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. 8,633,162 to Acheampong et al.
`Issue Date: January 21, 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. 8,633,162 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 8,633,162
`
`TABLE OF CONTENTS
`
`I. 
`II. 
`III. 
`
`B. 
`
`C. 
`
`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 ......................................... 7 
`VIII.  STATE OF THE ART .................................................................................... 8 
`IX.  CLAIM CONSTRUCTION ......................................................................... 16 
`X. 
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 42.104(b)) ....... 20 
`A.  Ground 1: Claims 1-10, 12-14, 16-20, and 22-24 would have
`been obvious over the '607 patent, the incorporated '979
`patent and Sall et al. ............................................................................ 21 
`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, and the '586
`patent ................................................................................................... 47 
`D.  Objective indicia of nonobviousness .................................................. 50 
`1. 
`Allergan's allegations of objective indicia are
`insufficient to show nonobviousness ....................................... 50 
`(a)  Allergan cannot show unexpectedly superior
`results ............................................................................. 50 
`There was no long-felt need satisfied by the
`claimed invention and no failure of others .................... 55 
`(c)  Allergan did not show industry praise ........................... 58 
`(d)  Allergan did not show commercial success ................... 58 
`XI.  CONCLUSION ............................................................................................. 60 
`
`(b) 
`
`
`
`
`- i -
`
`

`

`
`I.
`
`Petition for Inter Partes Review USPN 8,633,162
`
`
`INTRODUCTION
`APOTEX CORP. and APOTEX, INC. petition for Inter Partes Review, seeking
`
`cancellation of claims of U.S. Patent No 8,633,162 to Acheampong et al. ("the
`
`'162 patent") (APO1001), which is purportedly owned by ALLERGAN, INC.
`
`II. OVERVIEW
`The claims of the '162 patent should be cancelled. They recite methods of
`
`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. APO1003, 1:14-15;APO1005, ¶¶4 and 15. The claimed methods use
`
`emulsions that 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, ¶¶4 and 168.
`
`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,
`
`5:9-12; APO1004, 1; APO1005, ¶¶17, 58, and 63. A prior art publication of
`
`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
`
`with CsA for increasing tear production and for the treatment of dry eye/KCS.
`
`
`
`- 1 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`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
`
`that its emulsions containing 0.05% CsA and 1.25% castor oil would have been
`
`"readily envisaged" and "would have been obvious" and that the differences
`
`between the claimed formulation and the prior art "are insignificant." APO1019,
`
`951; APO1005, ¶98. 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, ¶98.
`
`During prosecution of the challenged claims, Allergan asserted 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. . . ." APO1019, 2133, ¶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
`
`
`
`- 2 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`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, 2157, ¶7; APO1005, ¶242. 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, 2157, ¶7; APO1005, ¶242. 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; APO1005, ¶242; APO1007,
`
`¶45.
`
`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.
`
`APO1004, 1; APO1023, 2; APO1005, ¶241. Therefore, POSAs were aware that, at
`
`0.05%, CsA was already at the top of the dose response curve. APO1005, ¶241.
`
`
`
`- 3 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`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, ¶242.
`
`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, ¶241; APO1007, ¶45. Sall states, “[t]here was
`
`no dose-response effect.” APO1004, 1, Abstract; APO1005, ¶80. 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, ¶241; 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, ¶234; APO1007, ¶¶44-45. Petitioner is at least
`
`reasonably likely to prevail in showing unpatentability, and trial should be
`
`instituted.
`
`
`
`- 4 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '162 patent is available for IPR and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the '162
`
`patent. This Petition is filed in accordance with 37 CFR § 42.106(a). A Power of
`
`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
`
`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
`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
`
`correspondence regarding this Petition to counsel at the above addresses. Petitioner
`
`consents to service by email at the addresses above.
`
`
`
`- 5 -
`
`

`

`
`V.
`
`Petition for Inter Partes Review USPN 8,633,162
`
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(A))
`
`Petitioner requests IPR and cancellation of claims 1-24. Petitioner's full
`
`statement of the reasons for the relief requested is set forth in detail in § X.
`
`VI. THE CLAIMS
`The claims of the '162 patent recite treatment methods comprising topically
`
`administering twice a day to the eye of a human an ophthalmic emulsion
`
`comprising 0.05% cyclosporin A and 1.25% castor oil together with various
`
`excipients to treat dry eye disease. Claims 1, 18, and 23 are the independent
`
`claims. Claim 1 is exemplary and is reproduced below:
`
`1. A method of treating dry eye disease, the method comprising
`topically administering to the eye of a 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 treating dry eye
`disease.
`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
`
`emulsion that contains only 50% as much castor oil." Claim 16 specifies that the
`
`emulsion "demonstrates a reduction in adverse event in the human, relative to a
`
`
`
`- 6 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`second emulsion . . . comprising cyclosporin A in an amount of 0.1% " with an
`
`equal amount of castor oil. And claims 11 and 21 specify that "when the emulsion
`
`is administered to the eye of a human . . . the blood of the human has substantially
`
`no detectable concentration of cyclosporin A."
`
`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
`
`ordinary creativity. With respect to the subject matter of the '162 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 the 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 the biological or chemical sciences, and have at least about five years of
`
`experience in formulation of topical ophthalmics.
`
`A POSA 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 the September
`
`2003 earliest possible priority date of the '162 patent, the state of the art included
`
`the teachings provided by the references discussed in each of the unpatentability
`
`
`
`- 7 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`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.
`
`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
`
`and 1:37-39; APO1005, ¶50. 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, ¶50. 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, ¶50. 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, ¶50.
`
`Additionally, castor oil in water emulsions – without cyclosporin or any
`
`other active agent – were known to provide therapeutic benefits for dry eye
`
`patients. APO1005, ¶55. And as explained by Dr. Xia, extended retention of the
`
`
`
`- 8 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`castor oil on the surface of the eye was known to "retard water evaporation from
`
`the eye which alleviates dry eye symptoms." APO1005, ¶65, APO1002, 10, 4:1-3.
`
`The art recognized that ocular treatment with castor oil emulsions resulted in an
`
`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.
`
`APO1002, 10, 3:66-4:3; APO1005, ¶55.
`
`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, ¶58. More specifically, the
`
`'979 patent states
`
`that "[t]he activity of cyclosporines
`
`.
`
`.
`
`.
`
`is as an
`
`immunosuppressant and in the enhancement or restoring of lacrimal gland tearing."
`
`APO1003, 2, 1:37-39; APO1005, ¶58.
`
`The '979 patent exemplifies topical ophthalmic emulsions having four
`
`different concentrations of CsA and four different concentrations of castor oil –
`
`including 0.05% and 0.10% CsA, and 1.25% and 0.625% castor oil. APO1003, 3,
`
`4:33-43; APO1005, ¶60. In each of these examples, the excipients in the
`
`formulations remain in constant amounts – the same amounts claimed in the
`
`
`
`- 9 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`challenged claims. APO1003, 3, 4:33-43. 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, ¶61.
`
`The '979 patent teaches that the ratio of CsA to castor oil preferably is below
`
`0.16. APO1003, 3, 3:16-17; APO1005, ¶61. And the '979 teaches that a "more
`
`preferred" ratio of CsA to castor oil is "between 0.12 and 0.02." APO1003, 3, 3:17-
`
`20; APO1005, ¶61.
`
`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, ¶63. The '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, ¶63. 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);
`
`
`
`- 10 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`APO1005, ¶65. The '607 patent further states that "the instillation of the emulsion
`
`increases the measured tear volume." APO1002, 11, 6:61-63; APO1005, ¶65.
`
`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; APO1005, ¶68. The '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, ¶72.
`
`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, ¶72.
`
` 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; APO1005, ¶72.
`
`
`
`- 11 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
` 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.
`
` 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
`
`with a high comfort level and low irritation potential." APO1002, 10, 3:25-31;
`
`APO1005, ¶72.
`
` 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.
`
`Pat. No. 5,474,979." APO1002, 10, 3:48-51; APO1005, ¶72.
`
`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, ¶¶73 and 105; 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.'")
`
`
`
`- 12 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`Sall et al. 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 human "patients were treated twice daily with either CsA,
`
`0.05% or 0.1%, or vehicle." APO1004, 1-2, Abstract; APO1005, ¶75. Sall
`
`measured several efficacy parameters in the patients including tear production,
`
`severity of dry eye disease, and comfort of the emulsion. APO1004, 3; APO1005,
`
`¶75. Sall also 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, ¶75.
`
`Sall noted that the castor oil vehicle itself provided statistically significant
`
`benefits over baseline for clinical several 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, ¶81.
`
`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
`
`
`
`- 13 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`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, ¶82. Sall found that "[t]here was no
`
`dose response effect" of the cyclosporin treatment between the 0.05% and 0.1%
`
`CsA concentrations. APO1004, 1, Abstract; APO1005, ¶80. 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, ¶82.
`
`Acheampong et al. 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. § 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, ¶84. 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, ¶84. Acheampong collected blood samples
`
`from subjects at morning drug level troughs, as well as 1, 2, and 4 hours after
`
`administration. APO1017, 4; APO1005, ¶84. Acheampong found that for the
`
`0.05% CsA emulsion both the trough and maximal blood levels were below the
`
`
`
`- 14 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`limit of detection by LC/MS-MS (less than 0.1 ng/ml). See APO1017, 6, Table 1;
`
`APO1005, ¶85.
`
`The '586 patent. U.S. Patent No. 5,578,586 ("the '586 patent"; APO1031)
`
`to Glonek et al. is entitled "Aqueous film coating for wetting eye surfaces." The
`
`'586 patent 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
`
`expected to cause blurring. The duration of blur is dependent upon the time
`
`required for the emulsion to differentiate and form separate layers replicating a tear
`
`film. Consequently, blurring is likely to occur until the emulsion differentiates."
`
`APO1031, 4, 6:37-42; APO1005, ¶87. The '586 patent discloses a topical emulsion
`
`for dry eye treatment "whereby blurred vision is reduced or eliminated and the
`
`residence time of tear film on the eye is prolonged." APO1031, 3, 3:3-7;
`
`APO1005, ¶87.
`
`The '586 patent compared the effects of increasing the surfactant to oil ratio
`
`in several emulsions by keeping the oil concentration constant and successively
`
`increasing the surfactant concentration. APO1031, 11, 20:24-25; APO1005, ¶89.
`
`The '586 patent reports that the best results were obtained at an intermediate
`
`concentration range of the surfactant, while higher concentrations of surfactant led
`
`to increased blurring because the emulsion did not break down appropriately
`
`
`
`- 15 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`quickly in the eye. APO1031, 11, 20:27-30; APO1005, ¶89. As Dr. Xia explains,
`
`"the '586 patent teaches that higher surfactant to oil ratios can result in an
`
`excessively stable ophthalmic emulsion that can cause blurring upon application to
`
`the eye." APO1005, ¶90. Additionally, as explained by Dr. Xia, based on the
`
`teachings of the '586 patent together with the background knowledge in the art, a
`
`POSA would have recognized that “the surfactant to oil ratio affects the emulsion
`
`break time, with higher relative amounts of oil causing the emulsion to break more
`
`rapidly upon instillation to the eye.” APO1005, ¶90.
`
`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 '162 patent. Terms not explicitly discussed below should be construed to have
`
`their plain and ordinary meanings consistent with the specification.
`
`Claims 4, 6, 9, and 18 of the '162 patent recite that the emulsion of the
`
`claimed method comprises a "buffer." APO1001, 11, 15:35-36, 15:39-40, 15:46-
`
`48, and 16:20-35. And claims 5, 10 and 19 specify that "the buffer is sodium
`
`hydroxide." APO1001, 11, 15:37-38, 15:49-50, and 16:36-37. Based on the plain
`
`language of the claims, a POSA would understand that the patentee intended the
`
`term "buffer" to encompass sodium hydroxide. APO1005, ¶35. See Phillips v.
`
`AWH Corp., 415 F.3d 1303, 1313 ("the person of ordinary skill in the art is
`
`
`
`- 16 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`deemed to read the claim term not only in the context of the particular claim in
`
`which the disputed term appears, but in the context of the entire patent, including
`
`the specification.")
`
`Claims 11 and 21 recite a method wherein the topical ophthalmic emulsion
`
`is administered to an eye of a human, "the blood of a human has substantially no
`
`detectable concentration of the cyclosporin A." APO1001, 11, 15:51-53 and
`
`16:41-44 (emphasis added). The '162 patent states "[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, 5:64-6:3; APO1005, ¶36.
`
`Based on the express language of the specification of the '162 patent, a
`
`POSA would consider the blood of a human to have substantially no detectable
`
`concentration of the CsA if the treatment method resulted in a blood concentration
`
`of less than 0.1 ng/ml. APO1005, ¶37.
`
`Neither claim 11 nor 21 recites any particular time after treatment for
`
`measuring the blood levels of CsA. APO1005, ¶38. Also, the specification is silent
`
`on when after treatment CsA blood level measurements are conducted. APO1005,
`
`¶38. As explained by Dr. Xia, "a POSA administering ophthalmic CsA would be
`
`
`
`- 17 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`cognizant of potential systemic effects if CsA levels in the blood became elevated."
`
`APO1005, ¶38. As Dr. Xia explains, "POSAs
`
`typically measure blood
`
`concentration in two possible ways: 1) 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, ¶38; 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, ¶39.
`
`Claims 1, 13, 14, 22, and 23 recite that the emulsion is "effective,"
`
`"substantially therapeutically effective as a second emulsion," or achieves "at
`
`least as much therapeutic effectiveness as a second emulsion." The '162 patent
`
`does not specifically define these terms. APO1005, ¶40. However, the '162 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, 1:21-25; APO1005, ¶40. In the context of the claims, a POSA would
`
`understand "effective" according to its plain and ordinary meaning which is
`
`capable of achieving a desired result. APO1005, ¶40. Similarly, a POSA would
`
`understand "substantially therapeutically effective as a second emulsion" according
`
`
`
`- 18 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`
`to its plain and ordinary meaning, which is that the claimed emulsion is capable
`
`achieving a desired result approximately as well as treatment with a second
`
`emulsion. APO1005, ¶41. Likewise, a POSA would understand "at least as much
`
`therapeutic effectiveness as a second emulsion" according to its plain and ordinary
`
`meaning, which is that the claimed emulsion is capable achieving a desired result
`
`as well as or better than treatment with a second emulsion. APO1005, ¶41.
`
`Claim 15 recites that the emulsion of the method "breaks down" more
`
`quickly in the eye of a human as compared to a second emulsion containing only
`
`50% as much castor oil. The '162 patent states that "a relatively high concentration
`
`of hydrophobic component is believed to provide for a more quick or rapid
`
`breaking down or resolving of the emulsion in the eye, which reduces vision
`
`distortion which may be caused by the presence of the emulsion in the eye and/or
`
`facilitates the therapeutic effectiveness of the composition." APO1001, 4, 2:43-49;
`
`APO1005, ¶42. The '162 patent also states that the emulsion break down time can
`
`be "measured by split-lamp techniques to monitor the composition in the eye for
`
`phase separation." APO1001, 11, 15:3-4; APO1005, ¶42. Accordingly, a POSA
`
`would understand the term "break down" as used in claim 15 to mean that the
`
`emulsion differentiates into two separate layers on the eye ˗ an aqueous layer and
`
`an oil layer. APO1005, ¶42.
`
`
`
`- 19 -
`
`

`

`Petition for Inter Partes Review USPN 8,633,162
`
`
`Claim 16 recites that the emulsion demonstrates a reduction in "adverse
`
`
`
`events" relative to a second emulsion. And claim 17 specifies that the adverse
`
`events are "side effects." The '162 patent