SENJU EXHIBIT 2135
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 59
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Clle as 318 1’.Supp.2(§ 9'34 (E.D.Tux. Zfllll
`
`975
`
`the
`
`evidence.
`
`35 U.S.C.A.
`
`8. Patents @'62(2)
`
`of
`ance
`{,4 271(c)(2).
`
`Generally, testimony concerning pate
`ent anticipation must be testimony from
`one skilled in the art and must identify
`each claim element, state the witness’ in-
`terpretation of the claim element, and ex-
`plain in detail how each claim element is
`disclosed in the prior art reference; testi-
`mony is insufficient if it is merely concl11—
`sory. 35 U.S.C.A. § 102.
`
`9. Patents @P62(l)
`
`Evidence of secondary considerations,
`such as unexpected results or commercial
`success,
`is irrelevant
`to the analysis of
`whether a patent in invalid as anticipated.
`35 U.S.G.A. § 102.
`
`1!}. Patents @66(1.I2)
`
`Patents for a drug used to treat glau-
`coma and ocular hypertension were not
`invalid as anticipated by a prior art refer-
`ence describing pliarmaceutically accept-
`able compounds for controlling intraocular
`pressure in patients with glaucoma and
`ocular hypertension; prior art reference
`failed to describe a fixed combination of
`brimonidine and timoloi or a method of
`
`treafing giaucoma using such a combina-
`tion. 35 U.S.C.A. § 102.
`
`ll. Patents @==*16(2, 3), 16.13, 36.1(1)
`A determination of obviousness is a
`
`legal determination based on four factual
`inquiries: (1) the scope and content of the
`prior art; (2) the differences between the
`patent claims and the prior art;
`(3)
`the
`level of ordinary skill in the art; and (4)
`secondary considerations of non—obvious-
`ness. 35 U.S.C.A. § 103.
`
`12. Patents G7-v16.5(1)
`
`When the patented invention is a com-
`bination of known elements, in evaluating a
`claim of invalidity for obviousness,
`the
`court must determine whether there was
`
`an apparent reason to combine the known
`elements in the fashion claimed by the
`patent at issue by considering the teach-
`
`2. Patents ®='72(l}
`
`A patent is invalid as anticipated if a
`single prior art reference discloses each
`element of
`the claimed invention.
`35
`U.S.C.A.§ 102.
`
`3. Patents @365
`
`A prior art reference may anticipate a
`patent claim, and, thus, render it invalid.
`when the claim limitation or limitations not
`
`expressly found in that reference are none
`theless inherent in it.
`35 U.S.C.A. § 102.
`
`4. Patents @=-*58
`
`If a claim limitation is not explicitly
`disclosed in an allegedly anticipating prior
`art reference,
`the party alleging patent
`invaiidity bears the burden of showing that
`the limitation is inherently disclosed by the
`reference. 35 U.S.C.A. § 102.
`
`_
`5. Patents G‘-’65
`To establish that a claim limitation is
`
`inherent in an allegedly anticipating prior
`art reference, the anticipatory feature or
`result must be consistent, necessary, and
`inevitable, not simply possible or probable,
`and it should be clear that it would be so
`
`recognized by persons of ordinary skill.
`35 U.S.C.A. § 102.
`
`6. Patents ©='65
`
`In order to establish patent invalidity,
`an anticipating reference must describe
`the patented subject matter with sufficient
`clarity and detail to establish that the sub-
`ject matter existed in the prior art and
`that such existence was recognized by per—
`sons of ordinary skill
`in the field of the
`invention. 35 U.S.C.A. § 102.
`
`7. Patents W65
`
`Anticipation of a patent, rendering it
`invalid, requires enablement, whereby the
`prior art reference must teach one of ordi-
`nary skill in the art to make or carry out
`the claimed invention without undue ex-
`
`perimentation. 35 U.S.C.A. § 102.
`
`PAGE 2 OF 59
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`PAGE 2 OF 59
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`

`
`976
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`ings of multiple references, the effects of
`demands known to the design cominunity
`or present
`in the market])lace, and the
`background knowledge possessed by a per-
`son having ordinary skill
`in the art.
`35
`U.S.C.A. § 103.
`
`13. Patents <¢’36.1(l}, 36.2(1l
`
`Secondary considerations that provide
`evidence of the non—obviousness of a pat-
`ent include copying, commercial success,
`failure of others,
`long-felt need, general
`skepticism of those in the art, and unex-
`pected results. 35 U.S.C.A. § 103.
`14. Patents <3‘-=36.2(’i’)
`
`A presumption arises that the patent-
`ed invention is commercially successful, as
`evidence that it is not invalid for obvious
`
`ness, when a patentee can demonstrate
`commercial success, usually shown by sig-
`nificant sales in a relevant market, and
`that the successful product is the invention
`disclosed and claimed in the patent.
`35
`U.S.C.A. § 103.
`
`15. Patents @-v16.5(4)
`
`If there is no proof that there were a
`finite number of identified and predictable
`solutions in the prior art at the time of the
`patented invention, this cuts against a find-
`ing of
`invalidity for obviousness.
`35
`U.S.C.A § 103.
`
`16. Patents ®='l6(3, 4)
`Patent obviousness is analyzed from
`the perspective of one of skill in the art at
`the time of the invention, and the use of
`hindsight is not permitted.
`35 U.S.C.A.
`§ 103.
`
`17. Patents $16.25
`
`Patents for a drug used to treat glau-
`coma and ocular hypertension were not
`rendered invalid for obviousness by a prior
`art reference describing pharmaeeutically
`acceptable compounds for controlling in-
`traocular pressure in patients with glauco-
`ma and ocular hypertension; person of or-
`dinary skill
`in art would not have had
`
`reason, after reading prior art reference,
`to develop claimed combination of hrimoni-
`dine and timolol given unpredictable na-
`ture of field, patentee’s clinical studies of
`drug demonstrated unexpected results,
`and there was a long felt need for a fixed
`combination product to treat glaucoma at
`time of patented invention.
`35 U.S.C.A.
`§ 103.
`
`Patents <=b328(2)
`
`5,502,052. Cited as Prior Art.
`
`Patents €=*328(2)
`7,030,149, 7,320,976, 7,323,463, 7,642,-
`258. Vaiid and Infringed.
`
`W. Chad Shear, Fish & Richardson, Dal-
`las, TX, A. Martina Tyreus Hufnal, Fish &
`Richardson, Wilmington, DE, Aine M.
`Skew, Deanna J. Reichel, Elizabeth M.
`Flanagan, Jonathan E. Singer, Susan M.
`Goletti, Fish & Richardson, Minneapolis,
`MN, Gregory Phillip Love, Todd Y.
`Brandt, Stevens Love Hill & Holt PLLC,
`Longview, TX, Juanita R. Brooks, Fish &
`Richardson, San Diego, CA, Otis W Car-
`roll, Jr., Ireland Carroll & Kelley, Tyler,
`TX, for Plaintiffs.
`
`Barry P. Golob, Kerry B. McTigue, Wil-
`liam Blake Coblentz, Duane Morris LLP,
`Washington, DC, Ian Scott, Duane Morris
`LLP, New York, NY, Joseph M. Bennett-
`Paris, Duane Morris, Atlanta, GA, Richard
`T. Ruzich, Robert M. Gould, Duane Morris
`LLP, Chicago,
`IL, William Ellsworth
`Davis, III, The Davis Firm, PC, Longview,
`TX, for Defendants.
`
`FINDINGS OF FACT AND
`CONCLUSIONS OF
`LAW
`
`'1‘. JOHN WARD, District Judge.
`INTRODUCTION
`
`I.
`
`This is a consolidation of four patent
`infringement suits brought by Plaintiff Al-
`
`PAGE 3 OF 59
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`PAGE 3 OF 59
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`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cill: H5818 F.Supp.2(I ‘JT4 (E.D.Tcx. Zflll)
`
`977
`
`lergan, Inc.’s (“Allergan”) pursuant to the
`I-latch—Waxman Act.‘ See Drug Price
`Competition and Patent Term Restoration
`Act, which is commonly referred to as the
`Hatch—Waxman Act, in 1984. Pub. L. No.
`98-417, 98 Stat. 1585. Defendants Sandoa,
`Inc. (“Sandoz”); Alcon Laboratories, Inc.,
`Alcon Research, Ltd., Alcon, Inc., and Fal-
`con Pharmaceuticals, Ltd. (“Alcon”); Apo-
`tex, Inc. and Apotex Corp. (“Apotex”); and
`Watson Laboratories, Inc. (“Watson”) (col-
`lectively “Defendants”) are each seeking
`approval from the Food and D1‘ug Admin-
`istration (“FDA”) to market generic copies
`of Allergan’s Combigan® product, used for
`the treatment of glaucoma and ocular hy-
`pertension."‘
`In this consolidated action,
`Allergan alleges that Defendants’ proposed
`generic pharmaceutical products infringe
`the asserted claims of United States Pat-
`
`ent Nos. 7,030,149 (“the '149 patent”);
`7,320,976 (“the ’976 patent”);
`7,323,463
`(“the 5163 patent”); and 7,642,258 (“the
`'258 patent”) (collectively, the “patents-in-
`suit”). The Court held a four-day bench
`trial in the case on August 2, 2011 through
`August 5, 2011.
`
`Pursuant to Fed.R.Civ.P. 52, and after
`having considered the entire record in this
`case and the applicable law,
`the Court
`concludes that:
`(1) each of the Defendants
`infringe claim 4 of the ‘I49 Patent, claim I
`of the '9’f6 patent, claims 1-6 of the ’-'-163
`Patent, and claims 1-9 of the ’258 Patent;
`and {2} the patents-in-suit are not invalid.
`These findings of fact and conclusion of
`law are set forth in further detail below.
`
`The Court’s findings of fact are based on
`the admissible evidence. Any finding of
`fact that is actually a conclusion of law
`
`should be treated as such. Any conclusion
`of law that is actually a finding of fact
`should be treated as such.
`
`II. FINDINGS OF FACT
`
`A. The Parties
`
`1. Allergan, Inc. is a Delaware corpora-
`tion with its principal place of business at
`2525 Dupont Drive,
`Irvine, California
`92612.
`
`is a Colorado corpora-
`2. Sandoz Inc.
`tion with its principal place of business at
`506 Carnegie Center, Suite 400, Princeton,
`New Jersey 08540.
`
`is a Dela-
`3. Alcon Laboratories, Inc.
`ware corporation, with a place of business
`in Texas.
`
`4. Alcon Research, Ltd. is a Delaware
`corporation, with a place of business in
`Texas.
`
`5. Alcon, Inc. no longer exists, based
`on a merger with N ovartis AG.
`
`is a
`6. Falcon Pharmaceuticals, Ltd.
`Texas corporation, with a place of business
`in Texas.
`
`7. Apotex, Inc. is a Canadian corpora-
`tion with a place of business at 150 Signet
`Drive, Toronto, Ontario, Canada MQL 1T9.
`
`8. Apotex Corp. is a Delaware corpora-
`tion with its principal place of business at
`2400 North Commerce Parkway, Suite 400,
`Weston, Florida, 33326.
`
`9. Watson Laboratories, Inc. is a Neva-
`da corporation with a place of business at
`400 Interpace Parkway, Parsippany, NJ
`07054.
`
`Inc. v. Hi—Tech
`I. A fifth action, Allcrgarr,
`Pl1m'nrmc'al' C{)., }'m:., C.A. No. 2:09—cv—l82
`(TJW) was also consolidated with these four
`actions.
`Ilowcvcr, Allcrgan and I-Ii-Tech re-
`solved the dispute and filed a stipulation of
`dismissal [I1]. 168), which was ordered by
`this court on May 3|, 201 l.
`(D.I. 175.)
`
`these consolidated suits relate
`2. Specifically,
`to the filing of Abbreviated New Drug Appli-
`cation ("ANDA") No. 91-08?‘ by Sandoz,
`ANDA N0. 9l—574 by Alcon, ANDA N0. 93-
`442 by Aputex, and ANDA No, 201949 by
`Watson with the FDA. pursuant to the Federal
`Food, Drug, and Cosmetic Act.
`
`PAGE 4 OF 59
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`PAGE 4 OF 59
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`

`
`978
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`B. Glaucoma and Ocular Hyperten-
`sion
`
`to attempt to reduce IOP. (Id. at 7124-9
`(Noecker).J
`
`10. Glaucoma is an incurable disease of
`
`the eye that causes gradual damage to the
`optic nerve resulting in vision loss that,
`ultimately, can lead to blindness.
`(D.I.
`238, Trial Tr. Day 1(AM) at 5I:24—52:2;
`52:2l—53:7 (Wl1itcup).)"‘ About 2 million
`people in the United States are diagnosed
`with glaucoma every year.
`(Id. at 52:'i'~10
`(Whitcup).)
`
`11. VVhile incurable, glaucoma can be
`managed by pharmaceutical and surgical
`treatment options that slow the progres-
`sion of the disease.
`(D.I. 242, Trial Tr.
`Day 3(AM} at 71:4—9 (Noecker).} One
`such treatment option is to use medication
`to lower the intraocular pressure {“IOP")
`in the eye.
`(Id. at 72:2{}—73:7 [Noecker).)
`Scientists and medical professionals be-
`lieve that the elevated IOP found in glau-
`coma patients; contributes to the gradual
`retinal deterioration and loss of vision that
`are characteristics of the disease.
`(D.I.
`238, Trial Tr. Day 1(AM) at 53:15-21;
`54:10-21 (Whitcup); D.I. 242, Trial Tr.
`Day 3(AM) at 66:3-15 (Noecker).} Intrau-
`cular pressure is measured in millimeters
`of mercury (“mm Hg”).
`(D.I. 242, Trial
`T1‘. Day 3(AM) at 66:3—8 (Noecker}.) For
`each miiiimeter of mercury IOP is low-
`ered, patients are 10% less likely to suffer
`visual field loss.
`(Id. at 67:14-18 (Noeck-
`er).)
`
`12. Patients suffering from ocular hy-
`pertension (“OHT”) also have elevated
`IOP and, although not diagnosed with
`glaucoma, must be observed closely for its
`onset.
`(D.I. 242, Trial Tr. Day 3{AM) at
`66:21-67:25 (Noecker).)
`These patients
`can utilize the same pharmaceutical and
`surgical options used by glaucoma patients
`
`3. As used herein, "DTX," "PTX," and ".lTX"
`refer to Defendants’ exhibit, Plaintiffs exhibit,
`and Joint Exhibit respectively, and will be
`followed by the exhibit number.
`"Trial Tr.
`Day" refers to Ihc lrial lranscripl and will be
`
`C. Treatment of Glaucoma and Ocu-
`
`lar Hypertension with Brimoni-
`dine and Timolol
`
`13. One treatment method for patients
`with glaucoma 01' ocular hypertension is
`the use of eye drops. This form of treat-
`ment is the most convenient and accept-
`able to patients.
`{D.I. 242, Trial Tr. Day
`3(AM) at. 71:4-9; 81:20-84:25 (Noecherl)
`
`14. There are at least 20 different glau-
`coma drugs on the market today that can
`be used in such treatments.
`(D.I. 238,
`Trial Tr. Day RAM) at 54:22—55:5 (White-
`up).) Those that are commonly used in
`clinical practice fall into several different
`classes of medication, and have different
`mechanisms of action.
`(D.I. 240, Trial Tr.
`Day 2(.AMJ at 50:10-18; (Tanna); D.I. 242,
`Trial Tr. Day 3(AM) at 72:6—78:8 (Noeck—
`er).) Most relevant here are two classes
`of medication, alphaz adrenergic agonists
`and so—called “beta blockers”
`
`15. Brimonidine
`
`tartrate
`
`0.2% was
`
`marketed by Allergan as Alphagan®, and
`was first developed by Allergen as a new
`glaucoma medication in the late 1980s and
`early 1990s.
`(D.I. 239, Trial Tr. Day
`1(PM) at '75:8—10 (Batoosi11gh).) B1'imoni-
`dine is an alpha; adrenergic agonist that
`lowers IOP in glaucoma patients by reduc-
`ing fluid production in the eye while also
`increasing outflow of that fluid from the
`eye.
`(D.I. 238, Trial Tr. Day 1(AM) at
`59:22-460:’? {Whitcup); D.I. 239, Trial Tr.
`Day 1(PM) at 74:14—75:7 (Batoosingh).)
`The FDA approved Alphagan® in 1996.
`(D.I. 239, Trial Tr. Day 1{PM) at 'i'5:8—l0
`(Batoosingh).}
`
`followed by [he day, page number, and line
`numbers. For example, "Trial Tr. Day l(AM}
`at 53:15-21" refers to the morning trial tran-
`script, day 1, page 53, lines 55-21.
`
`PAGE 5 OF 59
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`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Ciie as 318 F.Su];Ip.2d 9'l'4 (E.D.TI:x. 2011]
`
`979
`
`16. Unlike many giaucorna medications,
`which are closed twice a day (once in the
`morning and once in the evening,
`i.e.,
`“BI”) or once a day (once in the morning
`or evening,
`i.e., "QD”), the FDA only ap-
`proved Alphagan® for dosing three times
`a day (i.c., "TID”) due to a lowered effica-
`cy of the drug with less frequent dosing.
`(PTX—'i'5 at AGN_COMBI0478532; D.I.
`238, Trial Tr. Day HAM) at 60:11—24
`(Whitcup); D.I. 239, Trial Tr. Day 1(PM)
`at 7511-89-19 {Batoosingh).} As
`ex-
`plained further below, BID dosing with
`Alphagan® 02% results in an approxi-
`matoly 3.25 to 3.5 mm Hg higher IOP in
`the afternoon than TID. (D.I. 239, Trial
`Tr. Day 1(PM} at 79:24—80:4 (Batoosingh);
`D‘1‘X—13'i' at DEF‘S(B;’T) 000346; PTX—134
`at AGN_COMBI0676465; D.I. 241, Trial
`Tr. Day 2(PM) at 4:24-5:19.) This differ-
`ence is both numerically significant and
`clinically relevant.
`(D.I. 239, Trial Tr. Day
`1(PM) at 80:5—8 (Batoosingh}; D.I. 241,
`Trial Tr. Day 2(PM) at 5:10-19 (Tanna).)
`This was referred to at trial as the “after-
`
`(D.I. 239, Trial Tr. Day
`noon trough.”
`1(PM) at 77:13-17; 7823-7 (Batoosingh}.)
`
`17. Although this third recommended
`dose, along with a substantial incidence of
`allergy, was a significant drawback of bri-
`monidine, it still achieved commercial suc-
`cess as a therapy for glaucoma patients.
`(D.I. 239, Trial 'I‘r. Day 1(PM) at 90:16-
`91:10 (Batoosingh).) Allergen attempted
`to secure FDA approval for Alphagan® as
`a BID drug but was unable to do so.
`(Id.
`at 75:14-20 (Batoosingh}.]
`
`18. Upon Alphagan®’s introduction to
`the market, it was apparent that brirnoniv
`dine 0.2% had significant and problematic
`side-effects that limited its utility.
`(D.I.
`239, Trial Tr. Day 1(PM) at 90:6—91:10
`(Batoosingh).)
`Brimonidine
`0.2% was
`found to cause a high rate of ocular aller-
`gy, which led patients to discontinue using
`the drug.
`(Id) Once a patient develops an
`allergy to brimonidine, brimonidine is no
`
`longer available as a treatment option for
`that patient.
`(D.I. 242, Trial Tr. Day
`3(AM) at7-'-1:11-16 (Noecker].) Additional-
`ly, brimonidine was also known to cause
`systemic side effects, including somnolence
`and dry mouth.
`(D.I. 239, Trial Tr. Day
`1(PM) at 9(J:6—91:l{} (Bat0osingh).) The
`high incidence of these various side effects
`i11 patients treated with brimonidine mo-
`notherapy is reported throughout the lit-
`erature.
`(See,
`c.g.,
`P'1‘X—130
`at
`AGN_COMBI{l67'?278;
`PTX—77
`at
`AGN_COMBI0481545.)
`
`19. These side effects of Alphagan®
`were so significant that, as soon as Alpha-
`gan® was approved, Allergan began look-
`ing for a way to ameliorate them. After
`A]phagan®'s
`approval, Allergan began
`working on developing a better product,
`ultimately developing two products with
`lower concentrations of brimonidine that
`
`reduced many of problems that had been
`seen with Alphagan®.
`(D.I. 239, Trial Tr.
`Day 1(PM)
`at 91:11-23
`(Batoosingh).}
`These products were known as AIphagan®
`P 0.15% and 0.1%.
`
`20. As with A]phagan®, Allergen at-
`tempted to secure FDA approval for BID
`dosing for Alphagan® P. (D.I. 239, Trial
`Tr. Day 1(PMJ at 92:15-20 (Batoosingh).)
`This effort was unsuccessful, and both A]-
`phagan® P 0.15%, and Alphagan® P 0.1%,
`were
`approved only for TID dosing.
`(PTX—75; D.I. 239, Trial Tr. Day l(PM) at
`91:24-92:14 (Batoosinghl) Allergan re-
`ceived approval for Alphagan® P 0.15%
`and Alphagan® P 0.1% in 2001 and 2006,
`respectively.
`(PTX-75; D.I. 239, Trial Tr.
`Day 1{PM) at 92:21-22 (Batoosingh); D.I.
`242, Trial Tr. Day 3(AM) at 12:14-18 (Le-
`Cause).) Alphagan® P 0.15% was ap-
`proved on March 16, 2001, over a year
`before the fiiing date of the patents—in—suit.
`(D.I. 243. Trial Tr. Day 3(PMJ at 79:17—25
`(Noecker).)
`Clinical
`studies on Alpha-
`gan® P 0.15% showed that it was signifi-
`
`PAGE 6 OF 59
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`

`
`980
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`cantly less likely to cause allergic reactions
`and certain systemic side—effects than was
`originai Alphagan®.
`(D.I. 242, Trial Tr.
`Day 3(AM) at 13821-13 (Noecke1‘).)
`
`21. Timoiol, a beta-blocker, was devel-
`oped by Merck in the 19708. The FDA
`first approved it as a treatment for glauco-
`ma in
`1978.
`(D.I. 241,
`’IH'iai Tr. Day
`2(PM) at 58:22-25 (Tanna}.) Timolol
`is
`typically prescribed either once or twice
`daily.
`(D.I. 240, Trial Tr. Day 2(AM) at
`95:1-=1-15 (Tanna).) Timoiol lowers IOP by
`suppressing aqueous humor production.
`(D.I. 242, Trial Tr. Day 3(AM) at 81:11-19
`(Noeckei-).)
`
`22. Although timolol is an established
`and commonly used drug, it is known to
`have serious and potentially life—threaten-
`ing side effects,
`including pulmonary and
`cardiovascular side—effects.
`(D.I. 243, T1'i-
`al Tr. Day 3(PM) at 125:25—127:11; 129:5-
`18 (Laskar).) Timolol
`is known to slow
`both heart and respiratory rates, and to
`lower blood pressure.
`(DTX—135 at 1960
`(stating that the systemic absorption of
`beta-blockers like tirnolol “can produce sig-
`nificant side effects such as bradycardia,
`arrhythmias, bronchoconstriction, or bron-
`chospasm as a result of interaction with
`the beta, and beta; receptors in the heart,
`lungs, and blood vessels. The use of non-
`selective beta-blocker therapy is contrain-
`dicated in patients with actual or suspected
`cardiovascular or pulmonary dysfunction
`as beta-blockers can produce further ar-
`rhythmias or bronchospasm.”); DTX 123
`at 1:64-67; DTX 157 at 45-46; D.I. 243,
`Trial Tr. Day 3(PM) at 125:25-127:1} (Las-
`kar).)
`
`23. Because of these side effects, treat-
`ment with timolol is cont1'aindicated in a
`
`(D.I. 242, Trial Tr.
`number of patients.
`Day 3(AM) at 74:17-75:20 {Noecker).)
`For example, the label of the Aiphagan®
`
`products contains the following warning
`about using brimonidine with a beta-bloclv
`or like timolol:
`
`a
`as
`a}pha—agonists,
`since
`However,
`class, may reduce pulse and blood pres-
`sure, caution in using concomitant drugs
`such as beta-blockers (ophthalmic and
`systemic), antihypertensives and,/or car-
`diac glycosides is advised.
`(DTX—129 at DEFS(B;T) 000233.)
`
`D. Glaucoma Treatment with Multi-
`
`ple Medications: Fixed and Un-
`fixed Combinations
`
`24. Although there are many individual
`medications available, for many patients,
`one glaucoma medication is not enough to
`treat their disease effectively.
`(D.I. 238,
`Trial Tr. Day 1(AM) at 54:22-55:17 (White-
`up).} For patients whose glaucoma cannot
`be effectively controlled with a single drug,
`the most common form of treatment. is the
`serial or concomitant administration of two
`
`or more different medications, provided in
`two or more separate bottles, at least sev-
`eral minutes apart to prevent one of the
`drops from washing the other out.
`(D.I.
`238, Trial Tr. Day IIIAM) at 55:1—56:2;
`56:14-57:16 {Whitcup).)
`
`25. This type of treatment is referred
`to by various terms, including adjunctive,
`concomitant, or serial
`therapy, and the
`combination of the products is considered
`“unfxed” because the amount the patient
`gets of each drug at any particular time is
`dependent on the treatment regimen pre-
`scribed by the doctor and on whether the
`patient properly administers the drugs.
`(D.I. 239, Triai Tr. Day 1(PM) at 64:10-
`66:3 (Batoosingh).) By contrast, a “fixed
`combination“
`combines
`two glaucoma
`drugs in the same bottle.
`(D.I. 2210, Trial
`Tr. Day 2(AM) at 17:21-18:3 (Tanna).)
`It
`
`4. As used herein. “fixed combination" and
`"single composition" are used interchange-
`
`ably.
`
`PAGE 7 OF 59
`
`PAGE 7 OF 59
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cite as 818 F.Supp.2(| 9?-I [E.D.Tex. 2011}
`
`981
`
`is “fixed” because the patient gets the
`same amount of each drug each time a
`drop of the combination is delivered to the
`eye.
`(D.I. 239, Triai Tr. Day 1(PM) at
`64:10-24 (BaI;oosingh).)
`
`26. There are advantages to using on-
`fixed combinations over
`fixed combina-
`
`tions. For exampie, if a patient needs a
`smaller dose of one medication, a physician
`can prescribe a smaller dose of that medi-
`cation without modifying the dose of the
`other. Unfixed combinations
`thus give
`physicians wide flexibility in treatment op-
`tions.
`{D.I. 239, Trial Tr. Day 1{PM} at
`64:10-20 (Batoosingh); D.I. 240, Trial Tr.
`Day 2(AM) at 132:l4-133:3 (Tanna); D.I.
`242, Trial
`'I‘r. Day 3(AM) at 79:?-18
`(Noecker).)
`
`27. Serial or concomitant administra-
`
`tion of two drugs is different than adminis-
`tering them in a fixed combination.
`(D.I.
`238, Trial Tr. Day RAM) at 56:14-57:19
`(Whit;cup).) When two ophthalmic prod-
`ucts are used together in a concomitant
`regimen, they do not interact in a patient’s
`eye. The human eye maintains only a
`small volume of liquid, approximately 10
`microliters, on its outer surface. Eye-
`tlrops (about 35-40 microliters) are ab-
`sorbed or drain away quickly through the
`eye’s drainage ducts.
`(Id; D1. 242, Trial
`Tr. Day 3(AM} at 6424-6523 (Noecker)
`(“And then the biggest problem is
`the
`window of delivery.
`It’s there, you blink a
`bunch, and the eye is gone. So you have
`about a minute to get this right and get it
`into the eye. So if you’re a little slow out
`of the gate,
`it’s gone.”).) Thus, under
`recommended dosing, which requires ad-
`ministration of drugs in an adjunctive regi-
`men at least five minutes apart, the second
`administered drug given as part of an ad-
`junctive regimen would not interact with
`the first administered drug.
`(D.I. 238,
`Trial
`'I‘r. Day HAM) at 57:13-16 (White-
`1111).)
`
`28. Because serial therapy with an un-
`fixed combination can necessitate applica-
`tion of
`five or more
`separate doses
`throughout the day, compliance can be dif-
`licult.
`(D.I. 239, Trial Tr. Day IEPM) at
`64:25-66:6 (Batoosingh).) Most patients,
`particularly the elderly (who are most sus-
`ceptible to developing glaucoma),
`fail
`to
`comply with such demanding dosing regi-
`mens.
`(D.I. 240, Trial Tr. Day 2(AM) at
`15:2-16:3 (T-anna).) As
`a consequence,
`their disease is not adequately treated and
`may progress more rapidly than it would
`with proper treatment.
`
`29. Although, in theory, the problem of
`patient compliance could be addressed by
`the use of fixed combinations, historically,
`they have been difficult to develop. As of
`2001, there was only one marketed, FDA-
`approved
`fixed
`combination, Cosopt®.
`(D.I. 238, Trial Tr. Day HAM) at 68:6-12
`{Whit.cup).) Alcon’s l3etoptic® Pilo fixed
`combination product was approved in 1997
`but was never marketed.
`(PTX-129 at
`AGN_COMBI06762992-, D.I. 238, Trial Tr.
`Day 1(AM} at 68:13-25 (Whitcup).} As Dr.
`Whitcup described, development of a fixed
`combination is the “most difficult” task in
`
`(D.I.
`ophthalmologicai drug development.
`238, Trial Tr. Day 1(AM) at 65:19-23
`(VVhitcup).)
`
`30. The FDA has repeatedly expressed
`skepticism about fixed combination prod-
`ucts and has set a high bar for approval.
`In the early 2000s, the FDA referred to
`the clinical results it had seen with fixed
`
`combination products as “very disappoint-
`ing," and the applications for several dif-
`ferent combination ophthaimic products at
`that
`time remained pending and unap-
`proved.
`(PTX-129
`at
`AGNOOM-
`BM672993 {quoting the FDA’s Dr. Wiiey
`Chambers as saying that the results for
`combination products “hafve] been very
`disappointing to a number of people in-
`cluding myself’); PTX-53 at AGN_COM-
`
`PAGE 8 OF 59
`
`PAGE 8 OF 59
`
`

`
`982
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`BI0437800 (“Dr. Chambers did say he
`thinks the results with the combination
`
`drops have been ‘terribly disappointing.’ "};
`D.I. 238, Trial
`'I‘r. Day HAM) at 89:18-
`91:1l
`(Whitcup).} Despite the fact that
`there are at least 20 different glaucoma
`drugs on the market, almost all of which
`are used in one unfixed combination or
`
`another, there are only two fixed combina-
`tion glaucoma products currently approved
`and sold for glaucoma treatment in the
`United States—Cosopt® and the product
`at
`issue in this litigation, Combigan®.
`(D.I. 238, Trial Tr. Day 1{AM) at 54:22-
`55:5; 68:6—12 fWhitcup).)
`
`E. The Patents—in—Suit
`
`31. The patents-in-suit are U.S. Patent
`Nos. 7,030,149 (“the '149 patent”); 7:320,-
`976 (“the ’976 patent”); 7,323,463 (“the
`’463 patent”); and 7,642,258 (“the ’258 pat-
`ent”). The effective filing date for each of
`the patents—in—suit is April 19, 2002.
`(See
`JTX 1, JTX 2, JTX 3, and JTX 4 at p. 1.)
`
`32. The named inventors of the pat-
`ents—in—suit are Chin—Ming Chang, Gary J.
`Beck, Cynthia C. Pratt, and Amy L. Ba-
`toosingh.
`(JTX 1, JTX 2, JTX 3, and JTX
`4 at p. 1.)
`
`33. The four patents-in-suit generally
`relate to a fixed combination composition
`of 0.2% hrimonidine and 0.5% timolol, a
`method of treating glaucoma or ocular hy-
`pertension by administering the aforemen-
`tioned composition twice daily, or an arti-
`cle of manufacture comprising packaging
`material indicating that twice daily admin-
`istration of the composition is useful for
`treating glaucoma or ocular hypertension.
`(See JTX 1-4.) Like the briznonidine tar-
`trate and timolol maleate single agent
`products [Alphagan® and Timoptic®), the
`combination product of the patents-in—suit
`is applied topically to the eye.
`{See e.g.,
`JTX 1 at Abstract.)
`
`34. The patents-in-suit also describe
`suitable preservatives for the combination
`
`ll. 29 ct seq.)
`(See id. at col. 2,
`product.
`The patents-in-suit list BAK as the first
`such preservative. The patents-in-suit ac-
`knowledge that “typically such preserva-
`tives are employed at a level of from
`0.004% to 0.02%”. (Id) The patents-in-suit
`further state that the preservative, prefer-
`ably BAK, “may be employed at a level of
`from 0.001% to less than 0.01%, eg. from
`0.001% to 0.008%, p1‘eferably about 0.005%
`by weight.” (lit)
`
`issued on April
`35. The 'l49 patent
`18, 2006, and is
`titled “Combination of
`Brimonidine and Tiniolol for Topical Oph-
`thalmic Use.” The application for the '14.‘)
`patent was filed on April 19, 2002.
`(JTX
`1 at p. 1.) The ’149 patent has four
`claims to methods of treating glaucoma
`or ocular hypertension with a 0.2% bri-
`monidine ta1'trate,’0.5% timolol formulation
`
`administered twice a day. Claims 1-3, as
`construed by the Court, require that com-
`bination treatment.
`to be as effective as
`serial administration with 0.2% brimoni—
`
`dine 3 times a day and 0.5% timolol twice
`a day.
`The Court granted summary
`judgment of non-infringement
`to Defen-
`dants of claims 1 through 3 before trial.
`Claim 4 of the '149 patent covers the im-
`provement in the prior three times a (lay
`brimonidine therapy “without loss of 2:01-
`cacy" whereby the brimonidine is com-
`bined with timolol
`in twice daily dosing.
`(JTX-1.) As construed by the Court in its
`Maximum: order, “Without
`loss of effica-
`cy” means “without decrease in lowering
`intraocular pressure (IOP).”
`(D.1. 151 at
`20-21.}
`
`36. The ’976 patent issued on January
`22, 2008, and is
`titled “Combination of
`Brimonidine and Timolol for Topical Oph-
`thalmic Use.” The application for the “E376
`patent was filed on October 14, 2003, and
`is a continuation of the application for the
`'149 patent.
`(JTX 2 at p. 1.) The ’0?6
`patent has one claim to a method of treat-
`
`PAGE 9 OF 59
`
`PAGE 9 OF 59
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cite H5818 F.Supp.2d 974 {E.D.Tex. Zfllll
`
`983
`
`ing glaucoma or ocular hypertension with a
`therapeutically effective amount of a for-
`mulation containing 0.2% brimoliidine tar-
`trate and 0.5% timolol administered twice
`
`a day.
`
`(JTX-2.)
`
`37. The 'd63 patent issued on January
`29, 2008. and is
`titled “Combination of
`Brimonidine and Timoiol for Topical Oph-
`thaimic Use.” The application for the ’463
`patent was filed on February 3, 2003, and
`is a division of the application for the 'l49
`patent.
`(JTX 3 at p. 1.) The '463 patent
`has six claims to compositions containing
`0.2% brimonidine tartrate and 0.5% timolol
`
`and articles of manufacture containing
`these compositions along with packaging
`material
`indicating use twice a day for
`glaucoma treatment.
`(J‘1‘X—3.}
`
`38. The '258 patent issued on January
`5, 2010, and is titled “Combination of Bri-
`monidine and Timolol for Topical Ophthal-
`mic Use.” The application for
`the ’258
`Patent was filed on August 24, 2007, and is
`a continuation-in-part of the application for
`the '976 patent.
`(JTX 4 at p. 1.) The '258
`patent also has nine claims to certain com-
`positions containing 0.2% hrimonidine tar-
`trate and 0.5% timolol and articles of man-
`
`ufacture that include_those compositions.
`{JTX—4.)
`
`39. The claims of the patents-in—suit all
`have an effective filing date of April 19,
`2002.
`
`'9'i'6, and ’463 patents
`40. The ’149,
`provide two examples, one relating to the
`formulation of the combination product
`and the second to a clinical study using the
`combination product.
`
`41. Example I of the patents—in—suit de-
`scribes what is stated to be a representa-
`tive pharmaceutical composition of the in-
`
`vention. As set out in the corresponding
`Table, the composition includes mono and
`dibasic sodium phosphate as buffers, sodi-
`um hydroxide and hydrochloric acid to ad-
`just pH,
`if necessary, and BAK as the
`preservative.
`
`‘.976, and '463 patents
`42. The '14.‘),
`share a common specification, and the ‘Z58
`patent is a continuation-in-part of the ‘I49
`patent. The specification of the '258 pat-
`ent is the same as the specifications of the
`’149,
`'976, and “-463 patents, but adds two
`additionai Examples.
`(See Trial Tr. Day
`2(PM) at 45:24.-—4ti:3; 46:12-14 {Laskar).)
`The new Example II 5 in the '258 patent is
`the Same as the composition described in
`Example I, but specifies that "0.5% timolol
`free base is used instead of timoiol ma-
`
`Ieate” and states that “{t]he composition is
`effective as described in Example I, but is
`more stable." Example III is also the
`same as the composition described in Ex-
`ample I, but specifies that “0.5% timolol
`free base is used instead of timolol maleate
`and 0.18% brimonidine free base is used
`instead of brimonidine tartrate” and states
`
`that “{t]he composition is effective as de-
`scribed in Example I, but is more stable.” 6
`Allergan has asserted ail claims of ail four
`patents—in—suit against
`the Defendants.
`(See infra. at fn 3.)
`
`43. The patents-in-suit discuss the pri-
`or art concomitant (serial) administration
`of brimonidine and timolol.
`(See, e.g., JTX
`1 at col. 1:7—12;
`see also Trial Tr. Day
`2{AM) at 1437-25 {Tanna}.)
`Specifically,
`the patents—in—suit discuss the prior art
`serial administration of Alphagan® (bri-
`monidine 0.2%) TID and Timoptic® (0.5%
`tiinoloi maleate) BID. (See, e.g., JTX 1 at
`
`5. The Examples in the ‘Z38 patent arc mis-
`riurnbered. The specification adds an "i3xa1n-
`ple II" \vl1it:h is in addition to the two exam-
`ples which appear in the 'l49 patent. The
`Example 11 appears twice in the specification
`of the “Z58 patcnt at columns 9 and 10.
`
`6. Due to the simiiarilies in the specifications
`of the pa1ents—in—sui1,
`the Court's Findings
`may reference only the ‘I49 specification.
`However. the same disclosure is provided by
`each of the specifications of the patents-—in—
`suit.
`
`PAGE 10 OF 59
`
`PAGE 10 OF 59
`
`

`
`984
`
`818 FEDERAL. SUPPLEMENT, 2d SERIES
`
`see also Trial Tr. Day
`11. 58-64;
`col. 2,
`1{AM) at 142:9—l3 (Beck).) Ms. Amy Ba-