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. 8,129,431 to Sawa et al.
`Issue Date: March 6, 2012
`Title: Aqueous Liquid Preparation Containing 2-Amino-3-(4-
`bromobenzoyl)phenylacetic Acid
`
`_____________________
`
`Inter Partes Review No.: IPR2014-01041
`_____________________
`
`SECOND CORRECTED DECLARATION OF UDAY B. KOMPELLA,
`PH.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Metrics EX1003
`
`i
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`

`
`
`
`I. 
`
`II. 
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1 
`
`List of Documents Considered ........................................................................ 5 
`
`
`
`III.  My background and qualifications ................................................................ 10 
`
`IV.  Person of ordinary skill in the art (POSA) .................................................... 13 
`
`V. 
`
`The ’431 patent .............................................................................................. 14 
`
`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. 
`
`C. 
`
`D. 
`
`E. 
`
`BAC was the preservative of choice in ophthalmic formulations ...... 19 
`
`It was known that non-ionic surfactants stabilized aqueous
`preparations containing an NSAID and BAC ..................................... 21 
`
`Tyloxapol is a non-ionic surfactant that was known and widely
`used in ophthalmic formulations by January 2003 ............................. 22 
`
`There is nothing inventive in the ’431 patent in view of the prior
`art ......................................................................................................... 27 
`
`VII.  Obviousness of Claims 1-22 of the ’431 patent ............................................ 28 
`
`A. 
`
`B. 
`
`The basis of my analysis with respect to obviousness ........................ 28 
`
`Obviousness Ground 1 - Ogawa in view of Sallmann ........................ 30 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`Independent Claims 1 and 18 .................................................... 32 
`
`Claims 2, 5, 11 and 19 .............................................................. 44 
`
`Claims 3 and 4 ........................................................................... 48 
`
`Claims 6 and 15 ......................................................................... 51 
`
`ii
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`

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`
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`
`
`5. 
`
`6. 
`
`7. 
`
`8. 
`
`9. 
`
`Claims 7, 8, 13, 14, 16 and 17 .................................................. 54 
`
`Claims 9 and 10 ......................................................................... 58 
`
`Claim 12 .................................................................................... 61 
`
`Claims 21, and 22...................................................................... 63 
`
`Claim 20 .................................................................................... 64 
`
`VIII.  The claimed invention of the ’431 patent does not possess unexpectedly
`superior properties ......................................................................................... 65 
`
`A. 
`
`B. 
`
`Tyloxapol’s stabilization of an aqueous ophthalmic bromfenac
`preparation is not unexpected in view of the prior art ........................ 65 
`
`The stabilization of bromfenac preparations by tyloxapol is not
`observed across the entire range of the claimed preparations ............. 69 
`
`1. 
`
`2. 
`
`The supposed unexpected stability of aqueous bromfenac
`preparations is not observed across the entire range of claimed
`pH .............................................................................................. 69 
`
`The supposedly unexpected increase in stability of aqueous
`bromfenac preparations is not observed across the entire range
`of claimed benzalkonium chloride homologues ....................... 72 
`
`C. 
`
`Tyloxapol’s stabilization of the preservative effect of BAC is not
`unexpected in view of prior art ........................................................... 73 
`
`D.  No long-felt, unmet need existed for an ophthalmic NSAID
`preparation formulated with BAC ....................................................... 75 
`
`E. 
`
`F. 
`
`The claimed bromfenac preparations were not met with
`skepticism ............................................................................................ 77 
`
`The claimed bromfenac ophthalmic formulations have not
`received any praise .............................................................................. 78 
`
`G.  Additional evidence of secondary considerations ............................... 78 
`
`IX.  Conclusion ..................................................................................................... 78
`
`iii
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`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`Introduction
`
`
`
`
`
`I.
`
`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. 8,129,431 (“the ’431 patent”), EX1001, which issued on March 6, 2012, from
`
`U.S. Application No. 10/525,006 (“the ’006 application”), naming Shirou Sawa
`
`and Shuhei Fujita as the inventors. The ’006 application is 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 ’431 patent is January 21, 2003, the filing date of the
`
`Japanese priority application. I further understand that, according to the USPTO
`
`records, the ’431 patent is currently assigned to Senju Pharmaceutical Co., Ltd.
`
`(“Senju,” “the patentee,” or “the patent owner”).
`
`4. Claim 1 of the ’431 patent is reproduced below.
`
`
`
`
`1
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`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`
`
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`
`
`1. An aqueous liquid preparation consisting essentially
`of the following two components, wherein the first
`2-amino-3-(4-bromobenzoyl)-
`component
`is
`phenylaceticacid 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 and the second component is tyloxapol, wherein
`said liquid preparation is formulated for ophthalmic
`administration, and wherein when a quaternary
`ammonium compound
`is
`included
`in said
`liquid
`preparation, the quaternary ammonium compound is
`benzalkonium chloride.
`
`(EX1001, 11:66-12:9) (emphasis added).
`
`5. Claims 2-17 depend, either directly or indirectly, from claim 1 and further
`
`recite certain salts of bromfenac, concentrations of tyloxapol and/or bromfenac or
`
`its sodium salt, the pH of the preparations, and additional additives. (EX1001,
`
`12:10-13:14).
`
`6. Claim 18 of the ’431 patent is reproduced below.
`
`18. An aqueous liquid preparation consisting essentially
`of:
`(a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`pharmacologically acceptable salt thereof or a hydrate
`2
`
`
`
`
`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`thereof, wherein the hydrate is at least one selected from
`a 1/2 hydrate, 1 hydrate, and 3/2 hydrate,
`(b) tyloxapol,
`(c) boric acid,
`(d) sodium tetraborate,
`(e) EDTA sodium salt,
`(f) benzalkonium chloride,
`(g) polyvinylpyrrolidone,
`(h) sodium sulfite,
`wherein said
`liquid preparation
`ophthalmic administration, and
`wherein benzalkonium chloride is the only quaternary
`ammonium compound which is included in said liquid
`preparation.
`
`is formulated for
`
`
`
`
`
`(EX1001, 13:15-14:9.)
`
`7. Claims 19-22 depend from claim 18 and further recite the concentrations
`
`of tyloxapol and bromfenac or its sodium salt. (EX1001, 14:10-22).
`
`8. In preparing this Declaration, I have reviewed the ’431 patent and
`
`considered the file history of the ‘431 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
`
`
`
`
`3
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`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`
`
`
`
`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
`
`independent claims 1 and 18 of the ’431 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 2-5, 7-14, 16-19,
`
`21 and 22 were described in Ogawa (EX1004), Sallmann (EX1009), 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 claims 2-5, 7-14, 16-19, 21 and 22, and
`
`
`
`
`4
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`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`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), Sallmann (EX1009), Australian Patent No. AU-B-
`
`22042/88 (“Fu”) (EX1011) and/or other prior art references discussed in this
`
`declaration to arrive at the claimed invention as recited in claims 6, 15, and
`
`20 of the ’431 patent, and would have had a reasonable expectation of
`
`success in making the claimed inventions.
`
`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
`
`declaration would have rendered obvious the claimed invention to a person
`
`
`
`
`
`of ordinary skill in the art.
`
`II.
`
`List of Documents Considered
`
`9. In formulating my opinion, I have considered the following documents:
`
` Exhibit
`#
`
`1001
`
`1002
`
`
`
`
`Description
`
`Sawa et al., U.S. Patent No. 8,129,431 B2, "Aqueous Liquid
`Preparation Containing 2-Amino-3-(4-Bromobenzoyl) Phenylacetic
`Acid"
`Hara, Yoshiyuki , "Bromfenac sodium hydrate," Clinics & Drug
`Therapy 19:1014-1015 (2002)
`
`5
`
`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
` Exhibit
`#
`
`Description
`
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`Second Corrected Declaration of Dr. 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)
`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
`
`6
`
`
`
`
`
`
`
`
`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
` Exhibit
`#
`
`Description
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`Selected pages from Webster’s Deluxe Unabridged Dictionary 1254
`(2nd ed. 1979) (definition of “ophthalmic”)
`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)
`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)
`Bergamini et al., U.S. Patent No. 5,597,560, "Diclofenac And
`Tobramycin Formulations For Ophthalmic And Otis Topical use"
`Wong, Michelle, International Patent No. WO 94/15597,
`"Ophthalmic Compositions Comprising
`Benzyllauryldimethylammonium Chloride" (filed January 11, 1993;
`issued July 21, 1994)
`Reddy, Indra K., Ocular Therapeutics and Drug Delivery: A Multi-
`Disciplinary Approach: 42-43, 390 (1996)
`Story, M., et al., European Patent No. 0274870, "Micelles
`containing a non-steroidal antiinflammatory compound" (filed
`December 12, 1987; issued July 7, 1988)
`"Borax (Sodium tetraborate)," Biochemicals and Reagents: 175,
`Sigma-Aldrich (2000-2001)
`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)
`Aviv, H., International Patent No. WO 94/05298, "Submicron
`Emulsions as Ocular Drug Delivery Vehicles"
`
`7
`
`
`
`
`
`
`
`
`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
` Exhibit
`#
`
`Description
`
`1027
`
`1028
`
`1029
`
`1030
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`Gennaro, A., “Boric Acid,” Remington: The Science and Practice of
`Pharmacy 20: 1041, University of Sciences, United States (2000)
`Wade, A., and Weller, P., "Edetic Acid," and "Sodium
`Metabisulfite," Handbook of Pharmaceutical Excipients 2: 176-
`179, 451-453, American Pharmaceutical Association, United States
`(1994)
`Selected pages from the file history of U.S. Patent No. 8,129,431,
`March 28, 2005 Amendment.
`"Duract™," Physician’s Desk Reference 52:3035-3037 (1998)
`"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)
`"Acular®" and "Azopt™," Physician’s Desk Reference 54: 486-487,
`491-492 (2000)
`Doughty, M., "Medicines Update for optical practitioners- Part 11.,"
`Optician 5853 (223), (2002)
`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)
`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)
`
`8
`
`
`
`
`
`
`
`
`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`Description
`
`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)
`Kawabata et al., Canadian Patent No. CA 2 383 971 A1,
`"Prophylactic and Therapeutic Medicaments for Ophthalmic Uses"
`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"
`Patani, G., et al., "Bioisoterism: A Rational Approach in Drug
`Design," Chem. Rev. 96: 3147-3176 (1996)
`Ostrovskii, V.A., et al., "Acid-base properties of 5-substituted
`tetrazoles," Chemistry of Heterocyclic Compounds 17: 412-416
`(1981)
`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
`The United States Pharmacopeia 24: The National Formulary 19:
`1809-1813, 1864-1866, The United States Pharmacopeial
`Convention, Inc. (1999)
`Ali, et al., U.S. Patent No. 6,071,904, "Process for Manufacturing
`Ophthalmic Suspensions"
`Curriculum Vitae of Dr. Uday B. Kompella, Ph.D.
`
`9
`
` Exhibit
`#
`
`1039
`
`1040
`
`1041
`1042
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`
`
`
`
`
`
`
`

`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`
`
`
`
`III. My background and qualifications
`
`10.
`
`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
`
`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 EX1053, and it
`
`provides a comprehensive description of my academic and employment history.
`
`11. 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.
`
`12.
`
`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.
`
`
`
`
`10
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`
`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`13. 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
`
`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.
`
`14. 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
`
`11
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`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
`
`to Dr. Kompella –at UNMC/UCD 07/01/06-06/30/11 (role: PI on UNMC/UCD
`
`component at 30% effort).
`
`15.
`
`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
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`pharmacokinetics of
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`intravitreal nonsteroidal anti-inflammatory drugs for
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`intraocular inflammation,” Br. J. Ophthalmol. 93(10):1387-1390 (2009). I have
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`been an editor of three textbooks regarding various aspects of drug delivery. I
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`have also given over 200 invited presentations. See e.g., Merck Ophthalmic Drug
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`Delivery SIE, Hilton Orlando Bonnett Creek, Orlando, FL. “Drug delivery for the
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`posterior segment of the eye.” October 21, 2011.
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`16. As listed in my curriculum vitae, I have also received numerous
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`awards pertaining to my research and teaching. For example, in 2014 I was
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`awarded the Gold Fellow Status, American Association for Research in Vision
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`and Ophthalmology, and in 2012 I received the ARVO/AFER/Pfizer/Carl Camras
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`Translational Research Award in Ophthalmology. In addition, I have routinely
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`received funding for my research through grant and contract support.
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`17.
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`In addition
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`to gaining expertise
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`through educational
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`training,
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`professional experiences, and research experiences described above, I have kept
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`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
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`abreast of the field of drug delivery and formulation of aqueous liquid
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`preparations by reading scientific literature, attending or presenting at scientific
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`conferences, and attending or presenting at academic symposia. I have also been
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`invited to participate in the peer review process for various scientific journals, and
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`have reviewed manuscripts submitted by other scientists relating to ocular drug
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`delivery. Some of the scientific journals for which I have reviewed scientific
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`manuscripts include: Current Eye Research, Experimental Eye Research, Expert
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`Opinion on Drug Delivery, Journal of Ocular Pharmacology and Therapeutics,
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`and Investigative Ophthalmology & Visual Science. I have also served as Editor
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`and on the Editorial Board for a variety of publications and I am currently the
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`Editor-in-Chief for a
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`journal called Expert Opinion on Drug Delivery.
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`Furthermore, I have collaborated with, or have communicated with, many
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`researchers in the field of formulations and drug delivery, including ophthalmic
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`formulations. Accordingly, I am an expert in the field of ophthalmic formulations
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`and drug delivery.
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`IV. Person of ordinary skill in the art (POSA)
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`18.
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`I understand that a POSA is a hypothetical person who is presumed to
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`be aware of all pertinent art, thinks along conventional wisdom in the art, and is a
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`person of ordinary creativity. With respect to the ’431 patent, a POSA would
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`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
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`have had education and/or experience in ophthalmic formulations and drug
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`delivery, and knowledge of the scientific literature concerning the same,
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`specifically
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`pharmaceutical
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`formulations
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`comprising
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`anti-inflammatory
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`compounds such as NSAIDs, for ophthalmic administration as of 2003. The
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`education and experience levels may vary between persons of ordinary skill, with
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`some persons holding a basic Bachelor’s degree, but with 5-10 years of relevant
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`work experience, or others holding more advanced degrees—e.g., Pharm.D.,
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`Ph.D., or M.D.—but having fewer years of experience. A POSA may also work
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`as part of a multi-disciplinary team and draw upon not only his or her own skills,
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`but also take advantage of certain specialized skills of others in the team, to solve
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`a given problem.
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`V. The ’431 patent
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`19.
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`I have considered the disclosure of the ’431 patent in light of general
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`knowledge in the relevant field as of the earliest possible priority date of the ’431
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`patent, which I understand to be January 21, 2003.
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`20. The ’431 patent specification is directed to an aqueous liquid
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`preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid (otherwise
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`known as bromfenac (see EX1030, 2-3) or its pharmacologically acceptable salt
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`thereof or a hydrate thereof. Bromfenac has the following chemical structure:
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`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
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`(EX1001, 1:24-34). The bromfenac aqueous liquid preparations described in the
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`’431 patent also include an alkyl aryl polyether alcohol type polymer or a
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`polyethylene glycol fatty acid ester. (EX1001, Abstract).
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`21. The ’431 patent further specifies
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`that
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`the pharmacologically
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`acceptable salt of bromfenac can be the sodium salt, and that the bromfenac
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`hydrate can be 1/2 hydrate, 1 hydrate or 3/2 hydrate.1 (EX1001, 3:22-25; 4:20-
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`27). In addition, the ’431 patent specifies that among alkyl aryl polyether alcohol
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`type polymers, tyloxapol is especially preferred. (EX1001, 4:65-67).
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`22. The ’431 patent is more specifically directed to an aqueous liquid
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`ophthalmic preparation containing bromfenac and tyloxapol, with or without the
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`preservative benzalkonium chloride (“BAC”), that is stable within a pH range
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`1 1/2 hydrate corresponds to a ratio of 1 molecule of water per 2 molecules
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`of a drug; 1 hydrate corresponds to a ratio of 1 molecule of water per 1 molecule of
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`a drug; and 3/2 hydrate corresponds to a ratio of 3 molecules of water per 2
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`molecules of a drug. (EX1031, 3).
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`that gives no irritation to the eye, and in which a decrease in the preservative
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`effect of BAC (when present) is inhibited. (EX1001, 2:14-22; 6:5-10).
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`VI. State of the art as of January, 2003
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`A. Non-steroidal anti-inflammatory compounds were known and
`approved for ophthalmic use
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`23. Prior to 2003, non-steroidal anti-inflammatory drugs (NSAIDs) were
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`widely used for managing postoperative ocular inflammation, preventing and
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`treating cystoid macular edema after cataract surgery, preventing intraoperative
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`miosis during cataract surgery, relieving symptoms of seasonal allergic
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`conjunctivitis, and reducing ocular discomfort following refractive surgery.
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`(EX1017, 77:1).
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`24. As of January 21, 2003, a number of NSAIDs, formulated for
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`ophthalmic use, were FDA-approved and sold in the United States. For example,
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`diclofenac 1% (Voltaren®, Novartis) was approved in 1991 for minimizing
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`postoperative inflammation after cataract surgery. (EX1032). Diclofenac has the
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`following chemical structure:
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`Inter Partes Review of USPN 8,129,431
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`25. An ophthalmic formulation of ketorolac tromethamine 0.5% (Acular®
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`Ophthalmic Solution, Allergan) was approved in 1992 for treating seasonal
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`allergic conjunctivitis. (EX1017, 78:1). Ketorolac has the following chemical
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`structure:
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`26. Flurbiprofen 0.03% (Ocufen® Ophthalmic Solution, Allergan) and
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`suprofen 1% (Profenal® Ophthalmic Solution from Alcon) were approved in 1986
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`and 1988, respectively, for inhibiting miosis during cataract surgery. (EX1017,
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`78:1). Flurbiprofen has the following chemical structure:
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`
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`27. The NSAID bromfenac and its salts and hydrates were also known
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`prior to January 21, 2003. (EX1002). Bromfenac, shown again below, shares
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`certain structural characteristics with the other NSAIDs diclofenac, ketorolac and
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`flurbiprofen. Specifically, each of these NSAIDs possesses a –C-COOH group
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`attached to an aryl ring. The –COOH moiety is called a carboxylic acid, and in
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`Inter Partes Review of USPN 8,129,431
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`this report I sometimes refer to these NSAIDs bearing a carboxylic acid moiety as
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`“acidic” NSAIDs. As I also explain below, this shared carboxylic acid group
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`causes theses NSAIDs to make an interaction with the preservative benzalkonium
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`chloride (“BAC”) in solution at the pH used for ophthalmic preparations.
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`Bromfenac
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`28.
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` In fact, by 2003, bromfenac had already been shown to have an
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`enhanced anti-inflammatory action when compared to other known NSAIDs.
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`(EX1002, 2:2:4-3:1:1; and EX1033, 15:1-16:34, Table 1). For example,
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`bromfenac was 4-fold more effective
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`than diclofenac
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`in an
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`in vitro
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`cyclooxygenase inhibition assay,2 and was able to inhibit cyclooxygenase 11-fold
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`better than indomethacin, another NSAID. (EX1033, 15:1-16:34, Table 1;
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`EX1002, 2:1:4-2:1).
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`2 Anti-inflammatory activity of the NSAIDs was tested by polarographically
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`monitoring the inhibition in the rate of oxygen consumption in the conversion of
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`arachidonic acid to prostaglandin H2 by prostaglandin H synthase
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`(cyclooxygenase). (EX1033, 13:25-31).
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`Inter Partes Review of USPN 8,129,431
`Declaration of Dr. Uday B. Kompella (EX1003)
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`29.
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` By 2003, researchers in the field had already prepared and patented
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`ophthalmic preparations of bromfenac. For example, in 1990, over a decade prior
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`to the earliest priority date of the ’431 patent, Ogawa disclosed and claimed an
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`ophthalmic formulation of bromfenac containing, among other additives, the
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`surfactant polysorbate 80 and BAC. (EX1004, abstract and 10:4-18). The
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`formulation described in Ogawa was approved and commercially marketed in
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`Japan in 2000 under the name Bronuck®. (EX1034, 1:2). In 1997, Desai
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`described stable aqueous ophthalmic preparations of bromfenac and described that
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`the formulations could also include, among other additives, a polymeric
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`quaternary ammonium compound, BAC, and tyloxapol. (EX1005, 4:14-55; 3:38-
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`39; 2:36-44; claim 8). In 1995, Yanni described stable ophthalmic formulations of
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`bromfenac by making ester and amide bromfenac derivati