IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`
`AKORN, INC.
`Petitioner
`v.
`SENJU PHARMACEUTICAL CO., LTD
`MITSUBISHI CHEMICAL CORPORATION
`Patent Owner
`
`U.S. Patent No. 6,114,319 C1 to Kimura et al.
`Issue Date: September 5, 2000
`Title: Compositions Containing Difluprednate
`_____________________
`
`Inter Partes Review No. Unassigned
`_____________________
`
`Petition for Inter Partes Review of U.S. Patent No. 6,114,319 C1 Under
`35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`

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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`I.
`II.
`III.
`
`2.
`
`3.
`
`INTRODUCTION ................................................................................ 1
`OVERVIEW ......................................................................................... 1
`STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS .................................................................................... 7
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) .......................... 7
`V.
`STATEMENT OF THE PRECISE RELIEF REQUESTED
`AND THE REASONS THEREFORE (37 C.F.R. §
`42.22(A)) .............................................................................................. 8
`VI. THE CLAIMS ...................................................................................... 9
`VII. PERSON OF ORDINARY SKILL IN THE ART (POSA) ................. 9
`VIII. STATE OF THE ART ........................................................................ 10
`IX. CLAIM CONSTRUCTION ............................................................... 22
`X.
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. §
`42.104(b)) ........................................................................................... 27
`A. Ground 1: Claims 1-4, 6-10, 12-14 and 18 would have been
`obvious over the '848 patent in view of Ding .....................................27
`1.
`Parts by weight of oil per part by weight of
`difluprednate ............................................................................ 38
`Parts by weight of water per part by weight of
`difluprednate ............................................................................ 43
`Parts by weight of the emulsifier per part by weight of
`difluprednate. ........................................................................... 45
`Objective indicia do not support patentability ....................................50
`1.
`Alcon did not compare its formulation to the closest
`prior art. .................................................................................... 51
`A POSA would have expected that an emulsion
`formulation would increase the tissue penetration and
`bioavailability of difluprednate ................................................ 54
`XI. CONCLUSION .................................................................................. 60
`
`B.
`
`2.
`
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`I.
`
`INTRODUCTION
`Akorn, Inc. petitions for Inter Partes Review, seeking cancellation of claims
`
`1-4, 6-10, 12-14, and 18 of U.S. Patent No. 6,114,319 C1 to Kimura et al. ("the
`
`'319 patent") (AKN1001), which is purportedly owned by Senju Pharmaceutical
`
`Co., Ltd. and Mitsubishi Chemical Corp. ("patent owner"). Claims 1-4, 6-10, 12-
`
`14, and 18 are the remaining claims as a result of a patent-owner initiated ex parte
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`reexamination proceeding. AKN1001, Ex Parte Reexam Certificate, 2:5-16. The
`
`'319 patent is exclusively licensed to Alcon Pharmaceuticals Ltd. and Alcon
`
`Laboratories, Inc. The patent owner and licensees are collectively referred to
`
`herein as "Alcon."
`
`II. OVERVIEW
`The challenged claims should be canceled. Each recites an emulsion in the
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`form of an eye drop, nasal drop, or ear drop comprising the steroid difluprednate,
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`an oil selected from a recited group, water, and an emulsifier. Claim 18, the
`
`narrowest claim, specifies that the oil is castor oil and the emulsifier is
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`polyoxyethylene (20) sorbitan monooleate (also known as polysorbate 80).
`
`Before May 14, 1997, the earliest possible priority date of the '319 patent,
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`artisans recognized that difluprednate was a potent steroid that showed superior
`
`anti-inflammatory and anti-allergic actions against disorders of the eye when
`
`applied locally. AKN1006, 1:25-28. And artisans appreciated that because of
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`difluprednate's potency, it could be used at a lower dose or a reduced dosing
`
`frequency compared to other steroids used to treat the same ailments. AKN1006,
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`10:37-43.
`
`Prior art U.S. Patent No. 5,556,848 ("the '848 patent"), discloses an aqueous
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`ophthalmic suspension of difluprednate for administration to the eye. AKN1006,
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`Abstract. The '848 patent's difluprednate suspensions disclosed solid particles of
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`difluprednate dispersed in an aqueous liquid. AKN1006, 2:15-19. But artisans
`
`would have recognized several drawbacks to the difluprednate suspensions of '848
`
`patent. AKN1006, 6:22-25 & 55-57; AKN1018, ¶43.
`
`For example, the suspensions of the '848 patent contained difluprednate
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`particles that a person of ordinary skill in the art ("POSA") would have expected to
`
`cause ocular irritation because of their relatively large size. AKN1006, 6:22-25 &
`
`55-57; AKN1018, ¶51. A POSA would have been aware that such ocular irritation
`
`would be uncomfortable for a patient. Id. And a POSA would have been aware that
`
`ocular irritation may lead to poor bioavailability of the instilled drug because
`
`irritation causes excessive tearing and rapid drainage of the instilled dose.
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`AKN1011, 1585; AKN1018, ¶45. A POSA would have appreciated that a particle
`
`size of less than 10 µm is desirable to minimize ocular irritation, but the particles
`
`in the aqueous suspensions of the '848 patent were up to about seven times larger
`
`(75 µm).
`
` AKN1011, 7; AKN1006, 6:22-25 & 55-57; AKN1018, ¶51.
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`Accordingly, a POSA would have appreciated that the aqueous suspensions of the
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`'848 patent would likely irritate the eye, leading to reduced bioavailability of the
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`drug and discomfort to the patient. AKN1018, ¶44 & 45.
`
`A POSA also would have recognized that the aqueous suspensions of the
`
`'848 patent may not be stable, may tend to settle, and to form drug agglomerates.
`
`AKN1006, 1:53-57 & 6:55-57; AKN1011, 7; AKN1018, ¶50. The '848 patent
`
`discloses that difluprednate particles can aggregate and settle, forming "a hard
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`deposit layer (caking)." AKN1006, 1:53-57. Consequently, patients were required
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`to vigorously shake aqueous preparations of difluprednate to resuspend the
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`particles before administration. AKN1011, 7; AKN1018, ¶47. However,
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`inadequate shaking was a known "determinant factor contributing to poor drug
`
`levels available to the eye," because patients often did not sufficiently resuspend
`
`the drug before administering a dose. AKN1022, 16 (emphasis added). AKN1011,
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`7; AKN1018, ¶49. Accordingly, POSAs appreciated that the settling of drug
`
`particles was a cause of under-dosing and variable-dosing of topical ophthalmics.
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`AKN1022, 190; AKN1009, 1:25-33; AKN1018, ¶48 & 49.
`
`The prior art PCT publication WO 95/31211 ("Ding") discloses emulsion
`
`vehicles for administering a poorly water-soluble drug to the eye. AKN1012, 1:8-
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`14; AKN1018, ¶54. Ding discloses emulsion compositions containing drugs such
`
`as steroids, which are poorly water-soluble, in an emulsion with castor oil and
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`polysorbate 80. AKN1012, 9:24-30; AKN1018, ¶54 & 59. Ding teaches that the
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`emulsion is physically stable with little particles or particle aggregation present
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`because the drug in the emulsion is dissolved in the oil phase. AKN1012, 6:32-34;
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`AKN1018, ¶56. Ding states that its emulsions provide "a high comfort level and
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`low irritation potential" for ocular drug delivery. AKN1012, 1:8-14 & 5:34-6:2;
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`AKN1018, ¶¶57, 59. In each of its working examples, Ding discloses emulsion
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`vehicles containing castor oil, polysorbate 80, and water for formulating such an
`
`emulsion. AKN1012, 10:3-11:10; AKN1018, ¶57. And Ding teaches that an
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`"emulsifier and dispersing agent such as polysorbate 80 will reduce the irritation
`
`potential of an emulsion utilizing castor oil." AKN1012, 8:23-25; AKN1018, ¶41.
`
`A POSA would have had a reason to formulate the '848 patent's
`
`difluprednate in the emulsion of Ding, because Ding's emulsion provides one or
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`more of the advantages – improved comfort level, improved dose uniformity, and
`
`better drug penetration to ocular tissues – compared to aqueous suspensions.
`
`AKN1018, ¶¶55 & 57. A POSA would have recognized that the problems of eye
`
`irritation and drug precipitation, along with the patient discomfort, consequent
`
`poor patient compliance, and reduced bioavailability could be eliminated or
`
`significantly reduced by using an emulsion. AKN1012, 5:34-37 & 11:36-
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`12:3;AKN1018, ¶¶55, 57, 59, 62, 63, & 65-69. So a POSA, aware of the
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`drawbacks associated with difluprednate aqueous suspensions, would have been
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`motivated to create an emulsion preparation of difluprednate based on the
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`teachings of Ding. AKN1018, ¶77-78, & 88.
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`A POSA also would have had a reasonable expectation of success in
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`combining the difluprednate of the '848 patent with the emulsions of Ding, because
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`Ding teaches that poorly water-soluble steroids are suitable in the emulsion and
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`difluprednate is such a steroid. AKN1018, ¶59 & 89. And it would have required
`
`no more than ordinary skill of a POSA to make the emulsion suitable for its
`
`intended use. AKN1018, ¶¶89 & 90. POSAs knew that difluprednate was safe and
`
`efficacious for formulation into eye drops and administration to the eye.
`
`AKN1006, Abstract; AKN1018, ¶39 & 42. And Ding teaches that poorly water-
`
`soluble steroids are suitable for use in Ding's emulsion to provide a "low irritation
`
`potential." AKN1012, 9:24-30; AKN1018, ¶59. Accordingly, a POSA would have
`
`simply been combining a well-known steroid drug with a prior art emulsion
`
`vehicle to arrive at the claimed emulsion. AKN1018, ¶90. A combination of prior
`
`art elements to achieve only predictable results is quintessentially obvious; and
`
`nothing more led to the '319 patent. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398,
`
`415-421 (2007).
`
`And objective indicia of nonobviousness cannot support the patentability of
`
`the challenged claims. During prosecution, Alcon alleged that its claimed emulsion
`
`"provided superior delivery to lesions" compared to the aqueous difluprednate
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`formulations of the '848 patent. AKN1017, 129 (Response dated December 16,
`
`1998). But a showing of unexpectedly superior results requires a comparison to the
`
`closest prior art. In re Merchant, 575 F.2d 865, 868 (CCPA 1978); AstraZeneca
`
`Pharms. LP v. Teva Pharms. U. S., Inc., 583 F.3d 766, 775 (Fed. Cir. 2009). The
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`closest prior art is determined by comparing the claims with the disclosure of each
`
`cited reference to determine the number of claim limitations in common with each
`
`reference, bearing in mind their relative importance. AstraZeneca, at 775.
`
`However, Alcon did not compare its emulsion to the closest prior art,
`
`because the emulsions taught by Ding have more claim elements, and more
`
`important claim elements, in common with the claims of the '319 patent than the
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`aqueous suspensions of the '848 patent. AKN1012, 9:26-30 & 10:1-10; AKN1006,
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`2:17-22 & 6:31-54; AKN1018, ¶¶124 & 125. As Alcon conceded, it is "the
`
`emulsion of the present invention" that provides the superior delivery of
`
`difluprednate. AKN1017, 144 (Response dated September 13, 1999). Dr. Xia
`
`agrees that it is the emulsion that provides the improved delivery of difluprednate.
`
`AKN1018, ¶125. Accordingly, Alcon did not compare its claimed formulation to
`
`the closest prior art.
`
`Additionally, even if Alcon's comparison was the correct one ˗ and it was
`
`not ˗ Alcon's results are what a POSA would have expected. AKN1018, ¶126.
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`Before 1997, POSAs were aware of several publications that demonstrated the
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`superiority of ophthalmic emulsions in drug delivery compared to aqueous
`
`preparations. AKN1020, 3; AKN1012, 6:5-10 & 18:7-15, AKN1010, 11:63-66;
`
`AKN1018, ¶54-70. And emulsions were known to be especially beneficial "for
`
`providing increased bioavailability of an ophthalmic drug," including poorly water-
`
`soluble drugs such as steroids. AKN1010, 4:66-5:2, 14:8-20 & 16:1-3; AKN1020,
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`3; AKN1012, 6:5-10 & 9:24-30; AKN1018, ¶¶67-70. Accordingly, there was
`
`nothing unexpected about the results that Alcon submitted to the PTO during
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`prosecution. Id. Therefore, Alcon's evidence of alleged unexpected results fails.
`
`As discussed in detail below, each claim of the '319 patent would have been
`
`obvious and should be canceled.
`
`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '319 patent is available for IPR and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the '319
`
`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
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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: AKORN, INC.
`
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`Related Matters (37 C.F.R. § 42.8(b)(2)): Alcon Laboratories, Inc. et al.
`
`Inc. v. Akorn, Inc., C.A. No. 2:15-cv-00285-MCA-JBC (D. N.J.)
`
`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
`Chandrika Vira (Reg. No. 60,607)
`Ralph W. Powers III (Reg. No. 63,504)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8672 (telephone)
`202.772.8876 (telephone)
`202.371.2540 (facsimile)
`cvira-PTAB@skgf.com
`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.
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(A))
`
`Petitioner requests IPR and cancellation of claims 1-4, 6-10, 12-14, and 18,
`
`i.e., all claims of the '319 patent. Petitioner's full statement of the reasons for the
`
`relief requested is set forth in detail in § X. In support of the proposed Ground for
`
`unpatentability, this Petition is accompanied by a declaration of Petitioner's
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`technical expert, Dr. Erning Xia (AKN1018).
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`VI. THE CLAIMS
`Each claim of the '319 patent recites an emulsion in the form of an eye drop,
`
`a nasal drop, or an ear drop comprising the steroid difluprednate, an oil, water, and
`
`an emulsifier. Claims 1 and 18 are the independent claims and are below:
`
`Claim 1. A difluprednate emulsion in the form of an eye drop, a nasal
`drop or an ear drop comprising (a) difluprednate, (b) an oil selected
`from the group consisting of castor oil, peanut oil, cotton seed oil,
`soybean oil, olive oil and a medium chain fatty acid triglyceride, (c)
`water and (d) an emulsifier.
`Claim 18. A difluprednate emulsion in the form of an eye drop, a
`nasal drop or an ear drop comprising difluprednate, castor oil, water
`and polyoxyethylene (20) sorbitan monooleate.
`VII. PERSON OF ORDINARY SKILL IN THE ART (POSA)
`A POSA is a hypothetical person who is presumed to be aware of all
`
`pertinent art, thinks along conventional wisdom in the art, and is a person of
`
`ordinary creativity. A POSA of eye, nasal, or ear formulations would have had
`
`knowledge of the scientific literature regarding inflammatory eye, nasal, or ear
`
`disorders and useful therapies including, e.g., topical steroids and their formulation
`
`into delivery vehicles, as of May 1997. With respect to the subject matter of the
`
`'319 patent, a POSA typically would 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
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`topical eye, nasal, or ear pharmaceuticals, 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 the formulation of eye,
`
`nasal, or ear pharmaceuticals.
`
`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 on the team to solve a given problem. For example, a clinician
`
`having experience in treating inflammation of the eye, nose, or ear with topical
`
`pharmaceutics may be part of the team. As of the May 1997, the state of the art
`
`included the teachings of the references discussed in the unpatentability ground set
`
`forth below. Additionally, a POSA would have been aware of other important
`
`information and references relating to inflammation of the eye, nose, or ear; the
`
`causes of such inflammation; and the formulation of useful treatments.
`
`VIII. STATE OF THE ART
`Before 1997, difluprednate was a well-known synthetic steroid drug with
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`known potent anti-inflammatory and anti-allergic effects. AKN1004, 1:2-4 & 62-
`
`69; AKN1018, ¶¶38 & 39. Difluprednate was first described in 1973 and is a
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`derivative of 6α,9α-difluoroprednisolone acetate. AKN1004, 1:2-4 & 68-69;
`
`AKN1018, ¶38. Difluprednate was known to be structurally very similar to
`
`prednisolone acetate; and like prednisolone acetate, difluprednate was shown to be
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`useful in topical formulations for the treatment of various inflammatory and
`
`allergic eye disorders. Id; AKN1006, Abstract, 1:25-31. As with other steroids,
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`artisans appreciated that difluprednate was poorly soluble in water. AKN1001,
`
`1:30-31; AKN1006, 1:34-35; AKN1018, ¶40. And, as with other poorly soluble
`
`drugs, artisans had difficulty creating aqueous formulations of difluprednate.
`
`AKN1006, 1:34-37, AKN1018, ¶40. However, artisans recognized difluprednate
`
`had therapeutic advantages, because it showed greater potency against ocular
`
`inflammation than other similar steroids. AKN1006, 10:36-41; AKN1018, ¶39.
`
`Prior to 1997, ophthalmic aqueous suspensions containing steroids were
`
`known in the art. AKN1006, Abstract; AKN1022, 14- 16; AKN1018, ¶42.
`
`Aqueous steroid suspensions typically made use of small solid particles of the
`
`steroid in an aqueous vehicle. AKN1006, 2:15-23; AKN1011, 7; AKN1018, ¶42.
`
`However, POSAs appreciated numerous difficulties and disadvantages associated
`
`with ophthalmic suspensions. AKN1011, 7; AKN1009, 1:25-33, AKN1022, 16;
`
`AKN1019, 3-4; AKN1023, 1 & 4; AKN1018, ¶43. Difficulties with aqueous
`
`suspensions included 1) patient discomfort and ocular irritation due to the large
`
`size of drug particles, 2) difficulties in ensuring dosage uniformity, 3)
`
`agglomeration and caking of drug particles, and 4) poor bioavailability of the drug
`
`in the target tissue for the above reasons. AKN1009, 1:25-33; AKN1011, 7;
`
`AKN1022, 16; AKN1019, 3-4; AKN1023, 1 & 4; AKN1018, ¶43.
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`Before 1997, the art recognized that the size of the particles in an aqueous
`
`suspension played a significant role in the suspension's propensity to cause
`
`irritation to patients. Id. And before 1997, artisans appreciated that particles should
`
`be less than 10 µm in size to minimize irritation to the eye. AKN1011, 7;
`
`AKN1022, 15; AKN1018, ¶44. However, a drug particle size of less than 10 µm
`
`could be difficult to achieve for certain drugs formulated in aqueous suspensions
`
`because of their low solubility and tendency to agglomerate into larger particles.
`
`AKN1018, ¶44; AKN1011, 7; AKN1022, 15. Accordingly, eye irritation remained
`
`a well-recognized drawback for many aqueous formulations of poorly water-
`
`soluble drugs before 1997. AKN1011, 7; AKN1022, 14-15; AKN1023, 1;
`
`AKN1018, ¶44.
`
`Before 1997, artisans appreciated that drug particle size plays an important
`
`role in the bioavailability of the instilled drug. AKN1011, 7; AKN1022, 15;
`
`AKN1018, ¶45. Ocular irritation brought on by larger drug particles in the eye
`
`produces excessive reflex tearing, leading to rapid drainage of the instilled dose,
`
`which in turn lowers drug penetration to the target tissue. Id. As Dr. Xia explains,
`
`"Before 1997, POSAs were aware of the drawbacks of ophthalmic suspensions and
`
`the relationships between particle size, increased irritation, and decreased
`
`bioavailability of the drug." AKN1018, ¶45. So before 1997, artisans were aware
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`that ocular irritation was inversely correlated with bioavailability of the instilled
`
`drug. AKN1011, 7, AKN1022, 15; AKN1023, 1; AKN1018, ¶45.
`
`Before 1997, POSAs also appreciated that to become bioavailable, a drug
`
`particle in a suspension must become dissolved in the tear fluid. AKN1011, 7;
`
`AKN1023, 4; AKN1018, ¶52. A drug can penetrate into eye tissues only after it is
`
`in solution. Id. And POSAs appreciated that the dissolution time for a given
`
`amount of a drug was influenced by the total surface area of the drug, e.g. a block
`
`of salt took longer to dissolve in water than an identical weight of fine granules of
`
`salt. Id. Accordingly, in 1997, POSAs appreciated that as particle size in a
`
`suspension increases, the time required for a given amount of drug to dissolve in
`
`the tear fluid after instillation increases. Id.
`
`Accordingly, before 1997, POSAs appreciated that the larger the particle
`
`size of a drug in aqueous suspension, the more likely it is that excessive tearing
`
`would expel the drug from the eye before dissolution and absorption could take
`
`place. AKN1011, 7; AKN1022, 15; AKN1018, ¶53. So, particle size and its
`
`attendant irritation of the eye were considered difficulties when formulating poorly
`
`water-soluble drugs for topical ophthalmic applications. Id. And POSAs sought to
`
`minimize irritation to the eye, thereby improving patient comfort and improving
`
`bioavailability of the drug. Id.
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`Also prior to 1997, POSAs appreciated that particles of poorly water-soluble
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`drugs often settled to the bottom of their container upon storage, sometimes caking
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`into larger clumps of particles. AKN1006, 1:53-61; AKN1011, 7; AKN1018, ¶47.
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`Users were required to vigorously shake the container to redisperse the drug
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`particles before instilling a dose. AKN1011, 7; AKN1022, 16; AKN1019, 1;
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`AKN1018, ¶47. Inadequate shaking of a suspension before instillation was known
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`to lead to dose variation, uneven distribution on the eye surface, and poor
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`bioavailability of the drug upon administration. AKN1018, ¶47; AKN1022, 16;
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`AKN1019, 3-4; AKN1009, 1:25-33. For example, Hollingsbee et al. noted that
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`"[o]phthalmic suspensions often suffer
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`from
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`the disadvantage
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`that
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`the
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`pharmaceutically active compound separates out on standing so that the suspension
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`must be reformed [by shaking] before use." AKN1009, 1:25-29 (emphasis added).
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`Hollingsbee added that, "Some authorities believe that such prolonged shaking is
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`required to achieve sufficient homogeneity that [many] patients are administering
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`drops which are under strength." AKN1009, 1:29-33 (emphasis added).
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`In 1993, Olejnik et al. reported that the drawback of inadequate shaking and
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`the consequent poor bioavailability of aqueous steroid suspensions, stating that
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`"[i]rregularities
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`in efficacy of drug suspensions, particularly
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`for
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`topical
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`corticosteroids, was addressed as a result of inadequate dosing . . . . Lack of
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`compliance of patients in adequately shaking prednisolone acetate suspensions was
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`a determinant factor contributing to poor drug levels available to the eye."
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`AKN1022, 16 (emphasis added). Accordingly, POSAs appreciated that aqueous
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`suspensions suffered from an under-dosing difficulty and could also lead to
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`variable dosing, depending on the amount of shaking conducted before a particular
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`instillation. AKN1009, 1:25-33; AKN1019, 3-4; AKN1022, 16; AKN1018, ¶49.
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`Before 1997, formulators developed emulsion vehicles for ophthalmic
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`delivery as an alternative to suspension formulations. AKN1012, 1:8-14;
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`AKN1020, 1; AKN1010, Abstract; AKN1009, 1:56-58 & 5:62-6:10; AKN1015,
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`Abstract; AKN1016, Abstract; AKN1018, ¶54. And artisans used emulsions to
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`formulate "poorly water-soluble drugs" including "anti-inflammatory steroids
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`which are oil soluble and effectively water insoluble" for application to the eye.
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`AKN1009, 5:62-6:1. Before 1997, the art recognized that topical ophthalmic
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`emulsion formulations provided significant advantages over aqueous suspensions
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`regarding the difficulties of 1) ocular irritation, 2) dosage uniformity, 3)
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`precipitation and caking of the drug, and 4) the resulting poor bioavailability, as
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`explained below. Id; AKN1018, ¶55.
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`For example, drugs formulated in emulsions cause less irritation to the eye
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`because the drug is generally dissolved in the emulsion, rather than suspended as
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`solid drug particles, as in aqueous suspensions. AKN1012, 6:32-34 & 5:34-37;
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`AKN1009, 5:62-63 & 11:5-6; AKN1018, ¶56. As Dr. Xia explains, "POSAs
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`recognized that emulsions reduced the reflexive tearing associated with the
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`irritation of suspensions." AKN1018, ¶56; AKN1011, 7.
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`Also, because the drug is generally in a dissolved state in an emulsion,
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`POSAs appreciated that emulsions did not suffer from the dosage uniformity
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`problems of suspensions because caking and precipitation were not associated with
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`emulsions. AKN1012, 5:34-37 & 6:32-34; AKN1009, 1:25-33 & 56-61;
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`AKN1020, 2; AKN1018, ¶¶55 & 56 . Similarly, because the drug in an emulsion is
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`already in solution, POSAs appreciated that the drug could more rapidly penetrate
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`eye tissue compared to the same drug in a suspension formulation. AKN1018, ¶65;
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`AKN1009, 5:62-63, 10:28-48 & 11:5-6; ANK1020, 3.
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`POSAs also appreciated that emulsions could have a longer residence time
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`in the eye than aqueous formulations and that a longer residence time could also
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`enhance drug penetration. AKN1018, ¶68; AKN1015, 7; AKN1016, 1. For
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`example, in 1992, Muchtar stated that the emulsion, "by virtue of its structure
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`(presence of tiny oil droplets and surfactant in the formulation) might retain the
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`drug in the eyes and enhance its corneal penetration," leading to the observed
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`increased drug effect associated with emulsions. AKN1015, 7. And similarly, in
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`1994, Muchtar stated that emulsions "can improve drug absorption through the
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`cornea and prolong the residence time of the drug in the eye while minimizing
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`potential local and systemic side effects." AKN1016, 1. A POSA would have
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`appreciated that the longer ocular residence time of emulsions could allow the drug
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`formulation to be in contact with the ocular surface for a longer time than aqueous
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`suspensions, thus transferring more drug to the tissue before being expelled. Id.;
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`AKN1018, ¶68. And POSAs appreciated that the increased residence time of
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`emulsions could improve drug penetration and thus drug bioavailability in the
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`target tissue. AKN1015, 7; AKN1018, ¶68.
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`Additionally, emulsions were known to be well suited as ophthalmic
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`vehicles for steroids. AKN1012, 9:23-30; AKN1020, 1 & 3; AKN1009, 5:62-6:10;
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`AKN1002, 1:39-45; AKN1018, ¶69 & 70. For example, as early as 1964, stable,
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`castor oil in water emulsions of 6-prednisone (a poorly water-soluble steroid) were
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`known in the art to be useful to formulate eye drop, ear drop, and nasal drop
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`compositions. AKN1002, 1:39-45 & 59-61; AKN1018, ¶69. Similarly, in 1984,
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`Hollingsbee taught that several steroids, including prednisolone acetate, were
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`particularly preferred medicaments for formulation in ophthalmic emulsions.
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`AKN1009, 5:62-6:10; AKN1018, ¶66. And in 1995, Ding stated that steroids
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`including, prednisolone acetate, "may be emulsified with castor oil and polysorbate
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`80 resulting in a composition with . . . low irritation potential." AKN1012, 9:23-30;
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`AKN1018, ¶59.
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`Before 1997, artisans were aware that polysorbate 80 was a useful emulsifier
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`in castor oil emulsions for ophthalmic use. AKN1012, 1:8-14 & 10-11 (Examples
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`1-4); AKN1009, 6:23-28 & 10:28-48; AKN1018, ¶41. And POSAs were aware
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`that polysorbate 80 and Tween 80 were synonyms for polyoxyethylene (20)
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`sorbitan monooleate. AKN1021, 3; AKN1018, ¶31. Also, POSAs were aware that
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`polysorbate 80 is a non-ionic surfactant that is "non-toxic, non-irritant, and
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`applicable to the eye." AKN1006, 3:34-41, AKN1018, ¶41.
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`Also before 1997, POSAs knew that ophthalmic emulsions generally
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`provided better tissue penetration and bioavailability of poorly water-soluble drugs
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`than aqueous suspensions. AKN1020, 3; AKN1012, 18:7-11; AKN1010, 11:63-66;
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`AKN1018, ¶¶55 & 67-69. For example, in 1994, Kassem et al. investigated the
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`ophthalmic bioavailability of the steroid hydrocortisone (a poorly water-soluble
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`steroid) comparing emulsions versus aqueous vehicles. AKN1020, 2-3; AKN1018,
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`¶67. Kassem reported that the bioavailability of the emulsions was much higher
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`than that from the aqueous solution. Id. Kassem stated, "[i]t is obvious that the
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`bioavailability of hydrocortisone could be more than doubled by the appropriate
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`selection of the emulsion system" AKN1020, 4; AKN1018, ¶67. And Kassem
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`reported that the emulsions containing castor oil, as opposed to the two other oils
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`tested, provided the greatest increase in the bioavailability of hydrocortisone. Id;
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`AKN1018, ¶62. Aviv also compared the ocular bioavailability of drugs in
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`emulsions versus an aqueous suspension. AKN1010, 11:22-66. Aviv reported that
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`compared to an aqueous suspension, "a higher bioavailability of the drug is
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`Petition for Inter Partes Review of USPN 6,114,319 C1
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`obtained for the [emulsion] compositions of the invention while at the same time
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`greatly reduced irritation is achieved" AKN1010: 11:63-66; AKN1018, ¶62.
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`U.S. Patent No. 5,556,848 to Kimura et al. ("the '848 patent") is entitled
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`"Ophthalmic suspension containing difluprednate." The '848 patent issued on
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`September 17, 1996, and is prior art to the challenged patent under 35 U.S.C.
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`§ 102(b). The '848 patent discloses that difluprednate is a steroid with potent anti-
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`inflammatory and anti-allergic effects and is therefore useful for the treatment of
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`many inflammatory and allergic eye disorders. AKN1006, 1:13-20 & 1:25-31;
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`AKN1018, ¶42. For example, the
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`'848 patent states that its ophthalmic
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`difluprednate suspension "is useful for the treatment and prevention of disorders of
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`the eye, such as allergic conjunctivitis, vernal conjunctivitis, blepharitis marginalis,
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`catarrhal conjunctivitis and uveitis." AKN1006, Abstract.
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`The '848 patent also provides data that shows that difluprednate has superior
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`ophthalmic anti-inflammatory and anti-allergi