UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC. AND APOTEX CORP.,
`Petitioners
`
`v.
`
`AUSPEX PHARMACEUTICALS, INC.,
`Patent Owner
`_____________________
`
`Case IPR2021-01507
`U.S. Patent No. 8,524,733
`Issued: September 3, 2013
`
`Title:
`BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`
`
`Doc. # DC-15149014
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`
`
`INTRODUCTION ......................................................................................... 1
`
` MANDATORY NOTICES ........................................................................... 6
`
`A.
`
`B.
`
`C.
`
`Real Party-In-Interest ............................................................................ 6
`
`Related Matters ...................................................................................... 6
`
`Designation of Lead and Back-Up Counsel .......................................... 6
`
`D. Notice of Service Information ............................................................... 6
`
` REQUIREMENTS FOR INTER PARTES REVIEW .............................. 7
`
`A. Grounds for Standing ............................................................................ 7
`
`B.
`
`Identification of Challenge .................................................................... 7
`
` BACKGROUND ............................................................................................ 8
`
`A. Knowledge in the Prior Art Would Have Led a POSITA to the
`Claimed Invention ................................................................................. 8
`
`1.
`
`2.
`
`3.
`
`4.
`
`Tetrabenazine Was a Long-Known Therapeutic
`Compound with Drawbacks ........................................................ 9
`
`Certain Positions of Tetrabenazine Were Known to Be
`Essential for Activity and Were Also Sites of Metabolism ......10
`
`Strategic Deuteration Was Known to Slow Metabolism in
`Compounds Like Tetrabenazine ...............................................12
`
`Deuteration Was Also Known to Impart Other
`Therapeutic Benefits .................................................................16
`
`B.
`
`The ’733 Patent ...................................................................................16
`
`1.
`
`2.
`
`The Specification ......................................................................16
`
`The Claims ................................................................................18
`
`- ii -
`
`

`

`C.
`
`The Prosecution History: The Examiner Was Missing Key
`Disclosures and Was Led to Error by Unsupported Arguments
`About Unexpected Results ..................................................................19
`
` DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ................................................................................23
`
`A.
`
`B.
`
`Legal Standards ...................................................................................23
`
`Ground 1: Claims 1-3 Would Have Been Obvious Over Zheng
`in View of Naicker ’921 and Kohl ......................................................25
`
`1.
`
`A POSITA Would Have Been Motivated to Combine
`Prior Art Teachings Regarding Tetrabenazine and
`Deuteration to Arrive at the Claimed Invention .......................26
`
`a.
`
`b.
`
`c.
`
`Zheng Would Have Motivated a POSITA to Select
`Tetrabenazine as a Lead Compound and Seek to
`Improve It .......................................................................26
`
`Naicker ’921 Would Have Motivated a POSITA
`To Deuterate Tetrabenazine in Order to Improve
`Its Activity and Highlights Methoxy Groups
`Specifically as Promising Sites for Deuteration .............28
`
`Kohl Discloses Benefits from Deuterating
`Methoxy Groups and Also Teaches the Other
`Claim Limitations ...........................................................32
`
`2.
`
`3.
`
`A POSITA Would Have Had a Reasonable Expectation
`of Arriving at the Claimed Compounds and
`Compositions ............................................................................35
`
`The Patentee Failed to Show Unexpected Results
`Sufficient to Rebut Obviousness ...............................................36
`
`a.
`
`b.
`
`The Results Were Not Unexpected ................................36
`
`Patentee’s Evidence of Reduced Side Effects Was
`Based on a Legally Irrelevant Comparison ....................39
`
`- iii -
`
`

`

`4.
`
`Ground 1 Presents New References and Disclosures That
`Were Not Before the Examiner and Highlights the
`Examiner’s Error in Accepting Evidence of Unexpected
`Results .......................................................................................40
`
`C.
`
`Ground 2: The ’733 Patent Claims Would Have Been Obvious
`Over Zheng in View of Foster AB and Kohl ......................................42
`
`1.
`
`A POSITA Would Have Been Motivated to Combine
`Prior Art Teachings Regarding Tetrabenazine and
`Deuteration to Arrive at the Claimed Invention .......................43
`
`a.
`
`b.
`
`c.
`
`Zheng Would Have Motivated a POSITA to Select
`Tetrabenazine as a Lead Compound and Seek to
`Improve It .......................................................................43
`
`Foster AB Would Have Motivated a POSITA to
`Deuterate Tetrabenazine in Order to Improve
`Tetrabenazine’s Activity and Highlights Methoxy
`Groups as Promising Sites for Deuteration ....................43
`
`Kohl Discloses Benefits from Deuterating
`Methoxy Groups and Also Teaches Other
`Dependent Claim Limitations .........................................45
`
`A POSITA Would Have Had a Reasonable Expectation
`of Arriving at the Claimed Compounds and
`Compositions ............................................................................46
`
`The Patentee Has Not Shown Unexpected Results
`Sufficient to Rebut Obviousness ...............................................47
`
`a.
`
`b.
`
`The Results Were Not Unexpected ................................47
`
`Patentee’s Evidence of Reduced Side Effects Was
`Based on a Legally Irrelevant Comparison ....................49
`
`Ground 2 Presents New References and Disclosures That
`Were Not Before the Examiner and Highlights the
`Examiner’s Error in Accepting Evidence of Unexpected
`Results .......................................................................................50
`
`2.
`
`3.
`
`4.
`
`- iv -
`
`

`

`D. Ground 3: Claims 1-3 Would Have Been Obvious Over Gano
`in View of Schwartz and Gant ’991 ....................................................51
`
`1.
`
`A POSITA Would Have Been Motivated to Combine
`Prior Art Teachings Regarding Tetrabenazine and
`Deuteration to Arrive at the Claimed Invention .......................52
`
`a.
`
`b.
`
`c.
`
`Gano Would Have Motivated a POSITA to Select
`Tetrabenazine as a Lead Compound and Seek to
`Improve It .......................................................................52
`
`Schwartz Teaches that the Methoxy Groups of
`Deutetrabenazine Were Sites of Metabolism .................53
`
`Gant ’991 Would Have Motivated a POSITA to
`Deuterate the Methoxy Groups of Tetrabenazine
`and Discloses the Other Claim Limitations. ...................54
`
`A POSITA Would Have Had a Reasonable Expectation
`of Arriving at the Claimed Compounds and
`Compositions ............................................................................58
`
`The Patentee Has Not Shown Unexpected Results
`Sufficient to Rebut Obviousness ...............................................59
`
`a.
`
`b.
`
`The Results Were Not Unexpected ................................59
`
`Patentee’s Evidence of Reduced Side Effects Was
`Based on a Legally Irrelevant Comparison ....................60
`
`Ground 3 Presents New References and Disclosures That
`Were Not Before the Examiner and Highlights the
`Examiner’s Error in Accepting Evidence of Unexpected
`Results .......................................................................................61
`
`2.
`
`3.
`
`4.
`
` CONCLUSION ............................................................................................62
`
`
`
`
`
`- v -
`
`

`

`LIST OF EXHIBITS
`
`
`Exhibit No.
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`U.S. Patent No. 8,524,733, “Benzoquinoline Inhibitors of Vesicular
`Monoamine Transporter 2” (the “’733 patent”)
`
`Declaration of Jeffrey P. Jones, Ph.D. (the “Jones Decl.”)
`
`Zheng, G. et al., Vesicular Monoamine Transporter 2: Role as a
`Novel Target for Drug Development, THE AAPS JOURNAL,
`8(4):E682-E692 (2006) (“Zheng”)
`
`Naicker, S. et al., U.S. Patent No. 6,503,921, “Deuterated rapamycin
`compounds, methods and uses thereof” (“Naicker ’921”)
`
`Kohl, B. et al., WO 2007/012650, “Isotopically Substituted Proton
`Pump Inhibitors” (2007) (“Kohl”)
`
`Foster A.B. et al., Isotope effects in O- and N-demethylations
`mediated by rat liver microsomes: An application of direct insertion
`electron impact mass spectrometry, CHEM.-BIOL. INTERACTIONS,
`9:327-340 (1974) (“Foster AB”)
`
`Gano, K.W., U.S. Patent No. 8,039,627, “Substituted 3-isobutyl-
`9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-
`a]isoquinolin-2-ol compounds and methods relating thereto”
`(“Gano”)
`
`Schwartz, D.E. et al., Metabolic studies of tetrabenazine, a
`psychotropic drug in animals and man, BIOCHEMICAL
`PHARMACOLOGY, 15:645-655 (1966) (“Schwartz”)
`
`Gant, T.G. et al., U.S. Pat. Pub. No. 2008/0280991, “Substituted
`Naphthalenes” (2008) (“Gant ’991”)
`
`- vi -
`
`

`

`Exhibit No.
`
`Description
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`Huntington Study Group, Tetrabenazine as antichorea therapy in
`Huntington disease – A randomized controlled trial, NEUROLOGY,
`66(3):366-372 (2006) (“Huntington Study”)
`
`Gant, T.G. et al., U.S. Pat. Pub. No. 2007/0149622 “Substituted
`phenethylamines with serotoninergic and/or norepinephrinergic
`activity” (2007) (“Gant ’622”)
`
`Mitoma, C. et al., Effect of deuteration of the O-CH3 group on the
`enzymic demethylation of o-nitroanisole. BIOCHIM. BIOPHYS. ACTA,
`136: 566-567 (1967) (“Mitoma”)
`
`Naicker, S. et al., U.S. Patent No. 6,613,739, “Deuterated
`cyclosporine analogs and their use as immunomodulating agents”
`(“Naicker ’739”)
`
`Chou, D.T.H. et al., U.S. Pat. Pub. No. 2007/0088075, “Deuterated
`aminocyclohexyl ether compounds and processes for preparing
`same” (“Chou”)
`
`Jones, J.P. et al., Isotopically Sensitive Branching and Its Effect on
`the Observed Intramolecular Isotope Effects in Cytochrome P-450
`Catalyzed Reactions: A New Method for the Estimation of Intrinsic
`Isotope Effects, J. AM. CHEM. SOC. 1986, 108, 7074-7078 (“Jones
`1986”)
`
`Jones, J.P. et al., Computational Models for Cytochrome P450: A
`Predictive Electronic Model for Aromatic Oxidation and Hydrogen
`Atom Abstraction, DRUG METABOLISM AND DISPOSITION, 2002, Vol
`30, No. 1 (“Jones 2002”)
`
`Paleacu, D., Tetrabenazine in the treatment of Huntington’s disease,
`NEUROPSYCHIATRIC DISEASE AND TREATMENT, 3(5):545–551 (2007)
`(“Paleacu”)
`
`- vii -
`
`

`

`Exhibit No.
`
`Description
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`Kilbourn, M.R. et al., Absolute Configuration of (+)-a-
`Dihydrotetrabenazine, an Active Metabolite of Tetrabenazine,
`CHIRALITY, 9(1):59-62 (1997) (“Kilbourn”)
`
`Foster R. et al., WO 95/26325, “Enhancement of the efficacy of
`drugs by deuteration” (1995) (“Foster R”)
`
`Ondo W.G. et al., Tetrabenazine Treatment for Huntington’s
`Disease-Associated Chorea, CLINICAL NEUROPHARMACOLOGY, Vol.
`25, No. 6, pp. 300-302 (2002) (“Ondo”)
`
`Burger’s Medicinal Chemistry and Drug Discovery, Volume 1, 5th
`edition, 1995, Ch. 6, pp. 129-180 (“Burger’s Ch. 6”).
`
`Burger’s Medicinal Chemistry and Drug Discovery, Volume 1, 5th
`edition, 1995, Ch. 9, pp. 251-300 (“Burger’s Ch. 9”).
`
`Foster, A.B., Deuterium Isotope Effect in Studies of Drug
`Metabolism, TRENDS PHARMACOL. SCI., pp. 524-527, Dec. 1984
`(“Foster AB 1984”)
`
`Fisher, M.B. et al., The complexities inherent in attempts to decrease
`drug clearance by blocking sites of CYP-mediated metabolism,
`CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT 2006 Vol
`9, No. 1, pp. 101-109 (“Fisher”)
`
`Atkins, W.M. et al., Metabolic Switching in Cytochrome P-450cam:
`Deuterium Isotope Effects on Regiospecificity and the
`Monooxygenase/Oxidase Ratio, J. AM. CHEM. SOC. 1987, 109, 3754-
`3760 (“Atkins”)
`
`Higgins, L. & Jones, J.P. et al., Evaluation of Cytochrome P450
`Mechanism and Kinetics Using Kinetic Deuterium Isotope Effects,
`BIOCHEM., 1998, 37, 7039-7046 (“Higgins & Jones 1998”)
`
`- viii -
`
`

`

`Exhibit No.
`
`1027
`
`Description
`
`Excerpts from the Application File History for the ’733 Patent, U.S.
`App. No. 12/562,621 (the “FH Excerpts”)
`
`
`
`
`
`
`
`- ix -
`
`

`

`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`
`Amgen, Inc. v. F. Hoffman–La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) .............................................................. 33, 44, 55
`
`Galderma Labs, L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .......................................................... 35, 36, 46, 57
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 22
`
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) ........................................................ 35, 36, 46, 57
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 37
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .......................................................................... 33
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 32
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .............................................................. 33, 44, 55
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015) .............................................................. 37, 46, 57
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) .....................................................................................passim
`
`Ohio Willow Wood Co. v. Alps South, LLC,
`735 F.3d 1333 (Fed. Cir. 2013) .............................................................. 34, 44, 56
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) .................................................................... 23, 24
`
`Perfect Web Techs., Inc. v. InfoUSA, Inc.,
`587 F.3d 1324 (Fed. Cir. 2009) .......................................................................... 23
`
`- x -
`
`

`

`Statutes
`
`35 U.S.C. § 102(b) ............................................................................................passim
`
`35 U.S.C. § 102(e) ............................................................................................. 48, 49
`
`35 U.S.C. § 103 ..............................................................................1, 7, 22, 24, 39, 48
`
`Other Authorities
`
`37 C.F.R. §§ 42.104(b) and 42.22(a)(1) .................................................................... 7
`
`- xi -
`
`

`

`
`
`INTRODUCTION
`
`Petitioners Apotex Inc. and Apotex Corp. request inter partes review and
`
`cancellation of Claims 1-3 of U.S. Patent No. 8,524,733 (the “’733 patent,” Ex.
`
`1001) for obviousness under pre-AIA 35 U.S.C. § 103. The ’733 patent claims the
`
`chemical compound deutetrabenazine, which is used for the treatment of various
`
`movement disorders, and compositions containing deutetrabenazine.
`
`The prior art provided a narrow, straight-line path for arriving at
`
`deutetrabenazine, and the inventors of the ’733 patent followed that path. They
`
`derived deutetrabenazine from tetrabenazine, a nearly identical compound used
`
`since the 1950s to treat, inter alia, the involuntary movements associated with
`
`Huntington’s disease. Seeking to improve the side-effect profile and slow the
`
`metabolism of tetrabenazine, the inventors employed a technique popularized in
`
`the 1960s known as “deuteration.” Deuteration involves the simple replacement of
`
`carbon-hydrogen (C–H) bonds with carbon-deuterium (C–D) bonds. By the
`
`September 18, 2008 priority date, many therapeutics had been modified by
`
`deuteration to improve activity and reduce side effects. The prior art even guided
`
`persons of skill in the art (“POSITA”) to deuterate certain functional groups,
`
`including methoxy groups, to obtain these benefits. Not surprisingly, the inventors
`
`here deuterated the two methoxy substituents of tetrabenazine and arrived at
`
`deutetrabenazine:
`
`- 1 -
`
`

`

`
`
`
`
`Tetrabenazine
`(prior art)
`
`Deutetrabenazine
`(See Ex. 1001, Claim 1)
`
`
`
`The deuteration path to therapeutic improvement was so well-trodden by the
`
`priority date that it had a “paint by numbers” character. Numerous references
`
`taught to (1) start with a therapeutically effective molecule, (2) identify important
`
`locations on that molecule, (3) deuterate at those locations, and (4) expect benefits
`
`such as improved activity and reduced side effects. Combinations of references
`
`that would guide a skilled person through this paint-by-numbers approach are
`
`included in each of the three grounds below.
`
`Ground 1: Zheng in view of Naicker ’921 and Kohl. Zheng teaches that
`
`tetrabenazine is an effective therapeutic compound. At the same time, Zheng also
`
`teaches that tetrabenazine has drawbacks, such as serious side effects, that would
`
`motivate a skilled person to seek to improve it. Importantly, Zheng additionally
`
`teaches that the methoxy groups of tetrabenazine are essential to its therapeutic
`
`activity. Naicker ’921 teaches to deuterate therapeutically important methoxy
`
`- 2 -
`
`

`

`groups and to expect benefits, such as reduced side effects. Similarly, Kohl
`
`teaches to deuterate at methoxy groups in order to slow metabolism of known
`
`therapeutics. Kohl further discloses the additional limitations of Claims 1-3
`
`relating to levels of deuterium enrichment and use in a pharmaceutical composition
`
`with a carrier.
`
`Ground 2: Zheng in view of Foster AB and Kohl. Zheng teaches that
`
`tetrabenazine is an effective therapeutic compound but that it had side effects,
`
`motivating a skilled person to seek to improve it. Zheng also teaches that the
`
`methoxy groups of tetrabenazine are essential to its therapeutic activity. Foster AB
`
`teaches to deuterate methoxy groups in order to slow metabolism and improve
`
`therapeutic activity. Similarly, Kohl teaches to deuterate at methoxy groups to
`
`slow metabolism, and also discloses the additional limitations of Claims 1-3.
`
`Ground 3: Gano in view of Schwartz and Gant ’991. Gano teaches that
`
`tetrabenazine is an effective therapeutic compound but that there is a need for
`
`tetrabenazine analogs that exhibit a longer half-life. Schwartz teaches that the
`
`methoxy groups are sites of metabolism in tetrabenazine. Gant ’991 teaches to
`
`deuterate sites of metabolism, including specifically methoxy groups, and to expect
`
`metabolic and therapeutic benefits such as a longer half-life. Gant ’991 also
`
`teaches the additional limitations of Claims 1-3.
`
`- 3 -
`
`

`

`During prosecution, many of these references and accompanying disclosures
`
`were not before the Examiner. In particular, the Examiner did not substantively
`
`consider any references disclosing the benefits of deuterating at methoxy groups,
`
`including those summarized in the figure below (with the methoxy groups
`
`annotated in red), which was prepared by Apotex’s expert, Dr. Jeffrey P. Jones:1
`
`
`
`
`
`
`1 Dr. Jones is Professor of Chemistry at Washington State University. He
`
`specializes in Medicinal Chemistry, especially metabolism of therapeutics,
`
`including isotope-labeled molecules.
`
`- 4 -
`
`

`

`(Ex. 1002 ¶¶ 47-51.) If the Examiner had been aware of the references identified
`
`above, she would not have allowed the claims.
`
`Moreover, the Examiner erred in accepting the patentee’s purported
`
`evidence of unexpected results. The patentee alleged that deutetrabenazine
`
`demonstrated slowed metabolism, increased bioavailability, lengthened half-life,
`
`and reduced side effects compared to tetrabenazine. But the prior art above
`
`teaches to expect each and every one of these results from deuterating at methoxy
`
`groups. Not only did the prior art teach to expect the kind of results alleged by the
`
`patentee but it also teaches to expect the degree reported by the patentee—
`
`approximately 50% reduction in the rate of metabolism and approximately doubled
`
`bioavailability. The patentee’s evidence was woefully deficient, and the Examiner
`
`erred in accepting it.
`
`In sum, there was nothing inventive about deuterating the methoxy groups of
`
`tetrabenazine. The ’733 patent’s claims would have been obvious in light of the
`
`prior art, and the Board should institute inter partes review to correct the
`
`Examiner’s error in granting them.
`
`- 5 -
`
`

`

` MANDATORY NOTICES
`
`A. Real Party-In-Interest
`
`Petitioners Apotex Inc. and Apotex Corp. are the real parties-in-interest.
`
`Additional real parties-in-interest are Apotex Pharmaceutical Holdings Inc. and
`
`Aposherm Delaware Holdings Corp.
`
`B. Related Matters
`
`Petitioner is unaware of any other matters related to the ’733 patent.
`
`C. Designation of Lead and Back-Up Counsel
`
`Petitioners identify the following:
`
`▪ Lead counsel:
`
`Vishal Gupta (Reg. No. 67,284)
`
`▪ Back-up counsel: John J. Molenda (Reg. No. 47,804)
`
`▪ Back-up counsel: Jordan P. Markham (Reg. No. 68,667)
`
`D. Notice of Service Information
`
`Petitioners identify the following:
`
`▪ Email address:
`
`▪ Mailing address:
`
`
`
`
`
`SJDeutetrabenazineIPR@Steptoe.com
`
`STEPTOE & JOHNSON LLP
`1114 Avenue of the Americas
`New York, NY 10036
`
`
`
`
`
`
`
`
`
`
`
`▪ Telephone number:
`
`212-506-3900
`
`▪ Fax number:
`
`
`
`212-506-3950
`
`- 6 -
`
`

`

`Please address all correspondence to lead counsel at the address shown
`
`above. Petitioners consent to electronic service at the above-listed email address.
`
` REQUIREMENTS FOR INTER PARTES REVIEW
`
`A. Grounds for Standing
`
`Petitioners certify that (1) the ’733 patent is available for inter partes review
`
`and (2) Petitioners are not barred or estopped from requesting review of any claim
`
`on the grounds identified in this Petition. The Office is authorized to charge all
`
`fees due in connection with this matter to Deposit Account No. 19-4293.
`
`B.
`
`Identification of Challenge
`
`Pursuant to 37 C.F.R. §§ 42.104(b) and 42.22(a)(1), Petitioners request
`
`review and cancellation of ’733 patent Claims 1-3 pursuant to the following
`
`statement of precise relief requested:
`
`Ground Claims
`
`Basis
`
`References
`
`1-3
`
`§ 103(a) Zheng in view of Naicker ’921 and Kohl
`
`1-3
`
`§ 103(a) Zheng in view of Foster AB and Kohl
`
`1-3
`
`§ 103(a) Gano in view of Schwartz and Gant ’991
`
`1
`
`2
`
`3
`
`
`
`- 7 -
`
`

`

` BACKGROUND
`
`A. Knowledge in the Prior Art Would Have Led a POSITA to the
`Claimed Invention
`
`As discussed below, the prior art provides a roadmap to make the compound
`
`that the ’733 patent claims—deutetrabenazine, a modified version of long-known
`
`tetrabenazine.
`
`
`
`
`
`Tetrabenazine
`(Prior art)
`
`Deutetrabenazine
`(Claim 1)
`
`
`
`Tetrabenazine was a known treatment for different syndromes and diseases,
`
`including various movement disorders. But it had drawbacks such as serious side
`
`effects and a short half-life. To address these drawbacks, the art teaches to replace
`
`certain hydrogen atoms of tetrabenazine with deuterium atoms, precisely the
`
`obvious modifications made to arrive at the claimed compound. (Ex. 1002 ¶¶ 31-
`
`70.)
`
`- 8 -
`
`

`

`1.
`
`Tetrabenazine Was a Long-Known Therapeutic Compound
`with Drawbacks
`
`Tetrabenazine was long known as a useful therapeutic compound. First
`
`introduced in 1956 as an antipsychotic drug, by the September 18, 2008 priority
`
`date,2 tetrabenazine had been “used to treat hyperkinetic movement disorders, such
`
`as chorea associated with Huntington’s disease, tics in Tourette’s syndrome, and
`
`movement stereotypes in tardive dyskinesia.” (Ex. 1003 (Zheng) at E683; see also
`
`Ex. 1017 (Paleacu) 2007 at 545; Ex. 1007 (Gano) at 1:31-32; Ex. 1010
`
`(Huntington Study) at 366; Ex. 1001 at 1:16-19; Ex. 1002 ¶ 32.)
`
`Despite its effectiveness, tetrabenazine had well-known drawbacks. First, it
`
`had side effects, such as “sedation, depression, akathisia, and parkinsonism.”
`
`(Ex. 1007 (Gano) at 1:32-34; Ex. 1003 (Zheng) at E683; Ex. 1001 at 1:41-46; Ex.
`
`1002 ¶ 34.) Second, tetrabenazine has a relatively short half-life, which
`
`necessitated administration of high or multiple (2-3) doses per day. (Ex. 1010
`
`(Huntington Study) at 371; Ex. 1007 (Gano) at 1:55-59, 7:66-8:1; Ex. 1002 ¶ 33.)
`
`The prior art acknowledges that lengthening tetrabenazine’s half-life would have
`
`
`2 The September 18, 2008 date of the provisional application from which the ’733
`
`patent claims priority is assumed to be the priority date by the petitioners and Dr.
`
`Jones for the purposes of this petition.
`
`- 9 -
`
`

`

`been advantageous since it would have allowed for the administration of a lower
`
`dose or fewer doses per day. (Ex. 1007 (Gano) at 7:64-66; Ex. 1002 ¶ 33.)
`
`Another advantage of lowering the dose would have been mitigation of side
`
`effects, because lower dosing results in less available substance responsible for
`
`side effects. (Ex. 1002 ¶ 34.)
`
`2.
`
`Certain Positions of Tetrabenazine Were Known to Be
`Essential for Activity and Were Also Sites of Metabolism
`
`It was known that tetrabenazine’s only methoxy groups, located at the C-9
`
`and C-10 positions, are “essential” for its activity. (Ex. 1003 (Zheng) at E685; Ex.
`
`1002 ¶ 35.)
`
`
`
`Thus, a POSITA would have focused on these positions when considering how to
`
`lengthen tetrabenazine’s half-life. (Ex. 1002 ¶ 36.)
`
`At the same time, a POSITA would have also understood, based on
`
`tetrabenazine’s structure, that these particular groups would have a high potential
`
`for reactivity in the body. (Ex. 1002 ¶¶ 37-41; see, e.g., Ex. 1003 (Zheng) at
`
`E685.) Indeed, one pathway of undesired metabolism of tetrabenazine involved
`
`- 10 -
`
`

`

`“O-demethylation of the methoxy groups,” i.e., removal of the methyl groups to
`
`form alcohols. (Ex. 1001 at 1:38-40 (citing Ex. 1008 (Schwartz); see also Ex. 1027
`
`(FH Excerpts) at 022; Ex. 1002 ¶ 41.)
`
`(Ex. 1002 ¶ 41.) Thus, a POSITA would have been additionally motivated to slow
`
`down metabolism of tetrabenazine by specifically inhibiting O-demethylation of
`
`the methoxy groups.3 (Ex. 1002 ¶¶ 40-41.)
`
`
`
`
`3 While there were two other known metabolic pathways for deutetrabenazine,
`
`viz., aliphatic hydroxylation at the isobutyl group and reduction at the ketone
`
`group, a POSITA would have focused only on the O-demethylation pathway.
`
`With respect to aliphatic hydroxylation at the isobutyl group, that pathway was
`
`destructive like the O-demethylation pathway, but it was energetically less
`
`favorable and thus less significant to therapeutic activity. (Ex. 1002 ¶ 41; Ex. 1016
`
`(Jones 2002) at 10.) As for ketone reduction, that pathway was productive unlike
`
`the O-demethylation pathway, since the reduced molecule is responsible for
`
`
`
`- 11 -
`
`

`

`3.
`
`Strategic Deuteration Was Known to Slow Metabolism in
`Compounds Like Tetrabenazine
`
`Strategic deuteration of drugs to slow metabolism, i.e., lengthen half-life,
`
`was well known, and a POSITA would have been motivated to use this technique.
`
`(See, e.g., Ex. 1004 (Naicker ’921) at 2:55-3:18; Ex. 1019 (Foster R) at 1-2, 18-19;
`
`Ex. 1013 (Naicker ’739) at 1:12-19, 6:42-44, 6:61-68; Ex. 1014 (Chou) ¶¶ 0007,
`
`0009; Ex. 1012 (Mitoma) at 566-67; Ex. 1002 ¶ 42.) Deuteration is an attractive
`
`approach for improving therapeutics because (1) after 50 years of use it has never
`
`been associated with adverse events and (2) the deuterated compound can
`
`generally be expected to exhibit the same therapeutic properties, because no new
`
`elements or chemical groups are introduced by the change. (Ex. 1002 ¶ 44;
`
`Ex. 1004 (Naicker ’921) at 2:57-67, 3:44-47; Ex. 1014 (Chou) ¶ 0009; Ex. 1011
`
`(Gant ’622) ¶ 0027; Ex. 1023 (Foster AB 1984) at 524, 526.)
`
`Deuteration was known to reduce the rate of metabolism, lengthening half-
`
`life. This was known to be particularly the case for metabolically labile bonds, i.e.,
`
`bonds that are broken as a result of a metabolic reaction. (Ex. 1002 ¶ 45.)
`
`
`tetrabenazine’s therapeutic activity such that a POSITA would not seek to block it.
`
`(Ex. 1002 ¶ 38; Ex. 1018 (Kilbourn) at 59; Ex. 1020 (Ondo) at 302; Ex. 1003
`
`(Zheng) at E684; Ex. 1001 at 1:34-37.)
`
`
`
`- 12 -
`
`

`

`Specifically, when the cleavage of a C–H bond is involved in a metabolic reaction,
`
`such as O-demethylation of tetrabenazine’s methoxy groups,4 it was known that
`
`metabolism is slowed at that position. (Ex. 1004 (Naicker ’921) at 3:9-13; Ex.
`
`1014 (Chou) ¶ 0010; Ex. 1009 (Gant ’991) ¶ 0092; Ex. 1011 (Gant ’622) ¶ 0026;
`
`Ex. 1002 ¶ 45; see also Ex. 1002 ¶¶ 54-60.) That is because bonds with heavier
`
`isotopes, such as deuterium, take more energy to break. (Ex. 1004 (Naicker ’921)
`
`at 2:61-3:2; Ex. 1009 (Gant ’991) ¶ 0086; Ex. 1014 (Chou) ¶ 0009; Ex. 1002 ¶
`
`45.)5 Indeed, it was known that “[a] reaction involving breaking a C−D bond can
`
`be up to 700 per cent slower than a similar reaction involving breaking a C−H
`
`
`4 O-demethylation was known to involve “the breaking of . . . a C–H bond.” (Ex.
`
`1012 (Mitoma) at 566; see also Ex. 1002 ¶ 47.)
`
`5 “[W]henever cleavage of an aliphatic C–H bond occurs, usually by oxidation
`
`catalyzed by a mixed-function oxidase, replacement of the hydrogen by deuterium
`
`will lead to [an] observable isotope effect.” (Ex. 1004 (Naicker ’921) at 3:10-13;
`
`see also Ex. 1014 (Chou) ¶ 0010; Ex. 1009 (Gant ’991) ¶ 0086; Ex. 1002 ¶ 75; see
`
`also Ex. 1002 ¶¶ 54-60.) The C–H bonds of methoxy groups are “aliphatic”
`
`because they are associated with carbons not involved in any double or triple
`
`bonds. (Ex. 1002 ¶ 75, FN 7.)
`
`
`
`- 13 -
`
`

`

`bond.” (Ex. 1004 (Naicker ’921) at 2:61-3:2 (emphasis added); see also Ex. 1014
`
`(Chou) ¶ 0009; Ex. 1009 (Gant ’991) ¶ 0086; Ex. 1002 ¶ 45.)6
`
`It was well-established by the September 18, 2008 priority date that
`
`deuterating methoxy groups in particular slowed drug metabolism for compounds
`
`like tetrabenazine. A wide range of representative examples are provided in the
`
`following table.
`
`Disclosure
`
`Deuterated
`Compound
`
`In 1967, Mitoma disclosed that deuterating the methoxy
`group of o-nitroanisole “resulted in approx. 50%
`reduction in the rate of O-demethylation” and “the
`difference in the rate of metabolism between unlabeled
`and deuterated o-nitroanisole must be due to differences
`in the rates of C–H and C–2H [i.e., C–D] bond
`breaking.” (Ex. 1012 at 567; Ex. 1002 ¶ 47.)
`
`
`
`
`6 This phenomenon, where replacing one of the atoms in the molecule of interest
`
`by one of its isotopes (e.g., replacing hydrogen with deuterium) results in the
`
`change in the rate of a chemical reaction (e.g., drug metabolism in the body), is
`
`referred to as an “isotope effect.” (Ex. 1002 ¶ 45.)
`
`- 14 -
`
`

`

`Disclosure
`
`Deuterated
`Compound
`
`In 1974, Foster AB disclosed that “[i]sotope effects of
`~2 have been found for the O-demethylation of p-
`nitroanisole, p-methoxyacetanilide, and p-
`dimethoxybenzene and the respective trideuteromethyl
`derivatives.” (Ex. 1006 at 327; Ex. 1002 ¶ 48.)
`
`In 2001, Naicker ’921 disclosed that deuterating a
`methoxy group of rapamycin provided benefits,
`including “reduce[d] formation of demethylated
`metabolites,” “[l]ower rates of oxidation, metabolism
`and clearance,” “greater and more sustained biological
`activity” “increase[d] potency” and “reduce[d] toxicity.”
`(Ex. 1004 at 4:25-36, 4:60-5:4; Ex. 1002 ¶ 49.)
`
`In 2005, Kohl disclosed deuteration at the methoxy
`group of H-pantoprazole resulted in an approximately
`50% reduction of the rate of metabolism by human
`microsomes. (Ex. 1005 at 13-14, 40, Examples 1 and 2,
`Table 1 on p. 40; Ex. 1002 ¶ 50.)
`
`In 2007, Gant ’991 disclosed that agomelatine, which
`was “likely metabolized by enzymatic oxidation of the
`C–H bonds of the O-methyl group,” demonstrated a
`20% increase in the half-life of an analogue deuterated
`at multiple positions, including the methoxy group,
`compared to non-isotopically enriched agomelatine. (Ex.
`1009 ¶¶ 0092, 0340; Ex. 1002 ¶ 51.)
`
`- 15