IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`HARVEST TRADING GROUP, INC.,
`Petition
`
`v.
`
`VIREO SYSTEMS, INC. AND
`UNEMED CORPORATION,
`
`Patent Owners
`
`U.S. PATENT NO. 8,354,450
`IPR 2016-00945
`
`U.S. PATENT NO. 8,962,685
`IPR 2016-00947
`
`DECLARATION OF ALEKHA K. DASH, R.Ph., Ph.D.
`
`Ex. 2010
`
`Vireo Systems, Inc. Ex. 2010 - 001
`
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`HARVEST TRADING GROUP, INC.,
`Petition
`
`v.
`
`VIREO SYSTEMS, INC. AND
`UNEMED CORPORATION,
`
`Patent Owners
`
`U.S. PATENT NO. 8,354,450
`IPR 2016-00945
`
`U.S. PATENT NO. 8,962,685
`IPR 2016-00947
`
`DECLARATION OF ALEKHA K. DASH, R.Ph., Ph.D.
`
`Ex. 2010
`
`Vireo Systems, Inc. Ex. 2010 - 001
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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`DECLARATION
`
`I, Alekha K. Dash, hereby declare and say:
`
`1.
`
`I am over the age of eighteen (18) and have personal knowledge of the
`
`matters set forth herein.
`
`2.
`
`I have been retained by counsel for Patent Owner Vireo Systems, Inc.
`
`to provide an expert declaration in support of Owner’s Preliminary Response to the
`
`Petition for Inter Partes Review filed by Harvest Trading Group, Inc (Paper 1).
`
`PROFESSIONAL BACKGROUND
`
`3.
`
`I hold a Bachelor of Pharmacy degree with first class honors from
`
`Jadavpur University in Calcutta, India in 1981, a Masters in Pharmacy in
`
`Pharmaceutics from Jadavpur University in 1983, and a Doctor of Philosophy in
`
`Pharmaceutics in 1990 from the University of Minnesota.
`
`4.
`
`I am a professor and the Gilbert F. Taffe, Jr. Endowed Chair in the
`
`Department of Pharmacy Sciences at the School of Pharmacy & Health Professions
`
`of Creighton University. I am also the Interim Associate Dean for Research in the
`
`School of Pharmacy and Health Professions. I have been employed as a professor
`
`and researcher at Creighton University since 1990.
`
`5.
`
`I have been a Fellow of the American Association of Pharmaceutical
`
`Scientists since 2012, and was an Academic Leadership Fellow in the American
`
`Association of Colleges of Pharmacy in 2008-2009. I have been a member of the on-
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`site evaluation team for the Accreditation Council for Pharmacy Education since
`
`2007. I have served as a chair or member on numerous professional association
`
`committees. I have served as a peer reviewer for 23 medical and pharmaceutical
`
`journals.
`
`6.
`
`Part of my academic and pharmaceutical research has included
`
`studying creatine and various creatine derivatives. In 1999 I received a grant for
`
`“Evaluation of the Solid-State Properties and Oral Bioavailability of Creatine
`
`Monohydrate.” I also served as Master’s thesis advisor for the graduate student
`
`involved in this research. In 2000 I received an additional fellowship grant for the
`
`study of “Solid-State Properties of Creatine Monohydrate.” In 2009-2010, I received
`
`a grant for the study of “Creatine Nitrate Solubility and Stability.” In 2015, I received
`
`a grant regarding the “Evaluation of Creatine Permeability Studies.”
`
`7.
`
`I am a named co-author on 11 abstracts, 5 peer-reviewed published
`
`journal articles, and a book chapter concerning creatine and creatine derivatives.
`
`These include the following publications:
`
`• Dash, A.K., Miler, D. W., Huai-Yan, H, Carnazzo, J. and Stout, J. R.,
`Evaluation of the Creatine Monohydrate Permeability Using Caco-2
`Monolayers as an In Vitro Model for Intestinal absorption, J. Pharm.
`Sci., 90 (2001) 1593-1598;
`
`• Dash, A. K., Mo, Y., and Pyne, A., Solid-State Properties of Creatine
`Monohydrate, J. Pharm. Sci., 91 (2002) 708-718;
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`• Dash, A. K. and Sawhney A., A Simple LC Method with UV Detection
`for the Analysis of Creatine and Creatinine and its Application to
`Several Creatine Formulations, J. Pharm. Biomed. Anal., 29 (2002)
`939-945;
`
`• Mo, Y., Dobberphul, D. and Dash, A. K., A Simple HPLC Method with
`Pulsed EC Detection for the Analysis of Creatine, J. Pharm. Biomed.
`Anal., 32 (2003) 125-132;
`
`• Ganguly, S., Jayappa, S. and Dash, A.K. Evaluation of the Stability of
`Creatine
`in Solutions Prepared
`from Effervescent Creatine
`Formulations, AAPS PharmSciTech 2003; 4 (2) Article 26;
`
`• Dash, A. K., and Singh, S. “Creatine Monohydrate,” in Analytical
`Profiles of Drug Substances and Excipients: Edited by H. Brittain, ed.,
`Academic Press, San Diego, CA, Volume 34 (2009) pp. 1-37.
`
`8.
`
`A full copy of my curriculum vitae is submitted with this Declaration
`
`as Ex. 2011.
`
`OVERVIEW AND MATERIALS REVIEWED
`
`9.
`
`I understand that Vireo is one of the co-owners of U.S. Patent Nos.
`
`8,354,450 (the “ ‘450 Patent”), 8,962,685 (the “ ‘685 Patent”), 8,026,385 (the “ ‘385
`
`Patent”), and 7,608,641 (the “ ‘641 Patent).
`
`10.
`
`I understand that the ‘450 Patent is subject to a petition for inter partes
`
`review in Proceeding No. IPR2016-00945, and that the ‘685 Patent is subject to a
`
`petition for inter partes review in Proceeding No. IPR2016-00947. I further
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`understand that the ‘450 Patent is identified as a continuation in part of the ‘385
`
`Patent, and the ‘385 Patent is a continuation of the ‘641. I further understand and
`
`that the ‘685 Patent is a divisional of the ‘450 Patent.
`
`11.
`
`In connection with this matter, I have reviewed the ‘450 Patent, the ‘685
`
`Patent, the ‘641 Patent, Exhibits 1001-1034 filed with the Petition in IPR2016-
`
`00945, Exhibits 1101-1134 filed with the Petition in IPR-00947, and the following
`
`additional documents:
`
`Document
`
`U.S. Pat. No. 7,608,641
`Declaration of Jason Wiggers
`Declaration of Samir A. Saleh
`The American Heritage Dictionary of the English Language (3d ed.
`1992)
`Chambers Dictionary of Science & Technology (2007)
`The Merck Index (8th ed. 1968)
`Remington: The Science and Practice of Pharmacy, Vol. 1 (19th ed.
`1995)
`Grant, D.J.W. and Brittain H.G., “Solubility of Pharmaceutical Solids,”
`in Physical Characterization of Pharmaceutical Solids (1995) (ed.
`Brittain, H.G.)
` http://www.mpbio.com/detailed
`“Creatinine,” MP Biomedicals,
`_info.php?family_key=02153916&country=223 (last accessed July 31,
`2016)
`Krstulovic, A.M. & C.R. Lee, “Defining drug purity through
`chromatographic and related methods: current status and perspectives,”
`J. Chromatography B 689 (1997), 137-153
`
`Owner
`Exhibit
`2009
`2012
`2013
`2014
`
`2015
`2016
`2017
`
`2018
`
`2019
`
`2020
`
`
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`LEVEL OF ORDINARY SKILL IN THE ART
`
`12.
`
`I have reviewed the opinion of Dr. Richard Van Breemen (“Van
`
`Breemen”) concerning the level of ordinary skill in the art practicing the ‘450 Patent
`
`and the ‘685. Van Breemen defines the level of skill as “at least a master’s degree or
`
`the equivalent thereof in biological sciences or chemistry with several years of
`
`experience performing chemical synthesis and analysis.” (IPR2016-00945, Ex.
`
`1007, ¶ 10; IPR2016-00947, Ex. 1107, ¶ 10). I agree with this definition, with the
`
`caveat that a person of ordinary skill could also be someone with several years of
`
`experience in laboratory or commercial scale pharmaceutical or nutraceutical and/or
`
`chemical compound synthesis and analysis.
`
`CLAIM CONSTRUCTION
`
`13.
`
`I have reviewed the claim constructions positions taken by the
`
`Petitioner and Dr. Van Breemen. In response I provide opinions regarding the
`
`meaning of several of the terms.
`
`“Supplement”
`
`14.
`
`In my opinion, the term “supplement” indicates that the claimed
`
`creatine hydrochloride ingredient is provided to add to the diet (including by itself)
`
`of a human or animal, and in particular to improve muscle performance and
`
`development. Furthermore, the claimed supplement is distinguished from a drug
`
`having medicinal or curative properties and intended or indicated for therapeutic use.
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`Within the patent, the invention is often described as being directed to a supplement
`
`for muscle development. For example, the ‘450 Patent states the following:
`
`• “[The] present invention is directed to a third generation form of creatine,
`specifically a creatine hydrochloride salt, that drives significant
`improvements in muscle development and recovery due to its enhanced
`bioavailability.” (Ex. 1001, Abstract) (emphasis added).
`• “The present invention is also directed to a formula used to enhance
`athletic performance including creatine HCl, wherein the creatine HCl
`exhibits an aqueous solubility that is at least about 15 times greater than that
`of creatine monohydrate.” Id., 2:36-40 (emphasis added).
`• “The creatine HCl of the present invention may be used as a nutritional
`supplement for enhancing muscle performance and muscle mass in both
`humans and livestock, including muscle quality in livestock.” Id. 3:43-46
`(emphasis added).
`• The creatine-HCl leads to “improvements in muscle development and
`recovery as compared to creatine monohydrate.” Id. 3:50-52 (emphasis
`added).
`
`15.
`
`Therefore, a person of ordinary skill would understand that the patent
`
`is directed to a creatine hydrochloride product to strengthen muscle performance and
`
`development.
`
`16.
`
`In addition, a person of skill in the art distinguishes between
`
`supplements and nutraceuticals, which are not administered for a particular
`
`medicinal purpose, and a drug, which is. This distinction is important in part because
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`of the different regulatory regimes that apply depending on whether a substance is
`
`classified as a drug or a supplement. A drug is subject to particular controls and
`
`standards provided by the Food and Drug Administration (FDA), including specific
`
`uses, purity amounts, manufacturing requirements, and other limitations on creation,
`
`distribution, and use. In contrast, supplements are not subject to such requirements
`
`and are excluded from regulation by the FDA. A person of ordinary skill would
`
`understand that the reference to a “supplement” in the claims differentiates it from a
`
`“drug.”
`
`“Contaminants” and “95 Percent Free of Contaminants”
`
`17.
`
`Claims 2, 14, and 19 of the ‘450 Patent include the limitation that “the
`
`creatine HCl is at least 95 percent free of contaminants.” In the context of the ‘450
`
`Patent, and as to a person of at least ordinary skill in the art, I believe this clause
`
`refers to material or substance that makes creatine hydrochloride impure, e.g.,
`
`because of remaining unreacted reactants, byproducts associated with the reaction,
`
`impurities introduced during the reaction either from the solute or the solvent, or
`
`substances introduced after the reaction. That is, my understanding largely is in
`
`agreement with the Petitioner’s offered claim construction. I discuss this separately
`
`to emphasize that the use of this phrase recognizes that the “creatine HCl” referred
`
`to in the claims of the ‘450 Patent is not 100% pure creatine HCl, but is understood
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`to be the major component of the substance, with other substances potentially
`
`present in minor amounts.
`
`18.
`
`I understand that terms in related patent applications in the same patent
`
`family and sharing the same priority claim are generally construed consistently.
`
`Thus, to a person of at least ordinary skill in the art, it is my opinion that the
`
`comments regarding “supplement” and “contaminants” would apply equally for the
`
`‘685 Patent.
`
`OVERVIEW OF CREATINE HYDROCHLORIDE
`
`19.
`
`Creatine has been known since the 19th century to assist in the
`
`provision of energy in vertebrate animals, including humans. It is produced naturally
`
`by the human body through the synthesis of two amino acids, glycine and arginine.
`
`Creatine assists in the production of adenosine triphosphate (ATP), which in turn is
`
`used by human cells in intracellular energy transfer. As such, increased presence of
`
`creatine, particularly in muscle tissue, increases the cellular energy output. Creatine
`
`has the following structure:
`
`
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`20.
`
`In solid form, creatine hydrochloride is a creatine derivative salt formed
`
`from creatine paired with a hydrochloride counterion as shown below. In an aqueous
`
`solution, the creatine hydrochloride ionizes into its constituent counterions, creatine
`
`and hydrochloride. The amount of ionization depends on the pH of the aqueous
`
`solution. In such a solution, the creatine is a weak base, and the hydrochloride is a
`
`strong acid. While the creatine hydrochloride salt has been known for a long time, it
`
`has typically been treated as a known byproduct produced along with other creatine
`
`derivatives. Since this is a salt of weak base and strong acid when dissolved in water
`
`the resulting solution will be acidic. The pH of this solution can be easily determined
`
`mathematically knowing the pKb of the base, the molar concentration of the salt (c)
`
`in the water, and the ionization constant of the water (Kw) using the following
`
`equation:
`
`
`
`𝑝𝑝𝑝𝑝=12𝑝𝑝𝐾𝐾𝑤𝑤−12𝑝𝑝𝐾𝐾𝑏𝑏−12𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙
`
`
`
`
`
`O
`
`OH
`
`H2N
`
`N
`NH
`
`HCl
`
`
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` DISCLOSURE OF THE ‘641 PATENT
`
`21.
`
`The ‘641 Patent describes two methods for preparing creatine HCl. The
`
`first procedure for preparing creatine hydrochloride is described in lines 4-14 of
`
`column 3 of the ‘641 Patent, using the following steps. First, creatine monohydrate
`
`is blended with acetyl chloride in a vessel. Ethanol is added to the vessel to dissolve
`
`the blended mixture. The temperature of the solution is raised to be between 24° C
`
`and 50° C. The ‘641 Patent specifically discloses that 25° C is preferred. At these
`
`conditions, creatine hydrochloride salt precipitates in a granular form. These
`
`granules may then be collected and packaged for consumption.
`
`22.
`
`Combination of these two compounds (reactants) will result in an
`
`exothermic reaction, i.e., it will generate additional heat and increase the temperature
`
`of the reaction mixture. The ‘641 Patent also indicates that the preferred process
`
`operates in a temperature range of 25° C to 35° C. Since standard room temperature
`
`is around 23-25° C, and the combination of creatine monohydrate add acetyl chloride
`
`is an exothermic reaction, an ice bath can be used to maintain the temperature in the
`
`desired range if needed. The use of an ice bath to maintain a particular temperature
`
`is a well-known and standard procedure for decades.
`
`23.
`
`The second procedure for preparing creatine hydrochloride is described
`
`in lines 15-28 of column 3 of the ‘641 Patent, using the following steps. A diethyl
`
`ether solvent is provided, into which gaseous hydrochloride is bubbled. Creatine
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`monohydrate is then stirred into the diethyl ether solvent. This results in a creatine
`
`hydrochloride precipitate. The precipitate is filtered and washed using fresh diethyl
`
`ether. The precipitate is then dried to isolate the creatine hydrochloride and collect
`
`it for consumption. The ‘641 Patent teaches that there can be a range of
`
`concentrations of gaseous hydrochloride, so long as it exceeds the molar equivalent
`
`of the creatine monohydrate to be added to the solvent.
`
`24.
`
`I have reviewed the Declaration of Jason Wiggers outlining the
`
`preparation of the creatine HCl mixture pursuant to the disclosure of the ‘641 Patent
`
`and subsequent solubility testing. Based on the declaration, attached exhibits, and
`
`the teachings of the ‘641 Patent, I believe that the steps taken to prepare the samples
`
`follow the teachings of the ‘641 Patent, and utilize standard methods and techniques
`
`known to those of skill in the art as of the filing date of the ‘641 Patent.
`
`25.
`
`I have reviewed the Declaration of Samir Saleh outlining his purity
`
`testing of the creatine HCl mixture prepared as outlined in the Declaration of Jason
`
`Wiggers. Based on the declaration and attached exhibits, I believe that the steps
`
`taken to test the purity of the samples utilize standard methods and techniques known
`
`to those of skill in the art as of the filing date of the ‘641 Patent.
`
`
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`RESPONSE TO DR. VAN BREEMEN’S DECLARATION
`
`26.
`
`I have reviewed the opinions provided by Dr. Van Breemen as to the
`
`solubility and purity of creatine, creatine monohydrate, and creatine hydrochloride.
`
`I have also reviewed his cited materials and research background.
`
`27.
`
`Upon review of Van Breemen’s Declaration, I did not notice any
`
`specific experience, studies, or publications related to creatine. As set forth above,
`
`my professional background includes extensive experience, studies and publications
`
`related to creatine, and some of its salts.
`
`28.
`
`In paragraph 19 of Van Breemen’s Declaration in IPR2016-00945, he
`
`states that he “believe[s] Crt-HCl meeting the solubility and purity limitations of the
`
`‘450 Patent were available before 2003.” However, Van Breemen provides no basis
`
`or evidence for his “belief.”
`
`29.
`
`Similarly, in paragraph 17 of Van Breemen’s Declaration in IPR2016-
`
`00947, he states that he “believe[s] Crt-HCl meeting the solubility and purity
`
`limitations of the ‘685 Patent were available before 2003.” However, Van Breemen
`
`provides no basis or evidence for his “belief” and should not be given any weight.
`
`30.
`
`In fact, in my 15 years of researching different forms of creatine, I have
`
`become familiar with the compound creatine hydrochloride. However, until the
`
`Patent Owner Vireo began manufacturing and making creatine hydrochloride
`
`generally available (under the CON-CRET nutritional supplement brand), I was not
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`aware of any commercially available creatine hydrochloride that had the solubility
`
`and purity requirements as claimed in the ‘450 Patent and ‘685 Patent.
`
`31. While creatine HCl has been a recognized compound for many years,
`
`manufacturing creatine hydrochloride is a difficult process, requiring careful control
`
`of temperature, pressure, the solvents, and the solutes. All of these factors can affect
`
`the purity, yield, and solubility of creatine HCl. As a result, many of the products
`
`promoted as creatine hydrochloride are not very pure, and have a number of
`
`contaminants or impurities. These contaminants are often creatine monohydrate,
`
`creatinine hydrochloride, or creatine ethyl ester hydrochloride, but may include other
`
`creatine derivatives or impurities. The presence of these contaminants have a direct
`
`and unpredictable impact on the solubility of the overall product.
`
`32.
`
`For any references that exist in the literature regarding use of creatine
`
`hydrochloride, unless the literature discusses how the product is made, it is virtually
`
`impossible to know the solubility and/or purity of the product without testing.
`
`33.
`
`In paragraph 20 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 20 of Van Breemen’s Declaration in IPR2016-00945), he
`
`claims that “Crt-HCl salts do not exist in water” and that “when Crt-HCl is
`
`dissolved in water, the creatine molecule disassociates from the hydrochloride.” The
`
`first part of this statement, “Crt-HCl salts do not exist in water,” is not true. When
`
`creatine HCl is added to water it dissolves, dissociates and forms a molecular
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`dispersion. It still remains as the Crt-HCl in solution without changing to a different
`
`creatine salt form. When this solution is dried (either by evaporation or freeze
`
`drying) and the obtained solid is tested, one should expect Crt-HCl salt. This fact
`
`has already been tested and reported by Gufford in Ex. 1009. During a saturated
`
`solubility study of Crt-HCl, Gufford collected the solution, freeze-dried it, and tested
`
`for the melting point using differential scanning calorimetry (DSC). This confirmed
`
`the salt obtained was indeed Crt-HCl. (Ex. 1009, at 247-248). If this salt does not
`
`exist in water after the removal of water it would never be converted to Crt-HCl.
`
`34.
`
`Other analysis shows that creatine HCl salts do exist in water, and not
`
`all creatine molecules necessarily disassociate from the hydrochloride. This fact is
`
`confirmed by Exhibit 1009 to the Petition. Exhibit 1009 discusses a number of
`
`different salt forms of creatine, including creatine HCl salt. Figure 2, Ex. 1009, p.
`
`248, shows thermograms of a variety of the creatine salts “after lyophization of the
`
`saturation solubility tests to confirm that what was measured in solution was the salt
`
`and not the molecular creatine or creatinine.” Pg. 247. It describes that the results
`
`in Figure 2 “indicates that the solubility measurements are true representations of
`
`the salt saturation solubilities and not just the solubility of free creatine at that
`
`particular pH, described as the apparent solubility.” Pg. 247. If Van Breemen’s
`
`underlying assumption that creatine molecules completely disassociate from the
`
`HCl, then the thermograms shown in Figure 2 for creatine monohydrate would be
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`the same creatine HCl. Comparing the thermograms in Figure 2 between creatine
`
`monohydrate (graph (a)) and creatine HCl (graph (d)) demonstrates very different
`
`results. The difference in these thermograms directly result from the fact that some
`
`portions of the creatine HCl salt remain and do not completely disassociate.
`
`35.
`
`As discussed earlier, creatine HCl is a salt of a weak base (creatine) and
`
`strong acid (hydrochloric acid). When a salt formed by a weak acid and strong base
`
`dissolves in water, the solution becomes acidic, as shown by the equation below.
`
`
`
`
`
`𝐶𝐶𝐶𝐶𝐶𝐶.𝑝𝑝𝐶𝐶𝑙𝑙 (𝑆𝑆)+𝑝𝑝2𝑂𝑂=𝐶𝐶𝐶𝐶𝐶𝐶𝑝𝑝+ (𝑎𝑎𝑎𝑎)+ 𝐶𝐶𝑙𝑙− (aq)
`𝐶𝐶𝐶𝐶𝐶𝐶𝑝𝑝+ (𝑎𝑎𝑎𝑎)+ 𝑝𝑝2𝑂𝑂=𝐶𝐶𝐶𝐶𝐶𝐶 (𝑎𝑎𝑎𝑎)+ 𝑝𝑝3𝑂𝑂+(𝑎𝑎𝑎𝑎)
`The presence of 𝑝𝑝3𝑂𝑂+𝑖𝑖𝑖𝑖 𝐶𝐶ℎ𝑒𝑒 𝑤𝑤𝑎𝑎𝐶𝐶𝑒𝑒𝐶𝐶 makes the solution acidic. The pH of this
`
`solution can be easily determined by knowing molar concentration of the salt and
`
`pKb of the free base as discussed earlier.
`
`36.
`
`In paragraph 28 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 30 of Van Breemen’s Declaration in IPR2016-00945), he
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`seeks to compare the solubility of creatine with amino acids such as alanine to
`
`establish a relationship of the zwitterionic solubility of the molecule with pH. Van
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`Breemen claims creatine is a zwitterion and should have a solubility profile similar
`
`to the amino acid alanine. However, that is not case, as demonstrated by the graphs
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`Vireo Systems, Inc. Ex. 2010 - 016
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`IPR2016-00947
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`relied upon by Van Breemen, which are copied below. Specifically, between pH 8-
`
`10, creatine showed a decreased solubility, as opposed to the increased solubility
`
`shown in the case of amino acids. The profile for creatine shows an L–shaped curve,
`
`not a U-shaped curve as shown by the alanine. This demonstrates that the solubility
`
`of the zwitterions do not behave in the same way as asserted.
`
`
`
`37.
`
`Because creatine does not act as a zwitterion similar to the amino acids,
`
`Van Breemen’s analysis of the characteristics is based on a flawed assumption.
`
`38.
`
`In paragraph 31 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 33 of Van Breemen’s Declaration in IPR2016-00945), Van
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`Vireo Systems, Inc. Ex. 2010 - 017
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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`Breemen presents the results of an experiment that he claims “show that reducing
`
`the concentration of Crt-HCl in an aqueous solution causes an increase in pH.” This
`
`experiment does not show anything more to a person of ordinary skill in the art that
`
`he knows already. Rather, it only confirms what is generally known and accepted
`
`in scientific community, i.e., that a salt of weak base (creatine) and a strong acid
`
`(HCl) in water is known to produce an acidic pH, and that diluting these solutions
`
`will reduce the concentration of hydrogen ion, and thus increase the pH for each
`
`additional dilution with water.
`
`39.
`
`In paragraph 32 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 34 of Van Breemen’s Declaration in IPR2016-00945), Van
`
`Breemen claims that “[t]he presence of contaminants or impurities in the Crt-HCl
`
`preparation will not statistically impact the solubility of creatine unless they alter the
`
`pH of the solution.” This is not true, and directly contradicts known scientific
`
`principles and published scientific references.
`
`40.
`
`It is well-known that solubility of a solute in a solvent can be affected
`
`by impurities present both in the solvents and solute. (Ex. 2017, at 199-200). From
`
`solubility data, one can predict the percent purity of a solute using thermodynamic
`
`principles. For example, Grant and Brittain in “Solubility of Pharmaceutical Solids”
`
`show different solubility graphs depending on the purity of the analyte substance
`
`and the effect of the solute on the overall solubility of the solution. (Ex. 2018, at
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`Vireo Systems, Inc. Ex. 2010 - 018
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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`336-340). Figure 5 of Grant and Brittain shows the solubility plot for a completely
`
`pure substance. Here, the solution composition increases 1:1 with the system
`
`composition until the saturation point is reached, at which point the plot line goes
`
`flat. Any increase in the overall amount of the dissolved analyte or solute beyond
`
`the saturation point simply exists as a solid. The Figure below is Fig. 5 from Ex.
`
`2018, at 336.
`
`
`
`41. Where an impurity appears in the solute and there is no interaction
`
`between the substances, a second type of solubility plot is shown. Here, the solubility
`
`increases at a 1:1 ratio until the saturation point of one of the substances in the solute
`
`(either analyte or impurity) is reached. At that point, the solubility continues to
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`Vireo Systems, Inc. Ex. 2010 - 019
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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`increase by at a rate of less than 1:1 with additional increased solute. The material
`
`for which solubility is reached remains in solid form, while the other material
`
`continues to increase until its saturation point is reached. This is shown in the figure
`
`below, taken from Figure 6 at Ex. 2018 at 337.
`
`
`
`
`
`42.
`
`The above only applies when the primary solute (analyte) and the
`
`impurities are additive, that is, there is no interaction between the two in the solution.
`
`This is not always the case. In many cases the dissolved compounds will interact
`
`with each other, which can affect the solubility in unpredictable ways. (Ex. 2018, at
`
`338). For example, the solution may plateau, for a certain concentration of solute,
`
`but then continue to increase. The figure below is Figure 7 from Ex. 2018, at 339.
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`Vireo Systems, Inc. Ex. 2010 - 020
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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`43.
`
`In other situations, the interaction between the dissolved compounds
`
`may have a negative effect on solubility. The figure below is Figure 8 from Ex. 2018
`
`
`
`at 340.
`
`
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`Vireo Systems, Inc. Ex. 2010 - 021
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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`44.
`
`The situation is even more complex and unpredictable when multiple
`
`impurities are present.
`
`45.
`
`Since the contaminant can be more than one identified compound as
`
`described in the ‘450 and ‘685 Patents, it would be difficult to speculate that decrease
`
`in pH is the only contributing factor for the enhanced solubility as speculated by Dr.
`
`Van Breemen.
`
`46.
`
`The ‘641 Patent explains that non-target compounds, like creatine ethyl
`
`ester and hydrochloride and creatinine hydrochloride, may be produced when trying
`
`to make creatine HCl. As explained above, there may also be unreacted starting
`
`materials such as creatine monohydrate (as Van Breemen also identifies). The
`
`presence of these impurities in the mixture, as explained above, can have a
`
`significant impact on the solubility of the overall mixture. Thus, one cannot assume
`
`what the solubility of this mixture will be. Rather, it must be tested to determine the
`
`mixture’s solubility.
`
`47.
`
`In paragraph 33 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 34 of Van Breemen’s Declaration in IPR2016-00945), Van
`
`Breemen claims “[c]reatinine is soluble in water, and creatinine HCl impurities in
`
`Crt-HCl will not reduce the solubility of Crt-HCl.” As stated above, without
`
`knowing the thermodynamic properties and the interaction between impurities and
`
`the solute in solution, it will be difficult to predict these speculative and hypothetical
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`Vireo Systems, Inc. Ex. 2010 - 022
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`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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`results. This is pure speculation on Van Breemen’s part and not based on sound
`
`scientific principles. Because Van Breemen did not evaluate these properties and
`
`interactions as discussed above, his conclusion cannot be relied upon.
`
`48.
`
` In paragraph 34 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 34 of Van Breemen’s Declaration in IPR2016-00945), Van
`
`Breemen asserts that “[v]ariation in solubility is likely the result of residual CM in
`
`the Crt-HCl preparation, contributing also to lower yield, and not the presence of
`
`non-creatine impurities or contaminants.” This is a pure speculation on Van
`
`Breemen’s part without any supporting scientific basis or supporting evidence.
`
`There may still be impurities present depending on the process of production which
`
`can contribute to the difference in solubility as well.
`
`49.
`
`In paragraph 35 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 34 of Van Breemen’s Declaration in IPR2016-00945), Van
`
`Breemen claims that it “is difficult to quantify the presence of different salt forms of
`
`molecules like creatine.” I disagree, as there are many analytical and scientific
`
`methods known to those of skill in the art for the identification and quantization of
`
`impurities in pharmaceutical solids today. Chemical impurities are classified as
`
`organic, inorganic and residual solvents (Ex. 2020, at 140). These different
`
`impurities and their nature and amount can be determined through chromatographic
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`Vireo Systems, Inc. Ex. 2010 - 023
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`techniques. (Ex. 2020). As this article was published in 1997, it would have been
`
`known to a person of ordinary skill in 2003.
`
`50.
`
`In paragraph 38 of Van Breemen’s Declaration in IPR2016-00947 (and
`
`similarly in paragraph 40 of Van Breemen’s Declaration in IPR2016-00945), Van
`
`Breemen claims he can “accurately estimate the aqueous solubility of a saturated
`
`solution of Crt-HCl at equilibrium having a pH at or below 0.3 to be greater than
`
`700 mg/ml.” This is not a scientifically valid estimate or assumption because he is
`
`assuming that the curve continues to increase. In pharmaceutical analysis, this is not
`
`a valid assumption. Without additional experimentation, it is not possible to know
`
`the nature of the solubility curve. One cannot extrapolate a solubility at a pH of 0.3
`
`on the basis of a solubility at a pH of 2. The graph referred to by Van Breemen as
`
`Figure 2 in Exhibit 1107, paragraph 26 of his declaration submitted in IPR2016-
`
`00947 (and Exhibit 1007, paragraph 28 of his declaration submitted in IPR2016-
`
`00945) show that small changes in pH can have a significant impact on solubility,
`
`and that you cannot simply “extrapolate” as Van Breemen does. Indeed, if you
`
`extrapolated the data between a pH of 6 and 4 in Figure 2 provided by Van Breemen,
`
`one would “assume” that the solubility at a pH of 2 was approximately the same.
`
`51.
`
`Also a solution of creatine monohydrate with a pH this low would result
`
`in an exothermic reaction, would result in some cyclizati
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