I
`I-
`Le><IsNexIs®
`
`®
`
`
`
`
`Page I
`
`
`
`
`
`
`is
`Positive
`
`As of: Nov 02, 2015
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SYNTEX (U.S.A.) LLC, a Delaware corporation; ALLERGAN, lNC., a Delaware
`
`
`
`
`
`
`
`
`corporation, Plaintiffs, v. APOTEX INC., 21 Canadian corporation; APOTEX
`
`
`
`
`
`
`
`
`CORP., a Delaware corporation; and NOVEX PHARMA, a Canadian corporation.
`Defendants.
`
`
`
`
`
`
`No. C DI-02214 MJJ
`
`
`
`
`
`
`UNITED STATES DISTRICT COURT FOR THE NORTHERN DISTRICT OF
`
`
`
`
`
`
`
`
`CALIFORNIA
`
`
`
`
`
`2006 US. Dist. LEXIS 36089
`
`
`
`
`
`
`
`June 2, 2006, Decided
`
`
`
`June 2, 2006, Filed
`
`
`
`
`
`
`
`
`
`
`
`by Syntax
`SUBSEQUENT HISTORY: Affirmed
`
`
`
`
`
`
`
`
`
`
`(U.S..«*l.) LLC v. Apofex, Inc, 22} Fed. Apps‘. I002, 2007
`
`
`
`
`
`
`
`US. App. LEXIS 9276 (Fed. C:':-., 2007)
`
`
`
`
`
`
`
`
`
`Related proceeding at Roche Palo Alto LLC V. /lpotex.
`
`
`
`
`
`
`
`
`
`
`me, 2007 U.S. Dist. LEXIS 67058 (ND. Cal, Sept. H,
`
`2007)
`
`
`
`
`
`
`
`
`
`
`
`
`PRIOR HISTORY: Syntex (USA) LLC U. Aporex Ina,
`
`
`
`
`
`
`
`
`
`
`2006 U.S. Dist. LEXIS 34608 (MB. Cal, May I8, 2006)
`
`
`
`
`
`
`
`
`COUNSEL:
`[*1] For Syntex USA LLC, a Delaware
`
`
`
`
`
`corporation, Allergan Inc.,
`a Delaware corporation,
`Plaintiffs: Alexander L. Brainerd, Christine Saunders
`
`
`
`
`
`Haskett, Keith R. Weed, Nathan Shafroth, Heller Eh1'man
`
`
`
`
`
`
`
`
`
`
`
`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, Philadeiphia, PA; Cameron Kerrigan, Daniel B.
`
`
`
`
`
`
`
`
`Pollack, Squire Sanders & Dempsey LLP, Palo Alto,
`
`
`
`
`
`
`
`
`CA; Ronald S. Lemieux, Paul Hastings Janofsky &
`Walker LLP, Palo Alto, CA.
`
`
`
`
`
`
`
`
`
`
`
`
`
`For Allergen Inc., a Delaware corporation, Syntex USA
`
`
`
`
`
`LLC, a Delaware corporation, Counter-defendants: Al~
`
`
`
`
`
`
`exander I... Brainerd, Christine Saunders Haskett, Keith
`R. Weed, Nathan Shafroth, Heller Ehrman LLP, San
`
`
`
`
`
`
`
`Francisco, CA.
`
`
`
`
`
`
`
`
`JUDGES: MARTIN J. JENKINS, UNITED STATES
`
`
`
`
`
`DISTRICT JUDGE.
`
`
`
`
`
`OPINION BY: MARTIN .l. JENKINS
`
`
`
`
`
`
`
`OPINION
`
`
`
`FINDINGS OF FACTS AND CONCLUSIONS OF
`
`
`
`
`
`LAW ON RE-HEARING ON ISSUE OF OBVI-
`
`
`
`
`
`
`OUSNESS OF THE 493 PATENT AND PLAIN-
`
`
`
`
`
`
`TIFFS' REQUEST FOR PRELIMINARY IN.lUNC-
`
`
`
`
`TIVE RELIEF
`
`
`
`
`
`
`
`
`
`
`
`
`
`is Plaintiffs Syntex
`the Court
`Pending before
`
`
`
`
`
`
`
`(U.S./L] LLC and Allergan, lnc.'s Request for Prelimi-
`
`
`
`
`
`
`
`nary lnjunctive Relief. Concurrent [*2] with Plaintiffs‘
`
`
`
`
`
`
`
`
`
`Request, and pursuant to the Federal Circuit's decision in
`
`
`
`
`
`
`
`
`
`
`
`
`Symex {U.S./I.) LLC v. /lpofex, Inc. 407 F.3d .-'3 7.’ (Fed.
`
`
`
`
`
`
`
`
`Cr‘:-. 2005), is the Court's re-hearing on Defendants Apo-
`
`
`
`
`
`
`
`tex Inc_, Apotex Corp., and Novex Pharma's (collective-
`
`
`
`
`
`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
`
`IPR2015-01100
`
`Page 1 of 20
`
`SENJU EXHIBIT 2138
`LUPIN v. SENJU
`IPR2015-01100
`
`

`
`
`
`2006 U.S. Dist. LEXIS 36039, *
`
`
`
`
`
`Page 2
`
`
`
`
`
`
`
`
`
`
`
`needed to withstand Defendants‘ invalidity challenges,
`
`
`
`
`
`
`which included unenforceability clue to obviousness, lack
`
`
`
`
`
`
`
`of utility, lack ofenablenient, indefiniteness, and inequi-
`
`
`
`
`
`
`
`
`
`
`table conduct. Based upon its review ofthe 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 injunctivc relief. The
`
`
`
`
`
`
`Court therefore granted the preliminary injunction.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`parties have filed Opening Briefs (Doc. ii 469 (Plaintiffs'
`
`
`
`
`
`
`
`Corrected Opening Brief “POB"), Doc. # 464 (Defend-
`
`
`
`
`
`
`
`ants' Opening Brief "D013"), and Responsive Briefs
`
`
`
`
`
`
`
`
`
`(Doe. it 470 (Plaintiffs' Responsive Brief "PRB"), Doe. ii
`
`
`
`
`
`
`
`471 {Defendants‘ Responsive Brief "DRB"}. The Court
`
`
`
`
`
`
`
`
`has ca1'eful|y 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.
`
`
`
`1. Background
`
`
`
`
`
`
`
`
`
`
`
`Syntex owns US. Patent No. 5,Hl'),493 ("the 493
`
`
`
`
`
`patent"), entitled "Ophthalmic NSAID Formulations
`
`
`
`
`
`
`
`Containing a Quaternary Ammonium Preservative 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! U.S.C. § 355(;)(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-
`
`
`
`
`
`
`
`
`LAR(R). In their notice, Defendants stated that they be-
`
`
`
`
`
`
`
`
`
`
`
`lieved the 4'93 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
`
`
`
`
`
`
`
`
`
`
`2.-' U.S'.C. § 355 and 35 U.S.C. § 271(9). Plaintiffs there-
`
`
`
`
`
`
`
`
`after moved for summary judgment of infringement. The
`
`
`
`
`
`
`
`Coult 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. § 3550§)(5)(B)(iii), approval of
`
`
`
`
`
`
`
`
`
`
`
`ANDA 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 76-109 while the
`
`
`
`
`
`
`
`
`
`
`Court's decision on the issue ofthe 493 parent'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 from engaging in the commercial manufac-
`
`
`
`
`
`
`
`
`
`
`
`
`ture, use, or sale of any product, the approval of which is
`
`
`
`
`
`
`
`sought
`through ANDA ?6—l09, until
`the Court deter-
`
`
`
`
`
`
`
`
`
`mined the validity and enforceability ofthe 493 patient.
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`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 held 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
`
`
`
`
`
`
`
`
`
`ACULAR(R) directly infringed all of the claims of the
`
`
`
`
`
`
`
`
`
`
`
`493 patent 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
`
`
`
`
`
`
`
`
`injunction pursuant to Federal Rule of Civil Pro-
`[*6]
`
`
`
`
`
`
`
`cedure 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 16, 2005, Plaintiff filed an
`
`
`
`
`
`
`
`Application for a Tempo1'ary Restraining Order, seeking
`
`
`
`
`
`to prevent Defendants from 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 lnjunction and concurrent hearing on the issue of
`
`
`
`
`
`
`
`
`
`obviousness. (Does. it 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 Count now makes the fol-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`lowing factual findings and legal [*7]
`conclusions on
`
`
`
`
`
`
`
`
`the issue of obviousness and Plaintiffs‘ request for in-
`
`
`junetive relief. '
`
`
`
`Page 2 of 20
`
`

`
`
`2006 U.S. Dist. LEXIS 36089, *
`
`
`
`
`
`
`Page 3
`
`
`
`
`
`
`
`
`
`
`
`1
`As an initial matter, also pending before the
`Court is Plaintiffs‘ Motion to Remove from the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Record Evidence
`lnadvertently Placed in the
`
`
`
`
`
`
`
`
`
`Record at Trial (Doc.
`In their Motion,
`it 427).
`
`
`
`
`
`
`
`Plaintiffs argue that, although the Court only ad-
`
`
`
`
`
`
`
`mitted specific pages fi‘om Dr. Mitra's expert re-
`
`
`
`
`
`
`
`
`
`port during 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 Court only admitted selected
`
`
`
`
`
`
`
`pages from the report
`into evidence, Plaintiffs
`
`
`
`
`
`
`
`
`
`failed to correct 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 throu
`
`
`
`
`
`
`
`
`
`78, are just one of two sentences about each of the tables
`that he also testified about. So I would offer those
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`articular ages 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
`Hask
`
`ett:
`
`
`
`
`
`
`
`
`
`
`
`
`hearsay.
`
`
`
`
`
`
`
`
`
`
`I'll admit them as evidence ofthe opinion that he has
`
`
`
`
`The
`Cour
`t:
`
`
`
`
`
`
`
`
`given here. I'll admit them.
`
`
`
`
`
`
`
`(R.T.
`l39l:I2-l892:|9) (emphasis added).
`
`
`
`
`
`
`
`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, 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 report from the trial record.
`
`
`
`
`
`
`
`
`
`
`
`inventors of the 4'93 patent are Dr. Roger Fu and Debo-
`
`
`rah Lidgale.
`
`
`
`
`
`
`
`
`
`
`
`
`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 are the only in-
`
`
`
`
`
`
`dependent claims in the 493 parent.
`
`
`
`
`3. Independent Claim 1 claims:
`
`
`
`
`
`[*8] II. Obviousncss
`
`
`
`
`
`
`
`A. Findings of Fact
`
`
`
`
`1. Preliminary Factual Findings
`
`
`
`
`
`
`
`
`
`
`
`
`
`1. The 493 patent issued on May 5, I992 from Ap-
`
`
`
`
`
`
`
`
`plication No. 0?f624,02?, which was filed on December
`
`
`
`
`
`
`
`
`
`7, 1990, and which was a continuation of Application
`
`
`
`
`
`
`
`
`No. 0T;"096,I73, filed on September ll, I987. The joint
`
`
`
`acceptable
`An
`ophthalmologically
`
`
`non-steroidal
`anti-inflammatory
`drug
`
`
`formulation, comprising:
`
`
`
`
`
`
`ophthalmologically
`an
`
`
`non-steroidal
`acceptable
`
`
`anti-inflammatory carboxyl
`
`
`
`group—containing drug in
`amount
`for
`an effective
`
`
`
`
`
`
`ophthalmic treatment be-
`
`Page 3 of 20
`
`Page 3 of 20
`
`

`
`
`2006 U.S. Dist. LEXIS 36089, *
`
`
`
`
`
`
`
`Page 4
`
`
`
`
`
`
`
`
`specific than Claims 1-5. requiring formulations of spe-
`
`
`
`
`
`
`
`
`cific ingredients in specific amounts.
`(Trial Ex.
`1 at
`
`
`
`
`
`
`
`
`SYN0000205, 493 parent 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 formulation comprising" the formulation of
`
`
`
`
`
`
`
`
`
`
`
`Claim 1. (Trial Ex. 1, at SYN0000205, 493 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 SYN000U205, 493 patem at
`
`
`
`
`
`
`
`
`
`
`
`
`
`col. 9, [I65-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 15 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-inflammatory ca1'box—
`
`
`
`
`
`
`yl group-containing drug formulation, comprising:
`a
`
`
`
`
`
`
`quaternary ammonium preservative in an antimicrobially
`effective amount between 0.001% and 1.0% wtivol of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the formulation; and [Octoxynol 40]
`in a stabilizing
`amount between 0.001% and 1.0% wtfvol of the formu-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`lation." Dependent Claim 16 claims the preservative
`
`
`
`
`
`
`
`
`
`system of Claim 15 wherein the preservative is BAC.
`
`
`
`
`
`
`
`
`
`
`
`
`(Trial Ex.
`1, at SYN0000205, 493 pafem‘ at col. 10,
`11
`
`52-65.)
`
`
`
`
`
`
`
`
`
`8. An Information Disclosure Statement ("IDS") was
`
`
`
`
`
`
`
`filed along with both applications,
`identifying the fol-
`
`
`
`
`
`
`
`
`
`lowing prior art: 4,087,539 (I978) Muchowski e! mi;
`
`
`
`
`
`
`
`4,089,969 (1978) Muchowski er a.-'.; 4,097,579 (I978)
`
`
`
`
`
`
`
`
`Muchowski
`er’ ail; 4,232,038 (1980) Kluge et
`ai’.;
`
`
`
`
`
`
`
`4,336,151 (1982) Like [*l2]
`et ai.; 4,336,152 (1982)
`
`
`
`
`
`
`
`Like et 01.; 4,545,151 (1984) Waterbury; "lnfluence of
`
`
`
`
`
`
`
`(Ethoxy)5 Octyl Phenol on the Antibacterial Properties
`
`
`
`
`
`
`
`
`of Preservatives," M.T. Nadir, er fl'.f., Jomrriai of Phar-
`
`
`
`
`
`
`macy and Pharmacoiogy, Volume 29, Supplement, De-
`
`
`
`
`
`
`
`cember l977, page 67F; and "Ocufen (flurbiprofen 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 4'93
`
`
`
`
`
`
`
`patent under 35 US. C.
`35' I03: 4,087,538 (1978) Portnoff;
`
`
`
`
`
`
`4,230,724 (1980) Cooper ex 01.; 4,474,751 (1984) Has-
`
`
`
`
`
`
`
`
`
`lam er mi; 4,474,811 (1934) Masuda er all; 4,500,538
`
`
`
`
`
`
`
`(1985) Woltersdorf; 4,559,343 (1985) Han er mi;
`
`
`
`
`
`
`
`
`4,607,038 (1986) Ogata er mi; Japanese Ref. No. 23,318
`
`
`
`
`
`
`
`(1935); 4,349,563 (1982) Gilbert er al.; The Condensed
`
`
`
`
`
`Cheiiifcaf Dici‘.*'0naiy‘,
`Seventh Ed.; McCm'eheoi1’s
`
`
`
`
`
`"Em'1:fSi'fiei'S and Detergents" (1982) ("Mc'Cm‘che0n's");
`
`
`
`
`tween 0.001% and 10.0%
`
`
`
`wt.-‘vol;
`
`
`
`
`
`
`a quatemary amino-
`
`
`
`
`nium preservative in an an-
`
`timicrobially
`effective
`amount between 0.001 %
`
`
`
`
`
`
`and 1.0% wtfvol;
`
`
`
`
`
`
`
`ethoxylated allcyl
`an
`
`
`
`phenol that conforms gen-
`
`
`
`
`
`erally to the formula:
`[*9]
`
`
`
`C3H 1 7C6H4(OCl‘l2C
`
`
`
`
`
`H2)nOH where n has an
`
`
`
`
`
`
`average value of 40 in a
`
`
`
`stabilizing amount between
`
`
`
`
`
`0.001% and 1.0% wtfvolg
`
`
`
`
`
`and an aqueous vehicle q.s.
`
`
`
`[quantity
`sufficient]
`to
`100%.
`
`
`
`(Trial Ex.
`
`42-55.)
`
`
`
`
`
`
`
`
`
`
`1 at SYN0000204, 493 parent‘ at col. 3,
`
`
`
`
`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-
`
`
`
`
`mologieally 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 oplttlialmologieally
`
`
`
`acceptable
`non-steroidal
`anti—inflammatory earboxyl
`
`
`
`
`
`group-containing drug is ketorolac tromethamine; and
`
`
`
`
`
`
`
`
`dependent Claim 5 claims the formulation of Claim 1,
`
`
`
`
`
`
`
`
`further comprising a chelating agent in an amount be-
`
`
`
`
`
`
`
`
`
`tween 0.0l% and 1.0% wtlvol; a tonieifier q.s. to achieve
`
`
`
`
`
`
`
`
`
`isotonicity with lacrimal fluid; and IN NaO1-I or IN HCI
`
`
`
`
`
`
`
`
`
`
`q.s. to adjust pH to 7.40.4. (Trial Ex.
`1 at SYN0000204,
`
`
`
`
`
`
`
`
`
`493 parent at col 8, ll 56-68—col. 9, 11 1-10.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5. Dependent Ciaims 6 and 7 claim specific compo-
`
`
`
`
`
`
`
`
`sitions [*l0]
`included within Claim 1, wherein the
`
`
`
`ophthalmologically
`acceptable
`non-steroidal
`an-
`
`
`
`
`
`ti-inflainmatory carboxyl 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%; NaC1 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
`
`Page 4 of 20
`
`

`
`
`2006 US. Dist. LEXIS 36089, *
`
`
`
`
`
`
`Page 5
`
`
`
`
`
`
`
`
`
`
`"Tire Synergistic Effects of Nonionic Surfactants Upon
`
`
`
`
`
`
`
`Cationic Germicidal Agents," Schnrolka (I973). (Trial
`Exs. 024 at SYN0000245-48, 035 at SYN0000034-44,
`
`
`
`
`
`
`
`
`SYN0000050-52.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`l?07:lI-24; DOB at 5
`
`n.3.)
`
`2. The Prior Art References
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`l l. Plaintiffs assert that at trial, Defendants only as-
`
`
`
`
`serted that the combination of U.S. Patent‘ No. 4,545,.-'5}
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to Waterbury, U.S. Patent No. 4,349,563 to Gilbert at at'.,
`
`
`
`
`
`
`and U.S. Patent No. 4,559,343 to Han at m'., 1'endered
`
`
`
`
`
`
`
`
`
`
`
`
`obvious the claims of the -193 patent. Defendants, how-
`
`
`
`
`
`
`
`
`
`ever, contend that in addition to these references, they
`
`also relied on: (1) McCurcheon's; (2) the Phamraceutical
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Expert Report; (3) Gram‘ and Haekifs Chemical’ Die-
`
`
`
`
`
`
`
`
`
`rirmary; (4) the GAP product sheet; (5) the Cosmetic
`
`
`
`
`
`
`
`
`
`Dictionary; (6) the Nadir reference (Trial Ex. WC); (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 [* I4] ofobviousness, 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 McC'urcheon's.
`
`
`
`
`
`
`
`
`
`
`to Waterbury (the
`I2. U.S, Parent No. 4,45-4,15.’
`
`
`
`
`
`
`
`"F5! patent" andlor the "Waterbury patent") defines a
`
`
`
`
`
`number of non-steroidal anti-inflammatory drugs 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
`
`
`
`
`
`cornplexation between BAC and ketorolac trometham-
`
`
`
`
`
`
`
`
`
`
`
`
`me. It also does not discuss the use of EDTA or any oth-
`
`
`
`
`
`
`
`
`er chelating agent.
`(Trial Ex. 004; R.T.
`llS8:l-16,
`ll59:25ll 60:3, l'i'0?:25-l?l0:6.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 ofthe surfac-
`
`
`
`
`
`
`
`
`tant Polysorbate 80 (also referred to as "Tween 80").
`
`
`
`
`
`
`
`[*IS] The Waterbury patent, however, discloses Poly-
`
`
`
`
`
`Page 5 of 20
`
`sorbate 80 as a member in a list of stabilizers -- not sur-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`factants. (Trial Ex. 004 at
`l3:44-48, 56-57.) The only
`
`
`
`
`
`
`
`
`
`
`other stabiiizer disclosed in that list is glycerin, which is
`
`
`
`
`
`not a surfactant. (R.T. l'r'09:S-I0.)
`
`
`
`
`
`
`
`I5. U..S'. Prrtem No. 4,349,563 to Gilbert (the ‘"563
`
`
`
`
`
`
`
`
`
`
`
`
`p(t!e'.i'tt" andrlor‘ the "Gilbert patent") teaches the topical
`
`
`
`
`
`
`of
`the
`administration
`to
`eye
`non-steroidal
`an-
`
`
`
`
`
`
`
`ti-intlarnmatory agents, which as a class previously were
`
`
`
`
`
`
`
`thought to be ineffective in treating ocular in flamrnation.
`
`
`
`
`
`
`
`
`The Gilbert patent teaches that NSAIDS for ocular ad-
`
`
`
`
`
`
`rninistration should inciude various ingredients other
`
`
`
`
`
`
`itself,
`than the non-steroidal anti-inflammatory agent
`
`
`
`
`
`
`
`
`such as antimicrobial agents, antioxidants, and metal ion
`
`
`
`
`
`
`
`sequestering agents. The Gilbert patent does not, howev-
`
`
`
`
`
`
`
`er, mention ketorolac tromethamine. (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-
`
`
`
`
`
`
`(R.T.
`BAC
`plexation
`between
`and NSAIDs.
`
`
`
`
`
`
`
`
`
`
`l7ll:20-l'i'l2:'.-'.) It also does not discuss the use of
`
`
`
`
`
`
`
`
`
`EDTA or any other chelating agent. (Trial Ex. WJ.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`17. U..S'. Patent No. 4,559,343 to Han, et‘ at’. (the
`
`
`
`
`
`
`
`
`‘"343 patent" andior 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. (Trail Ex. AK.) Specifical-
`
`
`
`
`
`
`
`
`ly, the Han patent ctaims an aqueous, nonirritating, non-
`
`
`
`
`
`
`steroidal ophthalmic composition comprising the NSAID
`
`
`
`
`
`
`
`
`
`suprofen, a xanthine, a preservative, and a buffer, as well
`
`
`
`
`
`
`
`
`
`
`
`as methods for using this composition. (M) 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 Fl2'i'
`
`
`
`
`
`
`
`
`
`or tyloxapol are being used as stabilizers, or indicate
`
`
`
`
`
`
`
`
`what role these surfactants play in the example composi-
`
`
`
`
`
`
`
`
`
`
`tions at all. (Id) The 1-Ian patent does not discuss the
`
`
`
`
`
`
`concepts of long-term stability or anti-microbial effec-
`
`
`
`
`
`
`
`
`tiveness and does not discuss any problem of interaction
`
`
`
`
`
`
`or compiexation between BAC and ketorolac tro-
`
`
`
`
`
`
`
`
`
`
`methamine.
`lt [*l7]
`also does not discuss the use of
`
`
`
`
`
`
`
`EDTA or any other chelating agent. Ud.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`l8. MeCutcheon‘s is a compendium ofa large num-
`
`
`
`
`
`
`
`
`
`ber of emulsifiers and detergents. (Trial Ex. AL.) It de-
`
`
`
`
`
`
`
`
`scribes Igepal CA—89? (Octoxynol 40) as an "Enrulsifrer,
`
`stabilizer." I-lowever, McCuteheon’.r does not disclose the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`use of Octoxynol 40 in a phar'maceutical. (.-'d.) There is
`
`
`
`
`
`
`
`
`nothing in Me'Ctr!c:'ie0n’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
`
`
`
`
`
`
`
`McCutche:m’.r
`that suggests that Octoxynol 40 could
`
`
`
`
`
`
`
`
`
`
`safely be used in a pharmaceutical product or in an oph-
`
`
`
`
`
`
`thalmic formulation. There is nothing in ill/i'c‘C'tttc,heoti’s
`
`
`
`
`
`
`
`
`
`that suggests that the use of Octoxynol 40 would pre-
`
`
`
`
`
`
`serve the anti—microbia| effectiveness ofa preservative.
`
`
`
`
`
`
`
`
`
`
`
`
`19. None of the prior an references cited by De-
`
`
`
`
`
`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 Pharmaceutical
`
`
`
`
`
`
`
`
`
`
`Report authored by Dr. Fu and Ms. Lidgate ("the Syntex
`
`
`
`
`
`
`
`
`
`
`
`Report"), none ofthe prior art references [*I8]
`cited by
`
`
`
`
`
`
`Defendants mention Octoxynol 40, except for McCu!ch-
`
`
`
`
`
`
`
`eort's. Defendants‘ expert, Dr. Mitra, provided no testi-
`
`
`
`
`
`tnony at all regarding McCiitclreon’.r.
`
`
`
`
`
`
`
`
`testified that alt-
`2!. Plaintiffs‘ expert, Dr. Stella,
`
`
`
`
`
`
`
`
`hough McCi:teheon'.r refers to Octoxynol 40 as an emul-
`
`
`
`
`
`
`
`
`
`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 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.'I‘. 17l4:11-19; Trial Ex. 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-
`
`
`
`
`
`
`
`erences
`to arrive at
`the patented inventions.
`(R.T.
`
`l7l5:17-22.)
`
`
`
`
`
`
`
`
`
`
`23. Significantly, Defendants have not identified any
`
`
`
`
`
`
`
`
`
`prior an 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 trometharnine; (e) that it be used to prevent the
`
`
`
`
`
`
`
`formation
`complex
`between
`a
`carboxyl
`a
`of
`
`
`
`
`
`
`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. 07i'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 oi.; 4,089,969 (1978) Muchowski
`
`
`
`
`et at; 4,097,579 (1978) Muchowski at o!.; 4,232,038
`
`
`
`
`
`Page 6 of 20
`
`
`
`
`
`
`(I980) Kluge at m‘.; 4,336,151 (1982) Like er mi;
`
`
`
`
`
`
`
`
`
`4,336,152 (1982) Like er mi; 4,545,151 (1984) Water-
`
`
`
`
`
`
`
`
`bury; "lnfluence of (Ethoxy)5 Octyl Phenol on the Anti-
`
`
`
`
`
`
`bacterial Properties of l’reservatives," M.T. Nadir, er of,
`
`
`
`
`
`
`J0t‘tJ".'?.’.I'f of Pho.I't.'ictct* anal P:lmt'titrico."(Jgy, Volume 29,
`
`
`
`
`
`
`Supplement, December 1977, page 671’; and "0cufcn
`
`
`
`
`
`(flurbiprofen sodium) 0.03% [*20]
`Liquitilm sterile
`
`
`
`
`
`
`ophthalmic solution, Allcrgan, product description sheet.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`25.
`the examiner cited the following
`In addition,
`
`
`
`
`
`
`
`
`
`references in initially rejecting certain claims of the -.193
`
`
`
`
`
`
`
`
`
`
`
`patent under 35 U.S.C. § .-'03: 4,087,538 (1978) Ponnoff;
`
`
`
`
`
`
`4,230,724 (1980) Cooper er oi; 4,474,751 (1984) Has-
`
`
`
`
`
`
`
`lam er mi; 4,474,811 (1984) Masuda at