IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`BEFORE THE PATENTTRIALANDAPPEALBOARD
`Petitioner’s Demonstrative Exhibits
`
`April 4, 2019
`
`KVK-Tech, Inc., Petitioner, v. Shire, LLC, Patent Owner
`
`IPR2018-00290 (US Patent No.8,846,100)
`
`IPR2018-00293 (US Patent No.9,173,857)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`1
`
`
`
`BEFORE THE PATENTTRIALANDAPPEALBOARD
`Petitioner’s Demonstrative Exhibits
`
`April 4, 2019
`
`KVK-Tech, Inc., Petitioner, v. Shire, LLC, Patent Owner
`
`IPR2018-00290 (US Patent No.8,846,100)
`
`IPR2018-00293 (US Patent No.9,173,857)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`1
`
`
`
`Patent
`Owner’s Three
`IR, DR, SR
`Amphetamine
`Patents
`
`• Burnside 09/807,462 (filed October 20,1999)
`• Issued 6,605,300 (EX.1002) and RE41,148(EX.1048)
`• IR+DR/SR (EX.1002, 3:38-52,9:1-22.)
`
`• Couch 10/353,073 (filed June 29,2003)
`• Published as US 2004/0059002 (EX.1023)
`• IR+SR (EX.1023, ¶8.)
`
`• Sojai 11/383,066 (filed May 12,2006)
`• Issued as US 8,846,100 & 9,173,857(EX.1001)
`• IR+DR+SR
`
`2
`
`
`
`Where is the
`IR Bead
`Released?
`
`• Immediately “upon oral administration”
`(Burnside, EX.1002, 4:1-3).
`
`• In the stomach (Dr. Trout, EX.2001 ¶165;Dr.
`Polli, EX.2060 ¶38).
`
`3
`
`
`
`Where is the
`DR Bead
`Released?
`
`• “The entire dose is released in 30-60 minutes”
`when the enteric coating dissolves. (Burnside,
`EX.1002, 4:4-10.)
`
`• If the enteric coating is eudragit L30D-55 (e.g.,
`DR bead in Adderall XR), dissolves at pH 6.0.
`(EX.1002, 11:8-10; Polli Dec., EX.2060¶71.)
`
`• If the enteric coating is eudragit 4110D,
`dissolves at pH 6.8 (Id. ¶72; EX.1002 11:41-3.)
`
`4
`
`
`
`PH in GI Tract(EX.1039)
`
`Transit Time (ped.):
`Stomach: 1.1 hr.
`Small Intestine: 7.5 hr.
`Colon: 17.3 hr.
`(EX.1040)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`5
`
`
`
`SOJAI PATENTS
`
`BURNSIDE ‘300 PATENT
`
`EXAMPLE 4 SR BEAD
`
`EXAMPLE 4 SR BEAD
`
`DR Bead
`
`Talc
`
`90.00%
`
`DR Bead
`
`2.00%
`
`SURELEASE®
`
`8.00% SURELEASE®
`
`OPADRY® white
`
`90.00%
`
`8.00%
`
`2.00%
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`6
`
`
`
`Burnside Teaches SR AmphetamineBead
`
`“FIG. 6 illustrates the drug release
`profile of coated pellets described
`in Example 4 which exemplifies
`[the immediate release
`component and] the delayed
`release component of the present
`invention.”
`(EX.1002, 6:58-61.)
`
`• 70% released in 4 hours.
`• 80% released in 6 hours.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`7
`
`
`
`Where is the
`Burnside SR
`Bead
`Released?
`
`•
`
`In the intestines (Dr. Trout, EX.2001
`¶165).
`• 70% in small intestines; 20-30% in colon (Dr.
`Burgess EX.2071, p. 131:3-15).
`
`•
`
`Lower small intestines and colon (Dr. Polli,
`EX.2060, ¶202).
`
`8
`
`
`
`Sojai Claim 1 is Obvious
`
`Adderall XR +
`Burnside SR (Ex. 4)
`
`Burnside Ex. 5 +
`Burnside SR (Ex. 4)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`9
`
`
`
`Sojai Arguments over BurnsideIn Prosecution (EX.1005)
`
`• “The ‘300 patent discloses immediate Release beads and delayed pulsed release beads, but
`not sustained release beads.” (Id. at 535-536, Response to First OfficeAction.)
`
`• “The ‘300 patent teaches that ‘lag time’ (delay until release begins) of the delayed release
`component can be increased by applying a coating of, e.g., SURELEASE, over the enteric coating.”
`(Id. at 569-570, Response to Second OfficeAction.)
`• Applicants asserted that the “second delayed release bead” has an “atypical construction” not
`taught in Burnside. (Id. at 645-646, Response to Third OfficeAction.)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`10
`
`
`
`Patent Owner’s Acute ToleranceDefense
`
`“Acute tolerance is the rapid dissipation of the chemical effects
`of amphetamines after the drug produces its initial effects, even
`though plasma concentration is level.”
`
`“increasing (not sustained) plasma concentrations were
`necessary for continued therapeutic amphetamine effect
`throughout the day.”
`
`Polli Dec., EX.2060 ¶¶ 155-156.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`11
`
`
`
`Couch (EX.1023, 2051)
`
`[0006] The SR formulations of this invention will be effective
`to treat, e.g., ADHD, in the same manner as ADDERALL® XR.
`For example, they will be effective to treat ADHD in the
`unexpectedly good manner established in the data reported in
`Example 10. They will also be effective to treat ADHD with
`low incidence of side effects, including substance abuse,
`addiction, tolerance, tachyphylaxis, etc.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`12
`
`
`
`Tmax
`
`Efficacy
`
`Adderall IR
`
`3 hours
`
`10 hours
`
`Adderall XR
`v.
`Adderall IR
`
`Adderall XR
`
`7 hours
`
`At least 12 hours
`
`•
`
`Chart
`
`EX.1031, p. 1; EX.1032, p.1; McCracken, EX.1058, ¶¶ 35-39.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`13
`
`
`
`Dr.McCracken’s 2003 Study DemonstratesNo
`Acute Tolerance forAmphetamines
`
`“In my 2003 study, I actually showed that a single dose of Adderall 10 milligrams in
`the morning manifested efficacy as late as 10 and a half hours. So, therefore, many
`people don't need even a twice-daily dose of immediate-release amphetamine,
`which flies in the face of any claim of acutetolerance”
`
`McCracken Tr. EX.2082, 30:8-15.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`14
`
`
`
`McCracken2003 Study(EX.1037, Fig. 2)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`15
`
`
`
`“The respective slopes
`(i.e. rates) . . . aresimilar
`in the placebo and drug
`curves. Acute tolerance,
`by definition, would
`predict a loss of efficacy
`at a much faster rate
`than the placebo
`responses.”
`
`McCracken, EX.1058, ¶38
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`16
`
`
`
`Brown
`EX.2065
`Figure 1
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`17
`
`
`
`Criticism of Brown(EX.2065)
`
`• “Brown et al . . . has several limitations, . . .
`including an N of only 9
`and the fact that the dependent behavioral measures included only
`an activity monitor and the blood technician's ratings of the subjects’
`behavior during blood draws.” (Pelham EX1052 p. 227.)
`
`• “[i]t is likely that small subject number with a large standard
`deviation led to the failure in [Brown] to demonstrate a significantly
`increased time to Tmax in sustained-versus immediate-release
`dextroamphetamine.” (McGough EX1057 p. 689.)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`18
`
`
`
`Self-Criticism by Greenhill (EX.2044, p.1240)
`
`• “[T]he study has only 12 subjects, which severely limits the
`ability to address the apparent intersubject variability . . . .”
`
`• “without a placebo control and subjective reports from the
`patients, it is difficult to know if the reduced attention and
`deportment responses to the same plasma concentrations
`might be better explained by fatigue or boredom.”
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`19
`
`
`
`Self-Criticism by Brauer(EX.2053)
`
`Six normal adult subjects studies – no indication they had ADHD.
`
`“Although the results of this study are suggestive of . . . acute
`tolerance to some of the effects of d-amphetamine, the absence
`of a placebo control condition makes it difficult to rule out other
`possible interpretations of the data . . . such as uncontrolled
`variations related to circadian rhythms or to environmental events
`. . . these Issues can only be addressed by subsequent studies
`including a placebo control condition.”
`(EX. 2053 p. 4.)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`20
`
`
`
`Patent Owner’s Cited References forAcute
`Tolerance of Amphetamine
`
`Exhibit
`
`First Author
`
`AmphetamineStudy
`
`Study Size
`
`Placebo
`
`EX2044
`
`EX2046
`
`EX2053/2059
`
`EX2061
`
`EX2065
`
`Greenhill
`
`Spencer
`
`Brauer
`
`Swanson
`
`Brown
`
`Yes
`
`No
`
`Yes
`
`No
`
`Yes
`
`12 subjects
`
`No
`
`6 subjects
`
`No
`
`9 subjects
`
`No
`
`No
`
`No
`
`No
`
`Yes
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`21
`
`
`
`Swanson 2009(EX.2083)
`
`“[F]undamental principle of acute tolerance is not understood
`or recognized by all, which is reflected in the second
`generation CR formulations (see the absence of acute
`tolerance in the reviews by Banaschewski et. al., 2006 and
`Conner & Steingard, 2004) and by some investigators who
`have participated in the development of new CR formulations
`without an ascending drug profile ….” Id. p. 11.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`22
`
`
`
`None of these Cited References TeachAcute
`Tolerance forAmphetamines
`
`• EX.1002 (nitroglycerin)
`• EX.1010 (methylphenidate)
`• EX.1014 (no mention of acute tolerance)
`• EX.1027 (nitroglycerin)
`• EX.1031 (not acute tolerance)
`• EX.2019 (methylphenidate)
`• EX.2026 (no mention of acutetolerance)
`• EX.2034 (no mention of acutetolerance)
`• EX.2043 (no mention of acute tolerance oramphetamine)
`• EX.2045 (methylphenidate)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`23
`
`
`
`Summary of Arguments That AcuteTolerance
`Does Not TeachAway
`1. Not Argued by Patent Owner in Patents or File History.
`2. Couch (EX.1023, ¶6) states SR amphetamine has no acute
`tolerance.
`3. McCracken 2003 paper (EX.1037) refutes.
`4. Patent Owner’s prior art largely irrelevant to amphetamines.
`5. Few that are relevant (Greenhill, Brown, Brauer) rely on flawed
`studies (small, no placebo) or no studies.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`24
`
`
`
`Evidence of No FoodEffect
`• “Food has little effect on plasma amphetamine levels” (Tulloch EX. 1014 at 1406);
`• “There appears to be little effect of food on the extent of absorption of
`dextroamphetamine in either IR … or SR formulations ….” (Patrick EX. 2019 at 536):
`• “The release [of the SR bead] is happening well beyond where the food effect is
`relevant” (EX.2070, Jusko Tr. pp. 79-81);
`• Dr. McCracken opined that in his clinical thirty-plus experience, no amphetamine
`formulations has shown signs of a clinically significant food effects (EX.1058, ¶92, ¶100);
`• Adderall XR has no food effect (EX.1031, p.2);
`• Dexedrine SR has no food effect (EX.1054 p.2, EX.2084 p.3);
`• Mydayis has no food effect (EX.2004, p.15);
`• Dyanavel XR has no food effect (EX.1055, p.10);
`• Adzenys ER has no food effect (EX.1056, p.18.).
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`25
`
`
`
`Patent Owner’s Evidence of FoodEffect
`
`Patent Owner relies on other drug products for
`evidence of food effect; for example:
`
`Nifedipine and theophylline, EX.2036, 2037, 2048.
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`26
`
`
`
`Inherency of PK Claims(Reply, pp. 19-27)
`
`• Coating thickness
`• IR and DR beads are rapid release.
`• Burnside’s DR beads coating weight in preferred range of about 24 to 30 wt. %.
`(EX.1001, 8:30-33.)
`• SR beads in Burnside and Sojai (Example 4) have the same coating weight.
`
`• Dosage amount of 37.5 mg
`• All doses between 10 mg and 60 mg are effective for ADHD (EX.1031, p. 3).
`
`• Ratio of Bead Types
`• Adderall XR and Example 5 already at 1:1 ratio. (EX.1002; EX.1014, p. 1406).
`• Choose higher dose Adderall XR (20-30mg) for longer efficacy (EX.1058, ¶44).
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`27
`
`
`
`Possible Ratios in 37.5 mgCapsule (Reply 21-22)
`
`Three ratios below - all will treat ADHD (‘857, 4:64-5:18).
`
`1. Adderall XR (20 mg) plus 17.5 mg SR for a 1:1:1.75
`• May cause insomnia (EX.1010, pp. 1-2; EX.2060 ¶202)
`
`2. Adderall XR (25 mg) plus 12.5 mg SR for a 1:1:1 ratio.
`
`3. Adderall XR (30 mg) plus 7.5 mg SR for a 2:2:1 ratio.
`• May not have desirable late day efficacy.
`(Id.)
`
`Demonstrative Exhibit for Petitioner - Not Evidence
`
`28
`
`
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