IN THE UNITED STATES DISTRICT COURT
`FOR THE SOUTHERN DISTRICT OF FLORIDA
`
`
`UCB, INC. and UCB BIOPHARMA SPRL,
`
`
`Plaintiffs,
`
`
`
`
`
`
`
`C.A. No. 18-CV-60846
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`RESTRICTED CONFIDENTIAL
`INFORMATION – SUBJECT TO
`PROTECTIVE ORDER
`
`
`
`
`v.
`
`APOTEX INC.,
`
`
`
`
`
`
`
`
`
`
`
`
`Defendant.
`
`
`OPENING EXPERT REPORT OF SARFARAZ K. NIAZI, PH.D.
`
`
`
`
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`Apotex (IPR2019-00400) Ex. 1042 Un-redacted Non Public Version p. 001
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`

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`
`I.
`
`CONTENTS
`
`INTRODUCTION..............................................................................................................2
`Qualifications ...........................................................................................................2
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`
`
`
`
`
`Compensation ...........................................................................................................3
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`Cases in the Past Four Years ....................................................................................4
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` Materials Relied Upon .............................................................................................4
`
`II.
`III.
`IV.
`V.
`
`LEGAL STANDARDS ......................................................................................................4
`PERSON OF ORDINARY SKILL IN THE ART ..........................................................6
`SUMMARY OF OPINIONS .............................................................................................7
`BACKGROUND ................................................................................................................8
`General Principles of Formulation ...........................................................................8
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`
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`Active Pharmaceutical Ingredients Are Not Expected to Possess Preservative or
`Antimicrobial Properties ........................................................................................12
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`The Mechanisms of Actions of Antimicrobials Are Not Well Understood ...........16
`
`Levocetirizine .........................................................................................................18
`
`THE ’194 PATENT AND ITS PROSECUTION ..........................................................19
`VI.
`VII. OPINIONS ........................................................................................................................22
`A.
`Xyzal® and Xyzal Allergy 24HR® are Embodiments of Claims 1-11 of the ’194
`Patent ......................................................................................................................22
`
`B.
`
`C.
`
`D.
`
`It was Unexpected that Levocetirizine Would Have Antimicrobial Properties .....26
`
`The ’194 Patent and the Fanara Declaration Demonstrate that Levocetirizine
`Possesses Antimicrobial Properties ........................................................................28
`
`Based on the Unexpected Self-Preservative Effect of Levocetirizine, The
`Inventors Were Able to Prepare a Formulation with Unexpectedly Low Amounts
`of Parabens That Would Remain Substantially Free of Bacteria ...........................29
`
`VIII. CONCLUSION ................................................................................................................32
`IX.
`TRIAL EXHIBITS...........................................................................................................32
`X.
`SUPPLEMENTAL OPINIONS ......................................................................................32
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`Apotex (IPR2019-00400) Ex. 1042 Un-redacted Non Public Version p. 002
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`RESTRICTED CONFIDENTIAL INFORMATION 
`SUBJECT TO PROTECTIVE ORDER 
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`
`I, Sarfaraz K. Niazi, submit this report on behalf of Plaintiffs UCB, Inc. and UCB
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`Biopharma, Sprl (collectively, “Plaintiffs”) in this action. This report sets forth opinions related
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`to unexpected and surprising properties of the claimed inventions of the ’194 patent.
`
`I.
`
`INTRODUCTION
`
`
`
`Qualifications
`
`1.
`
`I am currently Adjunct Professor of Biopharmaceutical Sciences at the University
`
`of Illinois, College of Pharmacy. I am also Visiting Professor at the University of Houston College
`
`of Pharmacy.
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`2.
`
`In addition to my academic positions, I am also the founder and Executive
`
`Chairman of Pharmaceutical Scientist, LLC—a pharmaceutical and biological products consulting
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`company that is also assisting in the development of biosimilar products. In 2003, I also founded
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`what is now known as Adello Biologics, LLC and served as Executive Chairman until 2017. I no
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`longer have any equity interest in Adello. Additionally, I served as Director Technical Affairs for
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`Abbott International from 1988-1995.
`
`3.
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`My formulation experience dates back to my teaching tenure at the University of
`
`Illinois when I taught formulation sciences and supervised dozens of graduate theses, several of
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`which comprised creating new formulations and methods of testing and evaluation. At Abbott
`
`International, I was the first to suggest and initiate a generic line of pharmaceutical formulations
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`that resulted in several formulations including topical analgesics, and over 10 other narrow
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`therapeutic index drugs. I formulated, evaluated in humans, and created regulatory dossiers.
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`Additionally, in my consulting capacity, I have assisted major pharmaceutical companies in
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`developing complex generic dosage forms and in April I am invited by the FDA to teach the
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`science of formulation of complex generics. I have also developed several biologic drug
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`2
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`RESTRICTED CONFIDENTIAL INFORMATION 
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`formulations including PEGylation products, and sustained delivery of proteins. I own dozens of
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`United States patents on topical formulations, combination formulations, drug delivery modalities,
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`and new chemical entities.
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`4.
`
`I received my B.Sc. in Chemistry from Karachi University, Pakistan in 1966. In
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`1969, I received my B. Pharm, also from Karachi University. I then received my M.S. in
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`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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`5.
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`I am the sole author of 74 books, including the series “Handbook of Pharmaceutical
`
`Manufacturing Formulations.” This series teaches the principals of pharmaceutical formulations
`
`and manufacturing and is broken into six categories: Over the Counter Products; Semisolid
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`Products; Liquid Products; Uncompressed Solids; Compressed Solids; and Sterile Products. In
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`addition, I have also authored key handbooks on preformulation and bioequivalence testing. I am
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`the author of over 100 research articles and have been invited to hundreds of speaking engagements
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`worldwide. I am also a named inventor on over 80 patents. 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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`6.
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`A copy of my curriculum vitae, which contains more detail on my educational
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`background and professional career, is attached as Exhibit A.
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`
`
`Compensation
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`7.
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`I am being compensated for my work in this case at my usual rate of $500 per hour.
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`My per diem rate is $4,000.
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`3
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`Apotex (IPR2019-00400) Ex. 1042 Un-redacted Non Public Version p. 004
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`RESTRICTED CONFIDENTIAL INFORMATION 
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`
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`Cases in the Past Four Years
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`8.
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`During the past four years I have testified in 2016 in a case involving formulation
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`of products with oxygenation (Cadence Pharmaceuticals Inc., et al v. InnoPharma Licensing LLC
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`et al, 14-cv-01225 (D. Del.).
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` Materials Relied Upon
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`9.
`
`A list of the materials that I have considered in forming my opinions is attached as
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`Exhibit B. In addition to the materials listed in my Exhibit B, I have also relied on my education,
`
`training, general knowledge, and experience.
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`10.
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`The opinions that I express in this report are based on the information and evidence
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`currently available to me. I understand from counsel that I may be asked to revise or supplement
`
`my opinions as additional information becomes available. I further understand from counsel that
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`I may be asked to respond to any assertions or additional arguments that Apotex or its experts raise
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`during the course of this litigation.
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`11.
`
`If called at trial, I expect to explain the opinions and analyses described in this
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`report. I have not yet prepared any demonstratives for use at trial to support my testimony, but
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`may do so should I be called to testify. Further, I may provide background testimony or a tutorial
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`at trial regarding pharmaceutical formulating.
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`II.
`
`LEGAL STANDARDS
`
`12.
`
`I have been retained by Plaintiffs as an expert witness in the above-captioned
`
`matter. I understand that Apotex Inc. (“Apotex”) has filed an Abbreviated New Drug Application
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`(“Apotex’s ANDA”) seeking FDA approval to sell a generic version of Xyzal Allergy 24HR®,
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`which contains levocetirizine as its drug substance. I understand that Plaintiffs have brought this
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`litigation against Apotex in response to Apotex’s filing of its ANDA.
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`4
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`RESTRICTED CONFIDENTIAL INFORMATION 
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`13.
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`I understand that this litigation involves U.S. Patent No. 8,633,194 (the “’194
`
`patent”).
`
`14.
`
`I understand that the earliest priority date to which the ’194 patent is entitled is July
`
`14, 2004, and that Apotex has not challenged whether the ’194 patent is entitled to this priority
`
`date. Therefore, I have used this date as the relevant date for assessing what was known in the
`
`field at the time of the invention.
`
`15.
`
`I understand that Apotex alleges that the asserted claims of the ’194 patent are
`
`invalid because the inventions claimed therein would have been obvious to a person of ordinary
`
`skill in the art. I understand that an obviousness analysis requires an assessment of (1) the level
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`of ordinary skill in the art; (2) scope and content of the prior art; (3) differences between the prior
`
`art and the claimed invention; and (4) objective indicia of nonobviousness.
`
`16.
`
`I understand that Apotex bears the burden of proving invalidity in this litigation,
`
`including obviousness, and that Apotex may submit a report from one or more experts to support
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`Apotex’s views on those issues; in particular, items (1)-(3) in the paragraph above. I have been
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`informed by counsel that I may be asked to consider any expert report submitted on behalf of
`
`Apotex and to potentially submit a report in response.
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`17.
`
`For purposes of this report, I have been asked by counsel to focus on item (4) in the
`
`paragraph above, objective indicia of nonobviousness. In particular, I have been asked to focus
`
`on the unexpected or surprising properties, or the unexpected benefits, of a claimed invention,
`
`which I understand may be objective indicia of nonobviousness relevant to the obviousness
`
`analysis. Specifically, I understand that if an experiment demonstrates an unexpected or surprising
`
`result, then the result would likely not be obvious to a person of ordinary skill in the art. I further
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`5
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`Apotex (IPR2019-00400) Ex. 1042 Un-redacted Non Public Version p. 006
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`understand that if a claimed invention exhibits a surprising or unexpected result in comparison to
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`the closest comparators in the prior art, that such a result may demonstrate nonobviousness.
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`18.
`
`As further context for my opinions, I understand that in considering obviousness,
`
`what the prior art teaches and, in particular, if the prior art teaches away from the claimed
`
`invention, then a person of ordinary skill would be discouraged from following the path of the
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`claimed invention or would otherwise be led in a divergent direction. Further, I understand that
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`the level of predictability or complexity in a field, or any serendipity in arriving at the claimed
`
`invention, may be relevant to the nonobviousness of an invention.
`
`III.
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`PERSON OF ORDINARY SKILL IN THE ART
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`19. My understanding is that the term “person of ordinary skill in the art” (POSA) refers
`
`to a typical scientist or researcher having average skill in the technical field to which the patented
`
`inventions relate. It is my view that a person having ordinary skill in the art to which the ’194
`
`patent relates would have a Ph.D. or equivalent degree in Pharmaceutical Sciences, Industrial
`
`Pharmaceutics, or a related field and have at least three years of experience working with liquid,
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`particularly aqueous, pharmaceutical formulations. Alternatively, the individual would be a highly
`
`skilled scientist lacking a Ph.D. or equivalent degree, but would have more than five years of
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`experience working with liquid, particularly aqueous, pharmaceutical formulations.
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`20.
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`Further, it is my opinion that a person of ordinary skill in the art would be part of a
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`team comprising persons of ordinary skill in the art that are physicians with experience in the
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`treatment of allergies. Such a physician would have an M.D. or a D.O., at least three years of
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`experience in the treatment of allergies, including any residency, and be Board Certified in an area
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`applicable to the treatment of allergies.
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`6
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`Apotex (IPR2019-00400) Ex. 1042 Un-redacted Non Public Version p. 007
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`IV.
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`SUMMARY OF OPINIONS
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`21.
`
`I have been asked by Plaintiffs to assess the scope and content of the prior art and
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`opine on whether the claimed invention of the ’194 patent exhibits any unexpected or surprising
`
`properties. It is my opinion that nothing in the prior art taught or predicted that levocetirizine
`
`would have antimicrobial properties. In fact, as of the priority date, publications regarding
`
`predicting antibacterial properties had classified cetirizine—the racemic mixture of levocetirizine
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`and its dextrorotary enantiomer—as a compound that lacked antimicrobial effects, although this
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`was later disproven. Thus, the discovery of levocetirizine’s antimicrobial effects was unexpected
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`and surprising.
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`22.
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`It is also my opinion that nothing in the prior art would have taught a person of
`
`ordinary skill that they could use the low amount of parabens present in the liquid pharmaceutical
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`composition claimed in the ’194 patent and obtain a formulation that is substantially free of
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`bacteria. On the contrary, the prior art taught the importance of using significantly higher amounts
`
`of parabens in liquid, and particularly aqueous, pharmaceutical formulations due to their high risk
`
`of bacterial contamination. Thus, it was surprising and unexpected that the inventors of the ’194
`
`patent were able to obtain an aqueous pharmaceutical formulation with substantially lower
`
`amounts of paraben yet substantially free of bacteria.
`
`23.
`
`I am prepared to testify, if asked, on the ’194 patent and how a pharmaceutical
`
`formulator would interpret the information claimed in the patent. I am also prepared to testify as
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`to how a pharmaceutical formulator would develop formulations as of the ’194 patent’s priority
`
`date. Finally, I have considered the claims of the ’194 patent and, in my opinion, Xyzal Allergy
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`24HR® and Xyzal®, are both embodiments of the claims.
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`7
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`Apotex (IPR2019-00400) Ex. 1042 Un-redacted Non Public Version p. 008
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`V.
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`BACKGROUND
`
`24.
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`Below I have provided a general discussion of background information that is
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`applicable to my opinions. As I understand that I may be asked to prepare a second, rebuttal,
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`report, I may provide additional background information there that is relevant to any additional
`
`opinions I may offer.
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`
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`General Principles of Formulation
`
`25.
`
`Below, I have provided a brief background on the principles of formulation. While
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`I have tried to present this background in a concise, clear fashion, the exercise of formulation is
`
`rarely as routine or linear as I have presented it, and is instead generally riddled with trial-and-
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`error. See, e.g., I. Rácz, Drug Formulation at Ch. 3.1 (1989). Further, the considerations described
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`below co-depend on each other and must be balanced as, for example, a modification in excipients
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`can have significant effects on a formulation. See, e.g., I. Rácz, Drug Formulation at Ch. 3.3
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`(1989).
`
`26.
`
`One of the first things a POSA must consider is the active pharmaceutical ingredient
`
`(API) or drug substance itself. In particular, the POSA must consider the properties of the API
`
`that commonly affect formulation, including its physical and chemical stability, taste, and
`
`appearance. See, e.g., I. Rácz, Drug Formulation at Ch. 1.1, Ch. 1.1.1.1, Ch. 1.2 (1989). All of
`
`these factors may affect development of the ultimate drug product and are routinely considered by
`
`formulators at the outset of formulation work. See id.
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`27.
`
`As the ’194 patent focuses on the use of preservatives to combat microbial and
`
`fungal growth, I note here, and describe further below at §V.B, that the API’s own ability to act as
`
`a preservative is generally not considered because it is uncommon that the API possesses such
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`properties.
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`8
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`28.
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`The POSA must also consider the route of administration. See id. at Ch. 1.1.1.
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`Routes of administration include, among others, injection (e.g., subcutaneous, intravenous,
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`intradermal, parenteral, or intramuscular), inhalation, ophthalmic, oral, rectal, topical, and vaginal.
`
`See id. Each route of administration presents different formulation challenges particular to that
`
`route. See id. For example, a single-use intravenous injection faces much different challenges
`
`than a topical gel.
`
`29.
`
`As the ’194 patent focuses on the use of preservatives to combat microbial and
`
`fungal growth, it is worth nothing that certain routes of administration may require that the product
`
`be prepared in a “clean” environment (e.g., certain injectables) to avoid microbial and fungal
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`growth, or the POSA should anticipate that the product will be directly exposed to substantial
`
`amounts of external contaminants during normal patient use (e.g., oral liquid solutions used in a
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`multi-use formulation). Each different route of administration may present different challenges
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`with respect to microbial and fungal growth.
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`30.
`
`The POSA must also consider the type of preparation to use for that route, such as
`
`whether to use a solid, liquid, suspension, emulsion, coacervate, or gel form. Again, the type of
`
`preparation presents vastly different challenges including, chemical interactions that may
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`inactivate a preservative, binding of preservatives to inactive and active components, unbalanced
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`biphasic distribution in emulsions, precipitation of solutes at different storage conditions, and risk
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`of contamination based on the length for which a packaged product is used. For example, many
`
`non-ionic surfactors are known to inactivate preservatives. See W. P. Evans, The solubilization
`
`and inactivation of preservatives by non-ionic detergents, 16 Journal of Pharmacy and
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`Pharmacology 323 (1964).
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`9
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`31.
`
`Again, as the ’194 patent focuses on the use of preservatives to combat microbial
`
`and fungal growth, I note that the need for preservatives in different types of preparations vary
`
`widely. For example, oral tablets, as a solid form, are not nearly as susceptible to bacterial growth
`
`as an oral solution, especially aqueous oral solutions where water is present. See, e.g., The
`
`European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human
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`Use, Draft Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the
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`Dossier for Application for Marketing Authorisation of a Medicinal Product, at 8 (2003), available
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`at https://www.ema.europa.eu/en/documents/scientific-guideline/draft-note-guidance-excipients-
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`antioxidants-antimicrobial-preservatives-dossier-application_en.pdf (last accessed Mar. 21,
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`2019).
`
`32.
`
`As the claims of the ’194 patent focus on “a liquid pharmaceutical composition,”
`
`(see claim 1), I will focus the rest of my background discussion on liquid pharmaceutical
`
`compositions. Assuming that a POSA has chosen to develop a liquid pharmaceutical composition,
`
`they still face numerous challenges, as he or she must balance a number of factors such as
`
`solubility, viscosity, taste, microbial growth, appearance, chemical stability, physical stability,
`
`packaging (e.g., single-use v. multi-use formulations), and manufacturability of the formulation
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`itself. See, e.g., I. Rácz, Drug Formulation at Ch. 4.5 (1989). While many of these factors are the
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`same types of factors that must be considered in the context of the API by itself, it is important to
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`consider these factors in the context of the overall drug product, which includes the API and all
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`other ingredients/excipients, as well.
`
`33.
`
`As the ’194 patent focuses on the use of preservatives to combat microbial and
`
`fungal growth, it is important for the POSA to consider that liquid pharmaceutical compositions
`
`are particularly susceptible to microbial and fungal growth. See Draft Note for Guidance on
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`Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for Application for
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`Marketing Authorisation of a Medicinal Product, at 8. In particular, aqueous products (i.e.,
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`products with water present) are particularly susceptible to microbial and fungal growth because
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`water itself is a source of microbes and potential contamination. Thus, when working with liquid,
`
`and particularly, aqueous products, the POSA expects that the formulation will be exposed to
`
`substantial amounts of bacteria.
`
`34. With these considerations in mind, a POSA has a number of options to control
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`microbial and fungal growth in liquid pharmaceutical products. For example, a formulator may
`
`choose to pursue any of the below options:
`
`- A single-use product may be chosen because multi-use products are more susceptible
`to microbial and fungal growth because the patient exposes the product to the
`environment where contamination may occur;
`
`- Sugars and other excipients not typically classified as “preservatives” may have an
`antimicrobial and/or antifungal effect and therefore may be used as a substitute or
`compliment to ingredients typically classified as “preservatives”;
`
`- Within the field of “preservatives,” the POSA may choose between a wide range of
`classes of preservatives, and preservatives within those classes; and
`
`- A POSA working with preservatives may choose to combine different preservatives or
`classes of preservatives and has discretion over the amount of preservatives to use. The
`quantity or concentration of preservatives is inevitably linked to the risk of
`contamination that is proportional to the length of time a product will be used. For
`example, a drug product containing a large amount of API (e.g., 500 ml) may require
`more preservative in concentration than a single-dose packaging.
`
`See, e.g., Dániel Nemes, Interaction between Different Pharmaceutical Excipients in Liquid
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`Dosage Forms—Assessment of Cytotoxicity and Antimicrobial Activity, 23 Molecules 1827, 1827
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`(2018); Hang Guo and Chris Knutsen, Preservative Formulation and Effectiveness in Oral
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`Solutions and Suspensions, PDA Metro Meeting at 5 (Feb. 15, 2011).
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`35.
`
`Given that preservatives have been used for decades in pharmaceutical products
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`and for centuries in other types of products, there is a large volume of data regarding the usage of
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`preservatives that predates the ’194 patent, and a POSA would be comfortable with the general
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`use of preservatives in such formulations. See, e.g., Graham W. Gould, Preservation: past, present
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`and future, 56 Br. Med. Bull. 84-96 (2000); Sally L. Buck, et al., Methods used to evaluate the
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`effectiveness of contact lens care solutions and other compounds against Acanthamoeba: a review
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`of the literature, 26 CLAO J. 72-84 (2000); S. Brul and P. Coote, Preservative agents in foods.
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`Mode of action and microbial resistance mechanisms, 50 (Int. J. Food. Microbiol. 1-2 (1999);
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`Graham W. Gould, Methods for preservation and extension of shelf life, 33 Int. J. Food Microbiol.
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`51-614 (1996); S.J. Lehner, et al., Effect of hydroxypropyl-beta-cyclodextrin on the antimicrobial
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`action of preservatives, 46 J. Pharm. Pharmacol.,186-91 (1994); M. R. W. Brown and R. M. E.
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`Richards, Effect of Polysorbate (Tween) 80 on the Resistance of Pseudomonas Aeruginosa to
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`Chemical Inactivation, 16 J. Pharm. Pharmacol. Suppl. 51-5T (1964); W. P. Evans, The
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`Solubilisation and Inactivation of Preservatives by Non-Ionic Detergents, 16 J. Pharm. Pharmacol.
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`323-31 (1964).
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`36.
`
`A POSA would also consider formulations that have been successful in the past,
`
`and use these successful formulations as reference or comparison points. These reference points
`
`may be identified through the publication of data that shows inhibition of microbial and fungal
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`growth in particular formulations, or by the fact that a formulation was approved by regulatory
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`authorities such as the U.S. FDA or European EMEA. A POSA would place little weight in
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`formulations that have been suggested by others, but where there is no testing presented or
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`indication that a regulatory authority considered and approved the formulation.
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`
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`Active Pharmaceutical Ingredients Are Not Expected to Possess
`Preservative or Antimicrobial Properties
`
`37.
`
`Except in the situation where a POSA is working with an API intended to be
`
`antimicrobial or antifungal – for example, an antibiotic like penicillin – a POSA would not expect
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`the API itself to have antimicrobial or antifungal properties. In fact, while as noted above, the
`
`POSA must consider the properties of the API in designing a formulation, it is not typical or routine
`
`for a POSA, or anyone involved with the formulation, to test whether the API itself is antimicrobial
`
`or has antifungal properties.
`
`38.
`
`Further, APIs are often selected for pharmaceutical development because they do
`
`not interact with other substances in the body, which therefore minimizes the risk of side effects
`
`or drug-drug interactions. See, e.g., I. Rácz, Drug Formulation at Ch. 3.1 (1989). Consequently,
`
`in the abstract, a POSA would actually expect that the API does not have an antimicrobial or
`
`antifungal effect because they would expect that the API was selected for development precisely
`
`because it only acts on the particular target in the body of interest.
`
`39.
`
`In fact, in 2011, years after the discovery of levocetrizine’s antimicrobial effect in
`
`the early 2000s (see infra, §V.II.B), researchers conducted a study on the antimicrobial effects of
`
`antihistamines because, as they described:
`
`The use of antihistaminics in the drug regimen for patients who acquire microbial
`infection is inevitable and that gave rise to the need to assess the antimicrobial
`activity of antihistaminics. Few studies were previously carried out to demonstrate
`the antimicrobial activity of a number of antihistaminics which belonged mainly
`to
`the
`first generation especially
`the ethanolamine and phenothiazine
`antihistaminics; however, the published results are rather controversial.
`
`Moustafa A. El-Nakeeb, et al., In vitro Antibacterial Activity of Some Antihistamines Belonging to
`
`Different Groups Against Multi-Drug Resistant Clinical Isolates, 42 Braz. J. Microbiol. 980-991
`
`(2011) at 980. The researchers then elaborated on the controversial prior results, by explaining
`
`that prior research teams had published data showing varying minimum inhibitory concentrations
`
`(“MICs”)1 for the same antihistamines, and varying results even within a given study. Id. The
`
`
`1 MIC is the number that is the “lowest concentration of an antimicrobial that will inhibit the visible growth of a
`microorganism after overnight incubation.” Jennifer M. Andrews, Determination of minimum inhibitory
`
`13
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`researchers also noted that prior studies predominantly focused on first-generation antihistamines,
`
`and that second- or third- generation antihistamines, such as levocetirizine, had “almost received
`
`no attention from the microbiological point of view.” Id. Thus, there was still a need, seven years
`
`after the priority date, to assess whether antihistamines, particularly second- and third-generation
`
`antihistamines like levocetirizine, possess antimicrobial properties. Id.
`
`40.
`
`The El-Nakeeb publication also shows that there is no apparent correlation between
`
`antihistaminic and antibacterial properties. For example, the antihistamines azelastine,
`
`cyproheptadine, mequitazine, and promethazine were found to be active antibacterials, while
`
`diphenhydramine and cetirizine possessed weaker activity, and doxylamine, fexofenadine and
`
`loratadine were inactive even at the highest tested concentration (1 mg/ml). Id. at 983, Table 1.
`
`41. Moreover, as shown in the table below, there is no apparent chemical structural
`
`feature common to those antihistamines that possess antibacterial properties; therefore, one cannot
`
`predict from the chemical structure alone that an API would have antibacterial properties.
`
`
`concentrations, 48 J. Antimicrobial Chemotherapy Suppl. S1 5, 5 (2001). MICs are considered the “gold standard”
`for determining effectiveness of a preservative against a microorganism. See id.
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`Compound
`
`Chemical Structure
`
`Azelastine
`
`Cyproheptadine
`
`Mequitazine
`
`Promethazine
`
`Diphenhydramine
`
`Cetirizine
`
`Doxylamine
`
`
`
`
`
`
`
`
`
`
`
`Chemical Class
`
`Phthalazine derivative
`
`Antimicrobial
`Activity
`High activity
`
`
`Tricyclic
`benzocycloheptene
`
`High activity
`
`
`Phenothiazine
`
`High activity
`
`
`Phenothiazine
`
`High activity
`
`Diphenylmethane
`
`Low activity
`
`Piperazinyl derivative
`
`Low activity
`
`
`
`Ethanolamine
`
`No activity
`
`Fenofexidine
`
`
`
`Benzeneacetic acid
`
`No activity
`
`
`
`
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`Loratidine
`
`Benzocycloheptene
`
`No activity
`
`
`
`
`
`42.
`
`The researchers attempted to find a structural correlation because they noted, “[t]he
`
`variation in the magnitude of antibacterial effects among different antihistaminics is however
`
`difficult to explain since screening the literature revealed that no extensive studies were published
`
`on the antibacterial activity of the different classes of antihistaminics.” Id. at 985. In other words,
`
`the authors concluded, prior to their 2011 publication, there had been no extensive study of
`
`structural correlations between antihistaminic and antibacterial properties.
`
`43.
`
`Ultimately, the researchers concluded that the best predictor they could determine
`
`of antibacterial activity in antihistamines is activity at the bacterial cell surface. Id. However, this
`
`is a biological feature that cannot be readily determined without testing. While certain chemical
`
`structures may be more readily associated with surface activity, as the authors note, biological
`
`testing must occur before it could be determined that a chemical compound has suc