974
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`reserved the authority to make final claims
`detennination regarding pre-service and
`post service claims[.]" I d. at 2, 86-87 (em(cid:173)
`phasis added). Thus, Ingenix's discretion
`as Claims Administrator is limited to "ur(cid:173)
`gent care claims." See id. at 61. While
`the nature of Quintana's insurance claims
`are not expressly clear from the pleadings
`or motions, they appear to be "urgent care
`claims" over which Ingenix exercises dis(cid:173)
`cretion and responsibility to determine eli(cid:173)
`gibility and amount. I d. at 2. Consequent(cid:173)
`ly, for purposes of this case, Ingenix may
`very well be an ERISA fiduciary. See,
`e.g., Reich, 55 F.3d at 1049. Because the
`court has determined that Quintana's claim
`is outside the scope of § 502, however,
`such a finding is immaterial. See, e.g.,
`Memorial Hospital, 904 F.2d at 245.
`
`III. CONCLUSION
`
`For the above state reasons, the plain(cid:173)
`tiffs motion to remand the case to the
`state court from which it was previously
`removed is GRANTED. This case is RE(cid:173)
`MANDED to the 193rd Judicial District
`Court of Dallas County, Texas. The
`clerk shall mail a certified copy of this
`memorandum opinion and order to the dis(cid:173)
`trict clerk of Dallas County, Texas. 28
`U.S.C. § 1447(c).
`
`SO ORDERED.
`
`ALLERGAN, INC., Plaintiff,
`
`v.
`
`SANDOZ INC., Defendant.
`
`Allergan, Inc., Plaintiff,
`
`v.
`Alcon Laboratories, Inc., Alcon Re(cid:173)
`search, Ltd., Alcon, Inc. and Falcon
`Pharmaceuticals, Ltd., Defendants.
`
`Allergan, Inc., Plaintiff,
`
`v.
`Apotex Inc. and Apotex
`Corp., Defendants.
`
`Allergan, Inc., Plaintiff,
`
`v.
`
`Watson Laboratories, Inc., Defendant.
`
`Civil Action Nos. 2:09-cv-97, 2:09-
`cv-348 TJW, 2:10-cv-200 TJW,
`2:10-cv-344 TJW.
`
`United States District Court,
`E.D. Texas,
`Marshall Division.
`
`Aug. 22, 2011.
`Background: Patentee brought action
`against competitors, alleging infringement
`of patents for a drug used to treat glauco(cid:173)
`ma and ocular hypertension.
`Holdings: The District Court, T. John
`Ward, J., held that:
`(1) patents were not invalid as anticipated
`by prior art reference, and
`(2) patents were not invalid for obvious(cid:173)
`ness.
`Ordered accordingly.
`
`1. Patents <!:=312(4), 314(5)
`Patent infringement is a question of
`fact and must be proven by a preponder-
`
`Page 1 of 59
`
`SENJU EXHIBIT 2135
`LUPIN v. SENJU
`IPR2015-01099
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cite as 818 F.Supp.2d 974 (E. D. Tex. 2011)
`
`975
`
`the evidence.
`ance of
`§ 27l(e)(2).
`
`35 U.S.C.A.
`
`2. Patents <P72(1)
`A patent is invalid as anticipated if a
`single prior art reference discloses each
`35
`element of the claimed invention.
`U.S.C.A. § 102.
`
`3. Patents <P65
`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(cid:173)
`theless inherent in it. 35 U.S.C.A. § 102.
`
`4. Patents <P58
`If a claim limitation is not explicitly
`disclosed in an allegedly anticipating prior
`art reference, the party alleging patent
`invalidity bears the burden of showing that
`the limitation is inherently disclosed by the
`reference. 35 U.S.C.A. § 102.
`
`5. Patents <P65
`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 clea~· that it would be so
`recognized by persons of ordina~·y skill.
`35 U.S.C.A. § 102.
`
`6. Patents <P65
`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(cid:173)
`ject matter existed in the prior a~·t and
`that such existence was recognized by per(cid:173)
`sons of ordinary skill in the field of the
`invention. 35 U.S.C.A. § 102.
`
`7. Patents <P65
`Anticipation of a patent, rendering it
`invalid, requires enablement, whereby the
`prior art reference must teach one of ordi(cid:173)
`nary skill in the art to make or carry out
`the claimed invention without undue ex(cid:173)
`perimentation. 35 U.S.C.A. § 102.
`
`8. Patents <P62(2)
`Generally, testimony concerning pat(cid:173)
`ent anticipation must be testimony from
`one skilled in the art and must identify
`each claim element, state the witness' in(cid:173)
`terpretation of the claim element, and ex(cid:173)
`plain in detail how each claim element is
`disclosed in the prior art reference; testi(cid:173)
`mony is insufficient if it is merely conclu(cid:173)
`sory. 35 U.S.C.A. § 102.
`
`9. Patents <P62(1)
`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.C.A. § 102.
`
`10. Patents <P66(1.12)
`Patents for a drug used to treat glau(cid:173)
`coma and ocular hypertension were not
`invalid as anticipated by a prior art refer(cid:173)
`ence describing pha~·maceutically accept(cid:173)
`able compounds for controlling intraocular
`pressure in patients with glaucoma and
`ocula~· hypertension; prior art reference
`failed to describe a fixed combination of
`brimonidine and timolol or a method of
`treating glaucoma using such a combina(cid:173)
`tion. 35 U.S.C.A. § 102.
`
`11. Patents <P16(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 a~t; and (4)
`secondary considerations of non-obvious(cid:173)
`ness. 35 U.S.C.A. § 103.
`
`12. Patents <P16.5(1)
`When the patented invention is a com(cid:173)
`bination of known elements, in evaluating a
`claim of invalidity for obviousness, the
`comt must detennine whether there was
`an apparent reason to combine the known
`elements in the fashion claimed by the
`patent at issue by considering the teach-
`
`Page 2 of 59
`
`

`
`976
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`ings of multiple references, the effects of
`demands known to the design community
`or present in the marketplace, and the
`background knowledge possessed by a per(cid:173)
`son having ordinary skill in the art. 35
`U.S.C.A. § 103.
`13. Patents e:;o36.1(1), 36.2(1)
`Secondary considerations that provide
`evidence of the non-obviousness of a pat(cid:173)
`ent include copying, commercial success,
`failure of others, long-felt need, general
`skepticism of those in the art, and unex(cid:173)
`pected results. 35 U.S.C.A. § 103.
`14. Patents e:;o36.2(7)
`A presumption arises that the patent(cid:173)
`ed invention is commercially successful, as
`evidence that it is not invalid for obvious(cid:173)
`ness, when a patentee can demonstrate
`commercial success, usually shown by sig(cid:173)
`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 e:;o16.5(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(cid:173)
`ing of invalidity for obviousness.
`35
`U.S.C.A § 103.
`16. Patents e:;o16(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 e:;o16.25
`Patents for a drug used to treat glau(cid:173)
`coma and ocular hypertension were not
`rendered invalid for obviousness by a prior
`art reference describing pharmaceutically
`acceptable compounds for controlling in(cid:173)
`traocular pressure in patients with glauco(cid:173)
`ma and ocular hypertension; person of or(cid:173)
`dinary skill in art would not have had
`
`reason, after reading prior art reference,
`to develop claimed combination of brimoni(cid:173)
`dine and timolol given unpredictable na(cid:173)
`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 e:;o328(2)
`5,502,052. Cited as Prior Art.
`Patents e:;o328(2)
`7,030,149, 7,320,976, 7,323,463, 7,642,-
`258. Valid and Infringed.
`
`W. Chad Shear, Fish & Richardson, Dal(cid:173)
`las, TX, A Martina Tyreus Hufnal, Fish &
`Richardson, Wilmington, DE, Aine M.
`Skow, Deanna J. Reichel, Elizabeth M.
`Flanagan, Jonathan E. Singer, Susan M.
`Coletti, 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(cid:173)
`roll, Jr., Ireland Carroll & Kelley, Tyler,
`TX, for Plaintiffs.
`Barry P. Golob, Kerry B. McTigue, Wil(cid:173)
`liam Blake Coblentz, Duane Morris LLP,
`Washington, DC, Ian Scott, Duane Morris
`LLP, New York, NY, Joseph M. Bennett(cid:173)
`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
`T. JOHN WARD, District Judge.
`I. INTRODUCTION
`This is a consolidation of four patent
`infringement suits brought by Plaintiff AI-
`
`Page 3 of 59
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cite as 818 F.Supp.2d 974 (E.D.Tex. 2011)
`
`977
`
`lergan, Inc.'s ("Allergan") pursuant to the
`Hatch-Waxman Act. 1 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 Sandoz,
`Inc. ("Sandoz"); Alcon Laboratories, Inc.,
`Alcon Research, Ltd., Alcon, Inc., and Fal(cid:173)
`con Pharmaceuticals, Ltd. ("Alcon"); Apo(cid:173)
`tex, Inc. and Apotex Corp. ("Apotex"); and
`Watson Laboratories, Inc. ("Watson") (col(cid:173)
`lectively "Defendants") are each seeking
`approval from the Food and Drug Admin(cid:173)
`istration ("FDA") to market generic copies
`of Allergan's Combigan® product, used for
`the treatment of glaucoma and ocular hy(cid:173)
`pertension.2
`In this consolidated action,
`Allergan alleges that Defendants' proposed
`generic pharmaceutical products infringe
`the asserted claims of United States Pat(cid:173)
`ent 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 patent") (collectively, the "patents-in(cid:173)
`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 '149 Patent, claim 1
`of the '976 patent, claims 1-6 of the '463
`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(cid:173)
`tion with its principal place of business at
`2525 Dupont Drive,
`Irvine, California
`92612.
`
`2. Sandoz Inc. is a Colorado corpora(cid:173)
`tion with its principal place of business at
`506 Carnegie Center, Suite 400, Princeton,
`New Jersey 08540.
`
`3. Alcon Laboratories, Inc. is a Dela(cid:173)
`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 Novartis AG.
`
`6. Falcon Pharmaceuticals, Ltd. is a
`Texas corporation, with a place of business
`in Texas.
`
`7. Apotex, Inc. is a Canadian corpora(cid:173)
`tion with a place of business at 150 Signet
`Drive, Toronto, Ontario, Canada M9L 1T9.
`8. Apotex Corp. is a Delaware corpora(cid:173)
`tion with its principal place of business at
`2400 North Commerce Parkway, Suite 400,
`Weston, Florida, 33326.
`
`9. Watson Laboratories, Inc. is a Neva(cid:173)
`da corporation with a place of business at
`400 Interpace Parkway, Parsippany, NJ
`07054.
`
`1. A fifth action, Allergan, Inc. v. Hi-Tech
`Pharmacal Co., Inc., C.A. No. 2:09-cv-182
`(TJW) was also consolidated with these four
`actions. However, Allergan and Hi-Tech re(cid:173)
`solved the dispute and filed a stipulation of
`dismissal (D.!. 168), which was ordered by
`this court on May 31, 2011. (D.I. 175.)
`
`2. Specifically, these consolidated suits relate
`to the filing of Abbreviated New Drug Appli(cid:173)
`cation ("ANDA") No. 91-087 by Sandoz,
`ANDA No. 91-574 by Alcon, ANDA No. 91-
`442 by Apotex, and ANDA No. 201949 by
`Watson with the FDA, pursuant to the Federal
`Food, Drug, and Cosmetic Act.
`
`Page 4 of 59
`
`

`
`978
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`B. Glaucoma and Ocular Hyperten(cid:173)
`sion
`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 l(AM) at 51:24-52:2;
`52:21-53:7 (Whitcup).) 3 About 2 million
`people in the United States are diagnosed
`\vith glaucoma every year. (Id. at 52:7-10
`(Whitcup).)
`11. While incurable, glaucoma can be
`managed by pharmaceutical and surgical
`treatment options that slow the progres(cid:173)
`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 ("lOP")
`in the eye.
`(Jd. at 72:20-73:7 (Noecker).)
`Scientists and medical professionals be(cid:173)
`lieve that the elevated lOP found in glau(cid:173)
`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).) Intrao(cid:173)
`cular pressure is measured in millimeters
`of mercury ("mm Hg").
`(D.I. 242, Trial
`Tr. Day 3(AM) at 66:3-8 (Noecker).) For
`each millimeter of mercury IOP is low(cid:173)
`ered, patients are 10% less likely to suffer
`visual field loss.
`(Id. at 67:14-18 (Noeck(cid:173)
`er).)
`12. Patients suffering from ocular hy(cid:173)
`pertension ("OHT") also have elevated
`lOP and, although not diagnosed with
`glaucoma, must be observed closely for its
`(D.I. 242, Trial Tr. Day 3(AM) at
`onset.
`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 "JTX"
`refer to Defendants' exhibit, Plaintiffs exhibit,
`and Joint Exhibit respectively, and will be
`followed by the exhibit number.
`"Trial Tr.
`Day" refers to the trial transcript and will be
`
`to attempt to reduce lOP. (Jd. at 71:4-9
`(Noecker).)
`
`C. Treatment of Glaucoma and Ocu(cid:173)
`lar Hypertension with Brimoni(cid:173)
`dine and Timolol
`13. One treatment method for patients
`with glaucoma or ocular hypertension is
`the use of eye drops. This form of treat(cid:173)
`ment is the most convenient and accept(cid:173)
`able to patients.
`(D.I. 242, Trial Tr. Day
`3(AM) at 71:4-9; 81:20-84:25 (Noecker).)
`14. There are at least 20 different glau(cid:173)
`coma drugs on the market today that can
`(D.I. 238,
`be used in such treatments.
`Trial Tr. Day 1(AM) at 54:22-55:5 (White(cid:173)
`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(AM) at 50:10-18; (Tanna); D.I. 242,
`Trial Tr. Day 3(AM) at 72:6-78:8 (Noeck(cid:173)
`er).) Most relevant here are two classes
`of medication, alpha2 adrenergic agonists
`and so-called "beta blockers."
`15. Brimonidine
`tartrate 0.2% was
`marketed by Allergan as Alphagan®, and
`was first developed by Allergan as a new
`glaucoma medication in the late 1980s and
`early 1990s.
`(D.I. 239, Trial Tr. Day
`1(PM) at 75:8-10 (Batoosingh).) Brimoni(cid:173)
`dine is an alpha2 adrenergic agonist that
`lowers lOP in glaucoma patients by reduc(cid:173)
`ing fluid production in the eye while also
`increasing outflow of that fluid from the
`eye.
`(D.I. 238, Trial Tr. Day l(AM) at
`59:22-60:7 (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 75:8-10
`(Batoosingh).)
`
`followed by the day, page number, and line
`numbers. For example, "Trial Tr. Day l(AM)
`at 53:15-21" refers to the morning trial tran(cid:173)
`script, day 1, page 53, lines 15-21.
`
`Page 5 of 59
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cite as 818 F.Supp.2d 974 (E.D.Tex. 2011)
`
`979
`
`16. Unlike many glaucoma medications,
`which are dosed 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(cid:173)
`proved Alphagan® for dosing three times
`a day (i.e., "TID") due to a lowered effica(cid:173)
`cy of the drug with less frequent dosing.
`(PTX-75 at AGN_COMBI0478532; D.I.
`238, Trial Tr. Day l(AM) at 60:11-24
`(Whitcup); D.I. 239, Trial Tr. Day 1(PM)
`at 75:11-89-19
`(Batoosingh).) As ex(cid:173)
`plained further below, BID dosing with
`Alphagan® 0.2% results in an approxi(cid:173)
`mately 3.25 to 3.5 mm Hg higher lOP in
`the afternoon than TID. (D.I. 239, Trial
`Tr. Day 1(PM) at 79:24-80:4 (Batoosingh);
`DTX-137 at DEFS(B/T) 000346; PTX-134
`at AGN_COMBI0676465; D.I. 241, Trial
`Tr. Day 2(PM) at 4:24-5:19.) This differ(cid:173)
`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 refeiTed to at trial as the "after(cid:173)
`noon trough."
`(D.I. 239, Trial Tr. Day
`1(PM) at 77:13-17; 78:3-7 (Batoosingh).)
`17. Although this third recommended
`dose, along with a substantial incidence of
`allergy, was a significant drawback of bri(cid:173)
`monidine, it still achieved commercial suc(cid:173)
`cess as a therapy for glaucoma patients.
`(D.I. 239, Trial Tr. Day 1(PM) at 90:16-
`91:10 (Batoosingh).) Allergan attempted
`to secure FDA approval for Alphagan® as
`a BID drug but was unable to do so. (I d.
`at 75:14-20 (Batoosingh).)
`18. Upon Alphagan®'s introduction to
`the market, it was apparent that brimoni(cid:173)
`dine 0.2% had significant and problematic
`(D.I.
`side-effects that limited its utility.
`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(cid:173)
`gy, which led patients to discontinue using
`the drug. (!d.) 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) at 74:11-16 (Noecker).) Additional(cid:173)
`ly, brimonidine was also known to cause
`systemic side effects, including somnolence
`(D.I. 239, Trial Tr. Day
`and dry mouth.
`1(PM) at 90:6-91:10 (Batoosingh).) The
`high incidence of these various side effects
`in patients treated \Vith brimonidine mo(cid:173)
`notherapy is reported throughout the lit-
`erature.
`PTX-180
`at
`(See,
`e.g.,
`AGN_COMBI0677278;
`PTX-77
`at
`AGN_COMBI0481545.)
`19. These side effects of Alphagan®
`were so significant that, as soon as Alpha(cid:173)
`gan® was approved, Allergan began look(cid:173)
`ing for a way to ameliorate them. After
`Alphagan®'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 Alphagan®
`P 0.15% and 0.1 %.
`20. As with Alphagan®, Allergan at(cid:173)
`tempted to secure FDA approval for BID
`dosing for Alphagan® P. (D.I. 239, Trial
`Tr. Day 1(PM) at 92:15-20 (Batoosingh).)
`This effort was unsuccessful, and both Al(cid:173)
`phagan® P 0.15%, and Alphagan® P 0.1 %,
`were approved only for TID dosing.
`(PTX-75; D.I. 239, Trial Tr. Day 1(PM) at
`91:24-92:14 (Batoosingh).) Allergan re(cid:173)
`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(cid:173)
`Cause).) Alphagan® P 0.15% was ap(cid:173)
`proved on March 16, 2001, over a year
`before the filing date of the patents-in-suit.
`(D.I. 243, Trial Tr. Day 3(PM) at 79:17-25
`(Noecker).) Clinical studies on Alpha(cid:173)
`gan® P 0.15% showed that it was signifi-
`
`Page 6 of 59
`
`

`
`980
`
`818 FEDERAL SUPPLEMENT, 2d SERIES
`
`cantly less likely to cause allergic reactions
`and certain systemic side-effects than was
`original Alphagan®.
`(D.I. 242, Trial Tr.
`Day 3(AM) at 138:1-13 (Noecker).)
`21. Timolol, a beta-blocker, was devel(cid:173)
`oped by Merck in the 1970s. The FDA
`first approved it as a treatment for glauco(cid:173)
`ma in 1978.
`(D.L 241, Trial 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
`95:14-15 (Tanna).) Timolollowers lOP by
`suppressing aqueous humor production.
`(D.L 242, Trial Tr. Day 3(AM) at 81:11-19
`(Noecker).)
`22. Although timolol is an established
`and commonly used drug, it is known to
`have serious and potentially life-threaten(cid:173)
`ing side effects, including pulmonary and
`cardiovascular side-effects. (D.L 243, Tri(cid:173)
`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 timolol "can produce sig(cid:173)
`nificant side effects such as bradycardia,
`arrhythmias, bronchoconstriction, or bron(cid:173)
`chospasm as a result of interaction with
`the beta1 and beta2 receptors in the heart,
`lungs, and blood vessels. The use of non(cid:173)
`selective beta-blocker therapy is contrain(cid:173)
`dicated in patients with actual or suspected
`cardiovascular or pulmonary dysfunction
`as beta-blockers can produce further ar(cid:173)
`rhythmias or bronchospasm."); DTX 123
`at 1:64-67; DTX 157 at 45-46; D.L 243,
`Trial Tr. Day 3(PM) at 125:25-127:11 (Las(cid:173)
`kar).)
`23. Because of these side effects, treat(cid:173)
`ment with timolol is contraindicated in a
`number of patients.
`(D.L 242, Trial Tr.
`Day 3(AM) at 74:17-75:20 (Noecker).)
`For example, the label of the Alphagan®
`
`products contains the following warning
`about using brimonidine with a beta-block(cid:173)
`er like timolol:
`However, since alpha-agonists, as a
`class, may reduce pulse and blood pres(cid:173)
`sure, caution in using concomitant drugs
`such as beta-blockers (ophthalmic and
`systemic), antihypertensives and/or car(cid:173)
`diac glycosides is advised.
`(DTX-129 at DEFS(B/T) 000233.)
`
`D. Glaucoma Treatment with Multi(cid:173)
`ple Medications: Fixed and Un(cid:173)
`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.L 238,
`Trial Tr. Day 1(AM) at 54:22-55:17 (White(cid:173)
`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(cid:173)
`eral minutes apart to prevent one of the
`drops from washing the other out.
`(D.L
`238, Trial Tr. Day l(AM) 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
`"unfJXed" because the amount the patient
`gets of each drug at any particular time is
`dependent on the treatment regimen pre(cid:173)
`scribed by the doctor and on whether the
`patient properly administers the drugs.
`(D.L 239, Trial Tr. Day 1(PM) at 64:10-
`66:3 (Batoosingh).) By contrast, a "fixed
`combination" 4 combines
`two glaucoma
`drugs in the same bottle. (D.L 240, 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
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cite as 818 F.Supp.2d 974 (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
`(D.I. 239, Trial Tr. Day 1(PM) at
`eye.
`64:10-24 (Batoosingh).)
`26. There are advantages to using un(cid:173)
`fixed combinations over fixed combina(cid:173)
`tions. For example, if a patient needs a
`smaller dose of one medication, a physician
`can prescribe a smaller close of that medi(cid:173)
`cation without modifying the dose of the
`other. Unfixed combinations thus give
`physicians wide flexibility in treatment op(cid:173)
`tions.
`(D.I. 239, Trial Tr. Day 1(PM) at
`64:10-20 (Batoosingh); D.I. 240, Trial Tr.
`Day 2(AM) at 132:14-133:3 (Tanna); D.I.
`242, Trial Tr. Day 3(AM) at 79:7-18
`(Noecker).)
`27. Serial or concomitant administra(cid:173)
`tion of two drugs is different than adminis(cid:173)
`tering them in a fJXed combination.
`(D.I.
`238, Trial Tr. Day l(AM) at 56:14-57:19
`(Whitcup).) When two ophthalmic prod(cid:173)
`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(cid:173)
`drops (about 35-40 microliters) are ab(cid:173)
`sorbed or drain away quickly through the
`eye's drainage ducts.
`(Id.; D.I. 242, Trial
`Tr. Day 3(AM) at 64:24-65:3 (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(cid:173)
`ministration of drugs in an adjunctive regi(cid:173)
`men at least five minutes apart, the second
`administered drug given as part of an ad(cid:173)
`junctive regimen would not interact with
`the first administered drug.
`(D.I. 238,
`Trial Tr. Day 1(AM) at 57:13-16 (White(cid:173)
`up).)
`
`28. Because serial therapy with an un(cid:173)
`fixed combination can necessitate applica(cid:173)
`tion of five or more separate doses
`throughout the clay, compliance can be dif(cid:173)
`ficult.
`(D.I. 239, Trial Tr. Day 1(PM) at
`64:25-66:6 (Batoosingh).) Most patients,
`particularly the elderly (who are most sus(cid:173)
`ceptible to developing glaucoma), fail to
`comply with such demanding dosing regi(cid:173)
`(D.I. 240, Trial Tr. Day 2(AM) at
`mens.
`15:2-16:3 (Tanna).) 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 fL'<ed combinations, historically,
`they have been difficult to develop. As of
`2001, there was only one marketed, FDA(cid:173)
`approved
`fJXed combination, Cosopt®.
`(D.I. 238, Trial Tr. Day l(AM) at 68:6-12
`(Whitcup).) Alcon's Betoptic® Pilo fixed
`combination product was approved in 1997
`but was never marketed.
`(PTX-129 at
`AGN_COMBI06762992; D.I. 238, Trial Tr.
`Day l(AM) at 68:13-25 (Whitcup).) As Dr.
`Whitcup described, development of a fJXed
`combination is the "most difficult" task in
`ophthalmological drug development. (D.I.
`238, Trial Tr. Day 1(AM) at 65:19-23
`(Whitcup).)
`30. The FDA has repeatedly expressed
`skepticism about fJXed combination prod(cid:173)
`ucts and has set a high bar for approval.
`In the early 2000s, the FDA referred to
`the clinical results it had seen with fJXed
`combination products as "very disappoint(cid:173)
`ing," and the applications for several dif(cid:173)
`ferent combination ophthalmic products at
`that time remained pending and unap(cid:173)
`proved.
`(PTX-129
`at AGNCOM(cid:173)
`BI0672993 (quoting the FDA's Dr. Wiley
`Chambers as saying that the results for
`combination products "ha[ve] been very
`disappointing to a number of people in(cid:173)
`cluding myself'); PTX-53 at AGN_COM-
`
`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 Tr. Day 1(AM) at 89:18-
`91:11 (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(cid:173)
`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 (Whitcup).)
`
`E. The Patents-in-8uit
`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(cid:173)
`ent"). The effective f:tling 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(cid:173)
`ents-in-suit are Chin-Ming Chang, Gary J.
`Beck, Cynthia C. Pratt, and Amy L. Ba(cid:173)
`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% brimonidine and 0.5% timolol, a
`method of treating glaucoma or ocular hy(cid:173)
`pertension by administering the aforemen(cid:173)
`tioned composition twice daily, or an arti(cid:173)
`cle of manufacture comprising packaging
`material indicating that twice daily admin(cid:173)
`istration of the composition is useful for
`treating glaucoma or ocular hypertension.
`(See JTX 1-4.) Like the brimonidine tar(cid:173)
`trate and timolol maleate single agent
`products (Alphagan® and Timoptic®), the
`combination product of the patents-in-suit
`(See e.g.,
`is applied topically to the eye.
`JTX 1 at Abstract.)
`34. The patents-in-suit also describe
`suitable preservatives for the combination
`
`(See id. at col. 2, II. 29 et seq.)
`product.
`The patents-in-suit list BAK as the first
`such preservative. The patents-in-suit ac(cid:173)
`knowledge that "typically such preserva(cid:173)
`tives are employed at a level of from
`0.004% to 0.02%". (!d.) The patents-in-suit
`further state that the preservative, prefer(cid:173)
`ably BAK, "may be employed at a level of
`from 0.001% to less than 0.01 %, e.g. from
`0.001% to 0.008%, preferably about 0.005%
`by weight." (/d.)
`35. The '149 patent issued on April
`18, 2006, and is titled "Combination of
`Brimonidine and Timolol for Topical Oph(cid:173)
`thalmic Use." The application for the '149
`patent was filed on April 19, 2002.
`(JTX
`'149 patent has four
`1 at p. 1.) The
`claims to methods of treating glaucoma
`or ocular hypertension with a 0.2% bri(cid:173)
`monidine tartrate/0.5% timolol formulation
`administered twice a day. Claims 1-3, as
`construed by the Court, require that com(cid:173)
`bination treatment to be as effective as
`serial administration with 0.2% brimoni(cid:173)
`dine 3 times a day and 0.5% timolol twice
`a day. The Court granted summary
`judgment of non-infringement to Defen(cid:173)
`dants of claims 1 through 3 before trial.
`Claim 4 of the '149 patent covers the im(cid:173)
`provement in the prior three times a day
`brimonidine therapy "without loss of effi(cid:173)
`cacy'' whereby the brimonidine is com(cid:173)
`bined with timolol in twice daily dosing.
`(JTX-1.) As construed by the Court in its
`Ma1·kman order, "without loss of effica(cid:173)
`cy" means "without decrease in lowering
`(D.I. 151 at
`intraocular pressure (lOP)."
`20-21.)
`36. The '976 patent issued on January
`22, 2008, and is titled "Combination of
`Bri.monidine and Timolol for Topical Oph(cid:173)
`thalmic Use." The application for the '976
`patent was filed on October 14, 2003, and
`is a continuation of the application for the
`'149 patent.
`(JTX 2 at p. 1.) The '976
`patent has one claim to a method of treat-
`
`Page 9 of 59
`
`

`
`ALLERGAN, INC. v. SANDOZ INC.
`Cite as 818 F.Supp.2d 974 (E.D.Tex. 2011)
`
`983