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 PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`IPR2019-00400
`Patent 8,633,194
`
`C.
`
`D.
`
`E.
`
`INTRODUCTION ......................................................................................... 1
`I.
`II. THE ’194 PATENT AND ITS PROSECUTION ........................................ 2
`III. PETITIONER’S OBVIOUSNESS GROUNDS .......................................... 4
`IV.
`INSTITUTION SHOULD BE DENIED PURSUANT TO THE
`BOARD’S DISCRETION UNDER 35 U.S.C. § 325(d). ............................ 7
`A.
`The Legal Standard for 35 U.S.C. § 325(d) .......................................... 7
`B.
`Factor 1: The Similarities and Material Differences Between the
`Asserted Art and Prior Art Involved During Examination. .................. 8
`Factor 2: The Cumulative Nature of the Asserted Art and the Prior Art
`Evaluated During Examination. .......................................................... 12
`Factor 3: The Extent to Which the Asserted Art Was Evaluated
`During Examination, Including Whether the Prior Art Was the Basis
`for Rejection. ....................................................................................... 13
`Factor 4: The Extent of the Overlap Between the Arguments Made
`During Examination and the Manner in Which Petitioner Relies on the
`Prior Art or Patent Owner Distinguishes the Prior Art. ...................... 17
`Factor 5: Whether Petitioner Has Pointed Out Sufficiently How the
`Examiner Erred in Its Evaluation of the Asserted Prior Art. .............. 22
`Factor 6: The Extent to Which Additional Evidence and Facts
`Presented in the Petition Warrant Reconsideration of the Prior Art. .. 25
`INSTITUTION SHOULD BE DENIED PURSUANT TO THE
`BOARD’S DISCRETION UNDER 35 U.S.C. § 314(a). ........................... 27
`A.
`The Legal Standard for 35 U.S.C. § 314(a)......................................... 27
`B.
`The Co-Pending District Court Litigation ........................................... 28
`C.
`Petitioner’s Petition Creates Judicial Inefficiency By Asking the
`Board to Consider Arguments that the Office Already Considered
`
`F.
`
`G.
`
`V.
`
`-i-
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`

`

`D.
`
`IPR2019-00400
`Patent 8,633,194
`During Prosecution and the District Court Will Consider (General
`Plastic Factors 1, 6, and 7). ................................................................. 29
`Petitioner’s Petition Results in Prejudice Against UCB (General
`Plastic Factors 2 and 3). ...................................................................... 31
`Petitioner Has No Reasonable Excuse to Explain Its Delay (General
`Plastic Factors 4 and 5). ...................................................................... 33
`VI. CONCLUSION ............................................................................................ 33
`
`
`E.
`
`-ii-
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`

`

`IPR2019-00400
`Patent 8,633,194
`
`TABLE OF AUTHORITIES
`
`CASES
`Apotex Inc. v. Celgene Corp.,
`No. IPR2018-00685, Paper No. 8 (P.T.A.B. Sept. 27, 2018) ................. 12, 17, 24
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`No. IPR2017-01586, Paper No. 8 (P.T.A.B. Dec. 15, 2017) ......................passim
`Ben Venue Labs., Inc. v. Novartis Pharm. Corp.,
`146 F. Supp. 2d 572 (D.N.J. 2001) ..................................................................... 32
`General Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`No. IPR2016-01357, Paper No. 19 (P.T.A.B. Sept. 6, 2017) ......................passim
`Genetics Institute, LLC v. Novartis Vaccines and Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .......................................................................... 21
`Hologic, Inc. v. Biomérieux, Inc.,
`No. IPR2018-00567, Paper No. 9 (P.T.A.B. Aug. 4, 2018) ............................... 25
`Intel Corp. v. Godo Kaisha IP Bridge 1,
`No. IPR2018-00753, Paper No. 11 (P.T.A.B. Oct. 9, 2018) .......................passim
`Mylan Pharms, Inc. v. Bayer Intellectual Property Gmbh,
`No IPR2018-01143, Paper No. 13 (P.T.A.B. Dec. 3, 2018) .............................. 28
`Neil Ziegmann, N.P.Z., Inc. v. Stephens,
`No. IPR2015-01860, Paper No. 11 (P.T.A.B. Feb. 24, 2016) .............. 8, 9, 13, 17
`NHK Spring Co. v. Intri-PlexTechs., Inc.,
`No. IPR2018-00752, Paper No. 8 (P.T.A.B. Sept. 12, 2018) ............................. 28
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 21
`Smith & Nephew v. ConvaTec Techs. Inc.,
`No. IPR2013-00097, Paper No. 76 (P.T.A.B. Feb. 24, 2014) ............................ 26
`Unified Patents Inc. v. Berman,
`No. IPR2016-01571, Paper No. 10 (P.T.A.B. Dec. 14, 2016) ........................... 24
`
`-i-
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`

`

`IPR2019-00400
`Patent 8,633,194
`
`Winter v. Nat. Res. Def. Council, Inc.,
`555 U.S. 7 (2008) ................................................................................................ 30
`Statutes
`21 U.S.C. § 355(j) .................................................................................................... 28
`35 U.S.C. § 271(e)(2)(A) ......................................................................................... 28
`35 U.S.C. § 313 .......................................................................................................... 1
`35 U.S.C. § 314(a) ......................................................................................... 2, 27, 28
`35 U.S.C. § 316(a)(11) ............................................................................................. 29
`35 U.S.C. § 325(d) ............................................................................................passim
`
`
`-ii-
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`

`

`TABLE OF EXHIBITS
`
`Exhibit No.
`
`Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`IPR2019-00400
`Patent 8,633,194
`
`Abbreviation
`
`Dietrich
`
`DeLongueville
`
`Doron
`
`Gilliland I
`
`Gilliland II
`
`Routledge
`
`Dietrich et al., U.S. Patent Application
`2004/0058896 A1, Pharmaceutical
`Preparation Comprising An Active
`Dispersed On A Matrix
`
`DeLongueville et al., WIPO Publication
`Number WO 02/47689 A2, A Method for
`Preventing Urticaria
`
`Doron et al., Antibacterial effect of
`parabens against planktonic and biofilm
`Streptococcus sobrinus, 18 Int. J. of
`Antimicrobial Agents 575-78 (2001)
`
`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 et al., Kinetic evaluation of
`claimed synergistic paraben
`combinations using a factorial design, 72
`J. Applied Bacteriology (1992)
`
`Routledge et al., Some Alkyl Hydroxy
`Benzoate Preservatives (Parabens) Are
`Estrogenic, 153 Toxicology and Applied
`Pharmacology 12-19 (1998)
`
`FDA ANDA 211528 Tentative Approval
`
`
`
`
`-i-
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`

`

`IPR2019-00400
`Patent 8,633,194
`Pursuant to 35 U.S.C. § 313, Patent Owner UCB Biopharma Sprl (“UCB”),
`
`submits this Preliminary Response to Apotex Inc.’s (“Apotex”) Petition for Inter
`
`Partes Review (the “Petition” or “Pet.”) of U.S. Patent No. 8,633,194 (the “’194
`
`patent”).
`
`I.
`
`INTRODUCTION
`The ’194 patent claims liquid formulations of levocetirizine that are
`
`substantially free of bacteria despite extremely low amounts of preservatives. This
`
`invention was made possible only through the inventors’ finding that levocetirizine,
`
`an antihistamine, also surprisingly possesses antimicrobial properties. After seven
`
`years of prosecution, the Office ultimately allowed the claims when an inventor
`
`declaration explained how this surprising finding enabled the inventors to use
`
`drastically lower amounts of preservatives compared to typical liquid formulations.
`
`Petitioner now seeks to revisit the prosecution, by reiterating the Office’s
`
`prosecution rejections through two obviousness grounds (which themselves are
`
`nearly identical to each other): the combination of a prior art reference teaching
`
`either a levocetirizine formulation, or a formulation with the racemate cetirizine,
`
`with a second prior art reference that teaches the use of preservatives. These grounds
`
`bear no material difference from the Office’s prosecution rejections, and Petitioner
`
`makes no attempt to distinguish them.
`
`Not only are the arguments the same, but Petitioner also relies upon prior art
`
`-1-
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`

`

`IPR2019-00400
`Patent 8,633,194
`already submitted to—and considered—by the Office during prosecution. While
`
`Petitioner’s art was not expressly cited in a prosecution rejection, the art presents
`
`nothing new and is simply cumulative to what the Office had already cited in
`
`multiple prosecution rejections.
`
`Moreover, Petitioner conspicuously ignores the very reason why the claims
`
`were ultimately allowed—evidence demonstrating the surprising antimicrobial
`
`activity of the antihistaminic levocetirizine and the Examiner’s claim requirement
`
`of a lowered maximum amount of total preservatives. In fact, in the entirety of the
`
`petition, Petitioner nowhere mentions the inventor declaration that provided this
`
`evidence and that the Office found persuasive in allowing the claims.
`
`In light of the considerations of 35 U.S.C. § 314(a) and 35 U.S.C. § 325(d),
`
`the Board should exercise its discretion to decline to institute the petition.
`
`II. THE ’194 PATENT AND ITS PROSECUTION1
`Prosecution of the ’194 patent began in September 2006 and ended seven
`
`years later in December 2013 with issuance of the ’194 patent. Throughout that
`
`period, the Examiner considered, and twice rejected, the then-pending claims over
`
`
`1 For purposes of this Preliminary Response only, UCB does not dispute Apotex’s
`
`proposed person of ordinary skill in the art nor Apotex’s position that no claim
`
`construction is necessary for the purposes of this IPR.
`
`-2-
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`

`

`IPR2019-00400
`Patent 8,633,194
`prior art references that described formulations of levocetirizine that contained a
`
`combination of the parabens methyl- and propylparaben, including Dietrich et al.
`
`(US 2004/0058896 A1) (“Dietrich”) and DeLongueville et al., (WO 02/47689 A2)
`
`(“DeLongueville”), described in more detail below at § IV.B.
`
`In allowing the claims of the ’194 patent, the Examiner considered—and
`
`agreed—that the low amounts of preservatives used in the claimed formulations
`
`were neither the result of “routine optimization” (see Ex. 1013 at pp. 210-216 (2008-
`
`09-25 Non-Final Rejection); see Ex. 1013 at pp. 319-326 (2009-02-25 Final
`
`Rejection)) nor obvious in view of prior art references, described in more detail
`
`below at Section IV, that suggested the use of the two parabens in the claimed 9:1
`
`ratio. See Ex. 1013 at pp. 363-373 (2009-07-30 Non-Final Rejection).
`
`The Examiner’s ultimate conclusion of patentability came after one inventor
`
`submitted a declaration—described in more detail below at § IV.F—detailing the
`
`unexpected finding that the active ingredient, levocetirizine, itself possessed
`
`preservative effects. As the inventor explained, this discovery allowed the inventors
`
`to use substantially reduced amounts of parabens in the claimed invention. The
`
`Examiner explained: “A review of the data provided in the Declaration demonstrate
`
`that compositions containing levocetirizine and [methylparaben/propylparaben]
`
`with a ratio of 9/1 and total concentration of 0.675 mg/ml and 0.375 have
`
`antimicrobial effects. This is deemed surprising and unexpected.” See Ex. 1013 at
`
`-3-
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`

`

`IPR2019-00400
`Patent 8,633,194
`pp. 569-571 (2013-09-09 Examiner initiated interview summary) (emphasis added).
`
`After the Examiner required that the total amount of preservatives in the claimed
`
`formulations be limited to 0.75 mg/ml, the claims were allowed. See Ex. 1013 at p.
`
`590 (2013-09-27 Examiner initiated interview summary); see also id. at p. 612
`
`(2013-12-31 Issue Notification).
`
`As the ’194 patent explains, the self-preservative effect of levocetirizine, and
`
`the consequent ability to use lower amounts of preservatives in the formulation, goes
`
`to the heart of the invention:
`
`It has now surprisingly been found that the active substances belonging
`to
`the family of substituted benzhydryl piperazines [such as
`levocetirizine] possess a preservative effect in aqueous solutions.
`
`The purpose of the invention concerns a liquid pharmaceutical
`composition containing an active substance belonging to the family of
`substituted benzhydryl piperazines chosen among cetirizine,
`levocetirizine and efletirizine, and a reduced amount of preservatives.
`
`The present invention is based on the unexpected recognition that a
`pharmaceutical composition comprising an active substance belonging
`to the family of substituted benzhydryl piperazines and a reduced
`amount of preservatives is stable during a long period of time.
`Stability means
`the capacity
`to resists
`to
`[sic] microbial
`contamination.
`
`’194 Patent, Col. 1, ll. 51-65 (emphasis added).
`III. PETITIONER’S OBVIOUSNESS GROUNDS
`Petitioner presents two grounds in support of its Petition:
`
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`

`IPR2019-00400
`Patent 8,633,194
`Ground 1: Obviousness in view of WO ’094 in combination with
`the Handbook
`Ground 2: Obviousness in view of EP ’203 in combination with US
`’558 and the Handbook
`
`In Ground 1, Petitioner combines WO ’094 with excerpts from the Handbook.
`
`WO ’094 is an International Patent Application titled “Use of Levocetirizine for the
`
`Treatment of Persistent Allergic Rhinitis.” During prosecution, WO ’094 was
`
`submitted to the Office, and was considered by the Examiner. See Ex. 1013 at 242
`
`(disclosure of WO ’094) and 330 (showing that the Examiner marked WO ’094 as
`
`considered). Petitioner relies on WO ’094 for its teaching of a levocetirizine syrup
`
`with unspecified amounts of the preservatives, methylparaben, and propylparaben.
`
`See Petition at § X.C (citing WO ’094 at p. 4, ll. 33-35).
`
`The Handbook, meanwhile, is a reference book that describes over two-
`
`hundred excipients frequently used in pharmaceutical formulations. The Handbook
`
`too was submitted during prosecution and considered by the Examiner. See Ex. 1013
`
`at p. 469 (disclosure of Handbook), p. 514 (showing that the Examiner marked the
`
`Handbook as considered), p. 531 (2010-11-29 Information Disclosure Statement),
`
`p. 598 (showing that the Examiner marked the Handbook as considered). Petitioner
`
`relies on the Handbook to argue that: (1) methylparaben and propylparaben may be
`
`used in combination in pharmaceutical formulations in a 9:1 ratio, and (2) the
`
`Handbook’s reference to the “irritant potential of the parabens” would motivate a
`
`-5-
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`IPR2019-00400
`Patent 8,633,194
`person of ordinary skill to reduce the amounts of parabens present thus achieving
`
`the claimed invention. See Pet. at § X.C.
`
`In Ground 2, Petitioner reworks the same basic argument of Ground 1, except
`
`using EP ’203 and US ’558 in place of WO ’094, but still combining those references
`
`with the Handbook. EP ’203 is a European Patent Application Publication titled
`
`“Antiallergic Composition for Ophthalmic or Nasal Use.” As with WO ’094 and the
`
`Handbook, EP ’203 was submitted during prosecution and considered by the
`
`Examiner. See Ex. 1013 at p. 468 (disclosure of EP ’203), p. 513 (showing that the
`
`Examiner marked EP ’203 as considered). EP ’203 differs from WO ’094 in that it
`
`teaches a formulation using cetirizine, which is a racemic mixture of levocetirizine
`
`and a second enantiomer. Petitioner principally relies on EP ’203 for its Example 5,
`
`a
`
`formulation containing—among other
`
`things—cetirizine hydrochloride,
`
`methylparaben, and propylparaben. See Pet. at § X.C.
`
`US ’558 is a United States patent titled “Methods for treating allergic
`
`disorders using optically pure (-) cetirizine.” Petitioner relies on US ’558 for the
`
`proposition that a person of ordinary skill in the art would choose to substitute
`
`levocetirizine in place of formulations containing cetirizine. See id.
`
`Petitioner then combines EP ’203 and US ’558 with the Handbook citing the
`
`Handbook for the same reasons as in Ground 1. See id.
`
`Woven throughout its two obviousness grounds, Petitioner references
`
`-6-
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`

`

`IPR2019-00400
`Patent 8,633,194
`European opposition proceedings of the European counterpart patent, the inherent
`
`properties of levocetirizine, and a theory of obviousness based on overlapping
`
`ranges. See Pet. at § X.C. Petitioner raises none of these arguments as standalone
`
`obviousness arguments and, as demonstrated in more detail below, each is simply a
`
`repetition of the same underlying obviousness grounds considered by the Office
`
`during prosecution.
`
`IV.
`
`INSTITUTION SHOULD BE DENIED PURSUANT TO THE
`BOARD’S DISCRETION UNDER 35 U.S.C. § 325(d).
`Over the course of seven years, the Office thoroughly vetted the claims
`
`through multiple rejections bearing no material difference with the arguments
`
`Petitioner now presents. Petitioner relies on prior art considered by the Office,
`
`identifies no new arguments beyond what the Office considered, and does not
`
`identify any fault in the Office’s decisions. Petitioner’s petition should be denied
`
`under § 325(d).
`
`A. The Legal Standard for 35 U.S.C. § 325(d)
`35 U.S.C. § 325(d) permits the Board to exercise its discretion and deny
`
`institution when a petitioner raises arguments that were already made by the
`
`Examiner during prosecution of the challenged patent. See 35 U.S.C. § 325(d);
`
`Patent Trial and Appeal Board, Trial Practice Guide Update (August 2018) at 11
`
`(“Thus, in exercising its discretion whether to institute trial, the Board considers
`
`whether the same or substantially the same prior art or arguments were presented
`
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`IPR2019-00400
`Patent 8,633,194
`previously.”) (emphasis added); Becton, Dickinson & Co. v. B. Braun Melsungen
`
`AG, No. IPR2017-01586, Paper No. 8 at pp. 17-18 (P.T.A.B. Dec. 15, 2017)
`
`(informative); Neil Ziegmann, N.P.Z., Inc. v. Stephens, No. IPR2015-01860, Paper
`
`No. 11 at p. 2 (P.T.A.B. Feb. 24, 2016).
`
`In Becton Dickinson, the Board laid out six factors for the Board to consider
`
`in exercising its discretion under § 325(d):
`
`a) “the similarities and material differences between the asserted art and
`prior art involved during examination;
`b) the cumulative nature of the asserted art and the prior art evaluated
`during examination;
`c) the extent to which the asserted art was evaluated during examination,
`including whether the prior art was the basis for rejection;
`d) the extent of the overlap between the arguments made during
`examination and the manner in which Petitioner relies on the prior art
`or Patent Owner distinguishes the prior art;
`e) whether Petitioner has pointed out sufficiently how the Examiner erred
`in its evaluation of the asserted prior art; and
`f) the extent to which additional evidence and facts presented in the
`Petition warrant reconsideration of the prior art . . . .”
`Becton Dickinson, No. IPR2017-01586, Paper No. 8 at pp. 17-18.
`
`As shown below, each factor weighs heavily in favor of denying institution.
`
`B.
`
`Factor 1: The Similarities and Material Differences Between the
`Asserted Art and Prior Art Involved During Examination.
`There are no material differences between Petitioner’s four prior art
`
`references and the art involved during examination.
`
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`IPR2019-00400
`Patent 8,633,194
`In fact, three of the four references that comprise Petitioner’s obviousness
`
`grounds were submitted during prosecution and considered by the Examiner. See
`
`supra § III. And the fourth, US ’558, is cited only for the proposition that a person
`
`of ordinary skill would focus on the levocetirizine enantiomer of the racemic mixture
`
`formulation cited in EP ’203 (see Pet. at 46-47); a step unnecessary for the Examiner
`
`to consider during prosecution because the Examiner relied on closer references that
`
`actually taught levocetirizine formulations.
`
`Therefore, even though Petitioner’s prior art references may not have
`
`expressly been the subject of an office action, the prosecution record demonstrates
`
`that they were considered by the Examiner. This consideration alone has been found
`
`sufficient to deny institution. See Neil Ziegmann, No. IPR2015-01860, Paper No.
`
`11 at pp. 9-10.
`
`In situations unlike here where Petitioner’s references were not evaluated
`
`during prosecution, this factor can also consider whether the teachings of
`
`Petitioner’s references were evaluated. See Intel Corp. v. Godo Kaisha IP Bridge 1,
`
`No. IPR2018-00753, Paper No. 11 at pp. 14-15 (P.T.A.B. Oct. 9, 2018). Even this
`
`consideration weighs heavily in favor of denying institution because the Office twice
`
`rejected the then-pending claims based on combinations of prior art references that
`
`provide the exact same teachings as Petitioner’s prior art.
`
`First, the Examiner rejected the claims over prior art teaching levocetirizine
`
`-9-
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`IPR2019-00400
`Patent 8,633,194
`formulations with methyl- and propylparaben, the reason why Petitioner relies upon
`
`WO ’094 and EP ’230 in combination with US ’558:
`
` Dietrich is a United States patent application titled “Pharmaceutical
`Preparation Comprising an Active Dispersed on a Matrix.” See Ex.
`2001 at ¶¶ 438-39. Among the active ingredients listed in the abstract
`is levocetirizine. See id. at ¶ 62. Dietrich teaches that solutions or
`suspensions with active ingredients like levocetirizine can be used with
`“excipients which are normally used to produce solutions or
`suspensions.” See id. at ¶¶ 438-39. This teaching is why Dietrich was
`cited by the Examiner. See Ex. 1013 at pp. 214-215.
`
` DeLongueville is a PCT publication titled “A Method for Preventing
`Urticaria.” DeLongueville teaches that levocetirizine and other
`piperazines can be used to treat urticaria. See Ex. 2002. It also teaches
`levocetirizine
`oral
`solutions
`containing
`the
`preservatives
`methylparaben and propylparaben. See id. at p. 7. This teaching is why
`DeLongueville was cited by the Examiner. See Ex. 1013 at pp. 322-23,
`366-70, 403, 409-416, 511.
`Next, identical to Petitioner’s combination of these references with the
`
`Handbook and its teachings regarding methyl- and propylparaben, the Examiner
`
`combined Dietrich and DeLongueville with the below art that purportedly taught (a)
`
`combining methyl- and propylparabens in specific ratios and (b) a motivation to
`
`reduce the amount of parabens.
`
` Doron is an article titled “Antibacterial effect of parabens against
`planktonic and biofilm Sreptococcus sobrinus.” Doron et al.,
`Antibacterial effect of parabens against planktonic and biofilm
`Streptococcus sobrinus, 18 Int. J. of Antimicrobial Agents 575-78
`(2001) (“Doron”). Doron provides data demonstrating the antibacterial
`effect of methylparaben and propylparaben. See Ex. 2003 at p. 576-77,
`Figs. 1-2. It also demonstrates a synergistic effect when methylparaben
`and propylparaben are combined with each other, which were tested in
`amounts starting at 0.3 mg/ml of methylparaben, increasing amounts of
`
`-10-
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`

`IPR2019-00400
`Patent 8,633,194
`propylparaben, and ratios between 1:2 and 8.33:1. See id. These are
`the reasons why Doron was cited by the Examiner. See Ex. 1013 at pp.
`322-23, 348, 366, 409-17, 455-62, 511.
`
` Gilliland 1 is an article titled “The bacteridical activity of a methyl and
`propylparabens combination: isothermal and non-isothermal studies.”
`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 1”). Gilliland 1
`includes data showing the effect of methylparaben and propylparaben
`on the bacteria e. coli when used in amounts that have a 10:1 ratio and
`0.132 mg/ml combined total amount of parabens. See Ex. 2004 at pp.
`252-56. These are the reasons why Gilliland 1 was cited by the
`Examiner. See Ex. 1013 at pp. 367-71, 403, 409-17, 511.
`
` Gilliland 2 is an article titled “Kinetic evaluation of claimed synergistic
`paraben combinations using a factorial design.” Gilliland et al., Kinetic
`evaluation of claimed synergistic paraben combinations using a
`factorial design, 72 J. Applied Bacteriology (1992) (“Gilliland 2”). It
`too teaches that methylparaben and propylparaben have synergistic
`effects and provides data on their effect on e. coli. See Ex. 2005 at pp.
`258-61. Additionally, the various amounts of methylparaben and
`propylparaben tested include total amounts of parabens within the
`range of more than 0 and up to 1.125 mg/ml and ratios close to 9:1. See
`id. These are the reasons why Gilliland 2 was cited by the Examiner.
`See Ex. 1013 at pp. 367-70, 403, 409-416, 454, 511.
`
` Routledge is an article titled “Some Alkyl Hydroxy Benzoate
`Preservatives (Parabens) are Estrogenic.” Routledge et al., Some Alkyl
`Hydroxy Benzoate Preservatives (Parabens) Are Estrogenic, 153
`Toxicology and Applied Pharmacology 12-19 (1998) (“Routledge”).
`Routledge is a study finding that preservatives such as methylparaben
`and propylparaben may have an estrogenic effect and questions the
`safety of using these parabens in human products. See Ex. 2006. These
`are the reasons why Routledge was cited by the Examiner. See Ex.
`1013 at pp. 369-71, 403, 409-17, 455-62, 511.
`Thus, although the specific prior art references may differ between the
`
`Examiner’s rejections and Petitioner’s Grounds, there are no material differences
`
`-11-
`
`

`

`IPR2019-00400
`Patent 8,633,194
`between what those references teach. Accordingly, Factor 1 weighs in favor of
`
`denying institution of Petitioner’s petition. See Intel Corp., No. IPR2018-00753,
`
`Paper No. 11 at pp. 18-19 (considering structurally similar references as weighing
`
`in favor of denying institution); see also Apotex Inc. v. Celgene Corp., No. IPR2018-
`
`00685, Paper No. 8 at pp. 22-24 (P.T.A.B. Sept. 27, 2018).
`
`C.
`
`Factor 2: The Cumulative Nature of the Asserted Art and the
`Prior Art Evaluated During Examination.
`Of Petitioner’s four primary references, three were presented to, and
`
`considered by, the Examiner and therefore these references are clearly cumulative
`
`to what was considered during prosecution. See supra § III.
`
`Petitioner’s only primary reference that was not considered by the Examiner
`
`is US ’558. Petitioner relies on US ’558 patent to explain why a person of ordinary
`
`skill in the art would use levocetirizine in place of cetirizine in Example 5 of EP
`
`’203. See Pet. at 46-47. The combination of US ’558 and Example 5 of EP ’203
`
`therefore functions in the exact same way as Petitioner’s cited teaching in WO ’094
`
`and
`
`the Examiner’s cited
`
`teaching
`
`in Dietrich and DeLongueville—that
`
`formulations containing levocetirizine, methylparaben, and propylparaben were
`
`known in the art.
`
`Consequentially, the only primary reference not expressly considered by the
`
`Office during prosecution brings nothing new, and is in fact cumulative to the art
`
`considered during prosecution. See Becton Dickinson, No. IPR2017-01586, Paper
`
`-12-
`
`

`

`IPR2019-00400
`Patent 8,633,194
`No. 8 at pp. 21-22. This factor too weighs in favor of denying institution. See id.
`
`D.
`
`Factor 3: The Extent to Which the Asserted Art Was Evaluated
`During Examination, Including Whether the Prior Art Was the
`Basis for Rejection.
`As discussed above, multiple references in Petitioner’s petition—including
`
`the vast majority of its primary references—were already expressly considered by
`
`the Examiner during the ’194 patent prosecution. See supra §§ III, IV.B. That these
`
`references were considered by the Examiner is itself sufficient to show that the
`
`Examiner already evaluated the art, demonstrating that this factor weighs in favor of
`
`denying institution. Neil Ziegmann, No. IPR2015-01860, Paper No. 11 at pp. 9-10.
`
`But, as shown below, Petitioner’s references have also already been evaluated
`
`by the Examiner for the purposes of its arguments here. See Intel Corp., No.
`
`IPR2018-00753, Paper No. 11 at pp. 18-19 (considering use of references that were
`
`structurally similar to ones which serves as the basis for the Examiner’s rejections
`
`as weighing in favor of denying institution); Neil Ziegmann, No. IPR2015-01860,
`
`Paper No. 11 at p. 10 (“While the Office cited [one reference] and Petitioner cites
`
`other references . . .we are persuaded that prior art and arguments substantially
`
`similar to those set forth by Petitioner were previously presented to and considered
`
`by the Office.”).
`
`Argument
`Pharmaceutical
`compositions—
`
`Examiner’s
`Rejections
`Dietrich (Dietrich
`teaches
`
`Petitioner’s
`Ground 1
`WO ’094 (“WO
`’094 teaches liquid
`
`Petitioner’s
`Ground 2
`EP ’203 (“A
`POSA would have
`
`-13-
`
`

`

`including liquid
`formulations—
`containing
`levocetirizine
`were known in
`the art.
`
`Methylparaben
`and
`propylparaben
`were known
`preservatives in
`levocetirizine
`formulations.
`
`preparations for an
`active ingredient
`including
`levocetirizine and
`that solution and
`suspensions with
`such active may
`also include
`preservatives such
`as methylparaben
`and
`propylparaben.
`See Ex. 1013 at
`pp. 210-216
`(2008-09-25 Non-
`final rejection)).
`
`DeLongueville
`(DeLongueville
`teaches the use of
`levocetirizine
`liquid
`formulations. See
`Ex. 1013 at pp.
`407-419 (2010-01-
`15 Non-Final
`Rejection)).
`
`Dietrich (Dietrich
`teaches
`preparations for an
`active ingredient
`including
`levocetirizine and
`that solution and
`suspensions with
`such active may
`also include
`preservatives such
`as methylparaben
`
`compositions that
`comprise
`levocetirizine or a
`pharmaceutically
`acceptable salt
`thereof.” Pet. at
`21.)
`
`IPR2019-00400
`Patent 8,633,194
`focused on
`Example 5 of EP
`’203. . . which
`discloses a liquid
`(ophthalmic)
`pharmaceutical
`composition
`comprising
`racemic cetirizine
`and methylparaben
`and propylparaben
`as preservatives.”
`Pet. at 43-44)
`
`US ’558
`(“However, at the
`time of the priority
`date of the ’194
`patent, a POSA
`would have known
`that levocetirizine
`was the active
`enantiomer of
`racemic cetirizine.”
`Pet. at 47.)
`
`WO ’094 (“WO
`’094 teaches
`further that
`conventional
`preservatives (such
`as methylparaben
`and propylparaben)
`may be included in
`the disclosed
`levocetirizine
`formulations.” Pet.
`at 15.)
`
`EP ’203 (“A
`POSA would have
`focused on
`Example 5 of EP
`’203 . . .which
`discloses a liquid
`(ophthalmic)
`pharmaceutical
`composition
`comprising
`racemic cetirizine
`and methylparaben
`
`-14-
`
`

`

`and
`propylparaben.
`See Ex. 1013 at
`pp. 210-216
`(2008-09-25 Non-
`final rejection)).
`
`DeLongueville
`(DeLongueville
`teaches the use of
`levocetirizine in
`formulations such
`as liquid
`compositions
`containing
`methylparaben
`and
`propylparaben.
`See Ex. 1013 at
`pp. 407-419
`(2010-01-15 Non-
`Final Rejection)).
`
`Doron (Doron
`teaches
`combinations of
`parabens ranging
`from ratios of
`0.015:0.03 (1:2) to
`0.25:0.3 (8.33:1).
`See Ex. 1013 at
`pp. 407-419
`(2010-01-15 Non-
`Final Rejection)).
`
`Gilliland 2
`(Gilliland 2 notes
`four combinations
`of methylparaben
`and propylparaben
`
`9:1 or similar
`ratios of
`methylparaben
`and
`propylparaben
`were known in
`the art.
`
`IPR2019-00400
`Patent 8,633,194
`and propylparaben
`as preservatives.”
`Pet. at 47.)
`
`Handbook (“For
`example, the
`Handbook teaches
`‘[m]ethylparaben
`(0.18%) together
`with propylparaben
`(0.02%) has been
`used for the
`preservation of
`various parenteral
`pharmaceutical
`formulations.’”
`Pet. at 48)
`
`Handbook
`(“Handbook
`teaches that
`‘[m]ethylparaben
`(0.18%) together
`with propylparaben
`(0.02%) has been
`used for the
`preservation of
`various parenteral
`pharmaceutical
`formulations,’ i.e.,
`a ratio of 9/1
`methylparaben to
`propylparaben.”
`Pet. at 17.)
`
`-15-
`
`

`

`A formulation
`scientist would
`know to
`minimize the
`number of
`parabens
`present in the
`formulation.
`
`IPR2019-00400
`Patent 8,633,194
`
`Handbook (“As
`Dr. Laskar
`explains, despite
`the fact that
`parabens are
`‘widely used’ and
`combining
`methylparaben
`with other parabens
`results in
`synergistic effects,
`the Handbook
`reports ‘irritant
`potential of the
`parabens.’” Pet. at
`51.)
`
`with ratios of
`8.6/1, 10/1, and
`11.7/1. See Ex.
`1013 at pp. 407-
`419 (2010-01-15
`Non-Final
`Rejection)).
`
`Doron (“Doron
`indicates that
`reduced