UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________
`
`COMPLEX INNOVATIONS, LLC,
`Petitioner,
`
`v.
`
`AMGEN INCORPORATED
`
`Patent Owner
`
`_________________
`
`U.S. Patent 7,829,595
`
`_________________
`
`
`
`DECLARATION OF WALTER G. CHAMBLISS, Ph.D.
`
`
`1
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`
`
`
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`
`
`EX 1021
`IPR of U.S. Pat. No. 7,829,595
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________
`
`COMPLEX INNOVATIONS, LLC,
`Petitioner,
`
`v.
`
`AMGEN INCORPORATED
`
`Patent Owner
`
`_________________
`
`U.S. Patent 7,829,595
`
`_________________
`
`
`
`DECLARATION OF WALTER G. CHAMBLISS, Ph.D.
`
`
`1
`
`
`
`
`
`
`
`EX 1021
`IPR of U.S. Pat. No. 7,829,595
`
`
`
`
`
`I, Walter G. Chambliss, declare as follows:
`
`
`1.
`
`I have been retained by Hill, Kertscher, & Wharton, LLP, which
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`represents Complex Innovations, LLC, in connection with a petition for inter
`
`partes review of U.S. Patent No. 7,829,595, titled Rapid Dissolution Formulation
`
`of a Calcium Receptor-Active Compound (“595 Patent”). I understand that the 595
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`Patent is currently assigned to Amgen, Incorporated.
`
`
`
`SCOPE OF ANALYSIS
`
`2.
`
`I have reviewed and am familiar with the 595 Patent, which issued to
`
`Lawrence, et al. on November 9, 2010. I understand that the 595 Patent includes
`
`25 claims. I also understand that the Petition for inter partes review that
`
`accompanies this Declaration seeks to cancel claims 1-25 of the 595 Patent. My
`
`analysis and opinions will focus on all challenged claims 1-25.
`
`3. My analysis assumes that the time of invention is September 12, 2003,
`
`which is, in this case, the filing date for provisional application 60/502,219.
`
`4.
`
`I have reviewed and am familiar with various references, written
`
`materials, and literature, which are itemized below:
`
`a) Ex. 1001 U.S. Patent No. 7,829,595 to Lawrence, et al. (“595
`
`Patent”)
`
`b) Ex. 1002
`
`File History to the 595 Patent (“File History”)
`
`
`
`2
`
`
`
`
`
`
`
`c) Ex. 1003 U.S. Patent No. 6,211,244 to Van Wagenen, et al.
`
`(“Van Wagenen”)
`
`d) Ex. 1004 U.S. Patent No. 5,162,117 to Stupak, et al. (“Stupak”)
`
`e) Ex. 1005
`
`European Patent Application No. 1 321 142 A1 by
`
`Vitzling, et al. (“Vitzling”)
`
`f) Ex. 1006 U.S. Patent No. 5,879,706 to Carter, et al. (“Carter”)
`
`g) Ex. 1007 Canadian Patent Application No. 2,004,565 by Chang, et
`
`al. (“Chang”)
`
`h) Ex. 1008 U.S. Patent No. 8,703,196 to Babcock, et al. (“Babcock”)
`
`i) Ex. 1009 U.S. Patent No. 6,733,780 to Tyler, et al. (“Tyler”)
`
`j) Ex. 1010 U.S. Patent No. 4,931,286 to Johnson, et al. (“Johnson”)
`
`k) Ex. 1011
`
`Excerpts from The Pharmaceutical Codex: Principles and
`
`Practice of Pharmaceutics (12th ed.) (1994) (“Pharmaceutical Codex”)
`
`l) Ex. 1012
`
` Excerpts from the Handbook of Pharmaceutical
`
`Excipients (3rd ed.) (2000) (“HPE”)
`
`m) Ex. 1013
`
`Excerpts from Howard C. Ansel, et al., Pharmaceutical
`
`Dosage Forms and Drug Delivery Systems (7th ed.) (1999) (“Ansel”)
`
`n) Ex. 1014
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`Excerpts from Herbert A. Lieberman, Leon Lachman,
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`Joseph B. Schwartz (eds.), Pharmaceutical Dosage Forms: Tablets
`
`(2nd ed.) (1989) Vol. 1 (“Lieberman I”)
`
`3
`
`
`
`
`
`o) Ex. 1015
`
`Excerpts from Herbert A. Lieberman, Leon Lachman,
`
`Joseph B. Schwartz (eds.), Pharmaceutical Dosage Forms: Tablets
`
`(2nd ed.) (1989) Vol. 2 (“Lieberman II”)
`
`p) Ex. 1016
`
`Particle Size – U.S. Sieve Series and Tyler Mesh Series
`
`Equivalents (2002; updated 2013), found at
`
`www.azom.com/article.aspx?ArticleID=1417, last accessed August 7,
`
`2015 (“Particle Size”)
`
`q) Ex. 1017 New Agent Reduces PTH Levels in Hemodialysis Patients
`
`With Secondary Hyperparathyroidism, FORMULARY (April 2003)
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`Vol. 38, p. 197 (“Formulary”)
`
`r) Ex. 1018
`
`J.C. Chaumeil, Micronization: A Method of Improving
`
`the Bioavailability of Poorly Soluble Drugs, METH. FIND. EXP. CLIN.
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`PHARMACOL. (1998), pp. 211-215 (“Chaumeil”)
`
`s) Ex. 1019
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`Excerpt from Sir Colin Dollery (ed.), Therapeutic Drugs,
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`(1991) Vol. 2 (“Dollery”)
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`t) Ex. 1020 Gordon T. McInnes, et al., Effect of Micronization on the
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`Bioavailability and Pharmacologic Activity of Spironolactone, J.
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`CLIN. PHARMACOL. 22 (1982), pp. 410-417 (“McInnes”)
`
`5.
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`I have been asked to consider how a person of ordinary skill in the art
`
`(“POSITA”) would have understood the claims subject to inter partes review in
`
`
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`4
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`
`
`
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`light of the disclosure of the 595 Patent. I also have been asked how a POSITA
`
`would have understood and applied various references including the Van Wagenen
`
`Patent and the HPE, and whether various other references support them, including
`
`the Stupak, Carter, Babcock, Tyler, and Johnson Patents, the Vitzling and Chang
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`Patent Applications, and certain material from Ansel, the Pharmaceutical Codex,
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`Lieberman I, and Lieberman II.
`
`6.
`
`I am being compensated at my standard hourly rate of $800 dollars
`
`per hour for regular consulting and $1000 per hour for live testimony. My
`
`compensation is not dependent on the outcome of this inter partes review and in no
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`way affects the substance of my testimony in this matter.
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`
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`QUALIFICATIONS AND EXPERTISE
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`7. My resume/curriculum vitae is attached to this declaration as
`
`Exhibit A.
`
`8.
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`For over thirty-eight (38) years, I have been active in the field of
`
`pharmacy, with over thirty (30) active years in pharmaceutical drug development.
`
`9.
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`I hold a doctoral degree (Ph.D.) in Pharmaceutics granted by the
`
`University of Mississippi in 1982, as well as a Master of Science in Pharmaceutics
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`and Bachelor of Science in Pharmacy, granted by the University of Mississippi in
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`1980 and 1977, respectively.
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`
`
`5
`
`
`
`
`
`10.
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`I am currently the Director of Technology Management for the
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`University of Mississippi, a Research Professor with the Research Institute of
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`Pharmaceutical Sciences, and a Pharmaceutics Professor at the University of
`
`Mississippi, where I have been a faculty member since 1999. My recent teaching
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`responsibilities include lectures in undergraduate, graduate and post-graduate
`
`courses related to pharmaceutical formulations, pharmaceutical manufacturing, and
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`regulatory requirements for the development and manufacture of pharmaceutical
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`products.
`
`11.
`
`In addition to teaching, over the last eleven (11) years I have been
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`responsible for managing late stage pharmaceutical development projects, as well
`
`as managing intellectual property and licensing for the University.
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`12. Prior to joining the faculty at the University of Mississippi, I spent
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`eleven (11) years with Schering-Plough Healthcare Products, where I was involved
`
`in the launch of approximately thirty (30) new or improved products per year. I
`
`also served as the Vice President of Research and Development from 1993-1998.
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`
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`A PERSON OF ORDINARY SKILL IN THE ART
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`13.
`
`I have been advised and understand that a person having ordinary skill
`
`in the art (“POSITA”) is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. With this
`
`
`
`6
`
`
`
`
`
`understanding, a POSITA at the time of the invention claimed in the 595 Patent is
`
`a person holding a Bachelor of Science degree (or an equivalent) in chemistry,
`
`pharmacy or a related field with at least two years of relevant experience in
`
`pharmaceutical drug development, including formulation work.
`
`
`
`MY UNDERSTANDING OF CLAIM CONSTRUCTION
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`14.
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`I have been advised and understand that the claims are to be given
`
`their broadest reasonable construction in light of the specification as it would be
`
`read by a POSITA at the time of invention. I believe that all of the terms of the
`
`claims I have examined have plain and ordinary meanings to a POSITA and no
`
`construction of these terms is necessary.
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`
`
`MY UNDERSTANDING OF OBVIOUSNESS
`
`15.
`
`I have been advised and understand that a claimed invention is
`
`unpatentable if the differences between the invention and the prior art are such that
`
`the subject matter as a whole would have been obvious to a POSITA at the time
`
`the invention was made to which the subject matter pertains.
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`16.
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`It is my understanding that obviousness is a question of law based on
`
`underlying factual findings: (1) the scope and content of the prior art; (2) the
`
`
`
`7
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`
`
`
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`differences between the claims and the prior art; (3) the level of skill in the art; and
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`(4) objective considerations of nonobviousness.
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`17.
`
`I understand that for one or more references to render the claimed
`
`invention obvious, a POSITA must have a sufficient reason to combine the
`
`teachings of the references to arrive at the claims. I further understand that a basis
`
`to combine teachings from the references need not be stated expressly in any prior
`
`art reference. However, there must be an articulated reason with rational
`
`underpinnings to support a motivation to combine teachings.
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`18.
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`I understand that, when considering whether a patent claim is obvious,
`
`a POSITA should consider whether a teaching, suggestion, or motivation to
`
`combine the references exists so as to avoid impermissibly applying hindsight.
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`
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`PHARMACEUTICAL DRUG FORMULATIONS, GENERALLY
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`19. The development of a pharmaceutical composition at the time the
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`subject patent was filed, as well as in the present time, involved combining a
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`chemical compound, which has promising therapeutic activity, known in the art as
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`the drug substance or an active pharmaceutical ingredient (“API”), with one or
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`more pharmaceutically acceptable inactive ingredients (known in the art as
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`“excipients,” “adjuvants,” “carriers,” or “additives”) to develop a pharmaceutical
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`dosage form such as a tablet or a capsule for oral administration. I will use the
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`
`
`8
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`
`
`
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`present tense to describe the basic steps followed to develop a pharmaceutical
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`formulation since the same steps are used today and also were used at the time the
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`595 Patent was filed.
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`20. The goal in developing an oral dosage form is to design a stable
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`formulation that can be manufactured at a commercial scale, can be self-
`
`administered by the patient, and will release the API in the gastrointestinal tract at
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`the desired rate. The first step in developing a pharmaceutical formulation is to
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`characterize the API in a series of routine and well-known studies known in the art
`
`as preformulation studies. (Pharmaceutical Codex at pp. 178-197). I was taught
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`how to conduct preformulation studies in graduate school in the late 1970s to early
`
`1980s and conducted or supervised the conduct of preformulation studies in the
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`1980s and 1990s at three different pharmaceutical companies. The overall purpose
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`of preformulation studies is to determine if there are potential formulation
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`development issues that a formulator would need to address when developing a
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`pharmaceutically acceptable dosage form containing the API.
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`21. Preformulation studies to characterize the API include: determining
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`the various salt forms of the API; determining the aqueous solubility of the API at
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`various pH levels, determining the particle size of the API; determining the
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`morphology of the API (e.g., degree of crystallinity and the shape of the crystals);
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`
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`9
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`
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`and determining the stability of the API in the presence of moisture, light, elevated
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`temperature, and oxygen.
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`22. The majority of APIs are crystalline, however APIs often contain
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`some amorphous particles. (Pharmaceutical Codex at p. 179). Common crystal
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`shapes include cubic and needle shaped. (Id. at p. 180). The optimal shape of the
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`crystals is determined during preformulation studies and the shape can be altered
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`through commonly known processing techniques. (Id. at pp. 179-180). It is
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`commonly known that needle shaped particles will have poor flow properties. (Id.
`
`at p. 180).
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`23. Based on the data obtained in the preformulation studies, a series of
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`prototype formulations are made and evaluated for various properties such as
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`physical and chemical stability, manufacturability, in vitro dissolution, in vitro
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`disintegration, and in vivo oral bioavailability.
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`24. There are many different, well-known chemical compounds used as
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`excipients in pharmaceutical formulations. A POSITA would be very familiar with
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`the standard treatises that discuss excipients commonly used in pharmaceutical
`
`formulations. Based on my experience, the Handbook of Pharmaceutical
`
`Excipients (the “HPE”) has been the most commonly used reference book on
`
`pharmaceutical excipients for over twenty (20) years. I served on the International
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`Steering Committee for the 2nd, 3rd and 4th Editions of the HPE and wrote
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`
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`10
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`
`
`
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`monographs for excipients included in several editions. A POSITA looking for
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`information on excipients commonly used in tablet formulations would refer to the
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`HPE for information on the chemistry, physical properties, and applications in
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`pharmaceutical formulations of various excipients.
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`25. Excipients are generally classified into categories based on
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`functionality in the formulation. (See, e.g., Ansel, pp. 87-92; Lieberman I at pp. 91-
`
`121). A tablet formulation, for example, typically would contain as a minimum, the
`
`API, a binder/diluent (also known in the art as a filler) to add bulk to the tablet
`
`such that a patient can hold the tablet in his/her hand, a disintegrant to cause the
`
`tablet to break apart after it is swallowed, and a lubricant to keep the powder blend
`
`from sticking to parts of the tablet press during the compression process.
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`26. The influence of excipients commonly used in pharmaceutical
`
`formulations on the stability of the API is determined in what are known as
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`excipient-compatibility studies. (Pharmaceutical Codex, pp. 192-196). From
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`excipient-compatibility studies, a formulator would learn which excipients could
`
`be used in the solid oral dosage form and which excipients should be avoided.
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`Typically the API is mixed with each excipient and the mixture is tested under
`
`accelerated conditions. (Id.). In addition, the formulator selects which of the well-
`
`known, off-the-shelf, excipients to use in a formulation based on whether he/she is
`
`developing an immediate release or a modified release tablet or capsule. In the case
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`
`
`11
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`
`
`
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`of an immediate release dosage form a person of ordinary skill can simply select
`
`which excipients to use in prototype formulations based on the results of excipient-
`
`compatibility studies and his/her general knowledge of the functions of excipients
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`commonly used in immediate release tablets and capsules, such as fillers,
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`disintegrants and lubricants that do not function to slow down the release of the
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`API.
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`27. Prototype formulations will be developed based on the information
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`learned during preformulation studies. In the case of solid oral dosage forms, such
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`as tablets and capsules, the amount of each excipient to add to a formulation is
`
`based on considerations such as flowability of the powder, compressibility of the
`
`powder, moisture content of the powder blend and the final dosage form,
`
`disintegration time for the dosage form, dissolution rate of the API from the dosage
`
`form, and stability of the dosage form. (Id. at p. 196).
`
`28. The particle size of the API can affect the dissolution rate of the API
`
`from the dosage form, which likewise impacts the rate and extent at which the API
`
`will be absorbed in the body, the stability of the API, the manufacturability of the
`
`formulation, and the homogeneity of the dosage form. (See, e.g., Lieberman I at
`
`pp. 5-6; Pharmaceutical Codex at p. 181). A desired particle size range for the API
`
`is established during preformulation studies and through routine optimization.
`
`Problems can arise if the mean particle size of the API is too small such as a
`
`
`
`12
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`
`
`
`
`buildup of static charge, poor mixing and reduced stability. (Pharmaceutical Codex
`
`at pp. 181-184; Lieberman I at p. 5-6). Likewise, problems can arise if the mean
`
`particle size of the API is too large such as poor mixing, variable content
`
`uniformity, reduced rate of dissolution and poor in vivo bioavailability. (Id.).
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`Generally, a formulator will be motivated to reduce the mean particle size of an
`
`API that has particles greater than approximately 100 microns by grinding the API
`
`using standard milling equipment (also known in the art as “milling”). (Lieberman
`
`I at pp. 5-6). The particle size distribution of an API is easily determined and
`
`typically the median size and some indication of the distribution around the median
`
`are determined. (Pharmaceutical Codex at pp. 181-182; see, e.g., Lieberman II).
`
`29. A common way of manufacturing solid oral dosage forms is by
`
`mixing the API with the excipients and filling the powder blend into empty capsule
`
`shells, or compressing the powder blend into a tablet. This process is referred to in
`
`the art as direct compression in the case of a tablet and dry mixing in the case of a
`
`capsule.
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`30. Another common way of manufacturing a solid oral dosage forms is
`
`called “wet granulation”. In this case, the powder blend, containing a binder (an
`
`excipient that acts like a glue to hold the powder particles together) is wetted,
`
`typically with water, dried and milled to the desired granule size to ensure good
`
`flowability on a high speed tablet press or encapsulation machine. (See, e.g., Ansel
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`
`
`13
`
`
`
`
`
`at pp. 209-211). In the case of tablets, the desired size of granules depends on the
`
`size of the tablet punches that will be used to compress the tablet. (Id. at p. 211
`
`(“In general, the smaller the tablet to be produced, the smaller are the granules
`
`used”.)) Typically, granules resulting from a wet granulation process are milled to
`
`have a mean particle size between 12 and 20 Tyler mesh, which equates to between
`
`about 80 to about 140 microns. (Id. at p. 211; Particle Size at pp. 1-2).
`
`31. Tablets are commonly coated with a polymer (known in the art as a
`
`“film coat”) or sugar based coating. The coating can be clear or a pigment can be
`
`added to impart color. Coatings are added to, among other purposes, protect tablets
`
`from a humid environment, mask the taste of a bad tasting API, and make the
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`tablet easier to swallow. (Ansel at pp. 219-227). A film coat also can be used to
`
`modify the release of the API from the dosage form. (Id.)
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`
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`ANALYSIS OF THE 595 PATENT (Ex. 1001)
`
`32. The 595 Patent relates to the development of pharmaceutical
`
`compositions including tablets used in the treatment of, among other things,
`
`secondary hyperparathyroidism commonly associated with chronic kidney disease.
`
`(595 Patent, col. 4, lines 16-21; Formulary at p.197). To be more specific, the
`
`chemistry described in the 595 Patent pertains to a pharmaceutical composition
`
`
`
`14
`
`
`
`
`
`comprising cinacalcet hydrochloride in combination with excipients commonly
`
`used in tablet formulations. (E.g., id., claim 1 & Examples, col. 11-13).
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`33. Hyperparathyroidism results from impaired calcium homeostasis.
`
`(Van Wagenen, col. 6, lines 9-10). It is indicated by high levels of the parathyroid
`
`hormone (“PTH”) in the bloodstream. (Id., col. 16, lines 66-67). Further, increased
`
`levels of free calcium in the bloodstream is also associated with secondary
`
`hyperparathyroidism. (Id., col 17, line 44 – col. 18, line 15). Cinacalcet
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`hydrochloride is a calcium receptor-active compound (595 Patent, col. 1, lines 7-
`
`10) that can simultaneously reduce PTH and control calcium-phosphorus product
`
`in the bloodstream (Formulary at p.197).
`
`34. Although the 595 Patent was filed on September 10, 2004, as noted
`
`above, my analysis assumes that the time of invention is September 12, 2003 (the
`
`filing date for provisional application 60/502,219).
`
`35. The 595 Patent admits that cinacalcet hydrochloride was known in the
`
`art prior to the filing of the 595 Patent. (595 Patent, col. 1, lines 7-10 & Certificate
`
`of Correction at p.10) (“One example of a calcium receptor-active compound is
`
`cinacalcet HCl, which is described, for example, in U.S. Pat. No. 6,211,244 [Van
`
`Wagenen]”). Indeed, a number of patents filed prior to the 595 Patent cover
`
`cinacalcet hydrochloride, as demonstrated by their listing in the Food and Drug
`
`Administration’s Orange Book
`
`
`
`15
`
`
`
`
`
`(see http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No
`
`=021688&Product_No=001&table1=OB_Rx, last accessed August 12, 2015) and
`
`reference to them in the 595 Patent specification (col. 2, lines 18-28).
`
`36. Further, Van Wagenen teaches pharmaceutical compositions
`
`containing an API and an acceptable carrier. (Van Wagenen, col. 5, lines 26-35).
`
`37. Additionally, the treatment of hyperparathyroidism with a
`
`pharmaceutical composition comprising a therapeutically effective amount of an
`
`inorganic ion receptor-modulating agent, such as cinacalcet hydrochloride, was
`
`well known to a POSITA prior to the time of invention. (See, e.g., Van Wagenen,
`
`col. 5, line 48 – col. 6, line 18.)
`
`38. As discussed above and further below, at the time of the invention, the
`
`use of various excipients in the formulation of pharmaceutical products, including
`
`tablets, was well known. The 595 Patent uses then well-known formulation
`
`techniques to the formulation of the cinacalcet hydrochloride composition of
`
`claim 1.
`
`39. The specification of the 595 Patent focuses on an improved
`
`dissolution profile for a cinacalcet hydrochloride composition consisting of
`
`granules. (See, e.g., 595 Patent, col. 9, lines 22-48). According to the specification,
`
`the invention relates to “a pharmaceutical composition comprising a
`
`therapeutically effective amount of a calcium receptor-active compound and at
`
`
`
`16
`
`
`
`
`
`least one pharmaceutically acceptable excipient, wherein the composition has a
`
`controlled dissolution profile.” (Id., abstract). However, the claims of the 595
`
`Patent do not include any reference to a dissolution profile, improved or otherwise.
`
`40. The file history for the application that resulted in the ‘595 Patent
`
`supports my opinion that the claims discussed in this declaration are obvious in
`
`light of the general knowledge of a POSITA as bolstered by numerous prior art
`
`references. To the extent applicants argue unexpected or surprising results, I
`
`disagree that the specification or the file history reflects any unexpected or
`
`surprising results. During prosecution, applicants asserted to the USPTO that “the
`
`poor water solubility of cinacalcet hydrochloride reduces the options for
`
`formulating the compound for effective delivery and bioavailability.” (File History
`
`- Amendment and Reply Under 37 CFR 1.116, July 14, 2008 at p. 10). Applicants
`
`further asserted to the USPTO that “the skilled person would not harbor an
`
`expectation of formulating cinacalcet hydrochloride in an acceptably soluble and
`
`readily bioavailable composition with just any given combination of excipients”
`
`because the poor water solubility of this cinacalcet hydrochloride allegedly “limits
`
`options for formulations and can adversely impact the bioavailability of cinacalcet
`
`hydrochloride”). (Id. - Supplemental Amendment and Reply Under 37 CFR 1.111,
`
`December 23, 2008 at p. 8).
`
`
`
`17
`
`
`
`
`
`41. However, what the Applicants did not tell the USPTO was that at the
`
`time, formulation techniques for APIs with low solubility were well known. Based
`
`on my experience, and consistent with the literature, some APIs are highly water
`
`soluble, but the water solubility of many APIs is low, especially for APIs
`
`developed since the late 1990s. (See, e.g., Chaumeil at p. 211). It was well known
`
`in the art how to develop successful pharmaceutical formulations containing an
`
`API with poor water solubility. For example, Chaumeil teaches reducing the
`
`particle size of several APIs with poor water solubility in order to increase oral
`
`bioavailability. (See generally Chaumeil).
`
`42. Further, I have developed pharmaceutical formulations for a number
`
`of APIs that have poor water solubility, including spironolactone, which is water
`
`insoluble. (Dollery at S85). It has been known since the early 1980s that reducing
`
`the particle size of spironolactone will improve oral bioavailability. (See, e.g.,
`
`McInnes at pp. 410-417 (teaching the reduction of median particle size of
`
`spironolactone from 78.8 μm to 2.21 μm significantly increases oral bioavailability
`
`without any changes to the excipients contained in the tablet formulation)).
`
`
`
`ANALYSIS OF THE 244 PATENT (VAN WAGENEN – EX. 1003)
`
`43.
`
`I have reviewed and am familiar with U.S. Patent. No. 6,211,244
`
`issued to Van Wagenen, et al. (Ex. 1003 – Van Wagenen).
`
`
`
`18
`
`
`
`
`
`44. Van Wagenen (“Calcium Receptor-Active Compounds”) is a U.S.
`
`Patent disclosing calcium receptor-active compounds, including cinacalcet
`
`hydrochloride. (Id., col. 1, lines 1-9).
`
`45. Among the topics covered in Van Wagenen is the treatment of
`
`hyperparathyroidism by administering a pharmaceutical composition comprising a
`
`therapeutically effective amount of an inorganic ion receptor-modulating agent.
`
`(Id., col. 5, line 48 – col. 6, line 24; col. 17, line 44 – col. 18, line 15).
`
`46. Van Wagenen also teaches that “suitable dosage ranges, formulations,
`
`and dosage forms” can be “determined by one skilled in art based on the teachings
`
`provided in the application.” (Id., col. 44, lines 39-45).
`
`
`
`ANALYSIS OF THE HANDBOOK OF PHARMACEUTICAL EXCIPIENTS
`(“HPE”) (3rd ED.) (EX. 1012)
`
`47.
`
`In selecting particular excipients for use in a pharmaceutical
`
`composition containing cinacalcet hydrochloride, as discussed above, one skilled
`
`in the art would be aware of the HPE as a resource providing information on the
`
`uses of a variety of pharmaceutical excipients in composition formulation. The 3rd
`
`Edition of the HPE disclosed numerous excipients for use in pharmaceutical
`
`formulations in 2000. As discussed above, I was heavily involved in the editing of
`
`this HPE. The teachings of HPE are intended to be applied to APIs in general
`
`rather than being limited to specific APIs.
`19
`
`
`
`
`
`
`
`48. Among the excipients covered in the HPE are microcrystalline
`
`cellulose, povidone, starch, crospovidone, colloidal silicon dioxide, and
`
`magnesium stearate. (See generally HPE).
`
`
`
`ANALYSIS OF ANSEL (EX. 1013)
`
`49. Ansel, a well-known pharmaceutical treatise, teaches among other
`
`things the development of general types of pharmaceutical compositions (e.g.,
`
`granules, tablets, capsules and powders), the importance of particle size of the API
`
`and/or granulations, and the common types of excipients used in pharmaceutical
`
`compositions such as tablets (e.g., lubricants, binders, fillers and coating
`
`materials). (See generally Ansel).
`
`50. Among the excipients covered in Ansel are microcrystalline cellulose,
`
`povidone, starch, crospovidone, colloidal silicon dioxide, and magnesium stearate.
`
`(See generally Ansel).
`
`
`
`ANALYSIS OF THE 117 PATENT (STUPAK – EX. 1004)
`
`51.
`
`I have reviewed and am familiar with U.S. Pat. No. 5,162,117 to
`
`Stupak, et al. (Ex. 1004 – Stupak).
`
`52. Stupak is a U.S. Patent disclosing a controlled release flutamide
`
`composition. (Id., col. 1, lines 1-3).
`
`
`
`20
`
`
`
`
`
`53. Among other topics, Stupak discloses the use of starch in a
`
`pharmaceutical composition in the range of 15% to 35%. (Id., col. 2, lines 16-26).
`
`
`
`ANALYSIS OF THE 142 APPLICATION (VITZLING – EX. 1005)
`
`54.
`
`I have reviewed and am familiar with European Patent Application
`
`No. 1 321 142 A1 by Vitzling, et al. (Ex. 1005 – Vitzling).
`
`55. Vitzling is a European Patent Application for a solid pharmaceutical
`
`composition for oral administration of Tegaserod. (Id. at p.1).
`
`56. Among other topics, Vitzling discloses a pharmaceutical composition
`
`including 15% or less of a disintegrant, including, but not limited to crospovidone.
`
`(Id. at p. 2, ¶¶ 9 & 11).
`
`
`
`ANALYSIS OF THE 706 PATENT (CARTER – EX. 1006)
`
`57.
`
`I have reviewed and am familiar with U.S. Patent No. 5,879,706 to
`
`Carter, et al. (Ex. 1006 – Carter).
`
`58. Carter is a U.S. Patent for Valaciclovir tablets containing colloidal
`
`silicon dioxide. (Id., col. 1, lines 1-2).
`
`59. Among other topics, Carter discloses the use of colloidal silicon
`
`dioxide in the range of 0.05% to 3%. (Id., abstract; col. 2, lines 27-61).
`
`
`
`
`
`21
`
`
`
`
`
`ANALYSIS OF THE 565 APPLICATION (CHANG – EX. 1007)
`
`60.
`
`I have reviewed and am familiar with Canadian Patent Application
`
`No. 2,004,565 by Chang, et al. (Ex. 1007 – Chang).
`
`61. Chang is a Canadian Patent Application for a sustained release
`
`diltiazem formulation. (Id. at p.1).
`
`62. Among other topics, Chang discloses the use of magnesium stearate in
`
`the range of 0% to 2%. (Id. at p.9).
`
`
`
`ANALYSIS OF THE 196 PATENT (BABCOCK – EX. 1008)
`
`63.
`
`I have reviewed and am familiar with U.S. Pat. No. 8,703,196 to
`
`Babcock, et al. (Ex. 1008 – Babcock).
`
`64. Babcock is a U.S. Patent disclosing pharmaceutical compositions of
`
`dispersions of amorphous drugs mixed with polymers. (Id., col. 1, lines 1-3).
`
`65. Among other topics, Babcock discloses pharmaceutical compositions
`
`comprising matrix drug particles. (Id., col. 99, lines 58-61).
`
`
`
`ANALYSIS OF THE 780 PATENT (TYLER – EX. 1009)
`
`66.
`
`I have reviewed and am familiar with U.S. Patent No. 6,733,780 to
`
`Tyler, et al. (Ex. 1009 – Tyler).
`
`
`
`22
`
`
`
`
`
`67. Among other teachings, Tyler discloses coating compositions ranging
`
`from about 4% to about 6%. (Id., col. 3, lines 42-54).
`
`
`
`ANALYSIS OF THE 286 PATENT (JOHNSON – EX. 1010)
`
`68.
`
`I have reviewed and am familiar with U.S. Patent No. 4,931,286 to
`
`Johnson, et al. (Ex. 1010 – Johnson).
`
`69. Among other teachings, Johnson discloses coating compositions
`
`ranging from about 0.5% to about 5%. (Id., claim 3).
`
`
`
`ANALYSIS OF THE PHARMACEUTICAL CODEX (EX. 1011)
`
`70. Among the topics covered by the Pharmaceutical Codex, a well-
`
`known pharmaceutical treatise, is the fact that APIs may be crystalline, amorphous
`
`or a combination thereof; and that the optimal shape of crystalline particles is
`
`determined during preformulation studies. (Pharmaceutical Codex at p.179-180).
`
`
`
`ANALYSIS OF LIEBERMAN I (EX. 1014)
`
`71. Lieberman I, a well-known pharmaceutical treatise, teaches, among
`
`other things, example pharmaceutical compositions containing APIs and
`
`commonly used excipients in typical concentrations, and the importance of the
`
`particle size of the API. (See generally Lieberman I).
`
`
`
`23
`
`
`
`
`
`
`
`ANALYSIS OF LIEBERMAN II (EX. 1015)
`
`72. Lieberman II, a well-known pharmaceutical treatise, teaches, among
`
`other things, the importance of the particle size of the API and the use of a sieve
`
`analysis to determine particle distribution. (See generally Lieberman II).
`
`
`
`THE REFERENCED FORMULATIONS AND DOSAGES IN CLAIMS 1-23
`ARE RENDERED OBVIOUS BY PRIOR ART
`
`73. Each element of claims 1-25 is disclosed, shown, or suggested by Van
`
`Wagenen, the HPE, and the general knowledge of a POSITA, as bolstered by
`
`Stupak, Vitzling, Carter, Chang, Babcock, Tyler, Johnson, the Pharmaceutical
`
`Codex, Ansel, Lieberman I and/or Lieberman II. As discussed above, a POSITA
`
`would be motivated to combine the teachings of Van Wagenen and the HPE in
`
`light of the POSITA’s general knowledge. Presented below is my analysis that
`
`addresses each claim element. A POSITA would have been motivated to combine
`
`the Van Wagenen and HPE references based on his/her general knowledge and
`
`supported by the fact that well-known treatises, such as Ansel, Lieberman I, and
`
`Lieberman II, teach tablet formulations using particle sizes and excipients
`
`commonly used to make tablets including excipients used in the core of the tablet
`
`and excipients used in a standard tablet coating layer. Such a combination would
`
`be the natural result of routine formulation development as described above. In
`24
`
`
`
`
`
`
`
`other words, based on this prior art and general knowledge, a POSITA would
`
`expect that a pharmaceutical composition (e.g., a tablet) containing cinacalcet
`
`hydrochloride, a known API, could be made using commonly used excipients
`
`without undue experimentation.
`
`Claim 1
`
`74. Claim 1 states: “A pharmaceutical composition comprising (a) from
`
`about 10% to about 40% by weight of cinacalcet HCl; (b) from about 40% to about
`
`75% by weight of microcrystalline cellulose; (c) from about 1% to about 5% by
`
`weight of povidone; (d) from about 5% to about 35% by weight of starch; (e) from
`
`about 1% to about 10% by weight of crospovidone; (f) from about 0.05% to about
`
`1.5% by weight of colloidal silicon dioxide; and (g) from about 0.05% to about
`
`1.5% by weight of magnesium stearate; wherein the percentage by weight is
`
`relative to the total weight by composition.” (595 Patent, col. 14, lines 17-31).
`
`75.
`
` Van Wagenen teaches pharmaceutical compositions containing
`
`cinacalcet hydrochloride. (Id., col. 2, lines 18-28). Indeed, the 595 P
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