IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`METRICS, INC.
`Petitioner
`v.
`SENJU PHARMACEUTICAL CO., LTD.
`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: IPR2014-01043
`_____________________
`
`SECOND CORRECTED DECLARATION OF UDAY B. KOMPELLA,
`PH.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Metrics EX1003
`
`i
`
`
`
`
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I. 
`
`Introduction ......................................................................................................... 1 
`
`II.  List of documents I considered in formulating my opinion................................ 6 
`
`III.  My background and qualifications ................................................................ 10 
`
`IV.  Person of ordinary skill in the art (POSA) .................................................... 14 
`
`V.  The ’290 patent ................................................................................................. 15 
`
`VI.  State of the art as of January, 2003 ................................................................ 16 
`
`A.  Non-steroidal anti-inflammatory compounds were known and approved for
`
`ophthalmic use ...................................................................................................... 16 
`
`B.  BAC was the preservative of choice in ophthalmic formulations ................. 19 
`
`C.  It was known that non-ionic surfactants stabilized aqueous preparations
`
`containing an NSAID and BAC ........................................................................... 21 
`
`D.  Tyloxapol is a non-ionic surfactant that was known and widely used in
`
`ophthalmic formulations by January 2003 ........................................................... 22 
`
`E.  There is nothing inventive in the ’290 patent in view of the prior art ........... 26 
`
`VII.  Obviousness of Claims 1-30 of the ’290 patent ............................................ 28 
`
`A.  The basis of my analysis with respect to obviousness .................................. 28 
`
`B.  Obviousness Ground 1 - Ogawa in view of Sallmann .................................. 30 
`
`1.  Claim 1 ....................................................................................................... 31 
`
`
`
`ii
`
`

`
`
`
`2.  Claim 8 ....................................................................................................... 33 
`
`3.  Claim 14 ..................................................................................................... 35 
`
`4.  Claims 2, 9, 15 and 21 ................................................................................ 47 
`
`5.  Claims 3 & 16 ............................................................................................ 48 
`
`6.  Claims 4-5, 11, 17, & 23 ............................................................................ 49 
`
`7.  Claims 7, 13, 19 and 25 .............................................................................. 54 
`
`8.  Claims 6, 12, 18 and 24 .............................................................................. 59 
`
`9.  Claims 10, 20, & 22 ................................................................................... 61 
`
`10.  Claims 26-30 ........................................................................................... 62 
`
`VIII.  No Unexpected Results Over the Closest Prior Art ...................................... 67 
`
`A.  Tyloxapol’s stabilization of an aqueous ophthalmic bromfenac preparation is
`
`not unexpected in view of the prior art ................................................................. 68 
`
`B.  Scope of Stabilizing Effects .......................................................................... 71 
`
`IX.  No long-felt, unmet need existed for an ophthalmic NSAID preparation
`
`formulated with BAC ............................................................................................... 73 
`
`X.  The claimed bromfenac preparations were not met with skepticism ............... 75 
`
`XI.  The claimed bromfenac ophthalmic formulations have not received any
`
`praises ....................................................................................................................... 76 
`
`XII.  Additional evidence of secondary considerations ......................................... 76 
`
`XIII.  Conclusion ..................................................................................................... 76
`
`
`
`iii
`
`

`
`
`
`I.
`
`Introduction
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Metrics, Inc. for
`
`the above captioned inter partes review (“IPR”). I am being compensated for my
`
`time in connection with this IPR at my standard consulting rate, which is $750 per
`
`hour. My compensation is in no way dependent on the outcome of this IPR.
`
`3.
`
`I understand that the petition for inter partes review involves U.S.
`
`Patent No. 8,669,290 (“the ’290 patent”), Exhibit 1001, which issued on March 11,
`
`2014, from U.S. Application No. 13/687,242 (“the ’242 application”), naming
`
`Shirou Sawa and Shuhei Fujita as the inventors. The ’242 application is a division
`
`of application No. 13/353,653, now U.S. Pat. No. 8,497,304, which is a division of
`
`application No. 10/525,006 (“the ’006 application”), which was the U.S. National
`
`Stage of PCT Application No. PCT/JP2004/000350 (“the ’350 application), filed
`
`on January 16, 2004. The ’350 application claims priority to Japanese Application
`
`No. 2003-12427, filed on January 21, 2003. It is my understanding that the earliest
`
`possible priority date of the ’290 patent is January 21, 2003, the filing date of the
`
`Japanese priority application. I further understand that, according to the USPTO
`
`records, the ’290 patent is currently assigned to Senju Pharmaceutical Co., Ltd.
`
`(“Senju,” “the patentee,” or “the patent owner”).
`
`
`
`1
`
`

`
`
`
`4. Claim 1 of the ’290 patent is 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 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.
`(EX1001, 12:1-13)
`
`5. Claims 2-7 and 26 depend either directly or indirectly from Claim 1.
`
`Claims 2-7 recite the addition of a quaternary ammonium salt, concentrations of
`
`tyloxapol and/or bromfenac or its sodium salt, the pH of the preparations, and
`
`additional additives. Claim 26 recites a preservative efficacy standard.
`
`6. Claim 8 is reproduced below
`
`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-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
`
`
`
`2
`
`

`
`
`
`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.
`(EX1001, 12:41-53)
`
`7. Claims 9-13, and 27 depend directly or indirectly from claim 8. Claims
`
`9, and 11- 13 recite the addition of a quaternary ammonium salt, concentrations of
`
`tyloxapol and/or bromfenac or its sodium salt, the pH of the preparations, and
`
`additional additives. Claim 12 recites an aqueous formulation of claim 8 in which
`
`greater than 92% of the original amount of bromfenac remains in the preparation
`
`after 60°C for 4 weeks. Claim 27 recites a preservative efficacy standard.
`
`8. Claim 14 is reproduced below
`
`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-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; provided that the liquid
`preparation does not include mannitol.
`
`
`
`3
`
`

`
`
`
`(EX1001, 13:14-25)
`
`9. Claims 15-25 and 28-30 depend directly or indirectly from claim 14.
`
`Claims 15-19, 21, and 23-25 recite the addition of a quaternary ammonium salt,
`
`concentrations of tyloxapol and/or bromfenac or its sodium salt, the pH of the
`
`preparations, and additional additives. Claims 20 and 22 recite a preparation
`
`wherein greater than about 90% and 92%, respectively, of bromfenac remains in
`
`the preparation after storage at about 60°C for 4 weeks. Claims 28-30 recite a
`
`preservative efficacy standard.
`
`10. In preparing this Declaration, I have reviewed the ’290 patent and
`
`considered the file history of the ‘290 patent, and each of the documents cited
`
`herein, in light of general knowledge in the art as of January 2003. In formulating
`
`my opinions, I have relied upon my experience in the relevant art. I have also
`
`considered the viewpoint of a person of ordinary skill in the art (“POSA”) (i.e., a
`
`person of ordinary skill in the field of ophthalmic formulations and drug delivery
`
`including formulation of aqueous liquid anti-inflammatory preparations) as of
`
`January 2003. As described in detail below, I offer the following opinions in this
`
`declaration:
`
`a.
`
`A POSA would have had reason to combine the disclosures of U.S.
`
`Patent. No. 4,910,225 (“Ogawa”) (EX1004) and U.S. Patent No. 6,107,343
`
`(“Sallmann”) (EX1009) to arrive at the claimed invention as recited in
`
`
`
`4
`
`

`
`
`
`
`
`independent claims 1, 8 and 14 of the ’290 patent and such a POSA would
`
`have had a reasonable expectation of success in making the claimed
`
`preparations.
`
`b.
`
`The additional features recited in dependent claims 2-7, 9-13, and 15-
`
`25 were described in Ogawa (EX1004), Sallmann (EX1009), Australian
`
`Patent No. AU-B-22042/88 (“Fu”) (Exhibit 1011) , and/or other prior art
`
`references discussed in this declaration, which make up the general
`
`knowledge in the art related to aqueous formulations of anti-inflammatory
`
`drugs for ophthalmic administration. A POSA would have had reason to
`
`combine the teachings of Ogawa (EX1004), Sallmann (EX1009), and/or
`
`other prior art references discussed in this declaration to arrive at the
`
`claimed inventions of 2-7, 9-13, and 15-25 and such a POSA would have
`
`had a reasonable expectation of success in making the claimed inventions.
`
`c.
`
`A POSA would have also had a reason to combine the disclosures of
`
`Ogawa (EX1004), Sallman (EX1009) and Desai (1005) and/or other prior art
`
`references discussed in this declaration to arrive at the claimed invention as
`
`recited in claims 26-30.
`
`d.
`
`I have also considered arguments that may be asserted by Senju
`
`regarding secondary considerations of nonobviousness. Even in view of
`
`these potential arguments, the prior art references discussed in this
`
`5
`
`

`
`
`
`declaration would have rendered obvious the claimed invention to a person
`
`of ordinary skill in the art.
`
`II.
`
`List of documents I considered in formulating my opinion
`
`11. In formulating my opinion, I have considered the following documents:
`
`Exhibit
`#
`
`1001
`
`1002
`
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`Description
`
`Sawa et al., U.S. Patent No. 8,669,290 B2, "Aqueous Liquid
`Preparation Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic
`Acid"
`Hara, Yoshiyuki , "Bromfenac sodium hydrate," Clinics & Drug
`Therapy 19:1014-1015 (2002)
`Declaration of Professor Uday B. Kompella, Ph.D.
`Ogawa et al., U.S. Patent No. 4,910,225 "Locally Administrable
`Therapeutic Composition for Inflammatory Disease"
`Desai et al., U.S. Patent No. 5,603,929, "Preserved Ophthalmic
`Drug Compositions Containing Polymeric Quaternary Ammonium
`Compounds"
`Desai, et al., U.S. Patent No. 5,558,876, "Topical Ophthalmic
`Acidic Drug Formulations"
`Certified English translation of "Bromfenac sodium hydrate" in the
`Japanese Pharmacopoeia 2001 Edition: 27-29, Yakuji Nippo
`Limited (2001)
`FDA approved "BROMDAY™ (bromfenac ophthalmic solution,
`.09%) Product Label," U.S. Approval: March 24, 2005, ISTA
`Pharmaceuticals, Inc.
`Sallmann et al., U.S. Patent No. 6,107,343, "Ophthalmic And Aural
`Compositions Containing Diclofenac Potassium"
`Guttman et al., "Solubilization of Anti-inflammatory steroids by
`Aqueous Solutions of Triton-WR-1339," Journal of
`Pharmaceutical Sciences 50: 305-307 (1961)
`
`
`
`6
`
`

`
`
`
`
`
`Exhibit
`#
`
`Description
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Fu et al., Australian Patent No. AU-B-22042/88, "Preservative
`System For Ophthalmic Formulations"
`Yasueda et al., U.S. Patent No. 6,274,609, "Aqueous Liquid
`Pharmaceutical Composition Containing as Main Component
`Benzopyran Derivative"
`"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=OB_Rx
`"Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations," Appl. No. N203168, Active Ingredient
`Bromfenac
`Sodium,
`accessed
`at
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?A
`ppl_No=203168&TABLE1=OB_Rx, last accessed on February 14,
`2014
`U.S. Patent Application No. 13/687,242, 2/11/14 Notice of
`Allowance
`“ophthalmic,” Webster’s Deluxe Unabridged Dictionary: 1254, New
`Twentieth Century Dictionary, Simon and Shuster (1979)
`Kapin, PCT Publication No. WO 2002/13804, Kapin et. al.,
`“Method of Treating Angiogenesis-Related Disorders,” published
`Feb. 21, 2002.
`Flach, Allan., “Topical Nonsteroidal Antiinflammatory Drugs for
`Ophthalmic Uses,” Ophthalmic NSAIDs: 77-83 (1996)
`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)
`Regev, O., et al., "Aggregation Behavior of Tyloxapol, a Nonionic
`Surfactant Oligomer, in Aqueous Solution," Journal of Colloid and
`Interface Science 210: 8-17 (1999)
`
`7
`
`

`
`
`
`
`
`Exhibit
`#
`
`Description
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`Aviv, H., International Patent No. WO 94/05298, "Submicron
`Emulsions as Ocular Drug Delivery Vehicles"
`Bergamini et al., U.S. Patent No. 5,597,560, "Diclofenac And
`Tobramycin Formulations For Ophthalmic And Otis Topical Use"
`U.S. Patent Application No. 13/687,242, Applicant Remarks in
`support of amendment, November 28, 2012
`November 16, 1994 Desai Declaration under 37 CFR §1.132(Desai
`I) and July 2, 1996 Desai Declaration under 37 CFR §1.132 (Desai
`II)
`13/687,242, Applicant
`Patent Application No.
`U.S.
`Arguments/Remarks Made in an Amendment, 10/22/2013, pp. 1-15
`"monohydrate," Webster’s New World Dictionary of the American
`Language: 920, New World Dictionaries / Simon and Schuster
`(1980)
`"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
`Yanni et al., U.S. Patent No. 5,475,034, "Topically Administrable
`Compositions Containing 3-Benzoylphenylacetic Acid Derivatives
`for Treatment of Ophthalmic Inflammatory Disorders"
`"ISTA Pharmaceuticals Submits New Drug Application for
`Xibrom™ QD (once-daily), News Release, ISTA Pharmaceuticals
`(December 20, 2007)
`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)
`"Acular®" and "Azopt™," Physician’s Desk Reference 54: 486-487,
`491-492 (2000)
`
`8
`
`

`
`
`
`
`
`Exhibit
`#
`
`Description
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`1040
`1041
`
`1042
`
`1043
`
`1044
`
`Doughty, M., "Medicines Update for optical practitioners- Part 11.,"
`Optician 5853 (223), (2002)
`Reddy, Indra K., Ocular Therapeutics and Drug Delivery: A Multi-
`Disciplinary Approach: 42-43, 390 (1996)
`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)
`Wong, Michelle,
`International Patent No. WO 94/15597,
`"Ophthalmic
`Compositions
`Comprising
`Benzyllauryldimethylammonium Chloride" (filed January 11, 1993;
`issued July 21, 1994)
`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)
`FDA approved "ALREX™ (loteprednol etabonate ophthalmic
`suspension) 0.2% Product Label," U.S. Approval: 1998, Bausch &
`Lomb Pharmaceuticals
`FDA approved "LOTEMAX™ (loteprednol etabonate ophthalmic
`suspension) 0.5% Product Label," U.S. Approval: 1998, Bausch &
`Lomb Pharmaceuticals
`"TOBRADEX®" Physician’s Desk Reference 54: 490 (2000)
`"Alomide® 0.1%" Physician’s Desk Reference 50: 469 (1996)
`Johnson, R., et al., U.S. Patent No. 2,880,130, "Anti-Inflammatory
`Steroid Solutions"
`Johnson, R., et al., U.S. Patent No. 2,880,138, "Anti-Inflammatory
`Steroid Solutions"
`Kawabata et al., Canadian Patent No. CA 2 383 971 A1,
`“Prophylactic and Therapeutic Medicaments for Ophthalmic Uses”
`Patani, G., et al., "Bioisoterism: A Rational Approach in Drug
`Design," Chem. Rev. 96: 3147-3176 (1996)
`
`9
`
`

`
`
`
`Exhibit
`#
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`1052
`
`Description
`
`FDA approved "XIBROM™ (bromfenac ophthalmic solution,
`.09%) Product Label," ISTA Pharmaceuticals, Inc
`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
`FDA approved "PROLENSA™ (bromfenac ophthalmic solution,
`0.07%) Product Label," U.S. Approval: April 5, 2013, Bausch &
`Lomb Incorporated
`"Borax (Sodium tetraborate)," Biochemicals and Reagents: 175,
`Sigma-Aldrich (2000-2001)
`Ali, et al., U.S. Patent No. 6,071,904, "Process for Manufacturing
`Ophthalmic Suspensions"
`Story, M., et al., European Patent No. 0274870, "Micelles
`containing a non-steroidal antiinflammatory compound" (filed
`December 12, 1987; issued July 7, 1988)
`“Duract™,” Physician’s Desk Reference 52:3035-3037 (1998)
`Curriculum Vitae of Professor Uday B. Kompella, Ph.D.
`
`III. My background and qualifications
`
`12. I am an expert in the field of formulations and drug delivery,
`
`specifically pharmaceutical formulations for ophthalmic administration, including
`
`aqueous liquid preparations, and I have been an expert in this field since prior to
`
`2003. Throughout the remainder of this declaration, I will refer to the field of
`
`ophthalmic formulations, and specifically pharmaceutical formulations for
`
`ophthalmic administration, including those comprising anti-inflammatory drugs
`
`
`
`10
`
`

`
`
`
`
`
`such as NSAIDs, as the relevant field or the relevant art. In formulating my
`
`opinions, I have relied upon my training, knowledge, and experience in the
`
`relevant art. A copy of my current curriculum vitae is provided as Exhibit 1052,
`
`and it provides a comprehensive description of my academic and employment
`
`history.
`
`13. As an expert in the relevant field since prior to 2003, I am qualified to
`
`provide an opinion as to what a POSA would have understood, known, or
`
`concluded as of 2003. Since 1985, I have accumulated significant training and
`
`experience in the relevant field and related fields.
`
`14. I received a B.Pharm. from Birla Institute of Technology and Science in
`
`Pilani, India, in 1987, and M.Pharm. from Jadavpur University in Calcutta, India,
`
`in 1989, and a Ph.D. in Pharmaceutical Sciences from the University of Southern
`
`California, USA, in 1994.
`
`15. After completing my Ph.D., I was an Assistant Professor at Auburn
`
`University, Department of Pharmacal Sciences in Auburn, Alabama, from 1994
`
`until 1998. From 1998 until 2001, I was an Assistant Professor, and from 2002
`
`until 2008 an Associate Professor, at the University of Nebraska Medical Center
`
`(UNMC), Omaha, Nebraska in the Department of Pharmaceutical Sciences, with a
`
`courtesy appointment in the Department of Ophthalmology. I received my tenure
`
`in 2003 at University of Nebraska Medical Center. Starting in 2008, I became a
`
`11
`
`

`
`
`
`
`
`tenured Professor at the University of Colorado Denver (UCD), Aurora, Colorado,
`
`in the Department of Pharmaceutical Sciences, with a joint appointment in the
`
`Department of Ophthalmology.
`
`16. During my time as a professor, I have been a principal or co-
`
`investigator on many ophthalmic drug delivery studies. For example, I was the
`
`principal investigator on a grant from the FDA entitled “Effect of physicochemical
`
`properties of ophthalmic formulations on ocular bioavailability,” (U01FD004719,
`
`August 2012 through August 2013) and a multi-million dollar NIH R24 Grant for
`
`Collaborative Vision Research entitled “Transscleral drug delivery for retinal
`
`disorders”, which was a collaborative grant between Emory University, Georgia
`
`Tech, UNMC/UCD, and University of Pennsylvania, with ~$1,234,800 total costs
`
`to Dr. Kompella, at UNMC/UCD 07/01/06-06/30/11 (role: PI on UNMC/UCD
`
`component at 30% effort).
`
`17. I have co-authored over 150 scientific publications, about 50 of which
`
`deal with ocular drug delivery. See, e.g., Barañano, D.E., Kim, S.J., Edelhauser,
`
`H.F., Durairaj, C., Kompella, U.B., and Handa, J.T., “Efficacy and
`
`pharmacokinetics of
`
`intravitreal nonsteroidal anti-inflammatory drugs for
`
`intraocular inflammation,” Br. J. Ophthalmol. 93(10):1387-1390 (2009). I have
`
`been an editor of three textbooks regarding various aspects of drug delivery. I
`
`have also given over 200 invited presentations. See e.g., Merck Ophthalmic Drug
`
`12
`
`

`
`
`
`
`
`Delivery SIE, Hilton Orlando Bonnett Creek, Orlando, FL. “Drug delivery for the
`
`posterior segment of the eye.” October 21, 2011.
`
`18. As listed in my curriculum vitae, I have also received numerous awards
`
`pertaining to my research and teaching. For example, in 2014 I was awarded the
`
`Gold Fellow Status, American Association for Research
`
`in Vision and
`
`Ophthalmology, and in 2012 I received the ARVO/AFER/Pfizer/Carl Camras
`
`Translational Research Award in Ophthalmology. In addition, I have routinely
`
`received funding for my research through grant and contract support.
`
`19. In addition
`
`to gaining expertise
`
`through educational
`
`training,
`
`professional experiences, and research experiences described above, I have kept
`
`abreast of the field of drug delivery and formulation of aqueous liquid
`
`preparations by reading scientific literature, attending or presenting at scientific
`
`conferences, and attending or presenting at academic symposia. I have also been
`
`invited to participate in the peer review process for various scientific journals, and
`
`have reviewed manuscripts submitted by other scientists relating to ocular drug
`
`delivery. Some of the scientific journals for which I have reviewed scientific
`
`manuscripts include: Current Eye Research, Experimental Eye Research, Expert
`
`Opinion on Drug Delivery, Journal of Ocular Pharmacology and Therapeutics,
`
`and Investigative Ophthalmology & Visual Science. I have also served as Editor
`
`and on the Editorial Board for a variety of publications and I am currently the
`
`13
`
`

`
`
`
`
`
`Editor-in-Chief for a
`
`journal called Expert Opinion on Drug Delivery.
`
`Furthermore, I have collaborated with, or have communicated with, many
`
`researchers in the field of formulations and drug delivery, including ophthalmic
`
`formulations. Accordingly, I am an expert in the field of ophthalmic formulations
`
`and drug delivery.
`
`IV. Person of ordinary skill in the art (POSA)
`
`20. I understand that 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. With respect to the ’290 patent, a POSA would
`
`have had education and/or experience in ophthalmic formulations and drug
`
`delivery, and knowledge of the scientific literature concerning the same,
`
`specifically
`
`pharmaceutical
`
`formulations
`
`comprising
`
`anti-inflammatory
`
`compounds such as NSAIDs, for ophthalmic administration 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 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.
`
`14
`
`

`
`
`
`V. The ’290 patent
`
`21. I have considered the disclosure of the ’290 patent in light of general
`
`knowledge in the relevant field as of the earliest possible priority date of the ’290
`
`patent, which I understand to be January 21, 2003.
`
`22. The ’290 patent specification is directed to an aqueous liquid
`
`preparation containing 2-amino-3-(4-bromobenzoyl)phenlyacetic acid(otherwise
`
`known as bromfenac, (EX1051, 2-3) or its pharmacologically acceptable salt
`
`thereof or a hydrate thereof. (EX1001, 1:14-17) The bromfenac aqueous liquid
`
`preparations described in the ’290 patent also include an alkyl aryl polyether
`
`alcohol type polymer or a polyethylene glycol fatty acid ester. (EX1001, 1:20-22)
`
`23. The ’290 patent further specifies that the pharmacologically acceptable
`
`salt of bromfenac can be the sodium salt, and that the bromfenac hydrate can be
`
`1/2 hydrate, 1 hydrate or 3/2 hydrate.1 (EX1001, 4:24-27). In addition, the ’290
`
`patent specifies that among alkyl aryl polyether alcohol type polymers, tyloxapol
`
`is especially preferred. (EX1001, 4:65-67).
`
`
`1 1/2 hydrate corresponds to a ratio of 1 molecule of water per 2 molecules
`
`of a drug; 1 hydrate corresponds to a ratio of 1 molecule of water per 1 molecule of
`
`a drug; and 3/2 hydrate corresponds to a ratio of 3 molecule of water per 2
`
`molecules of a drug. (EX1026, 3)
`
`
`
`15
`
`

`
`
`
`
`
`24. The ’290 patent is more specifically directed to an aqueous liquid
`
`ophthalmic preparation containing bromfenac and tyloxapol, with or without the
`
`preservative, such as benzalkonium chloride (“BAC”), that is stable within a pH
`
`range that gives no irritation to the eye, and in which a decrease in the
`
`preservative effect of BAC (when present) is inhibited. (EX1001, 2:16-23, 28-34;
`
`62-64).
`
`VI. State of the art as of January, 2003
`
`A. Non-steroidal anti-inflammatory compounds were known and
`approved for ophthalmic use
`
`25. Prior to 2003, non-steroidal anti-inflammatory drugs (NSAIDs) were
`
`widely used for managing postoperative ocular inflammation, preventing and
`
`treating cystoid macular edema after cataract surgery, preventing intraoperative
`
`miosis during cataract surgery, relieving symptoms of seasonal allergic
`
`conjunctivitis, and reducing ocular discomfort following refractive surgery.
`
`(EX1018, 77:1).
`
`26. As of January 21, 2003, a number of NSAIDs, formulated for
`
`ophthalmic use, were FDA-approved and sold in the United States. For example,
`
`diclofenac 1% (Voltaren®, Novartis) was approved in 1991 for minimizing
`
`postoperative inflammation after cataract surgery. (EX1027). Diclofenac has the
`
`following chemical structure:
`
`16
`
`

`
`
`
`
`
`
`
`
`
`227. An ophthalmic fformulationn of ketorrolac tromeethamine 00.5% (Acuular®
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ophthaalmic Soluution, Alleergan) waas approveed in 19992 for treaating seassonal
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`allergicc conjuncttivitis. (EXX1018, 78:1). Keteerolac has
`
`
`
`
`
`structuure:
`
`
`
`
`
`
`
`
`
`
`
`the followwing chemmical
`
`
`
`Allergan)
`
`and
`
`
`
`228. Flurbipprofen 0.003% (Ocuufen® Ophhthalmic SSolution,
`
`
`
`
`
`
`
`suprofeen 1% (Proofenal® Opphthalmic SSolution frrom Alconn) were appproved in 11986
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and 19988, respecctively, forr inhibitinng miosis dduring cattaract surggery. (EX1
`
`
`
`
`
`018,
`
`
`
`78:1). Flurbiproffen has thee followingg chemical
`
`
`
`
`
`
`
`structure:
`
`
`
`
`
`
`
`229. The NSSAID brommfenac andd its salts aand hydratees were alsso known pprior
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to Januuary 21, 20003. (EX11002). Brromfenac,
`
`
`
`
`
`shown agaain below,
`
` shares ce
`
`rtain
`
`
`
`structuural characcteristics
`
`
`
`with the
`
`
`
`other NSSAIDs dicclofenac,
`
`
`
`keterolac
`
`and
`
`17
`
`

`
`
`
`
`
`flurbiprofen. Sppecifically, each of tthese NSAAIDs posseesses a –CC-COOH g
`
`
`
`
`
`
`
`
`
`
`
`
`
`roup
`
`
`
`attacheed to an arryl ring. TThe –COOOH moiety
`
`
`
`
`
`
`
`
`
`this repport I someetimes refeer to these
`
`
`
`
`
`
`
`NSAIDs bbearing a ccarboxylic
`
`
`
`
`
`acid moietty as
`
`
`
`is called aa carboxyllic acid, annd in
`
`
`
`
`
`this share
`
`
`
`d carboxyylic acid g
`
`roup
`
`
`
`“acidicc” NSAIDs. As I aalso explaiin below,
`
`
`
`
`
`
`
`
`
`cases tthese NSAAIDs to make an interaction wwith the preeservative
`
`
`
`
`
`
`
`
`
`
`
`
`
`benzalkonnium
`
`
`
`chloridde (“BAC”) in solutioon at the pHH used for r ophthalmiic preparattions.
`
`
`
`
`
`
`
`
`
`
`
`
`
`0. In fac
`3
`
`
`
`
`t, by 20003, bromfeenac had
`
`
`
`already bbeen showwn to havee an
`
`
`
`
`
`
`
`enhancced anti-innflammatorry action
`
`
`
`
`
`
`
`when commpared to
`
`other kn
`
`
`
`own NSAAIDs.
`
`6-8 and E
`(EX1002, 2:2:4-33:1:3; 3:2:
`
`
`
`
`
`
`X1028, 155:1-16:34,
`
`Table 1).
`
`
`
` For exammple,
`
`
`
`bromfeenac was
`
`4-fold
`
`
`
`more efffective
`
`
`
`thhan dicloffenac
`
`
`
`in
`
`an
`
`
`
`in vvitro
`
`
`
`cyclooxxygenase iinhibition
`
`
`
`
`
`
`
`
`
`
`
`assay,2 andd was ablee to inhibitt cyclooxyggenase 11--fold
`
`
`
`better
`
`
`
`than indoomethacin, another
`
`
`
`
`
`EX10002, 2:1:28-22:3).
`
`
`
`
`
`
`
`
`
`NSAID. (EX10288, 15:1-166:34, Tabl
`
`e 1;
`
`
`
`
`
`
`
`
`
`
`2 Anti-inflammmatory aactivity of the NSAIDDs was testted by polaarographiccally
`
`
`
`
`
`
`
`
`
`
`
`monitorring the inhhibition in the rate off oxygen coonsumptioon in the coonversion oof
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`arachidoonic acid to prostagla
`
`
`
`
`ynthase andin H syandin H2 bby prostagla
`
`
`
`
`
`
`
`(cyclooxxygenase). (EX10288, 13:25-311.)
`
`
`
`
`
`
`
`
`
`18
`
`

`
`
`
`
`
`31. By 2003, researchers in the field had already prepared and patented
`
`ophthalmic preparations of bromfenac. For example, in 1990, over a decade prior
`
`to the earliest priority date of the ’290 patent, Ogawa disclosed and claimed an
`
`ophthalmic formulation of bromfenac containing, among other additives, the
`
`surfactant polysorbate 80 and BAC. (EX1004, abstract and 10:4-18). The
`
`formulation described in Ogawa was approved and commercially marketed in
`
`Japan in 2000 under the name Bronuck®. (EX1029). In 1997, Desai described
`
`stable aqueous ophthalmic preparations of bromfenac and described that the
`
`formulations could also include, among other additives, a polymeric quaternary
`
`ammonium compound, BAC, and tyloxapol. (EX1005, 4:11-55; 3:38-39; 2:36-
`
`44; claim 8). In 1995, Yanni described stable ophthalmic formulations of
`
`bromfenac by making ester and amide bromfenac derivatives. (EX1028, 15:1-
`
`16:34, Table 1; 16: