UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`APOTEX, INC.
`Petitioner,
`v.
`UCB BIOPHARMA S.A.
`Patent Owner.
`
`U.S. Patent No. 8,633,194 to Fanara et al.
`Case No.: IPR2019-00400
`____________________
`
`
`DECLARATION OF DR. PAUL A. LASKAR, PH.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 001
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`

`

`Declaration of Paul A. Laskar, Ph.D.
`
`
`Table of Contents
`INTRODUCTION ...............................................................................1
`I.
`II. MY EXPERIENCE AND QUALIFICATIONS .......................................2
`III. LIST OF MATERIALS CONSIDERED .................................................9
`IV. LEGAL STANDARD ........................................................................ 11
`A. Obviousness ............................................................................. 11
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ................... 14
`V.
`VI. THE ’194 PATENT ........................................................................... 16
`VII. CLAIM CONSTRUCTION ................................................................ 18
`VIII. SCOPE AND CONTENT OF THE PRIOR ART ................................... 19
`B.
`Levocetirizine Was a Known Prior Art Compound and was
`Suitable for Liquid Preparations.................................................. 19
`C. Methylparaben and Propylparaben Are Widely Used
`Preservatives ............................................................................ 23
`1. WO ’094 (EX1007).......................................................... 25
`2.
`EP ’203 (EX1004) ........................................................... 26
`3.
`Handbook (EX1006) ........................................................ 27
`4.
`US ’558 (EX1015) ........................................................... 30
`INVALIDITY OF THE ’194 PATENT................................................. 31
`B. Ground 1: Claims 1-11 Would Have Been Obvious over WO
`’094 in view of the Handbook..................................................... 32
`1.
`Claim 1 .......................................................................... 32
`a)
`“A liquid pharmaceutical composition comprising
`(i) levocetirizine or a pharmaceutically acceptable
`salt of levocetirizine” .............................................. 34
`“a preservative mixture consisting essentially of a
`mixture of methyl parahydroxybenzoate and propyl
`
`IX.
`
`b)
`
`i
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 002
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`

`

`Declaration of Paul A. Laskar, Ph.D.
`
`
`c)
`
`d)
`
`5.
`6.
`7.
`8.
`9.
`
`parahydroxybenzoate in a ratio of 9/1 expressed in
`weight”.................................................................. 35
`(1) There is no Teaching Away in the Handbook
`.................................................................... 37
`“said [paraben] mixture being present in an amount
`of more than 0 and up to 0.75 mg/ml of the
`composition” .......................................................... 39
`“wherein said composition is substantially free of
`bacteria” ................................................................ 43
`Dependent Claim 2 .......................................................... 44
`Dependent Claim 3 .......................................................... 45
`Dependent Claim 4 .......................................................... 45
`Dependent Claims 5 and 10 ............................................... 45
`Dependent Claim 6 .......................................................... 46
`a)
`“wherein the hydrochloride salt of levocetirizine is
`present in amount of 0.5 mg/ml” ............................... 46
`“the mixture of methyl p-hydroxybenzoate and
`propyl p-hydroxybenzoate is present in amount of
`0.75 mg/ml.” .......................................................... 48
`10. Dependent Claim 7 .......................................................... 49
`11. Dependent Claim 8 .......................................................... 50
`12. Dependent Claim 9 .......................................................... 50
`13. Dependent Claim 11......................................................... 51
`a)
`“the composition is in the form of an oral solution
`comprising
`0.50
`mg/ml
`levocetirizine
`dihydrochloride”..................................................... 51
`“0.675 mg/ml methyl p-hydroxybenzoate, and
`0.075 mg/ml propyl p-hydroxybenzoate” ................... 52
`C. Ground 2: Claims 1-11 Are Obvious over EP ’203 in View of
`US ’558 and the Handbook ........................................................ 53
`2.
`Claim 1 .......................................................................... 54
`
`b)
`
`b)
`
`ii
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 003
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`

`

`Declaration of Paul A. Laskar, Ph.D.
`
`
`a)
`
`b)
`
`c)
`
`d)
`
`b)
`
`3.
`4.
`5.
`6.
`7.
`
`“A liquid pharmaceutical composition comprising
`(i) levocetirizine or a pharmaceutically acceptable
`salt of levocetirizine” .............................................. 57
`“a preservative mixture consisting essentially of a
`mixture of methyl parahydroxybenzoate and propyl
`parahydroxybenzoate in a ratio of 9/1 expressed in
`weight”.................................................................. 58
`“said [paraben] mixture being present in an amount
`of more than 0 and up to 0.75 mg/ml of the
`composition” .......................................................... 60
`“wherein said composition is substantially free of
`bacteria” ................................................................ 62
`Dependent Claim 2 .......................................................... 63
`Dependent Claim 3 .......................................................... 64
`Dependent Claim 4 .......................................................... 64
`Dependent Claims 5 and 10 ............................................... 64
`Dependent Claim 6 .......................................................... 65
`a)
`“wherein the hydrochloride salt of levocetirizine is
`present in amount of 0.5 mg/ml” ............................... 65
`“the mixture of methyl p-hydroxybenzoate and
`propyl p-hydroxybenzoate is present in amount of
`0.75 mg/ml” ........................................................... 67
`Dependent Claim 7 .......................................................... 67
`8.
`Dependent Claim 8 .......................................................... 68
`9.
`10. Dependent Claim 9 .......................................................... 69
`11. Dependent Claim 11......................................................... 69
`a)
`“the composition is in the form of an oral solution
`comprising
`0.50
`mg/ml
`levocetirizine
`dihydrochloride”..................................................... 70
`“0.675 mg/ml methyl p-hydroxybenzoate, and
`0.075 mg/ml propyl p-hydroxybenzoate” ................... 73
`SECONDARY CONSIDERATIONS ................................................... 74
`
`b)
`
`X.
`
`iii
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 004
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`I, Paul A. Laskar, Ph.D., do hereby declare and state as follows:
`
`1.
`
`I have been asked to provide testimony as to what one of ordinary skill
`
`in the art would have understood with respect to the patent at issue and various prior
`
`art discussed herein. I provide this testimony below:
`
`I.
`
`INTRODUCTION
`
`2.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this Declaration.
`
`3.
`
`I have been retained on behalf of Petitioner for the above-captioned
`
`inter partes review (“IPRs”). I am being compensated for my time in connection
`
`with this IPR at my standard consulting rate, which is $300 per hour for consulting;
`
`$375 per hour for deposition and testimony, including preparation; $125 per hour
`
`for non-working travel time. My compensation does not depend in any way on the
`
`outcome of any of the IPRs.
`
`4.
`
`It is my understanding that the Petitions for Inter Partes Review in this
`
`matter involves U.S. Patent No. 8,633,194 (“the ’194 patent”) (EX1001).
`
`5.
`
`The ’194 patent names Domenico Fanara, Jean Scouvart, Claire
`
`Poulain, and Michel Deleers as the purported inventors.
`
`6.
`
`It is also my understanding that Patent Owner contends the priority date
`
`of the ’194 patent is July 14, 2004—the filing date of EP Application No. 04016519.
`
`
`
`1
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 005
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`I further understand that the ’194 patent is assigned to UCB Pharma, S.A. (“UCB,”
`
`“Patentee,” or “Patent Owner”).
`
`7.
`
`As explained below, it is my opinion that all claims of the ’194 patent
`
`would have been obvious to the skilled artisan as of the time of the priority date of
`
`the ’194 patent. And therefore, these claims are invalid.
`
`II. MY EXPERIENCE AND QUALIFICATIONS
`I am an expert in the field of formulations and drug delivery including
`8.
`
`aqueous liquid preparations, and I have been an expert in this field since well before
`
`2004, which I understand is the priority date of the patents (the priority date issue
`
`will be discussed specifically later in this Declaration). In formulating my opinions,
`
`I have relied upon my training, knowledge, and experience in the relevant art. A
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`copy of my current curriculum vitae is attached to this Declaration as EX1003 and
`
`it provides a comprehensive description of my academic and employment history.
`
`9.
`
`As an expert in the relevant field since prior to 2004, I am qualified to
`
`provide an opinion as to what a Person of Ordinary Skill (“POSA” or “the skilled
`
`artisan”) would have understood, known, or concluded as of 2004. Indeed, since
`
`1965, I have accumulated significant training and experience in the field of aqueous
`
`liquid pharmaceutical formulations. Moreover, I have pharmaceutically formulated
`
`products using levocetirizine, methylparaben and/or propylparaben.
`
`
`
`2
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 006
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`10.
`
`I have a Ph.D. in Pharmaceutical Sciences from Oregon State
`
`University with a Minor in Biostatistics; an M.B.A. in General Management,
`
`International Management and Marketing from the University of California at
`
`Irvine; an M.S. in Pharmacy and a B.S. in Pharmacy from the University of Illinois;
`
`and a B.A. in General Science (Chemistry, Biology) from the University of
`
`Rochester.
`
`11.
`
`I am currently, and have been since October 2006, the President of Paul
`
`Laskar Associates, Inc., a pharmaceutical development consulting firm that I
`
`founded. My client base consists of start-up and established pharmaceutical
`
`companies with whom I consult in the areas of pharmaceutical development,
`
`including formulation development and evaluation. In connection with my
`
`consulting work, I assist in
`
`the development of various aqueous liquid
`
`pharmaceutical formulations
`
`including ophthalmic preparations and oral
`
`preparations. From 2003 to 2006, I was Senior Director, Pharmaceutical
`
`Development at Dey LP, at that time owned by Merck KGaA. In that capacity, I
`
`supervised the formulation development, clinical supply, technology transfer, pilot
`
`operations, and preclinical functions. While most of Dey’s projects were for
`
`inhalation, I worked on two generic ophthalmic projects.
`
`12. From 1994 to 2003, I was initially Director, then Vice President,
`
`Pharmaceutical Development, and subsequently Principal Director, Pharmaceutics
`
`
`
`3
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 007
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`and Technology, at Santen Inc., the U.S. subsidiary of the Japanese ophthalmic
`
`pharmaceutical company, Santen Ltd. My responsibilities included directing
`
`ophthalmic formulation development, stability assessment, technology transfer,
`
`preparation of internal reports and regulatory documents, and review of in-license
`
`candidates. The areas I supervised included: formulation development, analytical
`
`chemistry and stability assessment, clinical supplies, and non-clinical development.
`
`During my tenure with Santen Inc., three ophthalmic projects, Quixin, Betimol, and
`
`Alamast, resulted in successful New Drug Applications (“NDAs”) by the Food and
`
`Drug Administration (“FDA”) and commercial launch. A fourth NDA, Iquix, and a
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`prostaglandin compound, taflutan (now marketed in the U.S. as Zioptan®), to which
`
`I contributed to its formulation as well as chemistry, manufacturing, and control
`
`(“CMC”) development strategy, were approved subsequent to my leaving Santen
`
`Inc.
`
`13. From 1993 to 1994, I was Director, Pharmaceutical Development, at
`
`CoCensys, Inc., a start-up pharmaceutical company. During this time, I directed
`
`CMC development of two new chemical entities (“NCE”), one for oral use as a
`
`suspension and solid drug product, and the second as a parenteral. The oral NCE
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`was successfully formulated as a suspension and submitted as an investigational new
`
`drug (“IND”) application to the FDA.
`
`
`
`4
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 008
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`14. From 1982 to 1993, I was employed by Allergan, Inc., an ophthalmic
`
`specialty company. Initially, I was a Scientist, Product Development, then I became
`
`a Section Manager and eventually Manager in the same area, and, finally, Director,
`
`Product Development. While at Allergan, I was involved in the formulation and
`
`subsequent development of a number of ophthalmic and dermatological drug
`
`products, many of which were approved as NDAs by the FDA and their equivalents
`
`in other countries/jurisdictions. From 1973 to 1982, I was Assistant Professor of
`
`Pharmacy at the College of Pharmacy, University of Illinois Medical Center (now
`
`University of Illinois-Chicago Campuses) and then Associate Professor of Pharmacy
`
`at the School of Pharmacy at Creighton University. During this time, among the
`
`courses I taught were those in dosage form development including oral solutions,
`
`oral solids, ophthalmics, and dermatologicals.
`
`15. At present, I provide consulting services to start-up and established
`
`pharmaceutical companies for pharmaceutical projects. The nature of the projects
`
`include ophthalmics, sterile parenterals, dermatologicals, inhalation, and liquid and
`
`solid oral drug products. The areas in which I consult include active pharmaceutical
`
`ingredient (“API”) manufacture and qualification, formulation development,
`
`stability assessment, analytical development, manufacturing process development
`
`
`
`5
`
`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 009
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`and transfer, contract laboratory and drug product manufacturer identification and
`
`their management, and preparation of regulatory documents.1
`
`16.
`
`In the course of my employment and during my consulting practice, I
`
`have worked on two projects involving cetirizine, the racemic counterpart of
`
`levocetirizine. In the first project, cetirizine was formulated as a metered dose nasal
`
`spray. My involvement included reviewing existing CMC documentation for this
`
`in-license candidate including an assessment of the formulation, its stability, and
`
`ability to meet its physical, chemical, and microbiological specifications. In
`
`addition, I prepared a development plan and estimated timeline for its transfer into
`
`larger scale manufacturing.
`
`17.
`
`I was involved as a consultant in a second cetirizine project that was a
`
`preserved multidose ophthalmic drug product. Two cetirizine formulations were
`
`prepared both of which had acceptable stability. On the basis of comfort and
`
`preliminary efficacy studies, one formulation was chosen for further development.
`
`I was involved in the development of a process for the product’s manufacture,
`
`developing analytical methods to assess its stability, establishing specifications for
`
`physical, chemical, and microbiological attributes, and monitoring the formulation’s
`
`
`1 I reserve the right to further explain my background and qualifications in
`
`deposition where needed.
`
`
`
`6
`
`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 010
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`

`

`
`
`stability. I prepared regulatory documents at both the IND and NDA stages and
`
`participated in several meetings with the FDA. This project came to fruition when
`
`its NDA was approved. In the process of developing this cetirizine formulation and
`
`experiments, I developed a good understanding of cetirizine’s attributes including
`
`its preservative activity.
`
`18.
`
`I have worked with several parabens in the course of my education,
`
`years of teaching, and while working in the pharmaceutical industry, both as an
`
`employee and more recently as a consultant. By way of background, there are
`
`several paraben esters used pharmaceutically as antimicrobial preservatives. The
`
`parabens differ in the length of the alkyl group esterified to para-hydroxybenzoic
`
`acid. The alkyl groups most frequently used in pharmaceuticals and cosmetics range
`
`from methyl- to butylparaben, although there are others that have been described,
`
`though less frequently used.
`
`19.
`
`In my work, I have primarily used combinations of methyl- and
`
`propylparabens, both with and without another antimicrobial preservative in areas
`
`
`
`7
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 011
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`

`

`
`
`such as dermatology2, and aqueous preparations such as oral and ophthalmic
`
`solutions. In my experience with oral aqueous solutions and ophthalmic solutions,
`
`generally speaking, parabens have been able to reliably meet compendial
`
`antimicrobial effectiveness (“AET”) requirements. 3 Moreover, some formulation
`
`excipients have been demonstrated to augment the antimicrobial preservative
`
`activity enabling lower concentrations of other antimicrobial preservatives, such as
`
`parabens, to be used. One such category of excipients with this property are several
`
`
`2 Generally speaking, dermatologicals are more complex than oral solutions
`
`since the formulations include a lipid phase into which parabens can diffuse resulting
`
`in reduced preservative activity of the formulation.
`
`3 Of course, not every formulation is identical. On occasion, I have made
`
`formulations using parabens that have not met compendial preservative
`
`requirements, and so I, like any other formulator, would use another preservative.
`
`Of course, I have observed the same problem with other common preservatives. For
`
`example, if BAC is incompatible due to insolubility with a formulation, then it also
`
`could have problem meeting compendial preservative requirements. The same
`
`would be true if the preservative would degrade in the formulation or react with a
`
`component of the formulation. These are routine issues for a formulator, and they
`
`would just use another preservative.
`
`
`
`8
`
`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 012
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`

`
`
`members of the polyol family. Among the polyols demonstrating such an attribute
`
`are propylene glycol, glycerin, and sorbitol.
`
`III. LIST OF MATERIALS CONSIDERED
`In formulating my opinions, I have considered the materials referenced
`20.
`
`in this Declaration and the Exhibit List below. I also have reviewed the ’194 patent
`
`(EX1001) and its prosecution history as well as each of the documents cited herein
`
`in light of the general knowledge in the state of the art as of July 14, 2004.
`
`Petitioner
`Exhibit #
`
`Description
`
`1001
`1002
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`U.S. Patent No. 8,633,194 (“the ’194 patent”)
`Declaration of Dr. Laskar
`CV of Dr. Laskar
`European Patent Application Publication No. 0605203 A2 (“EP
`’203”)
`levocetirizine, and
`Wang D.Y., “Effect of cetirizine,
`dextrocetirizine on histamine-induced nasal response in healthy
`adult volunteers,” Allergy 56 (2001), pp. 339-343 (“Wang”)
`Kibbe, “Handbook of Pharmaceutical Excipients,” 3rd ed. 2000
`(the “Handbook”)
`International Patent Application No. WO 2004/050094 (“WO
`’094”)
`Tillement, Jean-Paul et al., “Compared pharmacological
`characteristics in humans of racemic cetirizine and levocetirizine,
`two
`histamine H1-receptor
`antagonists,” Biochemical
`
`
`
`9
`
`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 013
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`

`

`
`
`
`
`Issue 7, 1 October 2003,
`
`Pharmacology Volume 66,
`pages 1123-1126
`Potter, P.C., “Levocetirizine is effective for symptom relief
`including nasal congestion in adolescent and adult (PAR)
`sensitized to house dust mites,” Allergy (Oxford, United
`Kingdom) Volume 58, Issue 9, pages 893-899, Journal 2003
`Gandon, J.M. et al., “Lack of effect of single and repeated doses
`of Levocetirizine, a new antihistamine drug, on cognitive and
`psychomotor functions in healthy volunteers,” British Journal of
`Clinical Pharmacology (2002), 54(1), 51-58
`Orange Book Entry for XYZAL
`R.J. Davies et al., Antihistamines: topical vs. oral administration,
`Clinical and Experimental Allergy 26(3):11-17 (1996) (“Davies”)
`File Wrapper of ’194 patent
`Gennaro, A. R., Remington: The Science and Practice of
`Pharmacy 20th ed. (2000)
`U.S. Patent No. 5,698,558 to Nancy M. Grey (“US ’558”)
`EPO opposition
`Saeedi et al., “The treatment of atopic dermatitis with licorice
`gel,” Journal of Dermatological Treatment (2003) 14, 1–5
`Duconge et al., “Topical disposition of two strengths of a
`125I-rhEGF jelly in rat skin wounds,” Biopharm. Drug Dispos.
`25: 193–201 (2004)
`U.S. Patent No. 4,275,076
`U.S. Patent No. 5,643,584
`Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery
`Systems 7th ed. 1999
`
`1009
`
`1010
`
`1011
`1012
`
`1013
`
`1014
`
`1015
`1016
`1017
`
`1018
`
`1019
`1020
`
`1021
`
`10
`
`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 014
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`

`
`
`1022
`
`1023
`
`1024
`
`Soni et al., “Evaluation of the health aspects of methyl paraben:a
`review of
`the published
`literature,” Food and Chemical
`Toxicology 40 (2002) 1335–1373
`Sutton et al., “Development of the Antimicrobial Effectiveness
`Test as USP Chapter <51>” PDA Journal of Pharmaceutical
`Science and Technology, Vol. 56, No. 6, 300-311,
`November/December 2002
`Darwish et al., Effect of ethanol, propylene glycol and glycerol on
`the interaction of methyl and propyl p-hydroxybenzoate with
`Staphylococcus aureus and Pseudomonas aeruginosa,” Int. J. of
`Pharm. 147:51-60 (1997).
`
`IV. LEGAL STANDARD
`21. Although I am not a lawyer, I have been informed by counsel and
`
`provide my general understanding of the law of obviousness. I used these principles
`
`in conducting my analysis and drawing any conclusions.
`
`22.
`
`I understand that the first step in determining whether a patent claim
`
`would have been obvious is to construe the claims to determine claim scope and
`
`meaning. I understand that in IPR proceedings, the claims must generally be given
`
`“the meaning that the term would have to a person of ordinary skill in the art in
`
`question at the time of the invention.”
`
`A. Obviousness
`I understand that a patent claim is invalid if the differences between the
`23.
`
`claimed invention and prior art are such that the subject matter as a whole would
`
`
`
`11
`
`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 015
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`

`

`
`
`have been obvious at the time the invention was made to a person of skill in the art
`
`(“POSA”).
`
`24.
`
`I have been told the following factors (sometimes referred to as the
`
`Graham factors) are used in making an obviousness determination: a) the scope and
`
`content of the prior art; b) the differences between the prior art and the claimed
`
`invention; c) the level of ordinary skill in the pertinent art; and d) any secondary
`
`considerations evidencing non-obviousness.
`
`25.
`
`I also understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art. A claimed invention can be obvious when,
`
`for example, there is some teaching, suggestion, or motivation in the prior art that
`
`would have led a POSA to modify the prior art reference or to combine prior art
`
`reference teachings to arrive at the claimed invention.
`
`26.
`
`I also understand that the prior art references themselves do not have to
`
`provide an explicit teaching, suggestion, or motivation to combine prior art
`
`teachings; rather, the analysis may rely on interrelated teachings, market demands,
`
`the background knowledge possessed by a POSA, and/or common sense. Put
`
`another way, the motivation to combine or modify prior art references can come
`
`from any reason to do so, and is not limited to the reasons that may have motivated
`
`the patentee.
`
`
`
`12
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 016
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`27.
`
`I am also informed that a combination of familiar elements according
`
`to known methods is likely to be obvious when it does no more than yield predictable
`
`results. I also understand that when a person of ordinary skill would have reached
`
`the claimed invention through routine experimentation, the invention may be
`
`deemed obvious.
`
`28.
`
`I understand that various rationales are utilized to determine whether a
`
`claim
`
`is obvious, including, among others:
`
` (i) simple substitution or
`
`interchangeability of one known element for another to obtain predictable results;
`
`(ii) use of known techniques to improve similar methods or products in the same
`
`way; (iii) applying a known technique to a known method or product ready for
`
`improvement to yield predictable results; (iv) “obvious to try”—choosing from a
`
`finite number of identified, predictable solutions, with a reasonable expectation of
`
`success; and (v) known work in one field of endeavor prompting variations of it for
`
`use in either the same field or a different one based on design incentives or other
`
`market forces if the variations would have been predictable to one of ordinary skill
`
`in the art.
`
`29. As stated above, I understand that secondary considerations of
`
`non-obviousness are part of the obviousness inquiry. I understand that these
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`secondary considerations may include failure of others, copying, unexpectedly
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`superior results, perception in the industry, commercial success, and long-felt but
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`13
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 017
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`unmet need. I also understand that in order for secondary considerations of
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`non-obviousness to be applicable, they must have a nexus to the claimed subject
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`matter. I understand that this nexus (i.e., link) includes a connection between the
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`subject matter of the claim and the alleged secondary considerations.
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`30.
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`I understand that I cannot use hindsight in any obviousness analysis. In
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`connection with my opinions, I did not use hindsight, nor did I use the claims and/or
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`the disclosure of the ’194 patent as a blueprint for piecing together the prior art to
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`arrive at the claimed invention. As part of the obviousness analysis and to avoid
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`hindsight, I placed in mind back to the time of invention (i.e., the relevant priority
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`date (discussed further below)) and considered the thinking of POSA, guided only
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`by the prior art references and the then-accepted wisdom in the field.
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`V.
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`PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
`In arriving at my opinions, I have relied on my experience in the
`31.
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`relevant art and have considered the point of view of a person of ordinary skill in the
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`art as of the relevant priority date. It is my understanding that a POSA is a
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`hypothetical person who is presumed to be aware of all pertinent art, thinks along
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`conventional wisdom in the art, and is a person of ordinary creativity.
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`32. As of the relevant priority date, a POSA in the relevant field would have
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`had: (i) a Pharm.D. or Ph.D. in chemistry, biochemistry, pharmacy, pharmaceutics,
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`or in a related field, and at least two years of relevant experience in developing and
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 018
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`formulating aqueous pharmaceutical formulations; (ii) a master’s degree in the same
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`fields and at least five years of the same relevant experience; or (iii) a bachelor’s
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`degree in the same fields and at least seven years of the same relevant experience.
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`33. Further, a POSA would typically work as part of a multidisciplinary
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`team and 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, should the need
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`arise.
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`34.
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`In determining the qualifications of a POSA, I considered, among other
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`factors, the field of the alleged invention and use thereof described in the ’194 patent
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`and my experience with the educational level of practitioners in related fields. In
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`addition, my opinion is based upon my background, education, and personal
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`experience.
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`35. As mentioned above, I have personally worked on aqueous
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`pharmaceutical formulations containing cetirizine. As discussed below, as of the
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`relevant priority date, both cetirizine and its isomer, levocetirizine, were well-known
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`compounds and from my personal experience, there was nothing difficult or
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`challenging with formulating with this API that would not be considered routine
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`experimentation for a POSA. This is reflected in the prior art (discussed below).
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`That is, by the time of the relevant priority date, levocetirizine was known and
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`15
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 019
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`nothing in the art reflected any difficulty that would not be considered routine
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`experimentation for a POSA.
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`36. Moreover, as noted above I have also worked with parabens, including
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`methyl- and propylparabens. As discussed further below, the POSA would have
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`known that these were common preservatives used in aqueous pharmaceutical
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`formulations.
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`37. Based on my experience, I have the understanding and capabilities of a
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`person of ordinary skill as defined above prior to, and on, the relevant priority date,
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`and all testimony and opinions provided herein is from that perspective.
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`VI. THE ’194 PATENT
`I have reviewed and considered the ’194 patent in view of general
`38.
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`knowledge in the relevant field measured from the relevant priority date for the
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`’194 patent from the perspective of a POSA as defined above. Again, I reviewed
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`the ’194 patent not for the purposes of using hindsight in my analysis, but so that I
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`could understand the scope of the claims, the nature of the alleged invention, 4 and
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`4 For example, I have been informed that the second Graham factor requires
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`evaluation of the “differences between the prior art and the claims at issue.” To
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`provide such an analysis, an understanding of the “claims at issue” is needed, which
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`16
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 020
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`other matters germane to my analysis (e.g., claim construction issues, priority date
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`issues, and determining the definition of a POSA).
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`39.
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`I understand Patent Owner contends that the ’194 patent purportedly
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`covers the XYZAL® product by listing it in the Orange Book entry for XYZAL®.
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`See EX1011. At a high level, the challenged claims of the ’194 patent purportedly
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`directed to “a liquid composition containing an active substance belonging to the
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`family of substituted benzhydryl piperazines with reduced amounts of
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`preservatives.” EX1001, Abstract. The claimed active substance is levocetirizine
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`and salts thereof. EX1001, 2:16-21. The ’194 patent does not dispute that
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`levocetirizine is in the prior art and readily available. EX1001, 2:42-48.
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`40. The ’194 patent alleges that “[i]t has now been surprisingly found that
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`the active substances belonging to the family of substituted benzhydryl piperazines
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`possess a preservative effect in aqueous solutions,” (EX1001, 1:51-54) and a
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`pharmaceutical composition comprising one of these active substances “and a
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`reduced amount of preservatives is stable during a long period of time.” EX1001,
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`1:60-64. With respect to the preservatives, the ’194 patent states that “[b]est results
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`have been obtained with a preservative mixture of methyl parahydroxybenzoate and
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`necessitates a review of the patent.
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`17
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`Apotex, Inc. (IPR2019-00400), Ex. 1002, p. 021
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`propyl parahydroxybenzoate in a ratio of 9/1 expressed in weight.” EX1001,
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`3:45-48.
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`41.
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`I will provide further analysis of the ’194 patent later in this
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`Declaration.
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`VII. CLAIM CONSTRUCTION
`It is my understanding that in an IPR proceeding the claim terms
`42.
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`ordinarily should be given “the meaning that the term would have to a person of
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`ordinary skill in the art in question at the time of the invention.” I have been
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`informed that there is no prior claim construction determination concerning the ’194
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`patent in a civil action or a proceeding before the International Trade Commission.
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`43. The ’194 patent defines various terms within th