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. 8,685,930 to Acheampong et al.
`Issue Date: April 1, 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. 8,685,930 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
`
`

`

`Petition for Inter Partes Review USPN 8,685,930
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`TABLE OF CONTENTS
`
`
`I. 
`II. 
`III. 
`
`C. 
`
`INTRODUCTION .......................................................................................... 1 
`OVERVIEW ................................................................................................... 1 
`STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS .............................................................................................. 6 
`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)) ............................... 7 
`VI.  THE CLAIMS ................................................................................................ 7 
`VII.  A PERSON OF ORDINARY SKILL IN THE ART ..................................... 8 
`VIII.  STATE OF THE ART .................................................................................... 9 
`IX.  CLAIM CONSTRUCTION ......................................................................... 15 
`X. 
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. §
`42.104(b)) ..................................................................................................... 17 
`A.  Ground 1: Claims 1-36 are anticipated by the '979 patent .................. 18 
`B. 
`Ground 2: Claims 1-10, 12-22, 24- 34 and 36 would have
`been obvious over the '607 patent, the incorporated '979
`patent and Sall et al. ............................................................................ 31 
`Ground 3: Claims 11, 23, and 35 Would Have Been Obvious
`Over the '607 patent, the incorporated '979 patent, Sall et al.,
`and Acheampong et al. ........................................................................ 48 
`D.  Objective indicia of nonobviousness .................................................. 50 
`1. 
`Allergan's allegations of objective indicia are
`insufficient to show nonobviousness ....................................... 50 
`XI.  CONCLUSION ............................................................................................. 60 
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`I.
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`Petition for Inter Partes Review USPN 8,685,930
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`
`INTRODUCTION
`APOTEX CORP. and APOTEX, INC. petition for Inter Partes Review, seeking
`
`cancellation of claims 1-36 of U.S. Patent No 8,685,930 to Acheampong et al.
`
`("the '930 patent") (APO1001), which is purportedly owned by ALLERGAN, INC.
`
`II. OVERVIEW
`The claims of the '930 patent should be cancelled. They recite formulations
`
`of well-known topical ophthalmic emulsions for treating dry eye disease (also
`
`referred to as keratocunjunctivitis sicca or KCS (APO1003, 1:14-15)). APO1005,
`
`¶¶4 and 15. The claimed emulsions contain cyclosporin A (CsA) at 0.05% and
`
`castor oil at 1.25%, along with excipients at identical concentrations to those
`
`taught in the art. (Percent values refer to percent weight throughout this petition.)
`
`APO1005, ¶16. As described in detail below, the prior art '979 patent (APO1003)
`
`provides working examples that recite formulations for CsA in castor oil
`
`emulsions: one emulsion contains 0.05% CsA with 0.625% castor oil; and another
`
`emulsion contains 0.10% CsA with 1.25% castor oil. APO1003, 3, 4:33-43;
`
`APO1005, ¶58. As Allergan conceded during prosecution, the other ingredients of
`
`the examples in the '979 patent "are otherwise the same" as the challenged claims.
`
`APO1019, 949; APO1005, ¶134.
`
`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 8,685,930
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`genus of four CsA concentrations and a small genus of four castor oil
`
`concentrations. APO1005, ¶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 castor oil ratio. APO1003, 3, 3:17-20; APO1005, ¶88.
`
`Moreover, during prosecution of a parent application Allergan stated that, based on
`
`the '979 patent, "one of ordinary skill in the art 'would readily envisage' such a
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`composition [having 0.05% CsA and 1.25% castor oil], especially in view of
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`Example 1B: having selected 0.05% as the concentration of cyclosporin Example
`
`1B (wherein the ratio of cyclosporin to castor oil is 0.04) teaches that the
`
`concentration of castor oil should be 1.25% (0.05%/1.250% = 0.04 ). APO1019,
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`951; APO1005, ¶94.
`
`Oddly, Allergan did not face an anticipation rejection during prosecution of
`
`the '930 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, ¶95. In re
`
`Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962).
`
`The challenged claims also would have been obvious. APO1005, ¶19. 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, ¶¶56 and 61. A
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`Petition for Inter Partes Review USPN 8,685,930
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`prior art publication of clinical trials testing 0.05% CsA in a castor oil emulsion
`
`reported that such emulsions were safe and efficacious. APO1004, 1; APO1005,
`
`¶20. And prior art patents taught the use of 1.25% castor oil emulsions with CsA
`
`for the treatment of dry eye. APO1002, 10, 3:49-53; APO1003, 3, 4:33-43;
`
`APO1005, ¶58. So before the September 2003 alleged priority date of the
`
`challenged patent, POSAs were well aware of ophthalmically-acceptable 1.25%
`
`castor oil emulsion formulations containing 0.05% CsA for treatment of dry eye.
`
`APO1003, 3, 4:33-43; APO1004, 1; APO1005, ¶58.
`
`Furthermore, during the prosecution of a parent application, Allergan
`
`admitted that its emulsions containing 0.05% CsA and 1.25% castor oil "would
`
`have been obvious" and that the differences between the claimed formulation and
`
`the prior art "are insignificant." APO1019, 951; APO1005, ¶177. Allergan also
`
`admitted that there would have been a reasonable expectation of success in arriving
`
`at a formulation containing 0.05% CsA and 1.25% castor oil because the
`
`differences between such a formulation and the prior art "are too small to believe
`
`otherwise." APO1019, 951; APO1005, ¶177. During prosecution of the challenged
`
`claims, Allergan asserted in that it was unexpected that the combination of 1.25%
`
`castor oil and 0.05% CsA would be "equally or more therapeutically effective for
`
`the treatment of dry eye/keratoconjunctivitis sicca than the [prior art] formulation
`
`containing 0.10% by weight cyclosporin A and 1.25% by weight castor oil. . . ."
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`Petition for Inter Partes Review USPN 8,685,930
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`APO1019, 1230, ¶14 (emphasis added). But equivalent performance does not meet
`
`the standard for unexpectedly superior results, and in any case, does not control the
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`conclusion of obviousness over a strong case based on the prior art. Bristol-Myers
`
`Squibb Co. v. Teva Pharm. USA, Inc. 752 F.3d 967, 977 (Fed. Cir. 2014); Pfizer,
`
`Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007).
`
`Allergan submitted data purporting to show that the tissue penetration of the
`
`CsA contained in the prior art 0.1% CsA emulsion was superior to the tissue
`
`penetration of the emulsion of the claimed methods containing 0.05% CsA.
`
`APO1019, 1254, ¶7; APO1005, ¶277. And because less CsA from the 0.05% CsA
`
`emulsion penetrated tissue compared to the 0.10% CsA emulsion, Allergan argued
`
`that it was surprising that the claimed (0.05% CsA) composition had equal or
`
`better clinical therapeutic value. APO1019, 1254, ¶7; APO1005, ¶277. But as
`
`discussed below, Allergan's arguments do not show unexpectedly superior results
`
`because the prior art taught that increasing the CsA concentration beyond 0.05%
`
`had no clinical benefit, and regardless, Allergan did not show its results were
`
`superior to the prior art formulations. APO1004, 1, Abstract; APO1005, ¶276-77;
`
`APO1007, ¶62.
`
`In contrast to Allergan’s arguments before the Patent Office, 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.
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`Petition for Inter Partes Review USPN 8,685,930
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`APO1004, 1; APO1023, 2; APO1005, ¶276. Therefore, POSAs were aware that, at
`
`0.05%, CsA was already at the top of the dose response curve. APO1005, ¶276.
`
`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, ¶277.
`
`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, ¶73; APO1007,
`
`¶36. Sall shows that there is no statistically significant difference between the
`
`0.05% and 0.10% CsA treatment groups for any of the efficacy measurements
`
`reported. APO1004, 4-6; APO1005, ¶276; APO1007, ¶45. Sall states, “[t]here was
`
`no dose-response effect.” APO1004, 1, Abstract; APO1005, ¶185. So, a POSA
`
`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,
`
`and 4-6; APO1005, ¶276; APO1007, ¶¶68, 72, 79, and 84. Therefore, Allergan did
`
`not show unexpectedly superior results of the claimed method compared to the
`
`closest prior art. APO1005, ¶269; APO1007, ¶¶44-45. Petitioner is at least
`
`reasonably likely to prevail in showing unpatentability, and trial should be
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`instituted.
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`Petition for Inter Partes Review USPN 8,685,930
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`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '930 patent is available for IPR and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the '930
`
`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
`
`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).
`
`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.
`
`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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`
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`correspondence regarding this Petition to counsel at the above addresses. Petitioner
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`Petition for Inter Partes Review USPN 8,685,930
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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 1-36. 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).
`
`VI. THE CLAIMS
`Each claim of the '930 patent recites a topical ophthalmic emulsion
`
`comprising 0.05% cyclosporin A, 1.25% castor oil together with various
`
`excipients. Claims 1, 13, and 25 are the independent claims. Claim 1 is exemplary
`
`and is reproduced below:
`
`Claim 1. A topical ophthalmic emulsion for treating an eye of a
`human having keratoconjunctivitis sicca, wherein
`the
`topical
`ophthalmic emulsion comprises cyclosporin A in an amount of about
`0.05% by weight, polysorbate 80, acrylate/C10-30 alkyl acrylate
`cross-polymer, water, and castor oil in an amount of about 1.25% by
`weight; and wherein
`the
`topical ophthalmic emulsion
`is
`therapeutically effective in treating keratoconjunctivitis sicca.
`Dependent claims 11, 23, and 35 recite that "when the topical emulsion is
`
`administered to the eye of a human in an effective amount in treating
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`Petition for Inter Partes Review USPN 8,685,930
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`keratoconjunctivitis sicca, the blood of the human has substantially no detectable
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`concentration of the cyclosporin A."
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`VII. A 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 '930 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
`
`formulation of topical ophthalmics or (ii) a Master's degree in chemistry,
`
`biochemistry, pharmaceutics, or in a related field in biological or chemical
`
`sciences, and have at least about five years of experience in formulation of topical
`
`ophthalmics.
`
`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
`
`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
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`Petition for Inter Partes Review USPN 8,685,930
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`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
`
`CsA, a well-known immunosuppressant compound, was shown to significantly
`
`reduce inflammation in patients with dry eye. APO1015, 7; APO1003, 2, 1:10-11,
`
`1:37-39; APO1005, ¶48. Kunert demonstrated a significant decrease in various
`
`inflammatory markers in dry eye patients after treatment with an emulsion
`
`containing 0.05% CsA. APO1015, 3; APO1005, ¶48. And Turner et al.
`
`subsequently published a study showing a similar decrease in an inflammatory
`
`marker when patients were treated with a 0.05% CsA emulsion in castor oil, but no
`
`decrease in the inflammatory marker when patients were treated with 0.1% CsA or
`
`vehicle. APO1016, 5; APO1005, ¶48. 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, ¶48.
`
`Additionally, castor oil in water emulsions – without cyclosporin or any
`
`other active agent – were known to provide therapeutic benefits for dry eye
`
`patients. APO1005, ¶53. And as explained by Dr. Xia, long retention of the castor
`
`oil on the surface of the eye was known to "retard water evaporation from the eye
`
`which alleviates dry eye symptoms." APO1005, ¶63, APO1002, 10, 4:1-3.
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`Petition for Inter Partes Review USPN 8,685,930
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`The art recognized that ocular treatment with castor oil emulsions resulted in
`
`
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`an increased lipid layer on the surface of the tear fluid which could prevent
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`evaporation and lead to increased aqueous tear presence on the ocular surface.
`
`APO1002, 10, 3:66-4:3; APO1005, ¶53.
`
`The '979 patent. U.S. Patent No. 5,474,979 to Ding et al. ("the '979 patent";
`
`APO1003) is entitled "Nonirritating emulsions for sensitive tissue." The '979
`
`patent 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 therefrom." APO1003, 2, 1:12-15; APO1005, ¶56. The '979 patent
`
`exemplifies topical ophthalmic emulsions having four different concentrations of
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`CsA and four different concentrations of castor oil – including 0.05% and 0.10%
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`CsA, and 1.25% and 0.625% castor oil. APO1003, 3, 4:33-43; APO1005, ¶58. In
`
`each of these examples, the excipients in the formulations remain in constant
`
`amounts – the same amounts claimed in the challenged claims. APO1003, 3, 4:33-
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`43; APO1005, ¶59. And the pH range exemplified in the Examples is the same as
`
`the range claimed in the challenged claims. APO1003, 3, 4:33-43; APO1005, ¶59.
`
`The '979 patent teaches that the ratio of CsA to castor oil preferably is below
`
`0.16. APO1003, 3, 3:16-17; APO1005, ¶59. And the '979 teaches that a "more
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`Petition for Inter Partes Review USPN 8,685,930
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`preferred" ratio of CsA to castor oil is "between 0.12 and 0.02." APO1003, 3, 3:17-
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`20; APO1005, ¶59.
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`The '607 Patent. U.S. Patent No. 5,981,607 ("the '607 patent"; APO1002) to
`
`Ding et al. is entitled "Emulsion eye drop for alleviation of dry eye related
`
`symptoms in dry eye patients and/or contact lens wearers." The '607 patent 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 dry eye. APO1002, 1, Abstract, and 11, 6:1-11; APO1005, ¶61. The
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`'607 patent states that the emulsion has "a high comfort level and low irritation
`
`potential . . . for alleviating dry eye symptoms." APO1002, 10, 3:32-38; APO1005,
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`¶61. The '607 patent teaches that "[m]ost importantly, the emulsion of the present
`
`invention provides for long retention of the higher fatty acid glyceride when the
`
`emulsion is instilled into an eye. This in turn can retard water evaporation from
`
`the eye which alleviates dry eye symptoms." APO1002, 10, 3:66-4:3 (emphasis
`
`added); APO1005, ¶63.
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`The '607 patent exemplifies topically-acceptable ophthalmic emulsions
`
`containing castor oil and the same excipients at the same concentrations claimed in
`
`the challenged patent. APO1002, 11, 6:1-11, Example 1A-D; APO1005, ¶66. The
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`'607 patent states that its emulsions can be used "to advantage" with CsA as set
`
`forth in the '979 patent. APO1002, 10, 3:48-50; APO1005, ¶70.
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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
`
`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
`
`material to be incorporated by reference with sufficient particularity." Advanced
`
`Display Systems, Inc. v. Kent State University, 212 F.3d 1272, 1283 (Fed. Cir.
`
`2000).
`
`As explained by Dr. Xia, a POSA would recognize that the '607 patent
`
`references the '979 patent four times. APO1005, ¶70.
`
` 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.
`
` The '607 patent states "U.S. Pat. No. 5,474,979 hereinabove referenced and
`
`incorporated herein by reference thereto...." APO1002, 11, 5:22-23.
`
` 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 polysorbate 80
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`with a high comfort level and low irritation potential." APO1002, 10, 3:25-31.
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` The '607 patent states, "The emulsion may also be used to advantage for
`
`introducing an active agent such as cyclosporine [sic] as set forth in parent U.S.
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`Pat. No. 5,474,979." APO1002, 10, 3:48-51.
`
`Based on any one of these four incorporation statements, a POSA would
`
`recognize that the entire '979 patent is incorporated into the '607 disclosure, and
`
`would also recognize that the '607 patent specifically highlights the CsA-related
`
`teachings of the incorporated '979 patent. APO1005, ¶¶71 & 183; Advanced
`
`Display Systems, Inc., 212 F.3d at 1283; see also Harari v. Lee, 656 F.3d 1331,
`
`1335 (Fed. Cir. 2011)(holding that "the entire . . . application disclosure was
`
`incorporated by the broad and unequivocal language: 'The disclosures of the two
`
`applications are hereby incorporate[d] by reference.'")
`
`Sall. In April 2000, Sall et al. published a scientific article entitled "Two
`
`multicenter, randomized studies of the efficacy and safety of cyclosporin emulsion
`
`in moderate to severe dry eye disease." ("Sall"; APO1004). Sall qualifies as prior
`
`art under 35 U.S.C. § 102(b).
`
`Sall reports the results of two clinical trials of topical ophthalmic castor oil
`
`emulsions in which "patients were treated twice daily with either CsA, 0.05% or
`
`0.1%, or vehicle." APO1004, 1, Abstract; APO1005, ¶73. Sall measured several
`
`efficacy parameters in the patients including tear production, severity of dry eye
`
`disease, and comfort of the emulsion. APO1004, 3; APO1005, ¶73. Sall also
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`monitored the safety of the emulsion by cataloging all adverse events and by
`
`measuring blood CsA concentrations in patients. APO1004, 3, 4, and 6-7, Tables 1
`
`and 3; APO1005, ¶73.
`
`Sall noted that the castor oil vehicle itself provided statistically significant
`
`benefits over baseline for several clinical parameters measured (APO1004, 8), and
`
`suggested that the benefit of the vehicle may be linked to the "sustained residence
`
`time of the oil component on the ocular surface, which may help reduce the
`
`evaporation of natural tears." APO1004, 8; APO1005, ¶79.
`
`Sall discussed previous studies showing that an emulsion of 0.05% CsA was
`
`effective at reducing inflammatory cytokines and other immune activation
`
`markers, taking special note of a previous report that treatment with 0.05% CsA
`
`helped to repair the goblet cells of the conjunctiva. ("This finding is of particular
`
`importance" because goblet cell regrowth may signal an improved tear quality.)
`
`APO1004, 8 (emphasis added); APO1005, ¶79. Sall concludes that "these findings
`
`add to the growing body of evidence demonstrating a beneficial effect of topical
`
`CsA on dry eye disease. . . ." APO1004, 7; APO1005, ¶80.
`
`Acheampong. In 1998, Acheampong et al. ("Acheampong"; APO1017)
`
`published a study entitled "Cyclosporin distribution into the conjunctiva, cornea,
`
`lacrimal gland, and systemic blood following topical dosing of cyclosporin to
`
`rabbit, dog, and human eyes." Acheampong qualifies as prior art under 35 U.S.C.
`
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`Petition for Inter Partes Review USPN 8,685,930
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`
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`§ 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, ¶82. Acheampong administered twice-daily CsA emulsions having
`
`0.05%, 0.1%, 0.2%, and 0.4% CsA to 162 human subjects for twelve weeks.
`
`APO1017, 4; APO1005, ¶82. Acheampong collected blood samples from subjects
`
`at morning drug level troughs, as well as 1, 2, and 4 hours after administration.
`
`APO1017, 4; APO1005, ¶82. Acheampong found that for the 0.05% CsA emulsion
`
`both the trough and maximal blood levels were below the limit of detection by
`
`LC/MS-MS (less than 0.1 ng/ml). See APO1017, 6, Table 1; APO1005, ¶83.
`
`IX. CLAIM CONSTRUCTION
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
`
`given their broadest reasonable interpretations (BRI) in light of the specification of
`
`the '930 patent. Terms not explicitly discussed below should be construed to have
`
`their plain and ordinary meanings consistent with the specification.
`
`Claims 4, 6, 9, 16, 18, 21, 28, 30, and 33 of the '930 patent recite that the
`
`topical ophthalmic emulsion has a "buffer." And dependent claims 5, 10, 17, 22,
`
`29, and 34 specify that "the buffer is sodium hydroxide." Based on the plain
`
`language of the claims, a POSA would understand that the patentee intended the
`
`term "buffer" to encompass sodium hydroxide. APO1005, ¶37. See Phillips v.
`
`AWH Corp., 415 F.3d 1303, 1313 ("the person of ordinary skill in the art is
`
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`Petition for Inter Partes Review USPN 8,685,930
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`
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`deemed to read the claim term . . . in the context of the entire patent, including the
`
`specification.")
`
`Claims 11, 23 and 35 recite a topical ophthalmic emulsion "wherein when
`
`administered to an eye of a human, the blood of a human has substantially no
`
`detectable concentration of the cyclosporin A." APO1001, 11, 15:6-10, 15:46-
`
`50, and 16:40-45 (emphasis added). The '930 patent states that the "[c]yclosporin
`
`component concentration in blood preferably is determined using a liquid
`
`chromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), which test
`
`has a cyclosporin component detection limit of 0.1 ng/ml. Cyclosporin component
`
`concentrations below or less than 0.1 ng/ml are therefore considered substantially
`
`undetectable." APO1001, 6, 5:27-33; APO1005, ¶38. Based on the express
`
`language of the specification of the '930 patent, a POSA would consider the blood
`
`of a human to have substantially no detectable concentration of the CsA if the
`
`topical ophthalmic emulsion resulted in a blood concentration of less than 0.1
`
`ng/ml. APO1005, ¶39.
`
`None of claims 11, 23 or 35 recites any particular time after treatment for
`
`measuring the blood levels of CsA. APO1005, ¶40. As explained by Dr. Xia, "a
`
`POSA administering ophthalmic CsA would be cognizant of potential systemic
`
`effects if CsA levels in the blood became elevated." APO1005, ¶40. As Dr. Xia
`
`explains, "POSAs typically measure blood concentration in two possible ways: 1)
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`Petition for Inter Partes Review USPN 8,685,930
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`
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`in a time course by administering an ophthalmic preparation, taking serial blood
`
`sample time points, and determining peak/maximal concentration; or 2) after many
`
`days of administration of a drug, by taking a trough level blood sample just before
`
`a next dose is administered." APO1005, ¶40; APO1018, 3-4; APO1017, 4.
`
`Accordingly, a POSA would understand blood samples for CsA measurement
`
`could be taken at time points reflecting trough or peak levels. APO1005, ¶41.
`
`Independent claims 1, 13, and 25
`
`recite
`
`that
`
`the emulsion
`
`is
`
`"therapeutically effective." The
`
`'930 patent does not specifically define
`
`"therapeutically effective." APO1005, ¶42. However, the '930 patent states that the
`
`invention relates to "administering to an eye of a human or animal a therapeutically
`
`effective amount of a cyclosporin component to provide a desired therapeutic
`
`effect, preferably a desired ophthalmic or ocular therapeutic effect." APO1001, 4,
`
`1:20-24; APO1005, ¶42. A POSA would understand "therapeutically effective"
`
`according to its plain and ordinary meaning which is capable of achieving a desired
`
`result. APO1005, ¶42.
`
`X.
`
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 42.104(b))
`Apotex requests inter partes review of each claim of the '930 patent based
`
`on the grounds for unpatentability listed in the index below. Per 37 C.F.R.
`
`§ 42.6(d), copies of the references are filed herewith.
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`Ground 35 U.S.C. Section
`(pre-3/16/2013)
`1
`§ 102
`
`2
`
`3
`
`§ 103
`
`§ 103
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`Petition for Inter Partes Review USPN 8,685,930
`
`
`Index of References
`
`'930 Patent Claims
`
`'979 patent
`'607 patent, (the
`incorporated '979 patent),
`and Sall.
`'607 patent, (the
`incorporated '979 patent),
`Sall, and Acheampong.
`
`1-36
`1-10, 12-22, 24- 34
`and 36
`
`11, 23 and 35
`
` Grounds 1- 3 are not redundant. Ground 1 shows that each of the claims of
`
`the '930 patent is anticipated. Grounds 2 and 3 are not cumulative to Ground 1
`
`because they require resolution of different issues. For example, in assessing
`
`Ground 1, the Board will likely consider whether the cited art discloses a
`
`sufficiently small genus to anticipate each claim and whether certain limitations are
`
`inherent features of the emulsion. These issues are not present in Grounds 2 and 3;
`
`but in assessing Grounds 2 and 3, the Board will likely consider whether objective
`
`evidence of non-obviousness supports patentability, which is not relevant to
`
`Ground 1. Petitioner is reasonably likely to prevail in challenging the patentability
`
`of claims 1-36 on the basis of each ground and requests that trial be instituted
`
`accordingly.
`
`A. Ground 1: Claims 1-36 are anticipated by the '979 patent
`Independent Claims 1, 13 and 25: The anticipatory teachings detailed
`
`below for claim 25 also anticipate claims 1 and 13, but claim 25 specifies the most
`
`limitations. Accordingly, a claim chart is provided for independent claim 25, which
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`Petition for Inter Partes Review USPN 8,685,930
`
`
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`shows that each element of claim 25 is taught by the '979 patent. As noted in the
`
`chart below, claims 1 and 25 recite "keratoconjunctivitis sicca" while claim 13
`
`Disclosure of U.S. Patent No. 5,474,979
`"[A] nonirritating emulsion . . . suitable for topical
`application to ocular tissues . . ." APO1003, 4, 6:3-7
`(emphasis added).
`"The activity of cyclosporins, . . . is as an
`immunosuppressant and in the enhancement or
`restoring of lacrimal gland tearing." APO1003, 2,
`1:37-39.
`"Cyclosporins . . . [have] known immunosuppressant
`activity . . . effective in treating immune medicated
`[sic: mediated] keratoconjunctivitis sicca (KSC or
`dry eye disease) in a patient suffering therefrom."
`APO1003, 2, 1:10–16.
`"Cyclosporins . . . [have] known immunosuppressant
`activity . . . effective in treating immune medicated
`[sic: mediated] keratoconjunctivitis sicca (KSC or
`dry eye disease) in a patient suffering therefrom."
`APO1003, 2, 1:10-16.
`
`"The formulations set forth in Examples 1‐4 were
`
`made for treatment of keratoconjunctivitis sicca
`(dry eye) syndrome . . . ." APO1003, 4, 5:9-11.
`
`recites "dry eye."
`
`Claims 1, 13, & 25
`A topical ophthalmic
`emulsion for increasing
`tear production in an eye
`of a human
`
`
`[claims 1 & 25: "having
`keratoconjunctivitis
`sicca"]; [claim 13:
`"having dry eye"]
`
`wherein the topical
`ophthalmic emulsion
`comprises
`cyclosporin A in an
`amount of about 0.05%
`by weight,
`
`APO1003, 3, 4:33-43.
`"Preferably, . . . a weight ratio of the cyclosporin to
`castor oil is below 0.16. More preferably, . . . the
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`Petition for Inter Partes Review USPN 8,685,930
`
`
`Disclosure of U.S. Patent No. 5,474,979
`weight ratio of cyclosporin to castor oil is between
`0.12 and 0.02." APO1003, 3, 3:15-20.
`The weight ratio of 0.05% Cyclosporin A and 1.25%
`Castor oil is 0.04. APO1005, ¶92.
`See Example 1D showing polysorbate 80. APO1003,
`3, 4:33-43.
`See Example 1D showing Pemulen. APO1003, 3,
`4:33-43.
`"Pemulens are Acrylates/C10–30 Alkyl Acrylate
`
`Cross‐Polymers." APO1003, 3, 4:4-5.
`
`See Example 1D showing water.