IN THE UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD

Transcription

1 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 and 37 C.F.R , Mail Stop "PATENT BOARD" Patent Trial and Appeal Board U.S. Patent and Trademark Office P.O. Box 1450 Alexandria, VA

2 TABLE OF CONTENTS I. INTRODUCTION... 1 II. OVERVIEW... 1 III. STANDING (37 C.F.R (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 (A))... 6 VI. THE CLAIMS... 6 VII. PERSON OF ORDINARY SKILL IN THE ART... 7 VIII. STATE OF THE ART... 8 IX. CLAIM CONSTRUCTION X. IDENTIFICATION OF THE CHALLENGE (37 C.F.R (b)) A. Ground 1: Claims 1-10, 12-14, 16-20, and would have been obvious over the '607 patent, the incorporated '979 patent and Sall et al B. 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 C. Ground 3: Claim 15 Would Have Been Obvious Over the '607 patent, the incorporated '979 patent, Sall, and the '586 patent D. Objective indicia of nonobviousness Allergan's allegations of objective indicia are insufficient to show nonobviousness (a) Allergan cannot show unexpectedly superior (b) results There was no long-felt need satisfied by the claimed invention and no failure of others (c) Allergan did not show industry praise (d) Allergan did not show commercial success XI. CONCLUSION i -

3 I. 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

4 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 -

5 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,

6 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, Petitioner is at least reasonably likely to prevail in showing unpatentability, and trial should be instituted

7 III. STANDING (37 C.F.R (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 (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 (Customer ID No ). 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 New York Avenue, NW Washington, DC (telephone) (facsimile) eellison-ptab@skgf.com Back-Up Counsel Ralph W. Powers III (Reg. No. 63,504 ) STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C New York Avenue, NW Washington, DC (telephone) (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 at the addresses above

8 V. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE REASONS THEREFORE (37 C.F.R (A)) Petitioner requests IPR and cancellation of claims 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 -

9 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 -

10 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 -

11 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 -

12 challenged claims. APO1003, 3, 4: 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 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);

13 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, (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,

14 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.'")

15 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

16 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

17 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

18 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 (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: And claims 5, 10 and 19 specify that "the buffer is sodium hydroxide." APO1001, 11, 15:37-38, 15:49-50, and 16: 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

19 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 chromatographymass 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

20 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

21 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,

22 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 states "physicians can provide (prescribe) Composition II to more patients... with reduced risk of the occurrence of adverse events, e.g. side effects, drug interactions and the like, relative to providing Composition I." APO1001, 11, 15:12-16; APO1005, 43. Accordingly, a POSA would understand "adverse events" according to its plain and ordinary meaning to include all negative treatment occurrences connected to the administration of the emulsion of the claims, including side effects and unintended drug interactions. APO1005, 43. A POSA would understand "side effects" according to its plain and ordinary meaning to be a subset of adverse events distinct from drug interactions, and related to the unintended physiological consequences of treatment. APO1005, 44. X. IDENTIFICATION OF THE CHALLENGE (37 C.F.R (b)) Apotex requests inter partes review of each claim of the '162 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. Ground 35 U.S.C. Section (pre-3/16/2013) Index of References '162 Patent Claims '607 patent, '979 patent, 1-10, 12-14, 16-20, and Sall et al '607 patent, '979 patent, 11 and

23 Ground 35 U.S.C. Section (pre-3/16/2013) Index of References '162 Patent Claims Sall et al., and Acheampong et al '607 patent, '979 patent, 15 Sall et al., and '586 patent Petitioner is reasonably likely to prevail in challenging the patentability of claims 1-24 on the basis of each ground and requests that trial be instituted accordingly. A. Ground 1: Claims 1-10, 12-14, 16-20, and would have been obvious over the '607 patent, the incorporated '979 patent and Sall et al. Independent Claims 1, 18 and 23: Independent claims 1, 18, and 23 would have been obvious over the combination of the '607 patent, the incorporated '979 patent, and Sall et al. as shown below. APO1005, 96, 180, and 192. Each of independent claims 1, 18, and 23 recites a method comprising topically administering twice a day to the eye of a human an emulsion with 0.05% CsA and 1.25% castor oil. Claims 1 and 23 recite that the emulsion is effective in treating dry eye disease. Claim 18 recites a method of reducing side effects by using the emulsion. Each of the three independent claims is similar, and claim 23 is exemplary. Accordingly, a claim chart is provided for independent claim 23. Claim 23 Disclosures of U.S. Patent No. 5,981,607 (APO1002), U.S. Patent No. 5,474,979 (APO1003), and Sall et al. (APO1004) 23. A method of treating dry eye disease, "An eye drop composition for alleviation of dry eye related symptoms in dry eye patients...."

24 Claim 23 Disclosures of U.S. Patent No. 5,981,607 (APO1002), U.S. Patent No. 5,474,979 (APO1003), and Sall et al. (APO1004) APO1002, 1, abstract (emphasis added). "The present invention is directed to an emulsion... suitable for delivery of medications to sensitive areas such as ocular tissues as well as being suitable itself for alleviating dry eye symptoms." APO1002, 10, 3:32-38 (emphasis added). "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 (emphasis added). "The novel ophthalmic formulations CsA 0.05% and 0.1% were safe and effective in the treatment of moderate to severe dry eye disease...." APO1004, 1 (emphasis added). 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, "An eye drop composition for alleviation of dry eye related symptoms in dry eye patients and contact lens wearers includes an emulsion of a higher fatty acid glyceride, polysorbate 80 and an emulsion stabilizing amount of Pemulen in water suitable for topical application to ocular tissue." APO1002, 1, abstract (emphasis added). "Subjective tests on patients reporting ocular burning/stinging and ocular dryness are shown in FIGS. 5-6." APO1002, 12, 7:38-39 (emphasis added). "[A] nonirritating emulsion... suitable for topical application to ocular tissue." APO1003, 4, 6:3-7 (emphasis added). "[P]atients were treated twice daily with either CsA, 0.05% or 0.1 %, or vehicle." APO1004, 1 (emphasis added)

25 Claim 23 Disclosures of U.S. Patent No. 5,981,607 (APO1002), U.S. Patent No. 5,474,979 (APO1003), and Sall et al. (APO1004) 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 APO1003, 3, 4: "The emulsion may also be used to advantage for introducing an active agent such as cyclosporine as set forth in parent U.S. Pat. No. 5,474,979. APO1002, 10, 3:48-52 (emphasis added). "Preferably,... a weight ratio of the cyclosporin to castor oil is below More preferably,... the weight ratio of cyclosporin to castor oil is between 0.12 and 0.02." APO1003, 3, 3:15-20 (emphasis added). "Patients were treated twice daily with either CsA, 0.05% or 0.1%, or vehicle." APO1004, 1, Abstract (emphasis added). See Example 1 showing 1.25% castor oil. APO1002, 11, 6:1-12; APO1003, 3, 4: "Preferably,... a weight ratio of the cyclosporin to castor oil is below More preferably,... the weight ratio of cyclosporin to castor oil is between 0.12 and 0.02." APO1003, 3, 3:15-20 (emphasis added). "Both the CsA emulsions and vehicle were sterile, nonpreserved castor oil in water emulsions." APO1004, 2 (emphasis added). See Example 1 showing 1.0% polysorbate 80. APO1002, 11, 6:1-12; APO1003, 3, 4: See Example 1 showing 0.05% Pemulen. APO1002, 11, 6:1-12; APO1003, 3, 4: "Pemulens are Acrylates/C10 30 Alkyl Acrylate

26 Claim 23 Disclosures of U.S. Patent No. 5,981,607 (APO1002), U.S. Patent No. 5,474,979 (APO1003), and Sall et al. (APO1004) weight; Cross Polymers." APO1003, 3, 4:4-5 (emphasis added). glycerine in an amount of See Example 1 showing 2.2% glycerine. APO1002, about 2.2% by weight; sodium hydroxide; and 11, 6:1-12; APO1003, 3, 4: See Example 1 showing sodium hydroxide. APO1002, 11, 6:1-12; APO1003, 3, 4: "The ph of the emulsions can be adjusted in a conventional manner using sodium hydroxide to a near physiological ph level...." APO1003, 3, 4:14-16; APO1002, 11, 5:51-53 (emphasis added). water; See Example 1 showing water. APO1002, 11, 6:1-12; APO1003, 3, 4: "Both the CsA emulsions and vehicle were sterile, nonpreserved castor oil in water emulsions." APO1004, 2 (emphasis added). wherein the emulsion is effective in treating dry eye disease. "The formulations set forth in Examples 1 4 were made for treatment of keratoconjunctivitis sicca (dry eye) syndrome...." APO1003, 4, 5:9 11; see also APO1002, 11, 6:25-26 (emphasis added). "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 (emphasis added). "The novel ophthalmic formulations CsA 0.05% and 0.1% were safe and effective in the treatment of moderate to severe dry eye disease[.]" APO1004, 1 (emphasis added). The '607 patent exemplifies four different castor oil concentrations in its emulsions for the treatment of dry eye/kcs which are: 5.00%, 2.5%, 1.25%, and 0.625%. APO1002, 11, 6:1-11; APO1005, 67. The '607 patent states that the

27 "emulsion may be used to advantage for introducing an active agent such as cyclosporine as set forth in U.S. Pat. No. 5,474,979." APO1002, 10, 3:48-50; APO1005, 72. And the incorporated '979 patent exemplifies four different CsA concentrations in its castor oil emulsions, the lowest of which is 0.05% CsA. APO1003, 3, 4:33-43; APO1005, 60. Except for the castor oil and CsA concentrations, each of the remaining ingredients in each of Examples 1A-1D of the '607 patent and Examples 1A-1E of the '979 patent are identical and present at the same concentrations recited in the claims of the '162 patent, as shown in the bulleted list below. APO1005, 61 and 68. Similarly, aside from castor oil and CsA, "Composition II," exemplified in the specification of the '162 patent, contains the same ingredients at the same concentrations as those taught by of Examples 1A-1D of the '607 patent and Examples 1A-1E of the '979 patent, as shown in the bulleted list below. APO1005, 98. And "Composition II" falls within the scope of the emulsions recited by each of claims 1, 18, and 23. APO1005, 98, 185, and 196. Examples 1A-E of the '979 patent and Examples 1A-D of the '607 patent provide 1.0% polysorbate 80; claim 1 recites polysorbate 80; claims 18 and 23 recite polysorbate 80 at 1.0%; and Composition II includes polysorbate 80 at 1.0%. APO1005,

28 Examples 1A-E of the '979 patent and Examples 1A-D of the '607 patent provide Pemulen (a registered trademark for acrylate/c10-30 alkyl acrylate cross polymer (APO1001, 9, 11:43-46; APO1003, 3, 4:1-5)) at 0.05%; claim 1 recites acrylate/c10-30 alkyl acrylate cross polymer; claims 18 and 23 recite acrylate/c10-30 alkyl acrylate cross polymer at 0.05%; and Composition II includes Pemulen at 0.05%. APO1005, 146. Examples 1A-E of the '979 patent and Examples 1A-D of the '607 patent provide water (q.s.); each of claims 1, 18, and 23 recite water; Composition II includes purified water (q.s.). APO1005, 119. Examples 1A-E of the '979 patent and Examples 1A-D of the '607 patent provide glycerine at 2.2% as a tonicity component or a demulcent component; claim 1 does not recite this limitation; claim 18 recites a tonicity component or a demulcent component at 2.2%; claim 23 recites glycerine at about 2.2%; Composition II includes glycerine at 2.2%. APO1005, 150. Examples 1A-E of the '979 patent and Examples 1A-D of the '607 patent provide sodium hydroxide as a buffer; claim 1 does not recite a buffer; claim 18 recites a buffer; claim 23 recites sodium hydroxide; Composition II includes sodium hydroxide. APO1005, 134. Examples 1A-E of the '979 patent and Examples 1A-D of the '607 patent provide a ph range of ; claims 1 and 23 do not recite a ph range; claim

29 18 recites a ph range of about 7.2 to about 7.6; Composition II specifies a ph of APO1005, 154. CsA was known to be a powerful anti-inflammatory drug, and dry eye/kcs was known to be associated with inflammatory processes in the eye. APO1015, 7; APO1005, 46 and 50. The '979 patent states that in ocular bioavailability studies conducted in rabbits, "the therapeutic level of cyclosporin was found in the tissues of interest after dosage. This substantiates that cyclosporin in an ophthalmic delivery system is useful for treating dry eye.... " APO1003, 4, 5: So even if the '607 patent's incorporation statements were deemed to be ineffective, a POSA would still have had a reason to combine the CsA of the '979 patent with the emulsions of the '607 patent to reduce inflammation, increase tear production, and treat dry eye/kcs patients. APO1002, 10, 3:48-50; APO1005, In formulating an emulsion with CsA, a POSA would have been motivated to use the lowest effective dose of CsA because of CsA's known immunosuppressive activity, and a POSA would want to minimize the risk of side effects to users of the emulsion. APO1003, 2, 1:10-11; APO1005, 108. Accordingly, a POSA would have been motivated to use the 0.05% CsA concentration taught in the '979 patent. APO1005, 110. Sall provides additional guidance to a POSA formulating a dry eye therapy. APO1005, 107. Sall reports the outcome of human clinical trials for dry eye/kcs

30 human patients treated twice-daily with topical ophthalmic CsA in castor oil emulsions. APO1004, 1, Abstract; APO1005, 104. So a POSA would have looked to Sall when formulating a topical emulsion for dry eye treatment based on the teachings of the '607 patent and the '979 patent. APO1005, 107. Based on the teachings of Sall, a POSA would have had at least three reasons to use 0.05% CsA taught by the '979 patent with the emulsions disclosed in the '607 patent: 1) Sall shows that the 0.05% emulsion achieved a statistically significant improvement over vehicle in more clinical markers than the 0.1% emulsion (APO1004, 1, Abstract; APO1005, 107); 2) the 0.05% emulsion never resulted in any detectable blood levels of CsA, unlike the 0.1% emulsion, and tended to have reduced adverse events compared to the 0.1% CsA emulsion (APO1004, 1 and 7; APO1005, 108 and 175); and 3) in previous studies discussed by Sall, 0.05% CsA showed better reduction of inflammation and allowed better cell regrowth than 0.1% CsA. APO1004, 1, Abstract, and 7; APO1005, Sall's results would have taught a POSA that increasing the CsA dose beyond 0.05% would not be beneficial. APO1005, 107 and Sall shows that an emulsion of 0.05% CsA was as efficacious as 0.10% CsA at treating two objective measures of dry eye, corneal staining and categorized Schirmer values, compared to vehicle. APO1004, 1, Abstract, and 7; APO1005, 107. And Sall shows that the 0.05% CsA emulsion showed significant improvement over baseline

31 for three subjective measures of dry eye disease, while the 0.1% CsA emulsion showed no statistically significant difference over baseline in the same three parameters. APO1004, 1, Abstract, and 7; APO1005, 107. As Sall notes, "[t]here was no dose-response effect" between 0.05% and 0.1% CsA. APO1004, 1, Abstract; APO1005, 107. Sall also indicates that 0.05% CsA would be considered safer for patients than a 0.1% CsA emulsion. APO1005, 108. Sall found no detectable blood CsA in any patients treated with the 0.05% CsA emulsion. APO1004, 7; APO1005, 108. In contrast, Sall reported that the 0.10% CsA emulsion resulted in detectable blood levels in a subset of patients. APO1004, 7; APO1005, 108. Because CsA had known, broad-based immunosuppressant activities, a POSA developing dry eye therapies would have been motivated to keep blood CsA levels as low as possible, while maintaining efficacy. APO1003, 2, 1:10-11; APO1005, 108. As such, a POSA would have been directed to the 0.05% CsA concentration because of its good efficacy, while minimizing risks associated with higher blood levels of the drug. APO1005, 108. Results from previous studies discussed in Sall also would have guided a POSA to 0.05% CsA. APO1004, 7-8; APO1005, 109. Sall reviewed results obtained by Kunert (APO1015) and Turner (APO1016) using topical ophthalmic CsA emulsions containing either 0.05% CsA or 0.1% CsA. APO1004, 7-8;

32 APO1005, As Sall noted, Kunert observed "the density of conjunctival goblet cells... to be significantly greater after 6 months of treatment with CsA 0.05% than had been seen at baseline (an increase of 191%; P=0.014)" APO1004, 7-8; APO1005, 109. Sall called this finding of goblet cell regrowth "of particular importance" because of the goblet cells' normal role in producing healthy tear components. APO1004, 8; APO1005, 109. Similarly, Sall notes that Turner showed a desirable decrease in the levels of an inflammatory marker after treatment with a 0.05% CsA emulsion. APO1004, 7; APO1005, 110. When viewed in conjunction with Sall's discussion of prior studies, Sall's data would have motivated a POSA to use the 0.05% CsA concentration twice daily in an ophthalmic emulsion to maintain maximal efficacy in patients while minimizing the potential immunosuppressive effects of CsA. APO1005, 110. Accordingly, as explained by Dr. Xia, "a POSA would have been motivated to select 0.05% CsA for use in a topical emulsion." APO1005, 110. A POSA would have had a reason to combine the 0.05% CsA disclosed in the '979 patent and Sall, to the castor oil emulsion formulations disclosed in the '607 patent because dry eye/kcs was known to be a disease of inflammation and 0.05% CsA was known to have anti-inflammatory effects useful and safe for treatment of dry eye/kcs while minimizing the possibility of adverse events. APO1003, 2, 1:10-16; APO1004, 1-2; APO1005,

33 The '979 patent provides guidance on the ratio of CsA to castor oil in the emulsion, stating that the ratio should "[m]ore preferably" be "between 0.12 and 0.02." APO1003, 3, 3:17-20; APO1005, 113. Having determined the desired CsA concentration of 0.05% as discussed above, and applying the preferred ratio of CsA to castor oil, a POSA would have been directed to only two exemplified castor oil concentrations falling within the "more preferable" CsA to castor oil ratio: 1.25% and 0.625%. APO1005, 113. Faced with these options, a POSA would have readily chosen 1.25% castor oil to combine with 0.05% CsA because the '607 patent teaches that 1.25% castor oil emulsions have a longer residence time on the eye time than the 0.625% castor oil emulsions. APO1002, 8, Fig. 7, and 9, 2:63-65; APO1005, 114. As explained by Dr. Xia, "[a] POSA would have known that retention time of the emulsion on the ocular surface is an important parameter to consider when formulating a dry eye therapy." APO1005, 114; APO1002, 9, 2: For example, the '607 patent states, relief provided by previous dye eye therapies "is limited by the retention time of the administered artificial tear solution in the eye." APO1002, 9, 2:63-65; APO1005, 114. The '607 patent continues, "retention of the emulsion in the subject's eye is also important in achieving the objectives of the present invention." APO1002, 12, 8:27-29; APO1005, 114. Dr. Xia explains that based on these teachings, "a POSA would have appreciated that sufficient residence time in the

34 eye is beneficial to: 1) allow enough time for the active agent to diffuse into the target ocular tissue; and 2) prevent the evaporation of the tears for as long as possible while balancing comfort and other factors." APO1005, 115. The '607 patent provides ocular residence time data for castor oil emulsions containing 2.5%, 1.25%, 0.625%, and 0.125% castor oil. APO1002, 8, Fig. 7, and 12, 8:35-45; APO1005, 116. Data from the '607 patent show that as the percentage of castor oil increases, so does the residence time on the ocular surface. APO1002, 8, Fig. 7; APO1005, 116. Accordingly, the 1.25% castor oil emulsion provides a greater residence time on the ocular surface than the 0.625% castor oil emulsion. APO1002, 8, Fig. 7, and 12, 8:35-45; APO1005, 116. However, unlike the 2.5% castor oil emulsion, the 1.25% castor oil emulsion maintains the more preferable ratio of "between 0.12 and 0.02" CsA to castor oil. (0.05% CsA/1.25% castor oil = 0.04). APO1003, 3, 3:17-20; APO1005, 116. As explained by Dr. Xia, the preferred CsA/castor oil ratios of '979 patent are grounded in basic thermodynamic principles that would have been known to a formulator. APO1005, 117. As Dr. Xia states, "in an ophthalmic formulation, if a lipophilic drug (such as CsA) is present in a low concentration relative to an oil, diffusion of the drug out of the oil and into the aqueous target tissue is limited by basic diffusion thermodynamics. This is because the lipophilic drug, will tend to stay in the oil where the relative concentration of the drug is low." APO1005,

35 117. And as the '979 patent states, preparation of a formulation with "low thermodynamic activity (degree of saturation) of cyclosporin [] leads to a poorer drug bioavailability." APO1003, 2, 2:55-57; APO1005, 117. So in developing a 0.05% CsA emulsion, a POSA would have a reason to select 1.25% castor oil (instead of a higher amount) to stay within the more preferred ratio of CsA to castor oil, while improving residence time on the eye. APO1005, 117. Moreover, castor oil was known to cause eye irritation if used at too high of a concentration, which would also have directed a POSA towards the 1.25% emulsion over higher castor oil concentrations. APO1005, 117. See APO1003, 2, 2:39-45; APO1002, 11, 5: Claims 1 and 23 recite that the topical ophthalmic emulsion is effective in treating dry eye disease. But the cited art teaches that emulsions containing 0.05% CsA together with castor oil are effective at treating dry eye disease/kcs. APO1005, 58 and 80. For example, the '979 patent states "cyclosporin has been found as effective in treating immune medicated [sic, mediated] keratoconjunctivitis sicca (KCS or dry eye disease) in a patient suffering therefrom" and "[t]he activity of cyclosporins, as hereinabove noted, is as an immunosuppressant and in the enhancement or restoring of lacrimal gland tearing." APO1003, 2, 1:12-16; 1:37-39 (parenthetical omitted); APO1005, 58. The '607 patent also states that "instillation of the emulsion increases the measured tear

36 volume" and causes a "reduction in subject ocular burning/stinging and dryness" in clinical measurements conducted on dry eye/kcs patients. APO1002, 11, 6:62-63, and 12, 8:22-24; APO1005, 65. And Sall states that the 0.05% CsA emulsions was "safe and effective in the treatment of moderate to severe dry eye disease..." APO1004, 1, Abstract; APO1005, 104. The preamble of claim 18 recites a method of reducing side effects. Petitioner notes that unlike other claims of the '162 patent, claim 18 does not specify what the reduction in side effects is relative to. APO1001, 11, 16: Also, this preamble is not limiting on claim 18, because the body of the claim fully and intrinsically sets forth all of the limitations of the claimed invention. Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999). But even if the preamble were limiting, a reduction in side effects compared to treatment methods using higher dosages of CsA would have been expected by a POSA, as discussed in detail below with respect to claims 16 and 17. APO1005, 178. And as also discussed below with respect to claims 16 and 17, a reduction in side effects is an inherent property of the 0.05% CsA emulsion. APO1005, 179. Claims 1, 18, and 23 also recite that the emulsion is administered "at a frequency of twice a day." But Sall teaches that "patients were treated twice daily" with 0.05% CsA and castor oil emulsions." APO1004, 1, Abstract; APO1005, 104. And because Sall reports favorable results with twice a day dosing, a POSA