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 JASON WIGGERS
`
`Exhibit 2012
`
`
`
`
`
`
`
`
`
`Vireo Systems, Inc. Ex. 2012 – 001
`
`
`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 JASON WIGGERS
`
`Exhibit 2012
`
`
`
`
`
`
`
`
`
`Vireo Systems, Inc. Ex. 2012 – 001
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`DECLARATION
`
`I, Jason Wiggers, 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 am the Operations Manager of Vireo Systems, Inc. (“Vireo”). I have
`
`held this position since November 2007. My job responsibilities include overseeing
`
`of operations, which include but are not limited to research and development,
`
`manufacturing, and product development. I have 9 years of laboratory and
`
`commercial scale supplement and drug manufacturing experience. I have a
`
`bachelor’s degree in Biology with a minor in Chemistry at David Lipscomb
`
`University from 2004.
`
`3.
`
`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).
`
`4.
`
`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
`
`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.
`
`Vireo Systems, Inc. Ex. 2012 – 002
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`5.
`
`I was requested by Vireo’s counsel to prepare samples of creatine
`
`hydrochloride according to the methods described in the ‘641 Patent. I have
`
`reviewed the ‘641 Patent and am familiar with the procedures that it describes.
`
`6.
`
`To conduct the procedures, I supervised the work performed by
`
`Vireo-trained personnel. I specified the procedures used and am personally familiar
`
`with the testing, and I can testify to such if called to do so. The procedures
`
`performed under my supervision for purposes of the requested creatine
`
`hydrochloride preparation are attached hereto as Exhibit A.
`
`Method 1: Acetyl Chloride Mixture.
`
`7.
`
`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.
`
`8.
`
`In order to conduct this procedure, I directed that 8.89 grams (0.059
`
`mol) of creatine monohydrate be weighed out and placed into an Erlenmeyer flask.
`
`6 ml (0.084 mol) of acetyl chloride were measured in a 10 ml graduated cylinder.
`
`Vireo Systems, Inc. Ex. 2012 – 003
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`These weights equal the molar ratio of 1:1.4 described in the ‘641 Patent at column
`
`2, lines 53-56. In addition, 10 ml of SDA-35A ethanol were measured out in a 10
`
`ml graduated cylinder for dissolving, as instructed in the ‘641 Patent at column 2,
`
`lines 60-61. See Exhibit A, at p. 3.
`
`9.
`
`The reaction is exothermic. The ‘641 Patent, at column 2, lines 63-67,
`
`instructs that temperature should be maintained below 50° C to reduce the amount
`
`of creatinine hydrochloride and creatine ethyl ester hydrochloride contaminants
`
`produced by the reaction. Therefore, in order to stay within the instructed
`
`temperature range and minimize the impact of the heat energy associated with the
`
`reaction, I directed that the vessel containing the reactants be placed in an ice bath
`
`to manage or regulate the temperature of the reaction. This is a common and
`
`standard laboratory technique. The initial temperature was measured to be 14° C.
`
`Next, the acetyl chloride was poured into the flask and stirred to ensure a complete
`
`mixture. Due to the exothermic reaction, the temperature was then measured to be
`
`41° C, that is, within the directed temperature range of the ‘641 Patent. The ethanol
`
`was then added to dissolve the mixture. As the reaction continued, a slurry formed
`
`from the resulting precipitated salt. See Exhibit A, at p. 3.
`
`10.
`
`Once the temperature reached a steady 25° C, the slurry was emptied
`
`onto a sterile filter paper in accordance with standard procedures for isolating a
`
`precipitated compound. Additional ethanol was used to wash the precipitate. The
`
`Vireo Systems, Inc. Ex. 2012 – 004
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`excess liquid was removed, and then the entire composition was set to air dry at
`
`room temperature for 3 hours. The final sample product measured 11 grams. See
`
`Exhibit A, at p. 3.
`
`11.
`
`I directed that 100 mg of the dried sample be isolated in sterile
`
`packaging for pick up and transport by Samir Saleh for purity testing, and that 5 g
`
`of the dried sample be used for testing solubility as described further below.
`
`Method 2: HCl Gas Infusion
`
`12.
`
`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 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.
`
`13.
`
`In order to conduct this procedure, I directed that 5 ml of diethyl ether
`
`be poured into an Erlenmeyer flask, and 4.45 g of creatine monohydrate be
`
`measured out. Tubing for bubbling in gaseous hydrochloride was threaded into the
`
`flask and submerged in the ether. The entire apparatus was placed in the fume
`
`Vireo Systems, Inc. Ex. 2012 – 005
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`hood, and then 1.5 g of gas was bubbled into the ether. Once the tubing was
`
`removed, the creatine monohydrate was incrementally added to the ether-gas
`
`mixture and stirred while monitoring the temperature. The temperature reached a
`
`maximum of 38° C. After stabilization, the slurry was poured onto filter paper in
`
`order to recover the precipitate and washed with an additional 5 ml of ether. After
`
`excess liquid was removed, the precipitate was set to dry for 3 hours at room
`
`temperature to provide a dry sample. See Exhibit A, at pp. 4-5.
`
`14.
`
`I directed that 100 mg of the dried sample be isolated in sterile
`
`packaging for pick up and transport by Samir Saleh for purity testing, and that 5 g
`
`of the dried sample be used for testing solubility as described further below.
`
`Solubility Testing
`
`15.
`
`After the samples produced by Methods 1 and 2 were prepared, I
`
`directed that the solubility of the samples be tested. The procedure for solubility
`
`testing is set forth in Exhibit A, at p. 6.
`
`16.
`
`For each sample, 3.75 g of creatine HCl was weighed out and crushed
`
`into a very fine powder. This was then combined with 5 ml of purified water in a
`
`50 ml beaker. The solution was stirred for 2 minutes to achieve equilibrium. The
`
`solution was then poured over filter paper placed in a funnel, and the funnel was
`
`attached to a vacuum that emptied into a 500 ml Buchner flask. When the vacuum
`
`was activated, the liquid was pulled into the Buchner flask, leaving wet insolubles
`
`Vireo Systems, Inc. Ex. 2012 – 006
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`on the filter paper. The sample was air dried, then scraped onto measuring paper
`
`and weighed.
`
`17.
`
`To find the solubility, the amount of dried insoluble material is
`
`deducted from the total amount of the sample, and that result is divided by the
`
`amount of water. This is a standard way to measure solubility of a substance. The
`
`formula is as follows:
`
`((Original Sample Mass) – (Mass of Insoluble Remainder)) / (Volume of Water)
` = Aqueous Solubility
`
`18.
`
`For sample 1, the insoluble remainder had a mass of 0.09 g. This
`
`demonstrated that sample 1 had a solubility of 732 mg/ml, using the calculation of
`
`(3.75 g – 0.09 g) / 5 ml = 0.732 g/ml = 732 mg/ml.
`
`19.
`
`For sample 2, the insoluble remainder had a mass of 0.43 g. This
`
`demonstrated that sample 1 had a solubility of 664 mg/ml, using the calculation of
`
`(3.75 g – 0.43 g) / 5 ml = 0.664 g/ml = 664 mg/ml.
`
`Transport of Samples to Samir Saleh
`
`20.
`
`For samples picked up and transported by Saleh for purity testing, the
`
`samples were transferred in a sterile manner into sterilized packaging and sealed.
`
`The person making the transfer and myself then executed the chain of custody
`
`forms. Mr. Saleh picked up the sealed samples from the office/lab, as demonstrated
`
`on the chain of custody form attached hereto as Exhibit B.
`
`Conclusion
`
`Vireo Systems, Inc. Ex. 2012 – 007
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`Vireo Systems, Inc. Ex. 2012 – 008
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`EXHIBIT A TO EX. 2012
`
`Vireo Systems, Inc.
`
`Vireo Systems, Inc.
`
`Patent #7,608,641
`
` 6/20/2016
`
`Vireo Systems, Inc. Ex. 2012 – 009
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`Vireo Systems, Inc.
`
`Method of Manufacture 1: Acetyl Chloride
`
`Raw Materials:
`20 gram of Acetyl Chloride ( 18ml) sourced from Fluka Analytical, Lot #BCBM0208V
`30 gram of Creatine Monohydrate manufactured by Shanghai Baosui Co. Ltd, Batch #20150209
`30 ml of Ethanol SDA-35A from Superior Chemicals & Solvents, Lot #AK6372719
`
`Equipment:
`Ice
`Vacuum Filter System (vacuum pump, plastic perforated funnel, filter paper medium, 500 ml Buchner
`Flask)
`Ring stand and clamps
`50 ml Pyrex Beakers
`500 ml Pyrex Beaker
`125 ml Pyrex Erlenmeyer Flasks
`Highland HCB 1002 Balance
`Calibrated Accu-Safe 12" Lab Thermometer (0 - 230 ℉)
`Paper measuring tray
`10 ml Pyrex Graduated Cylinders
`Clock / Timer
`Glass Stir Rod
`Plastic Scraper
`
`Foreword:
`In processing this method of manufacturing the raw materials , samples 1 utilized a 1:1.4 ratio of
`Creatine Monohydrate to Acetyl Chloride by mole. Samples 1 was synthesized via Acetyl Chloride as
`chosen Acid Catalyst. This method detailed in Patent #7,608,641 has been shown to produce creatine
`hydrochloride.
`
`Sample 1: 1 mol CH20: 1.4 mol Acetyl Chloride
`Ethanol was added in all at once
`
`Vireo Systems, Inc. Ex. 2012 – 010
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`Vireo Systems, Inc.
`
`Procedure for Sample 1:
`1. Placed paper measuring tray on Balance and tared out weight
`2. Weighed Out 8.89 gram of Creatine Monohydrate
`3. Measured out 10 ml of SDA-35A in 10 ml graduated cylinder
`4. Measured 6 ml of Acetyl Chloride in 10 ml graduated cylinder
`5. Placed Creatine Monohydrate into 125 ml erlenmeyer flask
`6. Fill 500 ml beaker halfway with ice and water to create ice bath
`7. Submerged in ice bath and secure to ring stand
`8. Took Temperature ( 14℃)
`9. Poured in 6 ml of Acetyl Chloride
`10. Stirred for 1 min
`11. Took Temperature Measurement (41℃)
`12. Added Ethanol SDA-35A (10ml)
`13. Stirred for 2 min
`14. Waited for Temperature to reach 25 ℃ (approximately 2 minutes)
`15. Placed filter paper into vacuum filter system
`16. Emptied reacted slurry onto filter paper
`17. Washed slurry with 5 ml of Ethanol SDA-35A
`18. Turned on vacuum and maximized exposed surface area and waited until liquid excretion halted
`19. Removed filter paper with sample containing precipitates from vacuum filter system
`20. Set in controlled environment to air dry for 3 hours at room temperature
`21. Transferred sample to paper measuring tray
`22. Weighed Final Sample Product (11 gram) taring out paper measuring tray weight
`
`Final product was found via NMR spectroscopy to be at least 98 percent or greater pure creatine
`hydrochloride.
`
`Samples were prepared in sterile packaging for transport to Vanderbilt for purity testing.
`
`Vireo Systems, Inc. Ex. 2012 – 011
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`Vireo Systems, Inc.
`
`Method of Manufacture 2: HCl gas infusion
`
`Raw Materials:
`10 gram Creatine Monohydrate manufactured by Shanghai Baosui Co. Ltd, Batch #20150209
`3 gram HCl gas (from 60 lb Linde Electronics and Specialty Gases Tank)
`20 ml Diethyl Ether sourced from Fisher Scientific
`
`Equipment:
`Ice
`Vacuum Filter System (vacuum pump, plastic perforated funnel, filter paper medium, 500 ml Buchner
`Flask)
`Ring stand and clamps
`50 ml Pyrex Beakers
`500 ml Pyrex Beaker
`125 ml Pyrex Erlenmeyer Flasks
`Highland HCB 1002 Balance
`Calibrated Accu-Safe 12" Lab Thermometer (0 - 230 ℉)
`Paper measuring tray
`10 ml Graduated Cylinders
`Clock / Timer
`Glass Stir Rod
`Rubber Stoppers
`High Density PolyEthylene (HDPE) tubing
`
`Foreword:
`All procedures were executed under room temperature (25 ℃) and pressure (1 atm) unless otherwise
`stated. In processing this method of manufacturing the raw materials , sample 2 utilized a 1:1.4 ratio of
`Creatine Monohydrate and HCl gas. Sample 2 was created via HCl gas infusion into Diethyl Ether
`followed by stirring in Creatine Monohydrate. This method detailed in Patent #7,608,641 has been
`shown to produce creatine hydrochloride.
`
`Sample 2: 1 mol CH20: 1.4 mol HCl
`Monohydrate was added incrementally in gram doses to better control the exothermic reaction.
`
`Vireo Systems, Inc. Ex. 2012 – 012
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`
`Vireo Systems, Inc.
`
`
`Procedure for Sample 2:
`1. Put balance under fume hood
`2. Placed paper measuring tray on balance and tared out weight
`3. Weighed out 4.45 grams of Creatine Monohydrate
`4. Poured 5 ml of Diethyl Ether into a 10 ml graduated cylinder
`5. Transferred Diethyl Ether into 125 ml Erlenmeyer Flask
`6. Attached 125 ml Erlenmeyer Flask to Ring stand for stability
`7. Threaded HDPE tube through rubber stopper
`8. Connected HDPE tube from HCl Tank to 125 ml Erlenmeyer flask (with end of tube submerged
`in ether but not touching the bottom of the flask)
`9. Situated flask/ tube combo on the balance and tared weight
`10. Activated Fume hood
`11. Began bubbling in HCl gas until balance read 1.5 gram
`12. Pulled HCl gas tube out of flask and then cut off gas to avoid siphoning back up tube
`13. Turned off Fume Hood
`14. Added Creatine Monohydrate (4.45 gram)
`15. Agitated with glass stir rod for 2 min
`16. Monitored temperature with thermometer (38℃)
`17. Poured mixture onto filter paper in vacuum filtration system
`18. Washed with 5 ml of Diethyl Ether
`19. Let Vaccum Filter (detailed in Method 1) run for 2 minutes
`20. Turned off and let powder dry for 3 hours at room temperature
`21. Weighed dry sample taring out paper measuring tray weight
`
`
`
`Final product was found via NMR spectroscopy to be at least 98 percent or greater pure creatine
`hydrochloride.
`
`
`
`Samples were prepared in sterile packaging for transport to Vanderbilt for purity testing.
`
`
`
`Vireo Systems, Inc. Ex. 2012 – 013
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`Solubility Tests for Creatine HCl
`
`Vireo Systems, Inc.
`
`Materials:
`● 5 gram Creatine HCl synthesized via method 1
`● 5 gram Creatine HCl synthesized via method 2 *
`● 20 ml of Purified Water
`● Fischer Scientific Thermix Stirrer
`● Vacuum Pump
`● 50 ml Pyrex Beakers
`● 500 ml Pyrex Buchner Flask
`● Plastic Scraper
`● Ceramic Mortar and Pestle
`● Highland HCB 1002 Balance (0.00 gram resolution)
`● 5 ml Pyrex Graduated Cylinder
`● Filter Paper
`● Paper Measuring Tray
`● Plastic Perforated Funnel for filtration
`
`*Tests were run across 2 different lab batches of Creatine HCl
`
`Procedure:
`1. Placed paper measuring tray on balance and tared weight
`2. Weighed out 3.75 g of Creatine HCl
`3. Crushed powder very fine with mortar and pestle to best mimic retail product consistency
`4. Measured 5 ml of Purified Water
`5. Combined purified water and Creatine HCl in a 50 ml Beaker
`6. Dropped in magnetic stirring device
`7. Stirred for 2 min
`8. Attached vacuum hose to 500 ml Buchner flask
`9. Placed filter funnel into top of Buchner flask and filter paper into funnel
`10. Poured solution over filter paper
`11. Activated vacuum ( liquid will be pulled into Buchner flask while wet insolubles remained on
`filter paper)
`For 2 minutes (until all liquid has stopped dripping into Buchner flask)
`12. Let sample air dry
`13. Scraped all sample from filter paper onto measuring paper
`14. Weighed sample (Make sure balance has tared out weight of measuring paper)
`
`Vireo Systems, Inc. Ex. 2012 – 014
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`(Original Creatine HCl mass – measured sample remainder ) / volume of purified water = aqueous
`solubility
`(3.75 - .09 ) mg / 5 ml = 732 mg / ml
`
`Vireo Systems, Inc.
`
`Results:
`
`Sample 1: 1 mol CH20: 1.4 mol Acetyl Chloride
`732 mg/ml
`Sample 2: 1 mol CH20: 1.4 mol HCl gas
`664 mg/ml
`
`Vireo Systems, Inc. Ex. 2012 – 015
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`
`
`EXHIBIT B TO EX. 2012
`
`Vireo Systems, Inc. Ex. 2012 – 016
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
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