`
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`APOTEX CORP.
`Petitioner
`v.
`ALCON RESEARCH, LTD.
`Patent Owner
`
`U.S. Patent No. 8,268,299 to Kabra et al.
`Issue Date: September 18, 2012
`Title: Self Preserved Aqueous Pharmaceutical Compositions
`
`_____________________
`
`Inter Partes Review No. Unassigned
`_____________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,268,299 Under 35 U.S.C.
`§§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Petition for Inter Partes Review of USPN 8,268,299
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`TABLE OF CONTENTS
`
`2. 
`
`3. 
`
`INTRODUCTION .......................................................................................... 1 
`I. 
`OVERVIEW ................................................................................................... 1 
`II. 
`III.  GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS ......................................................................................................... 2 
`IV.  MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ..................................... 3 
`V. 
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a)) ...................................................... 3 
`VI.  CLAIM CONSTRUCTION ........................................................................... 4 
`VII.  PERSON OF SKILL IN THE ART & STATE OF THE ART ...................... 6 
`VIII.  Identification of Challenge (37 C.F.R. § 42.104(b)) ...................................... 7 
`1. 
`Ground 1: Claims 1, 2, 4, 8, 16, 17 and 20 Would
`Have Been Obvious Over Xia and Chowhan ............................ 8 
`Ground 2: Claims 1-4, 8, 9, and 13- 20 Would Have
`Been Obvious Over Xia, Chowhan and Gadd ......................... 22 
`Ground 3: Claims 5-7 and 28 Would Have Been
`Obvious Over Xia, the Travatan Label and Chowhan ............. 34 
`Ground 4: Claims 10-12 and 22-28 Would Have Been
`Obvious Over Xia, the TL, Chowhan and Gadd ..................... 42 
`Ground 5: Claims 13 and 14 Would Have Been
`Obvious Over Xia, Kiyobayashi, Chowhan and Gadd ............ 53 
`Ground 6: Claims 24 and 27 Would Have Been
`Obvious Over Xia, Kiyobayashi, the TL, Chowhan
`and Gadd; and .......................................................................... 56 
`Ground 7: Claim 28 Would Have Been Obvious Over Xia,
`Kiyobayashi, the TL and Chowhan ......................................... 56 
`IX.  Secondary Considerations ............................................................................ 59 
`X. 
`Conclusion .................................................................................................... 60 
`CERTIFICATION OF SERVICE (37 C.F.R. §§ 42.6(e), 42.105(a)) .................... 61 
`
`
`4. 
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`5. 
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`6. 
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`I.
`
`
`Petition for Inter Partes Review of USPN 8,268,299
`
`INTRODUCTION
`APOTEX CORP. ("Petitioner") petitions for Inter Partes Review (IPR),
`
`seeking cancellation of claims 1-28 ("challenged claims") of U.S. Patent No.
`
`8,268,299 to Kabra et al. ("the '299 patent") (APO 1001), which is owned by
`
`ALCON RESEARCH, LTD.
`
`II. OVERVIEW
`As shown herein, the challenged claims of the '299 patent should never have
`
`been issued because they are unpatentable over the art cited herein. Because
`
`Petitioner is at a minimum reasonably likely to prevail in showing unpatentability,
`
`the Petition should be granted and trial instituted on all of the challenged claims.
`
`The ophthalmic compositions recited in the claims of the '299 patent are
`
`simply an obvious repackaging of well-known components from prior art
`
`ophthalmic compositions in an attempt to evergreen a patent family. And the uses
`
`and properties of the components claimed in the '299 patent were recognized as of
`
`the earliest possible priority date of the patent. Alcon obtained the '299 patent by
`
`drafting claims that purport to be complicated – reciting specific ranges of
`
`concentrations and alleged properties of the claimed composition. But the claims
`
`of the '299 patent recite subject matter that was both simple and obvious as of the
`
`filing date of the '299 patent. All of the ranges of concentrations and properties
`
`recited in the claims were known in the prior art.
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`Petition for Inter Partes Review of USPN 8,268,299
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`The '299 patent purports to be founded on the alleged discovery that ions
`
`interfere with the antimicrobial activity of zinc. But this phenomenon was known
`
`for at least 30 years before the earliest possible priority date of the patent. The
`
`claims also recite that the claimed ophthalmic compositions satisfy standardized
`
`pharmacopeia tests. But these tests were satisfied by compositions having the
`
`claimed components well before the filing date of the '299 patent.
`
`Thus, the claims of the '299 patent recite ophthalmic compositions
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`containing known components having entirely expected properties. Petitioner is
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`reasonably likely to prevail in showing obviousness over the prior art. Inter partes
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`review of the '299 patent should be instituted.
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS
`Petitioner certifies that (1) the '299 patent is available for IPR and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the '299
`
`patent. This Petition is filed in accordance with 37 CFR § 42.106(a). Concurrently
`
`filed herewith is a Power of Attorney and an Exhibit List per § 42.10(b) and §
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`42.63(e), respectively. The required fee is paid via online credit card payment. The
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`Office is authorized to charge fee deficiencies and credit overpayments to Deposit
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`Acct. No. 19-0036 (Customer ID No. 45324).
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`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) is: APOTEX CORP.
`
`
`Petition for Inter Partes Review of USPN 8,268,299
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`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)): Administrative
`
`matters: In Petitions filed concurrently herewith, Petitioner seeks IPR of (i) U.S.
`
`Pat. No. 8,323,630, which is a continuation of the '299 patent and (ii) U.S. Pat. No.
`
`8,388,941 over references cited herein.
`
`Designation of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)):
`
`Lead Counsel
`Eldora L. Ellison (Reg. No. 39,967)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8508 (telephone)
`202.371.2540 (facsimile)
`eellison-PTAB@skgf.com
`
`Back-Up Counsel
`Ralph W. Powers, III (Reg. No.
`63,504)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8876 (telephone)
`202.371.2540 (facsimile)
`tpowers-PTAB@skgf.com
`
`Notice of Service Information (37 C.F.R. § 42.8(b)(4)): Please direct all
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`correspondence regarding this Petition to lead counsel at the above address.
`
`Petitioner consents to service by email at: eellison-PTAB@skgf.com and tpowers-
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`PTAB@skgf.com.
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a))
`
`Petitioner requests IPR and cancellation of claims 1-28. Petitioner's full
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`statement of the reasons for the relief requested is set forth in detail in § VIII.
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`Petition for Inter Partes Review of USPN 8,268,299
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`VI. CLAIM CONSTRUCTION
`Under 37 C.F.R. § 42.100(b), the challenged claims must be given their
`
`broadest reasonable interpretations ("BRI") in light of the patent specification.
`
`The BRI of the claim term "zinc ions at a concentration of" encompasses the
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`concentration of zinc salts used to prepare the claimed composition. As shown in
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`the specification of the '299 patent, the concentration of zinc ions in the claimed
`
`compositions is equal to the concentration of zinc salt added to form the
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`composition. (See APO 1001, 4:41-531.) Complete dissociation of zinc salts into
`
`zinc ions is presumed in aqueous compositions at relevant salt concentrations
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`because zinc salts are highly soluble in water. (APO 1002, ¶ 20.)
`
`Claims 24 and 28 recite concentrations of "zinc chloride ionized," and claim
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`27 recites a concentration of "ionized zinc chloride." These terms are not used in
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`the specification of the '299 patent and were not explicitly defined during
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`prosecution of the '299 patent. As zinc chloride is not ionized in ophthalmic
`
`compositions, the BRI for "zinc chloride ionized" and "ionized zinc chloride"
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`encompasses the concentration of zinc chloride added. (APO 1002, ¶ 22.)
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`The BRI of the claim term "polyol," as used in the '299 patent, encompasses
`
`
`1 All citations to U.S. Patents are shown as column number : line numbers.
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`"any compound having at least one hydroxyl group on each of two adjacent carbon
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`Petition for Inter Partes Review of USPN 8,268,299
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`atoms that are not in trans configuration relative to each other." (APO 1001, 6:19-
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`28; APO 1002, ¶¶ 23-24.)
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`The specification of the '299 patent does not define the term "self-
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`preserved." A person of ordinary skill in the art ("POSA") would have understood
`
`that "self-preserved" as used in the claims of the '299 patent refers to a solution that
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`is not susceptible to significant microbial growth because of the solution's
`
`antimicrobial properties. Therefore, the BRI of the term "self-preserved"
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`encompasses solutions that can be administered to patients in a multi-dose
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`container and need not be maintained aseptically because of their antimicrobial
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`properties. (APO 1002, ¶ 25.)
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`The specification of the '299 patent does not specifically define the term
`
`"anionic species." However, based on the use of the term in the '299 patent, a
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`POSA would have understood that "anionic species" refers to negatively charged
`
`ions. Generally, in aqueous solutions, ions are the result of dissolution of ionic
`
`compounds, such as salts. Thus, the BRI of "anionic species" encompasses any
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`element or molecule that is negatively charged in solution. (APO 1002, ¶¶ 26, 31.)
`
`The specification of the '299 patent states that "'substantially free of
`
`multivalent buffering anions' means that the composition either does not contain
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`any multivalent buffering anions or contains an amount of said anions that does not
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`Petition for Inter Partes Review of USPN 8,268,299
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`inhibit the ability of the composition to satisfy specified preservative efficacy
`
`standards (e.g., USP, EP or JP)." (APO 1001, 5:22-27.) Therefore, the BRI for the
`
`claim term "does not contain" multivalent buffering anions or metal cations other
`
`than zinc encompasses a composition containing multivalent buffering anions or
`
`metal cations other than zinc, so long as the composition also meets specified
`
`preservative efficacy standards. (APO 1002, ¶27-28.)
`
`The specification of the '299 patent states that "the phrase 'less than' relative
`
`to a specified concentration (e.g., 15 mM) means that the specified component
`
`(e.g., buffering anions) is either not present in the composition at all or is present at
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`a concentration less than the specified limit (e.g., 15 mM)." (APO 1001, 5:9-13.)
`
`Therefore, the BRI for the term "less than" encompasses a concentration of zero,
`
`i.e., the lack of a component. (APO 1002, ¶ 31.)
`
`All other terms of all challenged claims are presumed to take on their
`
`ordinary and customary meanings.
`
`VII. PERSON OF SKILL IN THE ART & STATE OF THE ART
`A person of ordinary skill in the art ("POSA") is presumed to be aware of all
`
`pertinent art, thinks along conventional wisdom in the art, and is a person of
`
`ordinary creativity. A person of ordinary skill in the art ("POSA") would have had
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`knowledge of the scientific literature concerning antimicrobial preservation,
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`Petition for Inter Partes Review of USPN 8,268,299
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`strategies for inhibiting microbial growth and the development of ophthalmic
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`formulations as of 2006. A POSA as of 2006 would typically have (i) a Ph.D. in
`
`microbiology or chemistry (or a related field) with at least a few years of
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`experience in the development of ophthalmic formulations, or (ii) a BS or MS in
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`microbiology or chemistry (or a related field) with significant practical experience
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`(5 or more years) in the development of ophthalmic formulations. A POSA may
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`would work as part of a multi-disciplinary team and draw upon not only his or her
`
`own skills, but also take advantage of certain specialized skills of others in the
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`team, to solve a given problem. For example, a microbiologist, a chemist and a
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`physician may be part of the team. (APO 1002, ¶ 15.)
`
`As evidenced by the references described herein, at least as of September 21,
`
`2006, the earliest possible priority date ("EPD") of the '299 patent, the subject
`
`matter claimed in claims 1-28 was well known to a POSA.
`
`VIII. Identification of Challenge (37 C.F.R. § 42.104(b))
`IPR of the challenged claims of the '299 patent is requested on the grounds
`
`listed in the index below. Per 37 C.F.R. § 42.6(d), copies of the references are filed
`
`herewith. In support of the proposed grounds for unpatentability, this Petition is
`
`accompanied by a declaration of technical expert Dr. Michael Miller (APO 1002),
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`which explains what the art would have conveyed to a POSA.
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`Petition for Inter Partes Review of USPN 8,268,299
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`Ground 35 U.S.C. (pre-
`March 16, 2013)
`§103
`
`1
`
`Index of References
`
`Xia and Chowhan
`
`§103
`§103
`
`§103
`
`§103
`
`§103
`
`§103
`
`2
`3
`
`4
`
`5
`
`6
`
`7
`
`
`
`Xia, Chowhan and Gadd
`Xia, the Travatan Label
`("TL") and Chowhan
`Xia, the TL, Chowhan and
`Gadd
`Xia, Kiyobayashi,
`Chowhan and Gadd
`Xia, Kiyobayashi, the TL,
`Chowhan and Gadd
`Xia, Kiyobayashi, the TL
`and Chowhan
`
`'299 Patent
`Claims
`1, 2, 4, 8, 16, 17
`and 20
`1-4, 8, 9, 13-21
`5-7 and 28
`
`10-12 and 22-28
`
`13 and 14
`
`24 and 27
`
`28
`
`1. Ground 1: Claims 1, 2, 4, 8, 16, 17 and 20 Would Have Been
`Obvious Over Xia and Chowhan
`International Patent Application Publication WO 2005/097067 to Xia (APO
`
`1003), titled "Zinc Preservative Composition and Method of Use" was published
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`on October 20, 2005. Xia claims priority to U.S. Appl. No. 10/812,543, filed
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`March 29, 2004 and qualifies as prior art to the '299 patent under 35 U.S.C.
`
`§102(e). U.S Patent No. 6,143,799 to Chowhan et al. (APO 1004), titled "Use of
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`Borate-Polyol Complexes in Ophthalmic Compositions" issued November 7, 2000.
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`Chowhan published more than one year before the EPD of the '299 patent and
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`qualifies as prior art to the '299 patent under 35 U.S.C. §102(b).
`
`A POSA would have had a reason to combine the teachings of Xia and
`
`Chowhan to arrive at the claimed invention because, as shown in the claim chart
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`below, both Xia and Chowhan teach ophthalmic compositions containing borate
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`Petition for Inter Partes Review of USPN 8,268,299
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`and polyols. (APO 1003, 14, 16; APO 1004, 3:44-47.) And Xia teaches that
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`"[m]any of the polycationic materials [antimicrobial agents], by themselves, do not
`
`have sufficient preservative efficacy to adequately preserve an ophthalmic
`
`composition … but can enhance preservative efficacy when used in conjunction
`
`with a soluble zinc compound." (APO 1003, 5.) Chowhan also discloses that
`
`borate-polyol systems "increase the antimicrobial efficacy of other antimicrobial
`
`agents when used in combination." (APO 1004, 2:10-12; APO 1002, ¶ 47.)
`
`Both Xia and Chowhan also teach that more traditional antimicrobial agents
`
`can cause irritation. Xia teaches that the "composition has the benefit of being
`
`adequately preserved without … irritation or discomfort caused by at least some
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`traditional preservative agents." (APO 1003, 4.) And Chowhan teaches that "small
`
`organic antimicrobials are often toxic to the sensitive tissues of the eye." (APO
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`1004, 1:49-55; APO 1002, ¶ 48.)
`
`Both Xia and Chowhan teach antimicrobial agents that work well in concert
`
`with other antimicrobial agents, but that traditional antimicrobial agents (such as
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`benzalkonium chloride) are to be avoided. (APO 1003, 4; APO 1004, 1:49-
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`55.)Thus, a POSA would have had a reason to combine the teachings of Xia and
`
`Chowhan to gain the benefits of the antimicrobial agents taught in each reference
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`without using traditional preservative agents. (APO 1002, ¶ 49.)
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`Petition for Inter Partes Review of USPN 8,268,299
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`As illustrated in the claim chart and discussion below, claims 1, 2, 4, 8, 16,
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`17 and 20 would have been obvious over Xia and Chowhan. From the teachings of
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`these references, a POSA would have arrived at the compositions of the claims
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`using only routine experimentation. And "where the general conditions of a claim
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`are disclosed in the prior art, it is not inventive to discover the optimum or
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`workable ranges by routine experimentation." See In re Aller, 220 F.2d 454, 456,
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`(CCPA 1955); see also In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003).
`
`Further, the concentration ranges disclosed in Xia and Chowhan overlap the
`
`claimed ranges of concentrations, establishing a prima facie case of obviousness.
`
`See Peterson, 315 F.3d at 1330.
`
`The '299 patent
`1. A multi-dose,
`self-preserved
`ophthalmic
`composition,
`comprising:
`
`Disclosure of Xia and Chowhan
`Xia states: "The present invention relates to a composition
`that includes a preservative-effective amount of a
`soluble zinc compound …. According to one embodiment,
`the composition is an ophthalmic solution." (APO 1003,
`3.) 2
`Chowhan states: "The ophthalmic compositions of the
`present invention comprise borate-polyol complexes."
`(APO 1004, 2:4 -12.)
`
`
`2 As used herein, boldface type in claim charts is added emphases.
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`The '299 patent
`zinc ions at a
`concentration of
`0.04 to 0.4 mM; and
`
`borate and polyol,
`
`
`the borate being
`present in the
`composition at a
`concentration of 0.1
`to 2.0% w/v and
`
`the polyol being
`present in the
`composition at a
`concentration of
`0.25 to 2.5% w/v,
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`Petition for Inter Partes Review of USPN 8,268,299
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`Disclosure of Xia and Chowhan
`Xia states: "the composition has a minimum of about
`0.001 [0.074 mM ZnCl2], wt.% 3, about 0.005 wt.% [0.37
`mM ZnCl2], … of a zinc compound per total weight of
`the composition…." (APO 1003, 5.)
`
`Xia states: "Suitable buffers may be added, such as
`borate…." (APO 1003, 14.)
`Chowhan states: "The borate-polyol complexes are
`utilized in the compositions of the present invention in an
`amount between about 0.5 to about 6.0 percent by
`weight (wt %), preferably between about 1.0 to about 2.5
`wt %." (APO 1004, 3:44-47.)
`Chowhan states: "the molar ratio of borate to polyol is
`generally between about 1:0.1 and about 1:10, and is
`preferably between about 1:0.25 and about 1:2.5." (APO
`1004, 3:10-34.)
`Examples 2 and 3 in Xia contain 0.850 wt.% boric acid.
`(APO 1003, 16.)
`Chowhan states: "borate-polyol complexes … in an
`amount between about 0.5 to about 6.0 percent by
`weight (wt %), preferably between about 1.0 to about 2.5
`wt %." (APO 1004, 3:44-47.)
`Xia states: "comfort agents such as … propylene glycol
`can also be added." (APO 1003, 14.)
`Chowhan states: "borate-polyol complexes … in an
`amount between about 0.5 to about 6.0 percent by
`weight (wt %), preferably between about 1.0 to about 2.5
`wt %." (APO 1004, 3:44-47.)
`
`
`3 As admitted by Alcon during prosecution of the '299 patent, the wt.% (%w/w) is
`
`approximately equal to the % w/v for purposes of the claims. See Alcon response
`
`to Office Action dated May 17, 2012, 8-9 (APO 1008).
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`The '299 patent
`the polyol
`comprising
`propylene glycol in
`the composition at a
`concentration of
`0.25 to 1.25% w/v
`and
`
`sorbitol in the
`composition at a
`concentration of
`0.05 to 0.5% w/v;
`wherein
`
`(i) the composition
`has a concentration
`of anionic species
`less than 15 mM;
`and
`
`
`(ii) the composition
`exhibits sufficient
`antimicrobial
`activity to allow the
`composition to
`satisfy USP 27
`preservative
`efficacy
`requirements.
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`Petition for Inter Partes Review of USPN 8,268,299
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`Disclosure of Xia and Chowhan
`Xia states: "comfort agents such as … propylene glycol
`can also be added." (APO 1003, 14.)
`Chowhan states: "Preferred polyols are … propylene
`glycol and sorbitol." (APO 1004, 3:6.)
`Chowhan states: "borate-polyol complexes … in an
`amount between about 0.5 to about 6.0 percent by
`weight (wt %), preferably between about 1.0 to about 2.5
`wt %." (APO 1004, 3:44-47.)
`Chowhan states: "Preferred polyols are … propylene
`glycol and sorbitol." (APO 1004, 3:6.)
`Chowhan states: "borate-polyol complexes … in an
`amount between about 0.5 to about 6.0 percent by
`weight (wt %), preferably between about 1.0 to about 2.5
`wt %." (APO 1004, 3:44-47.)
`Xia states: "The aqueous solutions of the present
`invention are typically adjusted with tonicity agents …
`(approximately equivalent to a 0.9 wt.% solution of
`sodium chloride or 2.8 wt.% glycerol solution). (APO
`1003, 10.)
`Chowhan states: "phosphate [an anion] is a good buffer
`but, when used in concentrations generally found in
`ophthalmic formulations, it reduces the antimicrobial
`activity of preservatives." (APO 1004, 1:45-48.)
`Xia states: "Based on the acceptance criteria for bacteria
`or fungus a solution is acceptable if the number of viable
`bacteria or fungus recovered per ml is reduced by at
`least 3.0 logs at day 14 and after the rechallenge at day
`14, the concentration of bacteria or fungus is reduced
`by at least 3.0 logs by day 28." (APO 1003, 15.) This test
`is more stringent than the USP 27. (APO 1002, ¶ 62.)
`Chowhan states: "An organism challenge approach based
`on the British Pharmacopoeia ("BP") 1988 Test for
`Efficacy of Preservatives in Pharmaceutical Products was
`used …." (APO 1004, 9:38-41.) This test is generally
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`Petition for Inter Partes Review of USPN 8,268,299
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`The '299 patent
`
`Disclosure of Xia and Chowhan
`more stringent than the USP 27. (APO 1002, ¶ 38.)
`
`Claim 1: Claim 1 would have been obvious over Xia and Chowhan. A
`
`POSA would have had a reasonable expectation of success in arriving at the
`
`composition of claim 1 from the combination of Xia and Chowhan. As shown in
`
`the claim chart above, Xia and Chowhan disclose all of the components of the
`
`ophthalmic composition of claim 1 at the concentrations claimed. As discussed at
`
`the beginning of this Ground, a POSA would have had a reason to combine the
`
`teachings of Xia and Chowhan. (APO 1002, ¶ 50.)
`
`As shown in the claim chart above, Chowhan discloses total concentrations
`
`of borate-polyol overlapping the individual borate, polyol, propylene glycol and
`
`sorbitol concentrations claimed. Chowhan discloses that the "borate-polyol
`
`complexes are utilized in the compositions of the present invention in an amount
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`between about 0.5 to about 6.0 percent by weight (wt%) …." (APO 1004, 3:45-
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`47, emphasis added.) The lowest total borate-polyol concentration recited in claim
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`1 is 0.4% (0.1% borate + 0.25% propylene glycol + 0.05% sorbitol) while the
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`highest total borate-polyol concentration recited in claim 1 is 4.5% (2.0% borate +
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`2.5% polyol). Thus, the total borate-polyol concentration range recited in claim 1 –
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`0.4 to 4.5% -- is subsumed by Chowhan’s total concentration range of about 0.5 to
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`about 6.0 percent. (APO 1002, ¶ 52.)
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`Petition for Inter Partes Review of USPN 8,268,299
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`And the ratios of borate to polyol recited in claim 1 were common in borate-
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`polyol systems as of the EPD of the '299 patent. At the low end of the ranges of
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`concentrations recited in claim 1 (0.1% borate + 0.25% propylene glycol + 0.05%
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`sorbitol), the borate-polyol ratio is 1:2.2. At the high end of concentrations recited
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`in claim 1 (2.0% borate + 1.25% propylene glycol + 0.5% sorbitol), the borate-
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`polyol ratio is 1:0.6. (APO 1002, ¶ 53.) Thus, the claim is directed to borate-polyol
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`ratios ranging from 1:0.6 to 1:2.2. But the Chowhan reference had already taught
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`this range of ratios of borate to polyol, as it discloses a borate to polyol ratio of
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`"preferably between about 1:0.25 and about 1:2.5." (APO 1004, 3:34.) Thus, a
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`POSA would have understood that claim 1 is directed to same borate and polyol
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`concentrations already disclosed in Chowhan. (APO 1002, ¶ 53.)
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`A POSA would have had a reason to substitute and mix polyols as disclosed
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`by Chowhan to obtain a formulation containing propylene glycol and sorbitol at
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`the concentrations claimed. (APO 1002, ¶ 54.) Chowhan teaches mixtures of
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`poylols, stating that the "borate-polyol complexes are formed by mixing boric acid
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`and/or its salts with polyols" and that the "water-soluble borate-polyol complexes
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`of the present invention may be formed by mixing borate with the polyol(s) of
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`choice in an aqueous solution." (APO 1004, 2:15-16, 3:10-13, emphasis added.) A
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`POSA would have also had a reason to substitute the polyols taught in Chowhan
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`for one another as these polyols have similar structures and were known to have
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`similar properties in ophthalmic solutions. Optimization of the borate, polyol,
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`Petition for Inter Partes Review of USPN 8,268,299
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`propylene glycol and sorbitol concentration ranges disclosed in Chowhan would
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`have been within the skill of a POSA as these components were result-effective
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`variables known to affect the properties of the solution. (APO 1002, ¶ 54.) A
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`result-effective variable is a parameter which can be adjusted to achieve a result.
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`See, e.g., Application of Antonie, 559 F.2d 618, 620 (CCPA 1977). The mere
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`optimization of a result-effective variable is insufficient to render a claim
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`patentable. See Peterson, 315 F.3d at 1330. As the CAFC has explained, "the prior
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`art need not provide the exact method of optimization for the variable to be result-
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`effective. A recognition in the prior art that a property is affected by the variable is
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`sufficient to find the variable result-effective." In re Applied Materials, Inc., 692
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`F.3d 1289, 1297 (Fed. Cir. 2012).
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`Anionic species: The compositions disclosed in Xia and Chowhan do not
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`require anionic species in addition to borate. Instead, Xia and Chowhan list anionic
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`species, such as chloride salts, as optional. So a POSA would have understood that
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`Xia and Chowhan teach compositions without sodium chloride. For example, Xia
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`states: "[t]he aqueous solutions of the present invention are typically adjusted
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`with tonicity agents … (approximately equivalent to a 0.9 wt.% solution of sodium
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`chloride or 2.8 wt.% glycerol solution)." (APO 1003, 10, emphasis added.) So Xia
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`makes it clear that adjusting the tonicity is optional and any adjustments can be
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`made with an agent other than an anionic species (e.g., with glycerol solution).
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`Petition for Inter Partes Review of USPN 8,268,299
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`Likewise, Chowhan states that "it is not always necessary to have an isotonic
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`solution" and that "osmolaltity can be adjusted by incorporating polyol with OH
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`groups in trans position, [or] sodium chloride…." (APO 1004, 4:52.) So Chowhan,
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`too, discloses that the tonicity of the composition may be adjusted and, if it is
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`adjusted, it may be adjusted with agents other than sodium chloride. Therefore, a
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`POSA would have understood that Xia and Chowhan disclose compositions with
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`chloride salt concentrations of zero. (APO 1002, ¶ 55.) As shown in the claim chart
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`above, the disclosure in Chowan that phosphate anions can interfere with
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`antimicrobial activity would have guided a POSA to keep the concentration of
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`anionic species as low as possible. Thus, Chowhan teaches that when anionic
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`species are to be added to ophthalmic compositions, their concentrations should be
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`kept as low as possible. (APO 1002, ¶ 56.)
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`During prosecution of the '299 patent, Alcon argued that Xia teaches away
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`from the claims, alleging that Xia requires sodium chloride in its compositions and
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`pointing the examiner to the examples of Xia, which include sodium chloride at a
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`concentration of 37 mM. (APO 1008, 8-9.) But the passages from Xia cited above
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`show that Xia does not require anionic species such as chloride salts in its
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`disclosed compositions. And "disclosed examples and preferred embodiments do
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`not constitute a teaching away from a broader disclosure of non-preferred
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`embodiments." See In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
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`And any attempt by Alcon to argue that Xia teaches away from the claims
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`would be contradicted by the '299 patent itself, because it contains an admission
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`that monovalent anions, such as the chloride in sodium chloride, have no effect on
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`the antimicrobial activity of the composition. Examples AA and AB of the '299
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`patent disclose identical base formulations except that example AB also contains
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`0.2 w/v% sodium chloride. (APO 1001, 24:26-67.) Thus, example AB includes
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`34.2 mM sodium chloride, whereas example AA lacks sodium chloride. (APO
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`1002, ¶ 57.) Despite differing in their concentration of monovalent anions, the
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`compositions of examples AA and AB have identical antimicrobial testing profiles.
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`(APO 1001, 25:1-29.) (APO 1002, ¶ 57.) So the data in the '299 patent show that
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`an almost identical concentration of sodium chloride (34.2 mM) to that disclosed in
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`the examples of Xia (37 mM) has no effect on antimicrobial activity. (APO 1002, ¶
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`59.) Thus, the sodium chloride concentration disclosed in the examples of Xia does
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`not teach away from the claims.
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`USP 27: A POSA would have recognized that a composition taught by the
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`combination of Xia and Chowhan would have inherently satisfied the USP 27
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`preservative efficiency requirements. (APO 1002, ¶ 61.) As shown above, the
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`combination of Xia and Chowhan teaches a composition having the same
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`components at the same concentrations as recited in claim 1. A POSA would have
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`had a reasonable expectation that an ophthalmic composition having the same
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`Petition for Inter Partes Review of USPN 8,268,299
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`ingredients in the same amounts as claimed would have satisfied the USP 27
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`requirements from the teachings of Xia and Chowhan that compositions containing
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`zinc and borate-polyol satisfied USP 27. (APO 1002, ¶ 59.)
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`And in any event, such an inherent property of a claimed composition does
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`not impart patentability to claims and need not have been recognized by a POSA.
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`The Federal Circuit has made this clear in Santarus, Inc. v. Par Pharm., Inc., 694
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`F.3d 1344 (Fed. Cir. 2012). In Santarus, the patentee argued that claims to a
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`method of treating a gastric acid disorder were not obvious because the claims
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`recite achieving the desired results with low levels of sodium bicarbonate and
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`achieving specific blood serum concentrations levels not disclosed in the prior art.
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`Id. at 1353. But the court found the claims would have been obvious, noting that
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`the prior art disclosed sodium bicarbonate ranges overlapping the claimed range.
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`Id. at 1353-1354. The court also found that the claimed blood serum concentrations
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`did not overcome the finding of obviousness, stating that "[t]o hold otherwise
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`would allow any formulation—no matter how obvious—to become patentable
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`merely by testing and claiming an inherent property." Id. at 1354. The facts are the
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`same here. The prior art teaches an ophthalmic composition having the same
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`components at the concentrations claimed. The recitation that the claimed
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`composition has sufficient antimicrobial activity to satisfy USP 27 requirements
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`does not make the claims patentable.
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`Petition for Inter Partes Review of USPN 8,268,299
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`Even if satisfying USP 27 requirements were not considered to be an
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`inherent property of the compounds of the prior art, a POSA would have only
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`required routine experimentation to prepare a composition that achieved USP 27
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`requirements as claimed. (APO 1002, ¶ 62.) A POSA would have understood that a
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`multi-dose ophthalmic composition would have been required to pass an
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`antimicrobial test at least as stringent as the USP. (APO 1002, ¶ 61.) A POSA
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`would have also had a reasonable expectation of success in formulating a
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`composition that achieves USP 27 req