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
`______________
`
`
`PATENT OWNER COMPLETE RESPONSE
`
`
`
`
`
`
`
`
`
`

`

`IPR2019-00400
`Patent 8,633,194
`
`TABLE OF CONTENTS
`
`Page
`I.
`PRELIMINARY STATEMENT ..................................................................... 1
`II.
`LEGAL STANDARD ..................................................................................... 2
`III. THE ’194 PATENT ......................................................................................... 4
`A.
`The ’194 Patent ...................................................................................... 4
`B.
`The Challenged Claims ......................................................................... 5
`C.
`Prosecution of the ’194 Patent ............................................................... 6
`IV. CLAIM CONSTRUCTION ............................................................................ 8
`V.
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 8
`VI. BACKGROUND ............................................................................................. 9
`A.
`Principles of Pharmaceutical Formulation ............................................ 9
`B. Antimicrobial Effectiveness Testing ................................................... 11
`C.
`Preservatives in Pharmaceutical Formulations ................................... 12
`D.
`Levocetirizine ...................................................................................... 15
`VII. SCOPE AND CONTENT OF THE PRIOR ART IDENTIFIED BY
`PETITIONER ................................................................................................ 17
`A.
`EP ’203 (EX1004) ............................................................................... 17
`B. WO ’094 (EX1007) ............................................................................. 19
`C.
`The Handbook (EX1006) .................................................................... 20
`D.
`Petitioner’s Prior Art Allegedly Teaching a 9/1 Ratio of
`Methylparaben to Propylparaben ........................................................ 24
`VIII. PETITIONER’S GROUND 1 DOES NOT DEMONSTRATE
`UNPATENTABILITY .................................................................................. 26
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`IPR2019-00400
`Patent 8,633,194
`
`
`B.
`
`D.
`
`TABLE OF CONTENTS
`(Continued)
`A. Only Hindsight Would Cause a POSA To Begin Formulation with the
`Syrup Example of WO ’094. ............................................................... 26
`Petitioner Does Not Show That A POSA Would Have Been Motivated
`to Combine the Handbook with WO ’094........................................... 29
`C. A POSA Would Not Reasonably Expect to Successfully Prepare the
`Claimed Invention. .............................................................................. 33
`Petitioner Failed to Establish Prima Facie Obviousness as the
`Handbook Teaches Neither the Claimed Amount Nor Ratio of
`Parabens. .............................................................................................. 35
`1.
`There is No Overlapping Range Disclosed Across the Prior
`Art. ............................................................................................ 35
`The Handbook Does Not Teach Dr. Laskar’s Calculated
`Total Amount of Parabens. ....................................................... 38
`Petitioner Relies on Non-Analogous Art to Support its
`Finding of a 9/1 Ratio of Parabens. .......................................... 42
`The Handbook and the Prior Art Teach Away from Minimizing the
`Amount of Preservatives Used in a Liquid Pharmaceutical
`Formulation. ........................................................................................ 44
`F. Unexpected Results Overcome Any Prima Facie Showing of
`Obviousness. ........................................................................................ 47
`G. Dependent Claims................................................................................ 49
`1.
`Dependent Claim 2 ................................................................... 49
`2.
`Dependent Claim 4 ................................................................... 50
`3.
`Dependent Claim 6 ................................................................... 50
`4.
`Dependent Claim 11 ................................................................. 52
`
`2.
`
`3.
`
`E.
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`IPR2019-00400
`Patent 8,633,194
`
`
`B.
`
`C.
`
`E.
`
`F.
`
`TABLE OF CONTENTS
`(Continued)
`IX. PETITIONER’S GROUND 2 REFERENCES DO NOT
`DEMONSTRATE UNPATENTABILITY ................................................... 52
`A. Only Hindsight Would Cause a POSA to Begin Formulation with
`Example 5 of EP ’203. ......................................................................... 53
`Petitioner Does Not Show that a POSA Would Be Motivated to
`Modify the Amount and Ratio of Parabens in Example 5 of EP ’203.
` ............................................................................................................. 54
`Petitioner Does Not Show that a POSA Would Have Been Motivated
`to Combine the Handbook with EP ’203............................................. 55
`D. A POSA Would Not Reasonably Expect to Successfully Prepare the
`Claimed Invention. .............................................................................. 56
`Petitioner Did Not Establish Prima Facie Obviousness Based on An
`“Overlapping Range.” ......................................................................... 56
`The Handbook and the Prior Art Teach Away from Minimizing the
`Amount of Preservatives Used in a Liquid Pharmaceutical
`Formulation. ........................................................................................ 57
`G. Unexpected Results Overcome Any Prima Facie Showing of
`Obviousness. ........................................................................................ 58
`H. Dependent Claims. .............................................................................. 58
`CONCLUSION .............................................................................................. 58
`
`X.
`
`
`
`
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`TABLE OF AUTHORITIES
`
`IPR2019-00400
`Patent 8,633,194
`
`
`Page(s)
`
`CASES
`Allergan, Inc. v. Sandoz, Inc.,
`796 F. 3d 1293 (Fed. Cir. 2015) ........................................................................... 4
`Arendi SARL v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) ...................................................................... 3, 46
`Comaper Corp. v. Antec, Inc.,
`596 F.3d 1343 (Fed. Cir. 2010) .......................................................................... 49
`Everett Laboratories, Inc. v. Breckenridge Pharm., Inc.,
`573 F. Supp. 2d 855 (D.N.J. Aug. 26, 2008) ...................................................... 37
`Galderma Labs., LP v. Tolmar, Inc.,
`737 F. 3d 731 (Fed. Cir. 2013) ............................................................................. 4
`Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A. DE C.V.,
`865 F.3d 1348 (Fed. Cir. 2017) .......................................................................... 49
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) ............................................................................ 42
`In re Coutts,
`726 Fed. Appx. 791 (Fed. Cir. 2018) .................................................................. 39
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ...................................................................... 3, 47
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .............................................................................. 47
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) ................................................................ 3, 29, 34
`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) ............................................................................ 48
`
`-i-
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`

`

`TABLE OF AUTHORITIES
`(Continued)
`
`IPR2019-00400
`Patent 8,633,194
`
`
`Page(s)
`
`In re Peterson
`315 F.3d 1325 (Fed. Cir. 2003) .................................................................... 35, 38
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .......................................................... 3, 29, 33, 55
`InTouch Technologies, Inc. v. VGO Communications, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .................................................................... 27, 54
`Iron Grip Barbell Co., Inc. v. USA Sports, Inc.
`392 F.3d 1317 (Fed. Cir. 2004) ...................................................................passim
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.
`688 F.3d 1342 (Fed. Cir. 2012) ............................................................................ 3
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .....................................................................................passim
`Millennium Pharms., Inc. v. Sandoz Inc. et al.,
`862 F.3d 1356 (Fed. Cir. 2017) .............................................................. 16, 28, 35
`Ex parte Obiaya,
`227 USPQ 58 (Bd. Pat. App. & Inter. 1985) ...................................................... 48
`OSI Pharms., LLC v. Apotex Inc.,
`2018-1925, 2019 WL 4892078 (Fed. Cir. Oct. 4, 2019) .................................... 35
`Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) .......................................................................... 28
`Pharmacosmos A/S v. Luitpold Pharms., Inc.,
`IPR2015-01490, Paper 54 (P.T.A.B. Jan. 4, 2017) ...................................... 29, 30
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) .............................................................................. 3
`Rosemount, Inc. v. Beckman Instruments, Inc.,
`727 F.2d 1540 (Fed. Cir. 1984) .......................................................................... 17
`
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`TABLE OF AUTHORITIES
`(Continued)
`
`IPR2019-00400
`Patent 8,633,194
`
`
`Page(s)
`
`Smith & Nephew v. ConvaTec Techs. Inc.,
`IPR2013-00097, Paper 76 (P.T.A.B. Feb. 24, 2014) ............................................ 8
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................... 48
`Woods v. DeAngelo Marine Exhaust, Inc.,
`692 F.3d 1272 (Fed. Cir. 2012) .......................................................................... 21
`
`
`
`
`
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`TABLE OF EXHIBITS
`
`Ex. Description
`
`2001 Dietrich et al., U.S. Patent Application 2004/0058896
`A1, Pharmaceutical Preparation Comprising An Active
`Dispersed On A Matrix
`
`IPR2019-00400
`Patent 8,633,194
`
`Abbreviation
`
`Dietrich
`
`2002 DeLongueville et al., WIPO Publication Number WO
`02/47689 A2, A Method for Preventing Urticaria
`
`DeLongueville
`
`2003 Doron et al., Antibacterial effect of parabens against
`planktonic and biofilm Streptococcus sobrinus, 18 Int.
`J. of Antimicrobial Agents 575-78 (2001)
`
`Doron
`
`2004 Gilliland et al., The bactericidal activity of a methyl
`and propyl parabens combination: isothermal and non-
`isothermal studies, 72 J. Applied Bacteriology 252-57
`(1992)
`
`Gilliland I
`
`2005 Gilliland et al., Kinetic evaluation of claimed
`synergistic paraben combinations using a factorial
`design, 72 J. Applied Bacteriology (1992)
`
`2006 Routledge et al., Some Alkyl Hydroxy Benzoate
`Preservatives (Parabens) Are Estrogenic, 153
`Toxicology and Applied Pharmacology 12-19 (1998)
`
`Gilliland II
`
`Routledge
`
`2007 FDA ANDA 211528 Tentative Approval
`
`2008 Exhibit 3005 – Public Redacted Version
`
`2009 Curriculum Vitae of Dr. Sarfaraz K. Niazi
`
`2010 Deposition Transcript of Dr. Paul A. Laskar (Oct. 2,
`2019)
`
`2011
`
`John P. Griffin et al., The Textbook of Pharmaceutical
`Medicine, 4th ed. (2002)
`
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`IPR2019-00400
`Patent 8,633,194
`
`Abbreviation
`
`Ex. Description
`
`2012 Kristian Strømgaard et al., Textbook of Drug Design
`and Discovery, 3d ed. (2002)
`
`2013
`
`I. Rácz, Drug Formulation (1989)
`
`2014 W. P. Evans, The solubilization and inactivation of
`preservatives by non-ionic detergents, 16 J. of
`Pharmacy and Pharmacology 323-331 (1964)
`
`2015
`
`John J. O’Neill and Catherine A. Mead, The parabens:
`bacterial adaptation and preservative capacity, 33 J.
`Soc. Cosmet. Chem. 75-84 (1982)
`
`2016 Routes of Administration Requiring Sterile
`Formulations, University of North Carolina Eshelman
`School of Pharmacy, available at
`https://pharmlabs.unc.edu/labs/parenterals/routes.htm
`
`2017 The European Agency for the Evaluation of Medicinal
`Products, Note for Guidance on Quality of Water for
`Pharmaceutical Use (2002)
`
`2018 The European Agency for the Evaluation of Medicinal
`Products, Note for Guidance on Inclusion of
`Antioxidants and Antimicrobial Preservatives in
`Medicinal Products (July 1997)
`
`2019 U.S. Food & Drug Administration, Q6A Specifications:
`Test Procedures and Acceptance Criteria for New
`Drug Substances and New Drug Products: Chemical
`Substances (December 2000)
`
`2020 The United States Pharmacopoeia 25th Revision,
`Rockville, MD (2001) (“USP 25”), <51> Antimicrobial
`Effectiveness Test
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`IPR2019-00400
`Patent 8,633,194
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`Abbreviation
`
`Ex. Description
`
`2021 The European Pharmacopoeia 5th Edition (2004) (“Eu.
`Ph. 5”), Ch. 5.1.3 Efficacy of antimicrobial
`preservation
`
`2022 The European Agency for the Evaluation of Medicinal
`Products, Evaluation of Medicines for Human Use,
`Draft Note for Guidance on Excipients, Antioxidants
`and Antimicrobial Preservatives in the Dossier for
`Application for Marketing Authorisation of a Medicinal
`Product (2003), available at
`https://www.ema.europa.eu/en/documents/scientific-
`guideline/draft-note-guidance-excipients-antioxidants-
`antimicrobial-preservatives-dossier-application_en.pdf
`
`2023 Tuula Kinnunen and Markku Koskela, Antibacterial
`and Antifungal Properties of Propylene Glycol,
`Hexylene Glycol, and 1,3-Butylene Glycol In Vitro, 71
`Acta Dermato-Venereologica 148-50 (1990)
`
`2024 Shane Cox Gad, Pharmaceutical Manufacturing
`Handbook: Production and Processes (2008)
`
`2025 U.S. Food & Drug Administration Inactive Ingredient
`Guide (Jan. 1996)
`
`2026
`
`Jennifer M. Andrews, Determination of minimum
`inhibitory concentrations, 48 J. Antimicrobial
`Chemotherapy Suppl. S1 5-16 (2001)
`
`2027 Thomas E. Haag and Donald F. Loncrini, Esters of
`Para-hydroxybenzoic Acid, Cosmetic and Drug
`Preservation 64-77 (1984)
`
`2028
`
`James H. Day, Anne K. Ellis, Elizabeth Rafeiro,
`Levocetirizine: a new selective H1 receptor antagonist
`for use in allergic disorders, 40 Drugs Today 415-421
`(2004)
`
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`Ex. Description
`
`IPR2019-00400
`Patent 8,633,194
`
`
`Abbreviation
`
`2029 Mark. T. D. Cronin, et al., Structure-Based
`Classification of Antimicrobial Activity, 42 J. Chem.
`Inf. Comput. Sci. 869-878 (2002)
`
`2030 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)
`
`2031 Dániel Nemes, Interaction between Different
`Pharmaceutical Excipients in Liquid Dosage Forms—
`Assessment of Cytotoxicity and Antimicrobial Activity,
`23 Molecules 1-19 (2018)
`
`2032 Acott, K. M., and Ted P. Labuza. Inhibition of
`Aspergillus niger in an intermediate moisture food
`system, 40 J. of Food Sci. 137-139 (1975)
`
`2033 Klindworth, Karen Joanne, et al., Inhibition of
`Clostridium perfringens by butylated
`hydroxyanisole, 44 J. of Food Sci. 564-567 (1979)
`
`2034 Declaration of Dr. Sarfaraz K. Niazi
`
`
`
`
`
`
`
`
`
`
`
`
`
`2035 EP 1768649
`
`2036 Additional Excerpt of Kibbe, “Handbook of
`Pharmaceutical Excipients,” 3d ed. 2000 (EX1006)
`
`
`“EP ’649”
`
`
`
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`PRELIMINARY STATEMENT
`Patent Owner UCB Biopharma Sprl (“Patent Owner”) respectfully requests
`
`IPR2019-00400
`Patent 8,633,194
`
`
`I.
`
`that the Board reject Apotex Inc.’s Petition for cancellation of Claims 1-11 of U.S.
`
`Patent No. 8,633,194 (the “’194 patent”).
`
`The ’194 patent claims a liquid pharmaceutical formulation involving the
`
`antihistamine levocetirizine and reduced amounts of preservatives present in a
`
`defined ratio. A commercial embodiment of the claimed invention is the children’s
`
`anti-allergy medication, Xyzal 24HR®. As the ’194 patent explains, and the
`
`Examiner recognized in allowing the claims, this novel invention resulted from the
`
`surprising, unexpected discovery that levocetirizine itself has antibacterial
`
`properties, which emboldened the inventors to substantially reduce the amount of
`
`preservatives in the formulation far below that of ordinary ones.
`
`Petitioner advances two grounds of alleged invalidity that rest on a common
`
`argument: A POSA at the time of the invention would have (1) known that
`
`levocetirizine could be formulated in liquid pharmaceutical formulations with
`
`methylparaben and propylparaben; (2) been motivated to use methylparaben and
`
`propylparaben in the claimed ratio (9/1) and amount (“more than 0 and up to 0.75
`
`mg/mL”) because a reference book (the Handbook) allegedly teaches an overlapping
`
`range found by combining a number of its disclosures; and (3) would have
`
`reasonably expected that the resulting formulation would remain “substantially free
`
`-1-
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`

`

`of bacteria.” None of Petitioner’s references support this conclusion.
`
`IPR2019-00400
`Patent 8,633,194
`
`
`To the contrary—Petitioner’s references actually teach that a POSA should
`
`not use less than 2 mg/mL of preservatives, and certainly not the amount of “more
`
`than 0 and up to 0.75 mg/mL” claimed. In fact, Petitioner’s only disclosure of a
`
`levocetirizine/cetirizine formulation that discloses ingredient amounts teaches a total
`
`of 3 mg/mL preservatives (far above 0.75 mg/mL) in a 2/1 ratio (not 9/1). This
`
`reference expresses no concern with the preservative amounts or the formulation’s
`
`safety (in fact, Petitioner contends it would be safe). There is no motivation to
`
`modify any formulation (and certainly not to the claimed ratio or amount) as
`
`Petitioner’s suggested reasons rely on misquoting its own prior art (as Petitioner’s
`
`expert admitted at his deposition), directly contradicting itself regarding the
`
`relevance of alleged side effects, and ignoring the consistent teachings of the
`
`remainder of the prior art.
`
`Petitioner has failed to show that the claims are obvious, and its request for
`
`cancellation should be rejected.
`
`II. LEGAL STANDARD
`When alleging obviousness based on a combination of prior art references, it
`
`is Petitioner’s “burden to demonstrate both ‘that a skilled artisan would have been
`
`motivated to combine the teachings of the prior art references to achieve the claimed
`
`invention, and that the skilled artisan would have had a reasonable expectation of
`
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`IPR2019-00400
`Patent 8,633,194
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`success in doing so.’” Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., 821
`
`F.3d 1359, 1367-68 (Fed. Cir. 2016) (quoting Kinetic Concepts, Inc. v. Smith &
`
`Nephew, Inc. 688 F.3d 1342, 1360 (Fed. Cir. 2012)); Procter & Gamble Co. v. Teva
`
`Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009); In re Cyclobenzaprine
`
`Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1068-69
`
`(Fed. Cir. 2012); In re Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir.
`
`2016). This burden remains on Petitioner always, especially “where the only issues
`
`to be considered are what the prior art discloses, whether there would have been a
`
`motivation to combine the prior art, and whether that combination would render the
`
`patented claims obvious.” Magnum Oil Tools, 829 F.3d at 1376.
`
`The trier of fact must avoid “hindsight bias and must be cautious of arguments
`
`reliant upon ex post reasoning.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421
`
`(2007). Invoking “‘common sense’—whether to supply a motivation to combine or
`
`a missing limitation—cannot be used as a wholesale substitute for reasoned analysis
`
`and evidentiary support, especially when dealing with a limitation missing from the
`
`prior art references specified.” Arendi SARL v. Apple Inc., 832 F.3d 1355, 1361-
`
`62 (Fed. Cir. 2016).
`
`When obviousness is alleged by arguing that the claimed invention falls
`
`within a range disclosed across multiple prior art references, the prior art must
`
`“plainly suggest[] that one skilled in the art look to the range appearing in the prior
`
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`IPR2019-00400
`Patent 8,633,194
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`art.” Iron Grip Barbell Co., Inc. v. USA Sports, Inc. 392 F.3d 1317, 1322 (Fed. Cir.
`
`2004). Moreover, “a relevant inquiry is whether there would have been a motivation
`
`to select the claimed composition from the prior art ranges.” Allergan, Inc. v.
`
`Sandoz, Inc., 796 F. 3d 1293, 1304-05 (Fed. Cir. 2015) (citing Galderma Labs., LP
`
`v. Tolmar, Inc., 737 F. 3d 731, 737-38 (Fed. Cir. 2013)). Prima facie obviousness
`
`established based on a prior art disclosure of a range, may be overcome “with
`
`evidence that (1) the prior art taught away from the claimed invention; (2) there were
`
`new and unexpected results relative to the prior art; or (3) there are other pertinent
`
`secondary considerations.” Id.
`
`III. THE ’194 PATENT
`A.
`The ’194 Patent
`The ’194 patent describes how multi-use
`
`liquid formulations are
`
`“continuously exposed to the risk of being contaminated by the microorganisms
`
`existing in the environment or the human body, each time the containers are used
`
`and their covers are opened or closed.” EX1001 at 1:42-50.
`
`The common and accepted solution to address this contamination risk was at
`
`the time of invention, and today, the addition of preservatives. EX2034 ¶ 53.1
`
`1 In support of this Response, Patent Owner submits a declaration from Dr.
`Sarfaraz Niazi. EX2034. Dr. Niazi is a well-qualified and credentialed expert in
`the field of pharmaceutical formulation, including the developer of a number of
`small molecule formulations and author of a number of books in the field of
`pharmaceutical formulation. EXS2034, 2009.
`
`-4-
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`

`IPR2019-00400
`Patent 8,633,194
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`The ’194 patent inventors discovered that the active ingredient levocetirizine
`
`unexpectedly possessed antibacterial properties, a fact they demonstrated through
`
`experimental testing. See, e.g., EX1001 at 1:51-54, Examples 1-4; see also EX1013
`
`at 554-562. Neither Petitioner, nor its expert, disputes that levocetirizine has this
`
`property, nor do they dispute that the property was unexpected. See infra §§ VI.D;
`
`VIII.F.
`
`Based on this unexpected discovery about levocetirizine, the ’194 inventors
`
`were able to develop a liquid pharmaceutical formulation that contains less
`
`preservatives than what was typically necessary but still met the standards for
`
`antimicrobial effectiveness. EX1001 at 1:51-65, 3:13-18, Example 4.
`
`The Challenged Claims
`B.
`The unexpected result of a liquid levocetirizine formulation with a reduced
`
`amount of preservatives is claimed by the challenged claims. For example,
`
`independent claim 1 of the ’194 patent claims:
`
`“A liquid pharmaceutical composition comprising
`levocetirizine or a pharmaceutically acceptable salt of
`(i)
`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,
`
`(ii)
`
`-5-
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`

`IPR2019-00400
`Patent 8,633,194
`
`wherein said composition is substantially free of bacteria.”
`EX1001, Claim 1.
`Dependent claims 2-11 include additional limitations including, for example,
`
`that the composition “is aqueous” (claim 2), “is in the form of oral solutions, nasal
`
`drops, eye drops, or ear drops” (claim 4), or is a specific formulation, such as, “in
`
`the form of an oral solution comprising 0.50 mg/mL levocetirizine dihydrochloride,
`
`0.675 mg/ml methyl p-hydroxybenzoate, and 0.075 mg/ml propyl p-
`
`hydroxybenzoate” (claim 11). EX1001, Claims 2-11.
`
`Prosecution of the ’194 Patent
`C.
`During prosecution, the patent applicants repeatedly emphasized the risk of
`
`bacterial contamination, explaining, for example, how “it is necessary that the liquid
`
`pharmaceutical composition remain free of bacterial contaminants not only up to the
`
`time of initial use, but also after the seal on the packaging is opened” and that “such
`
`an opened package must remain free of bacteria over the useful shelf life of the
`
`product.” EX1013 at 496-97 (September 21, 2010 Amendment and Response). The
`
`importance of controlling bacterial risk was reflected in an amendment requiring the
`
`composition to be “substantially free of bacteria.” EX1013 at 522 (November 29,
`
`2010 Amendment).
`
`Applicants also amended the claims to require reduced amounts of
`
`preservatives, which they supported by reference to the patent itself and an affidavit
`
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`IPR2019-00400
`Patent 8,633,194
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`from an inventor, Domenico Fanara, which showed that formulations with lowered
`
`amounts of preservatives were substantially free of bacteria. EX1013 at 535-62
`
`(November 29, 2010 Fanara Affidavit).
`
`In response to the Fanara Affidavit, the Examiner explained, based on the
`
`combined teachings of EX1014 and EX2005, that “one would expect that MP/PP
`
`[methylparaben/propylparaben] in a dose of about 1 mg/ml and slightly below would
`
`be expected to be antimicrobial in view of the prior art. However, based on the art
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`of record, one of ordinary skill would not expect that amounts of MP/PP much less
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`than 1 mg/ml would be effective.” EX1013 at 571 (2013-09-09 Examiner-Initiated
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`Interview Summary).
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`In response, applicants lowered the claimed total amount of preservatives to
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`“more than 0 and up to 0.75 mg/mL” and the Examiner allowed the claims,
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`explaining that “compositions containing levocetirizine and [methylparaben and
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`propylparaben] with ratio of 9/1 and total concentration of 0.675 mg/ml and 0.375
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`hav[ing] antimicrobial effects” are “deemed to be surprising and unexpected.”
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`EX1013 at 587-88 (Notice of Allowance).2
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`2 Petitioner’s passing references to European Opposition proceedings related to a
`counterpart to the ’194 patent should be ignored. Not only are European Patent
`Office proceedings “of limited relevance” to PTAB proceedings generally (see,
`e.g., Smith & Nephew v. ConvaTec Techs. Inc., IPR2013-00097, Paper 76 at 3
`(P.T.A.B. Feb. 24, 2014)) but there are marked differences in the claims involved
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`IV. CLAIM CONSTRUCTION
`In the Institution Decision, the Board construed the claim term “substantially
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`free of bacteria,” as “a low but clinically acceptable level of bacteria, which would
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`have been its ordinary meaning to the skilled artisan because the claimed
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`composition is a pharmaceutical, but the term ‘substantially’ leaves some flexibility
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`from absolute sterility.” Paper No. 17 at 12. Patent Owner agrees with this
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`construction, and adds that an understanding of whether a particular formulation
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`meets this requirement would be guided by antimicrobial effectiveness testing set
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`forth by the United States and/or European Pharmacopoeia. EX2034 ¶ 27; see also
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`infra § VI.B. Petitioner’s expert, Dr. Laskar, agreed at his deposition. EX2010
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`77:14-78.
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`Patent Owner otherwise maintains that no claim construction is necessary.
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`V.
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`PERSON OF ORDINARY SKILL IN THE ART
`Petitioner has offered that a POSA to which the ’194 patent pertains would
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`here. In particular, the European patent claims allowed parabens in a combined
`amount of up to 1.125 mg/mL, a limit expressly rejected in the U.S. in favor of
`the lower limit, “an amount of more than 0 and up to 0.75 mg/mL,” and none of
`the European claims required that the formulation be “substantially free of
`bacteria.” Further, the ’194 patent applicants submitted documents from the
`European Opposition proceedings during prosecution of the ’194 patent, and the
`Office nevertheless allowed the claims. See EX1013 at 469 (Information
`Disclosure Statement (IDS) Form (SB08), dated September 3, 2010), 495-96
`(Applicant Arguments/Remarks Made in an Amendment, dated September 21,
`2010).
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`have been someone who, “[a]s of the relevant priority date . . . would have had (i) a
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`Pharm. D. or Ph.D. in chemistry, biochemistry, pharmacy, pharmaceutics, or in a
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`related field, and at least two years of relevant experience in developing and
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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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`Paper No. 4 (“Pet.”) at 6.
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`Patent Owner only adds that the qualities of a POSA should focus more on
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`the type of experience that a person would have, as opposed to degrees and years of
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`experience (see EX2034 ¶ 22), but does not object to Petitioner’s proposed
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`definition.
`
`VI. BACKGROUND
`A.
`Principles of Pharmaceutical Formulation
`Pharmaceutical formulation is a complex field where a formulator must
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`account for numerous considerations—many of which are competing—at each step
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`of the process. See, e.g., EX2034 ¶¶ 29-39; EX2010 24:17-26:9, 44:9-46:5, 47:6-
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`19, 59:7-60:10. Although Dr. Laskar hardly discussed principles of pharmaceutical
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`formulation in his declaration, he emphatically agreed with this complexity at his
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`deposition. See, e.g., EX2010 26:10-27:5; 59:7-60:10. As Dr. Laskar described it,
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`pharmaceutical formulation is “not necessarily a linear process.” See EX2010 59:7-
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`60:10; see also EX2034 ¶ 31.
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`When developing a new formulation, some of the first things a POSA must
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`consider are the properties of the active pharmaceutical ingredient (“API”) itself,
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`including chemical stability, solubility, chirality, excipient compatibility, and
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`physical properties. See EX2034 ¶ 33. Each property must be considered as a POSA
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`begins to consider the parameters of a new formulation. See id.
`
`A POSA considers the route of administration as different routes have unique
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`considerations. See EX2034 ¶¶ 38-39; EX2010 25:15-17. For example, oral
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`solutions, which are typically multiuse, need to account for repeated bacterial
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`exposure that occur during use. See EX2034 ¶ 39. In contrast, a single-use
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`intravenous injection needs to be completely sterile since the formulation will by-
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`pass the body’s natural defense barriers. See id. at ¶ 38; EX2010 38:17-39:4.
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`The type of preparation must be considered, as different types—such as solids,
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`liquids, gels, creams, and emulsions—may contain different chemicals that will
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`interact with the API and other inactive ingredients in different ways. EX2034 ¶ 34.
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`For liquid formulations—such as those claimed by the ’194 patent—a POSA
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`must specifically consider solubility, viscosity, taste, microbial growth, appearance,
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`chemical stability, physical stability, packaging, and manufacturability. EX2034 ¶¶
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`35-36; EX2010 25:20-26:4.
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`Antimicrobial Effectiveness Testing
`B.
`Dr. Niazi has explained how a POSA would understand that the risk of
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`bacterial or microbial contamination would be substantial, as contamination could
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`endanger patient health or lives. EX2034 ¶¶ 50-51. Such concerns are particularly
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`important when, as with the ’194 patent, the formulation could be administered to
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`at-risk populations such as young children. See EX2034 ¶ 50; EX1001 at 4:25-27.
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`In the U.S. and Europe, regulators test for microbial risk using antimicrobial
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`effectiveness tests described in the United States and European Pharmacopoeias.
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`See EX2034 ¶¶ 41-42; EX2010 28:22-30:6. These tests involve subjecting a
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`formulation to different types of microorganisms, including those described in the
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`’194 patent. See EX1001 at Examples 1-4 (describing testing against Aspergillus
`
`niger, Candida albicans, Escheria coli, Pseudomonas aeruginosa, and
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`Staphylococcus aureus). The latter three of these are types of bacteria while A. niger
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`and C. albicans are fungi. If the microbes demonstrate growth above the acceptance
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`criteria, the formulation has not established microbial stability. See EX2034