IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`APOTEX CORP.
`APOTEX, INC.
`Petitioner
`v.
`ALLERGAN, INC.
`Patent Owner
`
`U.S. Patent No. 8,642,556 to Acheampong et al.
`Issue Date: February 14, 2014
`Title: Methods of Providing Therapeutic Effects Using Cyclosporin Components
`_____________________
`
`Inter Partes Review No. Unassigned
`_____________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,642,556 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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`

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`Petition for Inter Partes Review USPN 8,642,556
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`TABLE OF CONTENTS
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` 
`I. 
`II. 
`III. 
`
`INTRODUCTION .......................................................................................... 1 
`OVERVIEW ................................................................................................... 1 
`STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS .............................................................................................. 5 
`IV.  MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ..................................... 6 
`V. 
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFORE (37 C.F.R. § 42.22(A)) ............................... 6 
`VI.  THE CLAIMS ................................................................................................ 7 
`VII.  PERSON OF ORDINARY SKILL IN THE ART ......................................... 7 
`VIII.  STATE OF THE ART .................................................................................... 8 
`IX.  CLAIM CONSTRUCTION ......................................................................... 15 
`X. 
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. §
`42.104(b)) ..................................................................................................... 19 
`A.  Ground 1: Claims 1-20 are anticipated by the '979 patent ................. 20 
`B. 
`Ground 2: Claims 1-10, 12, 13, and 15-17 would have been
`obvious over the '607 patent, '979 patent, and Sall. ........................... 33 
`Ground 3: Claim 14 would have been obvious over the '607
`patent, the '979 patent, Sall, and the '586 patent ................................ 47 
`D.  Ground 4: Claims 11, 18, and 20 would have been obvious
`over the '607 patent, '979 patent, Sall, and Acheampong .................. 49 
`Ground 5: Claim 19 would have been obvious over the '607
`patent, '979 patent, Sall, the '586 patent, and Acheampong ............... 51 
`Objective indicia of nonobviousness ................................................. 51 
`F. 
`XI.  CONCLUSION ............................................................................................. 60 
`
`
`C. 
`
`E. 
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`I.
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`Petition for Inter Partes Review USPN 8,642,556
`
`
`INTRODUCTION
`APOTEX CORP. AND APOTEX, INC. petition for Inter Partes Review, seeking
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`cancellation of claims 1-20 of U.S. Patent No 8,642,556 to Acheampong et al.
`
`("the '556 patent") (APO1001), which is purportedly owned by ALLERGAN, INC.
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`II. OVERVIEW
`The claims of the '556 patent should be cancelled. They recite formulations
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`of well-known topical ophthalmic emulsions for treating dry eye disease (also
`
`referred to as keratocunjunctivitis sicca or KCS). APO1003, 1:14-15; APO1005,
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`¶¶4 and 15. The claimed emulsions contain cyclosporin A (CsA) at 0.05% and
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`castor oil at 1.25%, along with excipients at identical concentrations to those
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`taught in the art. (Percent values refer to percent weight throughout this petition.)
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`APO1005, ¶66. As described in detail below, the prior art '979 patent (APO1003)
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`provides working examples that recite formulations for CsA in castor oil
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`emulsions: one emulsion contains 0.05% CsA with 0.625% castor oil; and another
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`emulsion contains 0.10% CsA with 1.25% castor oil. APO1003, 3, 4:33-43;
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`APO1005, ¶65. And as Allergan conceded during prosecution, the other
`
`ingredients of the examples in the '979 patent "are otherwise the same" as the
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`challenged claims. APO1019, 949; APO1005, ¶¶16 and 116.
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`As explained by Apotex’s formulation expert Dr. Xia, a person of ordinary
`
`skill in the art (POSA) would have understood that the '979 patent discloses a small
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`Petition for Inter Partes Review USPN 8,642,556
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`genus of four CsA concentrations and four castor oil concentrations. APO1005,
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`¶17. Dr. Xia testifies that "a POSA would have readily envisioned a 0.05% CsA
`
`emulsion with 1.25% castor oil" because it is one of only seven exemplified CsA
`
`and castor oil concentrations within the '979 patent’s especially preferred CsA to
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`castor oil ratio. APO1003, 3, 3:17-20; APO1005, ¶100. Moreover, during
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`prosecution of a parent application Allergan stated that, based on the '979 patent,
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`"one of ordinary skill in the art 'would readily envisage' such a composition
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`[having 0.05% CsA and 1.25% castor oil], especially in view of Example 1B:
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`having selected 0.05% as the concentration of cyclosporin, Example 1B (wherein
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`the ratio of cyclosporin to castor oil is 0.04) teaches that the concentration of castor
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`oil should be 1.25% (0.05%/1.250% = 0.04 )." APO1019, 951; APO1005, ¶106.
`
`Oddly, Allergan did not face an anticipation rejection during prosecution of
`
`the '556 patent. But because the prior art '979 patent teaches a genus sufficiently
`
`small so that a POSA would have readily envisaged the claimed emulsions, the
`
`challenged claims are anticipated by the '979 patent. APO1005, ¶107. In re
`
`Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962).
`
`The challenged claims also would have been obvious. Both CsA and castor
`
`oil were known in the prior art as useful agents to treat dry eye. APO1002, 3:41-
`
`60; APO1003, 4, 5:9-12; APO1004, 1; APO1005, ¶¶63 and 68. A prior art
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`publication of clinical trials testing 0.05% CsA in a castor oil emulsion reported
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`Petition for Inter Partes Review USPN 8,642,556
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`that such emulsions were safe and efficacious for dry eye/KCS therapy. APO1004,
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`1; APO1005, ¶20. So before the September 2003 alleged priority date of the '556
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`patent, POSAs were aware of ophthalmically-acceptable castor oil emulsion
`
`formulations containing 0.05% CsA for the treatment of dry eye. APO1003, 3,
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`4:33-43; APO1004, 1; APO1005, ¶65.
`
`Furthermore, during the prosecution of a parent application, Allergan
`
`admitted that its emulsions containing 0.05% CsA and 1.25% castor oil "would
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`have been obvious" and that the differences between the claimed formulation and
`
`the prior art "are insignificant." APO1019, 951; APO1005, ¶187. Allergan also
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`admitted that there would have been a reasonable expectation of success in arriving
`
`at the formulations because the differences between the claimed formulations and
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`the prior art "are too small to believe otherwise." APO1019, 951; APO1005, ¶187.
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`During prosecution, Allergan asserted that it was unexpected that the
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`combination of 1.25% castor oil and 0.05% CsA would be "equally or more
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`therapeutically effective for the treatment of dry eye/keratoconjunctivitis sicca than
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`the [prior art] formulation containing 0.10% by weight cyclosporin A and 1.25%
`
`by weight castor oil. . . ." APO1019, 2578, ¶14 (emphasis added). But equivalent
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`performance does not meet the standard for unexpectedly superior results, and
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`moreover, does not control the conclusion of obviousness over a strong case based
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`Petition for Inter Partes Review USPN 8,642,556
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`on the prior art. Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc. 752 F.3d 967,
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`977 (Fed. Cir. 2014).
`
`Allergan submitted data purporting to show that a greater amount of CsA
`
`penetrated into the ocular tissue after administration of the prior art 0.1% CsA
`
`emulsion than after administration of the claimed 0.05% CsA emulsion. APO1019,
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`2602, ¶7; APO1005, ¶297. And Allergan argued, that because less CsA from the
`
`0.05% CsA emulsion penetrated tissue compared to the 0.10% CsA emulsion, it
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`was surprising that the claimed (0.05% CsA) composition had equal or better
`
`clinical therapeutic value. APO1019, 2602, ¶7; APO1005, ¶297.
`
`But prior art studies demonstrated that 0.05% CsA emulsions were at least as
`
`effective in treating dry eye as 0.10% CsA emulsions, or other emulsions
`
`containing even more CsA. APO1004, 1; APO1023, 2; APO1005, ¶296. Therefore,
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`POSAs were aware that, at 0.05%, CsA was already at the top of the dose response
`
`curve. APO1005, ¶296. And a POSA would not have expected more tissue
`
`penetration – or a higher CsA concentration – to improve clinical outcomes
`
`because additional CsA, beyond 0.05%, was known not to provide any added
`
`clinical benefit. APO1004, 1; APO1023, 2; APO1005, ¶297.
`
`For example, prior art publication, Sall et al. (APO1004) reports the results
`
`of clinical trials in which 0.05% and 0.10% CsA/castor oil in water emulsions were
`
`administered to humans twice a day. APO1004, 4-6; APO1005, ¶80; APO1007,
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`Petition for Inter Partes Review USPN 8,642,556
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`¶36. Sall shows that there is no statistically significant difference between the
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`0.05% and 0.10% CsA treatment groups for any of the efficacy measurements
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`reported. APO1004, 4-6; APO1005, ¶296; APO1007, ¶45. Sall states, “[t]here was
`
`no dose-response effect.” APO1004, 1, Abstract; APO1005, ¶195. So, a POSA
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`would not have been surprised that a 0.05% CsA emulsion worked as well as a
`
`0.1% emulsion, regardless of the CsA in the occular tissue. APO1004, 1, Abstract,
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`and 4-6; APO1005, ¶296; APO1007, ¶¶68, 72, 79, and 84. Therefore, Allergan did
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`not show unexpectedly superior results of the claimed emulsion compared to the
`
`closest prior art. APO1005, ¶289; APO1007, ¶¶44-45. Petitioner is at least
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`reasonably likely to prevail in showing unpatentability, and trial should be
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`instituted.
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`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '556 patent is available for IPR and (2)
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`Petitioner is not barred or estopped from requesting IPR of any claim of the '556
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`patent. This Petition is filed in accordance with 37 CFR § 42.106(a). A Power of
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`Attorney and an Exhibit List are filed concurrently herewith. The required fee is
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`paid online via credit card. The Office is authorized to charge fee deficiencies and
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`credit overpayments to Deposit Acct. No. 19-0036 (Customer ID No. 45324).
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`Petition for Inter Partes Review USPN 8,642,556
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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.,
`
`APOTEX INC., and APOTEX HOLDINGS INC.
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`Related Matters (37 C.F.R. § 42.8(b)(2)): None
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`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 counsel at the above addresses. Petitioner
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`consents to service by email at the addresses above.
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`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(A))
`
`Petitioner requests IPR and cancellation of claims 1-20. Petitioner's full
`
`statement of the reasons for the relief requested is set forth in detail in § X. In
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`support of the proposed grounds for unpatentability, this Petition is accompanied
`
`by declarations of experts Dr. Erning Xia (APO1005), Dr. Christopher Ta
`
`(APO1007), and Mr. Harry Boghigian (APO1010).
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`Petition for Inter Partes Review USPN 8,642,556
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`VI. THE CLAIMS
`Each claim of the '556 patent relates to a first topical ophthalmic emulsion
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`comprising 0.05% cyclosporin A, polysorbate 80, acrylate/C10-30 alkyl acrylate
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`cross-polymer, water, and 1.25% castor oil. Each claim compares this first
`
`emulsion to a second emulsion with respect to various properties. Claims 1-13, 15-
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`18, and 20 specify that the second emulsion has twice as much CsA as the first
`
`emulsion. Claims 14 and 19 specify that the second emulsion has 50% as much
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`castor oil as the first emulsion. Claim 1 is exemplary and recites that the "the first
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`topical ophthalmic emulsion provides overall efficacy substantially equal to a
`
`second topical ophthalmic emulsion. . . ."
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`VII. PERSON OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the art ("POSA") is a hypothetical person who
`
`is presumed to be aware of all the pertinent art, thinks along conventional wisdom
`
`in the art, and is a person of ordinary creativity. With respect to the subject matter
`
`of the '556 patent, a POSA would typically have had (i) an M.D. or a Ph.D. in
`
`chemistry, biochemistry, pharmaceutics, or in a related field in biological or
`
`chemical sciences, and have at least about two years of experience in the
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`formulation of topical ophthalmics or (ii) a Master's degree in chemistry,
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`biochemistry, pharmaceutics, or in a related field in biological or chemical
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`Petition for Inter Partes Review USPN 8,642,556
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`sciences, and have at least about five years of experience in formulation of topical
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`ophthalmics.
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`A person of ordinary skill typically 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 team to solve a given
`
`problem. For example, a clinician having experience in treating dry eye may be
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`part of the team. As of September 2003, the state of the art included the teachings
`
`provided by the references discussed in each of the unpatentability grounds set
`
`forth below. Additionally, a POSA would have been aware of other important
`
`information and references relating to dry eye, its causes, and useful treatments.
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`VIII. STATE OF THE ART
`The role of inflammation in dry eye was established by the late-1990s, when
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`CsA, a well-known immunosuppressant compound, was shown to significantly
`
`reduce inflammation in patients with dry eye. APO1015, 7; APO1016, 5;
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`APO1005, ¶55. Kunert demonstrated a significant decrease
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`in various
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`inflammatory markers in dry eye patients after treatment with an emulsion
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`containing 0.05% CsA. APO1015, 3; APO1005, ¶55. And Turner et al.
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`subsequently published a study showing a similar decrease in an inflammatory
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`marker when patients were treated with a 0.05% CsA emulsion in castor oil, but no
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`decrease when patients were treated with 0.1% CsA or vehicle. APO1016, 5;
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`Petition for Inter Partes Review USPN 8,642,556
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`APO1005, ¶55. Accordingly, before September 2003, castor oil emulsions of
`
`0.05% CsA were known to reduce the inflammation associated with dye eye
`
`disease. APO1015, 3; APO1016, 1, Abstract; APO1018, 2; APO1005, ¶55.
`
`Additionally, castor oil in water emulsions – without cyclosporin or any
`
`other active agent – were known to provide therapeutic benefits for dry eye
`
`patients. APO1002, 10, 4:1-3; APO1005, ¶60. And as explained by Dr. Xia, long
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`retention of the castor oil on the surface of the eye was known to "retard water
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`evaporation from the eye which alleviates dry eye symptoms." APO1005, ¶70,
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`APO1002, 10, 4:1-3. Accordingly, the art recognized that ocular treatment with
`
`castor oil emulsions resulted in an increased lipid layer on the surface of the tear
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`fluid which could prevent evaporation and lead to increased aqueous tear presence
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`on the ocular surface. APO1002, 10, 3:66-4:3; APO1005, ¶60.
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`The '979 patent. U.S. Patent No. 5,474,979 to Ding et al. ("the '979 patent";
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`APO1003) issued on December 5, 1995, and is prior art under 35 U.S.C. § 102(b).
`
`The '979 patent states that CsA "has been found as effective in treating immune
`
`mediated karatocunjunctivitis sicca (KCS or dry eye disease) in a patient suffering
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`therefrom." APO1003, 2, 1:12-15; APO1005, ¶63. The '979 patent exemplifies
`
`topical ophthalmic emulsions having four different concentrations of CsA and four
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`different concentrations of castor oil – including 0.05% and 0.10% CsA, and
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`1.25% and 0.625% castor oil. APO1003, 3, 4:33-43; APO1005, ¶65. The '979
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`Petition for Inter Partes Review USPN 8,642,556
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`teaches that a "more preferred" ratio of CsA to castor oil is "between 0.12 and
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`0.02." APO1003, 3, 3:17-20; APO1005, ¶66.
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`The '607 Patent. U.S. Patent No. 5,981,607 ("the '607 patent"; APO1002) to
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`Ding et al. issued on November 9, 1999 and is prior art under 35 U.S.C. § 102(b).
`
`The '607 patent teaches topical ophthalmic castor oil emulsions for the treatment of
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`dry eye. APO1002, 1, Abstract, and 11, 6:1-11; APO1005, ¶68. The '607 patent
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`states that the emulsion has "a high comfort level and low irritation potential . . .
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`for alleviating dry eye symptoms." APO1002, 10, 3:32-38; APO1005, ¶68. The
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`'607 patent teaches that "[m]ost importantly, the emulsion of the present invention
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`provides for long retention of the higher fatty acid glyceride when the emulsion is
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`instilled into an eye. This in turn can retard water evaporation from the eye which
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`alleviates dry eye symptoms." APO1002, 10, 3:66-4:3 (emphasis added);
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`APO1005, ¶70. The '607 patent states that its emulsions can be used "to advantage"
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`with CsA as set forth in the '979 patent. APO1002, 10, 3:48-50; APO1005, ¶77.
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`The '607 patent incorporates the '979 patent by reference. Incorporation
`
`by reference is a question of law determined from the vantage of a POSA. Hollmer
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`v. Harari, 681 F.3d 1351, 1355-56 (Fed. Cir. 2012). To incorporate material by
`
`reference a court must "determine whether the host document describes the
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`material to be incorporated by reference with sufficient particularity." Advanced
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`Display Systems, Inc. v. Kent State Univ., 212 F.3d 1272, 1283 (Fed. Cir. 2000).
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`Petition for Inter Partes Review USPN 8,642,556
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`As explained by Dr. Xia, a POSA would recognize that the '607 patent
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`
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`references the '979 patent four times: 1) The '607 patent identifies the '979 patent
`
`as part of its priority chain and states that "[t]he referenced applications/patent are
`
`to be incorporated herein by this specific reference thereto." APO1002, 9, 1:6-12;
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`APO1005, ¶77; 2) The '607 patent states "U.S. Pat. No. 5,474,979 hereinabove
`
`referenced and incorporated herein by reference thereto...." APO1002, 11, 5:22-23;
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`APO1005, ¶77; 3) The '607 patent states that "U.S. Pat. No. 5,474,979,
`
`hereinabove referenced and incorporated herein by reference thereto, teaches . . . a
`
`novel ophthalmic emulsion including cyclosporin in admixture with castor oil and
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`polysorbate 80 with a high comfort level and low irritation potential." APO1002,
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`10, 3:25-31; APO1005, ¶77; and 4) the '607 patent states, "The emulsion may also
`
`be used to advantage for introducing an active agent such as cyclosporine [sic] as
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`set forth in parent U.S. Pat. No. 5,474,979." APO1002, 10, 3:48-51; APO1005,
`
`¶77.
`
`Based on any one of the four incorporation statements, a POSA would
`
`recognize that the entire '979 patent is incorporated into the '607 disclosure, and
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`would also recognize that the '607 patent specifically highlights the CsA-related
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`teachings of the incorporated '979 patent. APO1005, ¶¶78 and 193; Advanced
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`Display Systems, Inc., 212 F.3d at 1283; see also Harari v. Lee, 656 F.3d 1331,
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`1335 (Fed. Cir. 2011)(holding "that the entire '579 application disclosure was
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`Petition for Inter Partes Review USPN 8,642,556
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`incorporated by the broad and unequivocal language: "'The disclosures of the two
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`applications are hereby incorporate[d] by reference.'" (brackets in original)).
`
`Sall. Sall et al. ("Sall," APO1004) published in April 2000 and qualifies as
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`prior art under 35 U.S.C. § 102(b). Sall reports the results of two clinical trials of
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`topical ophthalmic castor oil emulsions in which "patients were treated twice daily
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`with either CsA, 0.05% or 0.1%, or vehicle." APO1004, 1, Abstract; APO1005,
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`¶80. Sall measured several efficacy parameters in patients including tear
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`production, severity of dry eye disease, and comfort of the emulsion. APO1004, 3;
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`APO1005, ¶80. Sall also monitored the safety of the emulsion by cataloging all
`
`adverse events and by measuring blood CsA concentrations in patients. APO1004,
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`3, 4, and 6-7, Tables 1 and 3; APO1005, ¶80.
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`Sall noted that the castor oil vehicle itself provided statistically significant
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`benefits over baseline for several clinical parameters measured (APO1004, 8), and
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`suggested that the benefit of the vehicle may be linked to the "sustained residence
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`time of the oil component on the ocular surface, which may help reduce the
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`evaporation of natural tears." APO1004, 8; APO1005, ¶86.
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`Sall discussed previous studies showing that an emulsion of 0.05% CsA was
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`effective at reducing inflammatory cytokines and other immune activation
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`markers, taking special note of a previous report that treatment with 0.05% CsA
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`helped to repair the goblet cells of the conjunctiva. ("This finding is of particular
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`importance" because goblet cell regrowth may signal an improved tear quality.)
`
`APO1004, 8 (emphasis added); APO1005, ¶87. Sall concludes that "these findings
`
`add to the growing body of evidence demonstrating a beneficial effect of topical
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`CsA on dry eye disease. . . ." APO1004, 7; APO1005, ¶87.
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`Acheampong. Acheampong et al. ("Acheampong"; APO1017) published in
`
`1998 and qualifies as prior art under 35 U.S.C. § 102(b). Acheampong
`
`administered a CsA topical emulsion to human subjects and measured their
`
`resultant CsA blood levels at various time points. APO1017, 4; APO1005, ¶94.
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`Acheampong administered twice-daily CsA emulsions having 0.05%, 0.1%, 0.2%,
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`and 0.4% CsA to 162 human subjects for twelve weeks. APO1017, 4; APO1005,
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`¶94. Acheampong collected blood samples from subjects at morning drug level
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`troughs, as well as 1, 2, and 4 hours after administration. APO1017, 4; APO1005,
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`¶94. Acheampong found that for the 0.05% CsA emulsion both the trough and
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`maximal blood levels were below the limit of detection by LC/MS-MS (less than
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`0.1 ng/ml). See APO1017, 6, Table 1; APO1005, ¶95.
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`The '586 patent. U.S. Patent No. 5,578,586 ("the '586 patent"; APO1031)
`
`to Glonek et al. issued on November 26, 1996 and is prior art under 35 U.S.C.
`
`§ 102(b). The '586 patent states that "an emulsion over the surface of the eye is
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`expected to cause blurring. The duration of blur is dependent upon the time
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`required for the emulsion to differentiate and form separate layers replicating a tear
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`Petition for Inter Partes Review USPN 8,642,556
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`film. Consequently, blurring is likely to occur until the emulsion differentiates."
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`APO1031, 4, 6:37-42; APO1005, ¶89. The '586 patent discloses a topical emulsion
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`for dry eye treatment "whereby blurred vision is reduced or eliminated and the
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`residence time of tear film on the eye is prolonged." APO1031, 3, 3:3-7;
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`APO1005, ¶89.
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`The '586 patent examined the effects of increasing the surfactant to oil ratio
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`in several emulsion formulations by keeping the oil concentration constant and
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`successively increasing the surfactant concentration. APO1031, 11, 20:24-25;
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`APO1005, ¶91. The '586 patent reports that the best results were obtained at an
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`intermediate concentration range of the surfactant while higher concentrations of
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`surfactant led to increased blurring because the emulsion did not break down
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`appropriately quickly in the eye. APO1031, 11, 20:27-30; APO1005, ¶91. As Dr.
`
`Xia explains, "the '586 patent teaches that higher surfactant to oil ratios can result
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`in an excessively stable ophthalmic emulsion that can cause blurring upon
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`application to the eye." APO1005, ¶92. Additionally, as explained by Dr. Xia,
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`based on the teachings of the '586 patent together with the background knowledge
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`in the art, a POSA would have recognized that "the surfactant to oil ratio affects
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`the emulsion break time, with higher relative amounts of oil causing the emulsion
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`to break more rapidly upon instillation to the eye." APO1005, ¶92.
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`Petition for Inter Partes Review USPN 8,642,556
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`IX. CLAIM CONSTRUCTION
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
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`given their broadest reasonable interpretations (BRI) in light of the specification of
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`the '556 patent. Terms not explicitly discussed below are plain on their face and
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`should be construed to have their ordinary and customary meanings.
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`Claims 4, 6, and 9 of the '556 patent recite that the topical ophthalmic
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`emulsion has a "buffer." APO1001, 11, 16:17-19, 16:22-24, and 16:32-35. And
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`dependent claims 5 and 10 specify that "the buffer is sodium hydroxide."
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`APO1001, 11, 16:20-21 and 16:36-37. Based on the plain language of the claims, a
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`POSA would understand that the patentee intended the term "buffer" to encompass
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`sodium hydroxide. APO1005, ¶38. See Phillips v. AWH Corp., 415 F.3d 1303,
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`1313 ("the person of ordinary skill in the art is deemed to read the claim term not
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`only in the context of the particular claim in which the disputed term appears, but
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`in the context of the entire patent, including the specification.")
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`Claims 11 and 18-20 recite a topical ophthalmic emulsion wherein when
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`administered to an eye of a human, "the blood of a human has substantially no
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`detectable concentration of the cyclosporin A." APO1001, 11, 16:38-42 and 12,
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`18:4-16 (emphasis added). The
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`'556 patent states that the "[c]yclosporin
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`component concentration in blood preferably is determined using a liquid
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`chromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), which test
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`Petition for Inter Partes Review USPN 8,642,556
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`has a cyclosporin component detection limit of 0.1 ng/ml. Cyclosporin component
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`concentrations below or less than 0.1 ng/ml are therefore considered substantially
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`undetectable." APO1001, 6, 5:36-6:4; APO1005, ¶39. Based on the express
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`language of the '556 patent, a POSA would consider the blood of a human to have
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`substantially no detectable concentration of the CsA if the topical ophthalmic
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`emulsion resulted in a blood concentration of less than 0.1 ng/ml. APO1005, ¶40.
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`Neither the claims nor specification recite any particular time after treatment
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`for measuring the blood levels of CsA. APO1005, ¶41. As explained by Dr. Xia, "a
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`POSA administering ophthalmic CsA would be cognizant of potential systemic
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`effects if CsA levels in the blood became elevated." APO1005, ¶41. As Dr. Xia
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`explains, "POSAs typically measure blood concentration in two possible ways: 1)
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`in a time course by administering an ophthalmic preparation, taking serial blood
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`sample time points, and determining peak/maximal concentration; or 2) after many
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`days of administration of a drug, by taking a trough level blood sample just before
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`a next dose is administered." APO1005, ¶41; APO1018, 3-4; APO1017, 4.
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`Accordingly, a POSA would understand blood samples for CsA measurement
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`could be taken at time points reflecting trough or peak levels. APO1005, ¶42.
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`Claims 1 and 13 recite that the emulsion is "therapeutically effective".
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`Claim 1 also recites that the first emulsion "provides overall efficacy
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`substantially equal to" a second emulsion. Claim 13 recites that the first emulsion
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`Petition for Inter Partes Review USPN 8,642,556
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`achieves "at least as much therapeutic effectiveness as" a second emulsion. The
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`'556 patent does not specifically define these terms. APO1005, ¶43. However, the
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`'556 patent states that the invention relates to "administering to an eye of a human
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`or animal a therapeutically effective amount of a cyclosporin component to provide
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`a desired therapeutic effect, preferably a desired ophthalmic or ocular therapeutic
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`effect." APO1001, 4, 1:21-25; APO1005, ¶43. In the context of the claims, a
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`POSA would understand "therapeutically effective" according to its plain and
`
`ordinary meaning which is capable of achieving a desired result. APO1005, ¶43.
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`Similarly, a POSA would understand "provides overall efficacy substantially equal
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`to" a second topical ophthalmic emulsion according to its plain and ordinary
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`meaning, which is that the claimed emulsion is capable achieving a desired result
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`approximately as well as treatment with a second emulsion. APO1005, ¶44.
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`Likewise, a POSA would understand "at least as much therapeutic effectiveness
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`as" a second topical ophthalmic emulsion according to its plain and ordinary
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`meaning, which is that the claimed emulsion is capable achieving a desired result
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`as well as or better than treatment with a second emulsion. APO1005, ¶44.
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`Claim 14 recites that the first emulsion "breaks down" more quickly in the
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`eye of a human as compared to a second emulsion containing only 50% as much
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`castor oil. The '556 patent states that "a relatively high concentration of
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`hydrophobic component is believed to provide for a more quick or rapid breaking
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`Petition for Inter Partes Review USPN 8,642,556
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`down or resolving of the emulsion in the eye, which reduces vision distortion
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`which may be caused by the presence of the emulsion in the eye and/or facilitates
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`the
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`therapeutic effectiveness of
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`the composition." APO1001, 4, 2:42-48;
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`APO1005, ¶45. As explained by Dr. Xia, a POSA would understand the term
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`"breaks down" as used in claim 14 according to its customary meaning in the art;
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`that the emulsion differentiates into two separate layers on the eye ˗ an aqueous
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`layer and an oil layer. APO1005, ¶45.
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`Claim 15 recites that the emulsion demonstrates a reduction in "adverse
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`events" relative to a second emulsion. And claim 16 specifies that the adverse
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`events are "side effects." The '556 patent states "physicians can provide (prescribe)
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`Composition II to more patients . . . with reduced risk of the occurrence of adverse
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`events, e.g. side effects, drug interactions and the like, relative to providing
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`Composition I." APO1001, 11, 15:4-8; APO1005, ¶46. Accordingly, a POSA
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`would understand "adverse events" according to its plain and ordinary meaning to
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`include all negative
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`treatment occurrences potentially connected
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`to
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`the
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`administration of the emulsion of the claims, including side effects and unintended
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`drug interactions. APO1005, ¶46. A POSA would understand "side effects"
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`according to its plain and ordinary meaning to be a subset of adverse events
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`distinct from drug interactions, and related to the unintended physiological
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`Petition for Inter Partes Review USPN 8,642,556
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`consequences of treatment, including eye irritation such as burning eye and
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`stinging eye. APO1005, ¶¶47-49.
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`X.
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`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 42.104(b))
`Apotex requests inter partes review of each claim of the '556 patent based
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`on the grounds for unpatentability listed in the index below. Per 37 C.F.R.
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`§ 42.6(d), copies of the references are filed herewith.
`
`Ground 35 U.S.C. Section
`(pre-3/16/2013)
`1
`§102
`
`2
`
`3
`
`4
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`5
`
`§103
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`§103
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`§103
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`§103
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`Index of References
`
`The '979 patent
`'607 patent, (the incorporated '979
`patent), and Sall
`'607 patent, (the incorporated '979
`patent), Sall, and the '586 patent
`'607 patent, (the incorporated '979
`patent), Sall, and Acheampong
`'607 patent, (the incorporated '979
`patent), Sall, '586 patent, and
`Acheampong
`
`'556 Patent
`Claims
`1-20
`1-10, 12, 13,
`and 15-17
`14
`
`11, 18, and
`20
`19
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`Grounds 1-5 are not redundant. Ground 1 shows that each of the claims of
`
`the '556 patent is anticipated. Grounds 2-5 are not cumulative to Ground 1 because
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`they require resolution of different issues. For example, in assessing Ground 1, the
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`Board likely will consider whether the cited art discloses a sufficiently small genus
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`to anticipate each claim and whether certain limitations of the claims are inherent
`
`features of the emulsion. These issues are not present in Grounds 2-5; but, in
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`assessing Grounds 2-5, the Board