Trials@uspto.gov
`571-272-7822
`
` Paper No. 57
`
`Date: June 9, 2020
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`APOTEX INC.,
`Petitioner,
`
`v.
`
`UCB BIOPHARMA SPRL,
`Patent Owner.
`____________
`
`IPR2019-00400
`Patent 8,633,194 B2
`____________
`
`
`
`Before ROBERT A. POLLOCK, RYAN H. FLAX, and
`KRISTI L. R. SAWERT Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`Denying Patent Owner’s Motion to Exclude Evidence
`37 C.F.R. § 42.64
`Denying Petitioner’s Corrected Motion to Exclude Evidence
`37 C.F.R. § 42.64
`Decisions on Motions to Seal
`37 C.F.R. §§ 42.1 and 42.54
`
`
`
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
`INTRODUCTION
`I.
`This is a Final Written Decision in an inter partes review challenging
`the patentability of claims 1–11 of U.S. Patent No. 8,633,194 B2 (“the ’194
`patent,” Ex. 1001). We have jurisdiction under 35 U.S.C. § 6.
`Petitioner has the burden of proving unpatentability of a claim by a
`preponderance of the evidence. 35 U.S.C. § 316(e) (2018). Having reviewed
`the arguments of the parties and the supporting evidence, we find that
`Petitioner has not demonstrated by a preponderance of the evidence that
`claims 1–11 are unpatentable. For the reasons set forth below, we also deny
`the parties’ motions to exclude evidence and grant, in-part, the proffered
`motions to seal.
`
` Procedural History
`Apotex Inc. (“Petitioner”) filed a corrected Petition for an inter partes
`review of claims 1–11 of the ’194 patent. Paper 4 (“Pet.”). UCB Biopharma
`Sprl (“Patent Owner” or “UCB”) timely filed a Preliminary Response. Paper
`11 (“Prelim. Resp.”). The parties further submitted an authorized Reply and
`Sur-Reply to the Preliminary Response. Paper 13; Paper 16. In view of the
`then-available, preliminary record, we concluded that Petitioner satisfied the
`burden, under 35 U.S.C. § 314(a), to show that there was a reasonable
`likelihood that Petitioner would prevail with respect to at least one of the
`challenged claims. Accordingly, on behalf of the Director (37 C.F.R.
`§ 42.4(a) (2018)), and in accordance with SAS Inst. Inc. v. Iancu, 138 S. Ct.
`1348, 1353 (2018) and the Office’s Guidance on the Impact of SAS on AIA
`
`2
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`Trial Proceedings (Apr. 26, 2018),1 we instituted an inter partes review of
`all the challenged claims, on all the asserted grounds. Paper 17 (“Inst.
`Dec.”), 21.
`After institution, Patent Owner filed a Response. Paper 22 (“PO
`Resp.”). Petitioner filed a Reply. Paper 33 (“Reply”). Patent Owner filed a
`Sur-reply. Paper 38 (“Sur-reply”).
`Petitioner filed a Corrected Motion to Exclude Evidence directed to
`Exhibits 2024, 2030, 2031, and 2034. Paper 43. Patent Owner opposed that
`motion (Paper 48) and Petitioner filed a Reply (Paper 49). Patent Owner
`filed a Motion to Exclude Exhibits 1031–1038, 1040, 1041, and 1044. Paper
`44. Petitioner opposed that motion (Paper 47) and Patent Owner filed a
`Reply (Paper 50). Also before us are three motions to seal pursuant to the
`default protective order. Papers 18, 28, 35.
`On April 22, 2020, the parties presented arguments at oral hearing, the
`transcript of which is of record. Paper 56 (“Tr.”).
`
` Real Parties-in-Interest
`Petitioner identifies itself, Apotex Corp., Apotex Holdings Inc., and
`Apotex Pharmaceuticals Holdings Inc. as real parties-in-interest. Pet. 3.
`Patent Owner asserts that its real parties-in-interest are UCB Biopharma
`Sprl, UCB, Inc., UCB Pharma S.A., UCB S.A., and UCB Manufacturing
`Inc. Paper 7, 2; Ex. 2008 (public version).
`
`
`1 https://www.uspto.gov/patents-application-process/patent-trial-and-appeal-
`board/trials/guidance-impact-sas-aia-trial.
`3
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
` Related Proceedings
`The ’194 patent is at issue in UCB, Inc. v. Apotex Inc., No. 0-18-cv-
`60846 (S.D. Fla.). See Paper 7, 2; Paper 10, 2. On April 1, 2019, the district
`court in this related litigation issued an Order staying that case pending our
`review of the ’194 patent. Ex. 3001 (order granting Apotex, Inc.’s motion to
`stay pending inter partes review and administratively closing the case); see
`also Paper 43, 6 (noting that the concurrent district court case remains
`stayed).
`Patent Owner also notes the ’194 patent was previously at issue in
`UCB, Inc. v. Apotex Inc., 1:18-cv-03404 (S.D.N.Y.), which was voluntarily
`dismissed. Paper 7, 2.
`
` Asserted Grounds of Unpatentability
`Petitioner asserts two grounds of unpatentability (Pet. 7, 8):
`
`Ground
`1
`
`Claims
`Challenged
`1–11
`
`35 U.S.C. §
`103(a)2
`
`Reference(s)/Basis
`Handbook3, WO ’0944
`
`
`2 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”), amended 35 U.S.C. §§ 102 and 103. Because the
`challenged claims of the ‘194 patent have an effective filing date before the
`effective date of the applicable AIA amendments, we refer to the pre-AIA
`versions of 35 U.S.C. § 103 throughout this Decision.
`3AMERICAN PHARMACEUTICAL ASSOCIATION, HANDBOOK OF
`PHARMACEUTICAL EXCIPIENTS (Arthur H. Kibbe, Ph.D. ed., 3d ed. 2000).
`Ex. 1006.
`4 International Patent Application Publication No. WO 2004/050094,
`published June 17, 2004. Ex. 1007.
`
`4
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
`Ground
`2
`
`Claims
`Challenged
`1–11
`
`35 U.S.C. §
`103(a)
`
`Reference(s)/Basis
`Handbook, EP ’203,5 US
`’5586
`
`In support of its patentability challenges, Petitioner relies on, inter
`alia, the testimony of Dr. Paul A. Laskar, Ph.D. See Exs. 1002, 1050 (first
`and second Declarations, respectively); Ex. 1003 (curriculum vitae); Exs.
`2010 and 2037 deposition transcripts). In opposition to these challenges,
`Patent Owner relies on, inter alia, the testimony of Dr. Sarfaraz K. Niazi,
`Ph.D. See Ex. 2014 (Declaration); Ex. 2098 (curriculum vitae); Ex. 1043
`(deposition transcript).
`
` The ’194 Patent and Relevant Background
`According to the ’194 patent’s specification, its “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.” Ex. 1001, 1:60–64; see also id. at 1:64–65 (defining
`stability as “the capacity to resist[] . . . microbial contamination”). Such
`combinations can be administered orally, by spray inhalation, and nasal
`installation and may be formulated as drops, nasal drops, eye drops, ear
`drops, and oral preparations such as a syrup. Id. at 5:8–29.
`
`
`5 European Patent Application Publication No. 0605203 A2, published July
`6, 1994. Ex. 1004.
`6 U.S. Patent No. 5,698,558, issued Dec. 16, 1997. Ex. 1015.
`5
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
`The Specification further states that “[p]referably, the active substance
`is selected from the group of cetirizine, levocetirizine, and their
`pharmaceutically acceptable salts.” Id. at 2:19–21. By way of background,
`we understand that these compounds have antihistamine activity. Cetirizine,
`the active ingredient in the commercially available allergy relief product
`Zyrtec, is a racemic mixture of (R) and (S) enantiomers; the levorotary R-
`enantiomer (as levocetirizine dihydrochloride) is the active ingredient in the
`commercially available Xyzal and Xyzal Allergy 24HR products. See
`Ex. 1001, 2:22–48; Ex. 1008, 1123;7 Ex. 1011; Ex. 2007; and Ex. 3003.
`The Specification suggests that compositions including cetirizine or
`levocetirizine can employ a wide variety of preservatives (see, e.g.,
`Ex. 1001, 3:19–44), but “[b]est results have been obtained with a mixture of
`methyl parahydroxybonzoate and propyl parahydroxybonzoate in a ratio of
`9/1 expressed in weight” (id. at 3:45–48). And, whereas the Specification
`asserts that 3 mg/ml of parahydroxybenzoate esters is “a normal
`concentration to preserve aqueous solutions” (id. at 1:64–2:4), it highlights
`embodiments in which
`the pharmaceutical composition contains an amount of
`p-hydroxybenzoate esters (methyl p-hydroxybenzoate/propyl
`p-hydroxybenzoate in a ratio of 9/1 expressed in weight) selected
`in the range of 0.0001 and 1.5 mg/ml of the composition.
`Preferably, it contains an amount selected in the range of 0.01
`
`
`7 Jean-Paul Tillement et al., Compared pharmacological characteristics in
`humans of racemic cetirizine and levocetirizine, two histamine H1-receptor
`antagonists, 66(7) BIOCHEM. PHARMACOL. 1123–26 (2003).
`6
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
`and 1.125 mg/ml. More preferably it contains an amount of
`preservatives selected in the range of 0.1 and 1 mg/ml.
`Id. at 3:49–56; see also id. at 9:38–11:7 (Example 4 including oral
`levocetirizine solution having 9/1 ratio of methyl p-hydroxybenzoate/propyl
`p-hydroxybenzoate which comprise 0.75 mg/ml of the composition).
`With respect to terminology, we accept Dr. Laskar’s testimony that
`the methyl parahydroxybenzoate and propyl parahydroxybenzoate recited in
`the ’194 patent are also known as methylparaben and propylparaben,
`respectively, and generically as “parabens.” See, e.g., Ex. 1002 ¶¶ 53, 54, 80
`n.14 (citing Ex. 1006, 340, 450); see also, e.g., Ex. 1013, 536 (alternative
`spelling as “methyl paraben” and “propyl paraben). Methyl- and
`propylparaben are also referred to as MP and PP, respectively, in the
`prosecution history. See. e.g., Ex. 1013, 536–37.
`
` Challenged Claims
`The ’194 patent includes 12 claims. Of these, Petitioner challenges
`claims 1–11, of which only claim 1 (reproduced below with paragraphing
`added) is independent:
`1. A liquid pharmaceutical composition comprising
`(i) levocetirizine or a pharmaceutically acceptable salt of
`levocetirizine, and
`(ii) a preservative mixture consisting essentially of a mixture
`of methyl parahydroxybenzoate and propyl parahydroxy-
`benzoate in a ratio of 9/1 expressed in weight, said mixture
`being present in an amount of more than 0 and up to 0.75
`mg/ml of the composition,
`wherein said composition is substantially free of bacteria.
`
`7
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`Ex. 1001, 13:6–13.
`Among the dependent claims before us, claim 4 recites that “the
`composition is in the form of oral solutions, nasal drops, eye drops or ear
`drops”; claim 11 is limited to “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”; and claims 8–10 are cast as
`methods of making the composition according to claim 1. Id. at 13:19–21,
`14:5–22.
`
` Relevant Prosecution History
`During the prosecution leading to the issuance of the ’194 patent, the
`Examiner rejected certain claims as obvious over the combination of
`Dietrich, DeLongueville, Doron, Gilliland I, Gilliland II, and Routlege.
`Ex. 1013, 454–463; Exs. 2001–2006 (references cited in full at Prelim.
`Resp., i). In response, Applicants amended then-pending claim 1 to include
`the “consisting essentially of” and “substantially free of bacteria”
`limitations. See Ex. 1013, 492, 495 (emphasis added). With these additions,
`claim 1 recited:
`1. A liquid pharmaceutical composition comprising
`(i) levocetirizine or a pharmaceutically acceptable salt of
`levocetirizine, and
`(ii) 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
`1.125 mg/ml of the composition,
`wherein said composition is substantially free of bacteria.
`8
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`See id. at 492 (paragraphing and emphasis added). In conjunction with these
`amendments, Applicants submitted a Declaration of named inventor
`Domenico Fanara, asserting that “[t]the combined parabens in typical
`pharmaceutical preparations is at least about 2 mg/ml, as shown by an
`accepted pharmaceutical treatise (see, Remington, The Science and Practice
`of Pharmacy, 21st ed., 2005, pp. 748–749, Ex. B, hereinafter ‘the Remington
`treatise’).” Id. at 536, ¶ 7. Mr. Fanara testified, however, that “[i]n the course
`of developing liquid pharmaceutical formulations of levocetirizine and its
`salts, we were surprised to discover that levocetirizine itself can act as an
`anti-microbial.” Id. at ¶ 8. Mr. Fanara also submitted evidence purporting to
`show the antibacterial efficacy of levocetirizine solutions having 0.375
`mg/ml or 0.750 mg/ml of parabens consisting of methylparaben (MP) and
`propylparaben (PP) in a 9/1 ratio. See id. at 536–37, ¶¶ 10–11. Upon
`distinguishing the specific teachings of DeLongueville, Doron, Gilliland I,
`and Gilliland II, Mr. Fanara stated that the combination of those references
`“does not teach or suggest that a pharmaceutical formulation could be
`prepared that is maintained substantially free of bacteria and having the a
`[sic] total of MP and PP of no greater than 1.125 mg/ml, and no other
`preservative.” Id. at 537–39, ¶¶ 12–17.
`A subsequent Interview Summary Record shows that the Examiner
`was not persuaded by Applicants’ argument that Remington taught a
`combined paraben concentration of at least about 2 mg/ml. Id. at 571.
`Rather, the Examiner found that “Remington discloses that parabens are
`common preservatives used in liquid pharmaceutical dosage forms and their
`typical concentrations levels range from about 0.1% [1 mg/ml] and up.”
`9
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`Based on this reading of Remington—and Gilliland II’s teaching that
`methylparaben and propylparaben have synergistic effects in combination—
`the Examiner determined that one of ordinary skill in the art at the time of
`the invention “would expect that MP/PP [methylparaben and propylparaben]
`in a dose of about 1 mg/ml and slightly below would be . . . antimicrobial in
`view of the prior art,” but “would not expect that amounts of MP/PP much
`less than 1 mg/ml would be effective.” Id.
`The Examiner then indicated that claims reciting a combined paraben
`concentration of 0.75 mg/ml would be patentable, as follows:
`A review of the data provided in the Declaration demonstrate that
`compositions containing [levocetirizine] and MP/PP with ratio
`of 9/1 and total concentration of 0.675 mg/ml and 0.375 have
`antimicrobial effects. This is deemed to be surprising and
`unexpected. Examiner noted that one of ordinary skill in the art
`would not expect to have antimicrobial effects at these
`concentrations based on the art of record, however based on the
`art of record the upper limit of MP/PP amount of 1 mg/ml in
`claim 5 and 1.125 mg/mg in claim 1 would not be unexpected.
`The upper limit of claim 15 of 0.75 mg/ml is also considered to
`be unobvious in view of the prior art. Examiner suggests
`incorporating the upper limit of claim 15 (i.e.[,] 0.75 mg/ml) as
`the upper limit in claim 1 to make the instant claims allowable.
`Id. In light of the above, claim 1 was amended to recite the combined
`paraben concentration of 0.75 mg/ml, as issued. Id. at 590, 612.
`
`II. ANALYSIS
`
` Principles of Law
`“In an [inter partes review], the petitioner has the burden from the
`onset to show with particularity why the patent it challenges is
`
`10
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
`Cir. 2016) (citing 35 U.S.C. § 312(a)(3) (requiring inter partes review
`petitions to identify “with particularity . . . the evidence that supports the
`grounds for the challenge to each claim”)). This burden of persuasion never
`shifts to Patent Owner. See Dynamic Drinkware, LLC v. Nat’l Graphics,
`Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015) (discussing the burden of proof in
`inter partes review).
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which that
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved based on underlying factual
`determinations including: (1) the scope and content of the prior art; (2) any
`differences between the claimed subject matter and the prior art; (3) the level
`of ordinary skill in the art; and (4) objective evidence of nonobviousness, if
`present. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`In analyzing the obviousness of a combination of prior art elements, it
`can be important to identify a reason that would have prompted one of skill
`in the art “to combine . . . known elements in the fashion claimed by the
`patent at issue.” KSR, 550 U.S. at 418. A precise teaching directed to the
`specific subject matter of a challenged claim is not necessary to establish
`obviousness. Id. Rather, “any need or problem known in the field of
`endeavor at the time of invention and addressed by the patent can provide a
`reason for combining the elements in the manner claimed.” Id. at 420.
`11
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`Accordingly, a party that petitions the Board for a determination of
`unpatentability based on obviousness must show 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 success in doing so.” In re
`Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016) (internal
`quotation marks and citations omitted). Under the proper inquiry,
`“obviousness cannot be avoided simply by a showing of some degree of
`unpredictability in the art so long as there was a reasonable probability of
`success.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).
`Evidence of unexpected results and other objective indicia of
`nonobviousness “must always when present be considered,” and can serve as
`an important check against hindsight bias. See Cyclobenzaprine
`Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063
`1075–76, 1079 (Fed. Cir. 2012) (quoting Stratoflex, Inc. v. Aeroquip
`Corp.,713 F.2d 1530, 1538–39 (Fed. Cir.1983)). Unexpected results must be
`shown to be unexpected compared with the closest prior art. Kao Corp. v.
`Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir.2006). There is, however,
`no requirement that the closest prior art be commercialized. See In re
`Merchant, 575 F.2d 865, 869 (CCPA 1978).
`In addition, unexpected properties, even if found, do not necessarily
`control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc. 480
`F.3d 1348, 1372 (Fed. Cir. 2007). For example, a “marked superiority” in an
`expected property may be enough in some circumstances to demonstrate
`patentability, whereas a “mere difference in degree” may be insufficient. In
`12
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`re Papesch, 50 CCPA 1084, 315 F.2d 381, 392 (CCPA 1963); In re
`Merck, 800 F.2d 1091, 1099 (Fed. Cir. 1986) (evidence that a new drug had
`more potent sedative and anticholinergic effects than the prior art
`insufficient to outweigh the evidence of obviousness).
`We analyze the instituted grounds of unpatentability in accordance
`with these principles.
`
` Person of Ordinary Skill in the Art
`In determining the level of skill in the art, we consider the type of
`problems encountered in the art, the prior art solutions to those problems, the
`rapidity with which innovations are made, the sophistication of the
`technology, and the educational level of active workers in the field. Custom
`Accessories, Inc. v. Jeffrey-Allan Indus. Inc., 807 F.2d 955, 962 (Fed. Cir.
`1986); Orthopedic Equip. Co. v. U.S., 702 F.2d 1005, 1011 (Fed. Cir. 1983).
`Petitioner contends that a person of ordinary skill in the art as of the
`relevant date would have
`(i) a Pharm. D. or Ph.D. in chemistry, biochemistry, pharmacy,
`pharmaceutics, or in a related field, and at least two years of
`relevant experience in developing and formulating aqueous
`pharmaceutical formulations; (ii) a master’s degree in the same
`fields and at least five years of the same relevant experience; or
`(iii) a bachelor’s degree in the same fields and at least seven years
`of the same relevant experience.
`Pet. 6 (citing Ex. 1002, ¶ 32–33); see Reply 7–8. Patent Owner does not
`dispute Petitioner’s proposed definition of the skilled artisan. See Prelim.
`Resp. 2 n.1; PO Resp. 8–9; Ex. 2034 ¶ 21–23. And as Petitioner’s proposed
`definition is consistent with the cited prior art and the Specification, we
`
`13
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`adopt it here. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir.
`2001) (explaining that specific findings regarding ordinary skill level are not
`required “where the prior art itself reflects an appropriate level and a need
`for testimony is not shown” (quoting Litton Indus. Prods., Inc. v. Solid State
`Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985))).
`
` Claim Construction
`We interpret the challenged claims “using the same claim construction
`standard that would be used to construe the claim in a civil action under
`35 U.S.C. [§] 282(b).” See 37 C.F.R. § 42.100(b) (2019). Under that
`standard, we presume that a claim term carries its “ordinary and customary
`meaning,” which “is the meaning that the term would have to a person of
`ordinary skill in the art in question” at the time of the invention. In re
`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007) (quoting
`Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir. 2005)). Any special
`definition for a claim term must be set forth in the specification with
`reasonable clarity, deliberateness, and precision. In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994). Limitations, however, may not be read from the
`specification into the claims (In re Van Geuns, 988 F.2d 1181, 1184 (Fed.
`Cir. 1993)), nor may the Board “construe claims during [an inter partes
`review] so broadly that its constructions are unreasonable under general
`claim construction principles” (Microsoft Corp. v. Proxyconn, Inc., 789 F.3d
`1292, 1298 (Fed. Cir. 2015), overruled on other grounds by Aqua Products,
`Inc. v. Matal, 872 F.3d 1290 (Fed. Cir. 2017)).
`
`14
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
`As noted by Petitioner, columns 2 and 3 of the ’194 patent’s
`Specification provide express definitions for some terms. Pet. 6; see also
`Ex. 1001, 2:22–3:48 (defining, e.g., cetirizine, levocetirizine,
`pharmaceutically acceptable salts, and preservatives). The parties agree that
`no terms require express construction. Pet. 6; Prelim. Resp. 2 n.1., PO Resp.
`8.
`
`In our Institution Decision, however, we construed the claim term
`“substantially free of bacteria,” as “having, at most, a low, but clinically
`acceptable, level of bacteria, which would have been its ordinary meaning to
`the skilled artisan because the claimed composition is a pharmaceutical, but
`the term ‘substantially’ leaves some flexibility from absolute sterility.” Inst.
`Dec. 12. We also noted that “claim 1 does not recite any requirement for the
`level of resistance to bacterial contamination provided by the invention, nor
`require that the composition is at any point exposed to bacteria, merely that
`it is ‘substantially free of bacteria.’” Id. at 17. Neither party disputes our
`initial definition, or offers an alternative, and we apply it here for clarity. See
`Pet. Reply 16; PO Resp. 8. And, although Patent Owner further proposes
`that “whether a particular formulation meets this requirement would be
`guided by antimicrobial effectiveness testing set for by the United States
`and/or European Pharmacopoeia,” such further construction is not necessary
`here. See PO Resp. 8 (citing Ex. 2034 ¶ 27; Ex. 2010 77:14–78).
`No other terms require express construction. See Vivid Techs., Inc. v.
`Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (“[O]nly those
`terms need be construed that are in controversy and only to the extent
`necessary to resolve the controversy.”); see also Nidec Motor Corp. v.
`15
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`Zhongshan Broad Ocean Motor Co. Matal, 868 F.3d 1013, 1017 (Fed. Cir.
`2017) (applying Vivid Techs. in the context of an inter partes review).
`
` Obviousness in view of the Handbook and WO ’094 (Ground 1)
`As Ground 1, Petitioner challenges claims 1–11 as obvious in view of
`WO ’094 and the Handbook. Pet. 19–43; Reply 3–24. Petitioner’s challenge
`includes a detailed claim chart mapping the teachings of these references to
`each element of claim 1. Pet. 19–21. Patent Owner Opposes. PO Resp.
`26–52; Sur-reply 2–21. We have reviewed the evidence of record including
`the Petition and Petitioner’s expert declarations and Patent Owner’s
`arguments and evidence, including its experts’ declarations. We begin our
`analysis with an overview of the references asserted under Ground 1.
`
`Overview of the Handbook (Exhibit 1006)
`1.
`The Handbook teaches that methylparaben and propylparaben are
`“widely used as . . . antimicrobial preservative[s] in cosmetics, food
`products, and pharmaceutical formulations.” Ex 1006, 340, 450.8 According
`to the Handbook, antimicrobial activity and solubility vary inversely with
`increasing paraben chain length. Id. at 340, 341. “A mixture of parabens is
`thus frequently used to provide effective preservation,” moreover, “[a]ctivity
`may be improved by using a combination of parabens, since additive effects
`occur.” Id. “Activity may also be enhanced, due to synergistic effects, by
`
`
`8 Where possible, we refer to native page numbers published in the cited
`documents.
`
`16
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`using combinations of parabens with other antimicrobial preservatives such
`as imidurea.” Id.9
`The Handbook teaches that methylparaben and propylparaben “are
`affirmed GRAS [(generally regarded as safe)] Direct Food Substances in the
`US at levels up to 0.1% [1 mg/ml]”10 and “[i]ncluded in the FDA Inactive
`Ingredients Guide (IM, IV, and SC injections, inhalations, ophthalmic
`preparations, oral capsules, solutions, suspensions and tablets, otic, rectal,
`topical, and vaginal preparations).” Id. at 342, 452. The Handbook teaches,
`for example, that “[m]ethylparaben (0.18%) [1.8 mg/ml] together with
`propylparaben (0.02%) [0.2 mg/ml] has been used for the preservation of
`
`
`9 Despite Petitioner’s initial assertion (and the ’194 patent’s Applicants’
`failure to dispute the Examiner’s finding) that combinations of parabens
`have synergistic antibacterial effects, we do not read the Handbook as
`teaching that combinations of parabens alone have such properties. See Pet.
`17, 23, 26, 29, 51; Ex. 1002 ¶¶ 85, 94, 102, 146; Ex. 1013, 339–40; PO
`Resp. (citing excerpts of Dr. Laskar’s deposition testimony); Tr. 68:8–10.
`Moreover, for the reasons set forth at pages 18–19 of Patent Owner’s Sur-
`reply, Petitioner has not established that it was known in the art that methyl-
`and propylparaben have synergistic effects. In any event, given that
`combinations of methyl- and propylparaben were well known in the prior
`art, any potential synergism has little relevance to the patentability of the
`asserted claims. See In re Huellmantel, 324 F.2d 998, 1003 (CCPA 1963)
`(“[W]e attribute no magic status to synergism per se since it may be
`expected or unexpected.”); Tr. 59:3–6.
`10 Dr. Laskar explains, and we accept, that the percentages of methyl- and
`propylparabens in a solution may be converted from w/v percent to
`milligrams per ml by multiplying the % value by a factor of 10. Ex. 1002
`¶¶ 71–73. Thus, for example, “0.015% w/v of methylparaben corresponds to
`0.15 mg/ml.” Id. ¶ 72. Dr. Niazi applies similar calculations. Ex. 2034 ¶ 135.
`Bracketed amounts reflect that conversion.
`17
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`various parenteral pharmaceutical formulations,” thus disclosing 2 mg/ml
`total parabens with a 9:1 ratio of methyl- to propylparaben. Id. at 340, 450
`(same). The Handbook, however, notes:
`Although parabens have also been used as preservatives in
`injections and ophthalmic preparations[,] they are now generally
`regarded as being unsuitable for these types of formulations due
`to the irritant potential of the parabens. These experiences may
`depend on
`immune responses
`to enzymatically formed
`metabolites of the parabens in the skin.
`Id. at 342.
`Despite this caution, the Handbook discloses additional information
`regarding concentrations of methylparaben and propylparaben suitable for
`particular applications, including “IM, IV, SC injections” and “Ophthalmic
`preparations.” Id. at 340, 450. With respect to methylparaben, the Handbook
`provides a table indicating the use of 0.065–0.25 % [0.65–2.5 mg/ml],
`0.015–0.2 % [0.15–2.0 mg/ml], 0.033 % [0.3 mg/ml], and 0.015–0.2 %
`[0.15–2.0 mg/ml] for injectable, oral, nasal, and ophthalmic solutions,
`respectively. Id. at 340. A similar table indicates the use of 0.005–0.2 %
`[0.05–2.0 mg/ml], 0.01–0.2 % [0.1–2.0 mg/ml], 0.017 % [0.17 mg/ml], and
`0.005–0.01 % [0.05–0.1 mg/ml] of propylparaben for injectable, oral, nasal,
`and ophthalmic solutions, respectively. Id. at 450. For convenience, we
`reproduce below a compilation of the data from these two tables in the
`Handbook for which Dr. Niazi has converted the concentration percentages
`into mg/ml:
`
`18
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
`
`
`PO Resp. 23–24 (citing Ex. 2034 ¶ 135). The above table is a compilation of
`data from the Handbook for which Dr. Niazi has converted the concentration
`percentages of methyl- and propylparaben into mg/ml.
`
`Overview of WO ’094 (Exhibit 1007)
`2.
`WO ’094 is directed to the use of levocetirizine for the treatment of
`persistent allergic rhinitis, wherein: “[a] preferred daily dosage provides
`from about 0.0005 mg to about 2 mg of levocetirizine or a pharmaceutically
`acceptable salt thereof, per kg of body weight per patient . . . [and] may be
`administered once per day of treatment, or divided into smaller dosages.”
`Ex. 1007, Abstract, 1:10–27, 2:35–3:2.
`WO ’094 further discloses that levocetirizine compositions may be
`formulated as, for example, aerosols, solids, creams, and liquids, including
`oral solutions such as syrups and drops. Id. at 4:8–29. Such dosage forms
`“may be prepared according to conventional methods used by pharmacists,”
`and include “substances conventionally used as preserving, stabilizing,
`moisture-retaining, and emulsifying agents.” Id. at 3:16–26.
`19
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2
`
`
`WO ’094 discloses that “[b]est results have been obtained with an oral
`dosage form, in particular liquid formulations such as syrup for children, and
`film-coated tablet for adults.” Id. at 4:24–25. In one preferred embodiment,
`WO ’094 discloses a film coated tablet comprising “levocetirizine
`dihydrochloride, magnesium stearate, cellulose, lactose and silicon dioxide.”
`Id. at 4:31–32. In another preferred embodiment, WO ’094 discloses a syrup
`formulation of “levocetirizine dihydrochloride, methyl- and propylparaben,
`saccharinum, and purified water.” Id. at 4:33–35.
`
`Analysis of Ground 1
`3.
`For Ground 1, Petitioner argues that one of ordinary skill in the art
`seeking to make a liquid pharmaceutical composition comprising
`levocetirizine would have looked first to WO ’094, which discloses a
`preferred oral syrup formulation of “levocetirizine dihydrochloride,
`methyl- and propylparaben, saccharinum, and purified water.” Pet. 21;
`Ex. 1007, 4:34–35; see section II(D)(2), above. Petitioner argues that
`because WO ’094 is silent as to the ratio and amounts of methyl- and
`propylparabens in the formulation, the skilled artisan would have looked to
`the Handbook for guidance. Pet. 22–23.
`
`a)
`
`“a mixture of methyl parahydroxybenzoate and propyl
`parahydroxybenzoate in a ratio of 9/1 expressed in
`weight”
`With respect to the ratio of methyl- to propylparabens, Petitioner
`points to the 9/1 ratio taught by the Handbook for non-oral (e.g., injectable)
`formulations. Id. at 23 (quoting Ex. 1006) (“[m]ethylparaben (0.18%) [1.8
`mg/ml] together with propylparaben (0.02%) [0.2 mg/ml] has been used for
`
`20
`
`

`

`IPR2019-00400
`Patent 8,633,194 B2