of experience working in the field
`under the supervision of a person having a Ph.D. in the
`pharmaceutical sciences. (R.T. 1707:11-24; DOB at 5
`n.3.)
`
`2. The Prior Art References
`
`11. Plaintiffs asse11 that at trial, Defendants only as(cid:173)
`serted that the combination of U.S. Patent No. 4,545,151
`to Waterbury, U.S. Patent No. 4,349,563 to Gilbe11 eta!.,
`and U.S. Patent No. 4,559,343 to Han et a!., rendered
`obvious the claims of the 493 patent. Defendants, how(cid:173)
`ever, contend that in addition to these references, they
`also relied on: (I) McCutcheon's; (2) the Pham1aceutical
`Expe11 Report; (3) Grant and Hackh's Chemical Dic(cid:173)
`tionmy; (4) the GAF product sheet; (5) the Cosmetic
`Dictionary; (6) the Nadir reference (Trial Ex. YK); (7)
`the Schmolka reference; and (8) the Condensed Chemi(cid:173)
`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(cid:173)
`termination on the issue [* 14] of obviousness, the Court
`will consider all the references that Defendants have cit(cid:173)
`ed. However, based on its review of the trial record, the
`Court finds that Defendants' obviousness challenge relied
`primarily on the Waterbury patent, the Gilbe11 patent, the
`Han patent, and McCutcheon's.
`
`12. U.S. Patent No. 4,454,151 to Waterbury (the
`"151 patent" and/or the "Waterbury patent") defines a
`number of non-steroidal anti-inflammatory drugs that
`were found to be efficacious in the treatment of inflam(cid:173)
`matory diseases.
`
`13. The Waterbury patent does not discuss the con(cid:173)
`cepts of long-term stability or anti-microbial effective(cid:173)
`ness and does not discuss any problem of interaction or
`complexation between BAC and ketorolac trometham(cid:173)
`ine. It also does not discuss the use of EDT A or any oth(cid:173)
`er chelating agent. (Trial Ex. 004; R.T. 1158:1-16,
`1159:2511 60:3, 1707:25-17 10:6.)
`
`14. Although the only example formulation in the
`Waterbury patent, Example I ("Composition of Oph(cid:173)
`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(cid:173)
`tant Polysorbate 80 (also refened to as "Tween 80").
`[* 15] The Waterbury patent, however, discloses Poly-
`
`15. U.S. Patent No. 4,349,563 to Gilbe11 (the '"563
`patent" and/or the "Gilbert patent") teaches the topical
`to
`the
`eye of non-steroidal
`an(cid:173)
`administration
`ti-inflammatory agents, which as a class previously were
`thought to be ineffective in treating ocular inflammation.
`The Gilbe11 patent teaches that NSAIDs for ocular ad(cid:173)
`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 Gilbe11 patent does not, howev(cid:173)
`er, mention ketorolac tromethamine. (Trial Ex. WJ.)
`
`16. Although the Gilbe11 patent states that "the
`presence of a stabilizer is not prefeJTed," the patent does
`teach the optional inclusion of Tween or Pluronic sur(cid:173)
`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(cid:173)
`tiveness [* 16] or any problem of interaction or com(cid:173)
`plexation
`between BAC
`and NSAIDs.
`(R.T.
`1711:20-1712:7.) It also does not discuss the use of
`EDT A or any other chelating agent. (Trial Ex. W J.)
`
`17. U.S. Patent No. 4,559,343 to Han, et al. (the
`"'343 patent" and/or the "Han patent") discloses that the
`addition of xanthines, such as caffeine, to ophthalmic
`solutions of acidic NSAIDs helps to reduce the iJTitation
`associated with the NSAIDs. (Trail Ex. AK.) Specifical(cid:173)
`ly, the Han patent claims an aqueous, noninitating, non(cid:173)
`steroidal ophthalmic composition comprising the NSAID
`suprofen, a xanthine, a preservative, and a buffer, as well
`as methods for using this composition. (I d.) Two of the
`examples of the Han patent disclose the use of NSAIDs
`with either BAC or thimerosal and either Pluronic F127
`or tyloxapol, but do not indicate whether Pluronic F127
`or tyloxapol are being used as stabilizers, or indicate
`what role these surfactants play in the example composi(cid:173)
`tions at all. (Jd.) The Han patent does not discuss the
`concepts of long-term stability or anti-microbial effec(cid:173)
`tiveness and does not discuss any problem of interaction
`or complexation between BAC and ketorolac
`tro(cid:173)
`methamine. It [* 17] also does not discuss the use of
`EDTA or any other chelating agent. (Jd.)
`
`18. McCutcheon's is a compendium of a large num(cid:173)
`ber of emulsifiers and detergents. (Trial Ex. AL.) It de(cid:173)
`scribes Igepal CA-897 (Octoxynol 40) as an "Emulsifier,
`stabilizer." However, McCutcheon's does not disclose the
`use of Octoxynol 40 in a pharmaceutical. (Jd.) There is
`nothing in McCutcheon's that suggests that Octoxynol 40
`could successfully be used to solve the interaction be(cid:173)
`tween a carboxyl-group-containing NSAID and a qua-
`
`Page 5 of 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 6
`
`temary ammonium preservative. There is nothing in
`McCutcheon's that suggests that Octoxyi10l 40 could
`safely be used in a pharmaceutical product or in an oph(cid:173)
`thalmic formulation. There is nothing in McCutcheon's
`that suggests that the use of Octoxynol 40 would pre(cid:173)
`serve the anti-microbial effectiveness of a preservative.
`
`I 9. None of the prior a11 references cited by De(cid:173)
`fendants disclose any functional equivalence between
`Octoxynol 40 and any of the surfactants disclosed by the
`Waterbury, Gilbert or Han patents.
`
`20. Apart from the September 1987 Pham1aceutical
`Repm1 authored by Dr. Fu and Ms. Lidgate ("the Syntex
`Report"), none of the prior m1 references [* 18] cited by
`Defendants mention Octoxynol 40, except for McCutch(cid:173)
`eon's. Defendants' expe11, Dr. Mitra, provided no testi(cid:173)
`mony at all regarding McCutcheon's.
`
`2 I. Plaintiffs' expe11, Dr. Stella, testified that alt(cid:173)
`hough McCutcheon's refers to Octoxynol 40 as an emul(cid:173)
`sifier/stabilizer, it uses those words in the context of
`mixing and stabilizing a non-water-miscible substance
`and water. This is an entirely different context fi·om the
`use ofthose words in the 493 patent, which discloses the
`use of Octoxynol 40 as a stabilizer in a solution consist(cid:173)
`ing of an NSAID and a quatemary ammonium preserva(cid:173)
`tive.(R.T.1714:11-19;Tria1Ex.1,claim 1.)
`
`22. Dr. Stella also testified that there was nothing in
`McCutcheon's that would have motivated one of ordinary
`skill in the art to combine it with the other prior art ref(cid:173)
`erences to aiTive at
`the patented inventions. (R.T.
`1715: 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(cid:173)
`ternary ammonium preservative; (c) that it be used in a
`formulation with [* 19] a quatemary ammonium pre(cid:173)
`servative, such as BAC; (d) that it be used in a fmmula(cid:173)
`tion with a carboxyl group-containing NSAID, such as
`ketorolac tromethamine; (e) that it be used to prevent the
`of a
`complex
`between
`a
`carboxyl
`formation
`group-containing NSAID and a quaternary ammonium
`preservative; or (f) that it would act to maintain the anti(cid:173)
`microbial effectiveness of a quaternary ammonium pre(cid:173)
`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. 07/096,173 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 eta/.; 4,089,969 (1978) Muchowski
`et a/.; 4,097,579 (1978) Muchowski et a/.; 4,232,038
`
`(1980) Kluge et a/.; 4,336,151 (1982) Like et a/.;
`4,336,152 (1982) Like et a/.; 4,545,151 (1984) Water(cid:173)
`bury; "Influence of (Ethoxy)5 Octyl Phenol on the Anti(cid:173)
`bacterial Prope11ies of Preservatives," M.T. Nadir, eta/.,
`Journal of Pharmacy and Pharmacology, Volume 29,
`Supplement, December 1977, page 67P; and "Ocufen
`(flurbiprofen sodium) 0.03% [*20] Liquifilm sterile
`ophthalmic solution, Allergan, product description sheet.
`
`25. In addition, the examiner cited the following
`references in initially rejecting ce11ain claims of the 493
`patent under 35 U.S. C. § 103: 4,087,538 ( 1978) Portnoff;
`4,230,724 (1980) Cooper et a/.; 4,474,751 (1984) Has(cid:173)
`lam eta/.; 4,474,811 (1984) Masuda eta/.; 4,500,538
`(1985) Woltersdorf; 4,559,343
`(1985) Han et a/.;
`4,607,038 (1986) Ogata eta/.; Japanese Ref. No. 23,318
`(1985); 4,349,563 ( 1982) Gilbe11 et a/.; The Condensed
`Chemical Dictionwy, Seventh Ed.; McCutcheon's
`"Emulsifiers and Detergents" ( 1982); "The Synergistic
`Effects of Nonionic Surfactants Upon Cationic Germi(cid:173)
`cidal Agents," Schmolka ( 1973). (Trial Exs. 024 at
`SYN0000245-48,035
`at
`SYN0000034-44,
`SYN0000050-52.)
`
`26. The results of Ms. Lidgate's study of formula(cid:173)
`tions containing ketorolac tromethamine, BAC, and three
`different surfactants-Octoxynol 40, Tween 80, and My1j
`52-were also disclosed to the Examiner during the ex(cid:173)
`amination of the parent Application No. 07/096,173.
`These results showed that solutions containing Oc(cid:173)
`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.
`695:1-701:14,761:2-762:9, 769:11-770:25.)
`
`27. The examiner of Application No. 07/096,173
`criticized the data comparing Octoxynol 40, Tween 80,
`and Myrj 52 for four reasons: (!) the data did not com(cid:173)
`pare Octoxynol 40 to the surfactants of the primary ref(cid:173)
`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
`claims, which did not set propm1ions for the components
`of the formulations; and ( 4) the data was not in dec lara(cid:173)
`tion fmm. (Trial Ex. 24 at SYN0000288.)
`
`28. The examiner's criticism number (1 ), that the
`surfactants of the primary references were overlooked, is
`no longer relevant at this stage in the proceedings. The
`data before the examiner compared Octoxynol 40 to the
`surfactant most mentioned
`in
`the primary
`refer(cid:173)
`ences-Tween 80. Fm1hermore, the Com1-unlike the ex(cid:173)
`aminer-also has before it evidence that Ms. Pulsipher
`tried to use the Pluronic F127 of Han, as well as Pluronic
`F 168, to solve the ketorolac tromethamine/BAC turbidity
`[*22] problem, and found that these surfactants were
`
`Page 6 of 20
`
`

`
`2006 U.S. Dist. LEXIS 36089, *
`
`Page 7
`
`unable to do what Octoxynol 40 later was discovered to
`do-namely, keep a solution of ketorolac tromethamine
`and BAC stable under variable conditions.
`(R.T.
`350:5-375: 15.)
`
`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(cid:173)
`toxynol 40 are listed as 0.004% and 0.02%, the concen(cid:173)
`trations of the other surfactants are listed as 0.0035% and
`0.01% for Tween 80 and 0.0015% and 0.01% for My1j
`52. Therefore, the "high" and "low" concentrations of
`Octoxynol 40 are higher, respectively, than the "high"
`and "low" concentrations of the other surfactants. How(cid:173)
`ever, comparing the results for the "low" concentration
`of Octoxynol 40 (the 0.004% column) with the "high"
`concentrations of Tween 80 and My1j 52 (the two col(cid:173)
`umns labeled 0.0 I%), indicates that Octoxynol 40 still
`outperforms the other surfactants. In other words, taking,
`for example, the observations made after one month at
`40 [degree] C, a concentration of 0.004% of Octoxynol
`40 was able to keep the solution clear, whereas 0.0 I%
`concentrations of Tween 80 and My1j 52-that is, concen(cid:173)
`trations [*23]
`two and a half times higher than the Oc(cid:173)
`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 in-elevant 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. 001.)
`
`31. Similarly, the examiner's criticism number (4),
`that the data from Ms. Lidgate's tests was not in declara(cid:173)
`tion form was specific to the prosecution context. The
`results of Ms. Lidgate's tests, suppmted by sworn trial
`testimony from Ms. Lidgate, are in the trial record. Ms.
`Lidgate's test data compares the performance of Oc(cid:173)
`toxynol 40 with
`the performance of other mi(cid:173)
`celle-forming, non-ionic surfactants, which Dr. Mitra
`says should all perform "equally well" and which De(cid:173)
`fendants have asse1ted 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(cid:173)
`garded [*24] because it contains inconsistencies. De(cid:173)
`fendants base this argument on the fact that the data
`shows that all solutions were clear at 60 [degree] C, both
`at 1 month and at 5 months, thus showing that the turbid(cid:173)
`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
`
`"very turbid" at 1 month, but only "turbid" at 5 months,
`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(cid:173)
`lutions containing Tween 80 and My1j 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(cid:173)
`bust" stability under a variety of conditions than did the
`solutions containing Tween 80 and My1j 52.
`
`33. Defendants have also argued that because the
`original claims of Application No. 07/096, 173 claimed
`"a stabilizing amount of a non ionic 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 naiTowed the claims to just the usc of Oc(cid:173)
`toxynol 40. The prosecution history in its entirety, there(cid:173)
`fore, suppmts a conclusion that the applicants did not
`believe all nonionic surfactants to be the same.
`
`34. Defendants also point to the applicants' state(cid:173)
`ment in the prosecution history that "such compounds
`[non-ionic polyoxyethylated octylphenol surfactants]