IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`MYLAN PHARMACEUTICALS, INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner.
`
`U.S. Patent No. 8,784,789 to Higashiyama
`Issue Date: July 22, 2014
`Title: Aqueous Liquid Preparations and Light-Stabilized Aqueous Liquid
`Preparations
`
`_____________________
`
`Inter Partes Review No.: IPR2016-00626
`
`Petition for Inter Partes Review of U.S. Patent No. 8,784,789
`Under 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`
`I.
`II.
`
`TABLE OF CONTENTS
`INTRODUCTION ....................................................................................... 1
`OVERVIEW................................................................................................ 1
`A.
`The ’789 Patent.................................................................................. 1
`STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS ........................................................................................... 3
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)).................................... 3
`A.
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)).......................... 3
`B.
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2))............................ 3
`1.
`Judicial Matters Involving the ’789 patent ............................... 3
`2.
`Administrative Matters ............................................................ 4
`Designation of Lead and Back-Up Counsel (37 C.F.R. §
`42.8(b)(3)) ......................................................................................... 4
`Notice of Service Information (37 C.F.R. § 42.8(b)(4)) ..................... 5
`D.
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a)).......................................... 5
`THE ’789 PATENT AND CLAIM CONSTRUCTION ............................... 5
`VI.
`VII. PERSON OF ORDINARY SKILL IN THE ART (“POSA”)....................... 6
`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ................. 7
`IX.
`Invalidity analysis........................................................................................ 7
`A.
`The Scope and Content of the Prior Art ............................................. 7
`1.
`Bepotastine Besilate was Known as Having Good
`Properties and Considered Suitable for Ophthalmic
`Preparations............................................................................. 7
`a)
`Tanabe Press Release (“Tanabe”) (EX1008).................. 8
`Adding Excipients, Including a Tonicity Agent, in
`Aqueous Liquid Preparations was Common ............................ 9
`a)
`U.S. Patent No. 6,174,914 (“Yanni”) (EX1004)........... 10
`b)
`Remington: The Science and Practice of Pharmacy
`20th Ed. (“Hecht”) (EX1005)....................................... 11
`Sodium Chloride was Known to Have Light-Stabilizing
`Properties and Testing for Light-Stability was Routine.......... 13
`
`C.
`
`2.
`
`3.
`
`III.
`
`V.
`
`Petition for Inter Partes Review of USPN 8,784,789
`
`i
`
`

`
`B.
`
`C.
`
`Petition for Inter Partes Review of USPN 8,784,789
`
`b)
`
`c)
`
`Ground 1A: Claims 1-11 are Obvious over Tanabe in view of
`Yanni............................................................................................... 14
`1.
`Independent Claim 1.............................................................. 14
`a)
`Tanabe and Yanni together teach a bepotastine
`besilate ophthalmic formulation................................... 15
`Yanni teaches “a light-stabilizing effective
`amount” of water-soluble metal chloride ..................... 16
`A POSA would have been motivated to combine
`Tanabe and Yanni........................................................ 19
`Tanabe provides motivation to prepare an
`ophthalmic formulation and Yanni provides
`a conventional ophthalmic formulation.............. 19
`Using sodium chloride and adjusting the
`amount would have been obvious ...................... 20
`Yanni discloses commonly used additives,
`thus combining it with Tanabe according to
`known methods would have yielded
`predictable results .............................................. 22
`Independent Claim 9.............................................................. 24
`Independent Claim 10............................................................ 26
`Dependent Claims 2 and 8 ..................................................... 28
`Dependent Claims 3 and 4 ..................................................... 29
`Dependent Claim 5 ................................................................ 30
`Dependent Claims 6 and 7 ..................................................... 30
`a)
`Yanni teaches “an eye drop”........................................ 30
`b)
`Using Yanni’s formulation for “a nasal drop”
`would have been obvious............................................. 31
`Dependent Claim 11 .............................................................. 32
`8.
`Ground 2A: Claims 1-11 are Obvious over Tanabe in view of
`Hecht ............................................................................................... 32
`1.
`Independent Claim 1.............................................................. 32
`a)
`Tanabe and Hecht together teach a bepotastine
`besilate ophthalmic formulation................................... 33
`Hecht teaches “a light-stabilizing effective
`amount” of water-soluble metal chloride ..................... 35
`A POSA would have been motivated to combine
`Tanabe and Hecht ........................................................ 36
`Tanabe provides motivation to prepare an
`ophthalmic formulation and Hecht provides
`a conventional ophthalmic formulation.............. 36
`
`2.
`3.
`4.
`5.
`6.
`7.
`
`b)
`
`c)
`
`ii
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`2.
`3.
`4.
`5.
`6.
`7.
`
`Using sodium chloride and adjusting the
`amount would have been obvious. ..................... 37
`Hecht discloses commonly used additives,
`thus combining it with Tanabe according to
`known methods would have yielded
`predictable results .............................................. 38
`Independent Claim 9.............................................................. 39
`Independent Claim 10............................................................ 42
`Dependent Claims 2 and 8 ..................................................... 44
`Dependent Claims 3 and 4 ..................................................... 44
`Dependent Claim 5 ................................................................ 45
`Dependent Claims 6 and 7 ..................................................... 46
`a)
`Hecht teaches “an eye drop” ........................................ 46
`b)
`Using Hecht’s formulation for “a nasal drop”
`would have been obvious............................................. 46
`Dependent Claim 11 .............................................................. 47
`8.
`Objective Indicia of Non-Obviousness............................................. 48
`1.
`No Unexpected Results Over the Closest Prior Art................ 49
`a)
`The range disclosed by the prior art is within the
`claimed ranges and thus would have the same
`properties..................................................................... 50
`A POSA would have expected light-stabilizing
`effects. ......................................................................... 52
`The alleged unexpected results are not
`commensurate in scope with the claim......................... 52
`Other Objective Indicia.......................................................... 55
`2.
`CONCLUSION ......................................................................................... 56
`
`b)
`
`c)
`
`D.
`
`X.
`
`iii
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012).................................................................passim
`Allergan Inc. v. Sandoz, Inc.,
`726 F.3d 1286 (Fed. Cir. 2013)........................................................................50
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014)........................................................................56
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012)........................................................................22
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991)....................................................................17, 36
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006)..........................................................................23
`In re Kao,
`639 F.3d 1057..................................................................................................50
`In re Peterson,
`315 F.3d at 1331 ........................................................................................53, 55
`In re Schreiber,
`128 F. 3d 1473 (Fed. Cir. 1997).................................................................31, 46
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007)...............................................................................6, 20, 38
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988)....................................................................49, 55
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2008)........................................................................55
`Purdue Pharma Prods. L.P. v. Par Pharm., Inc.,
`377 Fed App’x 978 (Fed. Cir. 2010) ................................................................56
`
`iv
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`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012)..................................................................18, 36
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983)........................................................................56
`Tokai Corp. v. Eason Enters., Inc.,
`632 F.3d 1358 (Fed. Cir. 2011)........................................................................57
`Vandenberg v. Dairy Equip. Co.,
`740 F.2d 1560 (Fed. Cir. 1984)........................................................................56
`
`v
`
`

`
`Petitioner
`Exhibit #
`1001
`
`1002
`
`1003
`1004
`1005
`
`1006
`
`1007
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`1015
`
`Petition for Inter Partes Review of USPN 8,784,789
`
`Petitioner’s Exhibit List
`
`Description
`Higashiyama, U.S. Patent No. 8,784,789, “Aqueous Liquid
`Preparations and Light-Stabilized Aqueous Liquid Preparations”
`(“the ’789 patent”)
`Higashiyama, U.S. Patent No. 8,877,168 “Aqueous Liquid
`Preparations and Light-Stabilized Aqueous Liquid Preparations”
`(“the ’168 patent”)
`Declaration of Dr. Amiji
`U.S. Patent No. 6,174,914 (“Yanni”)
`Remington: The Science and Practice of Pharmacy 20th Ed.
`(“Hecht”)
`Lloyd V. Allen Jr. et al. “Compounding Ophthalmic Preparations,”
`International Journal of Pharmaceutical Compounding 2(3) (1998)
`(“Allen”)
`Chemical and Pharmaceutical Bulletin 50(2) (“Araki I”)
`Press Release “Tanabe Seiyaku Granted Rights for Bepotastine
`Besilate for Ophtalmic [sic] Use to Senju Seiyaku (Japan)”
`(“Tanabe”)
`PCT International Patent Publication No. WO 01/080858 (“Araki
`II”)
`topical vs oral administration, Clinical and
`Antihistamines:
`Experimental Allergy 26(3):11-17 (1996) (“Davies”)
`“Stability Testing: Photostability Testing of New Drug Substances
`and Products” (“ICH Guideline”)
`“Formulation
`of
`a Stable Parenteral Product; Clonidine
`Hydrochloride Injection,” PDA Journal of Pharmaceutical Science
`& Technology 56(6):320-325 (1998) (“Kostecka”)
`Photoreactivity of LY277359 Maleate, a 5- Hydroxytryptamine3
`(5-HT3) Receptor Antagonist,
`in Solution, Pharmaceutical
`Research 8(10):1215-1222 (1991) (“Mosher”)
`Reserved
`Press Release “Regarding Extended Indication for Selective
`Histamine H1 Receptor Antagonist/Anti-Allergic Agent Talion®
`Tablets 5 and Talion® Tablets 10 in Treating Pruritus/Itching
`Accompanying Urticaria and Other Skin Diseases” (“Talion Press
`Release”)
`
`vi
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`1016
`
`1017
`1018
`1019
`1020
`1021
`1022
`1023
`1024
`1025
`1026
`1027
`1028
`1029
`1030
`1031
`1032
`1033
`
`Remington’s Pharmaceutical Sciences, pp. 1410-1419 (1980)
`(“Remington”).
`European Patent Publication No. EP 0 949 260 (“Kita”)
`CV of Dr. Amiji
`Declaration of Higashiyama of Nov. 6, 2007
`Supplemental Amendment of Nov. 13, 2007
`Final Office Action of Feb. 8, 2008
`Declaration of Higashiyama of Dec. 22, 2008
`Amendment of Jan. 5, 2009
`Office Action of May 8, 2009
`Office Action of April 9, 2010
`Final Office Action of Dec. 20, 2010
`Declaration of Higashiyama of Sept., 11, 2012
`Supplemental Amendment of Sept. 14, 2012
`Office Action of Aug. 30, 2013
`Amendment of May 30, 2014
`Notice of Allowance of June 12, 2014
`Amendment of April 24, 2012
`Final Office Action of Apr. 30, 2014
`
`vii
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`I.
`
`INTRODUCTION
`
`Micro Labs Ltd. and Micro Labs USA, Inc. (collectively, “Petitioner”)
`
`petitions for Inter Partes Review (“IPR”), seeking cancellation of claims 1-11
`
`(“challenged claims”) of U.S. Patent No. 8,784,789 to Higashiyama (“the ’789
`
`patent”) (EX1001), which is owned by Senju Pharmaceutical Co., Ltd. (“Senju” or
`
`“Patent Owner”).
`
`II. OVERVIEW
`
`The ’789 Patent
`A.
`The ’789 patent was issued on July 22, 2014 from U.S. Appl. No. 10/500,354
`
`(“the ’354 application”), which was filed on June 30, 2004 as a national phase
`
`application of PCT International Application No. PCT/JP03/09713 (“the ’713
`
`application”), which was filed on July 30, 2003 and claims priority to Japanese
`
`Patent Application No. 2002-223804 (“JP 804 application”), which was filed on July
`
`31, 2002. The ’789 patent names Masayo Higashiyama as the sole inventor.
`
`The ’789 patent purportedly is directed to “[a]n aqueous liquid preparation
`
`containing (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric
`
`acid or a pharmacologically acceptable acid addition salt
`
`thereof, which is
`
`stabilized with a water-soluble metal chloride.” (EX1001, Abstract). The claimed
`
`active
`
`ingredient,
`
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-
`
`pyridyl)methoxy]piperidino]butyric acid, is commonly referred to as bepotastine.
`
`1
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`The ’789 patent also discloses the acid addition salt monobenzenesulfonate, which
`
`is commonly referred to as bepotastine besilate.
`
`The ’789 patent states the water-soluble metal chloride is preferably “alkali
`
`metal chlorides such as sodium chloride, potassium chloride and the like, and
`
`alkaline earth metal chlorides such as calcium chloride and the like,” and that
`
`sodium chloride is particularly preferred.
`
`(EX1001, 3:17-22). The ’789 patent
`
`states the desirable concentration of the water-soluble metal chloride as follows:
`
`[T]he content of the water-soluble metal chloride is generally shown by
`a lower limit of about 0.15 w/v % and an upper limit of about 1.5 w/v
`%, preferably a lower limit of about 0.2 w/v % and an upper limit of
`about 1.2 w/v %. Particularly, as sodium chloride, it is not less than
`about 0.15 w/v %, about 0.2 w/v %, about 0.3 w/v %, and not more than
`about 1.0 w/v %, about 0.8 w/v %, about 0.6 w/v %. As potassium
`chloride, it is not less than about 0.15 w/v %, about 0.2 w/v %, about
`0.3 w/v %, and not more than about 1.0 w/v %, about 0.9 w/v %, about
`0.8 w/v %. As calcium chloride and as dihydrate, it is not less than
`about 0.2 w/v %, about 0.3 w/v %, and not more than about 1.5 w/v %,
`about 1.2 w/v %.
`
`(EX1001, 3:24-35). The ’789 patent also states the amount of the water-soluble
`
`metal chloride takes into account the osmotic pressure of the resulting preparation.
`
`(EX1001, 3:37-43). The ’789 patent further discloses common additives for
`
`aqueous formulations, such as buffers, preservatives, and chelating agents.
`
`(EX1001, 3:44-58).
`
`2
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`III.
`
`STANDING (37 C.F.R. § 42.104(A)); PROCEDURAL STATEMENTS
`
`Petitioner certifies that: (1) the ’789 patent is available for IPR; and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’789
`
`patent on the grounds identified herein. This Petition is filed in accordance with 37
`
`CFR § 42.106(a). Filed herewith are a Power of Attorney and an Exhibit List
`
`pursuant to § 42.10(b) and § 42.63(e), respectively. The required fee is paid when
`
`filing the petition, and the Office is authorized to charge any fee deficiencies and
`
`credit overpayments, to Deposit Acct. No. 160605 (Customer ID No. 00826).
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(A)(1))
`
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
`A.
`The following real parties-in-interest are identified: Mylan Pharmaceuticals
`
`Inc., which is the Petitioner in this matter and which is a wholly owned subsidiaries
`
`of Mylan Inc.; Mylan Inc., which is an indirectly wholly owned subsidiary of Mylan
`
`N.V.; Mylan N.V.; Micro Labs Ltd.; and Micro Labs USA, Inc.
`
`B.
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`1.
`Judicial Matters Involving the ’789 patent
`The ’789 patent is currently the subject of the following litigations: Bausch
`
`& Lomb Incorporated et al. v Micro Labs USA, Inc. et al., No. 1:14-cv-07406
`
`(D.N.J.); and Bausch & Lomb Incorporated et al. v Apotex Inc. et al., 1:15-cv-03879
`
`(D.N.J.).
`
`3
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`Administrative Matters
`2.
`The Public Patent Application Retrieval (Public PAIR) website indicates at
`
`least three related U.S. patents or pending applications: U.S. Patent No. 8,877,168
`
`(“the ’168 patent”) (EX1002) issued on November 4, 2014 based on U.S. Patent
`
`Application No. 14/314,678, which is a continuation of the ’789 patent; U.S. Patent
`
`No. 8,883,825 (“the ’825 patent”) issued on November 11, 2014 based on U.S.
`
`Patent Application No. 13/599,212, which is a division of the ’789 patent; and U.S.
`
`Patent Application No 14/511,393 (“the ’393 application”) is currently pending and
`
`is a continuation of the ’825 patent.
`
`C.
`
`Designation of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))
`Lead Counsel
`Back-Up Counsel
`Jitendra Malik, Ph.D.
`Lance Soderstrom
`Reg. No. 55823
`Reg. No. 65405
`ALSTON & BIRD LLP
`ALSTON & BIRD LLP
`4721 Emperor Blvd., Suite 400
`90 Park Avenue, 15th Floor
`Durham, NC 27703-8580
`New York, New York 10016-1387
`Telephone: 919-862-2200
`Telephone: 212-210-9400
`Fax: 919-862-2260
`Fax: 212-210-9444
`jitty.malik@alston.com
`lance.soderstrom@alston.com
`
`H. James Abe
`Reg. No. 61182
`ALSTON & BIRD LLP
`333 South Hope Street, 16th Floor
`Los Angeles, CA 90071
`Telephone: 213-576-1000
`Fax: 213-576-1100
`james.abe@alston.com
`
`4
`
`

`
`Lead Counsel
`
`Petition for Inter Partes Review of USPN 8,784,789
`
`Back-Up Counsel
`Joseph M. Janusz
`Reg. No. 70396
`ALSTON & BIRD LLP
`101 S. Tryon Street, Suite 4000
`Charlotte, NC 28205
`Telephone: 704-444-1000
`Fax: 704-444-1111
`joe.janusz@alston.com
`
`Notice of Service Information (37 C.F.R. § 42.8(b)(4))
`D.
`Please direct all correspondence to lead counsel at
`the above address.
`
`Petitioner
`
`consents
`
`to
`
`email
`
`service
`
`at:
`
`jitty.malik@alston.com,
`
`lance.soderstrom@alston.com, james.abe@alston.com, and joe.janusz@alston.com.
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(A))
`
`Petitioner requests IPR and cancellation of claims 1-11 of the ’789 patent. A
`
`detailed statement of the reasons for the relief requested is set forth below.
`
`VI. THE ’789 PATENT AND CLAIM CONSTRUCTION
`
`The challenged claims must be given their broadest reasonable interpretation
`
`in light of the specification of the ’789 patent. See 37 C.F.R. § 42.100(b). For the
`
`purpose of this IPR, Petitioner submits that the term “optionally at least one material
`
`selected from the group consisting of a buffer, a preservative, a chelating agent, and
`
`a flavor” as recited in claim 1 is interpreted to mean the claimed aqueous liquid
`
`preparation may or may not contain one or more of the recited components. Further,
`
`for the purpose of this IPR, Petitioner submits that the term “optionally (f) disodium
`
`5
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`edetate” as recited in claim 9 is interpreted to mean the claimed aqueous eye drop
`
`may or may not contain disodium edetate.
`
`Claims 1 and 10 recite “a light-stabilizing effective amount” with respect to
`
`the water-soluble metal chloride. For the purpose of this IPR, Petitioner submits that
`
`the term is interpreted to mean an amount or concentration of the water-soluble metal
`
`chloride that falls within the range recited in the respective claims of the ’789 patent.
`
`VII. PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
`
`A POSA is a hypothetical person who is presumed to be aware of all pertinent
`
`art, thinks along conventional wisdom in the art, and is a person of ordinary
`
`creativity. KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 420 (2007). A POSA in the
`
`field of the ’789 patent would have a Ph.D. in pharmaceutical sciences or related
`
`discipline, and several years of experience (such as industrial experience) in
`
`formulating chemical compounds in liquid aqueous pharmaceutical preparations
`
`(including ophthalmic preparations) or equivalent academic experience. (EX1003 ¶
`
`46). A POSA would also have knowledge of the scientific literature concerning the
`
`same as of the priority date. A POSA may also work as part of a multi-disciplinary
`
`team and draw upon not only his or her own skills, but also take advantage of certain
`
`specialized skills of others in the team, to solve a given problem.
`
`6
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(B))
`
`IPR of claims 1-11 of the ’789 patent is respectfully requested on the grounds
`
`listed below. Per 37 C.F.R. § 42.6(d), copies of the references are filed herewith. In
`
`support of the proposed grounds for unpatentability, this Petition includes the
`
`declaration of a technical expert, Dr. Amiji (EX1003), explaining what the art would
`
`have conveyed to a POSA as of the priority date. Dr. Amiji is an expert in the
`
`relevant field. (EX1018).
`
`Ground
`
`Reference(s)
`
`1A
`2A
`
`Tanabe in view of Yanni
`Tanabe in view of Hecht
`
`Basis
`
`§ 103
`§ 103
`
`Claims
`Challenged
`1-11
`1-11
`
`The above-mentioned and other prior art
`
`references provide further
`
`background in the art, further motivation to combine the references, and/or further
`
`show a reasonable expectation of success in combining the teachings of the primary
`
`references to arrive at the claimed formulations.
`
`IX.
`
`INVALIDITY ANALYSIS
`
`A.
`
`The Scope and Content of the Prior Art
`1.
`Bepotastine Besilate was Known as Having Good Properties
`and was Considered Suitable for Ophthalmic Preparations
`Bepotastine and its acid salt bepotastine besilate were known prior to July
`
`2002 as an effective pharmaceutical agent. (EX1008, 1). Bepotastine besilate was
`
`known to have excellent antihistaminic activity and anti-allergic activity. (EX1008,
`
`7
`
`

`
`Petition for Inter Partes Review of USPN 8,784,789
`
`1; EX1017, [0001]). Bepotastine besilate was known to be an H1 receptor antagonist
`
`and thus able to suppress certain symptoms by blocking histamine access to H1
`
`receptor sites.
`
`(EX1015, 1). The particular class of compounds that included
`
`bepotastine was known to be effective against various conditions and symptoms,
`
`including allergic rhinitis (i.e., a nasal condition), sneezing and coughing due to
`
`respiratory inflammation from a cold.
`
`(EX1017, [0002]). These conditions were
`
`commonly treated through the use of aqueous liquid preparations. (EX1003 ¶ 49).
`
`Bepotastine besilate was also known to have good solubility in water and
`
`thus would have been expected to be effective in eye-drop form. (EX1008, 1). It
`
`was known that antihistamines administered topically as ophthalmic and nasal
`
`administration, as opposed to oral administration, enhanced the anti-allergic or
`
`anti-inflammatory activity possessed by these drugs, and improved safety.
`
`(EX1010, Abstract, 13, 15).
`
`Tanabe Press Release (“Tanabe”) (EX1008)
`a)
`Tanabe Seiyaku, the manufacturer of Talion®, a bepotastine tablet, issued a
`
`press release on July 17, 2001, “Tanabe Seiyaku Granted Rights for Bepotastine
`
`Besilate for Ophtalmic [sic] Use to Senju Seiyaku (Japan)” (“Tanabe”) (EX1008),
`
`announcing its decision to license the rights to manufacture and market bepotastine
`
`besilate for ophthalmic use to Senju Seiyaku. (EX1008, 1). Because Tanabe was
`
`published at least one year prior to the July 31, 2002 priority date of the ’789 patent,
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`Petition for Inter Partes Review of USPN 8,784,789
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`it constitutes prior art under 35 U.S.C. § 102(b). Tanabe was not cited or relied upon
`
`by the Examiner during the prosecution of the ’789 patent.
`
`Tanabe discusses the use of bepotastine besilate tablets for the treatment of
`
`allergic rhinitis and the expected effectiveness of bepotastine besilate in eye-drop
`
`form against symptoms of seasonal and perennial allergic conjunctivitis due to its
`
`strong histamine antagonistic action.
`
`(EX1008, 1). Thus, before July 31, 2002,
`
`Tanabe had already disclosed that bepotastine besilate is suitable in the form of an
`
`eye drop.
`
`2.
`
`Adding Excipients, Including a Tonicity Agent, in Aqueous
`Liquid Preparations was Common
`Using additives and excipients were common practice. (EX1004 at 3:6-15;
`
`EX1005 at 827-30; EX1006 at 184-87; EX1003 ¶¶ 58-62). For example, adding a
`
`tonicity agent, most commonly sodium chloride, to an ophthalmic formulation was
`
`common practice. (See, e.g., EX1021, 5 (“Metal chlorides are routinely employed
`
`as isotonic agents . . . . An artisan skilled in the art would reasonably envisage the
`
`use of these metal chloride ‘isotonic agents’ . . . .”); EX1003 ¶ 58; EX1005, 829).
`
`Typically the amount of sodium chloride would range from 0.6 w/v % to 1.8 w/v %
`
`because it is tolerable to the eye.
`
`(EX1006, 186; EX1003 ¶ 53). A standard
`
`ophthalmic formulation would generally have the active ingredient, a tonicity agent
`
`like sodium chloride, a preservative like benzalkonium chloride, and it was also
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`Petition for Inter Partes Review of USPN 8,784,789
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`common to include buffers, pH adjusters, and stabilizers as needed. (EX1006, 185-
`
`86, 188; EX1004, 2:63-3:14, 3:36-54; EX1005, 827; EX1003 ¶¶ 58-62).
`
`U.S. Patent No. 6,174,914 (“Yanni”) (EX1004)
`a)
`U.S. Patent No. 6,174,914 (“Yanni”) (EX1004) was issued on January 16,
`
`2001 from U.S. Serial No. 09/333,454 filed June 15, 1999, which claims priority to
`
`provisional application No. 60/092,762, which was filed on July 14, 1998. Yanni
`
`issued on January 16, 2001. As a result, Yanni constitutes prior art under 35 U.S.C.
`
`§102(b). Yanni was not cited or relied upon by the Examiner during the prosecution
`
`of the ’789 patent.
`
`Yanni
`
`teaches an aqueous ophthalmic solution formulation for topical
`
`delivery of an active ingredient to the eye and a method of making the same.
`
`(EX1004, 2:10-16, 2:50-61). The preferred ophthalmic solution (Example 1)
`
`includes the salt of an active ingredient, sodium chloride, water, a buffer, a
`
`preservative, and pH adjusters.
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`Petition for Inter Partes Review of USPN 8,784,789
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`(EX1004, 3:36-54). Example 1 of Yanni teaches that sodium chloride is present at
`
`a concentration of 0.65 w/v%. The pH adjusters are added to adjust the pH to
`
`between 4.5 and 8 as needed. (EX1004, 3:2-5 (“[T]he pH is adjusted with a pH
`
`controller to be within a range suitable for use as an ophthalmic medicine,
`
`preferably within the range of 4.5 to 8.”)).
`
`b)
`
`Remington: The Science and Practice of Pharmacy
`20th Ed. (“Hecht”) (EX1005)
`Remington: The Science and Practice of Pharmacy Chap. 43 pp. 821-835
`
`(Alfonso R. Gennaro et al. eds., 20th ed. 2000) (“Hecht”) (EX1005) was published
`
`in 2000. Hecht’s publication date predates the July 31, 2002 priority date of the ’789
`
`patent by over a year. As a result, Hecht constitutes prior art under 35 U.S.C. §
`
`102(b). Hecht was not cited or relied upon by the Examiner during the prosecution
`
`of the ’789 Patent. During prosecution the Examiner relied upon Remington’s
`
`Pharmaceutical Sciences, pp.1410-19 (1980) (“Remington”) (EX1016), which
`
`disclosed tonicity agents and metal chlorides, including calcium chloride and
`
`potassium chloride.
`
`(See, e.g., EX1021, 4; EX1023, 4). The cited portion of
`
`Remington did not recite the exemplary solution that forms the grounds of invalidity
`
`discussed below with respect to Hecht. Accordingly, the Examiner did not consider
`
`the relevant portion of Hecht as presented below.
`
`Hecht discloses several stock solutions for use in ophthalmic preparations to
`
`deliver an active ingredient:
`
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`Petition for Inter Partes Review of USPN 8,784,789
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`VEHICLES—Sterile isotonic solutions, properly preserved, are
`suitable for preparing ophthalmic solutions (see Chapter 18). In most
`cases, when the concentration of active ingredient is low, i.e., less than
`2.5 to 3.0%, the drug can be dissolved directly in the isotonic vehicle.
`The finished solutions will be hypertonic somewhat but well within the
`comfort tolerance of the eye.
`
`(EX1005, 827). One of the disclosed stock solutions is a phosphate buffer
`
`containing solution (“Hecht Phosphate Buffered Solution”) that contains 0.5 gram
`
`(0.5 w/v %) sodium chloride, phosphate buffers, a chelating agent, and a
`
`preservative:
`
`(EX1005, 827).1 Hecht discusses adjusting the pH for stability and for user comfort.
`
`(EX1005, 828).
`
`1 Hecht discloses the Hecht Phosphate Buffered Solution and the boric acid-
`
`containing solution in one block. (See EX1005, 188) However, a review of the
`
`content shows that they are two separate and distinct solutions. (See EX1003 ¶ 57).
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`Petition for Inter Partes Review of USPN 8,784,789
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`3.
`
`Sodium Chloride was Known to Have Light-Stabilizing
`Properties and Testing for Light-Stability was Routine
`Photostability was routinely tested and even recommended for new drugs and
`
`products. (EX1011, 1, §1.A; EX1012, 320). Sodium chloride was known to have
`
`light-stabilizing properties for compounds containing a chlorophenyl group like
`
`bepotastine besilate.
`
`For example, sitafloxacin, which contains a chlorophenyl group, was known
`
`to undergo photo-degradation in aqueous solutions but the inclusion of sodium
`
`chloride improved photo-stability. (EX1007, 229, 232-34; EX1009, 1-2).
`
`It was
`
`also reported that the concentration of sodium chloride affected the light-stabilizing
`
`effect, where light-stabilizing effect was observed at concentrations as low as 0.01
`
`%, but further enhanced at 0.05% or higher, and particularly high at 0.1 % or higher.
`
`(EX1009, 8). Indeed, during prosecution of the ‘789 patent, the Examiner, who is
`
`considered to be a person of ordinary skill, explained that “since Araki [II, EX1009]
`
`teaches that sodium chloride is known to improve light stability of other active
`
`agents (such as sitafloxacin) in aqueous preparations, the skilled artisan would
`
`reasonably expect the amount of sodium chloride in Lehmussaari to impart a light-
`
`stabilizing effect.” (EX1029, 6); In re Sang Su Lee, 277 F.3d 1338, 1345 (Fed. Cir.
`
`2002) (explaining that Examiners are considered persons of ordinary skill in the art).
`
`Another chlorophenyl group containing compound in the prior art, LY277359
`
`(zatosetron) maleate was also known to be susceptible to photo-degradation, where
`
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`Petition for Inter Partes Review of USPN 8,784,789
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`solutions with 0.017, 0.077, 0.154, and 0.308 M concentration in chloride ion were
`
`tested. (EX1013, 1216-19). These concentrations correspond to 0.10 w/v %, 0.045
`
`w/v %, 0.90 w/v %, and 1.80 w/v %.
`
`(EX1003 ¶ 66). Mosher observed a direct
`
`relationship between chloride concentrations and photo-stability, wherein “[a] linear
`
`relationship [was] seen between chloride concentration and 1/kobs” which expressed
`
`the reaction rate. (EX1013, 1217-18). Hence, Mosher would have suggested to a
`
`POSA that the inclusion of sodium chloride, to increase chloride concentrations,
`
`would have improved stability. (EX1013, 1221 (“The reaction is slowed with the
`
`addition of sodium chloride attributed to a common ion effect
`
`(enhanced
`
`retroreaction).”); EX1003 ¶ 66).
`
`B.
`
`Ground 1A: Claims 1-11 are Obvious over Tanabe in view of
`Yanni
`1.
`Independent Claim 1
`The limitations of claim 1 are disclosed in Tanabe or Yanni as shown below:
`
`Claim
`1. An aqueous liquid preparation
`consisting of, in an aqueous solution,
`
`an active ingredient consisting of (+)-
`(S)-4-[4-[(4-chlorophenyl)(2-
`pyridyl)methoxy]piperidino]butyric
`
`Prior Art
`Tanabe – Tanabe is directed to an
`ophthalmic aqueous preparation of
`bepotastine besilate. EX1008, 1.
`
`Yanni – Yanni Example 1 is an
`ophthalmic solution formulation.
`EX1004, 3:36-54. See also id. at 1:20-
`25, 2:10-16, 2:50-61.
`Tanabe – Tanabe discloses
`bepotastine besilate for ophthalmic