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. 8,877,168 to Higashiyama
`Issue Date: November 4, 2014
`Title: Aqueous Liquid Preparations and Light-Stabilized Aqueous Liquid
`Preparations
`
`_____________________
`
`Inter Partes Review No.: IPR2016-01163
`
`Petition for Inter Partes Review of U.S. Patent No. 8,877,168
`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
`
`

`
`III.
`
`C.
`
`V.
`
`I.
`II.
`
`TABLE OF CONTENTS
`INTRODUCTION ...........................................................................................1
`OVERVIEW....................................................................................................1
`A.
`The ’168 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))..............................4
`1.
`Judicial Matters Involving the ’168 patent .................................4
`2.
`Administrative Matters ...............................................................4
`Designation of Lead and Back-Up Counsel and Service (37
`C.F.R. §§ 42.8(b)(3), 42.8(b)(4)) ..........................................................4
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a)) ............................................5
`THE ’168 PATENT AND CLAIM CONSTRUCTION .................................5
`VI.
`VII. PERSON OF ORDINARY SKILL IN THE ART (“POSA”).........................5
`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))...................6
`IX.
`Invalidity analysis............................................................................................7
`A.
`The Scope and Content of the Prior Art................................................7
`1.
`Bepotastine Besilate was Known as Having Good
`Properties and was 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 ..............................8
`a)
`U.S. Patent No. 6,174,914 (“Yanni”) (EX1004)..............9
`b)
`Remington: The Science and Practice of Pharmacy
`20th Ed. (“Hecht”) (EX1005).........................................10
`Sodium Chloride was Known to Have Light-Stabilizing
`Properties and Testing for Light-Stability was Routine ...........12
`
`Petition for Inter Partes Review of USPN 8,877,168
`
`2.
`
`3.
`
`i
`
`

`
`B.
`
`C.
`
`Petition for Inter Partes Review of USPN 8,877,168
`
`b)
`
`c)
`
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`
`Ground 1: Claims 1-14 and 16-30 are Obvious over Tanabe in
`view of Yanni ......................................................................................12
`1.
`Independent Claim 1 .................................................................12
`a)
`Tanabe and Yanni together teach a bepotastine
`besilate ophthalmic formulation.....................................14
`Yanni teaches “a light-stabilizing effective
`amount” of water-soluble metal chloride .......................15
`A POSA would have been motivated to combine
`Tanabe and Yanni...........................................................17
`(1)
`Tanabe provides motivation to prepare an
`ophthalmic formulation, which Yanni
`provides ................................................................18
`(2) A POSA would have conducted routine
`testing to determine the appropriate dose.............18
`(3) Using sodium chloride and adjusting the
`amount would have been obvious........................19
`(4) Yanni discloses commonly used additives,
`thus combining it with Tanabe according to
`known methods would have yielded
`predictable results.................................................21
`Independent Claim 16...............................................................22
`Independent Claim 23...............................................................25
`Dependent Claims 2 and 14 ......................................................27
`Dependent Claims 3, 17, and 24...............................................28
`Dependent Claim 4....................................................................28
`Dependent Claims 5-7, 18, 19, 25 ............................................29
`Dependent Claims 8-10, 20-22, 26-28......................................30
`Dependent Claims 11 and 12 ....................................................31
`a)
`Yanni teaches “an eye drop” ..........................................31
`b)
`Using Yanni’s formulation for “a nasal drop”
`would have been obvious ...............................................32
`10. Dependent Claim 13 .................................................................32
`11. Dependent Claims 29 and 30 ....................................................33
`Ground 2: Claims 1-14 and 16-30 are Obvious over Tanabe in
`view of Hecht ......................................................................................34
`1.
`Independent Claim 1 .................................................................34
`a)
`Tanabe and Hecht together teach a bepotastine
`besilate ophthalmic formulation.....................................36
`Hecht teaches “a light-stabilizing effective
`amount” of water-soluble metal chloride .......................37
`
`b)
`
`ii
`
`

`
`c)
`
`b)
`
`c)
`
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`
`A POSA would have been motivated to combine
`Tanabe and Hecht ...........................................................38
`(1)
`Tanabe provides motivation to prepare an
`ophthalmic formulation and Hecht provides
`a conventional ophthalmic formulation ...............39
`(2) A POSA would have conducted routine
`testing to determine the appropriate dose.............40
`(3) Using sodium chloride and adjusting the
`amount would have been obvious........................41
`(4) Hecht discloses commonly used additives,
`thus combining it with Tanabe according to
`known methods would have yielded
`predictable results.................................................42
`Independent Claim 16...............................................................43
`Independent Claim 23...............................................................46
`Dependent Claims 2 and 14 ......................................................48
`Dependent Claims 3, 17, and 24...............................................49
`Dependent Claim 4....................................................................49
`Dependent Claims 5-7, 18, 19, and 25......................................50
`Dependent Claims 8-10, 20-22, and 26-28...............................51
`Dependent Claims 11 and 12 ....................................................52
`a)
`Hecht teaches “an eye drop”...........................................53
`b)
`Using Hecht’s formulation for “a nasal drop”
`would have been obvious ...............................................53
`10. Dependent Claim 13 .................................................................54
`11. Dependent Claims 29 and 30 ....................................................55
`Objective Indicia of Nonobviousness .................................................56
`1.
`No Unexpected Results Over the Closest Prior Art..................56
`a)
`The range disclosed by the prior art is within the
`claimed ranges and thus would have the same
`properties ........................................................................57
`A POSA would have expected light-stabilizing
`effects..............................................................................59
`The alleged unexpected results are not
`commensurate in scope with the claim...........................60
`Other Objective Indicia.............................................................62
`2.
`CONCLUSION..............................................................................................63
`
`Petition for Inter Partes Review of USPN 8,877,168
`
`iii
`
`D.
`
`X.
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Advanced Cardiovascular Sys., Inc. v. Medtronic, Inc.,
`265 F.3d 1294 (Fed. Cir. 2001) ............................................................................1
`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) ..........................................................................56
`Atlas Powder Co. v. Ireco Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) ..........................................................................16
`Bausch & Lomb Incorporated et al. v Apotex Inc. et al.,
`1:15-cv-03879 (D.N.J.).........................................................................................4
`Bausch & Lomb Incorporated et al. v Micro Labs USA, Inc. et al.,
`No. 1:15-cv-03113 (D.N.J.)..................................................................................4
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ..........................................................................61
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955).....................................................................passim
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ..........................................................................20
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ......................................................................15, 37
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ..........................................................................56
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ...................................................................passim
`In re Lee,
`277 F.3d 1338 (Fed. Cir. 2002) ..........................................................................59
`
`iv
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`In re Schreiber,
`128 F.3d 1473 (Fed. Cir. 1997) ....................................................................30, 51
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007)..................................................................................5, 18, 40
`Merck & Co., Inc. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989) .............passim
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ......................................................................55, 61
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2008) ..........................................................................61
`Purdue Pharma Prods. L.P. v. Par Pharm., Inc.,
`377 Fed. App’x 978 (Fed. Cir. 2010) .................................................................61
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) ....................................................................15, 37
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) ..........................................................................62
`Tokai Corp. v. Eason Enters., Inc.,
`632 F.3d 1358 (Fed. Cir. 2011) ..........................................................................62
`Vandenberg v. Dairy Equip. Co.,
`740 F.2d 1560 (Fed. Cir. 1984) ..........................................................................62
`OTHER AUTHORITIES
`37 C.F.R. § 42.8 ..................................................................................................... 3-4
`37 C.F.R. § 42.100 .....................................................................................................5
`37 C.F.R. § 42.104 .................................................................................................3, 6
`37 C.F.R. § 42.106 .....................................................................................................3
`
`v
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`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. Mansoor M. Amiji
`Yanni et al., U.S. Patent No. 6,174,914 “Method of Inhibiting
`Cytokine Release from Human Ocular Cells” (“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”)
`Tetsuya Araki et al., “Photochemical Behavior of Sitafloxacin,
`Fluoroquinolone Antibiotic, in an Aqueous Solution,” Chemical
`and Pharmaceutical Bulletin 50(2) 229-234 (2002) (“Araki I”)
`Press Release “Tanabe Seiyaku Granted Rights for Bepotastine
`Besilate for Ophtalmic [sic] Use to Senju Seiyaku (Japan)”
`(“Tanabe”)
`Masanori Araki et al., PCT International Patent Publication No.
`WO 01/080858 “Stable Liquid Preparation” (“Araki II”)
`R.J. Davies et al., Antihistamines:
`topical vs. oral administration,
`Clinical and Experimental Allergy 26(3):11-17 (1996) (“Davies”)
`“Stability Testing: Photostability Testing of New Drug Substances
`and Products,” ICH Harmonized Tripartite Guideline (1996) (“ICH
`Guideline”)
`Dolores Kostecka et al., “Formulation of a Stable Parenteral
`Product; Clonidine Hydrochloride Injection,” PDA Journal of
`Pharmaceutical Science & Technology 56(6):320-325 (1998)
`(“Kostecka”)
`Gerold L. Mosher et al., “Photoreactivity of LY277359 Maleate, a
`5- Hydroxytryptamine3
`(5-HT3) Receptor Antagonist,
`in
`Solution,” Pharmaceutical Research 8(10):1215-1222 (1991)
`(“Mosher”)
`Reserved
`
`vi
`
`Petitioner
`Exhibit #
`1001
`
`1002
`
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`

`
`1015
`
`1016
`
`1017
`
`1018
`1019
`1020
`1021
`1022
`1023
`1024
`1025
`1026
`1027
`1028
`1029
`1030
`1031
`1032
`1033
`1034
`
`Petition for Inter Partes Review of USPN 8,877,168
`
`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”)
`Remington’s Pharmaceutical Sciences 16th Ed., pp. 1403-1419
`(1980) (“Remington”).
`Jun-ichiro Kita et al., European Patent Publication No. EP 0 949
`260 “Acid-Addition Salts of Optically Active Piperidine
`Compound and Process for Producing the Same” (“Kita”)
`CV of Dr. Mansoor M. Amiji
`Declaration of Higashiyama Under 37 CFR § 1.132 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
`Examiner Interview Summary of August 11, 2018 in ’678
`application
`
`vii
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`I.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals, Inc. (“Petitioner”) petitions for Inter Partes Review
`
`(“IPR”), seeking cancellation of claims 1-14 and 16-30 (“challenged claims”) of
`
`U.S. Patent No. 8,877,168 (“the ’168 patent”) (EX1002), which is owned by Senju
`
`Pharmaceutical Co., Ltd. (“Senju” or “Patent Owner”).
`
`II. OVERVIEW
`
`The ’168 Patent
`A.
`The ’168 patent was issued on November 4, 2014 from U.S. Appl. No.
`
`14/314,678 (“the ’678 application”), which was filed on June 25, 2014 as a
`
`continuation of U.S. Appl. No. 10/500,354 (“the ’354 application”), now U.S. Pat.
`
`No. 8,784,789 (“the ’789 patent”) (EX1001). The ’354 patent application 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. Both the ’168 patent and its parent
`
`application, i.e., the ’789 patent, name Masayo Higashiyama as the sole inventor.
`
`Petitioner notes that, at times in this paper, the prosecution history of the parent ’789
`
`patent will be discussed due to the similar nature of the alleged invention. EX1034
`
`at 2 (“Examiner noted that the claims are drawn to the same invention as the parent
`
`application . . . .”). Advanced Cardiovascular Sys., Inc. v. Medtronic, Inc., 265 F.3d
`
`1
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`1294, 1305 (Fed. Cir. 2001) (explaining that prosecution history of related
`
`applications is relevant where involving common limitations).
`
`The ’168 patent is purportedly 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.” (EX1002, Abstract). The claimed
`
`active
`
`ingredient,
`
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-
`
`pyridyl)methoxy]piperidino]butyric acid, is commonly referred to as bepotastine.
`
`The ’168 patent also discloses the acid addition salt monobenzenesulfonate, which
`
`is commonly referred to as bepotastine besilate. (EX1002, 1:34-38).
`
`The ’168 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. (EX1002, 3:17-22). With respect to the
`
`water-soluble metal chloride concentrations, the ’168 patent states:
`
`[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
`
`2
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`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 %.
`
`(EX1002, 3:24-35). The ’168 patent states that the water-soluble metal chloride
`
`amount takes into account the osmotic pressure of the resulting preparation.
`
`(EX1002, 3:37-43). The ’168 patent also discloses common aqueous formulation
`
`additives, such as buffers, preservatives, and chelating agents.
`
`(EX1002, 3:44-
`
`58).
`
`III.
`
`STANDING (37 C.F.R. § 42.104(A)); PROCEDURAL STATEMENTS
`
`Petitioner certifies that: (1) the ’168 patent is available for IPR; and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’168
`
`patent on the grounds identified herein. This Petition is filed in accordance with 37
`
`C.F.R. § 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 subsidiary
`
`3
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`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 ’168 patent
`The ’168 patent is currently the subject of the following litigation: Bausch &
`
`Lomb Incorporated et al. v Micro Labs USA, Inc. et al., No. 1:15-cv-03113 (D.N.J.);
`
`and Bausch & Lomb Incorporated et al. v Apotex Inc. et al., 1:15-cv-03879 (D.N.J.).
`
`Administrative Matters
`2.
`The Public Patent Application Retrieval (PAIR) website indicates at least
`
`three related patents or pending applications: U.S. Patent No. 8,784,789 (“the ’789
`
`patent”), which is a parent of the ’168 patent; U.S. Patent No. 8,883,825 (“the ’825
`
`patent”), which is a divisional of the ’789 patent; and U.S. Patent Application No.
`
`14/511,393 (“the ’393 application”), which is a continuation of the ’825 patent. The
`
`’789 patent is subject to IPR2016-00626 filed on February 25, 2016.
`
`C.
`
`Designation of Lead and Back-Up Counsel and Service (37 C.F.R.
`§§ 42.8(b)(3), 42.8(b)(4))
`Lead Counsel:
`Jitendra Malik, Ph.D.
`
`(Registration No. 55,823;
`
`jitty.malik@alston.com). Backup Counsel: Lance Soderstrom (Registration No.
`
`65,405; lance.soderstrom@alston.com); Hidetada James Abe (Registration No.
`
`61,182;
`
`james.abe@alston.com); Joseph M. Janusz (Registration No. 70,396;
`
`joe.janusz@alston.com). Please direct all correspondence to lead counsel at the
`
`4
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`following address: 4721 Emperor Boulevard, Suite 400, Durham, North Carolina
`
`27703. Petitioner consents to email service. Telephone: (919) 862-2200. Facsimile:
`
`(919) 862-2260.
`
`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 1-14 and 16-30 of the
`
`’168 patent. A detailed statement of the reasons for the relief requested is set forth.
`
`VI. THE ’168 PATENT AND CLAIM CONSTRUCTION
`
`The challenged claims must be given their broadest reasonable interpretation
`
`in light of the specification of the ’168 patent. See 37 C.F.R. § 42.100(b). Claim 1
`
`recites “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 at
`
`least within the range recited in the respective claims of the ’168 patent.
`
`In the
`
`corresponding inter partes review of the related ’789 patent, which also included the
`
`phrase “a light-stabilizing effective amount,” Patent Owner stated that no claim
`
`terms or phrases of the ’789 patent need express construction. Mylan Pharms., Inc.
`
`v. Senju Pharms. Co., Ltd., IPR2016-00626, Paper No. 8 at 3.
`
`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
`
`5
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`creativity. KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 420 (2007). A POSA in the
`
`field of the ’168 patent would have a Ph.D. in pharmaceutical sciences or a 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 ¶
`
`47). 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. Id.
`
`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(B))
`
`IPR of claims 1-14 and 16-30 of the ’168 patent is respectfully requested.
`
`Copies of the references are filed herewith. This Petition includes the declaration of
`
`a technical expert, Dr. Amiji (EX1003), explaining what the art would have
`
`conveyed to a POSA. Dr. Amiji is an expert in the relevant field. (EX1018).
`
`Ground
`1
`2
`
`Reference(s)
`Tanabe in view of Yanni
`Tanabe in view of Hecht
`
`Basis
`35 U.S.C. § 103
`35 U.S.C. § 103
`
`Claims Challenged
`1-14, 16-30
`1-14, 16-30
`
`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.
`
`6
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`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,
`
`1; EX1017, [0001]). Bepotastine besilate was known to be an H1 receptor antagonist
`
`and 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, 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 ¶¶ 50-62).
`
`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 and improved safety. (EX1010, Abstract, 13, 15).
`
`7
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`Tanabe Press Release (“Tanabe”) (EX1008)
`a)
`Tanabe Seiyaku, the manufacturer of the bepotastine tablet Talion®, 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 ’168 patent,
`
`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 ’168 patent.
`
`Tanabe discusses the use of bepotastine besilate tablets for 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). Tanabe also states that “bepotastine
`
`besilate is rich in water solubility, and suitable for applying [sic] eye-drop products.”
`
`(EX1008, 1). Thus, before July 31, 2002, Tanabe 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, 3:6-15;
`
`EX1005, 827-30; EX1006, 184-87; EX1003 ¶¶ 59-64). For example, adding a
`
`tonicity agent like sodium chloride to an ophthalmic formulation was common. (See,
`
`8
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`e.g., EX1021, 5; EX1003 ¶ 60; 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 ¶ 54). A standard ophthalmic formulation would generally
`
`have the active ingredient, a tonicity agent like sodium chloride, and a preservative
`
`like benzalkonium chloride, and it was also 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 ¶¶ 59-63).
`
`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
`
`was issued on January 16, 2001 and constitutes prior art under 35 U.S.C. § 102(b).
`
`Yanni was not cited or relied upon by the Examiner during prosecution.
`
`Yanni
`
`teaches an aqueous ophthalmic solution formulation for topical
`
`delivery of an active ingredient to the eye.
`
`(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.
`
`9
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`(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 predates the July 31, 2002 priority date of the ’168
`
`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 ’168 Patent. During prosecution, the Examiner relied upon Remington’s
`
`Pharmaceutical Sciences 16th ed., pp. 1410-19 (1980) (“Remington”) (EX1016),
`
`which disclosed tonicity agents and metal chlorides, including calcium chloride and
`
`10
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`potassium chloride. (See, e.g., 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. (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 also teaches that the concentration of the active ingredient
`
`is generally less than 2.5 to 3.0% such that the drug can be dissolved directly in the
`
`vehicle. (EX1005, 827). 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. (EX1003 ¶ 58).
`
`11
`
`

`
`Petition for Inter Partes Review of USPN 8,877,168
`
`3.
`
`Sodium Chloride was Known to Have Light-Stabilizing
`Properties and Testing for Light-Stability was Routine
`Photostability was routinely tested and recommended.
`(EX1011, 1, §1.A;
`
`EX1012, 320). Sodium chloride was known to have light-stabilizing properties with
`
`respect to compounds with chlorophenyl groups like bepotastine besilate. For
`
`example,
`
`it was found that sodium chloride improved the light-stability of
`
`sitafloxacin, which contains a chlorophenyl group. (EX1007, 229, 232-34; EX1009,
`
`1-2). The concentration of sodium chloride also affected the stability when tested in
`
`the concentration range of about 0.10 w/v % to 1.80 w/v %. (EX1009, 4, 8; EX1003
`
`¶ 67). LY277359 (zatosetron) maleate, which also has a chlorophenyl group, was
`
`also known to decompose through photo-dehalogenation. (EX1013, 1217-19). A
`
`direct relationship between chloride concentrations and the photostability was
`
`observed due to a common ion effect. (EX1013, 1216-18, 1221