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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
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`AKORN, INC.
`Petitioner
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD
`MITSUBISHI CHEMICAL CORPORATION
`Patent Owner
`
`U.S. Patent No. 6,114,319
`_____________________
`
`Inter Partes Review Case No. Unassigned
`_____________________
`
`DECLARATION OF ERNING XIA, PH.D
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`TABLE OF CONTENTS
`
`Introduction ..................................................................................................... 1
`I.
`II. My Background and Qualifications ................................................................ 3
`III. List of Documents I Considered in Formulating My Opinions ..................... 5
`IV. Person of Ordinary Skill in the Art ................................................................. 7
`V.
`The '319 Patent Specification and Claims ...................................................... 8
`VI. Claim Construction ....................................................................................... 10
`VII. State of the Art as of May 14, 1997 .............................................................. 16
`VIII. Summary Chart of Analysis Over the Art .................................................... 32
`IX. The Basis of my Analysis with Respect to Obviousness ............................. 32
`A. Ground 1: The '848 Patent and Ding Provide a Reason(s) to
`Arrive at the Invention of Claims 1, 2-4, 6-10, 12-14, and 18
`with a Reasonable Expectation of Success .........................................34
`1.
`Parts by weight of oil per part by weight of
`difluprednate ............................................................................ 48
`Parts by weight of water per part by weight of
`difluprednate ............................................................................ 52
`Parts by weight of the emulsifier per part by weight of
`difluprednate ............................................................................ 55
`Secondary Considerations of Non-obviousness ..................................60
`1.
`Alcon did not compare its formulation to the closest
`prior art. .................................................................................... 61
`A POSA would have expected that an emulsion
`formulation would increase the bioavailability of
`difluprednate compared to a suspension .................................. 63
`Conclusion .................................................................................................... 69
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`X.
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`2.
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`3.
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`B.
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`2.
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`I, Erning Xia, Ph.D., hereby declare as follows.
`I.
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`Introduction
`1. I am over the age of eighteen and competent to make this declaration.
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`2. I have been retained as an expert witness on behalf of AKORN, INC.,
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`("AKORN") for the above-captioned inter partes review (IPR). I am being
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`compensated for my time in connection with this IPR at my standard consulting
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`rate, which is $400 per hour.
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`3. I understand that this Declaration accompanies a petition for IPR
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`involving U.S. Patent No. 6,114,319 ("the '319 patent"), AKN1001, which resulted
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`from U.S. Patent Application No. 09/076,124 ("the '124 application"), filed
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`May 12, 1998. I also understand that the '319 patent claims priority to Japanese
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`Patent Application No. 9-124415, filed May 14, 1997.
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`4. The '319 patent names Masako Kimura, Shin-ichi Yasueda, Masazumi
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`Yamaguchi, and Katsuhiro Inada as the inventors. The '319 patent issued on
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`September 5, 2000 from the '124 application. I understand that, according to the
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`United States Patent and Trademark Office ("USPTO") records, the '319 patent is
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`currently assigned to Senju Pharmaceutical Co., Ltd. and Mitsubishi Chemical
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`Corp. ("patent owner"). I also understand that the '319 patent is exclusively
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`licensed to Alcon Pharmaceuticals, Ltd. The patent owner and licensee are
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`collectively referred to herein as "Alcon."
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`5. I understand that claims 1-17 of the '319 patent were subject to an ex
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`parte reexamination proceeding at the USPTO, initiated by the patent owner, and
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`that the USPTO issued a Reexamination Certificate on May 18, 2004 (AKN1001,
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`Ex Parte Reexam. Certificate). As a result of the reexamination, I understand that
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`original patent claims 5, 11, and 15-17 of the '319 patent were canceled, claim 1
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`was amended, and new claim 18 was added (AKN1001, Ex Parte Reexam.
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`Certificate, 2:5-16.
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`6. In preparing this Declaration, I have reviewed the '319 patent, the
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`remaining claims (1-4, 6-10, 12-14, and 18), and each of the documents cited
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`herein, in light of general knowledge in the art. In formulating my opinions, I have
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`relied upon my experience, education, and knowledge in the relevant art. In
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`formulating my opinions, I have also considered the viewpoint of a person of
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`ordinary skill in the art ("POSA") (i.e., a person of ordinary skill in the art of
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`ophthalmic, nasal, or otic (ear) drug formulations, defined further below in
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`paragraphs 17-19). Throughout this declaration, in rendering my opinion, I have
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`considered what the viewpoint of a POSA would have been prior to May 14, 1997,
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`the filing date of Japanese Patent Application No. 9-124415 to which the
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`challenged '319 patent claims priority.
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`II. My Background and Qualifications
`7. I am an expert in the field of topical ophthalmic drug formulation. I am
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`presently employed by Fulcrum International Technologies, Inc. I obtained a
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`Bachelor of Science degree in Pharmacy from Nanjing College of Pharmacy in
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`1982, a Master of Science degree
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`in Biopharmaceuticals
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`from China
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`Pharmaceutical University in 1985, and a Ph.D. in Pharmaceutics from the
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`University of Iowa in 1995.
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`8. I was an Assistant Professor and Research Associate for the College of
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`Pharmacy at the China Pharmaceutical University from August 1985 to December
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`1987, a Research Associate at Illinois State University from January 1988 to
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`December 1989, and a Research and Teaching Assistant for the University of Iowa
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`College of Pharmacy from 1990 to 1995. After receiving my Ph.D. in
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`Pharmaceutics, I held the positions of Senior Formulation Process Scientist and
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`Principal Formulation Process Scientist with Bausch & Lomb in Rochester, NY
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`from 1995-1999 and 1999-2001, respectively. I subsequently held the positions of
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`Senior Principal Formulation Process Scientist from 2001-2004, Research Fellow
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`from 2004-2005, and Site Leader/Research Fellow from 2006-2008 at Bausch &
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`Lomb.
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`9. I served as Program Director and Research Fellow at Valeant
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`Pharmaceuticals in Rochester, NY from 2009-2013. I currently hold the position of
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`Distinguished Research Fellow and Chief Technology Officer ("CTO") at Fulcrum
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`International Technologies, Inc. and have served in this position since September
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`of 2013. My curriculum vitae is provided as AKN1003.
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`10. I have experience formulating topical ophthalmic drugs. For example,
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`my doctoral research at
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`the University of Iowa (1990-1995) was on
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`biopharmaceutical considerations in the development of a topical ocular drug (N,
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`N'-Dimethyl-2-Phenylethylamine) for dry eye disease. My doctoral research
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`resulted in twelve publications, (including my doctoral dissertation), which are
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`listed as numbers 7-18 on my CV. AKN1003, 15-16. Also, in the 1990-1995
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`timeframe at the University of Iowa, I conducted ophthalmic preformulation and
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`formulation work in several ocular drug delivery systems. The ophthalmic
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`preformulation work included, for example, quantitatively determining structure-
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`activity relationships, studies involving ophthalmic drug solubility profiles,
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`partition coefficient, and corneal permeation, and lacrimal gland acinar cell
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`preparation.
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`11. In 1995, I joined Bausch & Lomb (B&L) in Rochester, NY as a senior
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`formulation process scientist, where I worked on ophthalmic formulations and
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`technology transfer to manufacture sites. While at B&L, my formulation focus was
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`on developing various ophthalmic eye drops with minimal irritation to ocular
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`tissues without sacrificing key product attributes.
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`12. Also during my employment at B&L, I worked on steroidal ophthalmic
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`preparations such as LOTEMAX® gel, an ophthalmic gel containing the poorly
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`water-soluble steroid loteprednol etabonate, which was used to treat post-operative
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`inflammation and pain following ocular surgery as well as dry eye disease caused
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`by inflammation.
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`13. I have received several honors in my career, including the Bausch &
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`Lomb In Focus Recognition in 2010, the Bausch & Lomb CSO Innovation Award
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`in 2007, the National Award for Science Spectrum Trailblazer in 2005, and the
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`National Emerald Award for Career Achievement in Industry in 2004.
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`14. During my nearly 30 years of experience in topical ophthalmic drug
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`formulations, I have authored or co-authored 36 scientific articles. I am also a
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`named inventor on 106 U.S. patents and patent applications. Each publication,
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`patent, and patent application is listed in my curriculum vitae, AKN1003.
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`15. Accordingly, I am an expert in the field of topical ophthalmic drug
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`formulation. My full background is detailed in my curriculum vitae. AKN1003.
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`III. List of Documents I Considered in Formulating My Opinions
`16. In formulating my opinions, I have considered all the references and
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`documents cited herein, including those listed below.
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`AKORN
`(AKN)
`Exhibit #
`1001
`
`1002
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
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`1011
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`1012
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`1013
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
`
`Description
`
`U.S. Patent No. 6,114,319 to Kimura, M., et al., entitled
`"Compositions Containing Difluprednate," issued Sept. 5, 2000
`("the '319 patent")
`GB Patent No. 955,891, entitled "Stable Preparations of
`Prednisone Derivatives and Process for the Manufacture
`Thereof," published April 22, 1964
`U.S. Patent No. 3,780,177 to Ercoli et al., entitled "17-Butyrate,
`21- Ester Derivatives of 6α, 9α-Difluroprednisolone,
`Compositions and Use," issued Dec. 18, 1973 ("the '177 patent")
`U.S. Patent No. 3,784,692 to Ercoli et al., entitled "17-
`Propionate, 21- Ester Derivatives of 6α, 9α-Difluroprednisolone,
`Compositions and Use," issued Jan. 8, 1974 ("the '692 patent")
`U.S. Patent No. 5,556,848 to Kimura et al., entitled "Ophthalmic
`Suspension Containing Diflupredonate [sic]," issued Sept. 17,
`1996 ("the '848 patent")
`Ex Parte Reexamination File History of U.S.P.N. 6,114,319
`(Reexam. Control No. 90/006,548)
`Sasaki et al., "Delivery of Drugs to the Eye by Topical
`Application," Chapter 11 in Progress in Retinal and Eye
`Research 15, No. 2, pp. 583-620 (1996).
`Hollingsbee, D., European Patent Appl. Publication No. 0 028
`110 B1, entitled "Autoclavable Emulsions," published May 6,
`1981 ("Hollingsbee")
`U.S. Patent No. 5,496,811 to Aviv et al., entitled "Submicron
`Emulsions as Ocular Drug Delivery Vehicles," filed Jan. 5, 1993,
`issued March 5, 1996 ("Aviv")
`Chapter 86, "Ophthalmic Preparations," in Remington's
`Pharmaceutical Sciences, 8th edition, A.R. Gennaro, ed., pp.
`1581-1595 (1990)
`PCT Publication No. WO 95/31211 to Ding, S., et al., entitled
`"Lacrimal Gland Specific Emulsions For Topical Application to
`Ocular Tissue," published November 23, 1995 ("Ding")
`Schoenwald, R.D. and Stewart, P., "Effect of Particle Size on
`Ophthalmic Bioavailability of Dexamethasone Suspensions in
`Rabbits," J. Pharm. Sci. 69:391-394 (1980)
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`AKORN
`(AKN)
`Exhibit #
`1014
`
`1015
`
`1016
`
`1017
`1019
`
`1020
`
`1021
`1022
`
`1023
`
`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
`
`Description
`
`Chapter 19, "Disperse Systems," in Remington's Pharmaceutical
`Sciences, 8th edition, A.R. Gennaro, ed., pp. 257-309 (1990)
`Muchtar, S., et al., "A Submicron Emulsion as Ocular Vehicle
`for Delta-8-tetrahydrocannabinol: Effect on Intraocular Pressure
`in Rabbits," Ophthalmic Res. 24:142-149 (1992)
`Muchtar, S., et al., "Emulsions as Drug Carriers for Ophthalmic
`Use," Colloids and Surfaces A: Physicochemical and
`Engineering Aspects 91:181-190 (1994)
`File History of USPN 6,114,319
`Apt, L. et al., "Patient Compliance With the Use of Topical
`Ophthalmic Corticosteroid Suspension," Am. J. Opthalmol.
`87:210 (1979)
`Kassem et al., "Preparation and Evaluation of Hydrocortisone
`Multiple Emulsions in Rabbit's Eye," Pharmazeutische Industrie
`56: 584-588 (1994)
`The Merck Index, Twelfth edition, "Polysorbates," 7742 (1996)
`Olejnik, O., "Conventional Systems in Ophthalmic Drug
`Delivery," in Ophthalmic Drug Delivery Systems, Mitra, A.K.,
`ed., Marcel Dekker, Inc., New York: 177-198 (1993)
`Chapter 83, "Solutions, Emulsions, Suspensions and Extracts" in
`Remington's Pharmaceutical Sciences, 8th edition, A.R. Gennaro,
`ed., pp. 1519-1544 (1990)
`
`IV. Person of Ordinary Skill in the Art
`17. I understand that a person of ordinary skill in the art ("POSA") is a
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`hypothetical person who is presumed to be aware of all of the pertinent art, thinks
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`along conventional wisdom in the art, and is a person of ordinary creativity. A
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`POSA of topical eye, nasal, or ear formulations would have had knowledge of the
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`scientific literature regarding inflammatory eye, nasal, or ear disorders and useful
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`therapies including, e.g., topical steroids and their formulation into delivery
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`vehicles, as of May 1997.
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`18. With respect to the subject matter of the '319 patent, a POSA typically
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`would have had: (i) an M.D. or Ph.D. in chemistry, biochemistry, pharmaceutics,
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`or in a related field in the biological or chemical sciences, and have at least about
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`two years of experience in the formulation of topical eye, nasal, or ear
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`pharmaceuticals; or
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`(ii) a Master's degree
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`in chemistry, biochemistry,
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`pharmaceutics, or in a related field in the biological or chemical sciences, and have
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`at least about five years of experience in the formulation of topical eye, nasal, or
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`ear pharmaceuticals.
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`19. A POSA typically would work as part of a multidisciplinary team and
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`draw upon not only his or her own skills, but also take advantage of certain
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`specialized skills of others in the team to solve a given problem. For example, a
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`clinician having experience in treating inflammatory disorders of the eye, nose, or
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`ear with topical pharmaceuticals may be part of the team.
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`V.
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`The '319 Patent Specification and Claims
`20. I understand that this declaration is being submitted together with a
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`petition for inter partes review of the claims of the '319 patent remaining after the
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`Ex Parte Reexamination Certificate issued on May 18, 2004 (i.e., claims 1, 2-4, 6-
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`10, 12-14, and 18). AKN1001, 10-12 and Ex Parte Reexam. Certificate, 2:18-27. I
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`have considered the disclosure of the '319 patent in light of general knowledge in
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`the art and the teachings of the scientific literature before the earliest possible
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`priority date of the '319 patent, which I understand to be May 14, 1997. I have also
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`reviewed
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`the file history of
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`the
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`'319 patent (AKN1017),
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`including
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`its
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`reexamination file history. AKN1007.
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`21. The '319 patent specification is directed generally to the field of topical
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`emulsion formulations, and more specifically to emulsions containing the steroid
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`difluprednate, for topical administration to the eye, nose, or ear. AKN1001,
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`Abstract. The '319 specification acknowledges that difluprednate was a known and
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`potent anti-inflammatory steroid used for percutaneous and subcutaneous
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`administration. AKN1001, 1:14-26. The
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`'319 patent specification further
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`acknowledges that difluprednate has extremely low solubility in water and that
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`aqueous suspensions of the drug had previously been used for administration to the
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`eye, ear, and nose. AKN1001, 1:26-36.
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`22. Each claim of the '319 patent recites an emulsion in the form of an eye
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`drop, a nasal drop, or an ear drop comprising the steroid difluprednate, an oil,
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`water, and an emulsifier. Claims 1 and 18 are the independent claims and are
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`reproduced below:
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`Claim 1. A difluprednate emulsion in the form of an eye drop, a nasal
`drop or an ear drop comprising (a) difluprednate, (b) an oil selected
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`from the group consisting of castor oil, peanut oil, cotton seed oil,
`soybean oil, olive oil and a medium chain fatty acid triglyceride, (c)
`water and (d) an emulsifier.
`Claim 18. A difluprednate emulsion in the form of an eye drop, a
`nasal drop or an ear drop comprising difluprednate, castor oil, water
`and polyoxyethylene (20) sorbitan monooleate.
`23. A POSA would understand that claim 18 is narrower than claim 1
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`because claim 1 recites "oil" and "an emulsifier," whereas claim 18 recites "castor
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`oil" and "polyoxyethylene (20) sorbitan monooleate," respectively.
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`VI. Claim Construction
`24. I understand that terms of the claims are to be given their broadest
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`reasonable interpretation in light of the language of the claims and specification of
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`the '319 patent.
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`25. "Emulsion." Claims 1, 2-4, 6-10, 12-14, and 18 recite the term
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`"emulsion." And independent claims 1 and 18 recite "a difluprednate emulsion."
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`AKN1001, 10-12 and Ex Parte Reexam. Certificate, 2:18-27. While not explicitly
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`defined, the '319 specification states that the emulsion can be "an aqueous
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`preparation of [an] oil-in-water type (O/W type) emulsion," and Examples 1 and 9
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`describe the preparation of an oil-in-water emulsion of difluprednate by mixing "an
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`oil phase," containing castor oil and difluprednate,
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`phase." AKN1001, 4:1-3; 4:64-8:39. Accordingly, a POSA would have understood
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`in "an aqueous
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`the term "emulsion" to have its plain and ordinary meaning, which is a mixture of
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`two or more liquids (in this case, oil and water), that are normally immiscible (not
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`capable of forming a homogeneous mixture), wherein one liquid (the dispersed
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`phase) is dispersed in the other liquid (the continuous phase), and typically
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`stabilized by one or more "emulsifiers" (defined below).
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`26. While the '319 specification states that "[t]he composition of the present
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`invention can be provided as an aqueous preparation of [an] oil-in-water type
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`(O/W type) emulsion" (AKN1001, 4:1-3), a POSA would have understood that oil
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`and water emulsions include: (1) an oil-in-water type emulsion, wherein the oil is
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`dispersed in the water; or (2) a water-in-oil type emulsion, wherein the water is
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`dispersed in the oil. This interpretation is also supported by a plain reading of
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`dependent claims 10 and 12-14, which specify an oil-in-water type emulsion,
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`informing a POSA that claims 1-4 (on which claims 10 and 12-14 depend)
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`encompass both oil-in-water and water-in-oil emulsion types.
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`27. Dependent claims 10 and 12-14 specify that the difluprednate emulsion
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`is an "oil-in-water type emulsion." AKN1001, 11:4-12:2. While the '319 patent
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`does not specifically define an oil-in-water type emulsion, the specification states
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`that "[t]he composition of the present invention can be provided as an aqueous
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`preparation of oil-in-water type (O/W type) emulsion, microemulsion and the
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`like." AKN1001, 4:1-3 (emphasis added). Accordingly, a POSA, in 1997, would
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`have understood the term oil-in-water type emulsion to have its plain and ordinary
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`meaning, which is an emulsion having the oil (the dispersed phase) dispersed in
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`water (the continuous phase). AKN1001, 3 :25-26.
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`28. "Emulsifier" and "surfactant." Claims 1, 2-4, and 6 recite the term
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`"emulsifier." AKN1001, 10:41-58 and Ex Parte Reexam. Certificate, 2:24. Claim 6
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`depends from claim 1 and recites that the emulsifier "comprises a surfactant."
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`AKN1001, 10:57-58.
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`29. A POSA would have understood the term emulsifier (also known as
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`emulsifying agent) to have its plain and ordinary meaning, which is a chemical
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`agent that promotes the formation of, and stabilizes, an emulsion. AKN1023, 18.
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`While not explicitly defined, the '319 specification states that, "[t]he composition
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`of the present invention is prepared by emulsifying oil, in which difluprednate has
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`been dissolved, and water, using an emulsifier . . . ." AKN1001, 4: 12-14. The '319
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`specification also states that "a surfactant, such as a nonionic surfactant having
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`surface activating capability and the like, may be contained as an emulsifier."
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`AKN1001, 3: 3-5. Accordingly, a POSA would have understood that surfactants
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`can act as emulsifiers. AKN1001, 10:57-58; AKN1014, 47-48. Also, a POSA
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`would have understood that one or more agents, such as surfactants, could be used
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`together as an emulsifier to help disperse, for example, the oil in the water and
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`thereby form the emulsion.
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`30. Claim 7 recites that the surfactant is "a nonionic surfactant" and claim 8
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`recites that the nonionic surfactants are "polyoxyethylene hydrogenated castor oils
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`and polyoxyethylenesorbitan fatty acid esters." AKN1001, 10:59-64. Claim 9
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`recites that the polyoxyethylenesorbitan fatty acid ester can be selected from
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`"polyoxyethylenesorbitan monooleate . . . ." AKN1001, 10:59-11:3. Accordingly,
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`based on a plain reading of the claims, a POSA would have appreciated that each
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`of the compounds recited in claim 9 is both an emulsifier and a nonionic surfactant.
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`31. Claim 18 specifies "polyoxyethylene (20) sorbitan monooleate" as a
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`component of the emulsion. AKN1001, Ex Parte Reexam. Certificate, 2:25-27. A
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`POSA would have appreciated that polyoxyethylene (20) sorbitan monooleate is
`
`also known as polysorbate 80 or Tween 80. AKN1021, 3; See also AKN1001, Ex
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`Parte Reexam. Certificate, 1:19-21, which reflects Alcon's amendment to the '319
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`specification "to clarify that polyoxyethylene (20) sorbitan monooleate is the
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`chemical name for polysorbate 80 disclosed throughout the specification."
`
`AKN1007, 15; AKN1001, Ex Parte Reexam. Certificate, 1:19-21. Alcon added
`
`claim 18 during ex parte reexamination and stated, "[n]ew claim 18 is directed to a
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`formulation containing castor oil and polysorbate 80. . . polyoxyethylene (20)
`
`sorbitan monooleate is the chemical name for polysorbate 80 disclosed throughout
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`the specification," and "[n]ew claim 18 further defines the oil and the emulsifier in
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`claim 1." AKN1007, 4. This amendment was consistent with a POSA's
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`understanding that polyoxyethylene (20) sorbitan monooleate is also known as
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`polysorbate 80. AKN1021, 3. Accordingly, from the '319 patent specification, the
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`ex parte reexamination prosecution history, and a plain reading of claims 1 and 6, a
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`POSA would have understood that surfactants can act as emulsifiers. AKN1001, 3:
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`3-5 and 10:57-58. And similarly, a POSA would have understood that
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`polyoxyethylene (20) sorbitan monooleate (also called polysorbate 80), as recited
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`in claim 18, is an example of a surfactant that can also act as an emulsifier.
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`32. "parts by weight." Claims 2-4 recite the phrase "parts by weight" of
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`oil, of water, and of the emulsifier, per part by weight of difluprednate. For
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`example, claim 4 recites that the emulsion of claim 1 comprises "10-5,000 parts by
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`weight of oil . . . per part by weight of difluprednate." AKN1001, 10:49-50. Based
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`on the '319 specification, its context from the claims, and its plain and ordinary
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`meaning in the art, a POSA would have understood "parts by weight," as used in
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`the claims, to represent a range of possible weight relationships between the oil,
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`the water, or the emulsifier, and the difluprednate. And a POSA would have
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`understood that the weight of the oil, the water, the emulsifier, and the
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`difluprednate is indicated by percent (%), which denotes the concentration by
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`weight of the component, per 100 units volume of the entire emulsion.
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`33. Below I provide specific examples of how a POSA would have
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`determined parts by weight for the components of two hypothetical emulsions (the
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`first containing one emulsifier and the second containing two emulsifiers).
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`34. The first hypothetical emulsion contains by weight: 0.1% difluprednate,
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`5% oil, 4.9% emulsifier, and 90% water. A POSA could calculate the part by
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`weight of each of the components (oil, emulsifier, and water) relative to the
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`difluprednate as follows:
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`• Parts by weight of the oil per part by weight of the difluprednate:
`5% (oil) ÷ 0.1% (difluprednate) = 50
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`• Parts by weight of the emulsifier per part by weight of the difluprednate:
`4.9% (emulsifier) ÷ 0.1% (difluprednate) = 49
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`• Parts by weight of the water per part by weight of the difluprednate:
`90% (water) ÷ 0.1% (difluprednate) = 900.
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`35. The second hypothetical emulsion contains by weight: 0.1%
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`difluprednate, 2% oil, 2.9% emulsifier A, 4% emulsifier B, and 91% water. A
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`POSA could compute the part by weight of each of the components (oil, emulsifier
`
`A and B, and water) relative to the difluprednate as follows:
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`• Parts by weight of the oil per part by weight of the difluprednate:
`2% (oil) ÷ 0.1% (difluprednate) = 20
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`• Parts by weight of emulsifier (A and B) per part by weight of the
`difluprednate:
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`(2.9% + 4.0%) (emulsifier A + emulsifier B)÷ 0.1% = 69
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`• Parts by weight of the water per part by weight of the difluprednate:
`91% (water) ÷ 0.1% (difluprednate) = 910.
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`36. Any term I have not expressly discussed above, I have given its plain
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`and ordinary meaning to a POSA consistent with the specification of the '319
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`patent.
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`VII. State of the Art as of May 14, 1997
`37. As of May 14, 1997, the state of the art known to a POSA included the
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`teachings of the references discussed below.
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`38. Difluprednate was a Potent Synthetic Steroid. Difluprednate (also
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`known by its chemical name 6α, 9α-difluoroprednisolone 17-butyrate 21-acetate or
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`DFBA) was synthesized in 1973 and was derived from prednisolone acetate.
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`AKN1004, 1:2-4 and 1:56-72; 4-6; AKN1005, 1: 2-4. Thus, well before 1997, a
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`POSA would have known that difluprednate was a synthetic steroid with potent
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`anti-inflammatory and anti-allergic effects. AKN1004, 1:55-2:5; AKN1005, 1:34-
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`40; AKN1006, 1:25-28. A POSA also would have known that difluprednate could
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`be used in the topical and systemic "treatment of inflammatory conditions and
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`diseases," such as arthritis, as well as the topical "treatment of dermatitis of
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`various type[s], psoriasis, and other allergic conditions that respond to the topical
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`application of anti-inflammatory steroids." AKN1004, 1:50-54 and 2:41-46.
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`39. A POSA also would have known that biological assays of difluprednate
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`showed higher anti-inflammatory activity (2-10 times for topical activity and 15-50
`
`times higher for systemic activity) than that of the corresponding 17-monoesters
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`and 17, 21-dieesters of betamethasone. (AKN1004, 11:49-55). "[T]he remarkable
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`activity of the specific compounds of this invention appears to result by the
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`combination of a 17-butyrate with a 21-ester group as defined above in 6α, 9α-
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`difluroprednisolone, thus providing potent anti-inflammatory steroids. . . ."
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`AKN1004:1:72-2:5 (emphasis added). And, before 1997, a POSA would have
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`appreciated that because of difluprednate's potency, it could be used at a lower
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`dose or reduced administration frequency compared to other steroids used to treat
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`the same ailments. (AKN1006, 10:36-42).
`
`40. Difluprednate was Poorly Soluble in Water. Before 1997, a POSA
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`would have known that difluprednate, like most steroids, was poorly soluble in
`
`water. AKN1006, 1:34-35. And a POSA would have appreciated that poorly water-
`
`soluble drugs, like difluprednate, were difficult to formulate into aqueous
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`preparations. AKN1006, 1:34-37; AKN1012, 2:25-31; AKN1011, 7; AKN1016, 1.
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`41. Suspensions and Emulsions. Before 1997, ophthalmic suspensions and
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`emulsions were known and used to deliver drugs with low water solubility.
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`AKN1008, 602-608; AKN1016, 181; AKN1022, 188. Also before 1997, POSAs
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`generally used non-ionic surfactants, such as e.g., polysorbates, in aqueous
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`suspensions and emulsions and found them safe and non-irritating for ophthalmic
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`preparations. AKN1021, 3; AKN1006, 3:34-49; AKN1012, 1:8-14. In emulsion
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`formulations, polysorbate 80 was a useful non-ionic surfactant that functioned as
`
`an emulsifier. AKN1021, 3; AKN1012, 10-11 (Examples 1-4). In suspension
`
`formulations, however, polysorbate 80 did not function as an emulsifier. Instead, in
`
`suspensions, polysorbate 80 functioned as an agent to enhance stability of the solid
`
`particles dispersed in the liquid agent of the suspension. AKN1006, 3:34-65.
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`42. Difluprednate Suspensions. Prior
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`to 1997, ophthalmic aqueous
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`suspensions containing steroids were known in the art. AKN1006, Abstract;
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`AKN1022, 14-16. And prior to 1997, ophthalmic suspensions containing the
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`steroid difluprednate were also known. AKN1006, Abstract U.S. Patent No.
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`5,556,848 to Kimura et al. ("the '848 patent") issued Sept. 17, 1996 disclosing an
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`aqueous difluprednate suspension for administration to the eye. AKN1006,
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`Abstract. Aqueous steroidal suspensions typically made use of small solid particles
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`of the steroid dispersed in an aqueous vehicle. AKN1006, 2:15-23; AKN1011, 7.
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`43. But prior to 1997, a POSA would have been aware of several drawbacks
`
`with ophthalmic suspensions, such as the difluprednate suspension described in the
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`'848 patent. AKN1011, 7; AKN1009, 1:25-33, AKN1022, 16; AKN1013, 1, 4;
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`AKN1019, 3-4. These difficulties included: (1) ocular irritation and patient
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`discomfort due to the presence and size of the drug particles; (2) poor dosage
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`uniformity of the drug due to particles not being redispersed by adequate shaking
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`Inter Partes Review of USPN 6,114,319
`Declaration of Erning Xia, Ph.D (AKN1018)
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`of the container; (3) a tendency of the drug particles to agglomerate, also leading to
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`dosage inconsistencies; and (4) a slow rate of dissolution of the drug from the
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`particle after application. AKN1011, 7; AKN1009, 1:25-33, AKN1022, 16;
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`AKN1013, 1, 4, AKN1019, 3-4. As discussed below, a POSA would have
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`understood that one or more of these noted shortcomings contributed to reducing
`
`the ocular bioavailability of the suspended drug in the target tissue. AKN1011, 7;
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`AKN1009, 1:25-33; AKN1022, 16; AKN1013, 1, 4; AKN1019, 3-4.
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`44. Ocular Irritation. Prior to 1997, POSAs would have recognized that
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`the presence of the drug particles themselves in the suspension, as well as the size
`
`of the particles, contributed to ocular discomfort and irritation. AKN1011, 7;
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`AKN1022, 15. And before 1997, it was appreciated in the art that ophthalmic
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`suspensions should contain particle sizes of less than 10µm in order to minimize
`
`irritation to the eye. AKN1011, 7; AKN1022, 15. But obtaining a consistent drug
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`particle size of less than 10