/1cat,ons under 37C FR 1 53 bl
`for new nonprov1s1onal a
`APPLICATION ELEMENTS
`See MPEP chapter 600 concernmg uttl1ty patent app/Jcation contents
`1. ~ *Fee Transmittal Form (e.g., PTO/SB/17)
`(Submit an or,ginal, and a duplicate for fee processing)
`7.
`[Total Pages ~
`2. ~ Specification
`(preferred arrangement set forth below)
`- Descriptive title of the Invention
`- Cross References to Related Applications
`- Statement Regarding Fed sponsored R&D
`- Reference in Microfiche Appendix
`- Background of the Invention
`- Brief Summary of the Invention
`- Brief Description of the Drawings (if filed)
`- Detailed Description
`- Claim(s)
`- Abstract of the Disclosure,
`
`6.
`
`8.
`
`9.
`
`10.
`
`On/
`
`3.
`
`4.
`
`ADDRESS TO:
`
`D Microfiche Computer Program (Appendix)
`
`Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, all necessary)
`
`a. D Computer Readable Copy
`b. D Paper Copy (identical to computer copy)
`c. D Statement verifying identity of above copies
`ACCOMPANYING APPLICATION PARTS
`Assignment Papers (cover sheet & document(s))
`37 C.F.R. §3 73(b) Statement D Power of Attorney
`
`(when there is an assignee)
`English Translation Document (1f applicable)
`
`D Copies of IDS
`
`Citations
`
`(cid:143) (cid:143)
`(cid:143) (cid:143)
`
`0)
`
`.{)5 - 0
`
`I - CL c_
`
`PTO/SB/05 (2198)
`Approved for use through 09/30/2000. 0
`0651a!I
`E
`Patent and Trademark Office: US DEPARTMENT~~
`
`Attorney Docket No.
`
`PC11872A
`
`First Named Inventor or Application Identifier
`
`D Bogle et al
`
`~ -
`C±J
`- ' - 1 .
`-
`n
`+
`~-~
`w Please type a plus sign (+) inside this box (cid:157)
`n
`=i_ ----------------------,------------...----------------....... cx:a....:=~
`UTILITY
`~ -
`==-
`PATENT APPLICATION
`~
`TRANSMITTAL
`
`Title
`
`·
`
`'
`
`u
`-
`TARTRATE SALTS OF 5,8,14-
`11 .04
`9]-HEXADECA-2(11 r,l>,5,7.~
`TRIAZATETRACYCL0[10.3.1 02
`PENTAENE AND PHARMACEUTICAL COMPOSITIONS THEREOF
`EL 768 265 645 US
`Express Mail Label No.
`Commissioner for Patents
`Box Patent Application
`Washin ton, DC 20231
`
`rzo7
`Information Disclosure
`11.
`l'V1
`~Drawing(s) (35 U.S.C 11.3)[Total sheets ~
`Statement (IDS)/PT0-1449
`D Oath or Declaration
`[Total pages C=:J
`12. ~ Preliminary Amendment
`a D Newly executed (original or copy)
`13. ~ Return Receipt Postcard (MPEP 503)
`( Should be specifically itemized)
`14 0 *Small Entity
`Statement filed in prior apphcat1on,
`O
`Status still proper and desired
`15. D Certified Copy of Priority Document(s)
`
`b. Ocopy from a prior application (37 CFR
`§1.63(d))
`(for contmuationldivisional with Box 17 compfeted)
`[Note Box 5 below]
`
`i.
`Signed statement attached deleting
`inventor(s) named in the prior application,
`see 37 C.F.R. §§1.63(d){2) and 1.33(b).
`
`(cid:143) DELETION OF lNVENTOR/S)
`5. D Incorporation By Reference (useable1fBox4bischecked)
`
`The entire disclosure of the prior application, from which a
`copy of the oath or declaration is supplied under Box 4b, is
`considered to be part of the disclosure of the accompanying
`application and is hereby incorporated by reference therein.
`
`Statement(s}
`(PTOISB/09-12)
`
`(if foreign pnority is claimed)
`
`16.
`
`[8J Other:
`
`This application claims the benefit of U S
`Provisional Ser. No. 60/290,861, filed May 14.
`2001.
`
`R ITEMS 1 & 14: IN ORDER TO BE ENTITLED TO PAY SMALL ENTITY
`NT/TY STATEMENT IS REQUIRED (37 C.F.R. § 1.27), EXCEPT
`A PRIOR APPLICATION IS RELIED UPON (37 C.F.R. § 1.28).
`If a CONTINUING APPLICATION, check appropriate box, and suppfy the requisite information below and in a pre/1mmary amendment
`D Continuation D Divisional D Continuation-in-part (GIP)
`of prior application No. - - " - - - -
`
`17.
`
`Prior application information-
`
`Examiner
`
`Group/Art Unit:
`
`D Customer Number or Bar Code Label
`
`CORRESPONDENCE ADDRESS
`18.
`(Insert Customer No. or Attach bar code label here) ~ Correspondence address below
`or
`
`Paul H. Ginsburo
`Name
`Pfizer Inc
`Address
`150 East 42nd Street, Patent Deoartment ( 150/05/49)
`Address
`I Zip Code
`l 10011-5612
`I NewYork
`I State
`City
`New York
`I c212)573-1939
`I Fax
`I (212)573-2369
`I Telephone
`United States Of America
`Country
`I 42,208
`,4/
`I Roy F. Waldron
`/J
`J..Registration No. (Attorney/Agent)
`NAME (Print/type)
`I Date
`I May 6, 2002
`.-r/1~,1 IL (/
`I
`- - -
`Sianature
`
`EXPRESS MAIL NO. EL 768 265 645 US
`
`UTILITY TRANSMITTAL PTO SB 05, 3/99, (1/1)
`
`Apotex Exhibit 1004.001
`
`

`

`- -W .
`
`~
`\U w
`C
`{ll
`
`FEE TRANSMITTAL
`
`~
`~ . = ~ Patent fees are subject to annual revision on October 1.
`
`o
`These are the fees effective October 1. 2001.
`Small Entity payments must be supported by a small entity statement,
`otherwise large entity fees must be paid. See Forms PTOISB/09-12.
`See 37 C.F.R. §§ 1.27 and 1.28.
`I ($)2448.oo
`Total Amount of Payment
`METHOD OF PAYMENT (check one)
`The commissioner is hereby authorized to charge
`indicated fees and credit any over payments to:
`
`1. 0
`Account I 16-1445
`Deposit I
`
`Deposit
`
`Number
`
`Account
`Name
`
`PFIZER INC
`
`~:harge Any Additional
`'.:'"f'ee Required Under
`F7 C.F.R. §§ 1.16 and 1.17.
`
`I
`I
`D Charge the Issue Fee Set in
`37 C.F.R § 1.18 at the Mailing
`of the Notice of Allowance.
`
`PTO/S6117(2/98)
`Approved for use through 09/30/2000
`..
`0MB 0651-0032 Patent and Trademark Office· U S DEPARTMENT OF COMMERCE
`Complete if Known
`NOT YET ASSIGNED
`
`Application Number
`
`Filing Date
`
`CONCURRENTLY HEREWITH
`
`First Named Inventor
`
`D. Bogle et al.
`
`Examiner Name
`
`NOT YET ASSIGNED
`
`Group/Art Unit
`Attorney Docket No.
`
`NOT YET ASSIGNED
`PC11872A
`
`FEE CALCULATION (continued)
`
`3. ADDITIONAL FEES
`Small Entity
`Large Entity
`Fee
`Fee
`Fee
`Fee
`Code
`Code
`{$)
`($)
`
`Fee Description
`
`Fee Paid
`
`105
`
`130
`
`205
`
`65
`
`Surcharge - late fee or oath
`
`127
`
`139
`
`147
`
`112
`
`50
`
`227
`
`25
`
`130
`
`2,520
`
`920*
`
`139
`
`147
`
`112
`
`113
`
`130
`
`2,520
`
`920*
`
`cover sheet
`Non-English specification
`For filing a request for reexamination
`
`I
`
`I
`
`I
`I
`
`u
`2. ,4[]
`Payment Enclosed:
`0 Check D Money Order D Other
`FEE CALCULATION
`
`§; ~ --
`F"3
`1. B'ASIC FILING FEE
`"
`L,~e Entitv
`Fee
`F~_g7]
`{$)
`Casi
`
`Small Entity
`Fee
`Fee
`($)
`Code
`
`Fee Description
`
`Fee Paid
`
`1ffi
`
`1~
`~'":. ~
`107''
`
`740
`
`201
`
`370
`
`Utility filing fee
`
`330
`
`206
`
`165 Design filing fee
`
`510
`
`207
`
`255
`
`Plant filing fee
`
`370
`
`Reissue filing fee
`
`115
`116
`
`117
`118
`
`128
`
`119
`
`120
`
`121
`
`113
`
`1,840*
`
`110
`400
`
`920
`1,440
`
`215
`216
`
`217
`218
`
`Requesting publication of SIR prior to
`Examiner action
`1,840* Requesting publication of SIR after
`Examiner action
`Extension for reply within first month
`Extension for reply within second
`month
`Extension for reply within third month
`
`55
`200
`
`460
`720
`
`1,960
`
`228
`
`980
`
`Extension for reply within fifth month
`
`320
`
`320
`
`280
`
`219
`
`220
`
`221
`
`160
`
`Notice of Appeal
`
`160
`
`140
`
`Filing a brief in support of an appeal
`
`Request for oral hearing
`
`Surcharge-late provisional filing fee or I
`I
`I
`l
`I
`I
`I
`I
`Extension for reply within fourth month I
`I
`I
`I
`I
`I
`I
`I
`I
`
`1,510 Petition to institute a public use
`proceeding
`Petition to revive - unavoidable
`Petition to revive - unintentional
`Utility issue fee (or reissue)
`
`55
`640
`
`640
`
`230
`
`310
`
`Design issue fee
`
`Plant issue fee
`
`138
`
`1,510
`
`138
`
`110
`1,280
`
`1,280
`
`460
`
`620
`
`240
`241
`
`242
`
`243
`
`244
`
`140
`141
`
`142
`
`143
`
`144
`
`122
`
`I
`I
`
`130
`
`122
`
`130
`
`Petitions to the Commissioner
`
`50
`
`123
`
`50
`
`I 740.ool
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`Fee Paid
`
`108
`
`114
`
`740
`
`208
`
`160
`
`214
`
`80
`
`Provisional filing fee
`
`SUBTOTAL (1) I ($)740.00
`
`2. EXTRA CLAIM FEES
`
`Tota! Claims ~ -20-= I 70
`Independent CD . 3-= I
`
`Extra
`Claims
`
`2
`
`Fee from
`below
`18
`
`84
`
`Claims
`
`Multiple Dependent
`
`I
`I
`I
`I
`I
`l
`I
`I
`I
`I
`I
`I
`I
`I
`I
`l
`I
`I
`I
`
`123
`
`126
`
`581
`
`146
`
`149
`
`180
`
`40
`
`740
`
`740
`
`126
`
`581
`
`246
`
`249
`
`180
`
`40
`
`370
`
`370
`
`Petitions related to provisional
`applications
`Submission of Information Disclosure
`Statement
`Recording each patent assignment per
`property {times number of properties)
`Filing a submission after final rejection
`(37 CFR 1.129{a)}
`For each additional invention to be
`examined {37 CFR 1.129(b))
`
`Other Fee (specify)
`
`Other Fee (specify)
`
`*Reduced by Basic Filing Fee Paid
`
`Date
`
`I May 6, 2002
`
`SUBTOTAL (3} I ($)0.00
`Complete (if Applicable)
`I 42,208
`Reg. Number
`I16-1445/PFIZER INC
`Deposit Account
`User ID
`
`I = I 1260.00
`I xi
`I xi
`I = I 168.00
`I 280.ool = I 280.00
`•• or number previously paid, if greater; For Reissues, see below
`Small Entity
`Large Entity
`Fee
`Fee
`Fee
`Fee
`($)
`Code
`Code
`($)
`9
`203
`18
`103
`
`Claims in excess of 20
`
`Fee Description
`
`42
`
`Independent daims in excess of 3
`
`140 Multiple dependent claim, if not paid
`
`102
`
`84
`
`104
`
`109
`
`110
`
`280
`
`84
`
`18
`
`202
`204
`
`209
`
`210
`
`SUBMITTED BY
`Tvoe or Printed Name
`Signature
`
`42
`
`9
`
`**Reissue independent claims over
`original patent
`**Reissue claims in excess of 20 and
`over original patent
`SUBTOTAL (2) I ($)
`1708.00
`
`I
`
`~
`
`I Rov F. Waldron-
`-,,,r A-> ~ /l
`I
`tJ -
`-
`
`EXPRESS MAIL NO. EL 768 265 645 US
`
`FEE TRANSMITTAL PTO SB 17. 3/99
`
`Apotex Exhibit 1004.002
`
`

`

`''EXPRESS MAIL" LABEL NO. EL 768 265 645 US, Date of Deposit: May 6, 2002.
`I hereby certify that this correspondence 1s bemg
`deposited with the United States Postal Service "Express Mail Post Office to Addressee" service under 37 CF R 1.10 on the date mdicated
`above and 1s addressed to Comm1ss10ner for Patents, Box Patent Application, W hmgton, D.C. 20231.
`By
`
`Patent Application
`Attorney Docket No. PC 11872A
`
`(Typed or printed name of person)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`IN RE APPLICATION OF: D. Bogle et al.
`
`SER. NO.: Not Yet Assigned
`
`FILING DATE: Concurrently Herewith
`
`TITLE: TARTRATE SALTS OF 5,8,14-
`9
`11 .04
`TRIAZATETRACYCLO[l 0.3. l .02
`•
`](cid:173)
`•
`HEXADECA-2(11 ),3,5,7,9-PENTAENE AND
`PHARMACEUTICAL COMPOSITIONS
`THEREOF
`
`Examiner: Not Yet Assigned
`
`Group Art Unit: Not Assigned
`
`Commissioner for Patents
`Box Patent Application
`Washington, D.C. 20231
`
`Sir:
`
`PRELIMINARY Alv1ENDMENT
`
`Prior to examination on the merits and calculation of filing fe~s, please enter the
`
`follm~ring amendments to the abstract, specification and claims. Marked up versions of the
`
`amendments to the abstract, specification and claims are found in the Appendix attached hereto.
`
`IN THE SPECIFICATION
`
`at page 1, line 3, insert the following new paragraph:
`
`This application claims the benefit of U.S. Provisional Application Ser. No. 60/290,861,
`
`filed May 14, 2001.
`
`REMARKS
`
`Applicants have inserted a statement on page 1 of the application to indicate the
`
`priority required by 37 C.F.R. § 1.78. This amendment adds no new matter to the application.
`
`Applicants believe the set of pending claims are condition for allowance and request the
`
`issuance of a Notice of Allowance.
`
`Apotex Exhibit 1004.003
`
`

`

`Patent Application
`Attorney Docket No. PCl 1872A
`
`If a telephone interview would assist the furtherance of the prosecution of this
`application, the Examiner is invited to contact the undersigned.
`
`Respectfully submitted,
`
`Date: _ _ .r_~_t ___ /_UnJ_'1 __
`t /
`
`Pfizer, Inc
`Patent Department
`150 East 42nd Street (150/05/49)
`New York, NY 10017
`(212) 733-5086
`
`-2-
`
`Apotex Exhibit 1004.004
`
`

`

`.lo
`
`Patent Application
`Attorney Docket No. PC11872A
`
`APPENDIX TO PRELIMINARY AMENDMENT
`
`MARKED-UP VERSIONS OF AMENDED SPECIFICATION AND CLAIMS
`IN THE SPECIFICATION
`
`at page 1, line 7, insert the following new paragraph:
`This application claims the benefit of U.S. Provisional Application Ser. No. 60/290,86L
`filed Mav 14. 2001.
`
`- 3 -
`
`Apotex Exhibit 1004.005
`
`

`

`PC11872A
`
`EXPRESS MAIL CERTIFICATION
`
`"Express Mail" Label No. EL 768 265 645 US, Date of Deposit: May 6, 2002. I hereby certify
`that the accompanying Specification: 37 pages; Claims: 7 pages; Abstract 1 page; Drawings: 20
`pages; Utility Patent Application Transmittal; Fee Transmittal (2 copies) and Preliminary
`Amendment; is being deposited with the United States Postal Service "Express Mail Post Office to
`Addressee" service under 37 C.F.R. 1. 10 on the date indicated above and is addressed to:
`Commissioner for Patents, Box Patent Application, Washington, D.C. 20031.
`
`By
`
`person transmitting and mailing)
`ROYF. WALDRON
`(Typed or printed name of person)
`
`Apotex Exhibit 1004.006
`
`

`

`PC11872A
`
`-1-
`
`'
`
`'
`
`9]-HEXADECA-
`11 .04
`TARTRATE SALTS OF 5,8,14-TRIAZATETRACYCLO[10.3.1.02
`2(11),3,5,7,9-PENTAENE AND PHARMACEUTICAL COMPOSITIONS THEREOF
`salts of 5,8, 14-
`
`present
`The
`triazatetracyclo[10.3.1.02
`
`the
`to
`directed
`is
`invention
`9]-hexadeca-2{11 ),3,5, 7,9-pentaene:
`11 .04
`•
`•
`
`tartrate
`
`5
`
`1 O
`
`15
`
`20
`
`25
`
`30
`
`35
`
`•
`
`and pharmaceutical compositions thereof. The present invention in particular is directed to
`the L-tartrate salt, and further to the various polymorphs of the L-tartrate salt, including two
`distinct anhydrous polymorphs (referred to herein as Forms A and B) and a hydrate
`In addition, the present invention is also directed
`polymorph (referred to herein as Form C).
`11.o4
`9]-hexadeca-2(11 ),3,5, 7,9-
`the D-tartrate salt of 5,8, 14-triazatetracyclo[10.3.1.02
`•
`to
`pentaene and the various polymorphs thereof; as well as the D,L-tartrate salt thereof and its
`polymorphs, and the meso-tartrate salt thereof and its polymorphs.
`11 .04·9]-hexadeca-2{11 ),3,5,7,9-
`5,8, 14-triazatetracyclo[10.3.1.02
`compound,
`The
`•
`pentaene, binds to neuronal nicotinic acetylcholine specific receptor sites and is useful in
`modulating cholinergic function. This compound is useful in the treatment of inflammatory bowel
`disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's
`disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue,
`pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep
`disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, drug/toxin-induced
`cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs,
`lead, arsenic, mercury), disease-induced cognitive impairment (e.g., arising from Alzheimer's
`disease (senile dementia), vascular dementia, Parkinson's disease, multiple sclerosis, AIDS,
`encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick's disease,
`Korsakoff's syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia,
`obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,
`progressive supramuscular palsy, chemical dependencies and addictions ( e.g., dependencies
`on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates,
`opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive(cid:173)
`compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,
`dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including
`petit mal absence epilepsy, attention deficit hyperactivity disorder (ADHD}, Tourette's Syndrome,
`in smoking
`including use
`particularly, nicotine dependency, addiction and withdrawal;
`cessation therapy.
`The tartrate salts of this invention may also be used in a pharmaceutical composition in
`combination with an antidepressant such as, for example, a tricyclic antidepressant or a
`
`Apotex Exhibit 1004.007
`
`

`

`-2-
`
`serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and
`
`depression associated with AD, PD, stroke, Huntington's chorea or traumatic brain injury (TBI}; in
`
`combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic
`
`receptors for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive
`
`5
`
`decline, AD, PD, stroke, Huntington's chorea and TBI; in combination with neurotrophic factors
`such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of
`ALS, cognitive dysfunction, age-related cognitive decline, AD, PD stroke, Huntington's chorea
`
`and TBI; or in combination with agents that slow or arrest AD such as cognition enhancers,
`
`amyloid aggregation inhibitors, secretase inhibitors, tau kinase inhibitors, neuronal anti-
`
`1 O
`
`inflammatory agents and estrogen-like therapy.
`
`including 5,8, 14-
`to neuronal nicotinic receptor sites,
`that bind
`Compounds
`11.04
`triazatetracyclo[10.3.1.02
`9]-hexadeca-2( 11 ),3,5, 7,9-pentaene, and its hydrochloride salt,
`'
`are referred to in WO 99/35131, published July 15, 1999 (corresponding to U.S Ser. No.
`09/402,010, filed September 28, 1999 and 09/514,002, filed February 25, 2000).
`The
`
`'
`
`15
`
`foregoing applications, owned in common with the present application and incorporated
`herein by reference in their entirety, generically recite pharmaceutically acceptable acid
`
`addition salts for the compounds referred to therein.
`
`The L-tartrate salt of the present invention exhibits properties, including those of high
`
`solid-state stability and compatibility with certain drug product formulation excipients, that
`11.04
`render it superior to previously known salts of 5,8,14-triazatetracyclo[10.3.1.02
`9
`·
`hexadeca-2{11),3,5,7,9-pentaene.
`Further, the D-tartrate and D,L-tartrate salts exhibit
`
`](cid:173)
`
`·
`
`properties that also make them appropriate for drug product formulation use.
`
`20
`
`25
`
`30
`
`35
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`Figure 1 is a powder X-ray diffraction of the anhydrous L-tartrate salt Form A of
`5,8, 14-triazatetracyclo[10.3.1.02
`11 .04
`9]-hexadeca-2( 11 ),3,5, 7,9-pentaene
`•
`•
`counts per second; X in degrees 2 theta).
`Figure 2 is the powder X-ray diffraction of the anhydrous L-tartrate salt Form B of
`11 .04
`9]-hexadeca-2(11 ),3,5, 7,9-pentaene (y axis
`5,8, 14-triazatetra-cycfo[10.3. 1.02
`is
`linear
`counts per second; X in degrees 2 theta).
`
`(y axis
`
`is
`
`linear
`
`'
`
`'
`
`Figure 3 is the powder X-ray diffraction of the L-tartrate salt hydrate Form C of
`9]-hexadeca-2( 11 ),3,5, 7,9-pentaene (y axis
`11 .04
`5,8, 14-triazatetra-cyclo[10.3. 1.02
`is
`linear
`'
`counts per second; X in degrees 2 theta).
`Figure 4A is the calculated powder X-ray diffraction pattern of the anhydrous Form B
`L-tartrate salt of 5,8, 14-triazatetra-cyclo[10.3.1.02
`11 .04
`9]-hexadeca-2( 11 ),3,5, 7 ,9-pentaene (y
`'
`axis is linear counts per second; X in degrees 2 theta}. Figure 4B is the calculated powder X(cid:173)
`
`'
`
`'
`
`ray diffraction pattern of the Form C L-tartrate salt hydrate of 5,8, 14-triazatetra-
`
`Apotex Exhibit 1004.008
`
`

`

`-3-
`
`'
`
`11.04
`cyclo[10.3.1.02
`9]-hexadeca-2( 11 ),3,5, 7 ,9-pentaene (y axis is linear counts per second; X
`•
`in degrees 2 theta).
`Figure 5A is the calculated powder X-ray diffraction pattern (lower trace) laid over the
`
`observed X-ray diffraction pattern {upper trace) for the anhydrous Form B L-tartrate salt of
`5,8,14-triazatetra-cyclo[10.3.1.02
`11 .04·9]-hexadeca-2(11),3,5,7,9-pentaene (y axis
`linear
`is
`•
`counts per second; X in degrees 2 theta). Figure 5B is the calculated powder X-ray
`diffraction pattern (lower trace) laid over the observed X-ray diffraction pattern (upper trace)
`for the Form C L-tartrate salt hydrate of 5,8, 14-triazatetra-cyclo[10.3.1.02
`11 .04
`9]-hexadeca-
`•
`2(11 },3,5,7,9-pentaene (y axis is linear counts per second; X in degrees 2 theta).
`Figure 6 is the overlay of the powder X-ray diffraction patterns of the Form A (lower
`trace), Form B (middle trace) and Form C (upper trace) L-tartrate salts of 5,8,14-triazatetra(cid:173)
`cyclo[10.3.1.02
`11 .04
`9]-hexadeca-2(11 ),3,5, 7,9-pentaene (y axis is linear counts per second; X
`'
`'
`in degrees 2 theta).
`Figures 7A, 7B and 7C are the solid state 13C NMR spectra of the L-tartrate salts of
`11 .04
`9]-hexadeca-2(11 ),3,5,7 ,9-pentaene Forms A, B and C,
`5,8, 14-triazatetra-cyclo[10.3.1.02
`respectively, as measured by cross-polarization magic angle spinning (CPMAS) at 295 K on a
`
`'
`
`'
`
`'
`
`Bruker 7mm wide-bore magic angle spinning (WB MAS) probe positioned in a Bruker Avance
`
`DRX 500 MHz NMR Spectrometer. Peaks marked with asterisks{*) are spinning sidebands
`which are displaced at multiples of the spinning frequencies along both sides of the real
`
`'
`
`peaks ( centerbands ).
`Figure SA is the X-ray crystal structure (absolute configuration) for the anhydrous
`11 .04·9]-hexadeca-2( 11 ),3,5, 7,9-
`Form B L-tartrate salt of 5,8, 14-triazatetra-cyclo[10.3.1.02
`•
`pentaene. Figure 8B is the X-ray crystal structure (absolute configuration) for the Form C
`11 .04·9]-hexadeca-2(11 ),3,5, 7,9-
`L-tartrate salt hydrate of 5,8, 14-triazatetra-cyclo[10.3.1.02
`pentaene.
`Figure 9A, 9B and 9C are the differential scanning calorimetric traces for the
`11 .04
`L-tartrate salts Forms A, B and C, respectively, of 5,8, 14-triazatetra-cyclo[10.3.1.02
`9
`'
`•
`hexadeca-2(11 ),3,5, 7 ,9-pentaene.
`Figure 10A and 10B are the powder X-ray diffraction patterns of the D,L-tartrate salt
`respectively, of 5,8, 14-triazatetracyclo[10.3.1.02
`11 .04·9]-hexadeca-
`Forms X and Y,
`•
`2(11 ),3,5,7,9-pentaene (y axis is linear counts per second; X in degrees 2 theta).
`Figure 11A and 11B are the differential scanning calorimetric traces for the
`11 .04
`D,L-tartrate salts Forms X and Y, respectively, of 5,8,14-triazatetra-cyclo[10.3.1.02
`hexadeca-2(11 ),3,5,7,9-pentaene.
`
`](cid:173)
`
`'
`
`·~(cid:173)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Apotex Exhibit 1004.009
`
`

`

`-4-
`
`SUMMARY OF THE INVENTION
`The
`present
`invention
`relates
`to
`the
`tartrate
`salts
`of
`5,8, 14-
`triazatetracyclo[10.3.1.02
`11 .04
`9]-hexadeca-2(11 ),3,5,7,9-pentaene. The tartrate salts of the
`•
`•
`invention include the L-tartrate, D-tartrate, D,L-tartrate and meso-tartrate salts.
`In particular,
`the present
`invention relates
`to
`the L-tartrate salt of 5,8, 14-
`triazatetracyclo[10.3.1.02
`11 .04
`9]-hexadeca-2(11 ),3,5,7,9-pentaene.
`In
`one
`embodiment
`of
`the
`invention,
`the
`L-tartrate
`of
`5,8, 14-
`triazatetracyclo[10.3.1.02
`11 .04
`9]-hexadeca-2(11 ),3,5,7,9-pentaene is the anhydrous L-tartrate
`•
`'
`salt, referred to herein as Form A. The L-tartrate Form A is characterized by the principal x-
`ray diffraction pattern peaks expressed in terms of 20 and ct-spacings as measured with
`copper radiation (within the margins of error indicated}:
`
`'
`
`'
`
`5
`
`1 O
`
`Angle 29 (! 0.2)
`
`d-value (A) (! 0.2)
`
`6.1
`12.2
`13.0
`14.7
`16.8
`19.4
`21.9
`24.6
`
`14.5
`7.2
`6.8
`6.0
`5.3
`4.6
`4.1
`3.6
`
`The L-tartrate crystal Form A is characterized in that it has a onset of melt at about
`223 °C as measured by differential scanning calorimetry at a heating rate of 5 degrees per
`minute. The L-tartrate Form A is also characterized in that when examined by solid state
`13C NMR cross-polarization magic angle spinning techniques, it exhibits the following principal
`resonance peaks (± 0.1ppm) downfield from 100 ppm (adamantane standard 29.5 ppm):
`178.4, 149.3, 147.4, 145.1, and 122.9 ppm.
`In
`another
`embodiment
`of
`the
`invention,
`the
`L-tartrate of 5,8, 14-
`triazatetracyclo[10.3.1.02
`11.04
`9]-hexadeca-2(11 ),3,5, 7,9-pentaene is another anhydrous L-
`'
`'
`tartrate salt polymorph, referred to herein as Form B. The L-tartrate salt Form B is
`characterized by the principal x-ray diffraction pattern peaks expressed in terms of 29 and d(cid:173)
`spacings as measured with copper radiation (within the margins of error indicated):
`
`15
`
`20
`
`Apotex Exhibit 1004.010
`
`

`

`-5-
`
`le 29 (::_ 0.2)
`
`d-value (A) (::_ 0.2)
`
`5.9
`12.8
`14.4
`15.3
`16.9
`17.2
`21.8
`23.8
`25.1
`
`15.0
`6.9
`6.1
`5.8
`5.2
`5.2
`4.1
`3.7
`3.5
`
`The L-tartrate salt Form B has a single crystal x-ray structure (absolute configuration)
`as set forth in Figure 8A Further, the Form B forms orthorhombic crystals belonging to the
`P2(1)2(1)2(1) space group. Form Bis further characterized in having an onset of melting at
`about 215 °C as measured by differential scanning calorimetry at a heating rate of 5 degrees
`per minute. Further, Form B of the invention is also characterized in having an aqueous
`solubility of about 156 mg/ml and a native pH of about 3.3 in aqueous solution. In addition,
`Form B has a hygroscopicity of approximately 0.2% at 90% relative humidity.
`The L-tartrate Form B is also characterized in that when examined by solid state 13C
`NMR cross-polarization magic angle spinning techniques, it exhibits the following principal
`resonance peaks (± 0.1 ppm) downfield from 100 ppm (adamantane standard 29.5 ppm):
`179.2, 178.0, 147.4, 145.2, 144.4, 124.8 and 122.5 ppm.
`In
`another embodiment of
`the
`invention,
`the
`L-tartrate of 5,8,14-
`11.04
`triazatetracyclo[10.3.1.02
`9]-hexadeca-2(11 ),3,5, 7,9-pentaene is
`the hydrate L-tartrate
`'
`'
`salt, referred to herein as Form C. The L-tartrate Form C is characterized by the principal x-
`ray diffraction pattern peaks expressed in terms of 20 and d-spacings as measured with
`copper radiation (within the margins of error indicated):
`
`5
`
`10
`
`15
`
`Angle 20 (:!: 0.2)
`5.9
`11.8
`16.5
`21.2
`23.1
`23.8
`26.5
`
`d-value (A) (::_ 0.2)
`15.1
`7.5
`5.4
`4.2
`3.8
`3.7
`3.4
`
`The hydrate L-tartrate crystal Form C has a single crystal structure as set forth in
`Figure 8B. Further, the hydrate Form C forms monoclinic crystals belonging to the P2(1)
`space group. Form C is further characterized in having an onset of a solid-solid transition at
`
`Apotex Exhibit 1004.011
`
`

`

`-6-
`
`5
`
`10
`
`15
`
`about 72 °C and an onset of melting transition at about 220 °C. Because Form B converts to
`the hydrate Form C upon contact with 100% relative humidity, Form Chas the same aqueous
`solubility as Form B.
`The L-tartrate Form C is also characterized in that when examined by solid state
`13C NMR cross-polarization magic angle spinning techniques, it exhibits the following principal
`resonance peaks (± 0.1ppm) downfield from 100 ppm (adamantane standard 29.5 ppm):
`179.0, 176.1, 147.5, 144.5 and 124.6 ppm.
`A further embodiment of the invention is directed to the D-tartrate salt of 5,8, 14-
`11.04·9]-hexadeca-2(11 ),3,5,7,9-pentaene.
`triazatetracyclo[10.3.1.02
`In particular, the present
`•
`invention is directed to the three D-tartrate salt polymorphs (referred to here as Forms A', B'
`and C') which exhibit the same x-ray diffraction characteristics, hygroscopicity, water content
`and thermal characteristics as Forms A, B and C of the L-tartrate salt.
`In another embodiment, the present invention relates to the D,L-tartrate salt of 5,8, 14-
`11 .04·9}-hexadeca-2(11 ),3,5, 7,9-pentaene, and
`triazatetracyclo[10.3.1.02
`in particular,
`two
`polymorphs, an anhydrous form (herein referred to as Form X) and a hydrate form (herein
`referred to as Form Y).
`The D,L-tartrate Form X is characterized by the principal x-ray diffraction pattern
`peaks expressed in terms of 20 and d-spacings as measured with copper radiation (within the
`margins of error indicated):
`
`•
`
`Angle 20 (! 0.2)
`6.0
`11.9
`15.0
`17.1
`22.1
`24.5
`
`I
`
`d-value (A) (! 0.2)
`14.6
`7.4
`5.9
`5.2
`4.0
`3.6
`
`20
`
`The D,L-tartrate Form X is further characterized in having an onset of a melting
`transition at about 212 °C.
`The D,L-tartrate Form Y is characterized by the principal x-ray diffraction pattern
`peaks expressed in terms of 28 and d-spacings as measured with copper radiation (within the
`margins of error indicated):
`
`Apotex Exhibit 1004.012
`
`

`

`-7-
`
`Angle 20 (2: 0.2)
`6.2
`12.0
`15.2
`18.1
`24.0
`25.1
`
`14.2
`7.4
`5.8
`4.9
`3.7
`3.5
`
`The D,L-tartrate Form Y is further characterized in having an onset of a solid-solid
`
`transition at about 131 °C and an onset of melting transition at about 217 °C.
`
`Another embodiment of the invention relates to a pharmaceutical composition
`
`5
`
`comprising at least one of polymorphic Forms A, B or C, preferably Form B, of the L-tartrate
`11.04
`9]-hexadeca-2(11),3,5,7,9-pentaene and a
`salt of 5,8, 14-triazatetracyclo[10.3.1.02
`•
`•
`pharmaceutically acceptable carrier or excipient, for use in the treatment of inflammatory
`
`bowel disease {including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's
`
`disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue,
`
`10
`
`pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep
`
`disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, drug/toxin-induced
`cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs,
`lead, arsenic, mercury), disease-induced cognitive impairment (e.g., arising from Alzheimer's
`
`disease (senile dementia), vascular dementia, Parkinson's disease, multiple sclerosis, AIDS,
`
`15
`
`encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick's disease,
`Korsakoffs syndrome and frontal and subcortical dementia), hypertension, bulimia, anorexia,
`
`obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,
`progressive supramuscular palsy, chemical dependencies and addictions (e.g., dependencies
`
`on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates,
`
`20
`
`opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive(cid:173)
`
`compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,
`
`dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including
`
`petit mal absence epilepsy, attention deficit hyperactivity disorder (ADHD), and Tourette's
`Syndrome.
`Another more preferred embodiment of the
`invention
`is wherein
`the
`
`25
`
`pharmaceutical composition is useful in the treatment of nicotine dependency, addiction and
`withdrawal; most preferably, for use in smoking cessation therapy.
`
`The present invention further relates to pharmaceutical compositions for the uses
`
`described in the foregoing paragraph comprising any one of the D-tartrate salt of, the D,L(cid:173)
`tartrate salt of, or the meso-tartrate salt of 5,8, 14-triazatetracyclo[10.3.1.02
`11 .04
`9}-hexadeca-
`2(11 ),3,5,7,9-pentaene.
`
`'
`
`'
`
`30
`
`Apotex Exhibit 1004.013
`
`

`

`-8-
`
`'
`
`'
`
`The present invention further relates to a method of treating inflammatory bowel
`disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's
`disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue,
`pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep
`disorders, jet lag, amyotrophic lateral sclerosis {ALS), cognitive dysfunction, drug/toxin-induced
`cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs,
`lead, arsenic, mercury), disease-induced cognitive impairment (e.g., arising from Alzheimer's
`disease (senile dementia), vascular dementia, Parkinson's disease, multiple sclerosis, AIDS,
`encephalitis, trauma, renal and hepatic encephalopathy, hypothyroidism, Pick's disease,
`Korsakoff's syndrome and frontal and subcortical dementia}, hypertension, bulimia, anorexia,
`obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,
`progressive supramuscular palsy, chemical dependencies and addictions {e.g., dependencies
`on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates,
`opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-
`compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,
`dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including
`petit mal absence epilepsy, attention deficit hyperactivity disorder (ADHD), and Tourette's
`Syndrome comprises administering to a subject in need of treatment a therapeutically
`effective amount of any of Forms A, B or C of the L-tartrate salt of 5,8, 14-
`11 .04
`9]-hexadeca-2( 11 ),3,5, 7 ,9-pentaene,
`triazatetracyclo[10.3.1.02
`preferably
`Form B.
`'
`Another more preferred embodiment of the invention relates to a method of treatment for
`nicotine dependency, addiction and withdrawal, in particular for use in smoking cessation
`therapy activity, comprising the administration of any of Forms A, B or C of the L-tartrate salt
`of 5,8, 14-triazatetracyclo[10.3.1 .02
`11 .04
`9]-hexadeca-2( 11 ),3,5, 7 ,9-pentaene, preferably Form
`•
`•
`B, to a subject in need thereof.
`The present invention further relates to methods of treatment described in the
`foregoing paragraph comprising the administration of any of the D-tartrate salt, the D,L(cid:173)
`11.04
`tartrate salt or the meso-tartrate salt of 5,8,14-triazatetracyclo[10.3.1.02
`9]-hexadeca-
`