UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS, LLC
`
`PETITIONER
`
`V.
`
`ALCON RESEARCH, LTD
`
`PATENT OWNER
`
`U.S. PATENT NO. 8,791,154
`
`INTER PARTES REVIEW CASE NO. IPR2016-00544
`
`DECLARATION OF ERNING XIA, PH.D
`
`APOTEX EX1002
`
`Page 1
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS, LLC
`
`PETITIONER
`
`V.
`
`ALCON RESEARCH, LTD
`
`PATENT OWNER
`
`U.S. PATENT NO. 8,791,154
`
`INTER PARTES REVIEW CASE NO. IPR2016-00544
`
`DECLARATION OF ERNING XIA, PH.D
`
`APOTEX EX1002
`
`Page 1
`
`
`
`
`
`
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`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 3
`I.
`II. Background and Qualifications ....................................................................... 4
`III. Person Of Ordinary Skill In The Art ............................................................... 7
`IV. The Technology Claimed In The ’154 Patent ................................................. 9
`V. Claim Construction ........................................................................................ 11
`VI. State Of The Art ............................................................................................. 12
`POLYETHYLENE GLYCOL ....................................................................... 14
`POLYVINYLPYRROLIDONE .................................................................... 17
`HYDROXYPROPYLMETHYLCELLUOSE ............................................... 19
`CYCLODEXTRINS AND COMPLEXES OF CYCLODEXTRIN
`WITH DRUGS AND SOLUBILIZING POLYMERS ....................... 20
`BAC 27
`BORATES ..................................................................................................... 30
`POLYOL ........................................................................................................ 31
`OSOMOLALITY AND pH ........................................................................... 32
`VII. Summary Of My Conclusions ....................................................................... 33
`A. Ground 1: Obviousness based on Bhowmick in view of Yanni
`and Castillo .......................................................................................... 33
`B. Ground 2: Obviousness based on Schneider in view of
`Hayakawa, Bhowmick and Castillo .................................................... 40
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`2
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`Page 2
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`I, Erning Xia, Ph.D., hereby declare as follows.
`
`I.
`
`Introduction
`
`1.
`
`I have been retained as an expert witness on behalf of ARGENTUM
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`PHARMACEUTICALS, LLC., ("ARGENTUM") for the above-captioned inter
`
`partes review (IPR). I am being compensated for my time by the hour in preparing
`
`this declaration, but my compensation is not tied to the outcome of this matter.
`
`2.
`
`I understand that this Declaration accompanies a petition for IPR
`
`involving U.S. Patent No. 8,791,154 ("the '154 patent"), Ex. 1001, which resulted
`
`from U.S. Patent Application No. 13/475,607 ("the '607 application"), filed May
`
`18, 2012. I also understand that the '154 patent claims priority to U.S. Provisional
`
`Patent Application No. 61/548,957, filed Oct 19, 2011 and U.S. Provisional Patent
`
`Application No. 61/487,789, filed May 19, 2011.
`
`3.
`
`The '154 patent names Daniel A. Gamache, Laman Alani, Malay
`
`Ghosh, Francisco Javier Galán, Núria Carreras Perdiguer, and Onkar N. Singh as
`
`the inventors. The '154 patent issued on June 29, 2014 from the '607 application. I
`
`understand that, according to the United States Patent and Trademark Office
`
`("USPTO") records, the '154 patent is currently assigned to Alcon Research, Ltd.
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`("Alcon".)
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`4.
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`In preparing this Declaration, I have reviewed the '154 patent, the
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`granted claims (1-27), the file history of the ‘154 patent, and each of the
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`documents cited herein, in light of general knowledge in the art. In formulating
`
`my opinions, I have relied upon my experience, education, and knowledge in the
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`relevant art. In formulating my opinions, I have also considered the viewpoint of a
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`person of ordinary skill in the art ("POSA") (i.e., a person of ordinary skill in the
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`art of ophthalmic drug formulations and treatment). Throughout this declaration,
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`in rendering my opinion, I have considered what the viewpoint of a POSA would
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`have been prior to May 19, 2011, the filing date of U.S. Provisional Patent
`
`Application No. 61/487,789, to which the challenged '154 patent claims priority.
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`In the event that the priority claim to the ‘789 patent is deemed invalid, I have also
`
`considered what the viewpoint of a POSA would have been prior to October 11,
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`2011, the filing date of U.S. Provisional Patent Application No. 61/548,957, to
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`which the challenged ‘154 patent also claims priority.
`
`II. Background and Qualifications
`
`5.
`
`I am an expert in the field of ophthalmic drug formulation, and I
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`have been an expert in this field since prior to 2003. I am presently employed by
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`Fulcrum International Technologies, Inc. I obtained a Bachelor of Science degree
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`in Pharmacy from Nanjing College of Pharmacy in 1982, a Master of Science
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`4
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`degree in Biopharmaceuticals from China Pharmaceutical University in 1985, and
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`a Ph.D. in Pharmaceutics from the University of Iowa in 1995.
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`6.
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`I was an Assistant Professor and Research Associate for the College
`
`of Pharmacy at the China Pharmaceutical University from August 1985 to
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`December 1987, a Research Associate at Illinois State University from January
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`1988 to December 1989, and a Research and Teaching Assistant for the University
`
`of Iowa, College of Pharmacy from 1990 to 1995. After receiving my Ph.D. in
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`Pharmaceutics, I held the positions of Senior Formulation Process Scientist and
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`Principal Formulation Process Scientist with Bausch & Lomb in Rochester, NY
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`from 1995-1999 and 1999-2001, respectively. I subsequently held the positions of
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`Senior Principal Formulation Process Scientist from 2001-2004, Research Fellow
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`from 2004-2005, and Site Leader/Research Fellow from 2006-2008 at Bausch &
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`Lomb.
`
`7.
`
`I have served as Program Director and Research Fellow at Valeant
`
`Pharmaceuticals in Rochester, NY from 2009-2013. I currently hold the position of
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`Distinguished Research Fellow and Chief Technology Officer ("CTO") at Fulcrum
`
`International Technologies, Inc. ("Fulcrum") and have served in this position since
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`September of 2013.
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`5
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`8.
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`I have experience formulating topical ophthalmic products for
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`treating dry eye, including products that decrease the evaporation of natural tears
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`and products that increase tear production. While serving as CTO at Fulcrum, I
`
`helped develop a water-soluble based nutritional product for eye fatigue called 7-
`
`Hours™. Previously, I led Vision Care research initiatives as Program Director at
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`Valeant Pharmaceuticals and dry eye initiatives and dry eye portfolio management
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`as a Research Fellow at Bausch & Lomb in Rochester, NY. Also, while at Bausch
`
`& Lomb, my colleagues and I often consulted with physicians to determine the
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`current ophthalmic needs in the market, and then made efforts to meet those needs.
`
`9.
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`I have received several honors in my career, including the Bausch &
`
`Lomb In Focus Recognition in 2010, the Bausch & Lomb CSO Innovation Award
`
`in 2007, the National Award for Science Spectrum Trailblazer in 2005, and the
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`National Emerald Award for Career Achievement in Industry in 2004.
`
`10.
`
`During my nearly 30 years of experience in topical ophthalmic drug
`
`formulation, I have authored or co-authored 36 scientific articles. I am also a
`
`named inventor on 106 U.S. patents and patent applications. Each publication,
`
`patent, and patent application is listed in my curriculum vitae, Ex. 1024.
`
`11.
`
`Accordingly, I am an expert in the field of topical ophthalmic drug
`
`formulation. My full background is detailed in my curriculum vitae, Ex. 1024.
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`III. Person Of Ordinary Skill In The Art
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`12.
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`I understand that a person of ordinary skill in the art ("POSA") is a
`
`hypothetical person who is presumed to be aware of all of the pertinent art, thinks
`
`along conventional wisdom in the art, and is a person of ordinary creativity. A
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`POSA with respect to topical eye formulations would have had knowledge of the
`
`scientific literature regarding inflammatory eye disorders and useful therapies
`
`including, e.g., topical aqueous solutions and their formulation into delivery
`
`vehicles, as of May 2011.
`
`13. With respect to the subject matter of the '154 patent, a POSA typically
`
`would have had: (i) an M.D., Pharm. D. or Ph.D. in chemistry, biochemistry,
`
`pharmaceutics, or in a related field in the biological or chemical sciences, and have
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`at least about two years of experience in the treatment ocular diseases and
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`formulations used to treat ocular diseases, including topical pharmaceuticals for
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`use in the eye; or (ii) a Master's degree in chemistry, biochemistry, pharmaceutics,
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`or in a related field in the biological or chemical sciences, and have at least about
`
`five years of experience in the treatment of ocular diseases and formulations used
`
`to treat ocular diseases, including topical pharmaceuticals for use in the eye; or (iii)
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`a bachelor’s degree in pharmacy, chemistry, biochemistry, pharmaceutics, or in a
`
`related field in the biological or chemical sciences, and have at least about 10 years
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`of experience in the treatment of ocular diseases and formulations used to treat
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`ocular diseases, including topical pharmaceuticals for use in the eye. The POSA
`
`would have an understanding of the basis of ocular allergy including knowledge of
`
`the structure and constitution of conjunctiva of the eye, Immunoglobulin E (IgE)
`
`antigen stimulated histamine release, cell-based and animal models and assays for
`
`assessing effectiveness of ophthalmic treatments, and knowledge of ophthalmic
`
`formulation excipients. These descriptions are approximate, and a higher level of
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`education or specific skill might make up for less experience, and vice-versa.
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`14. A POSA typically would work as part of a multidisciplinary 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
`
`formulations chemist with knowledge of a wide array of excipients suitable for use
`
`in ophthalmic formulations and their properties may be part of the team. A
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`clinician having experience in treating allergic disorders of the eye with topical
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`pharmaceuticals may also be part of the team.
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`15.
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`I believe that I would qualify as a person of at least ordinary skill in
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`the art as of May 19, 2010.
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`IV. The Technology Claimed In The ’154 Patent
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`16. The ’154 patent relates to ophthalmic aqueous solutions for the
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`treatment of ocular allergic conjunctivitis containing the drug olopatadine, and
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`methods of treating ocular allergy symptoms in human. Ex. 1001, Abstract, 2:41-
`
`45, 3:1-2, claims 1, 4, 8, 12 and 21. These compositions contain “relatively high”
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`concentrations of olopatadine including at least 0.67 w/v %, 0.7 w/v %, and not
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`more than 1.0 w/v% olopatadine. Id., 2:42-44; 4:1-2; claims 1, 4, 8 and 21. In
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`order to solubilize the relatively high concentrations of olopatadine in a stable
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`manner, the inventors purport to provide a unique set of excipients for solubilizing
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`the olopatadine. Id., 3:28-29. The excipients include a cyclodextrin derivative
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`selected from SAE-β-cyclodextrin, HP-γ-cyclodextrin, HP-β-cyclodextrin or
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`combinations thereof. Id., 2:45-52; claims 1, 4, 8 and 21. Typically, the solution
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`contains at least 0.5 w/v % but no greater than 2.0 w/v % HP- γ -cyclodextrin. Id.,
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`4:65-67; and claims 8 and 21. The composition also includes the common lactam
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`polymer polyvinylpyrrolidone (PVP) to aid in the solubilization of the olopatadine,
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`and a polyether (e.g., polyethylene glycol (PEG)) for enhancing solubility and/or
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`aiding in achieving the desired tonicity. Id., 2:52-57; claims 1, 4, 8 and 21. The
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`solutions typically contain 2.0 w/v % to 6.0 w/v % PVP and 2.0 w/v % to 6.0 w/v
`
`% PEG having a molecular weight of 300 to 500. Id. claims 4, 8 and 21.
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`9
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`17. The compositions also include a preservative such as benzalkonium
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`chloride (BAC), as well as borate and/or polyol to aid in achieving desired
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`preservation. Id., 2:60-67; claims 1, 2, 3, 4, 8 and 21. Typically, the compositions
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`contain greater than 0.003 w/v % but less than 0.03 w/v % BAC. Id., 9:6-14; claim
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`21. In order to enhance the residence time of the composition upon the cornea
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`when the composition is topically administered, the compositions may contain
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`viscosity enhancing agents such as hydroxylpropylmethyl cellulose (HPMC) at a
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`concentration of at least 0.15 w/v % but no greater than 1.0 w/v %. Id., 6: 41-50;
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`7: 9-14; claims 15, 16, 17, and 22. The compositions also include water. Id., 4: 24-
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`26; Examples 1-2; claims 1, 4, 8, and 21. The pH of the aqueous solution is 6.0 to
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`7.8 and the osmolality of the solution is 200 to 400 mOsm/kg. Id., 10: 4-9; claim
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`21.
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`18. The aqueous solutions may be administered to a human to treat at
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`least one ocular allergy symptom such as ocular itching. Id., 3:1-5; claims 12 and
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`14. The solution is topically applied to an eye by dispensing at least one drop of
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`the solution to the eye. Id., claim 13.
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`19. The ophthalmic compositions of the ’154 patent are also purported to
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`provide multiple advantages over previous olopatadine compositions. Among the
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`advantages alleged for the claimed compositions are the following. First,
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`compositions containing HP-γ-CD were unexpectedly found to be “more
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`susceptible to preservation” than those with while simultaneously having solubility
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`characteristics similar to the β-cyclodextrin derivatives also discussed. Id., 11: 33-
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`38. Second, although cyclodextrins are known to “entrap other drugs in a manner
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`that does not allow the drugs to later release and show efficacy, HP-γ-CD does not
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`interfere with olopatadine efficacy. Id., 45-50. However, as discussed below, the
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`claimed ophthalmic compositions of the ’154 patent would have been obvious to a
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`POSA and do not provide any surprising results or advantages.
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`V. Claim Construction
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`20.
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`I understand that terms of the claims are to be given their broadest
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`reasonable interpretation as understood by a POSA in light of the language of the
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`claims and specification of the '154 patent.
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`21.
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`“w/v %” Claims 1, 4, 8, 16,17, 21, and 22 each recite components in
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`terms of “w/v %.” While the ’154 Patent states the term means weight volume
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`percent (’154 Patent, 3:41-43), it does not provide the units used in determining the
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`weight volume percent. The expression “w/v %” is proposed to describe the mass
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`of the component in grams per 100 milliliters of solution multiplied by 100, as this
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`definition is the standard used in the formulations and topical eye pharmaceutical
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`industries. Pharmaceutical Calculations, 13th Ed., Ansell, 2010, Ex. 1036, 82-83.
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`VI. State Of The Art
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`22. Olopatadine hydrochloride ([(Z)-3-(dimethylamino)propylidene]-
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`6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride) is a selective
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`histamine H1-receptor antagonist that is used for the treatment of ocular symptoms
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`of seasonal allergic conjunctivitis and has the following formula:
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` PATADAY® label; Ex. 1038, 6.
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`.
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`23. Olopatadine and its pharmaceutically acceptable salts are disclosed in
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`EP 0214779, U.S. Pat. No. 4,871,865, EP 0235796 and U.S. Pat. No. 5,116,863
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`(Exs. 1029, 1027, 1032, 1028). U.S. Pat. No. 5,116,863 discloses olopatadine (Z-
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`11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid)
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`as a compound having an anti-allergic activity and is known to be an effective
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`treatment for symptoms of allergic rhinitis and urticaria (e.g., sneezing, nasal
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`discharge and nasal congestion), as well as in the treatment of various skin
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`diseases, such as eczema and dermatitis. Ex. 1028, 2:1-14. The compound may be
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`administered in a solid oral dosage form or as an ophthalmic solution. Id., 1:18-19.
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`24.
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`In the U. S, olopatadine hydrochloride is commercially available
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`under the brand names PATANOL® and PATADAY® as 0.1 % and 0.2% sterile
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`ophthalmic solutions, respectively, both marketed by Alcon. Exs, 1037, 1038
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`PATANOL® is indicated for the treatment of signs and symptoms of allergic
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`conjunctivitis and PATADAY® for the treatment of ocular itching associate with
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`eye allergy. Id. According to its labelling information, each mL of PATANOL®
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`contains olopatadine hydrochloride equivalent to 0.1% olopatadine, 0.01%
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`benzalkonium chloride, and unspecified amounts of sodium chloride, dibasic
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`sodium phosphate, hydrochloric acid and/or sodium hydroxide (to adjust pH) and
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`purified water. Ex. 1037. According to its labelling information, each mL of
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`PATADAY® solution contains olopatadine hydrochloride equivalent to 0.2%
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`olopatadine, and inactives such as 0.01% benzalkonium chloride and unspecified
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`amounts of povidone, dibasic sodium phosphate, sodium chloride, edentate
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`disodium, hydrochloric acid/sodium hydroxide (to adjust pH) and purified water.
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`Ex. 1038.
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`POLYETHYLENE GLYCOL
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`25. Polyethylene glycol, referred to as “PEG,” is a polymer containing
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`repeating -CH2CH2O- subunits and is used in the pharmaceutical industry as a
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`solvent, plasticizer, surfactant, ointment base, and a tablet and capsule lubricant,
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`among others. PEG has low toxicity, with absorption into the body less than 0.5%.
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`“PEG 400" indicates that the average molecular weight of the specific PEG is 400.
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`Ex. 1061, 4:2-4.
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`26. Polyethylene glycol 400 is also recognized by the U.S. Food and Drug
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`Administration as an active ingredient on its own – an ophthalmic demulcent. 21
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`C.F.R. §349.12, revised as of April 1, 2001, Ex. 1057. The U.S. Food and Drug
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`Administration authorizes an ophthalmic product containing 0.2 – 1.0% PEG 400
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`to recite that the product provides the pharmaceutical benefits of protecting and
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`lubricating mucous membrane surfaces and relieving dryness and irritation. Id.
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`27. PEG 400 itself has long been used to enhance the aqueous solubility
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`of hydrophobic, poorly water soluble compounds. As noted in AAPS Pharm. Sci.
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`Tech, 4 (1), pp 1-5, 2003 (“Nandi”), “[p]olyethylene glycol (PEG)-400 is one of
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`the most widely used cosolvents for improving the aqueous solubility of
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`hydrophobic drugs.” Ex. 1015, 1. For example, valdecoxib has a water solubility
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`of 0.01 milligrams per milliliter (mg/mL), which is equivalent to 0.1 w/v%. Ex.
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`14
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`1035, p. 1588 (Table 1). In studies of the solubility of valdecoxib in various
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`PEG:water solutions, a mixture having a volumetric ratio of 1:99 PEG 400:water
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`was examined. Id. The weight/volume percent of the PEG 400 may be calculated
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`from the volumetric ratio. Because the density of PEG 400 is 1.128 g/mL, this
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`mixture contains 1.126 g PEG 400 per 99 mL of water. Dividing the weight of the
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`PEG 400 by the volume of water provides a value of about 1.1 w/v% PEG 400 in
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`water. At 1.1 w/v% PEG 400, the solubility of valdecoxib increased to 0.92
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`mg/mL (or 9.2 w/v% from 0.1 w/v%). Id.
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`28. PEG 400 was also understood to enhance the physical stability of
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`olopatadine-containing solutions at PEG 400 concentrations of 2 w/v%. U.S. Pat.
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`No. 6,995,186 (“Castillo”) discusses topical solutions for treating allergic or
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`inflammatory disorders of the eye where the solutions include approximately 0.2-
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`0.6 w/v% olopatadine. Ex. 1006, 2:13-19, 32-34. In Table 5, Castillo discloses
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`Formulation M, a solution that contains 0.222 w/v% olopatadine hydrochloride
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`(equivalent to 0.2 w/v% olopatadine), 2 w/w% PEG 400, about 0.01 w/w%
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`benzalkonium chloride, 0.5 w/w% dibasic sodium phosphate (i.e., Na2HPO4), 0.3
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`w/w% sodium chloride, 0.01 w/w% edetate disodium, and where the solution has a
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`pH of 7.1 Additional solutions were disclosed with the same makeup except for the
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`addition of 2 w/w% PVP with a weight average molecular weight of 58,000
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`(Formulations N and L respectively), the omission of PEG 400 but including the
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`same type of PVP (Formulations K and N) or 0.333% w/w olopatadine.HCl and
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`the same three PEG 400/PVP variations (Formulations Q, R, S). Ex. 1006,
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`Example 7, Table 5. These solutions were subjected to freeze-thaw stability
`
`studies. The studies were carried out under two sets of conditions: the first
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`involved solutions with added pumice as a seeding agent to facilitate precipitation
`
`and crystallization, and the second lacked pumice. (Notably, while the example
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`refers to the same seed as “Example 4”, this is clearly a typographical error
`
`because Example 4 does not include a seeding agent while Example 6 includes the
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`pumice seeding agent.) Three vials of each solution, were tested under each set of
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`conditions. Each formulation was subjected to up to six freeze-thaw cycles where
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`one cycle was three days at low temperature (either 0 °C. or –20 °C.), followed by
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`one day at uncontrolled room temperature. The solutions were then visually
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`inspected and the results recorded. As illustrated in Table 6, none of the
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`formulations containing PEG 400 (Formulations L, M & R) showed any
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`precipitation. Id., Table 6. Although solutions with only PVP also avoided
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`1 Table 5 lists the components in w/w% based on water. Because 1 mL of water is
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`about 1 g, w/w% is essentially equivalent to w/v% in this instance.
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`precipitation at 0.222% w/w olopatadine (formulations K, N, O), Only
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`Formulation R with PEG 400 avoided precipitation at 0.333% w/w olopatadine.
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`Thus, Castillo shows that using PEG 400, both alone and with PVP, provides
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`olopatadine solutions with enhanced stability. Id., Example 7, Tables 5 &6
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`(Formulations L, M, & R).
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`29. Thus, Castillo shows that, in addition to the well-known solubility
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`enhancement and demulcent properties of PEG 400, 2 w/v% PEG 400 had been
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`demonstrated to enhance the stability of olopatadine containing solutions. Further,
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`Schneider describes aqueous solution compositions of olopatadine which include
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`polymers such as PEG that may act as lubricants or viscosity agents. Ex. 1007,
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`[0052].
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`POLYVINYLPYRROLIDONE
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`30. Polyvinylpyrrolidone also goes by the names “PVP” or “povidone.”
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`PVP is a known demulcent, and the U.S. Food and Drug Administration authorizes
`
`an ophthalmic product containing 0.1 – 2.0% PVP to recite that the product
`
`provides the pharmaceutical benefits of protecting and lubricating mucous
`
`membrane surfaces and relieving dryness and irritation. There are various varieties
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`of PVP based on the molecular weight, as illustrated in the table below.
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`17
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`
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`Molecular
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`10,000
`
`30,000
`
`40,000
`
`58,000
`
`360,000
`
`Weight
`
`K-value
`
`12-18
`
`27-33
`
`28-32
`
`29-32
`
`90-103
`
`Synonym
`
`PVP K15
`
`PVPK30
`
`PVP K30
`
`PVP K30
`
`PVP K90
`
`Ex. 1058.
`
`31. The “K-value” is the Fikentscher K-value, derived from a solution
`
`viscosity of the polymer in water, thus it is related to an intrinsic viscosity and the
`
`average molecular weight. “Viscosity correlation for aqueous PVP solutions”, J
`
`Applied Polymer Science, Volume 90, Issue 4 Page 1153-1155, 2003, Ex. 1059,
`
`Abstract, 1st Col. As the synonyms for PVP are related to its K-value, it is
`
`generally more accurate to discuss PVP in terms of its weight average molecular
`
`weight.
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`32. Prior to May 19, 2010, PVP was known to increase the solubility and
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`enhance the physical stability of olopatadine-containing solutions. PVP was
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`known to be generally beneficial for inclusion in ophthalmic anti-allergy
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`compositions. PVP was known to be generally beneficial for inclusion in
`
`ophthalmic anti-allergy compositions. Ex. 1043, 124. As discussed above, Castillo
`
`discloses topical solutions for treating allergic or inflammatory disorders of the eye
`
`where the solutions include approximately 0.2-0.6% olopatadine and are effective
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`as once-a-day products. Ex. 1006, 2:13-19. In addition to the olopatadine, Castillo
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`18
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`Page 18
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`
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`discloses including an amount of PVP sufficient to enhance the stability of the
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`solutions. Id., 2:19-22. The particular concentrations of PVP suggested by
`
`Castillo are 0.1 w/v% to 3 w/v%, where the weight average molecular weight of
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`the PVP used is disclosed to be 5,000 to 1,600,000, but most preferably from
`
`50,000 to 60,000. Id., 3:17-25. Schneider teaches aqueous solution compositions
`
`of olopatadine which include polymers such as PVP that may act as lubricants or
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`viscosity agents. Ex. 1007, [0052]. Likewise, Hayakawa describes using PVP as
`
`the viscous vehicle for its topical ophthalmic formulations containing olopatadine.
`
`Ex. 1008, 6:50-58.
`
`HYDROXYPROPYLMETHYLCELLUOSE
`
`33. Hydroxypropylmethylcelluose (also known as “hypromellose” or
`
`HPMC) is recognized by the U.S. Food and Drug Administration as an ophthalmic
`
`demulcent at concentrations of 0.2 to 2.5%. C.F.R. §349.12. On July 3, 2003, the
`
`U.S. Food and Drug Administration (based on an action and recommendation from
`
`the United States Pharmacopeia (USP)) changed the listed name of
`
`hydroxypropylmethyl-cellulose to “hypromellose” but did not change its
`
`classification as an ophthalmic demulcent. 68 Fed. Reg. 106, 32981-32983, Ex.
`
`1060. Thus, much like PEG 400 and polyvinylpyrrolidone, the U.S. Food and
`
`Drug Administration authorizes an ophthalmic product containing 0.2 – 2.5%
`
`hydroxypropylmethylcelluose to be labeled as providing the pharmaceutical
`
`19
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`Page 19
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`
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`benefits of protecting and lubricating mucous membrane surfaces and relieving
`
`dryness and irritation. Ex. 1057.
`
`34. Bhowmick teaches the use of HPMC to further stabilize the inclusion
`
`complexes of olopatadine and cyclodextrins in aqueous topical solutions. Ex.
`
`1004, 2:26-27; 6:23-26. Bhowmick discloses that the HPMC may be used at
`
`concentrations ranging from about 0.001 % to about 5%, and more preferably in
`
`concentrations ranging from about 0.01 % to about 1 % w/v. Id., 7:10-13. Castillo
`
`provides a working example with HPMC (and absent PVP) that illustrates the same
`
`enhanced stability provided by PVP. Compare Ex. 1006, Example 6, Tables 3 & 4
`
`(Formulation H) with id., Example 7, Tables 5 & 6. Schneider describes aqueous
`
`solution compositions of olopatadine which include polymers that may act as
`
`lubricants or viscosity agents, such as HPMC, PEG, and PVP. Ex. 1007, [0052].
`
`Schneider explains that while there are solubility enhancing components for
`
`olopatadine, PDE4 itself increases the solubility of olopatadine in aqueous
`
`solutions. Id., [0042]
`
`CYCLODEXTRINS AND COMPLEXES OF CYCLODEXTRIN WITH
`DRUGS AND SOLUBILIZING POLYMERS
`35. Cyclodextrins are a group of structurally related natural products
`
`formed during bacterial digestion of cellulose and commonly used as
`
`pharmaceutical excipients for the solubilization of hydrophobic drugs. Ex. 1015,
`
`20
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`Page 20
`
`
`
`1; Ex. 1004, 4:17-19. These cyclic oligosaccharides consist of (α-1,4)-linked α-D-
`
`glucopyranose units and contain a somewhat lipophilic central cavity and a
`
`hydrophilic outer surface. Ex. 1004, 4:19-21. As shown in the Figure 1 below, the
`
`natural α-, β- and γ-cyclodextrins (α-CD, β-CD and γ-CD) consist of six, seven,
`
`and eight glucopyranose units, respectively. Id., 4:30-5:2; Ex. 1014, 115. Figure 2
`
`shows schematically how the glucopyranose units form the central cavity. The
`
`diameter of the central cavity in α-CD, β-CD and γ-CD varies, being 0.47-0.53 nm,
`
`0.6-0.65 nm, or 0.75-0.83 nm respectively. Ex. 1056, 1018 (Table 1).
`
`Figure 1
`
`
`
`21
`
`Page 21
`
`
`
`Figure 2
`
`
`
`The natural cyclodextrins, in particular β-CD, are of limited aqueous solubility,
`
`and complexes resulting from interaction of lipophiles with these cyclodextrins can
`
`also be of limited solubility, resulting in the precipitation of solid cyclodextrin
`
`complexes from water and other aqueous systems. Ex. 1044, 116, 1st col. This is
`
`thought to be due to relatively strong intermolecular hydrogen bonding in the
`
`crystal state. Ex. 1014, 80(2):144-50. Substitution of any of the hydrogen bond
`
`forming hydroxyl groups in cyclodextrins, even by lipophilic methoxy groups,
`
`results in dramatic improvements in the aqueous solubility of the cyclodextrin
`
`derivative. Id.
`
`36.
`
` Water-soluble cyclodextrin derivatives that are widely used in
`
`pharmaceutical formulations include the hydroxypropyl derivatives of β-CD and
`
`γ-CD (HP-βCD, HP-γ-CD) the randomly methylated β-cyclodextrin (RMβCD),
`
`22
`
`Page 22
`
`
`
`and sulfoalkylether cyclodextrins (SAE-CD) such as sulfobutylether-β-
`
`cyclodextrin (SBE-β-CD) and sulfobutylether-γ-cyclodextrin (SBE- γ CD). Ex.
`
`1004, 5:3-8. SAE-CDs have long been commercially available with different
`
`substitution levels of the SAE group, e.g., 1, 4, 7, and 8 sulfobutylether groups in
`
`SBE-βCD. Ex. 1034, 4.
`
`37. Cyclodextrins solubilize drugs by forming inclusion and non-
`
`inclusion complexes. “In aqueous solution, cyclodextrins form inclusion
`
`complexes with many drugs through a process in which the water molecules
`
`located in the central cavity are replaced by either the whole drug molecule, or
`
`more frequently, by some lipophilic portion of the drug structure. Since no
`
`covalent bonds are formed or broken during the drug-cyclodextrin complex
`
`formation, the complexes are in dynamic equilibrium with free drug and
`
`cyclodextrin molecules.” Ex. 1004, 5:21-24, 26-28.
`
`38. Bhowmick discloses that olopatadine aqueous solutions having a
`
`concentration of 0.17 w/v% or higher can be unstable over extended storage
`
`periods. Ex. 1004, 1:29-2:1. At such concentrations the olopatadine may
`
`precipitate or crystallize out of solution. Id., 2:1-2. In contrast, Bhowmick
`
`describes stable aqueous topical solutions of olopatadine hydrochloride
`
`incorporating a cyclodextrin such as an alkyl cyclodextrin, hydroxyalkyl
`
`cyclodextrin, carboxyalkyl cyclodextrin, or sulfoalkyl ether cyclodextrin. Id.,
`
`23
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`Page 23
`
`
`
`2:24-27, 3:15-20, 4:16-17, 5:3-8. HP-γ-CD, HP-β-CD, and SBE-β-CD are
`
`described as preferred cyclodextrins for use in the formulations. Id., 5:10-30.
`
`Bhowmick describes using these cyclodextrins in an amount sufficient to keep
`
`olopatadine in solution and prevent its precipitation or crystallization. (Id., 3:25-
`
`28). Bhowmick also discloses that olopatadine aqueous solutions containing HP-β-
`
`CD and BAC were stable over extended storage periods. Ex. 1004, Examples 1-8.
`
`While Bhowmick does not disclose an upper limit for the amount of olopatadine
`
`that may be solubilized using cyclodextrin, in the “most preferred embodiment”
`
`the dissolved amount is equivalent to about 0.17% to about 0.62 w/v% of
`
`olopatadine free base. Id., claim 6, 4:9-12. While Bhowmick discloses using at
`
`least cyclodextrins, BAC and HPMC with olopatadine to provide stable aqueous
`
`topical solutions, Bhowmick does not suggest excluding other potential unrecited
`
`components. Ex. 1004, claim 6. Further, while Schneider does not explicitly
`
`discuss cyclodextrins, Schneider admits there are other agents in the art for
`
`increasing the solubility of olopatadine. Ex. 1007, [0042].
`
`39. The foregoing conclusion is consistent with other art that indicates
`
`cyclodextrins were known to be useful in solubilizing mixtures of drugs in aqueous
`
`solutions containing as much as 1.5 w/v% olopatadine. WO 2009/003199
`
`(“Pipkin”, published 12/31/2008), Ex. 1022, 7:16-20, claims 28-29. Pipkin
`
`specifically describes solution formulations of olapatadine with corticosteroids and
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`24
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`Page 24
`
`
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`SAE-CD, propylene glycol, povidone, buffers, and other excipients, including
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`HPMC, PEG and BAC. Id., 8:18-26, 72:19-28. The cyclodextrins may be
`
`derivatives of β-CDs and γ-CDs. Id., 40:1-4. A POSA would have understood that
`
`the cyclodextrins in the compositions of Pipkin solubilize both the corticosteroids
`
`and the olopatadine, especially in view of, e.g., the Bhowmick reference.
`
`40. For solutions meant for ophthalmic administration, Bhowmick
`
`discloses preferred concentrations of, e.g., HP-β-CD range from about 1.0% to
`
`about 5%. Id., 6:1-6. Bhowmick also discloses that “the ratio of olopatadine or its
`
`pharmaceutically acceptable salt to hydroxypropyl β-cyclodextrin present in the
`
`inclusion complex is from about 1:1.65 to about 1:50 by weight.” Id., 6:18-21. In
`
`my opinion, a POSA would understand th
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