UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`TEVA PHARMACEUTICALS USA, INC.,
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`Petitioner
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`v.
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`MONOSOL RX, LLC,
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`Patent Owner
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`U.S. Patent No. 8,603,514
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`Case IPR2016: Unassigned
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`EXPERT DECLARATION OF JAYANTH PANYAM, Ph.D.
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`EXHIBIT NO. 1003 Page 1 of 58
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`TEVA PHARMACEUTICALS USA, INC.,
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`Petitioner
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`v.
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`MONOSOL RX, LLC,
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`Patent Owner
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`U.S. Patent No. 8,603,514
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`
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`Case IPR2016: Unassigned
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`EXPERT DECLARATION OF JAYANTH PANYAM, Ph.D.
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`EXHIBIT NO. 1003 Page 1 of 58
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`1. My name is Jayanth Panyam. I have been retained by counsel for
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`Teva Pharmaceuticals USA, Inc. (“Teva”). I understand that Teva is petitioning
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`for inter partes review of U.S. Patent No. 8,603,514 (the “’514 patent”), which is
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`assigned to Monosol RX, LLC (“Monosol”). I further understand that Teva is
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`requesting that the United States Patent and Trademark Office cancel claims 1-3, 9,
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`15, 62-65, 69-73, and 75 of the ’514 patent as unpatentable over Bess in view of
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`Chen, and Chen in view of Cremer. This expert declaration supports Teva’s
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`petition.
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`I.
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`Qualifications and Background
`A. Education and Experience; Prior Testimony
`1. My background, qualifications, and experience related to my opinions
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`expressed in this report are given in my curriculum vitae attached as Ex. 1036.
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`2.
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`I received my Bachelor’s degree in Pharmacy in 1997 from the T.N.
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`Dr. MGR Medical University. I continued my education at Banaras Hindu
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`University and received my Masters degree in Pharmaceutics in 1999. In 2003, I
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`received my Ph.D. in Pharmaceutical Science from the University of Nebraska
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`Medical Center.
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`3.
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`I have more than nine years of experience working in the
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`pharmaceutical sciences. I am currently a professor with tenure at the University of
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`Minnesota, in Minneapolis.
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1003 Page 2 of 54
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`4.
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`Throughout my career, I have published sixty peer-reviewed articles
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`and five book chapters related to pharmaceutical sciences. I have also been invited
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`to give presentations at more than thirty national meetings, including “Targeting
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`circulating tumor cells and metastases in breast cancer,” “Nanoparticles for Tumor-
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`targeted Drug Delivery: Challenges and Opportunities,” and “PLGA-induced
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`inflammation is a double-edged sword.”
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`5.
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`I am a member of the American Association of Pharmaceutical
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`Scientists, the Controlled Release Society, and the American Association of
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`Colleges of Pharmacy.
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`6.
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`I am named as an inventor on one issued patent entitled
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`“Nanoparticles for imaging and treating chlamydial infection,” as well as five
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`pending patent applications and invention disclosures.
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`7.
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`B.
`8.
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`I have previously testified as an expert in a deposition.
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`Bases for Opinions and Materials Considered
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`Ex. 1037 includes a list of the materials I considered, in addition to
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`my experience, education, and training, in providing the opinions contained herein.
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`C.
`9.
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`Scope of Work
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`I have been retained by Teva as a technical expert in this matter to
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`provide various opinions regarding the ’514 patent. I receive $750 per hour for my
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`services and $1,150 for time spent testifying at deposition, hearing, or trial. No
`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 3 of 58
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`part of my compensation is dependent upon my opinions given or the outcome of
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`this case. I do not have any other current or past affiliation as an expert witness or
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`consultant with Teva. I do not have any current or past affiliation with Monosol,
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`or any of the named inventors on the ’514 patent.
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`II.
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`Summary of Opinions
`10.
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`It is my opinion that the challenged claims – claims 1-3, 9, 15, 62-65,
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`69-73, and 75 – are obvious under 35 U.S.C. § 103 in view of the prior art,
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`including the references cited below, which collectively teaches and motivates a
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`person of ordinary skill in the art to make and use the same film formulation
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`compositions that are claimed by the ’514 patent.
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`11.
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`I have reviewed the uniform thin film drug delivery prior art, and find
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`that one of ordinary skill in the art would have understood that the Bess1 and Chen2
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`references, and the Cremer3 reference, render obvious the challenged claims of the
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`’514 patent.
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`12. The allegedly inventive concepts of the ’514 patent were all well-
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`known in the prior art. It was known at the time of the alleged invention of the
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`’514 patent that uniform suspensions are important for use in drug delivery.
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`Dispersion of pharmaceutical actives uniformly throughout a suspension was well
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`1 Bess, Ex. 1004.
`2 Chen, Ex. 1005.
`3 Cremer, Ex. 1006.
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 4 of 58
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`known in the art. Uniformity was known to be challenging for those compounds
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`that were not readily soluble, thereby forming suspensions. It would have thus
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`been obvious by the priority date to use uniform dispersion of pharmaceutical
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`actives throughout a suspension.
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`13.
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`It was also known that uniform suspensions of particulate agents
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`(before or after casting) were highly dependent on viscosity. One of skill in the art
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`would have understood that uniformity in film formulations meant for human use
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`was expected and readily achieved. (See, e.g., Ex. 1013, The Theory and Practice
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`of Industrial Pharmacy, at 56-57, 358-359, 368-369.)4 The ’233 patent5 discloses
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`that homogeneous suspensions of various polymers, including vinyl acetate and
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`cellulose, were used for cast films. (Ex. 1022, ‘233 patent, at Abstract.) These
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`films were also dried and considered to be homogenous. (Id. at 4:59-5:3.) Further,
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`it was well known in the art that the uniformity of particulates in a suspension was
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`directly related to the suspension’s viscosity. (Ex. 1013, The Theory and Practice
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`of Industrial Pharmacy, at 484.) The uniformity could also be affected by the
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`mixing time and speed used for making a suspension. (Id. at 491-492.) Stoke’s
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`law, well known in the art by 2001, taught that settling of particulates in a
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`suspension is directly related to, among other things, the density of the particles
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`4 Ex. 1013, The Theory and Practice of Industrial Pharmacy (Lachman et al., eds.,
`3d ed. 1986).
`5 Ex. 1022, U.S. Pat. No. 5,166,233.
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 5 of 58
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`and the viscosity of the solution. (Ex. 1014, Theory of Pharmaceutical Systems,
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`Volume II: Heterogeneous Systems, at 9.)6 Therefore, one of skill in the art would
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`understand that to achieve a desired uniformity, particularly for pharmaceutical
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`particles, one would necessarily consider the viscosity of the suspension.
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`14.
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`It was well known that uniform particle distribution within a film,
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`whether cast or sprayed onto a drug dosage form, such as a tablet, was critical. (Ex.
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`1013, The Theory and Practice of Industrial Pharmacy, at 362-364.) One way to
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`achieve uniformity of particulates, such as in the case of colorants, was to “mill[]”
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`the colorant in the coating solution. (Id. at 369.) It was also well known that the
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`viscosity of the coating solution would affect the “uniform dispersion of the
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`colorants[’]” particle dispersion. (See id. at 369; Ex. 1014, Theory of
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`Pharmaceutical Systems, Volume II: Heterogeneous Systems, 1973, p. 9.)
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`15.
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`It was well known that one could vary the viscosity of a suspension.
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`(Ex. 1013, The Theory and Practice of Industrial Pharmacy, at 484,491-492.)
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`16. Lachman, for example, discloses that adding specific polymers, which
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`have different viscosities, could “cause loss of . . . the tendency to agglomerate.”
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`(Id. at 654-55.) In other words, this could increase uniformity of the particles.
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`6 Ex. 1014, Cartensen, Theory of Pharmaceutical Systems, Volume II: Homogenous
`Systems (1973).
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 6 of 58
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`Chen7, too, taught that “the viscosity of the hydrocolloid” is important to the
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`properties of the composition. (Chen, Ex. 1005, at 13:1-6, Tables 9a, 9b.) Multiple
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`polymers with various viscosities were available and could be used in films. (Ex.
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`1013, The Theory and Practice of Industrial Pharmacy, at 365-368.)
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`17.
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`It would have also been obvious to employ mucoadhesive, uniform,
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`oral films comprising polymers to achive rapid dissolution of pharmaceutical
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`actives by the priority date. Mucosally-adhesive, oral dosage forms made of water-
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`soluble polymers used to deliver therapeutic agents have been known since at least
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`1997. (See Ex. 1023, Guo & Zerbe, “Water soluble film for oral administration,”
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`Proceedings of the 24th Int’l Symposium on Controlled Release of Bioactive
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`Materials, 227 (1997) (“Guo”), at 227; Ex. 1024, Cassidy et al., “Controlled buccal
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`delivery of buprenorphine,” J. Controlled Release, 25:21-29 (1993) (“Cassidy”) at
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`21-22; Ex. 1006, Cremer et al., Canad. Pat. No. CA2274910 (“Cremer”) at 10.)
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`18. Some mucosally-adhesive films left an unpleasant residue in an user’s
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`mouth after dissolution. (Ex. 1023, Guo at 227.) Rapidly dissolving films were
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`developed to alleviate this problem because they were manufactured without an
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`adhesive layer. These rapidly-dissolving films were used to deliver
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`pharmaceutically active agents and were typically made from water-soluble
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`polymers. (Id.; Ex. 1024, Cassidy at 21-22.) Rapidly dissolving films were
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`7 Chen, Ex. 1005.
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`DECLARATION OF JAYANTH PANYAM
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`manufactured using conventional techniques, such as casting and drying. (Ex.
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`1013, The Theory and Practice of Industrial Pharmacy, at 363.) The films were cut
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`to the desired size that satisfied appropriate requirements and then packaged. (Ex.
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`1023, Guo, at 227.) Chen discloses a cast film formulation formed from “a
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`substantially homogenous preparation” for oral delivery of a pharmaceutical
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`active. (Chen, Ex. 1005, at 4:24-32.) The components of the film were mixed to
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`ensure the components were “uniformly dispersed . . . in the hydrocolloid.” (Chen,
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`Ex. 1005, at 17:6-11.)
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`19. Hydrogel films were also known in the art. According to dissolution
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`studies, hydrogel films were uniform when compared to one another. (Ex. 1024,
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`Cassidy, at 25, Fig. 3.) Hydrogel films were also cast and contained
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`pharmaceutical actives for oral delivery to achieve “rapid absorption.” (Ex. 1024,
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`Cassidy, at 21-22.) It was well-known in the art that dosage forms delivering
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`pharmaceutical agents to patients needed to be uniform with respect to the amount
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`of drug found in each individual film dose. (See, e.g., Ex. 1023, Guo, at 227-28.)
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`Cassidy demonstrated, via dissolution studies, that the hydrogels exhibited uniform
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`dissolution of the measured components. (Ex. 1024, Cassidy, at 25, Fig. 3.)
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`20. A person of ordinary skill would have known to optimize uniformity
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`of pharmaceutical actives in drug dosage forms, including films. No later than
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`1989, the Pharmakopoea Europae suggested that “uniformity of the weight of
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`individually dosed drugs” should differ by no more than 5% across the dosage
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`forms. (See, e.g., Ex. 1025, U.S. Pat. No. 4,849,246 (“the ’246 patent”), at 1:63-
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`68.) And over the years, uniform films complying with this standard were
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`developed. (See Ex. 1026, U.S. Pat. No. 5,393,528 (“the ’528 patent”), at 9:11-12
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`(the active agent “is evenly dispersed throughout the film matrix.”); Ex. 1028,
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`Zerbe et al., U.S. Pat. No. 5,629,003, at 1:54-57 (“homogeneous, water-soluble
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`films intended for buccal administration of hormones”) (citing prior art to Zerbe).)
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`The ‘528 patent, like others well-known in the art, included polymers. (Ex.
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`1026,’528 patent, at Abstract, 10:66-11:3.) Uniform, cast films were also well
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`known in the art. (See, e.g., Ex. 1028, U.S. Pat. No. 5,629,003, at 3:40, 5:51-53;
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`Ex. 1029, Eur. Pat. No. EP0090560, at 4:15.) For example, in 1997 Guo disclosed
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`film formulations containing pharmaceutical actives that could be manufactured
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`using “conventional” techniques that “meet the requirements of the specific
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`application.” (Ex. 1023, Guo at 227.)
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`21. A person of ordinary skill would have known to use taste-masking
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`agents, particularly when the pharmaceutical active of interest was known to be
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`bitter or to have a bad taste. By 2001, many oral films included taste-masking
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`agents. (Ex. 1004, Bess at 6:8-7:40.) These were also used by Chen “to achieve
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`DECLARATION OF JAYANTH PANYAM
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`masking of taste for active agents that are bitter.” (Ex. 1005, Chen at 9:14-16.)
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`Chen further disclosed that “encapsulation of the active agents may also be utilized
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`to achieve masking of taste for active agents.” (Id. at 9:14-16.)
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`III. Legal Standards
`22.
`In preparation for forming the opinions set forth in this declaration, I
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`have been informed regarding the relevant legal principles. I have used my
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`understanding of those principles in forming my opinions. My understanding of
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`those principles is summarized below.
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`23.
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`I have been told that Teva bears the burden of proving invalidity by a
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`preponderance of the evidence. I am informed that this preponderance of the
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`evidence standard means that Teva must show invalidity is more probable than not.
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`I have taken these principles into account when forming my opinions in this case.
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`24.
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`I have also been told that claims should be construed given their
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`broadest reasonable interpretation in light of the specification from the perspective
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`of a person of ordinary skill in the art.
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`25.
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`I am told that the concept of patent obviousness involves four factual
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`inquiries: (1) the scope and content of the prior art; (2) the differences between the
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`claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4)
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`secondary considerations of non-obviousness.
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`26.
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`I am also informed that when there is some recognized reason to solve
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`a problem, and there are a finite number of identified, predictable and known
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`solutions, a person of ordinary skill in the art has good reason to pursue the known
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`options within his or her technical grasp. If such an approach leads to the expected
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`success, it is likely not the product of innovation but of ordinary skill and common
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`sense. In such a circumstance, when a patent simply arranges old elements with
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`each performing its known function and yields no more than one would expect
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`from such an arrangement, the combination is obvious.
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`IV. Person of Ordinary Skill in the Art
`27.
`I have been informed by counsel that the obviousness analysis is to be
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`conducted from the perspective of a person of ordinary skill in the art (a “person of
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`ordinary skill”) at the time of the invention.
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`28.
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`I have also been informed by counsel that in defining a person of
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`ordinary skill in the art the following factors may be considered: (1) the
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`educational level of the inventor; (2) the type of problems encountered in the art;
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`(3) prior art solutions to those problems; (4) rapidity with which innovations are
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`made; and (5) sophistication of the technology and educational level of active
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`workers in the field.
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`29. A person of ordinary skill in the art related to the ’514 patent would
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`include a person who possesses a Masters Degree, Ph.D. or their equivalent in
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`pharmaceutics or pharmaceutical sciences or a related field , and a number years of
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`relevant experience in developing dosage forms for drugs.
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`V. The ’514 Patent
`30.
`I have read the ’514 patent and the issued claims, entitled “Uniform
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`Films for Rapid Dissolve Dosage Form Incorporating Taste-Masking
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`Compositions.” The ’514 patent claims priority to several applications, listed on
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`the face of the patent, the earliest of which is October 12, 2001, which I understand
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`to be a provisional application. The ’514 patent issued December 10, 2013, and
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`names Robert K. Yang, Richard C. Fuisz, Garry L. Myers, and Joseph M. Fuisz as
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`inventors.
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`31. The ’514 patent was filed July 10, 2007, and is a continuation-in-part
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`of application No. 10/768,809, filed on Jan. 30, 2004, now Pat. No. 7,357,891, and
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`a continuation-in-part of application No. PCT/US02/32575, filed on Oct. 11, 2002,
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`and a continuation-in-part of application No. 10/074,272, filed on Feb. 14, 2002,
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`now Pat. No. 7,425,292; said application No. 10/768,809 is a continuation-in-part
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`of application No. PCT/US02/32594, filed on Oct. 11, 2002, and a continuation-in-
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`part of application No. 10/074,272; said application No. 10/768,809 is a
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`continuation-in-part of application No. PCT/US02/32542, filed on Oct. 11, 2002,
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`and a continuation-in-part of application No. 10/074,272, application No.
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`11/775,484, which is a continuation-in-part of application No. 10/856,176, filed on
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`May 28, 2004, now Pat. No. 7,666,337, and a continuation-in-part of application
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`No. 10/768,809.
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`32.
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`I understand that Teva is challenging claims 1- 3, 9, 15, 62- 65, 69-
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`73, and 75 of the ’514 patent. The ’514 patent includes two illustrative
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`independent claims, claims 1 and 62. Independent claim 1 recites:
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`A drug delivery composition comprising:
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`(i) a cast film comprising a flowable water-soluble or water
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`swellable film-forming matrix comprising one or more
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`substantially water soluble or water swellable polymers; and a
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`desired amount of at least one active; wherein said matrix has a
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`viscosity sufficient to aid in substantially maintaining non-self-
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`aggregating uniformity of the active in the matrix;
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`(ii) a particulate active substantially uniformly stationed in the
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`matrix; and
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`(iii) a taste-masking agent coated or intimately associated with
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`said particulate to provide taste-masking of the active; wherein
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`the combined particulate and taste-masking agent have a
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`particle size of 200 microns or less and said flowable water-
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`soluble or water swellable film-forming matrix is capable of
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`being dried without loss of substantial uniformity in the
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`stationing of said particulate active therein; and wherein the
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`uniformity subsequent to casting and drying of the matrix is
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`measured by substantially equally sized individual unit doses
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`which do not vary by more than 10% of said desired amount of
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`said at least one active.
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`33.
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`I understand that the claim terms in the ’514 patent are interpreted
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`according to their “broadest reasonable construction in light of the specification of
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`the patent in which it appears.” In rendering my opinions, I applied only one
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`specific construction:
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` “dried without the loss of substantial uniformity” (’514 Patent, Ex. 1001,
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`at claim 1 and 62) should be construed as “any method of drying.”8
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`8 In a copending litigation, under the Phillips claim construction standard,
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`Petitioner has proposed this term should be construed as “dried without employing
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`conventional convection air drying from the top.” (Reckitt Benckiser Inc. et al v.
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`Teva Pharmaceutical USA, Inc., CA. No. 14-01451-RGA, D.I. 91 Ex. A, Ex.
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`1009 at 2.) However, the broadest reasonable construction, consistent with Patent
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`Owner’s own proposed construction in the co-pending litigation, is proposed here.
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 14 of 58
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`I understand that in a co-pending litigation, Patent Owner’s expert witness on
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`validity of the ‘514 patent, Dr. Langer, testfied that the claims were not limited to
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`any particular form of drying, or any particular drying parameters.
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`34.
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`Independent claim 62 recites:
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`A drug delivery composition comprising:
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`(i) a cast film comprising a flowable water-soluble or water
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`swellable film-forming matrix comprising one or more
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`substantially water soluble or water swellable polymers; and a
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`desired amount of at least one active; wherein said matrix has a
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`viscosity sufficient to aid in substantially maintaining non-self-
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`aggregating uniformity of the active in the matrix;
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`(ii) a particulate active substantially uniformly stationed in the
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`matrix; and
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`(iii)
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`a taste-masking agent selected from the group consisting
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`of flavors, sweeteners, flavor enhancers, and combinations
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`thereof to provide taste-masking of the active; wherein the
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`particulate active has a particle size of 200 microns or less and
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`said flowable water-soluble or water swellable film-forming
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`matrix is capable of being dried without loss of substantial
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`uniformity in the stationing of said particulate active therein;
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`and wherein the uniformity subsequent to casting and drying of
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`the matrix is measured by substantially equally sized individual
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`unit doses which do not vary by more than 10% of said desired
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`amount of said at least one active.
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`35.
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`I understand that during the prosecution of the ’514 patent, the
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`pending claims were rejected as obvious over the Chen and Bess references.
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`Applicants argued, in response to this rejection, that “‘the uniformity subsequent to
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`casting and drying of the matrix is measured by substantially equally sized
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`individual doses which do not vary by more than 10% of said desired amount of
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`said at least one active’ in the claims overcomes the [Bess] and Chen references.”
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`(Ex. 1002, ‘514 File History at 163 (May 10, 2013 Amendment and Response
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`After Final Action).) Applicants also argued that Bess did not disclose the claimed
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`uniformity because the purported invention required a particular drying technique
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`that is not disclosed in Bess. (Ex. 1002, ‘514 File History, at 74 (April 4, 2011
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`Amendment and Response).) Additionally, Applicants argued the specification of
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`the ‘514 patent supported this position because it described an apparent deficiency
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`in teaching drying methods that could accomplish the claimed uniformity. (Ex.
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 16 of 58
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`1002, ‘514 File History at 74 (April 4, 2011 Amendment and Response); ‘514
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`patent at 4:7-11.)
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`36.
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`I understand, though, that Patent Owner now asserts that the claims do
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`not cover a particular drying process.9
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`37.
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`I understand that during prosecution, Applicants further discounted
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`Chen’s disclosure of uniformity in a film dosage form by focusing on Figure 5.
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`(Ex. 1002, ’514 File History, at 194-195 (June 18, 2013 Amendment After Notice
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`of Allowance).) Applicants argued that the Chen data disclosed a variation in the
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`amount of the active exceeding 10%.
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`9 It is my understanding Patent Owner’s own expert, Dr. Langer, has testified to the
`same interpretation at trial in a litigation involving the ’514 patent. Ex. 1010,
`Reckitt Benckiser Pharmaceuticals Inc., et al v. Watson Laboratories, Inc. et al,
`C.A. No. 13-cv-01674-RGA, November 4, 2015 Tr. Test at 556:10-15 (“Q. Now,
`the claim -- in none of the claims you looked at specifies parameters for drying, is
`that correct, it does not specify? A. Not parameters. But again, you would reed
`[sic] it in light of the specifications.”)
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 17 of 58
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`(Ex. 1002, ‘514 File History, at 194-195 (June 18, 2013 Amendment After Notice
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`of Allowance).)
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`VI. Background
`A.
`Polymers in General
`38.
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`In the pharmaceutical industry, polymers are used for various
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`purposes, such as coating, thickening, binding, controlled release, taste-masking,
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`solubility enhancement and packaging. (Ex. 1008, Physical Pharmacy, at 557.)
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`39.
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`In addition to pharmaceuticals, polymers are also ubiquitous in our
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`environment. They have the ability to be molded, extruded, cast, thermoformed
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`and laminated into almost any inanimate object from toys to airplanes.
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 18 of 58
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`40. A polymer is made of many repeating chemical units which are
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`termed “monomers.” These monomers are polymerized to one another using well
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`known methods, such as “addition” or “chain reaction” polymerization and
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`“condensation” or “stepwise” techniques.
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`41. Many biopolymers (i.e., polymers produced by living organisms) and
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`small molecules are “monodisperse,” which means that all molecules have the
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`same chain length and molecular weight. (Id. at 560.) However, synthetic polymers
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`are “heterodisperse,” which means they have different chain lengths and different
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`molecular weights. (Id. at 560.) These synthetic polymers are classified based upon
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`an average molecular weight and, sometimes, molecular weight distribution. (Id. at
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`560.)
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`42. Polymers can be depicted by the chemical structure of their
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`monomers. As an example, the structure for polyvinylpyrrolidone is depicted
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`below:
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`(a monomer unit of polyvinylpyrrolidone).
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 19 of 58
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`In this figure, “n” refers to the number of monomer units that make up the
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`polymer.
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`43. The molecular weight and composition of a polymer may vary
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`depending on the number of monomers or the chemical structures of the
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`monomers. (Id. at 557-558.) These changes result in polymers with different
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`properties, such as flexibility, solubility, and/or viscosity. Viscosity, for example,
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`can be adjusted by changing the concentration of the polymer and/or using
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`polymers of different average molecular weights. (Id. at 565-566.)
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`44. Another method of obtaining a polymer composition with different
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`properties is to create a multiple-polymer system using polymers with different
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`properties. (Id. at 557-558.) For example, a single polymer system may contain a
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`highly water-soluble polymer, such as hydroxypropyl methylcellulose, while a
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`two- polymer system may contain both a water-soluble polymer, such as
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`hydroxypropyl methylcellulose, and a water-insoluble polymer, such as
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`ethylcellulose.
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`45. Some examples of water-soluble polymers include methylcellulose,
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`hydroxypropyl methylcellulose, hydroxypropylcellulsoe, polyethylene glycol
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`(PEG), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, cellulose acetate
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`phthalate and sodium carboxymethylcellulose. Some examples of water-insoluble
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 20 of 58
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`polymers include ethyl cellulose, starch, carboxymethyl starch, and cross-linked
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`povidone. These water-insoluble polymers have the ability to absorb water and are
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`typically used for their gelling or thickening properties. Gums, which are naturally
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`occurring polymers from plants or animals, can be used for the same purpose. (See
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`id. at 557.)
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`46. Other polymers are well known for their use as taste-masking agents
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`in drug formulations. These include acrylic polymers, such as a butyl
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`methacrylate/(2-dimethylaminoethyl), methacrylate/methyl methacrylate
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`copolymer and polyvinylacetal diethylaminoacetate. (See, e.g., Ex. 1011, U. S. Pat.
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`No. 6,221,402,at 4:24-41.)
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`47. Some polymers are well known for use in film compositions,
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`including cast films. These include polyethylene oxide, which is water-swellable;
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`and hydrophilic cellulosic polymers, such as hydroxypropyl methylcellulose,
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`methylcellulose, and hydroxypropylcellulose, which are water-soluble. (Ex. 1012,
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`Fuller et al., Interactions in poly(ethylene oxide)—hydroxypropyl methylcellulose
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`blends, Polymer, 42:9583-9592 (2001), at 9583-9584.)
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`B.
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`Particles
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`48. Particles are solid materials that, in pharmaceutical suspensions,
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`generally range in size from 0.0005 to 0.01 millimeters. (Ex. 1008, Physical
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`Pharmacy, at 423.) Typically, particles in a mixture are not all of a uniform size, so
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`EXHIBIT NO. 1002 Page 21 of 58
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`particle size is expressed as an average and a distribution. Methods used to
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`determine the particle size distribution include sieving, microscopy, and
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`sedimentation. (Id. at 430-434.) Particle size can be changed by simply milling the
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`particles using a number of different techniques. (Ex. 1013, The Theory and
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`Practice of Industrial Pharmacy, at 654.)
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`C. Role of Viscosity
`49. Viscosity is “an expression of the resistance of a fluid to flow; the
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`higher the viscosity, the greater the resistance.” (Ex. 1008, Physical Pharmacy, at
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`453.) The unit of measure for viscosity is centipoise (cps). (Ex. 1013, The Theory
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`and Practice of Industrial Pharmacy, at 124.) For reference, the viscosity of water
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`is 1 cps, motor oil is 400 cps, and sour cream is 100,000 cps. Viscosity is important
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`to the physical stability of suspensions and, thus, to the uniformity of those
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`suspensions.
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`50. Suspensions are “heterogeneous systems consisting of two phases.
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`The continuous or external phase is generally a liquid or semisolid, and the
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`dispersed or internal phase is made up of particulate matter that is essentially
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`insoluble in, but dispersed throughout, the continuous phase . . . .” (Id. at 479.) In
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`contrast, a solution is a homogeneous system consisting of a single phase where
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`the particles have dissolved in the medium. Unlike a solution, a suspension will not
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`stay mixed indefinitely; the two phases of a suspension will eventually separate.
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`51. When one designs a suspension (for instance, to dose as a drug), one
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`seeks “to decrease the rate of the settling and to permit easy resuspendability of
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`any settled particulate matter.” (Id. at 479.) Polymers can be added to suspensions
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`to increase the viscosity of the external phase of a suspension. This slows the
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`settling of the particles.
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`52. The role of viscosity in the physical stability of suspensions has been
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`known at least since 1851. Indeed, Stoke’s law sets forth the relationship between
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`viscosity of the suspension and particle density, among other things, as shown
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`below:
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`whereρ is the density of the sphere, ρ0 is the density of the liquid, r is the radius of
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`the sphere, η is the viscosity of the liquid, v ͚ is the terminal constant velocity and g
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`is the gravitational acceleration. (Ex. 1014, Theory of Pharmaceutical Systems:
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`Volume II Heterogeneous Systems, at 9.)
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`53. Viscosity can play a role in the uniformity of particle distribution in a
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`suspension by affecting the physical stability of the suspension.
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`DECLARATION OF JAYANTH PANYAM
`EXHIBIT NO. 1002 Page 23 of 58
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`54. Delivering a uniform dose is one of the primary considerations when
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`dosing a suspension to a patient. In other words, the drug in the suspension must be
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`uniformly distributed throughout the bulk container prior to being removed from
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`the container and administered to the patient. Viscosity of the medium (e.g., water)
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`and/or the particle size of the active can be adjusted to maintain uniformity. In
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`other words, when the viscosity of the medium is decreased, then the particle size
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`and/or density must be adjusted to maintain the same settling velocity. If the
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`suspension cannot be easily poured, then the product is not viable. If the viscosity
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`is insufficient to prevent settling, the suspension must be shaken, stirred, or
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`agitated prior to use in order to re-suspend the active. (Ex. 1015, Remington’s
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`Pharmaceutical Sciences (18th ed. 1990), at 297; Ex. 1014 Theory of
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`Pharmaceutical Systems, Volume II: Heterogeneous Systems, at 5; Ex. 1008,
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`Physical Pharmacy, at 484.) This same principle also applies during the
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`manufacture of suspensions. In low-viscosity solutions, without s
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