Camden, New Jersey 04/05/2016 07:29:54 PM
`
`PATUNAS TARANTINO LLC
`BY: MICHAEL £. PATUNAS, ESQUIRE
`24 Commerce Street, Suite 606
`Newark, New Jersey 07102
`(973) 396-8740
`Mpatunas@patunaslaw.com
`ATTORNEYS FOR DEFENDANT LUPIN, INC.
`GOODWIN PROCTER LLC
`BY: ELIZABETH J, HOLLAND, ESQUIRE
`NATASHA E. DAUGHTRY, ESQUIRE
`SARAH FINK, ESQUIRE
`SHAUN deLACY, ESQUIRE
`DANIEL P. MARGOLIS, ESQUIRE
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`{212) 813-8800
`eholland@goodwinprocter.com, ndaughtry@goodwinprocter.com,
`Sfink@gocdwinprocter.com, sdelacy@goocwinpracter.com,
`dmargolis@goodwinprocter.com
`United Slates District Caurl
`
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB, INC., BAUSCH AND
`LOMB PHARMA HOLDINGS CORP.,
`
`Plaintiff,
`oyse
`
`LUPIN LTB., LUPIN
`PHARMACEUTICALS, INC.,
`Defendants.
`
`SEN3U PHARMACEUTICAE CO., LTD.,
`BAUSCH & LOMB, INC., BAUSCH AND
`LOMB PHARMA HOLDINGS CORP.,
`Plaintiff,
`-vs-
`
`INNOPHARMA LICENSING, INC., et
`al.,
`
`Defendants.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB, ENC., BAUSCH AND
`LOMB PHARMA HOLDINGS CORP.,
`Piaintiff,
`-vs-
`
`INNGPHARMA LICENSING, INC.,
`Defendants.
`
`CIVIL ACTION NUMBER:
`15-335 (JBS/KMWY}
`
`CEVIL ACTION NUMBER:
`14-6393 (JBS/KMW)
`
`CIVIL ACTION NUMBER:
`15-3240 (Jes/KMW)
`
`United States District Court
`Camden, New Jersey
`
`PEPPER HAMILTON LLP
`BY; MELISSA A, CHUDEREWICZ, ESQUIRE
`30i Carnegie Center, Suite 400
`Princeton, New Jersey 08543
`(605) 452-0806
`chuderem@pepperiaw.com
`ATTORNEYS FOR PLAINTIFF
`
`FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP
`BY: BRYAN C. DINER, ESQUIRE
`JUSTIN 3. HASFORD, ESQUIRE
`CHIAKI FUNWARA, ESQUIRE
`$01 New York Avenue, NW,
`Washington, 0,C, 20001-4413
`(202) 408-4000
`bryan.diner@finnegan.com, justin. hasfor¢@finnegan.cam,
`chiaki.fujiwara@finnegan.com
`ATTORNEYS FOR PLAINTIFF
`
`FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP
`BY: JESSICA M. LESIS, ESQUIRE
`303 Peachtree Street, NE
`Atlanta, GA 30308-3263
`(404) 653-6400
`jessica-lebis@finnegan,com
`ATFORNEYS FOR PLAINTIFF
`
`eopeNYmFomFBBwNm
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`BOoROBSOBOBORDReaaaafFYGSBBeS&S6SeNHmHhkweHeseSGowAaNHTOmWhkYYNW
`
`=
`
`UNITED STATES DISTRICT Court
`FOR THE DISTRICT OF NEW JERSEY
`
`SENTU PHARMACEUTICAL CO., LTG.,
`BAUSCH & LOMB,
`INC,, BAUSCH AND
`LOMB PHARMA HOLDINGS CORP.,
`Plaintiff,
`-vs-
`LUPIN LID., LUPIN
`INC.,
`PHARMACEUTICALS,
`Defendants.
`
`SENJU PHARMACEUTICAL CoO., LTD.,
`BAUSCH & LOMB,
`INC., BAUSCH AND
`LOHB PHARMA HOLDINGS CORE. ,
`Plaintiff,
`-vs-
`
`CIVIL ACTION NUMBER:
`14-667 (08s/RHH)
`
`CIVIL ACTION HUMBER:
`14-4149 (JBS/RMW)
`
`LUPIN LID., LUPIN
`IRC. ,
`FHARHACEOTICALS,
`Defendants.
`Hitcheli H. Cohen United States Courthouse
`One John F. Gerry Plaza
`Camien, New Jersey 08101
`Monday, April 4, 2016
`
`BEFORE:
`—
`
`THE HONORABLE JEROHE B. SIMANDLE
`CHIEF JUDGE
`UNITED STATES DISTRICT JURGE
`
`oe68MNRm&WwNH
`NBONHMNMWomHPRFBRHheHmMmMRHmROWhHAGYb&bFPSG&&®yumwHYB&B&NHKHOG
`
`Gnited States District Court
`Camden, New Jersey
`
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB, INC,, BAUSCH AND
`LOMB PHARMA HOLDINGS CORP.,
`Plaintiff,
`-vs-
`
`LUPIN LTB., LUPIN
`PHARMACEUTICALS, INC.,
`Defendants,
`
`SENIU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB, INC., BAUSCH AND
`LOMB PHARMA HOLDINGS CORP.,
`Plaintiff,
`-vS-
`
`LUPIN LTD., LUPIN
`PHARMACEUTICALS, INC.,
`Defendants.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB, INC,, BAUSCH AND
`LOMB PHARMA HOLDINGS CORP.,
`Plaintilf,
`-¥s-
`
`LUPIN LTD., LUPIN
`PHARMACEUTICALS,INC.,
`Defendants,
`
`CIVIL ACTION NUMBER:
`14-5144 (1BS/KMW)
`
`CIVIL ACTION NUMBER:
`15-335 (JBS/KMW)
`
`CIVIL ACTION NUMBER:
`14-5144 (JBS/KMW)
`
`1 2 3 4 § 6 7 & 9 0
`
`>onyno=
`-=aaf
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`= oo
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`=6539Doaws
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`MeSMNOONNKODa&BweHe&
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`Certified asx true and correct as required by Title 28, U.5.0.,
`Section 753.
`fS/ Lisa Marcus, CCR, CBR,
`/5/ Theodore Formaroli, CCR, CRR,
`fs/ Karen Friedlander, COR, Chh,
`/5/ Robert T. Tate, CCR, CRR,
`aTSaneFettm$/ Carol Farzeil, CCR, CAR
`
`1 of 92 sheets
`
`United States District Court
`Camden, New Jersey
`
`Page 1 to 4 of 254
`
`SENJU EXHIBIT 2326
`Lupin v Senju,
`IDEANTS ALIA oo TAmaAns= nvane
`IPR2015-01097, 1PR2015-01099,
`
`

`

`wedfmth&WwHB Page 5 to 8 of 254
`
`MS. FUJIWARA: Chiaki Fujiwara for plaintiffs Senju,
`et al., from Finnegan, Henderson.
`United States District Court
`United States District Court
`Camden, New Jersey
`Camden, New Jersey
`2 of 92 sheets
`
`176
`
`PAGE
`
`PLAINTIFF EXHIBITS JTX-001, ITX-006, JTX-210,
`JTK-147, PTX-745, JTX-22, and PTX-120 WERE
`RECEIVED IN EVIDENCE
`PLAINTIFF EXHIBIT PTX-165 WAS RECEIVED IN
`EVIDENCE
`
`DEFENDANT EXHIBIT PTX-1254 WAS RECEIVED IN
`EVIDENCE
`
`DEPUTY CLERK: Alt cise,
`
`THE COURT: Good morning.
`Be seated.
`Just a moment,
`
`Welcome to everybody. We're here to commence the
`
`nonjury trial it Senju Pharmaceutical vs. Lupin and Senju
`Pharmaceutical vs. Ianopharma, the Civil Action Numbers are
`14-9567, 14-4149, 14-5144, 15-335, and also 14-6893, and
`45-3240.
`
`Let me ask trial counsel] te please enter your
`appearances. Here I’m just asking for the appearances of
`those who are likely to speak during the course ofthe trial.
`$o let's begin with the plaintiffs,
`MR. LIPSEY: Charies Lipsey, Finnegan, Henderson, for
`the plaintiffs.
`MR. DINER: rian Diner, your Honor, Finnegan,
`Henderson, for the plaintiffs.
`
`MR. HASFORD: Justin Hasford, your Honor, Fianegan,
`Henderson, also for the plaintiffs.
`
`MS. LEBEIS: Jessica Lebels of Finnegan, Henderson,
`alsa for the plaintiffs.
`MR. SUKBDUANG: Sanya Sukduang, your Honor, from
`Finnegan, Henderson, on behalf of plaintiffs.
`
`PAGE
`
`ROBERT O. WILLIAMS, fil,
`DIRECT EXAMINATION OF ROBERT ©. WILLIAMS, If], BY
`MR. HASFORD
`CROSS EXAMINATION OF ROBERT O. WILLIAMS,II? BY
`MS. HOLLAND;
`REDIRECT EXAMINATION OF DR, WILLIAMS BY MR.
`HASFORD:
`178
`MARGARET JAYNE LAWRENCE
`VOIR DIRE EXAMINATION OF MARGARET JAYNE LAWRENCE 179
`BY MS. RAPALINO:
`
`100
`100
`
`155
`
`omNMmhhkWwWNHN
`NMBDOBOSORRRhakkka&£8NM|=SGwpBFHwRPHWfh&HMmsm
`
`ATTORNEYS FOR DEFENDANT LUPIN, LTD.
`GOODWIN PROCTER, LLP
`BY: EMILY L. RAPALINO, ESQUIRE
`53 State Street
`Boston, MA 02109
`(617) 570-1000
`erapalino@gooddwinprocter.com
`ATTORNEYS FOR DEFENDANT LUPIN, LTB.
`ALSTON & BIRD, LLP
`BY: BDEEPRO R. MUKERIEE, ESQUIRE
`LANCE 4. SODERSTROM, ESQUIRE
`STEPHANIE ROBERTS, ESQUIRE
`$0 Park Avenue
`New York, New Yark 16616
`{212) 210-9400
`deepro.mukerjee@alston.cam, lance.soderstrom@alston.com,
`stephanie.roberts@aiston.com
`ATTORNEYS FOR DEFENDANT INNGPHARMA LICENSING
`
`ALSTON & BIRD, LLP
`BY:
`JITENDRA MALIK, ESQUIRE
`4721 Emperor Boulevard
`Suite 400
`Durham, NC 27703-8580
`{919} 862-2200
`fitendra.malik@alston.com
`ATTORNEYS FOR DEFENDANT INNOPHARMA LICENSING
`
`ALSTON & BIRG, LLP
`BY: KIDETADA JAMES ASE, ESQUIRE
`333 South Hope Street
`16th Floor
`Los Angeles, CA 90071-3004
`(213) 576-1000
`james.abe@aiston.com
`ATTORNEYS FOR DEFENDANT LUPIN LIMITED
`
`ALSTON & BIRD, LLP
`BY:
`JOSEPH M. JANUSZ, ESQUIRE
`Bank of America Plaza
`Suite 4000
`Chariotte, NC 28280-4000
`(704) 444-1000
`joe.janusz@aiston.com
`ATTORNEYS FOR DEFENOANT INNGPHARMA LICENSING
`
`United States District Court
`Camden, New Jerse’
`
`SAIBER, LLC
`BY: ARNOLD B, CALMANN, ESQUIRE
`One Gateway Center
`20th Floor, Suite 1000
`Newark, New Jersey 07102
`(973) 622-3333
`abc@saiber.com
`ATTORNEYS FOR DEFENDANT INNOPHARMA LICENSING
`
`04/05/2016 07:29:54 PM
`
`

`

`04/05/2016 07:29:54 PM
`
`of whetherthe plaintiffs waived their privilege by producing
`the unredacted document and clawing it back six months later.
`And also I don't believe that there is a question about
`work product protection. Work product protection for these
`documents was not sought by the plaintiffs, Judoe Williams
`recognized it and jumped it together with attorney/client
`privilege.
`I don't think that that’s correct.
`If the
`plaintiffs raised atterney/client protection, then you can
`point that out to me in the argument tomorrow.
`I didn't see
`United States District Court
`
`9
`
`I'm sorry, can you spell your name for
`
`THE COURT:
`me? Did you sign in?
`MS. FUJIWARA: Chiaki Fujiwara.
`THE COURT: Oh, yes. Thank you.
`
`MS. CHUDEREWICZ: Melissa Chuderewicz from Pepper
`Hamilton on behalf of plaintiffs.
`THE COURT: Next on behalf of Lupin.
`MS. HOLLAND: Good morning, your Honor.
`Elizabeth Holland of Goodwin Proctor.
`
`MR. PATUNAS: Good morning, your Honor.
`Michael Patunas, Patunas Tarantino.
`
`MS. RAPALING: Good marning, your Honor.
`Emily Rapalino of Goodwin Proctor.
`
`MR. MARGOLIS: Good morning, your Honor.
`Dan Margolis with Goadwin Practor.
`MS. DAUGHTRY: Natasha Daughtry of Goodwin Proctor,
`THE COURT: And then on behalf of Innopharma.
`MR. MUKERJEE: Deepro Mukerjee of Alston Bird, your
`
`Honor.
`
`MR. SODERSTROM. Lance Soderstrom of Alston Bird,
`your Honor.
`MR. MALIK: Jitendra Malik with Alston Bird, your
`
`Honor.
`
`MR, CALMANN: Arnold Catmann from Saiber.
`
`THE COURT: Good morning.
`United States District Court
`
`Carden, New Jersey
`
`10
`
`All right. Are there any questions about the logistics
`of trial before we begin? Did anything come up that requires
`my attention that would make you more comfortable to speak to
`it at this point in time?
`MR. LIPSEY: Not for plaintiffs, your Honor.
`MS. HOLLAND: Wot for defendants, your Honor.
`THE COURT: Okay. You'll recall that there were
`three motions in limine in which I reserved decision and I'd
`
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`prefer not to take the time now to address them in an orai
`Opinion, but I will either at the end of the day today or else
`tarnorrow.
`
`And there's one motion in limine by the plaintiff,
`which wasactually the plaintiff's second motion in limine, it
`
`was to preclude evidence or argumentthat the plaintiff's
`asserted patentclaims are invalid as obvious based on
`plaintiff's internal documents and specifically identified
`non-prior art information. This was Docket Number i161. And
`I'm denying that mation.
`I’m denying that motion without
`prejudice to raise any specific objection and I'm daing so for
`reasons that will be stated in the oral Opinion.
`The defendants had two motions in limine. Their first
`
`motion in timine ts to preclude evidence consistent with
`admissions in the patent specifications. This was at Docket
`item 167 in the lead case. And that mation is also being
`denied without prejudice. What's consistent and inconsistent
`United States District Court
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`aonoonkk&hw
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`to
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`11
`12
`13
`14
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`77
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`can only be determined on an item by item basis, and there's
`much in dispute about what is admitted and what’s not
`
`admitted, quote, unquote, ia the patent specifications. So I
`will, again, explain the reasons in an oral Opinion.
`The third motion is the defendant's second motion in
`
`limine to preclude evidence of alleged unexpected results.
`This is Docket Item 169 in the fead case of 14-667. And that
`
`It's being denied because
`mation also is going to be denied.
`there's a very deep factual dispute about what's expected,
`unexpected, the degrees of difference, and whether the
`unexpected result was a change in kind, all of that needs to
`be explored at trial. And, again, f'll flesh out these
`réasons in on oral Opinion.
`Any questions so far?
`MR, LIPSEY: Not for plaintiffs, your Honor,
`
`16
`17
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`18
`20
`21
`22
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`00:07 25
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`THE COURT: Okay. There is also an appeal fram Judge
`Williams’ order regarding attorney/client privilege, and on
`that I would like to hear oral argument, not at this time
`because I know thatit's unlikely you'd be prepared to do so
`
`I would have the oral argument at some point tomorrow,
`now.
`if you need a day to decide who's going to argue it and
`collect your thoughts on that, aad also to see if there's any
`way it can be worked out overnight.
`
`Would you rather have it at 9:15 or at 4:30? I'm open
`to either.
`
`United States District Court
`
`Camden, New Jersey
`
`72
`
`MS. HOLLAND: Either one is fine with Lupin, your
`Honor, Whatever is preferable to you.
`MR, LIPSEY:
`If possible, 4:30. But, if not --
`THE COURT: Gkay.
`MR, LIPSEY:
`-- whatever is convenient for the Court.
`THE COURT:
`
`No,
`if there's a preference then for
`4:30, then we'll do 4:30 tomorrow,
`
`So 4:30 on Tuesday afternoon wewill have oral argument
`on the defendant's appeai! from Judge Williams' determination
`recognizing the attorney/client privilege,
`Before we leave that topic, I don't see that the issue
`of waiver is presented.
`In other words, there doesn't seem to
`have been a dispute presented to Judge Williams about the
`
`operation of the clawback provision that's been argued to me.
`But since it wasn't presented to Judge Williams, at least not
`that
`can tell from the papers, there's not a question here
`
`
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`3 of $2 sheets
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`Camden, New Jersey
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`Page 9 fo 12 of 254
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`Camden, New Jersey
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`

`

`13
`
`it anywhere in the papers. On its face it doesn’t seem that
`the documents would qualify for work product protection. But
`the atterney/client privilege dispute is, of course, very much
`alive.
`
`T hope that that focuses your arguments for tomorrow.
`Do you have any questions about what ['m asking you to
`address?
`
`Okay, So are we ready to begin with opening
`statements.
`
`MR, LIPSEY: We're ready, your Honor.
`THE COURT: Okay. Then, Mr. Lipsey, you may proceed.
`MR. LIPSEY: Okay. Fhank you.
`May it please the Court, I have some hard copy of my
`presentation, which I think the court reporter's mightfind
`useful in the transcription, and perhaps the Court and the
`Court's clerk might find usefui at some point,
`May I approach?
`THE COURT: Yes, please.
`Thank you.
`MR, LIPSEY: How many would you all like?
`MS, HOLLAND: As many as you're offering.
`MR. MUKERJEE: Charles, do you have any extra copies
`for Innopharma?
`I have one.
`MR. LIPSEY:
`MR. MUKERJEE: Thanks so much.
`United States District Court
`
`Camden, New Jersey
`
`14
`
`I'm not disappointed that you narrowed
`
`Camden, New Jersey 4 of 92 sheets
`
`MR, LIPSEY: May it please the Court, the case is
`about the product Prolensa®, which is bromfenac ophthalmic
`seluticn .07 percent. The approved indication is for the
`treatment of postoperative inflammation and reduction of
`ocular pain in patients who have undergone cataract surgery.
`And the Court will be pfeased to recall that while
`there are many patents in issue, we have agreed with the
`defendants that their right to market this product as a
`generic will stand orfall with the outcome on Claim 6 and 20
`of the '431 patent, which, in essence, claim formulations in
`varying degrees of detail containing bromfenac sodium and
`about .02 percent tyloxapoel. And that's what the case will
`largely be about.
`THE COURT:
`the dispute.
`MR, LIPSEY: We suspected that might be the case.
`Nor are we disappointed either, your Honor,
`We deal here with cataract surgery. And hapefully it’s
`something we all don't have a Jot of experience about.
`We have Dr. Trattler whe, unfortunately, can’t be here
`till next week, but he can explain to us the detaifs. But as
`you can see on the screen, what it involves, in essence, is
`cutting open the eye and removing the clouded natural lens and
`replacing that natural lens with an artificial one and then
`allowing the patient to recuperate, And inflammation results
`United States District Court
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`from that abuse of the eye, and we will hear thatit's
`
`important to control that inflammation less there be some very
`serious adverse consequences. There's also pain associated,
`as you can imagine, with the incision and recovery.
`And, as we all know, the eye is ane of the most
`sensitive organs in the body to begin with. And whenit's
`been surgically damaged,it's even more so. And the drugs
`that are used to treat this inflammation are administered, at
`least in the case of the product here, as drops directly into
`the eye.
`
`And so there are some complications and challenges in
`preparing such a formulation and our evidence will focus on
`
`these. These comelargely out of the Ogawa patent, which is
`the principal piece of prior art.
`
`You have to have a clinically effective ingredient.
`The key is to get the ingredient ta penetrate the eye
`to get to the tissues that need to be prevented from
`inffammation,
`
`Maintenancein the eye of clinically effective
`
`concentration is difficuit because the surface area of the eye
`is quite small, the length of time the drug is actually in
`contact with the surface area is quite small, and so there’s a
`
`challenge getting an adequate amountof drug into the eye.
`Irritability, of course, is an issue in @ surgically
`compromised eye, stinging and burning principally, and most of
`United States District Court
`
`Camden, New Jersey
`
`the evidence will focus on that,
`
`And then there are questions of the stability of the
`formulation. We'll hear that making liquid formulations is a
`more difficult proposition than making a solid oral dosage
`form. Things happen more readily when drugs are in solution,
`reactions can occur which don’t normally occur when they're
`dry, they can occur more quickly, the varicus ingredients can
`interact with each other. And $olife is difficult in the
`
`liquid formulation world and even more so in the ophthalmic
`formulation world,
`
`There are two kinds of stability that we'll be talking
`about. One is chemical stability and that is the active
`ingredient actually getting degraded and broken down into
`something that's not an active ingredient and there’s several
`reactions, chemicareactions by which that can occur. One
`we'll be talking about is oxidation. Another is hydrolysis,
`And then there’s the question of the physical stability
`of the formulation, and that tends to manifestitself by the
`formulation having a cloudy appearance when the ingredients
`actually start to separate from each other, And there will be
`some testimony about that as well.
`There is in the world of ophthalmic formulation a
`dizzying array of ingredients that can be contained or are
`available as options for inclusion.
`I've listed some of them
`
`here on Slide 5 that I've extracted directly from the
`United States District Court
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`04/05/2016 07:29:54 PM
`
`Camden, New Jersey
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`Page 13 to 16 of 254
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`

`

`
`
`molecules that we'll be talking about. The ones on top are
`anti-inflammatory drugs and they are, more specifically, what
`are called in the trade nonstercidal anti-inflammatory drugs.
`The initials N-S-A-§-D-S being amalgamated by people, and
`probably by us at the trial, as NSAIDS. And when we refer to
`NSAIDS, that doesn't tell us what the structure of the
`molecule is, your Honor, it tells you what the therapeutic
`class is and that's to distinguish them fram molecules which
`have been used before such as steroids. Steroids are very
`powerful drugs that fave a whele constellation of potentially
`adverse side effects and we are not talking about steroids.
`Now, we will be led through this issue by Dr. Steve
`Davies who has a Ph.D. from the University of Oxfard. He is
`the Waynflete professor of chemistry at the University of
`Oxford. He's got 550 publications. And his research include
`organic and medicinal chemistry.
`And the defendants were kind encugh to share with us
`some of their slides, and I've used one here becauseit
`highlights 1 think what the difference in the proofs are going
`to be, at least the difference in the focus of the proofs, and
`that is defendants’ arguments and evidence largely will focus
`on these molecules as if they're fungible marbles or bowling
`balls all with this carboxylic acid group, which is the C,
`double-bond G, OH you see and which they have emphasized as
`their theory of the case requires. And the fact of the matter
`United States Disirict Court
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`is our evidence will focus on the importance of structural
`differences elsewhere in the molecule, all of which need to be
`considered in assessing what can be expected of that molecule
`and what is unpredicted fram that molecule.
`And one of the concepts that Dr. Davies is going to
`teach us about, which is important here particuiarly in these
`aqueous systems, is the concept of hydrogen bonding. And
`this, when I tried tc learn it in high school, escaped me
`completely until I realized that the water molecule looks like
`Mickey Mouse. It's got a big oxygen atom,it's got two little
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`hydrogen atoms, H,O, But the hydrogen atoms are not equally
`spaced on the molecule, they're actually both on one side of
`the molecule and that causes one side of this mejiecule where
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`the Mickey Mouse ears are to have a partial positive charge
`and the end that has the big oxygen atom hasa partial
`negative charge and that allows water whenit is in the liquid
`form for those molecules to attract each other through
`aydrogen bonding, the slightly positive hydrogen atom being
`attracted to the slightly negative oxygen Mickey Mouse face,
`And that's what makes water such a marvelous solvent, is those
`molecules actually stick together and that explains why the
`boiling point of water is as high as it is for such a small
`molecule.
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`And those same kinds of interactions can occur between
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`water and organic chemicals and, indeed, between different
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`organic chemicals because a numberof the functional groups,
`which Dr. Davies is going to telf us about, have that same
`property of having a partial positive charge on one end anda
`Partial negative charge cn the other. An important one that
`we'll see in a lot of these molecules is the carhonyl group,
`which is in the center here. And again, the oxygen that’s
`hanging out in the space in the air has a partial negative,
`that's where the electrons like to be, as Dr. Davies will
`explain, the rest of the group has a partial positive charge.
`And so whenthatis in an aqueous énvironment, the ears of
`Mickey Mouse, two of them actually, can associate themselves
`or becomeclosely associated with that slightly negatively
`charged oxygen.
`And the same thing happens with, expect in the opposite
`direction, with the molecule or functional group known as a
`primary amine, which we have here on the right. And there --
`now the hydrogen atoms there have a partial positive charge,
`the nitrogen has a partial negative charge, and so the face of
`Mickey Mouse can now associate with those positively charged
`hydrogen atomsin that primary amine. And this hydrogen
`bonding that goes on can increase the solvation, the
`association of water solvent with these molecules, alter
`substantially their sclubility, it can also alter the
`interaction with other excipients that may be in the drug
`product, which also have slightly polar moieties.
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`documentary exhibits that will be coming into evidence. And
`these are categories, these are functional categories, and
`within each of those categories there are a very large number
`of different chemicals that are used in this regard. There
`are entire books written describing each of the various
`chemical options and how theydiffer from each other and,
`indeed, they do differ from each other.
`And we'll be guided through that morass by Dr. Rebert
`Williams who is Ph.D. in pharmaceutics. He is the Johnson &
`Johnson Centennial Chair at the University of Texas in Austin.
`He has more than 400 publications. His research focusis in
`development formulation and delivery of drugs. And, in
`essence, what we're going to hear from Dr. Williams is that
`the mantra, oh, that's routine experimentation, which most
`defendants in caseslike this advance and which the defendants
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`here have advanced, is in the case of aphthalmic formulations
`is a gross oversimplification of what happens. The individual
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`components can interact with each other in unpredictable ways
`and affect their properties in unpredictable ways, each drug
`has to be considered based on its own unique properties. And,
`as he will say more eloquently than 1, knowing the abjective
`and getting there is often separated by trial and error,
`failures and frustration.
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`Now, there are also chemistry aspects to the case.
`What we have on Slide 7 here are the structure of some of the
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`surfactants, as the word sounds,it's kind of a made up word.
`Surface active agent intends to refer, as we will hear, to
`molecules that could alter the surface tension of a liquid,
`particularly water in our case. And the simplest and clearest
`example of a surfactant, just to get aur feet wet, no pun
`intended, is soap or detergent. And we have here the
`simplified demonstrative exhibit. And the surfactants tend te
`have one end, it is water living, hydrophilic is the word you
`may hear, and another end, it is oil loving, oleophilic or
`water hating, hydrophobic, and they can associate into these
`sphericai, not always spherical, but these arrangements
`whereby the ends that like to be in water are near the water
`and other ends are all associated with each other and can hold
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`And what Dr. Davies will teach us is that you now look
`at these molecules aot like fungible bowling balls with acid
`groups but loak at them as a whole. And he will show us that
`there are indeed different numbersof different types of and
`different arrangements of these molecules that are capable of
`engaging in hydrogen bonding. And those are highlighted here
`in red.
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`And you can see that for bromfenac, which is the
`molecule we're interested in, as Dr, Davies will explain,
`there are really more opportunities for hydrogen bonding with
`that molecule than for any of the others we're likely to
`discuss. And a particular feature of this molecule is that
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`primary amine, that NH, group that’s there, which is not
`shared by way of these other molecules.
`While we have these up, there are two other molecules
`that we'll talk about. The one on the bottom is not really an
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`NSAID at all but it has come into play because at one point
`earlier in the case the defendants were relying onit te
`suggest the invention was obvious, And then this nepafenac is
`a horse of an entirely different color, you can see it doesn’t
`have that carboxylic acid group at all. And, in fact, that
`molecule as it sits is not an active drug.
`In order to work,
`it has to be delivered into the eye and then enzymesin the
`eye actually will convert that into something that can operate
`as an anti-inflammatory.
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`Something else we'll taik about are surfactants. And
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`other molecules that are not readily soluble in water in that
`area. Just add soap or detergent can hold oil droplets that
`are not soluble in water, in solution in water so we can wash
`them awayoff the dishes.
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`Now, my diagram here, the ends that are water loving
`need not necessarily be globular, they might [cok like tails,
`but they are nonetheless water loving. And the ends that are
`oil soluble need not look like tails, they might in fact be
`globules and some are in some of the molecules we'll see. But
`the concept is the same and Dr. Davies will explain that to
`us.
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`And what he is particularly going to explain with
`surfactants is there is a large number of them, they vary from
`each other in structure and their properties are different
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`and, therefore, what interactions, if any, they're going to
`have with complex systems with many different components is
`unpredictable. And we doen't really need to take Dr. Davies’
`word for that because right out of the documentary evidence
`that he has cited, we have the quote. And this particular
`article happens to have been cited in other patent cases that
`have dealt with surfactant.
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`"The range of available surfactants is wide, and so,
`too, are the mechanisms of solubilization and the effects the
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`surfactants have on the solubilized material. Examples are
`knewn of enhanced drug activity and of inactivation, of
`increased stability, and instability; the interactions of the
`surfactants with components of the body must also be
`considered."
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`And the point is that’s a complex and unpredictable
`world, which bears directly on the issue of obviousness, which
`your Honor will have to decide.
`Now, these are some of the -- these are models of some
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`of the surfactants that we'll be talking about. And every
`time we draw one of these structural formula, we put a model
`on the board, it is our best effort, and scientists’ best
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`effort, a depiction of how the structures differ. Obviously
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`the molecules are minusculely small, they're flexible, they
`interact with their environment in complicated ways. But this
`is the best we can do to try to depict the differences.
`The one on theleft is polysorbate 80, that was the
`surfactant that was in the closest prier art, which we'll see
`in @ moment is the Ogawa patent that actually described
`bromfenac eyedrop. And the surfactant, which the inventors of
`the “431 patent discovered, had a whole cascade of benefits
`
`for use in the point of 2 percent concentration, is tyloxapol.
`You can seeit's structurally exceedingly different and we
`contend, and our evidence will shaw you, could not have
`predicted that molecule would have positive effects in a
`bromfenac formulation.
`
`Some others that we will see are these octoxynol
`melecules, which are structurally similar, at least in the
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`globular end, which in this case happens to be theoil loving
`end, and they vary from each other simply in the length of the
`tail, which is the water-toving tail. The red atarns are
`oxygen atoms and the presence of the oxygen atoms in these
`tails causes them to be associated easily with water, as Dr.
`Davies will explain, and as you can see from the structure of
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`those molecules that they do not look like either polysorbate
`80 or tyloxapol.
`Now,there are also medical issues, as one might
`imagine, with treating postsurgery inflammation in the eye.
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`We will be guided through those by Dr. Trattler, as I've said,
`who will be here next week. He has specialized in cornea and
`cataract surgery since 1997, been an investigator on nearly 70
`clinical trials for ophthalmic products, including bromfenac.
`He conducts about 60 surgeries a month, and has actually used
`many of the drugs that are both in the prior art as well as
`Prolensa®, and will be here to tell us how important some of
`the differences between them are. And again, part of what he
`will teil us is also reflected in the prior art documentary
`evidence.
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`And there are two principal medical issues that come
`up, anc the first is really captured here by Bowman whichis
`one of the references they had originally cited te us. And
`Bowman points out that there are problems with these NSAID
`agents, and that is, that stinging and burning sensations are
`commonly experienced during thefirst few minutes after
`topical administration on the eye. Not only are patients who
`experience such stinging likely to avoid reguiarly taking
`their medication, they also receive less benefit from each
`application. Specifically, the stinging causes tearing which
`washes away the drug. Having physically removed a portion of
`the drug fram the eye by tearing, the bioavailability of the
`drug is reduced.
`Soa, the stinging and burning issue, which ts somewhat
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`downplayed, understandably, by the defendants, is an important
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`are separated from each other by semething like .5, that still
`is a threefold difference in terms of the alkalinity or
`acidity that you are dealing with, and we'll hear about that,
`So, that was the problem that Ogawa acknowledged, and
`specifically what he found out was that when he made up these
`formulations with bromfenac and subjected them to long-term
`stability tests, he found these red insoluble matter in it,
`and we pointed out the sections in Ogawa where that's
`mentioned. And what you will hear in the testimony is that
`when there's a color change like that, that's almost always
`the indication of some kind of chemical degradation, and most
`particuiarly of an oxidative chemical reaction that results in
`that color change.
`So, what Ogawa was concerned with was a chemical
`stability problem, not a physical stability problem. And we
`will see, as we go through the evidence, there are some
`patents that deal with cherica? stability. Ogawa deals with
`the problem with this red junk showing up in his formulation,
`a chemical stability problem. Same of them deal with physical
`stability problems where the ingredients separate from each
`ot