James E. Felman, Esq.Kynes, Markman & Felman, P.A.

Dr. Gregory DudleyAssociate Professor and Associate Chair

Department of Chemistry and Biochemistry Florida State University

What is at Stake“the first instance in the history of the Republicin which the government has sought to seizeassets – and potentially imprison its citizens –based on conduct that it literally would not havebeen possible for the citizenry to know wasconsidered unlawful. Indeed, through thisaction the Plaintiff seeks to convert ourgovernment from one of laws not merely to oneof men, but to a government of a single man – aDEA chemist named Terrance Boos”

The Analogue Act

The term controlled substance analogue is defined by Title 21 U.S.C. § 802(32)(A) as a substance-

(i) the chemical structure of which is substantially similar to the chemical structure of a controlled substance in schedule I or II;(ii) which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II; or(iii) with respect to a particular person, which such person represents or intends to have a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II.

The mens rea from the underlying Section 841offense carries over to violations of the analogueoffense – to be guilty “the defendant must knowthat the substance at issue meets the definitionof a controlled substance analogue”United States v. Turcotte, 405 F.3d 515 (7th Cir. 2005)United States v. Roberts, 363 F.3d 118(2d Cir. 2004)United States v. Sullivan, 714 F. 3d 1104 (8th Cir. 2013)

But See…

United States v. McFadden, No. 13-4349 (4th Cir. May 21, 2014)

United States v. Klecker, 348 F. 3d 69 (4th Cir. 2003)

United States v. DeSurra, 865 F. 2d 651(5th Cir. 1989)

Yesterday, after six days of evidence the government’sattorneys informed defense counsel and the Court thatthe government’s experts had advised them that day thatthe Turcotte inference is not scientifically sound …counsel for the government accordingly asked that theTurcotte inference be removed in light of their experts’positions.”

United States v. Lane, et al., 2013 WL 3716601 (July 13, 2013)

“The Turcotte inference permits a jury to infer that if Defendant knew that an analogue has a physiological effect substantially similar to or greater than a controlled substance, then the Defendant also knew that the alleged analogue had a chemical structure substantially similar to the controlled substance.” Citing Turcotte at 527.

Timeline of Substances & Scheduling

March 1, 2011“The Fed 5”

JWH-018JWH-073JWH-200CP-47, 497Cannabicyclohexanol(CP-47, 497-C8)

U.S. Synthetic Drug Abuse and Prevention Act 2012

July 9, 2012

AM694AM2201CP-47,497Cannabicyclohexanol orCP-47,497 C8-homologJWH-018 and AM678JWH019JWH-073JWH-081

JWH-122JWH-200JWH-203JWH-250JWH-398SR-19 and RCS-4SR-18 and RCS-8

5 Structural Arrangements

May 16, 2013

XLR-11UR-144AKB48

Chemistry

Brief tutorial on molecular structureGregory Dudley, PhD

Associate Professor and Associate Chair

Department of Chemistry and Biochemistry

Florida State University----------------------------Education and training:

• B.A. FSU 1995(Chemistry / Biochemistry)

• PhD MIT 2000(Organic Chemistry)

• NIH Fellow MSKCC 2000-2002(Molecular Pharmacology and Chemistry)

----------------------------For more information:

gdudley@chem.fsu.eduhttp://www.chem.fsu.edu/dudley/

http://www.dudley-consulting.com/

Ethanol (C2H6O)

Ibuprofen (Advil)

∆9-THC

(functionalgroups: define

reactivity)

(carbon framework: defines shape and size)

My opinion For Prong One, chemical structures can and should

be compared without prejudice toward any specific pharmacological effect: i.e., independent of Prong Two or Three. pharmacology data cannot change structural similarity

Subjective structural comparisons can and should be made from the perspective of a medicinal chemist, weighing structural differences as they pertain to molecular size, shape, and general chemical reactivity. Caveat: subject to biases of the medicinal chemist

sildenafil(Viagra)

vardenafil(Levitra)

Benchmarks from medicinal chemistry

ibuprofen (Advil)naproxen (Aleve)

These substances were developed in different labs at different times andpatented separately: each was a “non-obvious” new invention

Benchmark DEA comparisons

but… DEA asserts that JWH-

018 and UR-144 are “substantially similar”

and JWH-018 and XLR-11 are “substantially similar”

Similarities: indole and pentyl group (common)Differences: flat, stable, aromatic naphthalene vs.

globular, strained, aliphatic tetramethylcyclopropaneGrey area: bridging carbonyl (C=O) group,

diaryl ketone vs. aryl alkyl ketone

Objective analysis of chemical structures

17

JWH-018 and UR-144

18

My opinions UR-144 and JWH-018 are not “substantially similar” in

chemical structure as required by the Analogue act XLR-11 and JWH-018 are not “substantially similar” in

chemical structure as required by the Analogue act

Structural differences are greater than those of other compounds deemed dissimilar

No reasonable person could have known that the DEA thought otherwise

A closer call

Reasonable chemists might disagree; similarity

assessment is often context-dependent

Here, DEA assessment of JWH-018 vs. CB-13 is a

near-perfect standard for making the comparison

: good case for dissimilar

Chemical reactivity difference: PB-22 is prone to hydrolysis, especially

in vivo

Related consideration: Sentencing guidelines

In the case of a controlled substance that is not specifically referenced in this guideline, determine the base offense level using the marihuana equivalency of the most closely related controlled substance referenced in this guideline. In determining the most closely related controlled substance, the court shall, to the extent practicable, consider the following:

(A) Whether the controlled substance not referenced in this guideline has a chemical structure that is substantially similar to a controlled substance referenced in this guideline.(B) Whether the controlled substance not referenced in this guideline has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance referenced in this guideline.(C) Whether a lesser or greater quantity of the controlled substance not referenced in this guideline is needed to produce a substantially similar effect on the central nervous system as a controlled substance referenced in this guideline.

What to do about methylone?

500:1 380:1

20,000:1

???

Constitutional Issues

Vagueness“[A] statute which either forbids or requires the doing of an act in terms so vague that men of common intelligence must necessarily guess at its meaning and differ as to its application violates the first essential of due process of law.” Connally v. General Constr. Co., 269 U.S. 385, 391 (1926).

“[B]ecause we assume that man is free to steer between lawful and unlawful conduct, we insist that laws give the person of ordinary intelligence a reasonable opportunity to know what is prohibited, so that he may act accordingly.” Grayned v. City of Rockford, 408 U.S. 104, 108 (1972).

Uncertainty regarding “substantial similarity”The term “substantially similar in chemical structure” is not a term used in the field of chemistry, but a legal term. There are not at present any scientific guidelines for the application of that term.

“uninterpretable”Professor Paul Doering, University of Florida

“essentially nonsense”Dr. Terrance Stouch, President of Science for Solutions, LLC, and Adjunct Professor at Duquesne University

The scientific equivalent to asking a mathematician whether 3 is “substantially similar” to 4.

June 2011http://www.deadiversion.usdoj.gov/mtgs/drug_chemical/2011/boos.pdf

A person of ordinary intelligence prior to July 2012faced with the chemical structures and existingpharmacological data regarding UR-144 and XLR-11would have been left to “guess” whether either is acontrolled substance. And if any such person,before guessing, first consulted with professors atthe leading universities in this state and otherexperts in the field of chemistry, that person wouldhave ended up guessing incorrectly. Because noperson of ordinary intelligence had a reasonableopportunity to know that which literally nine out often chemists believes is not so, the Act isunconstitutionally vague as applied to UR-144 andXLR-11.

Pharmacology

Brief tutorial on pharmacology and cannabinoid receptorspharmacology: the branch of medicine concernedwith the uses, effects, and modes of action of drugs

Key terms (oversimplified)

Cannabinoid: a substance that binds to cannabinoid receptors

CB1: cannabinoid receptor in brain, produces psychotropic effectsCB2: cannabinoid receptor outside CNS, therapeutic target for pain, etc

Ki (binding affinity): how tightly the active molecule binds to the receptor

EC50 (cell response assay): what the cell does when the molecule binds (and how much of the substance is needed)

ED50 (animal testing): how the substance affects a living system

My opinion For Prong Two, specific pharmacological effects can

and should be compared on the basis of objective pharmacological data obtained from properly controlled scientific experiments involving pure substances administered in specific doses under predefined conditions. Caveat: data subject to experimental error

Knowledge of chemical structure is neither necessary nor relevant to an objective analysis of experimental data on pharmacology.

Cannabinoid CB1 pharmacologyJWH-018Ki = 9 nM (binds tightly)EC50 = 4.4 nM (strong “agonist”)Animal tests: active in vivo on CB1

CB-13IC50 = 15 nM (bings tightly)EC50 = 6.1 nM (strong “agonist”)Animal tests: active in vivo on CB1

but… CB-13 does not cross blood-brain barrier

UR-144Ki = 150 nM (binds weakly) or 29 nM (binds tightly)EC50 = 1295 nM (weak “agonist”)Animal tests: active in vivo on CB1

Quiz: Are these Analogues of DET?

Controlled substance No: not hallucinogenic in humans

Yes:US v Klecker

No:US v Forbes

No:Prescription migraine medicine

Not yet:pharmacology data suggests no effect on brain receptors

Prong 2Given the dearth of available scientific data regarding UR-144 and XLR-11 during the relevant time period (and after), persons of ordinary intelligence could not reasonably have known that either substance meets prong two of the Act.

Daubert Issues

THE COURT: Listen to me. The question is, do you agree or do you not agree as to whether or not there is consensus within the scientific community that the methodology that you utilized to determine whether or not these compounds are substantially similar within the definition of the [Analogue] Act exists? Is there consensus or is there not?

Mr. Boos: I think today has demonstrated there is not.

United States v. Fedida, Case No. 6:12-cr-209, Transcript of Hearing, Dec. 6, 2012, pg 251

Q: Do you know whether or not your methodology of concluding that these things are substantially similar in chemical structure has been subjected to any sort of peer review and publication? Have you published your methodology?

A: We have not.

Q: Do you have any idea what the -- the potential rate of error might be in your approach to determining that these are substantially similar in their chemical structure?

A: We haven't analyzed it from that angle.United States v. Fedida, Case No. 6:12-cr-209, Transcript of Hearing, Dec. 6, 2012, pg 251-252

Q: Are you aware of any way that anyone couldtest the conclusions that you reach with respect tosubstantial similarity in chemical structure?

A: I am not aware of one.

The Smoke Shop, LLC v. United States, Case No. 12-CV-1186,Transcript of Hearing, February 28, 2013, pg 222-223

Q: Do you have any idea what the rate of errormight be in your methodology of determiningwhether two substances are substantially similar intheir chemical structure?

A: I am not aware of a rate of error.

The Smoke Shop, LLC v. United States, Case No. 12-CV-1186,Transcript of Hearing, February 28, 2013, pg 223

Brady Disclosures regarding UR-144

“I am writing to request that you produce prior to thehearing scheduled in this matter for Thursday, December6, 2012, any Brady material regarding:

any documents, including memoranda, correspondence,emails, electronic documents, notes, or digital, audio, orvideo recordings, reflecting any concern, doubt, contraryor conflicting opinions, or questions by anyone within theDepartment of Justice (DOJ) or the Drug EnforcementAdministration (DEA), or any entity or program within oraffiliated with the DOJ or the DEA, including the DEAOffice of Diversion Control (ODC), regarding whetherthe substances known as “XLR-11,” “UR-144,” or “5FUR-144” are controlled substance analogues;”

Brady Request, United States v. Fedida

Q: Do you believe that your methodology in determining that these substances are substantially similar in their chemical structure has general acceptance in the scientific community?

A: I believe I've arrived at a sound decision based on the science, and those individuals or scientists in my shop have also arrived at the same conclusion.

Q: Who decided that UR-144 was an analogue of JWH-018? Was that you?

A: That was a decision made by the chemists in our department after deliberation.

United States v. Fedida, Case No. 6:12-cr-209, Transcript of Hearing, Dec. 6, 2012, pg 250, 254

Q: Now, it's you, essentially, along with your colleagues I guess you said that decided that UR-144 and XLR-11 are analogues of JWH-018?

A: We decided that it could be treated as a potential analogue if intended for human consumption.

Q: Did anybody within the D.E.A. disagree with you?

A: Not that I’m aware of.

Q: Did anybody express any doubt or concern about it?

A: Not that I’m aware of.

The Smoke Shop, LLC v. United States, Case No. 12-CV-1186, Transcript of Hearing, February 28, 2013, pg 226-27

The disclosure thus suggests:

(1) DEA established an “analogue committee” to govern its assessments under the Act;

(2) the analogue committee has “protocols” to govern DEA’s process of assessing analogues;

(3) these protocols do not permit ODC to make analogue assessments without the involvement of OFS; and

(4) ODC is violating these protocols by excluding OFS on a “recurring” basis.

FDA Misbranding Statutes21 U.S.C. § 331(a)The introduction or delivery for introduction into interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded

21 U.S.C. § 352A drug or device shall be deemed to be misbranded –(a) False or misleading labelIf its labeling is false or misleading in any particular.

21 U.S.C. § 333(a)(1), (2)

(1) Any person who violates a provision of section 331 of this title shall be imprisoned for not more than one year or fined not more than $1,000, or both.

(2) Notwithstanding the provisions of paragraph (1) of this section, if any person commits such a violation after a conviction of him under this section has become final, or commits such a violation with the intent to defraud or mislead, such person shall be imprisoned for not more than three years or fined not more than $10,000, or both.

Index of Course Materials

1) Two-and three-dimensional renderings of the chemical structures of XLR-11 and JWH-018

2) Motion to Dismiss Second Amended Complaint or for a More Definite Statement and Request for Hearing

3) Documents provided by the Government in Response to Brady Request in US v Fedida

4) Expert Report of Joseph P. Bono 5) Expert Reports of Anthony P. DeCaprio, Ph.D6) Expert Report of Gregory B. Dudley, Ph.D7) Expert Report of Heather L. Harris 8) Expert Report of Terry Kenakin, Ph.D9) Expert Reports of James R. McCarthy, Ph.D10) Expert Report of Lindsay E. Reinhold 11) Expert Report of Terry R. Stouch, Ph.D12) Expert Report of Guido F. Verbeck, Ph.D13) Transcript of December 6, 2012, hearing in Hummel/Fedida14) Transcript of February 28, 2013, evidentiary hearing in The Smoke Shop 15) Brief of Amicus Curiae National Association of Criminal Defense Lawyers