IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
INNOPHARMA INC., INNOPHARMA LLC,
MYLAN PHARMACEUTICALS INC., and MYLAN INC.
Petitioner,
v .
SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
BAUSCH & LOMB PHARMA HOLDINGS CORP.
Patent Owner.
U.S. Patent No. 8,669,290 to Sawa et al.
Issue Date: March 11, 2014
Title: Aqueous Liquid Preparation Containing
2-Amino-3-(4-
bromobenzoyl) Phenylacetic Acid
Inter Partes Review No.: IPR2015-00902
Petition for Inter Partes Review of U.S. Patent No. 8,669,290 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
TABLE OF CONTENTS
Page
I. INTRODUCTION ........................................................................................... 1
II. OVERVIEW .................................................................................................... 1
A. The ’290 patent ...................................................................................... 2
B. The Scope and Content of the Prior Art ................................................ 4
1. Aqueous Opthalmic Preparation of Bromfenac .......................... 4
2. Tyloxapol and Related Surfactants in NSAID Aqueous
Ophthalmic Preparations ......................................................... 5
C. The Differences Between the Challenged Claims and the Prior
Art .......................................................................................................... 6
III. STANDING (37 C.F.R. § 42.104(a); PROCEDURAL
STATEMENTS) ............................................................................................10
IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ....................................11
A. Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) .........................11
B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) ............................11
1. Judicial Matters: ........................................................................11
2. Administrative Matters: ............................................................13
C. Designation of Lead and Back-Up Counsel (37 C.F.R. §
42.8(b)(3)): ..........................................................................................15
D. Notice of Service Information (37 C.F.R. § 42.8(b)(4)): ....................15
ii
V. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
REASONS THEREFOR (37 C.F.R. § 42.22(a)) ..........................................15
VI. THE ’290 PATENT AND CLAIM CONSTRUCTION ...............................16
VII. PERSON OF SKILL IN THE ART (“POSA”) & STATE OF THE
ART ...............................................................................................................17
VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) .................18
A. Independent Claims 1, 8, and 14 .........................................................19
1. Ogawa in View of Sallmann .....................................................19
B. Dependent Claims ...............................................................................32
1. Claims 2, 9, 15, and 21—Quaternary Ammonium Salt ............32
2. Claims 3 and 16—Sodium Salt of Bromfenac .........................35
3. Claims 4-5, 7, 11, 13, 17, 19, 23, and 25—Bromfenac
Sodium and Tyloxapol Concentrations.................................37
4. Claims 6, 12, 18, and 24—pH Ranges ......................................42
5. Claims 10, 20 and 22—Storage Stability..................................43
6. Claims 26-30—Preservative Efficacy Test ...............................44
C. Objective Indicia of Nonobviousness .................................................48
1. No Unexpected Results Over the Closest Prior Art ..................48
2. Other Objective Indicia .............................................................50
IX. CONCLUSION ..............................................................................................53
CERTIFICATE OF SERVICE
iii
TABLE OF AUTHORITIES
Page(s)
CASES
Amneal Pharmaceuticals, LLC v. Supernus Pharmaceuticals, Inc., IPR2013-
00368 ......................................................................................................................................48
Chapman v. Casner,
315 Fed. App’x 294 (Fed. Cir. 2009) .......................................................................38, 43
Friskit, Inc. v. Real Networks, Inc.,
306 F. App’x 610 (Fed. Cir. 2009) .................................................................................50
Galderma Labs., L.P., v. Tolmar, Inc.,
737 F.3d 731 (Fed. Cir. 2013) ...................................................................................39, 40
In re Aller,
220 F.2d 456 ...................................................................................................................41, 47
In re Baxter Travenol Labs.,
952 F.2d 388 (Fed. Cir. 1991)..............................................................................31, 44, 47
In re De Blauwe,
736 F.2d 699 (Fed. Cir. 1984)..........................................................................................48
In re Malagari,
499 F.2d 1297 (C.C.P.A. 1974) .......................................................................................43
In re Merchant,
575 F.2d 865 (C.C.P.A. 1978) .........................................................................................48
In re Peterson,
315 F.3d 1325 (Fed. Cir. 2003) ...........................................................................41, 43, 50
In re Woodruff,
919 F.2d 1575 (Fed. Cir. 1990) .......................................................................................43
Iron Grip Barbell Co., Inc., v. USA Sports, Inc.,
392 F.3d 1317 (Fed. Cir. 2004) ......................................................................................38
iv
KSR International Co. v. Teleflex Inc.,
550 U.S. 398 (2007) ...........................................................................................2, 17, 25, 32
Metrics, Inc. v. Senju Pharmaceutical Co., Ltd., IPR2014-01043 .........1, 11, 12, 13, 16
Newell Cos., Inc. v. Kenney Mfg. Co.,
864 F.2d 757 (Fed. Cir. 1988)..........................................................................................48
Ormco Corp. v. Align Tech., Inc.,
463 F.3d 1299 (Fed. Cir. 2006) .......................................................................................51
Purdue Pharma Prods. L.P. v. Par Pharm., Inc.,
377 Fed App’x 978 (Fed. Cir. 2010) ..............................................................................52
Sakraida v. AG Pro, Inc.,
425 U.S. 273 (1976) ..........................................................................................................25
Santarus v. Par Pharm,
694 F.3d 1344 (Fed. Cir. 2012) ...........................................................................31, 44, 47
Sinclair & Carroll Co., v. Interchemical Corp.,
325 U.S. 327 (1945) ...........................................................................................................24
Stratoflex, Inc. v. Aeroquip Corp.,
713 F.2d 1530 (Fed. Cir. 1983) .................................................................................51, 52
Sundance, Inc. v. DeMonte Fabricating Ltd.,
550 F.3d 1356 (Fed Cir. 2008) ....................................................................................7, 28
Titanium Metals Corp. of Amer. v. Banner,
778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) ...........................................................40
Tokai Corp. v. Eason Enters., Inc.,
632 F.3d 1358 (Fed. Cir. 2011) .......................................................................................52
Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
683 F.3d 1356 (Fed Cir. 2012) ..................................................................................25, 29
STATUTES
35 U.S.C. § 102(b) ..............................................................................................................19, 20
35 U.S.C. § 103 .....................................................................................................................1, 18
v
35 U.S.C. § 315(a)(1) .........................................................................................................10, 11
35 U.S.C. § 315(c) ....................................................................................................................13
OTHER AUTHORITIES
37 C.F.R. § 42.6(d) .................................................................................................. 18
37 C.F.R. § 42.8(b)(1) .............................................................................................. 11
37 C.F.R. § 42.8(b)(2) .............................................................................................. 11
37 C.F.R. § 42.8(b)(3) .............................................................................................. 15
37 C.F.R. § 42.8(b)(4) .............................................................................................. 15
37 C.F.R. § 42.10(b) ................................................................................................ 10
37 C.F.R. § 42.22 ..................................................................................................... 13
37 C.F.R. § 42.22(a) ................................................................................................. 15
37 C.F.R. § 42.63(e) ................................................................................................. 10
37 C.F.R. § 42.100(b) .............................................................................................. 16
37 C.F.R. § 42.104(a) ............................................................................................... 10
37 C.F.R. § 42.104(b) .............................................................................................. 18
37 C.F.R. § 42.106(a) ............................................................................................... 10
37 C.F.R. § 42.122(b) .............................................................................................. 13
vi
Petitioner’s Exhibit List
InnoPharma
Exhibit # Description
1001 Sawa et al., U.S. Patent No. 8,669,290, “Aqueous Liquid Preparation
Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic Acid”
1002 Certified English translation of: Hara, Yoshiyuki , “Bromfenac
sodium hydrate,” Clinics & Drug Therapy 19:1014-1015 (2002)
1003 Declaration of Paul A. Laskar, Ph.D.
1004 Ogawa et al., U.S. Patent No. 4,910,225 “Locally Administrable
Therapeutic Composition for Inflammatory Disease”
1005 Desai et al., U.S. Patent No. 5,603,929, “Preserved Ophthalmic
Drug Compositions Containing Polymeric Quaternary Ammonium
Compounds”
1006 Desai, et al., U.S. Patent No. 5,558,876, “Topical Ophthalmic
Acidic Drug Formulations”
1007 Certified English translation of “Bromfenac sodium hydrate” in the
Japanese Pharmacopoeia 2001 Edition: 27-29, Yakuji Nippo
Limited (2001)
1008 FDA approved “BROMDAYTM (bromfenac ophthalmic solution,
.09%) Product Label,” U.S. Approval: March 24, 2005, ISTA
Pharmaceuticals, Inc.
1009 Sallmann et al., U.S. Patent No. 6,107,343, “Ophthalmic And Aural
Compositions Containing Diclofenac Potassium”
1010 Guttman et al., “Solubilization of Anti-inflammatory steroids by
Aqueous Solutions of Triton-WR-1339,” Journal of Pharmaceutical
Sciences 50: 305-307 (1961)
1011 Fu et al., Australian Patent No. AU-B-22042/88, “Preservative
System For Ophthalmic Formulations” 1012 Yasueda et al., U.S. Patent No. 6,274,609, “Aqueous Liquid
Pharmaceutical Composition Containing as Main Component
Benzopyran Derivative”
vii
InnoPharma
Exhibit # Description
1013 “Orange Book: Approved Drug Products with Therapeutic
Equivalence Evaluations,” Appl. No. N203168, U.S. FDA, accessed
at
http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?
Appl_No=203168&Product_No=001&table1=0B_Rx
1014 “Orange Book: Approved Drug Products with Therapeutic
Equivalence Evaluations,” Appl. No. N203168, Active Ingredient
Bromfenac Sodium, accessed at
http://wvvw.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Ap
p 1 No=203168&TABLE1=0B Rx, last accessed on January 24, 2014
1015 Reserved
1016 Reserved
1017 Kapin, et. al., International Patent No. WO 2002/13804, “Method
for Treating Angiogenesis-Related Disorders Using Benzoyl
Phenylacetic Acid”
1018 Flach, Allan., “Topical Nonsteroidal Antiinflammatory Drugs for
Ophthalmic Uses,” Ophthalmic NSAIDs: 77-83 (1996)
1019 Schott, H., “Comparing the Surface Chemical Properties and the
Effect of Salts on the Cloud Point of a Conventional Nonionic
Surfactant, Octoxynol 9 (Triton X-100), and of Its Oligomer,
Tyloxapol (Triton WR-1339),” Journal of Colloid and Interface
Science 205: 496-502 (1998)
1020 Regev, 0., et al., “Aggregation Behavior of Tyloxapol, a Nonionic
Surfactant Oligomer, in Aqueous Solution,” Journal of Colloid and
Interface Science 210: 8-17 (1999)
1021 Aviv, H., International Patent No. WO 94/05298, “Submicron
Emulsions as Ocular Drug Delivery Vehicles”
1022 Bergamini et al., U.S. Patent No. 5,597,560, “Diclofenac And
Tobramycin Formulations For Ophthalmic And Otis Topical Use”
1023 U.S. Patent Application No. 13/687,242, Applicant Remarks in
support of amendment, November 28, 2012
viii
InnoPharma
Exhibit # Description
1024 Reserved
1025 U.S. Patent Application No. 13/687,242, Applicant
Arguments/Remarks Made in an Amendment, 10/22/2013, pp. 9-15
1026 "monohydrate," Webster’s New World Dictionary of the
American Language: 920, New World Dictionaries / Simon and
Schuster (1980).
1027 "Voltaren," Orange Book: Approved Drug Products with
Therapeutic Equivalence Evaluations, Appl. No. N020037, U.S.
FDA, accessed at
http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?
A ppl_No=020037&TABLE1=OB_Rx
1028 Yanni et al., U.S. Patent No. 5,475,034, "Topically
Administrable Compositions Containing 3-Benzoylphenylacetic
Acid Derivatives for Treatment of Ophthalmic Inflammatory
Disorders".
1029 "ISTA Pharmaceuticals Submits New Drug Application for
XibromTM QD (once-daily), News Release, ISTA
Pharmaceuticals (December 20, 2007)
1030 Prince, S., et al., "Analysis of benzalkonium chloride and its
homologs: HPLC versus HPCE," Journal of Pharmaceutical and Biomedical Analysis 19: 877-882, Elsevier Science B.V.,
Netherlands (1999)
1031 "Acular®" and "AzoptTM," Physician’s Desk Reference 54:
486- 487, 491-492 (2000).
1032 Doughty, M., "Medicines Update for optical practitioners- Part
11," Optician 5853 (223), (2002).
1033 Reddy, Indra K., Ocular Therapeutics and Drug Delivery: A
Multi-Disciplinary Approach: 42-43, 390 (1996).
ix
InnoPharma
Exhibit # Description
1034 Fan, T., "Determination of Benzalkonium Chloride in
Ophthalmic Solutions Containing Tyloxapol by Solid-Phase
Extraction and Reversed-Phase High-Performance Liquid
Chromatography," Journal of Pharmaceutical Sciences 82 (11):
1172-1174, American Pharmaceutical Association, United
States (1993).
1035 Wong, Michelle, International Patent No. WO 94/15597,
"Ophthalmic Compositions Comprising
Benzyllauryldimethylammonium Chloride" (filed January 11,
1993; issued July 21, 1994).
1036 Guy et al., U.S. Patent No. 5,540,930, "Suspension of Loteprednol
Etabonate for Ear, Eye, or Nose Treatment" (filed October 25,
1993; issued July 30, 1996).
1037 FDA approved "ALREXTM (loteprednol etabonate ophthalmic
suspension) 0.2% Product Label," U.S. Approval: 1998, Bausch
& Lomb Pharmaceuticals.
1038 FDA approved "LOTEMAXTM (loteprednol etabonate
ophthalmic suspension) 0.5% Product Label," U.S. Approval:
1998, Bausch & Lomb Pharmaceuticals.
1039 "TOBRADEX®" Physician’s Desk Reference 54: 490 (2000).
1040 "Alomide® 0.1%" Physician’s Desk Reference 50: 469 (1996).
1041 Johnson, R., et al., U.S. Patent No. 2,880,130, "Anti-
Inflammatory Steroid Solutions".
1042 Johnson, R., et al., U.S. Patent No. 2,880,138, "Anti-
Inflammatory Steroid Solutions".
1043 Kawabata et al., Canadian Patent No. CA 2 383 971 A1,
“Prophylactic and Therapeutic Medicaments for Ophthalmic
Uses”.
1044 Patani, G., et al., "Bioisoterism: A Rational Approach in
Drug Design," Chem. Rev. 96: 3147-3176 (1996).
1045 FDA approved "XIBROMTM (bromfenac ophthalmic
solution, .09%) Product Label," ISTA Pharmaceuticals, Inc.
x
InnoPharma
Exhibit # Description
1046 Senju Pharmaceutical Co., Ltd. Press Releases, "The approval of
BRONUCK® (bromfenac sodium hydrate ophthalmic solution)
as an import drug in China," http://www.senju.co.jp/, accessed at
http://www.senju.co.jp/english/news/__icsFiles/afieldfile/2009/11
/1 8/2009111814br.pdf, published November 17, 2009, 1 page.
1047 FDA approved "PROLENSATM (bromfenac ophthalmic
solution, 0.07%) Product Label," U.S. Approval: April 5,
2013, Bausch & Lomb Incorporated
1048 "Borax (Sodium tetraborate)," Biochemicals and Reagents:
175, Sigma-Aldrich (2000-2001).
1049 Ali, et al., U.S. Patent No. 6,071,904, "Process for
Manufacturing Ophthalmic Suspensions".
1050 Story, M., et al., European Patent No. 0274870, "Micelles
containing a non-steroidal antiinflammatory compound"
(filed December 12, 1987; issued July 7, 1988)
1051 “DuractTM,” Physician’s Desk Reference 52:3035-3037 (1998).
1052 Curriculum Vitae of Paul A. Laskar, Ph.D.
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
1
I. INTRODUCTION
InnoPharma Licensing, Inc., InnoPharma Licensing LLC, InnoPharma Inc.,
InnoPharma LLC, Mylan Pharmaceuticals Inc., and Mylan Inc. (collectively,
“Petitioner”) petition for Inter Partes Review, seeking cancellation of claims 1-30
(“challenged claims”) of U.S. Patent No. 8,669,290 (“the ’290 patent”) (EX1001),
owned by Senju Pharmaceutical Co., Ltd. (“Patent Owner”).
II. OVERVIEW
The Board has already issued its Decision Instituting Inter Partes Review
(“Decision”) on all challenged claims of the ’290 patent on the Ogawa/Sallmann
ground raised herein. Metrics, Inc. v. Senju Pharmaceutical Co., Ltd., IPR2014-
01043 (Paper 19). In its Decision, the Board found that Petitioner Metrics, Inc.
had demonstrated a reasonable likelihood that claims 1-30 of the ’290 patent are
unpatentable for failing to satisfy the nonobviousness requirement of 35 U.S.C.
§ 103. Id. The Board instituted IPR of the challenged claims on the ground that
claims 1-30 are reasonably likely to be obvious over Ogawa and Sallmann under
35 U.S.C. § 103. Id. at Paper 19, pg. 16. Petitioner hereby files its own petition on
the same ground and concurrently seeks to join the instituted IPR proceedings on
these challenged claims.
The challenged claims all are directed to a stable aqueous formulation of
bromfenac (a non-steroidal anti-inflammatory drug (“NSAID”)) with tyloxapol (a
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
2
non-ionic surfactant). At the relevant time, tyloxapol was a known non-ionic
surfactant in aqueous formulations of NSAIDs while bromfenac was a known
NSAID previously formulated with another non-ionic surfactant, polysorbate 80.
Thus, the purported inventors of the aqueous preparations of the challenged claims
simply switched polysorbate 80 for tyloxapol (both well-known non-ionic
surfactants). Or, viewed another way, the purported inventors of the challenged
claims of the ’290 patent merely switched diclofenac for bromfenac (both well-
known structurally similar NSAIDs). Swapping known alternatives from the
prior art, according to their known functions to achieve predictable results, is
not innovation. See, e.g., KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416
(2007) (“[W]hen a patent claims a structure already known in the prior art that is
altered by the mere substitution of one element for another known in the field, the
combination must do more than yield a predictable result.”).
A. The ’290 patent
The challenged claims of the ’290 patent are directed to stable
aqueous liquid preparations for ophthalmic administration. Independent claims 1,
8, and 14 are reproduced below:
1. A stable aqueous liquid preparation comprising: (a) a first
component; and (b) a second component; wherein the first
component is 2-amino-3-(4-bromobenzoyl)phenylacetic acid
or a pharmacologically acceptable salt thereof or a hydrate
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
3
thereof, wherein the hydrate is at least one selected from a
1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first component
is the sole pharmaceutical active ingredient contained in the
preparation; the second component is tyloxapol and is
present in said liquid preparation in an amount sufficient to
stabilize said first component; and wherein said stable liquid
preparation is formulated for ophthalmic administration.
8. A stable aqueous liquid preparation comprising: (a) a first
component; and (b) a second component; wherein the first
component is 2-amino-3-(4-bromobenzoy)phenylacetic acid
or a pharmacologically acceptable salt thereof or a hydrate
thereof, wherein the hydrate is at least one selected from a
1/2 hydrate, 1 hydrate, and 3/2 hydrate the first component is
the sole pharmaceutical active ingredient contained in the
preparation; the second component is tyloxapol; wherein
said stable liquid preparation is formulated for ophthalmic
administration; and wherein the stable aqueous liquid
preparation is characterized in that greater than about 90% of
the original amount of the first component remains in the
preparation after storage at about 60° C. for 4 weeks.
14. A stable aqueous liquid preparation comprising: (a) a
first component; and (b) a second component; wherein the
first component is 2-amino-3-(4- bromobenzoy)phenylacetic
acid or a pharmacologically acceptable salt thereof or a
hydrate thereof, wherein the hydrate is at least one selected
from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
4
component is the sole pharmaceutical active ingredient
contained in the preparation; the second component is
tyloxapol; wherein said stable liquid preparation is
formulated for ophthalmic administration; provided that the
liquid preparation does not include mannitol.
(EX1001, 12:1-13; 12:41-53; 13:14-25)1 (emphasis added).
In pertinent part, each of the three independent claims of the ’290 patent is
directed to a stable, aqueous liquid preparation comprising two components:
(1) bromfenac (or its salts and hydrates); and (2) tyloxapol.
In the context of the ’290 patent, the word “comprising’ means that, at a
minimum, the claimed ophthalmic formulation must contain both bromfenac (as
the sole active ingredient) and tyloxapol. However, the formulation may further
include any other unlisted ingredient, including “conventional various additives
such as isotonics, buffers, thickeners, stabilizers, chelating agents, pH controlling
agents, perfumes and the like.” (EX1001, 6:9-12; claims 7, 13, 19, 25).
B. The Scope and Content of the Prior Art
1. Aqueous Ophthalmic Preparation of Bromfenac
Bromfenac, diclofenac, and ketorolac were well-known NSAIDs useful for
treating inflammation in the eye. (EX1002, 2:1:2; EX1003,2 ¶¶ 25-31).
1 Citations are as follows: X:YY-ZZ (col:lines; patent); X:Y:Z
(page:col:para; journal article); X:Y (page:para; journal article).
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
5
Bromfenac, diclofenac, and ketorolac are NSAIDs possessing a carboxylic acid
group (—COOH). By January 21, 2003, bromfenac had been formulated with
non-ionic surfactants, including but not limited to tyloxapol and polysorbate 80, in
aqueous preparations for ophthalmic delivery.
The Ogawa patent (EX1004) described (and exemplified) an aqueous
ophthalmic formulation containing: (1) bromfenac and (2) polysorbate 80.
(EX1004, 9:5-10:19). Similarly, U.S. Patent No. 5,603,929 to Desai et al. (“the
Desai ’929 patent”) described a storage-stable ophthalmic formulation containing
bromfenac, and optionally any one of a number of conventional surfactants,
including tyloxapol. (EX1005, 3:38-41; see also, Hara (EX1002), U.S. Patent No.
5,558,876 to Desai et al. (“the ’876 Desai patent”) (EX1006), BRONUCK,
Japanese Pharmacopeia (EX1007), and BROMDAY Prescribing Information
(EX1008)).
2. Tyloxapol and Related Surfactants in NSAID Aqueous
Ophthalmic Preparations
By January 21, 2003, tyloxapol and related alkylaryl polyether surfactants
were well-known non-ionic surfactants formulated in the prior art with NSAIDs.
For example, the Sallmann patent (EX1009) described liquid ophthalmic
2 This Petition is accompanied by the Declaration of Paul A. Laskar, Ph.D.
(EX1003).
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
6
formulations containing (1) diclofenac sodium (an NSAID) and (2) tyloxapol
surfactant. (EX1009, 2:6-8, 4:52-62).
Tyloxapol, like polysorbate 80, was successfully used to stabilize aqueous
ophthalmic formulations as early as the 1960s. (EX1009, 4:62; EX1010, 4:2:2-
4:2:4; EX1003, ¶¶ 36-41). Notably, the prior art taught that tyloxapol was
effective in stabilizing NSAIDs, like bromfenac. (EX1003, ¶ 36; EX1011). The
prior art further disclosed examples where tyloxapol was a preferred non-ionic
surfactant for use in ophthalmic formulations containing acidic NSAIDs, like
bromfenac (EX1009, 4:62; EX1003, ¶¶ 36, 41, 62), and where tyloxapol was
superior to polysorbate 80 as a surfactant in aqueous liquid formulations of an
acidic compound. (EX1012, 7:20-43). In fact, in the prior art, only a finite
number of non-ionic surfactants, including tyloxapol and polysorbate 80, had been
used in approved ophthalmic formulations. (EX1012, 4:51-64; EX1009, 4:52-62).
C. The Differences Between the Challenged Claims and the Prior Art
Petitioner relies on its primary prior art references, Ogawa (EX1004) and
Sallmann (EX1009) in combination with each other. Each discloses a prior art
ophthalmic formulation of an NSAID and a non-ionic surfactant, similar to what is
claimed in the ’290 patent. The challenged claims of the ’290 patent differ from
prior art aqueous liquid ophthalmic formulations of an NSAID only in the
substitution of one well-known NSAID (bromfenac) for another well-known
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
7
NSAID (diclofenac), or alternately, in the replacement of one well-known non-
ionic surfactant (tyloxapol) for another well-known non-ionic surfactant
(polysorbate 80), as illustrated in the following.
’290 Patent
Claim 1
Ogawa
Example 6
(EX1004)
Sallmann
Example 2
(EX1009)
NSAID Bromfenac Bromfenac Diclofenac
Surfactant Tyloxapol Polysorbate 80 Tyloxapol
When viewed against the prior art, it is clear that the alleged inventors of the
’290 patent did nothing more than swap one well-known component from a prior
art formulation with another known to be used for the same purpose. Thus, the
alleged inventors simply substituted tyloxapol (from Sallmann) for polysorbate 80
(both well-known non-ionic surfactants) in the formulation described in Ogawa.
Alternately, the alleged inventors merely switched bromfenac (from Ogawa) for
diclofenac—both well-known structurally similar NSAIDS—in the formulation
described in Sallmann. Swapping known alternatives from the prior art is not
innovation. Sundance, Inc. v. DeMonte Fabricating Ltd., 550 F.3d 1356, 1366-
1367 (Fed Cir. 2008) (“a combination is more likely to be obvious where it ‘simply
arranges old elements with each performing the same function it had been known
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
8
to perform’ and yields no more than one would expect from such an
arrangement”).
All that the challenged claims accomplished was the mere obvious
replacement of known components, according to their known functions, to achieve
predictable results. (EX1003, ¶¶ 61-64). A person of ordinary skill in the art at the
time (“POSA”) could have readily performed these simple component
substitutions—tyloxapol for polysorbate 80 or bromfenac for diclofenac—because
the functions of these components were well known in the art and the results of the
substitutions were predictable. (EX1003, ¶¶ 61-64).
Finally, the prior art disclosed only a finite number of non-ionic surfactants
for ophthalmic formulations. As such, it would have been obvious to try
substituting any of these known non-ionic surfactants (including tyloxapol) for
polysorbate 80 in order to modify the teachings of Ogawa and arrive predictably at
the claimed inventions, with a reasonable expectation of success.
Further, Sallmann disclosed ophthalmic formulations containing NSAIDs,
including diclofenac and ketorolac, together with non-ionic ethoxylated
octylphenol surfactants, including tyloxapol. (EX1003, ¶ 57). A POSA would
have been motivated to substitute bromfenac for diclofenac in Sallmann’s
ophthalmic formulations because of the structural and functional similarities
between bromfenac and diclofenac (EX1002, 2:1:4-2:2:1; EX1003, ¶ 68), and the
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
9
known preference for bromfenac over diclofenac (EX1002; EX1003, ¶ 68). The
prior art also disclosed a finite number of NSAIDs for ophthalmic application,
such that it would have been obvious to try substituting any of these known anti-
inflammatory compounds (including bromfenac) for diclofenac in order to
modify the teachings of Sallmann and arrive predictably at the claimed
inventions, with a reasonable expectation of success. (EX1002, 2:2:2-3:1:1;
EX1003, ¶ 68).
The subject matter of many of the challenged claims of the ’290 patent is
commercially embodied by Prolensa®, a product marketed by Bausch & Lomb Inc.
(“B&L”). (EX1013 & EX1014). Patent protection on Prolensa® represents the
third attempt by the patent owner3 to protect its bromfenac monopoly. The patent
owner previously owned patent protection for two other bromfenac ophthalmic
products—Xibrom® and Bromday
®—both of which were covered by the prior art
Ogawa patent (EX1004), and over which the ’290 patent is obvious. And while
some dependent claims of the ’290 patent recite more particular excipients,
concentration ranges, pH ranges, and preservative efficacy standards, these
nominal differences fall far short of imparting patentability, as discussed below.
3 Senju and B&L (and its predecessor-in-interest, ISTA Pharmaceuticals).
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
10
III. STANDING (37 C.F.R. § 42.104(a); PROCEDURAL STATEMENTS)
Petitioner certifies that (1) the ’290 patent is available for IPR; and
(2) Petitioner is not barred or estopped from requesting IPR of any claim of the
’290 patent on the grounds identified herein. This Petition is filed in accordance
with 37 C.F.R. § 42.106(a). Concurrently 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 through, and the Office is authorized to charge any fee
deficiencies and credit overpayments to, Deposit Acct. No. 160605 (Customer ID
No. 00826).
Petitioner is aware that counsel for the patent owner has previously taken the
position that there is a perceived conflict between the America Invents Act and the
Hatch-Waxman Act and that the PTAB should exercise its discretion to deny IPR
petitions filed by ANDA applicants. Specifically, patent owner’s counsel has
asserted that the filing of a Paragraph IV Certification by an ANDA applicant is
the equivalent of filing a civil action challenging the validity of a patent and, as
such, prohibits the applicant from filing a petition for IPR pursuant to 35 U.S.C.
§ 315(a)(1). The Board previously has determined that the action of filing “[a]
Paragraph IV certification may represent an out-of-court challenge to patent
invalidity, but it does not constitute ‘a civil action challenging the validity’ of any
patent claim.” Metrics, Inc. v. Senju Pharmaceutical Co., Ltd., IPR2014-01043
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
11
[Paper 19, pg. 9] (finding no conflict between the Hatch Waxman Act and the IPR
provisions of the AIA). Thus, filing a Paragraph IV certification does not foreclose
Petitioner’s access to an IPR under 35 U.S.C. § 315(a)(1).
IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
A. Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
The real parties in interest for this petition are InnoPharma Licensing Inc.,
InnoPharma Licensing LLC, InnoPharma Inc., InnoPharma LLC, Mylan
Pharmaceuticals Inc., and Mylan Inc.
B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
1. Judicial Matters:
Petitioner is aware of the following district court actions which involve the
’290 patent:
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. Metrics, Inc., Mayne Pharma Group Limited and
Mayne Pharma (USA), Inc., C.A. No. 1:14-cv-03962-JBS-KMW (D.N.J.
filed Jun. 20, 2014),
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. Lupin, Ltd. and Lupin Pharmaceuticals, Inc.,
C.A. No. 1:14-cv-04149-JBS-KMW (D.N.J. filed Jun. 26, 2014),
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
12
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. Metrics, Inc., Mayne Pharma Group Limited and
Mayne Pharma (USA), Inc., C.A. No. 1:14-cv-04964-JBS-KMW (D.N.J.
filed Aug. 7, 2014),
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. Metrics, Inc., Coastal Pharmaceuticals, Inc.,
Mayne Pharma Group Limited and Mayne Pharma (USA), Inc., C.A. No.
4:14-cv-00141-BO (E.D.N.C. filed Aug. 8, 2014),
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. InnoPharma Licensing, Inc., InnoPharma
Licensing, LLC, InnoPharma, Inc., and InnoPharma, LLC, C.A. No. 1:14-
cv-06893-JBS-KMW (D.N.J. filed Nov. 3, 2014),
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. Apotex Inc. and Apotex Corp., C.A. No. 1:15-cv-
00336-JBS-KMW (D.N.J. filed Jan. 16, 2015),
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. Paddock Laboratories, LLC L. Perrigo
Company, and Perrigo Company., C.A. No. 1:15-cv-00337-JBS-KMW
(D.N.J. filed Jan. 16, 2015), and
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
13
Senju Pharmaceutical Co., Ltd., Bausch & Lomb, Inc., and Bausch & Lomb
Pharma Holdings Corp. v. Paddock Laboratories, LLC L. Perrigo
Company, and Perrigo Company., C.A. No. 1:15-cv-00087-SLR (D. Del.
filed Jan. 26, 2015).
2. Administrative Matters:
The ’290 patent is presently the subject of an instituted IPR styled Metrics,
Inc., Mayne Pharma and Johnston Matthey, Inc. v. Senju Pharmaceutical Co.,
Ltd., Bausch & Lomb, Inc., and Bausch & Lomb Pharma Holdings Corp., which is
assigned Case No. IPR2014-01043. Petitioner seeks joinder with that IPR, for the
reasons expressed in the concurrently filed Motion for Joinder under 35 U.S.C.
§ 315(c), 37 C.F.R. §§ 42.22 and 42.122(b).
Petitioner has filed concurrently with this Petition, a Petition for Inter Partes
review of U.S. Pat. No. 8,129,431 (“the ’431 patent”), which issued on March 6,
2012 and claims priority to a parent application of the ’290 patent. The ’431 patent
also is presently the subject of an instituted IPR styled Metrics, Inc., Mayne
Pharma and Johnston Matthey, Inc. v. Senju Pharmaceutical Co., Ltd., Bausch &
Lomb, Inc., and Bausch & Lomb Pharma Holdings Corp., which is assigned Case
No. IPR2014-01041.
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
14
Petitioner is also aware of at least the following related family members:
U.S. Patent No. 8,497,304, a division of the ’431 patent, issued on July 30, 2013
and claims common priority to the application that issued as the ’290 patent.
U.S. Patent No. 8,754,131 (“the ’131 patent”), a division of the ’290 patent,
issued on June 17, 2014 and claims common priority to the application that issued
as the ’290 patent.
U.S. Patent No. 8,871,813 (“the ’813 patent”), a division of the ’131 patent,
issued on October 28, 2014 and claims common priority to the application that
issued as the ’290 patent.
U.S. Patent No. 8,927,606, a division of the ’813 patent, issued on January
6, 2015 and claims common priority to the application that issued as the ’290
patent.
U.S. Application Serial Nos. 14/269,692 and 14/502,014 are pending and
claim common priority to the application that issued as the ’290 patent.
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
15
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.
Reg. No. 55823
ALSTON & BIRD LLP
4721 Emperor Boulevard, Suite 400
Durham, North Carolina 27730-8580
919.862.2200 (telephone)
919.862.2260 (facsimile)
Bryan L. Skelton, Ph.D.
Reg. No. 50893
ALSTON & BIRD LLP
4721 Emperor Boulevard, Suite 400
Durham, North Carolina 27730-8580
919.862.2200 (telephone)
919.862.2260 (facsimile)
Lance Soderstrom
Reg. No. 65405
ALSTON & BIRD LLP
90 Park Avenue
15th Floor
New York, New York 10016-1387
212.210.9400 (telephone)
212.210.9444 (facsimile)
D. Notice of Service Information (37 C.F.R. § 42.8(b)(4)):
Please direct all correspondence to lead counsel at the above address.
Petitioner consents to email service at [email protected],
[email protected], and [email protected].
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 1-30 of the ’290 patent. A
detailed statement of the reasons for the relief requested is set forth in Section VIII.
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
16
VI. THE ’290 PATENT AND CLAIM CONSTRUCTION
The ’290 patent issued on March 11, 2014, from U.S. Appl. No. 13/687,242,
which is a division of U.S. Appl. No. 13/353,653 (issued as U.S. Patent No.
8,497,304), which is a further division of U.S. Appl. No. 10/525,006, which was a
U.S. National Stage patent application of Patent Cooperation Treat Appl. No.
PCT/JP2004/000350, filed on January 16, 2004, now U.S. Pat. No. 8,129,431.
Accordingly, the effective filing date (“EFD”) of the ’290 patent is January 16,
2004. The earliest possible priority date for the ’290 patent is January 21, 2003,
the filing date of Japanese Appl. No. 2003-12427.
In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
given their broadest reasonable interpretations in light of the specification of the
’290 patent. The Board has recently determined that “[n]o claim term [in the
challenged claims] requires express construction” for the purposes of rendering a
decision to institute review. Metrics, Inc. v. Senju Pharmaceutical Co., Ltd.,
IPR2014-01043 [Paper No. 19, pg. 10].4
4 To the extent Patent Owner asserts any differing claim constructions,
Petitioner reserves the right to respond thereto in later briefing.
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
17
VII. PERSON OF SKILL IN THE ART (“POSA”) & STATE OF THE ART
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, 550 U.S. at 420. With respect to the ’290 patent, a
POSA would have had education and/or experience in the field of ophthalmic
formulations and drug delivery, and knowledge of the scientific literature
concerning the same, specifically pharmaceutical formulations for ophthalmic
administration, including those comprising anti-inflammatory compounds (such as
NSAIDs) as of 2003. The education and experience levels may vary between
persons of ordinary skill, with some persons holding a basic Bachelor’s degree, but
with 5-10 years of relevant work experience, or others holding more advanced
degrees—e.g., Pharm.D., Ph.D., or M.D.—but having fewer years of experience.
A person of ordinary skill may 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.
As of January 21, 2003, the state of the art pertinent to the ’290 patent was
such that aqueous liquid preparations containing NSAIDs (including bromfenac)
and tyloxapol were disclosed, and well known. In addition to the disclosures of
prior art discussed above, Desai disclosed a formulation that included bromfenac
and tyloxapol, in addition to other ingredients. (EX1005, Abstract, 2:18-23, 3:30-
Petition for Inter Partes Review
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45, 6:13-17 & 6:25-28; see also, EX1017, 4:1-23, 6:8-9, 8:13-22 & Formulation 3;
EX1003, ¶¶ 31, 39). It was also known that NSAID compounds were suitable and
desirable for ophthalmic administration (EX1018, 1:1; EX1003, ¶¶ 25-29), and
that the NSAID bromfenac was specifically employed in ophthalmic formulations.
(EX1002; EX1003, ¶¶ 29-31). Likewise, ethoxylated octylphenol surfactants,
including tyloxapol, had been used to stabilize NSAIDs in ophthalmic
preparations for at least a half-century, including in combination with the NSAIDs
diclofenac and ketorolac more than a year before the EFD. (EX1010, 4:2:2-4:2:4;
EX1003, ¶¶ 33-37).
VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
IPR of claims 1-30 of the ’290 patent is respectfully requested on the
specific grounds of unpatentability outlined 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, Paul A.
Laskar, Ph.D. (EX1003), explaining what the art would have conveyed to a POSA
as of January 21, 2003. Dr. Laskar is an expert in the field of ophthalmic
formulations.
References Basis Claims Challenged
Ogawa and Sallmann
§ 103 1-30
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Claims 1-30 of the ’290 patent are unpatentable as obvious over the prior art.
Claims 1, 8, and 14 are the only independent claims. The grounds for
unpatentability of each independent claim will be addressed in turn before
addressing the unpatentability of the dependent claims or any possible objective
indicia of nonobviousness. Prior art references in addition to the primary
references of Ogawa and Sallmann provide further background in the art, further
motivation to combine the teachings of Ogawa and Sallmann, and further support
for why a POSA would have had a reasonable expectation of success in combining
the teachings of Ogawa and Sallmann to arrive at the aqueous ophthalmic
preparations recited in the claims of the ’290 patent.
A. Independent Claims 1, 8, and 14
1. Ogawa in View of Sallmann
U.S. Patent No. 4,910,225 (“Ogawa”) (EX1004) issued March 20, 1990 and
qualifies as prior art to the challenged claims under 35 U.S.C. § 102(b). Ogawa
describes a specific example (Example 6) of an aqueous preparation comprising
the sodium salt of bromfenac (sodium 3-(4-bromobenzoy1)-2-aminophenylacetate
monohydrate), and the non-ionic surfactant polysorbate 80. Ogawa further
describes that the formulation of Example 6 maintains greater than 92% of the
original amount of bromfenac after storage at 60 °C for 4 weeks. (EX1004, 10:49-
51 and 14:45-50).
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(EX1004, 10:5-18).
U.S. Patent No. 6,107,343 (“Sallmann”) (EX1009) issued August 22, 2000
and qualifies as prior art to the challenged claims under 35 U.S.C. § 102(b).
Sallmann describes a specific example (Example 2) of an aqueous preparation
comprising diclofenac potassium and the non-ionic surfactant tyloxapol.
(EX1009, 8:1-15).
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a. Claim 1
Claim 1 would have been obvious to a POSA reading Ogawa in view of
Sallmann for two independent reasons, as shown below:
’290 patent claim 1 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
1. A stable aqueous liquid
preparation
Ogawa Example 6 (EX1004, 10:5-18) and
Sallmann Example 2 (EX1009, 8:1-15) are
both aqueous liquid preparations.
comprising: (a) a first
component; and (b) a second
component;
wherein the first component is
2- amino-3-(4-bromobenzoy1)-
phenylacetic acid or a
pharmacologically acceptable
salt thereof or a hydrate thereof,
Ogawa Example 6 Ophthalmic Solution
contains sodium 3-(4-bromobenzoy1)-2-
aminophenyl-acetate (bromfenac)
monohydrate. (EX1004, 10:5-9).
wherein the hydrate is at least
one selected from a 1/2 hydrate,
1 hydrate, and 3/2 hydrate;
Ogawa Example 6 Ophthalmic Solution
contains sodium 3-(4-bromobenzoy1)-2-
aminophenyl-acetate(bromfenac)
monohydrate. (EX1004, 10:5-9).
the first component is the sole
pharmaceutical active
ingredient contained in the
preparation;
Ogawa Example 6 Ophthalmic Solution
contains sodium 3-(4-bromobenzoy1)-2-
aminophenyl-acetate (bromfenac)
monohydrate as the only pharmaceutical
active ingredient
the second component is
tyloxapol,
Sallmann Example 2 contains tyloxapol
(EX1009, 8:1-10).
and is present in said liquid
preparation in an amount
sufficient to stabilize said first
component;
Ogawa Table 11 describes that Example 6
Ophthalmic Solution, after 4 weeks at 60 °C
is not less than 90% of the original amount
of bromfenac (EX1004, 10:49-52 and 14:45-
50).
Petition for Inter Partes Review
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’290 patent claim 1 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
and wherein said stable liquid
preparation is formulated for
ophthalmic administration.
Ogawa: “An ophthalmic composition
according to the invention can treat
effectively inflammatory eye disease ...”
(EX1004, Abstract).
Sallmann: “[t]he present invention relates to
an ophthalmic composition for treating
inflammatory ocular conditions, for treating
glaucoma...which composition comprises a
therapeutically effective amount of
diclofenac potassium and a carrier.”
(EX1009, 1:60-65)
(i) It would have been obvious to substitute tyloxapol from Sallmann’s Example 2 for polysorbate 80 in Ogawa’s Example 6
A POSA would have had reason to combine Ogawa and Sallmann to arrive
at the formulation recited in claim 1 of the ’290 patent. (EX1003, ¶ 49). Both
Ogawa and Sallmann relate to ophthalmic formulations of structurally-similar
acidic NSAIDs containing a non-ionic surfactant for ophthalmic administration,
and are within the pertinent art to the claims of the ’290 patent. (Id.).
As shown in the claim chart above, the only difference between the stable
aqueous preparation of Ogawa’s Example 6 and claim 1 is that Ogawa’s Example
6 includes polysorbate 80 as the non-ionic surfactant, whereas claim 1 recites
tyloxapol, another known non-ionic surfactant. Sallmann’s Example 2 provides
Petition for Inter Partes Review
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the missing non-ionic surfactant tyloxapol in an aqueous liquid ophthalmic
formulation of another NSAID (diclofenac potassium).
Prior to January 21, 2003, the prior art described ophthalmic formulations of
acidic NSAIDs containing a non-ionic surfactant like tyloxapol. (EX1004, 3:48-53
& 10:5-18; EX1011, 12:1-8; EX1019, 1:1:2; EX1020, 1:2:1 & 2:Scheme 1;
EX1017, 4:1-23, 6:8-9, 8:13-22 & Formulation 3; EX1009, 8:1-15; EX1003, ¶¶ 36,
38-39).
Sallmann teaches that tyloxapol may be a better surfactant than polysorbate
80. Specifically, Sallmann teaches that tyloxapol (another non-ionic surfactant)
was the preferred surfactant for use in aqueous ophthalmic preparations of
diclofenac (another acidic NSAID). (EX1009, 4:62). A POSA would have known
that substituting polysorbate 80 with tyloxapol would successfully, and
predictably, result in a stable ophthalmic formulation of bromfenac because
tyloxapol and polysorbate 80 had previously been used interchangeably as
surfactants in ophthalmic formulations. (EX1021, 13:8-10; EX1022, 4:24-31;
EX1003, ¶ 40). Moreover, Ogawa teaches that the aqueous liquid bromfenac
preparations formulated with polysorbate 80 is stable and will be useful for
ophthalmic administration. (EX1004, 10:5-18, 10:50-52 and 14:45-50; EX1003,
¶¶ 50, 53). Sallmann teaches that tyloxapol is a preferred solubilizer. (EX1009,
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4:62; EX1003, ¶ 62). Sinclair & Carroll Co., v. Interchemical Corp., 325 U.S.
327, 334 (1945).
In addition to being a better surfactant, it was also known that tyloxapol was
a better solubilizer than polysorbate 80 for acidic compounds in aqueous
ophthalmic formulations. (EX1012, Tables 4 & 5; EX1003, ¶¶ 63-65, FN13). A
POSA would have had a reasonable expectation of success substituting tyloxapol
for polysorbate 80, because Ogawa provides working examples of bromfenac
preparations formulated with polysorbate 80 and a POSA would have understood
from the state of the art that tyloxapol is superior to polysorbate 80 in solubilizing
another acidic ophthalmic drug. (EX1004, 10:5-18; EX1012, Tables 4 & 5;
EX1003, ¶¶ 63-65, FN13). In addition, the prior art disclosed multiple stable
aqueous preparations of acidic NSAIDs formulated with tyloxapol (and other
closely related non-ionic surfactants). (EX1009, 8:1-15; EX1011, 18:5-28,
Examples 2 & 5; EX1003, ¶¶ 38-39).
Accordingly, a POSA would have had a reasonable expectation of success in
substituting tyloxapol for polysorbate 80, because the prior art included multiple
examples of stable aqueous preparations containing NSAIDs (similar to
bromfenac) formulated with tyloxapol (and other closely related non-ionic
surfactants). (EX1009, 8:1-15; EX1011, 18:5-28, Examples 2 & 5; EX1003, ¶¶
39-41, 61).
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A POSA would have found it obvious to try to prepare a bromfenac
ophthalmic formulation containing tyloxapol as the surfactant, because tyloxapol
was one of three preferred surfactants—i.e., there was a finite number of
predictable solutions known—used to stabilize a similar NSAID (diclofenac).
(EX1009, 4:56-62; EX1003, ¶ 62). Wm. Wrigley Jr. Co. v. Cadbury Adams USA
LLC, 683 F.3d 1356, 1364-65 (Fed Cir. 2012). The law is clear that “[W]hen a
patent ‘simply arranges old elements with each performing the same function it
had been known to perform’ and yields no more than one would expect from
such an arrangement, the combination is obvious.” KSR, 550 U.S. at 416 (citing
Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976)).
(ii) It would have been obvious to substitute bromfenac from Ogawa’s Example 6 for diclofenac in Sallmann’s Example 2
As an alternative to switching non-ionic surfactants in the aqueous
ophthalmic preparations of Ogawa and Sallmann, it would have also been obvious
to switch NSAIDs. Thus, it would have been obvious to use bromfenac from
Ogawa’s Example 6 instead of diclofenac in Sallmann’s Example 2.
Example 2 in Sallmann describes an ophthalmic formulation containing
diclofenac (an acidic NSAID) and tyloxapol. (EX1009, 8:1-15; EX1003, ¶ 57).
The only difference between the ophthalmic formulation of Example 2 in Sallmann
and the ophthalmic preparation recited in challenged claim 1 is the choice of
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NSAID. The acidic NSAID in Sallmann’s example is diclofenac potassium,
whereas the acidic NSAID in challenged claim 1 is bromfenac (or a
pharmacologically acceptable salt or a hydrate thereof).
Bromfenac and diclofenac are both NSAIDs sharing several structural
features, most notably a phenylacetic acid moiety (phenyl-CH2-COOH).
(EX1003, ¶ 29).
Bromfenac and diclofenac were both proven to be effective NSAIDs in the
prior art. The prior art disclosed that NSAID compounds were suitable and
desirable for ophthalmic administration. (EX1018, 1:1; EX1003, ¶¶ 25-28). By
January 2003, a number of NSAIDs had been formulated and marketed for
ophthalmic administration. For example, diclofenac 1% (Voltaren®
, Ciba
Ophthalmic) was approved by the FDA in 1991 for minimizing post-operative
inflammation after cataract surgery (EX1018, 2:1); and by July 2000, bromfenac
sodium hydrate 0.1% (Bronuck®
, Senju) was introduced in Japan for the
treatment of post-operative inflammation. (EX1002, 2:Title). The Bronuck®
formulation was later marketed in the United States as Xibrom®
and Bromday®
.
Petition for Inter Partes Review
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(EX1003, ¶¶ 43-44). Notably, the Bronuck®
, Xibrom®
, and Bromday®
formulations were all commercial embodiments of the Ogawa patent, which
issued in 1991. (EX1003, ¶¶ 43-44).
Prior art references such as Hara (EX1002) described bromfenac as superior
to diclofenac and provided a POSA with a reason to substitute the bromfenac in
Ogawa’s Example 6 for the diclofenac in Sallmann’s Example 2. For example,
Hara describes “[b]romfenac sodium hydrate [as] a type of NSAID that was
developed in order to address the needs of clinical sites, and it is indicated for use
in a broad range of [ophthalmic] conditions, from inflammation of the outer ocular
area to post-operative inflammation of the anterior ocular segment.” (EX1002,
2:1:2). Hara compared bromfenac with three other NSAIDs that existed in the
prior art: pranoprofen, indomethacin, and diclofenac sodium. (EX1002, 2:2:2-
3:1:1). Hara concluded that bromfenac “shows superior efficacy in treating
anterior eye inflammation and post-operative inflammation.” (EX1002, 3:2:2).
Specifically, with respect to comparing bromfenac and diclofenac, Hara explains
that bromfenac “is indicated for use in a broad range of conditions, from
inflammation of the outer ocular area to post-operative inflammation of the
anterior ocular segment” (EX1002, 2:1:2), but states that, by contrast, “the range
of application [of diclofenac] is limited.” (EX1002, 2:2:5-3:1:1).
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As explained by Dr. Laskar, a POSA in January 2003, familiar with
Sallmann and Ogawa, would have had a reason to combine their teachings and
choose bromfenac over diclofenac because Sallmann teaches an aqueous liquid
ophthalmic formulation of diclofenac formulated with tyloxapol, and Hara teaches
that bromfenac [sodium hydrate], as disclosed in Ogawa, is broadly applicable for
treatment of various ophthalmic conditions, and preferable as compared to
diclofenac. (EX1003, ¶¶ 66-67). Thus, a POSA, reading Sallmann and Ogawa,
and knowing the state of the art as described in Hara, would have had reason to
substitute the bromfenac of Ogawa’s Example 6 for diclofenac in Sallmann’s
Example 2. (EX1003, ¶¶ 67-68).
The results of substituting bromfenac for diclofenac in Sallmann’s Example
2 would have been predictable. A POSA would have known that substituting
bromfenac for diclofenac would have yielded predictable results because both
are NSAIDs with similar pharmacological properties. (EX1002, 2:1:4-2:2:1;
EX1003, ¶ 68). See Sundance, Inc., 550 F.3d at 1366-67 (“a combination is more
likely to be obvious where it ‘simply arranges old elements with each performing
the same function it had been known to perform’ and yields no more than one
would expect from such an arrangement”).
Furthermore, a POSA facing a design-need to formulate a stable bromfenac
solution would have found it at least obvious to try to prepare an aqueous liquid
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bromfenac preparation comprising tyloxapol because, as illustrated by Hara, the
state of the art was such that there were only four NSAID ophthalmic drugs
available on the market by 2003, i.e., a finite number of predictable solutions,
“resulting in limited choices.” (EX1002, 2:2:2-3:1:2; EX1003, ¶ 68). Wm.
Wrigley Jr. Co. 683 F.3d at 1364-65. As Dr. Laskar explains in his declaration, a
POSA would have had a reasonable expectation of success because Sallmann sets
forth all of the excipients for an aqueous liquid ophthalmic formulation of an
NSAID, and references embodying the state of the art, such as Hara, provide an
expectation that an aqueous liquid preparation of bromfenac will be safe, effective,
and broadly applicable. (EX1003, ¶¶ 66-68). Therefore, in view of Sallmann and
Ogawa, a POSA would have reasonably expected to be able to make and use an
aqueous liquid ophthalmic preparation within the scope of claim 1 of the ’290
patent.
b. Claim 8
Claim 8 is an independent claim that differs from claim 1 in that it requires
that greater than about 90% of the original amount of bromfenac remains in the
claimed preparation after storage at about 60°C for 4 weeks. Claim 8 is
reproduced below (emphasis added).
8. A stable aqueous liquid preparation comprising: (a) a first
component; and (b) a second component; wherein the first
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component is 2-amino-3-(4-bromobenzoyl) phenylacetic
acid or a pharmacologically acceptable salt thereof or a
hydrate thereof, wherein the hydrate is at least one selected
from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate the first
component is the sole pharmaceutical active ingredient
contained in the preparation; the second component is
tyloxapol; wherein said stable liquid preparation is
formulated for ophthalmic administration; and wherein the
stable aqueous liquid preparation is characterized in that
greater than about 90% of the original amount of the first
component remains in the preparation after storage at about
60° C for 4 weeks.
Claim 8 is obvious over Ogawa in view of Sallmann. The limitations of
claim 8 which are common to claim 1 are obvious over Ogawa’s Example 6 in
view of Sallmann’s Example 2 for the same reasons discussed above for claim 1.
The limitation of claim 8 requiring that “greater than about 90%” of the
original bromfenac remains after storage at 60 °C for 4 weeks is also described in
Ogawa. (EX1004, 10:50-52 and 14:45-50). Ogawa’s Example 6 was tested under
the very same conditions (60 °C for 4 weeks) as recited in claim 8, and as shown in
Example 11 of Ogawa, more than 90% of the original bromfenac in the preparation
remained after 4 weeks. (EX1004, 10:50-52 and 14:45-50).
A POSA would not expect that using tyloxapol instead of polysorbate 80 as
the surfactant in Ogawa’s Example 6 would have a negative impact on the amount
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of bromfenac remaining in the formulation after 4 weeks at 60 °C. (EX1003, ¶¶ 55,
59, 61-62). Thus, a POSA would reasonably expect that switching surfactants—
employing the tyloxapol from Sallmann’s Example 2 instead of polysorbate 80 in
Ogawa’s Example 6—would maintain greater than about 90% stability after 4
weeks at 60 °C as recited in claim 8. (EX1003, ¶¶ 55, 59, 61-62). Furthermore,
regardless of an actual disclosure, this degree of stability represents a “latent”
property of an otherwise obvious preparation— a preparation suggested by Ogawa
and Sallmann—and the inventors’ mere recognition of that property does not
render nonobvious the modified preparation of Ogawa and Sallmann. See In re
Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“Mere recognition of
latent properties in the prior art does not render nonobvious an otherwise known
invention.”); see also, Santarus v. Par Pharm, 694 F.3d 1344, 1354 (Fed. Cir.
2012) (an obvious formulation does not “become patentable merely by testing and
claiming an inherent property.”). Claim 8 is obvious.
c. Claim 14
Independent claim 14 differs from claim 1 only in that it requires that the
stable liquid ophthalmic preparation does not contain mannitol.
Claim 14 is obvious over Ogawa in view of Sallmann. The limitations of
claim 14 which are common to claim 1 are obvious over Ogawa’s Example 6 in
view of Sallmann’s Example 2 for the same reasons discussed above for claim 1.
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Further, neither Example 6 in Ogawa nor Example 2 in Sallmann contains
mannitol. Thus, for the same reasons discussed above for claim 1, a POSA would
have had a reasonable expectation of success in formulating a stable
bromfenac/tyloxapol ophthalmic solution without mannitol. Claim 14 is also
obvious.
B. Dependent Claims
The challenged dependent claims each merely recite concentrations or
ranges of specific ingredients or certain pH ranges, preservative efficacy standards,
or additional pharmaceutical excipients which the ’290 patent characterizes as
“conventional.” (EX1001, 6:9-29). See KSR Int’l Co., 550 U.S. at 417 (a claim
likely is obvious if it is no “more than the predictable use of prior art elements
according to their established functions”). As explained further below, and in Dr.
Laskar’s declaration, each of these dependent claims would have been prima facie
obvious to a POSA based on the prior art.
1. Claims 2, 9, 15, and 21—Quaternary Ammonium Salt
Claims 2, 9, 15, and 21 recite the further requirement that the claimed
formulation contains a quaternary ammonium salt. (EX1001, 12:13-14, 12:54-55,
and 13:26-27). This further limitation is included in the examples in Ogawa and
Sallmann, and for the same reasons discussed above for independent claims 1, 8,
and 14, these dependent claims are obvious in view of the prior art.
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’290 patent claim 2 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
2. The aqueous liquid
preparation according to
claim 1
See discussion above for claim 1.
further comprising a
quaternary ammonium
salt
Ogawa Example 6 (EX1004, 10:5-18) and Sallmann
Example 2 (EX1009, 8:1-15) both include
benzalkonium chloride (“BAC”), a quaternary
ammonium salt.
’290 patent claim 9 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
9. The aqueous liquid
preparation according
to claim 8
See discussion above for claim 8.
further comprising a
quaternary ammonium
salt
Ogawa Example 6 (EX1004, 10:5-18) and Sallmann
Example 2 (EX1009, 8:1-15) both include
benzalkonium chloride (“BAC”).
’290 patent claim 15 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
15. The aqueous liquid
preparation according
to claim 14
See discussion above for claim 14.
further comprising a
quaternary ammonium
salt
Ogawa Example 6 (EX1004, 10:5-18) and Sallmann
Example 2 (EX1009, 8:1-15) both include
benzalkonium chloride (“BAC”) which is a
quaternary ammonium salt.
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’290 patent claim 21 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
21. The aqueous liquid
preparation according to
claim 20
See discussion above for claim 14 and below for
claim 20.
further comprising a
quaternary ammonium
salt
Ogawa Example 6 (EX1004, 10:5-18) and Sallmann
Example 2 (EX1009, 8:1-15) both include
benzalkonium chloride (“BAC”) which is a
quaternary ammonium salt.
The aqueous formulations of Ogawa’s Example 6 and Sallmann’s Example
2 include a quaternary ammonium salt, benzalkonium chloride (“BAC”).
(EX1004, 10:5-18; EX1009, 8:1-15).
Prior to January 21, 2003, it was known that acidic NSAIDs (such as
bromfenac and diclofenac), containing an ionizable carboxylic acid group, form
complexes with quaternary ammonium preservatives, such as BAC, in ophthalmic
formulations. (EX1003, ¶¶ 29, 33). The interaction of the acidic NSAID with
BAC results in complexes that were known to precipitate out of the ophthalmic
formulation, which is problematic because it: (1) renders the preservative (e.g.,
BAC) less available to serve its function; and (2) reduces the availability of the
NSAID (e.g., bromfenac). (EX1003, ¶ 33). In addition, the prior art disclosed
multiple stable aqueous preparations of acidic NSAIDs formulated with BAC and
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tyloxapol (and other closely related non-ionic surfactants). (EX1009, 8:1-15;
EX1011, 18:5-28, Examples 2 & 5; EX1003, ¶¶ 32, 35-36, 39).
For at least these reasons a POSA would have had a reasonable expectation
of successfully formulating a stable ophthalmic formulation comprising
bromfenac, tyloxapol, and a quaternary ammonium salt, such as BAC.
2. Claims 3 and 16—Sodium Salt of Bromfenac
Claims 3 and 16 recite the further requirement that the pharmacologically
acceptable salt of bromfenac is a sodium salt of bromfenac. (EX1001, 12:15-17;
13:28-30). This further limitation is included in the examples in Ogawa and
Sallmann and, for the same reasons discussed above for independent claims 1 and
14, these dependent claims are obvious in view of the prior art.
’290 patent claim 3 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
3. The aqueous liquid preparation
according to claim 1,
See discussion above for claim 1.
wherein the first component is a
2-amino-3-(bromobenzoyl)
phenylacetic acid sodium salt.
Ogawa Example 6 (EX1004, 10:5-18)
includes bromfenac sodium.
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’290 patent claim 16 Disclosure in Ogawa (EX1004)
and Sallmann (EX1009)
16. The aqueous liquid
preparation according to claim
14,
See discussion above for claim 14.
wherein the first component is a
2-amino-3-(bromobenzoyl)
phenylacetic acid sodium salt.
Ogawa Example 6 (EX1004, 10:5-18)
includes bromfenac sodium.
Requiring the sodium salt of bromfenac does not impart patentability to
these dependent claims since the prior art, including Ogawa, describe a clear
preference for the sodium salt of bromfenac. (EX1004, 10:5-18).
Like the challenged claims, Example 6 of Ogawa also contains the
sodium salt of bromfenac. (EX1004, 10:8-9; EX1003, ¶ 74). As explained
above with regard to independent claims 1, 8, and 14, a POSA would have had a
reason to combine the teaching of Ogawa with the teaching of Sallmann. Given
that Ogawa discloses the sodium salt form of bromfenac specifically—i.e., in every
working Example—a POSA would have had a reason to select the bromfenac
sodium salt of Ogawa to arrive at the formulations recited in claims 3 and 16.
(EX1003, ¶ 74). The POSA would have had a reasonable expectation of success in
employing the sodium salt of bromfenac because the same salt was already shown
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in Ogawa to have been successfully formulated with a non-ionic surfactant.
(EX1003, ¶74).
Hara also expressly discloses the sodium salt of bromfenac. (EX1002, Title,
2:1:2 & 3:1:2; EX1003, ¶ 74). Given that the only salt form disclosed in Hara is
the sodium salt form, a POSA yet another reason to choose bromfenac sodium salt
in view of the combination of Ogawa and Sallmann to arrive at the claimed
formulations as recited in claims 3 and 16. (EX1003, ¶ 74). The disclosure of
Hara only furthers the reasonable expectation of success because Hara shows that
bromfenac sodium salt was successfully formulated in an ophthalmic formulation
with a non-ionic surfactant, e.g., Bronuck®—(bromfenac) which also contains the
sodium salt form. (EX1002, Title & 2:1:3; EX1003, ¶ 44). Furthermore, a POSA
would have known that substituting bromfenac sodium salt for diclofenac
potassium salt would have yielded predictable results because both were
commercially available NSAIDs, in approved ophthalmic formulations, with
similar pharmacological properties. (EX1003, ¶¶ 66-69).
3. Claims 4-5, 7, 11, 13, 17, 19, 23, and 25—Bromfenac Sodium
and Tyloxapol Concentrations
a. Bromfenac Sodium Concentration
Dependent claims 4, 11, and 23 recite a bromfenac sodium salt concentration
from 0.01 w/v% to about 0.2 w/v%. Claim 5 depends from claim 4 and further
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specifies that the bromfenac sodium concentration is about 0.1 w/v%. Dependent
claims 7, 13, 19, and 25 recite a bromfenac sodium salt concentration from 0.02
w/v% to about 0.1 w/v%. Dependent claim 17 recites a bromfenac sodium salt
concentration from 0.05 w/v % to about 0.2 w/v %. These added “bromfenac
sodium salt concentration” limitations do not render these claims patentable over
the prior art.
Example 6 of Ogawa contains bromfenac sodium salt at a concentration of
0.1 w/v% which is the same concentration recited in claim 5 and within the ranges
recited in claims 4, 7, 11, 13, 17, 19, 23, and 25 of the ’290 patent. (EX1004, 4:42-
46 & 10:8-9). Further, Ogawa discloses that the concentration of the active
ingredient in the liquid preparation of the claimed invention may range from about
0.001% to about 10%. (EX1004, 4:42-46; EX1003, ¶ 76).
Since Ogawa’s disclosure of 0.1 w/v % of bromfenac sodium salt is a
species within the genus of claimed bromfenac sodium salt ranges, this limitation
does not impart patentability to claims 4, 7, 11, 13, 17, 19, 23, and 25. Chapman v.
Casner, 315 Fed. App’x 294, 297-98 (Fed. Cir. 2009) (claim directed to the genus
was rendered obvious by references disclosing the species).
Additionally, because the claimed bromfenac sodium salt concentration
ranges recited in claims 4, 7, 11, 13, 17, 19, 23, and 25, overlap the concentration
described in Ogawa, the ranges would have been obvious. Iron Grip Barbell Co.,
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Inc., v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004). Further, the ’290
patent does not describe any criticality associated with the claimed concentration
ranges, the prior art does not teach away from the claimed ranges, and there are
no unexpected results or other pertinent objective indicia attributable to the
specific claimed bromfenac sodium salt concentration ranges sufficient to
overcome the conclusion that these claims are obvious. Galderma Labs., L.P., v.
Tolmar, Inc., 737 F.3d 731, 737-738 (Fed. Cir. 2013).
Moreover, the Hara reference expressly discloses the same bromfenac
sodium salt concentration of 0.1 w/v % as described in Ogawa’s Example 6.
(EX1002, 3:1:2). Given the foregoing, 4, 7, 11, 13, 17, 19, 23, and 25 are obvious.
b. Tyloxapol Concentration
Dependent claims 4, 11, 17, and 23 recite a tyloxapol concentration from
0.01 w/v% to about 0.05 w/v%. This added “tyloxapol concentration” limitation
does not render these claims patentable over the prior art.
Sallmann’s Example 2 discloses a tyloxapol concentration of 0.1 w/v % and
Sallmann generally describes a range from 0.01 w/v % to 500 w/v % in an
ophthalmic formulation containing 0.1 w/v % diclofenac. (EX1009, 8:10, 4:65-
67; EX1003, ¶ 80). As discussed above with respect to claim 1, a POSA would
have combined the teachings of Ogawa and Sallmann to modify Example 6 in
Ogawa to substitute tyloxapol for polysorbate 80. A POSA would have had a
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reason to substitute tyloxapol for polysorbate 80 in Ogawa’s ophthalmic
bromfenac formulation because Sallmann teaches that tyloxapol is a preferred
solubilizer. (EX1003, ¶¶ 61-65).
Although the tyloxapol concentration utilized in Sallmann’s Example 2 does
not overlap with the claimed tyloxapol range of claims 4, 11, 17 and 23, a prima
facie case of obviousness exists where, as here, the claimed ranges and prior art
ranges do not overlap but are close enough that one skilled in the art would have
expected them to have the same properties. (EX1003, ¶ 80). Titanium Metals
Corp. of Amer. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court
held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel,
0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference
disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and
0.94% nickel, 0.31% molybdenum, balance titanium.).
Alternatively, because the claimed tyloxapol range falls within Sallmann’s
generally disclosed range, Petitioner has established a prima facie case that the
tyloxapol ranges of claims 4, 11, 17 and 23 are obvious. The obviousness of these
claims cannot be rebutted because: (i) the prior art does not teach away from the
claimed ranges; and (ii) there is no indication that the claimed ranges are critical.
(EX1001, Table 1). Galderma Labs., L.P., 737 F.3d at 737-38.
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Further, a POSA would have arrived at a tyloxapol concentration of 0.01
w/v to about 0.05 w/v % using only routine experimentation based on the
disclosure of Sallmann. (EX1003, ¶ 81). In re Aller, 220 F.2d 456; In re Peterson,
315 F.3d 1325, 1330 (Fed. Cir. 2003). Additionally, there is no evidence in the
’290 patent or its file history of any criticality associated with the range of
tyloxapol as claimed. (EX1001). Nor is there any evidence to suggest that the
claimed tyloxapol ranges achieve unexpected results relative to the prior art range.
As such, the obviousness of these claims cannot be rebutted.
c. Additional Additives
In addition to reciting a bromfenac sodium salt concentration of about 0.02
w/v% to about 0.1 w/v%, claims 7, 13, 19, and 25 also recite certain additives.
(EX1001, 12:31-40; 13:3-14; 13:38-48; 14:3-15). However, such “additive”
limitations also do not render these claims patentable over the prior art relied on
because they are conventional and well-known in the prior art employed in
aqueous ophthalmic preparations. (EX1003, ¶¶ 83-87).
For example, Ogawa describes that it would have been desirable to use a
solution containing: (i) the preservative BAC to inhibit microbial growth;
(ii) the buffer boric acid/borate to prevent pH changes; (iii) the thickener PVP to
act as a carrier; (iv) the stabilizer sodium sulfite to prevent oxidation reactions;
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and (v) a chelating agent, such as EDTA sodium salt. (EX1004, 3:62-67; 4:33-
34 & Example 6; EX1003, ¶ 84).
Similarly, Sallmann discloses that it would have been desirable to use a
solution containing: (i) the preservative BAC to inhibit microbial growth;
(ii) the buffer borate to prevent pH changes; (iii) the thickener PVP to act as a
carrier; (iv) the stabilizer sodium hydrogen sulfite to prevent oxidation
reactions; and (v) the chelating agent disodium edetate. (EX1009, 8:1-15, 4:23-
30, 5:8-10, 5:47-53, 10:22 & 14:14; EX1003, ¶ 87).
Accordingly, each of Ogawa and Sallmann expressly teaches each of the
additives recited in claims 7, 13, 19, and 25. Thus, because the prior art clearly
disclosed desirability of relevant aqueous solutions containing each of the additives
recited in claims 7, 13, 19, and 25, a POSA would have had a reasonable
expectation of success to arrive at the solutions claimed therein, and those claims
are obvious.
4. Claims 6, 12, 18, and 24—pH Ranges
Claims 6, 12, 18, and 24 recite pH ranges from “about 7.5 to about 8.5.”
(EX1001, 12:29-30; 13:1-2; 13:36-37, 14:1-2). These pH limitations, however, do
not render these claims patentable over the prior art, as they are not only previously
disclosed but are common and conventional pH ranges for ophthalmic
preparations. (EX1003, ¶¶ 89-91).
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For example, Ogawa expressly discloses a pH from about 7.5 to about 8.5.
(EX1004, 3:48-53; EX1003, ¶ 89). Overlapping ranges establish a prima facie
case of obviousness. In re Peterson, 315 F.3d at 1329-30; In re Woodruff, 919
F.2d 1575, 1578 (Fed. Cir. 1990); In re Malagari, 499 F.2d 1297, 1303 (C.C.P.A.
1974). Because Ogawa discloses a pH that falls within the pH ranges of claims 6,
12, 18, and 24, those pH ranges are obvious and do not render the claimed
preparations patentable. Chapman, 315 Fed. App’x at 297-98.
5. Claims 10, 20 and 22—Storage Stability
Dependent claim 20 recites the further limitation that the claimed aqueous
liquid preparations contain about 90% of the original amount of bromfenac after
storage at about 60°C for 4 weeks. (EX1001, 13:49-53). Dependent claims 10 and
22 recite the further limitation that the claimed aqueous liquid preparations contain
about 92% of the original amount of bromfenac after storage at about 60°C for 4
weeks. (EX1001, 12:56-60, 13:56-60).
As discussed above for claim 1, Ogawa describes the same storage
conditions of 60 °C for 4 weeks, and reports the amount of bromfenac sodium
remaining as greater than the 92% and 90% limitations of claims 10, 20, and 22 of
the ’290 patent. Specifically, Ogawa Table 11 describes that Example 6
Ophthalmic Solution, after 4 weeks at 60 °C, contains about 100% of the original
amount of bromfenac sodium. (EX1004, 10:50-52 and 14:45-50; EX1003, ¶ 94).
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Because this further storage stability limitation is described in Ogawa, claims 10,
20, and 22 are obvious for the same reasons discussed for claims 8 and 14, from
which they depend. (EX1003, ¶¶ 93-94). Furthermore, regardless of an actual
disclosure, this degree of stability represents a “latent” property of an otherwise
obvious preparation— a preparation suggested by Ogawa and Sallmann—and the
inventors’ mere recognition of that property does not render nonobvious the
modified preparation of Ogawa and Sallmann. See In re Baxter Travenol Labs.,
952 F.2d 388, 392 (Fed. Cir. 1991) (“Mere recognition of latent properties in the
prior art does not render nonobvious an otherwise known invention.”); see also,
Santarus v. Par Pharm, 694 F.3d 1344, 1354 (Fed. Cir. 2012) (an obvious
formulation does not “become patentable merely by testing and claiming an
inherent property.”).
6. Claims 26-30—Preservative Efficacy Test
Dependent claims 26-30 recite the further limitation that the ophthalmic
formulations satisfy the preexisting preservative efficacy standards promulgated by
the appropriate regulatory agencies, in this case EP-criteria A and B of the
European Pharmacopeia (“EP-criteria A” or “EP-criteria B”) —standards that must
be met in order to produce a medically acceptable ophthalmic composition. This
requirement does not impart patentability to any of these dependent claims.
(EX1001, 14:15-15:8).
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EP-criteria A and EP-criteria B are standard efficacy tests for antimicrobial
preservation in which a test preparation is inoculated with five microorganisms—
(1) Pseudomonas aeruginosa, a gram-negative bacteria, (2) Staphylococcus
aureus, a gram-positive bacteria, (3) Escheria coli, a gram-negative bacteria,
(4) Candida albicans, a vegetative bacteria yeast, and (5) Aspergillus niger, a
mold. (EX1003, ¶ 96). The formulations are kept at room temperature, and at
regular time intervals samples are removed so that the number of viable
microorganisms may be determined either by plate count or membrane filtration.
(EX1003, ¶ 96).
The preservative properties of a preparation are sufficient to meet the
EP-criteria B standard where viable cell counts of bacteria (S. aureus and P.
aeruginosa) 24 hours and 7 days after inoculation, decrease to not more than 1/10
and not more than 1/1000, respectively, and thereafter, the cell count levels off or
decreases. (EX1003, ¶ 97). Further, viable cell count of fungi (C. albicans, A.
niger) 14 days after inoculation decrease to not more than 1/10 and, thereafter, the
cell count keeps the same level as that of 14 days after inoculation. (EX1003, ¶
97).
As discussed above, Ogawa discloses a stable ophthalmic formulation
containing bromfenac, polysorbate 80, benzalkonium chloride (a quaternary
ammonium salt), and boric acid, among other additives. (EX1004, 10:5-18). In
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view of Sallmann, a POSA would have had a reasonable expectation of
successfully substituting tyloxapol for polysorbate 80 in the formulation
disclosed in Ogawa, because Ogawa provides working examples of bromfenac
preparations formulated with polysorbate 80 and a POSA would have
understood from the state of the art that tyloxapol is superior to polysorbate 80
in solubilizing acidic ophthalmic drugs. (EX1004, 10:5-18; EX1012, Tables 4
& 5; EX1003, ¶¶ 98). Further, the prior art disclosed multiple stable aqueous
preparations of acidic NSAIDs formulated with BAC and tyloxapol (and other
closely related non-ionic surfactants). (EX1009, 8:1-15; EX1011, 18:5-28,
Examples 2 & 5; EX1003, ¶ 98).
A POSA would have combined the teachings of Ogawa and Sallmann,
substituting tyloxapol for polysorbate 80, and would have had a reasonable
expectation of success that the presence of a quaternary ammonium salt, such as
BAC, in combination with boric acid would satisfy the required preservative
efficacy standards including the standards put forth by the European
Pharmacopeia (1994).5,6
(EX1003, ¶ 99). Regardless of an actual disclosure, this
5 The United States Pharmacopeia and the European Pharmacopeia establish
written (documentary) and physical (reference) standards for medicines, food
ingredients, and dietary supplement products and ingredients. These standards are
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claimed degree of microbial stability represents a “latent” property of an
otherwise obvious preparation—a preparation suggested by Ogawa and
Sallmann—and the inventors’ mere recognition of that property does not render
nonobvious the modified preparation of Ogawa and Sallmann. See In re Baxter
Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“Mere recognition of latent
properties in the prior art does not render nonobvious an otherwise known
invention.”); see also, Santarus v. Par Pharm, 694 F.3d 1344, 1354 (Fed. Cir.
2012) (an obvious formulation does not “become patentable merely by testing
and claiming an inherent property.”).
Furthermore, a POSA would have been motivated to modify the solution to
meet the applicable standards—which would have been known in the state of the
art—in order to produce a medically and commercially acceptable ophthalmic
composition. (EX1003, ¶¶ 100-101). In re Aller, 220 F.2d 454, 456-57 (C.C.P.A.
used by regulatory agencies and manufacturers to ensure that these products are of
the appropriate identity, as well as strength, quality, purity, and consistency.
(EX1003 ¶ 96).
6 The EP B-Criteria of the European Pharmacopeia are less demanding than
the EP A-Criteria. Therefore, a formulation that satisfied the EP A-Criteria would
necessarily satisfy the EP B-Criteria as well.
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1955) (holding that “where the general conditions of a claim are disclosed in the
prior art, it is not inventive to discover the optimum or workable ranges by routine
experimentation”). As such, claims 26-30 are obvious.
C. Objective Indicia of Nonobviousness
Although objective indicia of nonobviousness must be taken into account,
they do not necessarily control an obviousness determination. Newell Cos., Inc. v.
Kenney Mfg. Co., 864 F.2d 757, 768 (Fed. Cir. 1988). Petitioner addresses below
potential objective indicia arguments that Patent Owner may attempt to raise. To
the extent Patent Owner does assert any objective indicia in this proceeding,
detailed consideration of Patent Owner’s evidence should not be undertaken until
Petitioner has had an opportunity to respond to it. Amneal Pharmaceuticals, LLC
v. Supernus Pharmaceuticals, Inc., IPR2013-00368 [Paper 8, pp. 12-13].
1. No Unexpected Results Over the Closest Prior Art
To establish unexpected results, Patent Owner must compare its invention
with the closest prior art. In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984); In
re Merchant, 575 F.2d 865, 868 (C.C.P.A. 1978).
Ogawa discloses examples of ophthalmic formulations containing
bromfenac, BAC, and the non-ionic surfactant polysorbate 80 (EX1004, 10:5-18;
EX1003, ¶ 103) and, therefore, Ogawa is considered the closest prior art for this
inquiry. Patent Owner’s self-serving argument during prosecution—that “there is
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49
no suggestion to avoid degradation of acidic drugs, such as bromfenac, by using
tyloxapol” or applicant “surprisingly found that the degradation of bromfenac
could be avoided by specifically including tyloxapol in the preparation”—fails to
establish unexpected superiority against the teachings of Ogawa. (EX1023, 8;
EX1025, 4; EX1003, ¶ 103).
a. Tyloxapol’s Stabilizing Effects
Tyloxapol’s stabilizing effects described in the ’290 patent are not
unexpected. The patentees allege in the ’290 patent that liquid aqueous
preparations of bromfenac formulated with tyloxapol exhibit greater bromfenac
stability than those formulated with polysorbate 80. (EX1001, 7:57-64). The
stabilizing property of tyloxapol was well-known in the prior art and was not
“unexpected,” for the reasons already discussed above.
Furthermore, the prior art taught that non-ionic surfactants in the same
ethoxylated octylphenol family as tyloxapol, such as Octoxynol 9 and Octoxynol
40, stabilized ophthalmic formulations of NSAIDs and BAC. (EX1011, 20:23-27;
EX1003, ¶¶ 104-105). Tyloxapol is, and was known in the prior art as, an
oligomeric form of Octoxynol 9. (EX1019, 1:1:2; EX1020, 1:2:1; EX1003, ¶¶
105-106). Ethoxylated octylphenol surfactants, a class that includes tyloxapol,
were known to be superior to polysorbate 80 in stabilizing aqueous liquid
preparations of NSAIDs and BAC. (EX1011, 12:1-8 & Example 5; EX1003, ¶
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of U.S. Patent No. 8,669,290
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107). Accordingly, at least for these reasons, the prior art shows that the
stabilizing effect of tyloxapol was not unexpected, but rather, expected.
b. Scope of Stabilizing Effects
Patent Owner has not demonstrated that any purported unexpected results
attributable to tyloxapol, including its stabilizing effects, occur over the entire
claimed range of aqueous liquid bromfenac preparations. In re Peterson, 315 F.3d
at 1331 (holding that evidence of unexpected results must be commensurate in
scope with the claims to which it pertains). For example, the claims of the ’290
patent encompass preparations having a wide pH range—spanning from at least
7.5 to 8.5. But the patent provides the stability analysis of tyloxapol at a very
small range of 8.16, 8.17 and 8.19. There is no indication that tyloxapol provides
the same stability at other pH ranges. (EX1003, ¶¶ 108-110).
2. Other Objective Indicia
First, Patent Owner cannot establish that the claims of the ’290 patent met
any long-felt, but unmet, need. Bromfenac ophthalmic formulations existed
(Xibrom® and Bromday
®) prior to Prolensa
®, the purported commercial
embodiment of certain of the claims of the ’290 patent. (EX1003, ¶¶ 44, 111-113).
Further, the long-felt, but unmet, need should be a need created by inadequacies in
the technical knowledge, not by business-driven market forces that are unrelated to
technical considerations. Friskit, Inc. v. Real Networks, Inc., 306 F. App’x 610,
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
51
617-618 (Fed. Cir. 2009). To the extent there was even any need for the claimed
bromfenac ophthalmic formulations claimed in the ’290 patent, it would have been
met by the disclosures of Ogawa and Hara, each of which describes stable
ophthalmic bromfenac formulations. (EX1003, ¶ 113). And Bronuck®, which was
commercially available in July 2000, was a stable formulation. (EX1002, 2:Title &
3:1:2). Bronuck® is a commercial embodiment of the Ogawa patent. (EX1003, ¶
112).
Patent Owner cannot demonstrate that the claimed bromfenac preparations
were met with skepticism or that other POSAs tried but failed to solve the problem
allegedly solved by the ’290 patent. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d
1530, 1540 (Fed. Cir. 1983). Any evidence of failure of others must suggest that
the prior attempts failed because they lacked the claimed elements. Ormco Corp.
v. Align Tech., Inc., 463 F.3d 1299, 1313 (Fed. Cir. 2006). A stable ophthalmic
bromfenac formulation was already commercially launched in July 2000.
(EX1002, 2:Title). At least for this reason, there can be no genuine skepticism.
(EX1003, ¶¶ 114-115).
Patent Owner cannot show that the claimed invention of the ’290 patent was
met with any praise in the industry. Stable bromfenac ophthalmic formulations
were already marketed in products relating to the prior art (EX1003, ¶¶ 43-44, 116)
and the prior art disclosed similar stable formulations. (EX1003, ¶¶ 36-39).
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of U.S. Patent No. 8,669,290
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Next, a showing of “copying in the ANDA context where a showing of
bioequivalence is required for FDA approval” is not compelling evidence of
nonobviousness. Purdue Pharma Prods. L.P. v. Par Pharm., Inc., 377 Fed App’x
978, 983 (Fed. Cir. 2010). Thus, any argument by Patent Owner that ANDA
submissions suggest nonobviousness because of copying is without merit.
Further, commercial acquiescence requires Patent Owner to show that any
license in the ’290 patent arose out of recognition and acceptance of the patent and
a nexus to the merits of the claimed invention. Stratoflex, Inc., 713 F.2d at 1539.
Because the ’290 patent has not received any special recognition or acceptance
from the ophthalmic formulation industry, Patent Owner cannot demonstrate that
any license to B&L establishes nonobviousness. (EX1003, ¶ 116).
Finally, commercial success requires Patent Owner to show that: (i) that a
claimed embodiment (Prolensa®) is successful commercially, e.g., has substantial
market share; and (ii) there is a nexus between the success and the novel features
of the claims. Tokai Corp. v. Eason Enters., Inc., 632 F.3d 1358, 1369-70 (Fed.
Cir. 2011). To date, Patent Owner has not come forward with any evidence of
commercial success and the prosecution history is devoid of any such evidence.
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of U.S. Patent No. 8,669,290
53
IX. CONCLUSION
Petitioner has demonstrated by a preponderance of the evidence that claims
1-30 of the ’290 patent are unpatentable as obvious over the prior art combinations
cited herein, and respectfully requests that the Board so finds.
RESPECTFULLY SUBMITTED,
ALSTON & BIRD LLP
Date: March 19, 2015
/Jitendra Malik/
Jitendra Malik (Reg. No. 55823)
4721Emperor Boulevard, Suite 400
Durham, North Carolina 27703
Telephone: 919-862-2200
Fax: 919-862-2260
Lead Counsel for Petitioner
InnoPharma Licensing Inc., InnoPharma
Licensing LLC, InnoPharma Inc.,
InnoPharma LLC, Mylan
Pharmaceuticals Inc., and Mylan Inc.
CERTIFICATION OF SERVICE
Pursuant to 37 C.F.R. §§ 42.6(e), 42.8(b)(4) and 42.105, the undersigned
certifies that on the 19th day of March 2015, a complete copy of the foregoing
Petitioner’s Petition for Inter Partes Review of U.S. Patent No. 8,669,290, Power
of Attorney, Exhibit List, and all supporting exhibits, were served via UPS® to the
Patent Owner by serving the correspondence address of record for the ’290 patent:
WENDEROTH, LIND & PONACK, L.L.P.
1030 15th Street, N.W.,
Suite 400 East
Washington, DC 20005-1503
Courtesy copies of the foregoing were also served via UPS® on counsel of
record for the Petitioner and Patent Owner in Metrics, Inc. v. Senju Pharmaceutical
Co., Ltd., IPR2014-01043 as follows:
Senju Pharmaceutical Co., Ltd., et al.
M. Andrew Holtman
Finnegan, Henderson, Farabow, Garrett & Dunner LLP
901 New York Avenue, NW
Washington DC 20001-4413
Jonathan R. Stroud
Finnegan, Henderson, Farabow, Garrett & Dunner LLP
901 New York Avenue, NW
Washington DC 20001-4413
Metrics, Inc., et al.
Patrick D. McPherson
Duane Morris LLP
505 9th Street, N.W., Suite 1000
Washington DC 20004-2166
Petition for Inter Partes Review
of U.S. Patent No. 8,669,290
2
Vincent L. Capuano
Duane Morris LLP
100 High Street, Suite 2400
Boston, MA 02110
Respectfully submitted,
ALSTON & BIRD LLP
By: /Jitendra Malik/
Jitendra Malik, Ph.D.
Registration No. 55,823
4721 Emperor Boulevard, Suite 400
Durham, North Carolina 27703-8580
(919) 862-2200
Bryan L. Skelton, Ph.D.
Registration No. 50,893
4721 Emperor Boulevard, Suite 400
Durham, North Carolina 27703-8580
(919) 862-2200
Lance Soderstrom
Registration No. 65,405
90 Park Avenue
15th Floor
New York, New York 10016-1387
212.210.9400
Attorneys for Petitioners InnoPharma
Licensing, Inc., InnoPharma Licensing LLC,
InnoPharma Inc., InnoPharma LLC, Mylan
Pharmaceuticals Inc., and Mylan Inc.