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. 8,648,048 to Acheampong et al.
`Issue Date: February 11, 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. 8,648,048 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 8,648,048
`
`I. 
`II. 
`III. 
`
`B. 
`
`C. 
`
`TABLE OF CONTENTS
`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)) ..................................... 5 
`V. 
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFORE (37 C.F.R. § 42.22(A)) ............................... 6 
`VI.  THE CLAIMS ................................................................................................ 6 
`VII.  PERSON OF ORDINARY SKILL IN THE ART ......................................... 8 
`VIII.  STATE OF THE ART .................................................................................... 9 
`IX.  CLAIM CONSTRUCTION ......................................................................... 17 
`X. 
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. §
`42.104(b)) ..................................................................................................... 21 
`A.  Ground 1: Claims 1-10, 12-14, 16-20, 22 and 23 would have
`been obvious over the '607 patent, the incorporated '979
`patent and Sall et al. ............................................................................ 22 
`Ground 2: Claims 11 and 21 Would Have Been Obvious
`Over the '607 patent, the incorporated '979 patent, Sall et al.,
`and Acheampong et al. ........................................................................ 45 
`Ground 3: Claim 15 Would Have Been Obvious Over the
`'607 patent, the incorporated '979 patent, Sall et al., and the
`'586 patent ............................................................................................ 47 
`D.  Objective indicia of nonobviousness .................................................. 49 
`1. 
`Allergan's allegations of objective indicia are
`insufficient to show nonobviousness ....................................... 50 
`XI.  CONCLUSION ............................................................................................. 60 
`
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`

`
`
`I.
`
`Petition for Inter Partes Review USPN 8,648,048
`
`
`INTRODUCTION
`Apotex Corp. and Apotex, Inc. petition for Inter Partes Review, seeking
`
`cancellation of claims 1-23 of U.S. Patent No 8,648,048 to Acheampong et al.
`
`("the '048 patent") (APO1001), which is purportedly owned by Allergan, Inc.
`
`II. OVERVIEW
`The claims of the '048 patent should be cancelled. They recite methods of
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`administering topical ophthalmic emulsions known to be useful for treating dry eye
`
`disease (also referred to as keratocunjunctivitis sicca or KCS (APO1003, 1:14-
`
`15))and increasing tear production in humans by administering the emulsion twice
`
`a day. APO1005, ¶¶4 and 15. The claimed methods use emulsions that contain
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`cyclosporin A (CsA) at 0.05% and castor oil at 1.25%, along with excipients at
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`identical concentrations to those taught in the art. (Percent values refer to percent
`
`weight throughout this petition.) APO1005, ¶¶4 and 168.
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`Both CsA and castor oil were known in the prior art as useful agents to treat
`
`dry eye/KCS and increase tear production. APO1002, 11, 6:25-28; APO1003, 4,
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`5:9-12; APO1004, 1; APO1005, ¶¶17, 58, and 63. A prior art publication of
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`clinical trials testing 0.05% CsA in a castor oil emulsion reported that such
`
`emulsions were safe and efficacious when administered twice a day. APO1004, 1;
`
`APO1005, ¶17. And prior art patents taught the use of 1.25% castor oil emulsions
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`with CsA for increasing tear production and for the treatment of dry eye/KCS.
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`

`

`Petition for Inter Partes Review USPN 8,648,048
`
`
`
`APO1002, 10, 3:49-53; APO1003, 3, 4:33-43; APO1005, ¶60. So, before the
`
`September 2003 alleged priority date of the challenged patent, POSAs were well
`
`aware of methods of treatment using ophthalmically-acceptable castor oil emulsion
`
`formulations containing 0.05% CsA for treatment of dry eye disease/KCS and
`
`increasing tear production. APO1003, 3, 4:33-43, APO1004, 1; APO1005, ¶60.
`
`Furthermore, during prosecution of a parent application, Allergan admitted
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`that its emulsions containing 0.05% CsA and 1.25% castor oil would have been
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`"readily envisaged" and "would have been obvious" and that the differences
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`between the claimed formulation and the prior art "are insignificant." APO1019,
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`951; APO1005, ¶98. Allergan also admitted that there would have been a
`
`reasonable expectation of success in arriving at a formulation containing 0.05%
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`CsA and 1.25% castor oil because the differences between such a formulation and
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`the prior art "are too small to believe otherwise." APO1019, 951; APO1005, ¶98.
`
`During prosecution of the challenged claims, Allergan asserted that it was
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`unexpected that the combination of 1.25% castor oil and 0.05% CsA would be
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`"equally or more
`
`therapeutically effective
`
`for
`
`the
`
`treatment of dry
`
`eye/keratoconjunctivitis sicca than the [prior art] formulation containing 0.10% by
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`weight cyclosporin A and 1.25% by weight castor oil. . . ." APO1019, 1649, ¶14
`
`(emphasis added). But equivalent performance does not meet the standard for
`
`unexpectedly superior results, and in any case, does not control the conclusion of
`
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`- 2 -
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`

`

`Petition for Inter Partes Review USPN 8,648,048
`
`
`
`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, 1673, ¶7; APO1005, ¶238. 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, 1673, ¶7; APO1005, ¶238. But as
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`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; APO1005, ¶238; APO1007,
`
`¶45.
`
`In contrast to Allergan’s arguments before the Patent Office, prior art studies
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`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, ¶237. Therefore, POSAs were aware that, at
`
`0.05%, CsA was already at the top of the dose response curve. APO1005, ¶237.
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`Petition for Inter Partes Review USPN 8,648,048
`
`
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`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, ¶238.
`
`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, ¶75; 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, ¶237; APO1007, ¶45. Sall states, “[t]here was
`
`no dose-response effect.” APO1004, 1, Abstract; APO1005, ¶237. 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 concentration in the ocular tissue. APO1004,
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`1, Abstract, and 4-6; APO1005, ¶237; 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, ¶230; APO1007, ¶¶44-45. Petitioner
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`is at least reasonably likely to prevail in showing unpatentability, and trial should
`
`be instituted.
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`- 4 -
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`

`

`Petition for Inter Partes Review USPN 8,648,048
`
`
`
`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '048 patent is available for IPR and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the '048
`
`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).
`
`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.
`
`Designation of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)):
`Lead Counsel
`Back-Up Counsel
`Ralph W. Powers III (Reg. No. 63,504 )
`Eldora L. Ellison (Reg. No. 39,967)
`STERNE, KESSLER, GOLDSTEIN & FOX
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`P.L.L.C.
`1100 New York Avenue, NW
`1100 New York Avenue, NW
`Washington, DC 20005
`Washington, DC 20005
`202.772.8508 (telephone)
`202.772.8876 (telephone)
`202.371.2540 (facsimile)
`202.371.2540 (facsimile)
`eellison-PTAB@skgf.com
`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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`
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`- 5 -
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`

`
`V.
`
`Petition for Inter Partes Review USPN 8,648,048
`
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(A))
`
`Petitioner requests IPR and cancellation of claims 1-23. 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
`The claims of the '048 patent recite treatment methods comprising topically
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`administering twice a day to the eye of a human an ophthalmic emulsion
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`comprising 0.05% cyclosporin A and 1.25% castor oil together with various
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`excipients to increase tear production or treat KCS. Claims 1, 18, and 22 are the
`
`independent claims. Claim 1 recites:
`
`1. A method of increasing tear production in the eye of a human, the
`method comprising topically administering to the eye of the human in
`need thereof an emulsion at a frequency of twice a day, wherein the
`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 effective in increasing tear
`production.
`
`
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`- 6 -
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`

`

`Petition for Inter Partes Review USPN 8,648,048
`
`
`Claim 15 specifies that the "emulsion breaks down more quickly in the eye
`
`
`
`of a human once administered to the eye of the human . . . compared to a second
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`emulsion that contains only 50% as much castor oil." Claim 16 specifies that the
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`emulsion "demonstrates a reduction in adverse event in the human, relative to a
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`second emulsion . . . comprising cyclosporin A in an amount of 0.1%" with an
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`equal amount of castor oil.
`
`Claim 18 recites:
`
` 18. A method of treating keratoconjunctivitis sicca, the method
`comprising the step of topically administering to an eye of a human in
`need thereof an emulsion at a frequency of twice a day, the emulsion
`comprising: cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight; polysorbate 80 in
`an amount of about 1.0% by weight; acrylate/C10-30 alkyl acrylate
`cross-polymer in an amount of about 0.05% by weight; a tonicity
`component or a demulcent component in an amount of about 2.2% by
`weight; a buffer; and water; wherein the emulsion is effective in
`treating keratoconjunctivitis sicca and wherein the topical ophthalmic
`emulsion has a pH in the range of about 7.2 to about 7.6.
`And claims 11 and 21 specify that "when the emulsion is administered to the
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`eye of a human . . . the blood of the human has substantially no detectable
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`concentration of cyclosporin A."
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`

`

`Petition for Inter Partes Review USPN 8,648,048
`
`
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`VII. PERSON OF ORDINARY SKILL IN THE ART
`A 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
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`ordinary creativity. With respect to the subject matter of the '048 patent, a POSA
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`would typically have had (i) an M.D. or a Ph.D. in chemistry, biochemistry,
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`pharmaceutics, or in a related field in the biological or chemical sciences, and have
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`at least about two years of experience in the formulation of topical ophthalmics or
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`(ii) a Master's degree in chemistry, biochemistry, pharmaceutics, or in a related
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`field in the biological or chemical sciences, and have at least about five years of
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`experience in formulation of topical ophthalmics.
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`A POSA typically would work as part of a multi-disciplinary team and draw
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`upon not only his or her own skills, but also take advantage of certain specialized
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`skills of others in the team to solve a given problem. For example, a clinician
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`having experience in treating dry eye may be part of the team. As of the September
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`2003 earliest possible priority date of the '048 patent, the state of the art included
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`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
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`important information and references relating to dry eye, its causes, and useful
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`treatments.
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`Petition for Inter Partes Review USPN 8,648,048
`
`
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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; APO1003, 2, 1:10-11
`
`and 1:37-39; APO1005, ¶50. Kunert demonstrated a significant decrease 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, ¶50. 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 in the inflammatory marker when patients were treated with 0.1% CsA or
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`vehicle. APO1016, 5; APO1005, ¶50. Accordingly, before September 2003, castor
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`oil emulsions of 0.05% CsA were known to reduce the inflammation associated
`
`with dye eye disease. APO1015, 3; APO1016, 1, Abstract; APO1018, 2;
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`APO1005, ¶50.
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`Additionally, castor oil in water emulsions – without cyclosporin or any
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`other active agent – were known to provide therapeutic benefits for dry eye
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`patients. APO1005, ¶55. And as explained by Dr. Xia, extended retention of the
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`castor oil on the surface of the eye was known to "retard water evaporation from
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`the eye which alleviates dry eye symptoms." APO1005, ¶65, APO1002, 10, 4:1-3.
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`The art recognized that ocular treatment with castor oil emulsions resulted in an
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`Petition for Inter Partes Review USPN 8,648,048
`
`
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`increased lipid layer on the surface of the tear fluid which could prevent
`
`evaporation and lead to increased aqueous tear presence on the ocular surface.
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`APO1002, 10, 3:66-4:3; APO1005, ¶55.
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`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
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`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
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`immune medicated [sic] karatocunjunctivitis sicca (KCS or dry eye disease) in a
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`patient suffering therefrom." APO1003, 2, 1:12-15; APO1005, ¶58. More
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`specifically, the '979 patent states that "[t]he activity of cyclosporines . . . is as an
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`immunosuppressant and in the enhancement or restoring of lacrimal gland tearing."
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`APO1003, 2, 1:37-39; APO1005, ¶58.
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`The '979 patent exemplifies topical ophthalmic emulsions having four
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`different concentrations of CsA and four different concentrations of castor oil –
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`including 0.05% and 0.10% CsA, and 1.25% and 0.625% castor oil. APO1003, 3,
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`4:33-43; APO1005, ¶60. In each of these examples, the excipients in the
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`formulations remain in constant amounts – the same amounts claimed in the
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`challenged claims. APO1003, 3, 4:33-43; APO1005, ¶61. And the pH range
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`exemplified in the Examples is the same as the range claimed in the challenged
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`claims. APO1003, 3, 4:33-43; APO1005, ¶61.
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`Petition for Inter Partes Review USPN 8,648,048
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`The '979 patent teaches that the ratio of CsA to castor oil preferably is below
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`
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`0.16. APO1003, 3, 3:16-17; APO1005, ¶61. And the '979 teaches that a "more
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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, ¶61.
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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. is entitled "Emulsion eye drop for alleviation of dry eye related
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`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
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`teaches topical ophthalmic castor oil emulsions for the treatment of dry eye.
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`APO1002, 1, Abstract, and 11, 6:1-11; APO1005, ¶63. The '607 patent states that
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`the emulsion has "a high comfort level and low irritation potential . . . for
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`alleviating dry eye symptoms." APO1002, 10, 3:32-38; APO1005, ¶63. The '607
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`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, ¶65. The '607 patent further states that "the instillation of the emulsion
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`increases the measured tear volume." APO1002, 11, 6:61-63; APO1005, ¶65.
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`The '607 patent exemplifies topically-acceptable ophthalmic emulsions
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`containing castor oil and the same excipients at the same concentrations claimed in
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`Petition for Inter Partes Review USPN 8,648,048
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`
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`the challenged patent. APO1002, 11, 6:1-11; APO1005, ¶68. The '607 patent states
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`that its emulsions can be used "to advantage" with CsA as set forth in the '979
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`patent. APO1002, 10, 3:48-50; APO1005, ¶72.
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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
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`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 University, 212 F.3d 1272, 1283 (Fed. Cir.
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`2000).
`
`As explained by Dr. Xia, a POSA would recognize that the '607 patent
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`references the '979 patent four times. APO1005, ¶72.
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` 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
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`specific reference thereto." APO1002, 9, 1:6-12; APO1005, ¶72.
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` The '607 patent states "U.S. Pat. No. 5,474,979 hereinabove referenced and
`
`incorporated herein by reference thereto...." APO1002, 11, 5:22-23; APO1005,
`
`¶72.
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` The '607 patent states that "U.S. Pat. No. 5,474,979, hereinabove referenced and
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`incorporated herein by reference thereto, teaches . . . a novel ophthalmic
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`
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`Petition for Intter Partes
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`Review USSPN 8,6488,048
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`emu
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`lsion incluuding cycloosporin in
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`admixture
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`te 80 polysorbat with castoor oil and p
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`withh a high coomfort leveel and low
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`irritation
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`
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`potential."" APO10022, 10, 3:255-31;
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`APOO1005, ¶722.
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` The
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`'607 pateent states,
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`"The emuulsion maay also bee used to
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`advantagee for
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`introoducing an
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`active ageent such ass cyclosporrine [sic] aas set forthh in parent
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`U.S.
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`Pat. No. 5,474,,979." APOO1002, 10,, 3:48-51; AAPO1005,, ¶72.
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`BBased on aany one off these fouur incorpooration stattements, aa POSA wwould
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`recognize that thee entire '9779 patent iis incorporrated into
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`the '607 ddisclosure,
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` and
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`would aalso recognize that tthe '607 paatent spec
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`ifically higghlights thhe CsA-rellated
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`teachinggs of the
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`incorporatted '979 ppatent. APPO1005, ¶¶¶73 and 1105; Advannced
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`Displayy Systems,
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`Inc., 212
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`F.3d at 12283; see allso Hararii v. Lee, 6656 F.3d 1
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`1335 (FFed. Cir.
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`2011)(hollding that
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`"the entiire [] appplication ddisclosure
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`incorporated by thhe broad aand unequiivocal langguage: 'Thhe disclosuures of the
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`applicattions are heereby incoorporate[d] by referennce'")
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`SSall et al.
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`In April 22000, Sall
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`et al. pubblished a
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`scientific
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`article enttitled
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`"Two mmulticenterr, randomized studiees of the eefficacy annd safety
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`of cyclospporin
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`emulsioon in modeerate to sevvere dry eyye disease.
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`" ("Sall"; AAPO1004)). Sall quallifies
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`as priorr art under 35 U.S.C. § 102(b).
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`SSall reportss the resultts of two cclinical triaals of topiccal ophthaalmic castoor oil
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`emulsioons in whiich humann "patientss were treaated twicee daily witth either CCsA,
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`Petition for Inter Partes Review USPN 8,648,048
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`0.05% or 0.1%, or vehicle." APO1004, 1-2, Abstract; APO1005, ¶75. Sall
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`measured several efficacy parameters in the patients including tear production,
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`severity of dry eye disease, and comfort of the emulsion. APO1004, 3; APO1005,
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`¶75. Sall also monitored the safety of the emulsion by cataloging all adverse events
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`and by measuring blood CsA concentrations in patients. APO1004, 3, 4, and 6-7,
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`Tables 1 and 3; APO1005, ¶75.
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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, ¶81.
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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.)
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`APO1004, 8 (emphasis added); APO1005, ¶82. Sall found that “[t]here was no
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`dose response effect” of the cyclosporin treatment between the 0.05% and 0.1%
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`CsA concentrations. APO1004, 1, Abstract; APO1005, ¶80. Sall concludes that
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`Petition for Inter Partes Review USPN 8,648,048
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`"these findings add to the growing body of evidence demonstrating a beneficial
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`effect of topical CsA on dry eye disease. . . ." APO1004, 7; APO1005, ¶82.
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`Acheampong et al. In 1998, Acheampong et al. ("Acheampong";
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`APO1017) published a study entitled "Cyclosporin distribution
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`into
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`the
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`conjunctiva, cornea, lacrimal gland, and systemic blood following topical dosing of
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`cyclosporin to rabbit, dog, and human eyes." Acheampong qualifies as prior art
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`under 35 U.S.C. § 102(b). Acheampong administered a CsA topical emulsion to
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`human subjects and measured their resultant CsA blood levels at various time
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`points. APO1017, 4; APO1005, ¶84. Acheampong administered twice-daily CsA
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`emulsions having 0.05%, 0.1%, 0.2%, and 0.4% CsA to 162 human subjects for
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`twelve weeks. APO1017, 4; APO1005, ¶84. Acheampong collected blood samples
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`from subjects at morning drug level troughs, as well as 1, 2, and 4 hours after
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`administration. APO1017, 4; APO1005, ¶84. Acheampong found that for the
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`0.05% CsA emulsion both the trough and maximal blood levels were below the
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`limit of detection by LC/MS-MS (less than 0.1 ng/ml). See APO1017, 6, Table 1;
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`APO1005, ¶85.
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`The '586 patent. U.S. Patent No. 5,578,586 ("the '586 patent"; APO1031)
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`to Glonek et al. is entitled "Aqueous film coating for wetting eye surfaces." The
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`'586 patent issued on November 26, 1996, and is prior art under 35 U.S.C.
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`§ 102(b).
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`Petition for Inter Partes Review USPN 8,648,048
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`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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`film. Consequently, blurring is likely to occur until the emulsion differentiates."
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`APO1031, 4, 6:37-42; APO1005, ¶87. 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, ¶87.
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`The '586 patent compared the effects of increasing the surfactant to oil ratio
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`in several emulsions by keeping the oil concentration constant and successively
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`increasing the surfactant concentration. APO1031, 11, 20:24-25; APO1005, ¶89.
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`The '586 patent reports that the best results were obtained at an intermediate
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`concentration range of the surfactant, while higher concentrations of surfactant led
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`to increased blurring because the emulsion did not break down appropriately
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`quickly in the eye. APO1031, 11, 20:27-30; APO1005, ¶89. As Dr. Xia explains,
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`"the '586 patent teaches that higher surfactant to oil ratios can result in an
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`excessively stable ophthalmic emulsion that can cause blurring upon application to
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`the eye." APO1005, ¶90. Additionally, as explained by Dr. Xia, based on the
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`teachings of the '586 patent together with the background knowledge in the art, a
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`POSA would have recognized that "the surfactant to oil ratio affects the emulsion
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`Petition for Inter Partes Review USPN 8,648,048
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`break time, with higher relative amounts of oil causing the emulsion to break more
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`rapidly upon instillation to the eye." APO1005, ¶90.
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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 '048 patent. Terms not explicitly discussed below should be construed to have
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`their plain and ordinary meanings consistent with the specification.
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`Claims 4, 6, 9, and 18 of the '048 patent recite that the emulsion of the
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`claimed method comprises a "buffer." APO1001, 11, 15:28-29, 15:32-33, 15: 39-
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`41, and 16:17-32. And dependent claims 5, 10 and 19 specify that "the buffer is
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`sodium hydroxide." APO1001, 11, 15:30-31, 15:42-43, and 16:33-34. Based on the
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`plain language of the claims, a POSA would understand that the patentee intended
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`the term "buffer" to encompass sodium hydroxide. APO1005, ¶35. See Phillips v.
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`AWH Corp., 415 F.3d 1303, 1313 ("the person of ordinary skill in the art is
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`deemed to read the claim term not only in the context of the particular claim in
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`which the disputed term appears, but in the context of the entire patent, including
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`the specification.")
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`Claim 11 recites a method wherein when the topical ophthalmic emulsion "is
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`administered to an eye of a human in an effective amount in increasing tear
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`production, the blood of a human has substantially no detectable concentration
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`Petition for Inter Partes Review USPN 8,648,048
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`of the cyclosporin A." APO1001, 11, 15:44-47 (emphasis added). Claim 21
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`contains a similar limitation and states "wherein, when the emulsion is
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`administered to the eye of a human in an effective amount in treating
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`keratoconjunctivitis sicca, the blood of a human has substantially no detectable
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`concentration of the cyclosporin A." APO1001, 11, 16:37-41 (emphasis added).
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`The '048 patent states that the "[c]yclosporin component concentration in blood
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`preferably is determined using a liquid chromatography-mass spectroscopy-mass
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`spectroscopy (LC-MS/MS), which test has a cyclosporin component detection
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`limit of 0.1 ng/ml. Cyclosporin component concentrations below or less than 0.1
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`ng/ml are therefore considered substantially undetectable." APO1001, 6, 5:64-6:3;
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`APO1005, ¶36.
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`Based on the express language of the specification of the '048 patent, a
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`POSA would consider the blood of a human to have substantially no detectable
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`concentration of the CsA if the treatment method resulted in a blood concentration
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`of less than 0.1 ng/ml. APO1005, ¶37.
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`Neither claim 11 nor 21 recites any particular time after treatment for
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`measuring the blood levels of CsA. APO1005, ¶38. 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, ¶38. As Dr. Xia
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`explains, "POSAs typically measure blood concentration in two possible ways: 1)
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`Petition for Inter Partes Review USPN 8,648,048
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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, ¶38; 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, ¶39.
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`Claims 1, 13, 14, 18, and 22 recite that the emulsion is "effective,"
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`"substantially therapeutically effective as a second emulsion," or achieves "at
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`least as much therapeutic effectiveness as a second emulsion." The '048 patent
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`does not specifically define these terms. APO1005, ¶40. However, the '048 patent
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`states that the invention relates to "administering to an eye of a human or animal a
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`therapeutically effective amount of a cyclosporin component to provide a desired
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`therapeutic effect, preferably a desired ophthalmic or ocular therapeutic effect."
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`APO1001, 4, 1:21-25; APO1005, ¶40. In the context of the claims, a POSA would
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`understand "effective" according to its plain and ordinary meaning which is
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`capable of achieving a desired result. APO1005, ¶40. Similarly, a POSA would
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`understand "substantially therapeutically effective as a second emulsion" according
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`to its plain and ordinary meaning, which is that the claimed emulsion is capable
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`achieving a desired result approximately as well as treatment with a second
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`emulsion. APO1005, ¶41. Likewise, a POSA would understand "at least as much
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`Petition for Inter Partes Review USPN 8,648,048
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`therapeutic effectiveness as a second emulsion" according to its plain and ordinary
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`m