IPR2019-00400
`Patent 8,633,194
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`APOTEX INC.
`Petitioner,
`
`v.
`
`UCB BIOPHARMA SPRL,
`Patent Owner.
`______________
`
`Case IPR2019-00400
`Patent 8,633,194
`______________
`
`DECLARATION OF SARFARAZ K. NIAZI
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2034 Page 1
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`

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`TABLE OF CONTENTS
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`IPR2019-00400
`Patent 8,633,194
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`I.
`
`INTRODUCTION ......................................................................................... 1
`A.
`Background and Qualifications ............................................................. 1
`B.
`Compensation ........................................................................................ 4
`C. Materials Considered ............................................................................. 4
`SUMMARY OF OPINIONS ......................................................................... 4
`II.
`III. LEGAL STANDARDS .................................................................................. 5
`IV. PERSON HAVING ORDINARY SKILL IN THE ART ........................... 6
`V.
`THE CHALLENGED CLAIMS .................................................................. 7
`VI. CLAIM CONSTRUCTION .......................................................................... 8
`VII. GENERAL PRINCIPLES OF FORMULATION ...................................... 9
`VIII. CONTROLLING MICROBIAL GROWTH IN
`PHARMACEUTICAL FORMULATIONS .............................................. 13
`A.
`Testing for Antimicrobial Effectiveness ............................................. 14
`B. Microbial Contamination Risk in Pharmaceutical Formulations ........ 16
`C.
`Preservatives, and Other Options to Prevent Microbial Contamination
` ............................................................................................................. 17
`Parabens ............................................................................................... 20
`D.
`IX. LEVOCETIRIZINE AND ANTIHISTAMINES ..................................... 23
`X.
`THE ’194 PATENT ..................................................................................... 27
`A.
`The ’194 Patent .................................................................................... 27
`B.
`Prosecution History ............................................................................. 31
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`UCB Biopharma SPRL (IPR2019-00400)
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`C.
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`C.
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`IPR2019-00400
`Patent 8,633,194
`The European Opposition Proceedings are Irrelevant to This Petition.
` ............................................................................................................. 35
`XI. PETITIONER’S REFERENCES ............................................................... 37
`A.
`EP ’203 (EX1004) ............................................................................... 37
`B. WO ’094 (EX1007) ............................................................................. 42
`C.
`Handbook (EX1006) ........................................................................... 45
`D.
`US ’558 (EX1015) ............................................................................... 53
`E.
`Dr. Laskar’s References Allegedly Teaching a 9:1 Ratio of
`Methylparaben to Propylparaben ........................................................ 54
`XII. OPINION REGARDING GROUND 1: WO ’094 AND THE
`HANDBOOK DO NOT RENDER THE CHALLENGED CLAIMS
`UNPATENTABLE. ..................................................................................... 57
`A. WO ’094 Does Not Direct a POSA to Use an Oral Syrup. ................. 58
`B.
`A POSA Would Not Be Motivated to Use the Handbook to Determine
`the Amounts and Ratios of the Preservatives in the Formulation of
`WO ’094. ............................................................................................. 60
`The Handbook Does Not Teach a POSA to Use Methylparaben and
`Propylparaben in a “Ratio of 9/1 by Weight” and in an Amount of
`“More than 0 and Up to 0.75 mg/mL.” ............................................... 61
`1.
`Dr. Laskar’s “Overlapping Range” is Not Grounded in
`Principles of Pharmaceutical Formulation. ............................... 62
`The Prior Art Does Not Teach Using a 9:1 Ratio of
`Methylparaben and Propylparaben in a Liquid
`Pharmaceutical Formulation. .................................................... 66
`A POSA Would Not Be Motivated to Minimize the Amount
`of Preservatives in a Liquid Pharmaceutical Formulation. ....... 68
`A POSA Would Have No Reasonable Expectation of Succeeding in
`Making the Claimed Invention. ........................................................... 71
`The Invention of the ’194 Patent was Surprising and Unexpected. .... 72
`ii
`
`D.
`
`2.
`
`3.
`
`E.
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`1.
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`2.
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`IPR2019-00400
`Patent 8,633,194
`It was Unexpected that Levocetirizine Would Have
`Antibacterial Properties. ........................................................... 73
`The ’194 Patent Inventors Were Unexpectedly Able to
`Prepare a Formulation with Low Amounts of Parabens that
`Was Substantially Free of Bacteria. .......................................... 74
`F. Dependent Claims................................................................................ 78
`1.
`Dependent Claim 2 ................................................................... 78
`2.
`Dependent Claim 4 ................................................................... 78
`3.
`Dependent Claim 6 ................................................................... 79
`4.
`Dependent Claim 11 ................................................................. 80
`XIII. OPINION REGARDING GROUND 2: EP ’203, US ’558, AND THE
`HANDBOOK DO NOT RENDER THE CHALLENGED CLAIMS
`UNPATENTABLE. ..................................................................................... 81
`A.
`EP ’203 Does Not Direct a POSA to Example 5. ............................... 83
`B. Dr. Laskar Does Not Explain Why a POSA Would Be Motivated to
`Modify the Methylparaben and Propylparaben Amounts and Ratio in
`EP ’203 Example 5. ............................................................................. 84
`C. A POSA Would Not be Motivated to Combine the Teachings of the
`Handbook with Example 5 of EP ’203. ............................................... 85
`D. A POSA Would Have No Reasonable Expectation of Success in
`Making the Claimed Invention. ........................................................... 86
`The Handbook Does Not Teach a POSA to Use Methylparaben and
`Propylparaben in “a Ratio of 9/1” and in “an Amount of More than 0
`and up to 0.75 mg/mL.” ....................................................................... 87
`The Invention of the ’194 Patent was Surprising and Unexpected. .... 88
`F.
`G. Dependent Claims................................................................................ 88
`
`E.
`
`
`
`
`
`iii
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`I.
`
`INTRODUCTION
`
`I, Sarfaraz K. Niazi, Ph.D., have been retained by Fenwick & West
`
`IPR2019-00400
`Patent 8,633,194
`
`LLP, counsel for Patent Owner UCB Biopharma Sprl (“Patent Owner”), as an expert
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`witness in the above-captioned inter partes review of United States Patent No.
`
`8,633,194 (the “’194 patent”) (EX1001). I understand that Apotex, Inc. (“Apotex”)
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`has petitioned for inter partes review of the ’194 patent and requests that the United
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`States Patent and Trademark Office (“PTO”) cancel as unpatentable claims 1-11 of
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`the ’194 patent.
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`
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`This declaration sets forth my analyses and opinions based on the
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`materials I have considered thus far, as well as the bases for my opinions.
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`A. Background and Qualifications
` While a copy of my curriculum vitae is submitted as Exhibit 2009,
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`below I provide a high-level overview of my experience with pharmaceutical
`
`formulation, beginning with my education. In 1966, I received my B.Sc. in
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`Chemistry from Karachi University, Pakistan. I then received my B. Pharm, also
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`from Karachi University in 1969. I went on to receive my M.S. in Pharmaceutical
`
`Sciences from Washington State University in 1970, followed by my Ph.D. in
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`Pharmaceutical Sciences from the University of Illinois in 1974.
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`
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`From 1972 to 1988, I served full-time on the faculty of the University
`
`of Illinois College of Pharmacy, where I taught pharmacokinetics as well as
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`
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`1
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`IPR2019-00400
`Patent 8,633,194
`formulation science that included creating new formulations and methods of testing
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`and evaluation. As part of my research program, I trained several graduate students
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`who worked on a variety of formulations including the Selsun Blue shampoo,
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`creams, lotions, solutions, capsules, and many other dosage forms.
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`
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`I served as Director, Technical Affairs for Abbott International—a
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`subsidiary of Abbott Laboratories—from 1988-1995. At Abbott International I was
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`the first to suggest and initiate a generic line of pharmaceutical formulations that
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`resulted in several formulations including topical analgesics, and over 10 other
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`narrow therapeutic index drugs. These are drugs where even slight deviations from
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`the therapeutic amount of a drug can result in serious failures or adverse reactions.
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`During my time at Abbott, I formulated, evaluated in humans, and created regulatory
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`dossiers.
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`
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`In 2003, I founded what is now known as Adello Biologics, LLC
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`(recently acquired by Kashiv) and served as Executive Chairman until 2017.
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`
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`I am currently Adjunct Professor of Biopharmaceutical Sciences at the
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`University of Illinois, College of Pharmacy. I am also Visiting Professor at the
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`University of Houston College of Pharmacy.
`
`
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`In addition to my academic positions and industry positions, I am the
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`founder and Executive Chairman of Pharmaceutical Scientist, LLC—a
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`pharmaceutical and biological products consulting company that, among other
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`
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`2
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`IPR2019-00400
`Patent 8,633,194
`things, assists in the development of biosimilar products and formulation of small
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`molecule products. In my consulting capacity, I have assisted major pharmaceutical
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`companies in developing complex generic dosage forms and in April 2019 I was
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`invited by the FDA to teach the science of formulation of complex generics. I have
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`also developed several biologic drug formulations including PEGylation products,
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`and sustained delivery of proteins. I am a named inventor on dozens of United States
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`patents on topical formulations, combination formulations, drug delivery modalities,
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`and new chemical entities.
`
`
`
` I am the sole author of dozens of books, including the series
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`“Handbook of Pharmaceutical Manufacturing Formulations.” This series teaches
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`the principles of pharmaceutical formulation and manufacturing, and is broken into
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`six sections: Over the Counter Products; Semisolid Products; Liquid Products;
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`Uncompressed Solids; Compressed Solids; and Sterile Products. I am also the sole
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`author of the “Handbook of Preformulation: Chemical, Biological and Botanical
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`Drugs.”
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`
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`I am the author of over 100 research articles and have been invited to
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`hundreds of speaking engagements worldwide. I have been a licensed patent agent
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`with the United States Patent and Trademark Office since 2002.
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`
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`3
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`B. Compensation
`
`I am being compensated for my work in this case at my usual rate of
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`IPR2019-00400
`Patent 8,633,194
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`$500 per hour. My per diem rate is $4,000. My compensation is in no way
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`dependent on the outcome of this proceeding.
`
`C. Materials Considered
` The opinions that I express in this declaration are based on the
`
`information and evidence currently available to me. In forming the opinions set
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`forth in this declaration, I considered the materials submitted as Exhibits by
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`Petitioner and Patent Owner in this proceeding. I also relied on my knowledge of
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`pharmaceutical formulation, experience in the field, and my own scientific analysis.
`
`II.
`
`SUMMARY OF OPINIONS
`
`I have reviewed the specification, claims, and file history of the ’194
`
`patent, as well as the Petition for Inter Partes Review of U.S. Patent No. 8,633,194
`
`Under 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123 (“Petition” or
`
`“Pet.”), the references cited therein, the Declaration of Dr. Paul A. Laskar, Ph.D.
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`(EX1002) filed in support of the Petition, the Board’s Decision of Institution of Inter
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`Partes Review (Paper No. 17), and the Transcript of the Cross-Examination of Dr.
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`Paul A. Laskar dated October 2, 2019 (EX2010).
`
` For the reasons set forth below, I disagree with Petitioner’s arguments
`
`advanced in its Petition and with Dr. Laskar’s opinions that claims 1-11 of the ’194
`
`patent are invalid as obvious.
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`
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`4
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`III. LEGAL STANDARDS
`
`I understand that this petition involves U.S. Patent No. 8,633,194.
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`IPR2019-00400
`Patent 8,633,194
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`
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`I understand that the earliest priority date to which the ’194 patent is
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`entitled is July 14, 2004. Therefore, I have used this date as the relevant date for
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`assessing what was known in the field at the time of the invention.
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`
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`I understand that a patent claim may be unpatentable if the differences
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`between the claimed invention and the prior art would have been obvious to a person
`
`having ordinary skill in the art at the time of the invention. I understand that an
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`obviousness analysis is viewed from the perspective of a “person having ordinary
`
`skill in the art” (“POSA”). I understand that an obviousness analysis requires an
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`assessment of (1) the level of ordinary skill in the art; (2) scope and content of the
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`prior art; (3) differences between the prior art and the claimed invention; and (4)
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`objective indicia of nonobviousness, such as commercial success, long-felt but
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`unsolved needs, failure of others, industry acclaim, and unexpected results.
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`
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`I understand that in considering obviousness, it is relevant to consider
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`what the prior art teaches, and, in particular, if the prior art teaches away from the
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`claimed invention such that a person of ordinary skill would be discouraged from
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`following the path of the claimed invention or would otherwise be led in a divergent
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`direction.
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`5
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`IPR2019-00400
`Patent 8,633,194
`I understand that for a claimed invention to be obvious by combining
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`
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`more than one prior art reference, there must be a motivation to combine the
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`teachings of the references to achieve the claimed invention and that a person of
`
`ordinary skill must have a reasonable expectation of success that they would achieve
`
`the claimed invention.
`
`IV. PERSON HAVING ORDINARY SKILL IN THE ART
` My understanding is that the term “person of ordinary skill in the art,”
`
`which I abbreviate as POSA, refers to a typical scientist or researcher having average
`
`skill in the technical field to which the patented inventions relate.
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`
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`I understand that the Board adopted Petitioner’s definition of a POSA
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`in its decision to institute inter partes review. Paper No. 17 at 10-11. Specifically,
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`that a POSA is someone who, “as of the relevant date would have (i) a Pharm. D. or
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`Ph.D. in chemistry, biochemistry, pharmacy, pharmaceutics, or in a related field, and
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`at least two years of relevant experience in developing and formulating aqueous
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`pharmaceutical formulations; (ii) a master’s degree in the same fields and at least
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`five years of the same relevant experience; or (iii) a bachelor’s degree in the same
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`fields and at least seven years of relevant experience.” Id. at 10.
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`
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`In my opinion, the definition of a POSA should focus more on the type
`
`of experience the person has, rather than years of experience. In particular, a POSA
`
`in the field of the ’194 patent would have extensive experience formulating multiple
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`
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`6
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`IPR2019-00400
`Patent 8,633,194
`types of liquid pharmaceutical formulations including oral solutions, nasal drops,
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`eye drops, and ear drops. A POSA would also be keenly aware of the differences
`
`between these types of formulations, and how that affects the formulation strategy.
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` While my definition of a POSA may differ slightly from the definition
`
`adopted by the Board, my opinion about validity remains the same under either
`
`definition.
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`V. THE CHALLENGED CLAIMS
`
`I understand that claims 1-11 of the ’194 patent are alleged to be
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`unpatentable in the Petition (collectively, the “challenged claims”). In its entirety,
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`challenged claim 1 reads as follows (line breaks for clarity):
`
`(ii)
`
`“A liquid pharmaceutical composition comprising
`(i)
`levocetirizine or a pharmaceutically acceptable salt of
`levocetirizine, and
`a preservative mixture consisting essentially of a mixture of
`methyl parahydroxybenzoate and propyl parahydroxybenzoate
`in a ratio of 9/1 expressed in weight,
`said mixture being present in an amount of more than 0 and up
`to 0.75 mg/ml of the composition,
`wherein said composition is substantially free of bacteria.”
` Dependent claims 2-11 include additional limitations including, for
`
`example, that the composition “is aqueous” (claim 2), “is in the form of oral
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`solutions, nasal drops, eye drops, or ear drops” (claim 4), or is a specific formulation,
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`such as, “in the form of an oral solution comprising 0.50 mg/mL levocetirizine
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`
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`7
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`IPR2019-00400
`Patent 8,633,194
`dihydrochloride, 0.675 mg/ml methyl p-hydroxybenzoate, and 0.075 mg/ml propyl
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`p-hydroxybenzoate” (claim 11).
`
`VI.
`
` CLAIM CONSTRUCTION
`
`I understand that in the pre-institution phase, neither party proposed any
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`claim term for construction.
`
`
`
` In the Institution Decision, the Board stated that it will apply “the
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`common and ordinary meaning” to the claim term “substantially free of bacteria.”
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`The Board explained that the term means “having, at most, a low, but clinically
`
`acceptable, level of bacteria,” where the term “‘substantially’ leaves some flexibility
`
`from absolute sterility.” Paper No. 17 at 12. In my opinion, the “common and
`
`ordinary meaning” of the claim term is consistent with that adopted by the Board,
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`and I have applied the Board’s construction to my analysis, where applicable.
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`Further below in § VIII, I explain my understanding of the Board’s statement,
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`“having at most, a low, but clinically acceptable, level of bacteria,” where the term
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`“‘substantially’” leaves some flexibility from absolute sterility.”
`
` Dr. Laskar and Petitioner both refer to the claim terms “methyl
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`parahydroxybenzoate” and “propyl parahydroxybenzoate” by their more commonly
`
`used names, “methylparaben” and “propylparaben,” respectively. I agree with this
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`use of the terms.
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`8
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`VII. GENERAL PRINCIPLES OF FORMULATION
` Because the claims of the ’194 patent are directed to liquid
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`IPR2019-00400
`Patent 8,633,194
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`pharmaceutical formulations comprising the antihistamine levocetirizine and a
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`preservative mixture, below I provide a high-level overview of principles of
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`pharmaceutical formulation.
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` As an initial matter, I have considered the declaration of Dr. Laskar and
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`his deposition transcript. We agree on many of the principles of pharmaceutical
`
`formulation, antimicrobial effectiveness testing, and the use of preservatives, such
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`as parabens. Where appropriate, I have tried to identify where I understand we agree
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`so that my opinions can focus on where we disagree.
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` Pharmaceutical formulation is a complex, unpredictable process, where
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`the POSA seeks to consider, balance, and/or optimize a number of variables related
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`to the formulation, such as the formulation’s solubility, viscosity, taste, safety,
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`appearance, chemical stability, and physical stability. See, e.g., EX2011 at 96-97,
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`105-1061; EX2012 at 5, 9; EX2013 at Chs. 3.1, 4.5. These variables may be
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`influenced by additional variables that may or may not be within the POSA’s control,
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`such as the packaging (e.g., single-use v. multi-use formulations), route of
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`administration, and manufacturability. EX2011 at 96-97, 105-106; EX2012 at 5, 9;
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`EX2013 at Chs. 3.1, 4.5.
`
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`1 When possible, I refer to the page numbers as published in the cited document.
`9
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`Patent 8,633,194
` A POSA must carefully balance these factors and consider not only the
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`effect of the active pharmaceutical ingredient (API) on the formulation, but also the
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`effect of other excipients. For example, changing or modifying an excipient to
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`improve one property may have significant effects on other properties of the
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`formulation, causing a need for more modifications. As a result of these
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`complexities, development of new pharmaceutical formulations is generally riddled
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`with trial-and-error. See, e.g., EX2013 at Ch. 3.1; see also EX2012 at 5. Dr. Laskar
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`appears to agree with these views, including that pharmaceutical formulation is a
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`non-linear process. EX2010 at 24:17-26:9, 44:9-46:5, 47:6-19, 59:7-60:10.
`
` Pharmaceutical formulation typically begins with assessment of the
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`API. In particular, its physicochemical properties, which serve as the API’s
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`“boundaries for use,” are considered. See EX2011 at 97, 106; EX2012 at 5. These
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`physicochemical properties include the API’s chemical structure, stability,
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`solubility, chirality, excipient compatibility, and physical properties, including taste
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`and appearance. See, e.g., EX2013 at Ch. 1.1, Ch. 1.1.1.1, Ch. 1.2; EX2011 at 99-
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`105. This information may be determined by a POSA through experimental testing,
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`or may be provided by someone else, but a POSA would understand how this
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`information affects pharmaceutical formulation.
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` The POSA must consider the type of preparation to use, such as whether
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`to use a solid, suspension, emulsion, coacervate, gel or liquid form. See EX2011 at
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`
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`10
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`97-98; EX2010 at 24:17-25:14. The type of preparation presents vastly different
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`challenges including, chemical interactions that may affect the effectiveness of the
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`API or the preservative (if one is used), binding of preservatives to inactive and
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`active components, unbalanced biphasic distribution in emulsions, precipitation of
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`solutes at different storage conditions, and risk of contamination based on the length
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`for which a packaged product is used. For example, many non-ionic surfactants are
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`known to inactivate preservatives. See EX2014; EX1006 at 342, 452.
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` The POSA must also consider the properties of the preferred
`
`formulation. Generally speaking, the POSA will be provided with some guidance
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`about the preferred properties, such as the target patient population, the packaging
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`(e.g., single-use v. multi-use formulations), and the route of administration, each of
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`which I will explain below. Based on this guidance, the POSA would understand
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`what would be acceptable in terms of the formulation’s other properties, such as the
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`formulation’s solubility, viscosity, taste, need to minimize microbial growth,
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`appearance, chemical stability, physical stability, and manufacturability. EX2010 at
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`24:17-26:9. For example, taste is irrelevant for an injected formulation, but would
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`be an important factor for oral solutions.
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` Similarly, the vehicle used for the pharmaceutical preparation has an
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`impact on the excipients used based on their solubility profile. EX2010 at 24:17-
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`26:9. For example, in considering preservatives, propylparaben may be more
`
`
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`11
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`suitable in preparations with low oil/water ratios while methylparaben may be more
`
`appropriate for high oil/water ratios. See EX2015 at 75-76.
`
` The target patient population may inform preferences in the
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`formulation. For example, an oral solution may be preferred for a product intended
`
`for children or the elderly that have difficulty swallowing, whereas a tablet may be
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`preferred for healthy adults. Similarly, for an antihistamine like levocetirizine,
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`which is a quality of life drug, an oral solution would almost certainly be preferred
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`over a parenteral (i.e., non-oral) route of administration, such as intravenous,
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`subcutaneous or intramuscular injection. A POSA would not expect that a patient
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`would choose to inject themselves with an antihistamine, instead of choosing one of
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`the orally-administered options available on the market.
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` Potential routes of administration include, among others, injection (e.g.,
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`subcutaneous, intravenous, intradermal, parenteral, or intramuscular), inhalation,
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`ophthalmic, oral, rectal, topical, and vaginal. See EX2013 at Ch. 1.1.1; EX2011 at
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`97-98. Each route of administration presents different formulation challenges. See
`
`EX2013 at Ch. 1.1.1; EX2011 at 97-98. For example, because parenteral
`
`formulations are “sites that are outside of or beside the alimentary tract,” they “by-
`
`pass the body’s natural defense mechanisms.” See EX2016; EX2010 at 32:5-20,
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`38:17-39:4. Consequently, sterility is typically required, except for topical
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`treatments. See EX2016. To maintain sterility, parenteral formulations may be
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`
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`12
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`formulated with sterile water, instead of purified water, which can be used when
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`sterility is not required. See EX2017 at 2-3. Often, parenteral solutions are a single-
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`use administration that is directly injected into the body.
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`
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`In contrast, oral solutions, nasal drops, or ear drops do not require the
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`same level of sterility. See EX2016. Instead, the POSA would anticipate that the
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`product will be directly exposed to substantial amounts of external contaminants
`
`during normal patient use. See EX2011 at 108; EX2010 at 72:21-73:13; see infra §
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`VIII.B. For example, patients routinely drink directly out of bottles of oral solutions
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`(instead of using a spoon or cup) or touch their eye with an eye drop. Such actions
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`directly expose the formulation to bacteria and other contaminants. A POSA would
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`anticipate these common possibilities, understand them, and adjust accordingly by,
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`for example, using preservatives, as described below.
`
`VIII. CONTROLLING MICROBIAL GROWTH IN PHARMACEUTICAL
`FORMULATIONS
` Consistent with its “common and ordinary meaning,” the Board has
`
`construed the claim term “substantially free of bacteria” to mean “having, at most, a
`
`low, but clinically acceptable, level of bacteria,” where the term “‘substantially’
`
`leaves some flexibility from absolute sterility.” Paper No. 17 at 12. Below I explain
`
`how a formulation would be tested to determine whether it exceeds a “clinically
`
`acceptable level of bacteria,” and how a POSA would ensure that a formulation
`
`would meet these requirements.
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`A. Testing for Antimicrobial Effectiveness
` To understand whether a formulation, as the Board construed, has “at
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`IPR2019-00400
`Patent 8,633,194
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`most, a low, but clinically acceptable, level of bacteria,” where the term
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`“substantially” “leaves some flexibility from absolute sterility” (Paper No. 17 at 12),
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`a POSA would consider the guidelines provided by the U.S. and European
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`Pharmacopoeias. See e.g., EX2018; EX2019.
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` The European and United States Pharmacopoeias set standards that a
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`pharmaceutical formulation must meet to determine whether it has a clinically
`
`acceptable risk of antimicrobial contamination. See EX2020; EX2021; see also infra
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`§ VIII.C. The European standards are largely the same. See EX2021; see also
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`EX1023 at 308-309. I understand that Dr. Laskar does not dispute the similarity
`
`between the standards. EX2010 at 30:20-31:2, 33:1-8.
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` The testing presented in the ’194 patent is consistent with this view, as
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`the patent explains that “antimicrobial preservative effectiveness tests are realized
`
`according to the European Pharmacopoeia (Chap. 5.1.3).” See EX1001 at. 6:61-63.
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`
`
`I understand from his deposition that Dr. Laskar agreed with my view
`
`that microbiological qualities are governed by regulatory agencies (EX2010 at
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`28:22-19; 29:13-30:6) and that these compendial tests would be relevant for
`
`determining whether a pharmaceutical formulation meets regulatory standards in
`
`terms of acceptable bacterial level, and thus relevant to the claim term “substantially
`
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`IPR2019-00400
`Patent 8,633,194
`free of bacteria.” EX2010 at 77:14-78:6. Therefore, I do not further explain those
`
`views here.
`
` The table below sets forth the USP standards for antimicrobial
`
`effectiveness. Products falling within the scope of claim 1 belong to Category 1
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`(nasal products and ophthalmic formulations made with aqueous bases or vehicles)
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`and 3 (oral products with aqueous bases or vehicles).
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`IPR2019-00400
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`B. Microbial Contamination Risk in Pharmaceutical Formulations
` A POSA would understand that liquid pharmaceutical formulations,
`
`such as those of the challenged claims, are particularly susceptible to microbial and
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`fungal growth. See, e.g., EX2022 at 8.
`
` A POSA would understand
`
`that most
`
`liquid pharmaceutical
`
`formulations are aqueous (i.e., they contain water). This is particularly expected
`
`with antihistamines which, as noted above, are highly likely to be administered as
`
`an oral solution, or an eye, ear, or nasal drop, if they are in a liquid form. See supra
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`§ VII. Aqueous, liquid products are highly susceptible to microbial growth because
`
`water itself is a source of microbes and potential contamination. See EX2011 at 107;
`
`see also id. Thus, when working with liquid, and particularly, aqueous products, a
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`POSA expects that the formulation will be exposed to substantial amounts of
`
`bacteria. Notably, Petitioner’s definition of a POSA requires knowledge of
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`“aqueous formulations.” See, supra § IV.
`
` The challenge of addressing microbial contamination is further
`
`exacerbated in multi-use products (e.g., a bottle of cough syrup compared to single-
`
`dose products). Such multi-use products face repeated exposure to external
`
`contaminants during the life of the product. See EX2022 at 6.
`
`
`
` Patient behavior for certain pharmaceutical products may also increase
`
`risk of microbial contamination. For example, it is common for patients to drink the
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`medication straight from the bottle as opposed to using an associated medicinal cup.
`
`A POSA must consider all of these factors in determining how to prevent microbial
`
`contamination.
`
`C.
`
`Preservatives, and Other Options to Prevent Microbial
`Contamination
` A POSA would understand that the risk of bacterial or microbial
`
`contamination would be substantial, as contamination could endanger patient health
`
`or lives. Such concerns are particularly important when, as with the ’194 patent, the
`
`formulation could be administered to at-risk populations such as young children. See
`
`EX1001 at 4:25-27. In other words, a POSA would understand that one of their
`
`primary responsibilities is to ensure that their formulation is safe, and would defer
`
`to safety over other considerations.
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` Consistent with this concern, both the USP and FDA regulations stress
`
`the importance of ensuring microbial stability and therefore eliminating bacterial
`
`contamination risk:
`
`- “Antimicrobial effectiveness, whether inherent in the product or whether
`produced because of the addition of an antimicrobial preservative, must be
`demonstrated for all injections packaged in multiple-dose containers or for
`other products containing antimicrobial preservatives. Antimicrobial
`effectiveness must be demonstrated for multiple-dose topical and oral
`dosage fo