IN THE UNITED STATES PATENT AND TRADEMARK OFFICE 'H” plicants:
`
`
`
`
`03’Q?E«r9£'
`Doc1$No.: 62814—A/JPW/GJ
`
`Timothy Norris et al.
`
`
`
`‘. "
`
`~"——-
`
`Serial No.:
`
`09/711,272
`
`Examiner: T. McKenzie
`
`Filed
`
`For
`
`:
`
`:
`
`,November'9, 2000
`
`Group Art Unit: 1624
`
`STABLE POLYMORPH ON N-(3—ETHYNYLPHENYL)-6,7—BIS
`(2—METHOXYETHOXY)-4-QUINAZOLINAMINE
`HYDROCHLORIDE,
`METHODS
`OF
`PRODUCTION,
`AND
`PHARMACEUTICAL USES THEREOF
`
`1185 Avenue of the Americas
`New York, New York
`10036
`February 28, 2003
`
`"
`
`%
`§
`@
`7 “ E
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`EXPRESS MAIL CERTIFICATE OF MAILING N g ‘-3
`
`FOR ABOVE-IDENTIFIED APPLICATION E
`E
`“Express Mail” mailing label number: EL 525 964 463 US
`Date of Deposit:
`February 28, 2003
`-
`
`Assistant Commissioner for Patents
`Washington, D.C. 20231
`‘ Box AF
`SIR:
`4
`
`'
`
`'
`
`I hereby certify that this paper or fee is "being deposited to 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 the Assistant Commissioner for Patents
`
`3.’NaEhiEg;9n, DLC./29231, Box AF:
`//”:::
`
`
`
`
`
`
`”ame: /:;%f4g/
`
`//2§;(fZZé7
`
`Respectfully submitted,
`
`/’
`John P.
`
`' e
`
`Registration No. 28,678
`Gary J. Gershik
`Registration No. 39,992
`Attorney for Applicants
`Cooper & Dunham LLP
`1185 Avenue of the Americas
`New York, New York
`10036
`Tel
`(212) 278-0400
`
`APOTEX EX. 1005-001
`
`

`
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`Qhklaflfigfifiéapsoxrsn PROCEDURE
`RESPONSE UNDER 37 C.F.R. § 1.116
`
`GROUP ART UNIT 1624
`
`-
`
`Docket No3;628l4—A/JPW/GJG
`
`IN THE UNITED.STATES PATENT AND TRADEMARK OFFICE
`
`Applicants:
`
`Timothy Norris et al.
`
`Serial No.:
`
`09/711,272 I
`
`Examiner: T. McKenzie
`
`Filed
`
`For
`
`:
`
`:
`
`November 9, 2000
`
`Group Art Unit:
`
`l624
`
`STABLE POLYMORPH ON N-(3—ETHYNYLPHENYLf-6,7-
`BIS (2-METHOXYETHOXY)-4—QUINAZOLINAMINE
`HYDROCHLORIDE, METHODS OF PRODUCTION, AND
`PHARMACEUTICAL USES THEREOF
`
`Assistant Commissioner for Patents
`
`Washington, D.C.
`
`20231
`
`Box AF
`
`SIR:
`
`1185 Avenue of the Americas
`
`New York, New York
`
`10036
`
`February 28, 2003
`RECEWED
`
`MAR 0 6 20031
`
`TECH cewnza 1600/2900
`
`IN RESPONSE TO AUGUST 30, 2002 FINAL_OFFICE
`_AMmUDMmNr
`ACTION AND PETITION FOR A THREE—MONTH EXTENSION OF TIME
`
`This Amendment
`
`is submitted in response to the Final Office
`
`Action issued August 30, 2002 by the U.S. Patent-and Trademark
`
`Office in connection with the above—identified ‘application.
`
`0,
`6'
`
`ۤ\
`
`A response to the August 30, 2002 Final Office Action was due
`November 30,
`2002.
`'Applicants hereby request
`a
`three—month
`extension of
`time from November 30, 2002 to February 28, 2003
`for
`responding to the August 30, ‘2002 Final Office Action.
`
`required fee for
`The
`$930.00
`and
`a
`check
`
`the three—month extension of
`including
`this
`amount
`is
`
`time is
`enclosed.
`
`Therefore,
`
`a
`
`response to the August
`
`30,
`
`2002 Final Office
`
`Action is now due February 28,
`
`2003
`
`and this Amendment
`
`‘is
`
`being timely filed.
`
`03/04/2003 HUUGHGI
`
`00000112 09713272
`
`.
`
`01 FC:1253
`
`930.00 up
`
`(j:::/’
`
`APOTEX EX. 1005-002
`
`

`
`0
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page:
`
`2
`
`Please amend the subject application as follows:
`
`
`
`In the Claims
`
`Please cancel
`
`claims 55-57 without prejudice to applicants
`
`rights to pursue the subject matter of these claims in this or_
`
`a subsequent application.
`
`Please amend claims 1, 3, 5, 14-16, 23-32, 50, 52-54,
`
`58 and
`
`6l—64,
`
`and add new claims 73-91 under
`
`the provisions of
`
`37
`
`C.F.R. §1.121(c).
`The amended claims are presented below and
`the amendments
`to the claims are indicated in the markedeup
`
`set of claims attached hereto.
`
`
`(Amended)
`homogeneous crystalline polymorph
`of the
`hydrochloride
`s
`of
`N~(3—ethynylphenyl)—6,7—bis(24
`
`
`
`
`linamine
`designated
`-the
`B
`methoxyethoxy)—4-quina
`polymorph Athat
`exhibits
`n Xeray
`powder diffraction
`
`
`aks expressed in degrees
`pattern having characteristic
`
`.48,
`6.26,
`
`20.20, 21.10, 22.98, 24.46, 25.14, and 2
`
`2~theta
`
`at
`
`approximately
`
`13.39,
`
`16.96,
`
`1.
`
`
`
`
`
`3.
`
`(Amended)
`
`A
`
`
`
`stalline polymorph of
`
`the hydrochloride
`
`salt
`
`of N-(3—eth
`
`lphenyl)-6,7—bis(2—methoxyethoxy)—4—
`
`
`quinazolinamine designat
`
`an X-ray powder diffraction
`
`peaks expressed in degrees 2—the
`at approximately 6.26,
`12.48,
`13.39, 16.96, 20.20, "21.1o,
`
`and, 26.91, which is free of the A polymorph.
`
`the B polymorph that exhibits
`
`ttern having characteristic
`
`
`
`.98, 24.46,
`
`25.14
`
`
`
`(Amended)
`
`A
`
`C;;Z:
`§—DLb
`E('
`
`5.
`
`’
`
`_9
`5°‘
`E
`
`\
`
`mposition
`
`hydrochloride
`of
`polymorph
`the
`
`ethynylphenyl)—6,7—bis(
`.
`
`comprising
`
`a crystalline
`
`ethoxyethoxy)—4—quinazolinamine
`
`salt
`
`of
`
`N—(35
`
`ca?)
`
`
`
`C?
`
`.
`APOTEX EX. 1005-003
`
`a
`
`

`
`1?’)
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`
`Filed; November 9, 2000
`Page:
`3
`
`designa
`
`
`diffraction pat
`
`the B polymorph that exhibits an X—ray powder
`
`having characteristic peaks expressed
`
`
`
`% in degrees 2—theta at
`oximately 6.26, 12.48, 13.39,
`16.96, 20.20, 21.10, 22.98,
`24
`9
`25:14 and, 26.91,
`and
`
`é;2%(
`a carrier, wherein the
`composition
`ree of
`the A
`
`
`Apolymorph.
`J
`
`V
`
`9”.
`
`‘I.
`
`b
`{
`
`(Twice Amended) A method ogyffieating abnormal cell growth
`x"
`of a cell expressing /,e epidermal growth factor receptor
`(EGFR)
`in a mamma, which comprises administering to said
`
`mammal
`
`a
`
`th=”apeutically
`
`effective
`
`amount
`
`of
`
`the
`
` _polymorph :7 claim 3.
`
`‘s
`
`cell gro
`
`is brain,
`
`squamous cell, bladder, gastric,‘
`
`/
`
`(Ame
`The method of claim %, wherein the abnormal
`
`S}/é pancreatic,
`atic,
`glioblastoma multiforme' breast,
`
`’ XE] head,
`ineck,’7eso ‘agealr prostate,
`colorectal,
`lung,
`
`
`renal, kidney, ovarian,
`gynecological
`or thyroid cancer.
`
`_'7’
`
`WA96.
`
`
`F”
`(Amended) The method of claim
`, wherein the abnormal
`
`
`cell
`
`growth
`
`is
`
`non—small
`
`cell
`
`ng
`
`cancer
`
`(NSCLC),
`
`refractory ovarian cancer, or head and ne
`
`<—————*—~—”"”””'
`
`
`(Twice Am
`
`11"
`
`.
`
`cell growth
`
`ded)
`f
`
`A method for
`a
`
`the treatment of abnormal
`
`cell expressing the epidermal growth
`
`7//
`
`factor
`
`receptor
`
`(EGFR)
`
`in
`
`a mammal which
`
`comprises
`
`therapeutically effective
`a
`administering to sai mammal
`/L;4:
`claim 3 in combination with an
`amount of the polymorph
`in the group consisting of a l
`anti—tumor agent selected
`05C/L9
`alky
`ting
`agent,
`an
`anti-
`E?’ mitotic
`inhibitor,
`an
`metabolite,
`an intercalating antib'otic,
`a growth factor
`
`‘inhibitor,
`
`a
`
`cell
`
`cycle
`
`inhibito
`
`enzyme,
`
`a
`
`an
`
`
`APOTEX EX. 1005-004
`
`A
`
`

`
`K‘
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
` ' hibitor,
`
`
`a biological
`
`response modifier,
`
`anti—androgen.
`
`
`
`ded)
`
`A process for preparing a crystalline polymorph
`
`N~(3—ethynylphenyl)—6,7-bis(2-methoxyethoxy)-4-
`
`
`
`which
`
`step
`
`of
`
`free of
`
`ecrystallizing N-(3—ethynylphenyl)—6,7—bis(2—
`
`methoxyethox )—4—quinazolinamine
`solvent compri
`
`the A polymorph,
`
`‘which comprises
`
`the
`
`ing alcohol.
`
`hydrochloride
`
`in
`
`a
`
`(Amended) The pr cess of cflaiH1}y( wherein the solvent
`
`further
`
`comprises ater.
`
`
`
`fa
`
`(Amended)
`
`The
`
`proce s
`
`of
`
`claim
`
`wherein
`
`N—(3-
`
`-methoxyethoxy)—4—quinazolinamine
`ethynylphenyl)-6,7—bis
`of
`coupling
`a
`compound
`hydrochloride
`is uprepa ed‘
`by
`
`formula 6
`
`
`
`
`with a compound of formula 4
`
`NH2
`
`
`
`0
`
`APOTEX EX. 1005-005
`
`

`
`.
`
`0
`
`1
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`'
`
`Page:
`
`3;’?
`0
`5
`(Amended) The process of claim%, wherein said compound
`
`0 ‘formula 6
`
`is prepared by heating a compound of
`
`formula
`
`5
`
`LT
`
`CH3
`
`OH
`
`alkali and solvent.
`
`
`
`(Amended) The process of
`
`aim gg, wherein said compound
`
`of
`
`formula 4
`
`is prepared in
`
`chlorinating..a compound of
`
`formula 3
`
`
`
`
`
`Amended) A process for the production 0
`
`the polymorph
`
`B of claim 1 comprising the steps of:
`
`6? tr
`;fi§
`
`(
`
`a)
`
`substitution chlorination of starting qu nazolinamine
`
`compound of formula 3
`
`
`
`(/
`
`APOTEX EX. 1005-006
`
`2
`
`

`
`"Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed} November 9, 2000
`
`Page:
`
`6
`
`ha"ng an hydroxyl group,
`
`to provide a compound of formula 4
`
`}hC‘\0//A\\V//O
`
`H3C/ \/\o
`
`\\}3
`
`N
`
`qw-ff,‘
`
`4
`
`by
`
`reac ‘on
`
`thereof
`
`in
`
`a
`
`solvent mixture of
`
`thionyl
`
`chloride, methy.ene chloride and dimethylformamide,
`
`7
`
`,,__.._.———-——-
`
`b) preparation of a compound of formula 6
`
`guk/péq Ii
`
`£1 K
`
`
`by heating the compound of
`alkali and solvent;
`
`formula 5
`A
`
`»n a suspension of metal
`
`c)
`
`reaction of the compound of formu a
`
`6
`
`in situ with the
`
`4 wherein ‘the comoound of
`formula
`of
`compound
`replaces the chlorine in the compound of fo ula 4
`
`6
`formula
`to give the
`
`N—(3—ethynylphenyl)-6,7—bis(2-methoxyethoxy) 4—quinazolinamine
`
`hydrochloride;
`
`d)
`
`recrystallizing
`
`the N-(3—ethynylphe yl)-6,7—bis(2fi
`
`(24
`
`APOTEX EX. 1005-007
`
`

`
`‘
`
`1!
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page:
`
`7
`
`-
`
`.
`
`a
`
`1
`
`methoxyethoxy)—4—quinazolinamine
`
`hydrochloride,
`
`in
`
`alcohol,
`
`he polymorph B form.
`
`
`
`d)
`
`.The
`
`process
`
`of
`
`clainl
`
`jig
`
`wherein ‘
`
`the
`
`
`(Amended)
`The
`process
`
`substitution chlor'nation is quenched in the presence of
`aqueous sodium bicarb
`
`
`wherein
`
`the
`
`of
`
`claim ié,
`
`5?
`the
`wherein
`claim 95,
`
`enched in the presence of
`hydroxide,
`
`
`
`process
`
` 3%
`
`fgtfié
`/:/(®@
`jg.
`
`(Amended)
`
`The
`
`substitution chlorination is
`
`aqueous
`
`potassium
`
`
`
`aqueous
`
`potassium
`
`bicarbonate,
`
`aqueous potassium carbo
`
`carbonate, or a mixture thereof.
`
`
`
`te,
`
`aqueous
`
`sodium
`
`
`
`;¢.
`
`(Twice Amen ed) A method of inhibiting the development of
`
`
`basal or
`squa
`us cell
`exposed to the s
`or
`
`
`therapeutic
`
`carcinoma,
`
`said meth
`
`persons
`
`a
`
`comprising administering to said
`
`ly
`pharmaceutical composition
`
`omprised of at
`
`carcinoma of
`the skin in areas
`in persons of high risk to said
`
`effective
`
`amount
`
`of
`
`a
`
`least one of
`
`N-(3—ethynylphenyl)—6,7-b‘s(2—methoxyethoxy)-4-
`
`quinazolinamine,
`
`and pharmaceuti ally acceptable
`thereof in anhydrous and hydrate for s,
`
`
`so as to thereby
`
`salts
`
`cell
`
`squamous
`
`
`
`inhibit
`
`the
`
`development
`
`of
`
`basal
`
`o
`
`carcinoma of the skin.
`
`9*.
`
`‘S; EQL7
`
`
`
`
`ess
`
`of making
`
`a
`
`composition which
`
`methoxyethoxy)¥4—quinazolinam
`
`\
`
`Q‘
`§7fl¥
`
`A
`(Amended)
`?(:
`Sit) composition
`( hydrochloride
`
`pr
`
`comprise
`a
`salt
`
`
`of
`
`crystalline polymorph of
`
`the
`
`N-(3—ethynylphenyl)—6,7—bis(2—
`
`
`
`4/‘:
`
`designated
`
`the
`
`B
`
`0/
`
`APOTEX EX. 1005-008
`
`

`
`'Applicant:_Timothy Norris et al.
`Serial No: 09/711.272
`
`‘Filed: November 9, 2000
`. Pa—9..€=
`3
`
`powder diffraction
`an X—ray
`exhibits
`9.0 po ymorph Hthat
`hffpatt rn having characteristic peaks expressed in degrees
`;52~thet
`
`.at
`
`approximately
`
`6.26,
`
`12.48,
`
`13.39,
`
`16.96,
`
`V
`
`.10, 22.98, 24.46; 25 14 and, 26.91, which is
`
`e
`
`A
`
`polymorph,
`
`comprising
`
`admixing.
`
`the
`
`:T2o.2o,
`free
`of
`crystalline po
`(Amended)
`The proc ss of
`
`
`
`morph with a carrier.
`
`/
`claim ’§2, wherein the N¥(3—
`
`ethynylphenyl)—6,7—bis 2—methoxyethoxy)~4~quinazolinamine
`
`x
`
`‘H
`
`jg:/£7
`1?’
`
`/gyfiri
`
`1}
`jyg.
`
`hydrochloride in the poly orph 8 form is characterized by
`
`the X—ray powder diffraction
`
`attern shown in Figure 3.
`
`2!.
`
`(Amended) The process of claim 95, wherein the carrier is
`a pharmaceutically acceptable carrier.
`
`
`
`
`
`(Amended) A
`
`
`
`therapeutically effec ‘ve
`
`amount
`
`of
`
`the
`
`polymorph
`
`of
`
`aceutical composition which comprises a
`
`
`a
`and
`claim 3
`pharmace
`wherein the pharmaceutical
`compos
`
`/£;a§?“é7
`}f
`
`./
`
`l
`
`U’
`
`ically acceptable
`
`carrier,
`
`ion is free of
`
`the A
`
`polymorph.
`
`
`
`
`polymorph
`of
`ethynylphenyl —6,7—bis(2—methoxyethoxy)—4—quinazolinamine
`
`the
`» designated
`B
`polymorph
`by
`recrystallization
`comprising the step of:
`
`
`
`
`
`the
`
`hydrochloride
`
`salt‘
`
`of
`
`N-(3-
`
`heating
`
`to
`
`refl x
`
`hydrochloride salt of —(3—ethyny1phenyl)-6,7+bis(2~
`
`alcohol,
`
`water
`
`and
`
`the
`
`methoxyethoxy)—4—guinazo
`
`'namine
`
`so
`
`as
`
`to form a
`
`‘solution;
`
`
`
`cooling the solution to betwe
`
`clarifying the solution; and
`45¢
`
`
`
`about 65 and 70
`
`‘C;
`
`(:7
`
`APOTEX EX. 1005-009
`
`a)
`
`b)
`
`c)
`
`€;l/L9
`£5‘
`/£211
`
`‘
`
`

`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272 ‘
`Filed: November 9, 2000
`
`Page:
`
`9
`
`d)
`
`precipitating polymorph B
`
`by
`
`further cooling the
`
`Clarified solution.
`
`‘ ?é.
`
`(Amexded)
`
`A
`
`composition
`
`consisting of
`
`a
`
`homogeneous
`
`.crysta line polymorph of N-(3—ethynylphenyl)—6,7—bis(2—
`
`égfiq
`
`.
`
`Sfi
`Er
`
`methoxycthoxy)—4~quinazolinamine
`
`hydrochloride
`
`in
`
`form of
`
`polymorph
`
`B, ‘which
`
`is
`
`characterized by
`
`the
`
`the
`
`following oeaks:
`U-—"""""_—'"
`
`PolymorQhB
`K
`.
`Anode:Cu —VVavemnoth1 I 4056VVavden-U12:1.54439 Relhflensfi IL500
`Range # 1 — Coup!ed 3.000 to. 0.040 Stepsize:-0.040 StepTime 1.00
`Smoothing Width: 0300 Thresh d: 1.0
`EILW— me!)
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`
`1.5
`- 7 0 IIEIBEEE
`9’ EIIMI
`
`h I!!!
`4.7 1 3.35732
`4.5 EHEE 1.7
`
`
`
`OI,
`
`Polmo-hB
`.
`Anode:Ch1-VVavQenoth1 L54O56VVavebnoH12:1.53439 Relhflensn K1500
`
`Range# 1 — Coupted: 3.000 to 40.040 Stepsize 0.040 S pTime: 1.00
`Soothing Width:0.300 Threshold: 1.0
`’
`MEI I(reI)
`[HIKE
`EEI
`69”] Ex‘
`77) EVE10.0'
`
`EEEK
`3.9I
`B.
`5.6E.
`
`and at least one carrier.
`
`(/1
`
`CL
`
`APOTEX EX. 1005-010
`
`

`
`L
`
`_applicant: Timothy Norris et al.
`-erial No: 09/711,272
`
`Filed: November 9, 2000
`10
`
`Page:_
`
`J0
`VQ/
`
`63.
`
`(Amended)_A.method of treating“- subject with a
`
`tumor by
`
`inducing differentiat
`
`epidermal
`
`growth
`
`fac
`
`comprising contact’ri
`
`ion yo
`tumor cells‘ expressing an
`:5?’ receptor
`(EGFR)
`in the
`tumor
`‘he cells with an effective amount
`
`of
`
`the compound.o' claim 3, or
`
`a composition of claim 5
`
`so as to thersmy treat the subject.
`
`(Amended
`
`A method for the treatment of NSCLC (non small
`
`and
`cer), pediatric malignancies, cervical
`lung c
`cell
`other tumors ca sed or promoted by_human papilloma virus
`
`(HPV),
`
`endometria
`
`cancer,
`
`glioma, melanoma, Barrett's
`
`esophagus
`
`(pre—mali
`
`ant
`
`syndrome),
`
`adrenal
`
`cancers,
`
`neoplastic
`
`cutaneous
`
`'seases .or atherosclerosis
`
`in
`
`mammal
`
`comprising
`
`admin’
`
`tering
`
`to
`
`said
`
`mammal
`
`a
`
`a
`
`therapeutically
`
`effective
`
`a ount
`
`of
`
`a
`
`pharmaceutical
`
`composition
`
`comprised
`
`of
`
`at
`
`least
`
`one
`
`of
`
`N~(3-
`
`ethynylphenyl)?6,7—bis(2-m thoxyethoxy)~4—
`salts
`
`and pharmaceutically acceptable
`
`quinazolinamine,
`
`thereof in anhydrous and hydrate forms.
`( Please add new claims 73-91 as follows:
`
`X‘/
`ethod of claim fifif wherein the pharmaceutical
`(New) The
`composition c prises
`a crystalline polymorph of
`the
`
`hydrochloride
`
`s
`
`t
`
`of
`
`N—(3~ethynylphenyl)—6,7-bis(2—
`
`designated
`‘methoxyethoxy)—4—quin z linamine
`Xeray
`powder
`
`polymorph
`
`that
`
`exhib
`
`an
`
`the
`
`B
`
`diffraction
`
`pattern having characteris ‘c peaks expressed in degrees
`2?theta
`at
`approximately
`6. 6,
`12.48,
`13.39,
`16.96,
`
`20.20,
`
`21.10,
`
`22.98,
`
`24.46,
`
`25.
`
`4
`
`and,
`
`26.91,
`
`and a
`
`pharmaceutically
`acceptable
`carr' r,
`composition is free of the A polymorph.
`
`wherein
`
`the
`
`IF‘?
`
`APOTEX EX. 1005-011
`
`

`
`'
`
`$-
`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`,
`
`Page:
`
`ll«
`
`‘77;A.
`
`,
`
`ew) A method for the treatment of NSCLC (non small cell
`
`lun
`
`cancer), pediatric malignancies, cervical and other
`
`tumor
`
`caused or promoted by human papilloma virus (HPV),
`
`endome
`
`ial cancer, glioma, melanoma, Barrett's esophagus
`
`(pre-mal gnant
`
`syndrome),
`
`adrenal
`
`and
`
`skin "cancers,
`
`autoimmune
`
`neoplastic
`
`cutaneous
`
`diseases
`
`or
`
`atherosclero is iii
`a mammal comprising administering to
`said mammal
`therapeutically_ effective amount
`of
`la
`
`pharmaceutical mposition comprised of at
`
`least one of
`
`N—(3—ethynylph
`
`yl)~6,7—bis(2—methoxyethoxy)~4—
`
`quinazolinamine,
`
`an
`
`pharmaceutically acceptable
`
`salts
`
`2,
`
`thereof in anhydrous
`
`d hydrate forms,
`
`§
`
`L/£7
`£;'
`
`a)
`b)
`
`wherein the treatment further comprises,
`treatment with eithe
`or both anti—EGFR and anti—EGF
`.
`,
`antibodies,
`administration to said mammal of
`ea-member of the,
`group ‘consisting
`of
`i hibitors ‘off MM?
`(matrix-
`metallo—proteinase),
`VEGF
`(vascular
`endothelial
`
`growth factor receptor),
`
`far esyl
`
`transferase, CTLA4
`
`(cytotoxic T—lymphocyte antige
`
`4) and erbB2, MAb to
`
`VEGFr,
`
`rhuMAb—VEGF, erbB2 MAb an
`
`avb3 Mab, or
`
`C)
`
`radiation treatment.‘
`
`2%:
`
`(New) The method of claim )3, wherein t e abnormal cell
`
`growth is pancreatic cancer.
`
`/}6(/ (New) The method of claim }fi{ wherein the a normal cell
`
`_
`
`growth is colorectal cancer.
`
`‘
`
`}?fl
`
`(New) The method of claim lflf wherein the abno
`growth is prostate cancer)"
`
`al cell
`
`07
`
`APOTEX EX. 1005-012
`
`

`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`3?’? .
`
`372%:
`
`0
`4 E3.
`
`(Ne
`
`growt
`
`) The method of clainiiyg
`
`is breast cancer.
`
`wherein the abnormal cell
`
`(New) Th method of claim Jéfi wherein the abnormal cell
`
`growth is
`
`sophageal cancer.
`
`(New) The met od of claim K
`
`growth is ovari
`
`cancer.
`
`
`?
`, wherein the abnormal cell
`
`égl
`
`Q’
`
`/fiéf
`
`claim XL, wherein the abnormal cell
`(New) The method 0
`growth is glioblasto multiforme.
`..,.
`
`(New) The method of cl
`
`im jflfl wherein the abnormal cell
`
`growth is hepatic cancer.
`
`7 8
`
`.
`
`(New) The method of claim 4-, wherein the abnormal cell
`growth is renal cancer.
`
`({ifi4(
`
`(New) The method of claim
`
`growth is gastric cancer.
`
`q
`
`.
`
`(New) The method of claim
`
`the abnormal cell
`
`the abnormal cell
`
`growth is bladder cancer.
`
`4 ;%fi’
`
`N
`(New) The method of claim }£K wherei
`
`the abnormal cell
`
`growth is non—small cell lung cancer
`
`( CLC).
`
`‘{7§fl(/
`
`(New) The method of claim }fi; wherein t e abnormal cell
`
`growth is head and neck cancer.
`
`4‘/fl{
`
`(New) The method of claim
`small cell lung cancer
`(NSCLC).
`
`for
`
`the trea ment of non:
`
`70 0.0
`
`APOTEX EX. 1005-013
`
`

`
`-
`A
`h
`Applieantz Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`‘
`
`Page:
`
`1
`
`3
`
`Lrfl§3<’
`
`(New)
`
`The method
`
`of
`
`clainx JV?
`
`for
`
`the
`
`treatment
`
`of
`
`endometrial cancerr
`
`
`
`Cjgv
`/96?
`{;filfi4{’
`
`(New) The method_of c
`(New)
`The method
`of
`
`melanoma.
`
`'
`
`claim
`
`for the treatment of glioma.
`for
`the
`treatment of
`
`
`
`7/
`
`%
`
`APOTEX EX. 1005-014
`
`

`
`Applicant: Timothy Norris et a1.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`14
`
`REMARKS
`
`Claims 1-7, 14-32,
`
`50 and 52-72 were pending in the subject
`
`application.
`
`Of
`
`these, claim 61 was allowed and claims 69-72
`
`were
`
`indicated as
`
`allowable.
`
`Applicants
`
`have hereinaboye
`
`canceled claims 55-57,
`50,
`52-54,
`58
`and
`Accordingly,
`claims
`
`3,
`5, 14-16, 23-32,
`amended claims 1,
`new claims
`61-64,
`and
`added
`73-91.
`1-7,
`14-32,
`50,
`52-54
`and
`58-91 ‘are
`
`currently pending in the subject application.
`
`Support
`
`for
`
`the amendment
`
`to clainx 15 may be
`
`found,
`
`inter
`
`alia,
`
`on page 25,
`
`line 8,
`
`and CH1 page 43,
`
`line 17 of
`
`the
`
`subject application.’
`
`Support
`
`for
`
`the amendment
`
`to clainm 64 may be
`
`found,
`
`inter
`
`alia,
`
`on page 25,
`
`line 5,
`
`and on page, 27,
`
`line 10 of
`
`the
`
`subject app1ication2_
`
`Courtesy Copy of Information Disclosure Statement
`
`In Section 3 of
`
`the August
`
`30,
`
`2002 Office Action,
`
`the
`
`Examiner acknowledged receipt of
`
`the form PTO—1449 and of
`
`the
`
`post card receipt supplied by the applicants.
`
`However,
`
`the
`
`Examiner
`
`indicated that
`
`none of
`
`the
`
`references
`
`have been
`
`found.
`
`To
`
`ensure
`
`that
`
`the
`
`Patent Office
`
`files
`
`are
`
`~complete,
`
`applicants
`attaching a
`
`are
`filing this Amendment
`courtesy_ copy
`of
`the
`
`by Express Mail
`and
`Information Disclosure
`
`Statement
`
`filed June
`
`29,
`
`2001,
`
`including all
`
`of
`
`the
`
`87
`
`references.
`
`Applicants
`
`look forward to receiving the form
`
`PTO—l449 initialed by the Examiner upon consideration of
`
`the
`
`cited references.
`
`L
`
`APOTEX EX. 1005-015
`
`

`
`.
`
`e
`
`.
`
`‘
`
`Applicant: Timothy Norris et al.
`-Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 15
`
`Objections to Claims
`
`In Section’ 4,
`
`the Examiner objected to claims" 2-4 alleging
`
`they are substantial duplicates of claim l,
`
`and also objected
`
`to claims 6 and 7 alleging they are substantial duplicates of
`claim 5.
`The Examiner stated that
`a distinction is not seen
`
`between
`
`the
`
`limitations
`
`“substantially
`
`free
`
`of
`
`the
`
`A
`
`polymorph”
`
`[in clainx 3]
`
`and “substantially homogeneous”
`
`[in
`
`claim 1],
`
`and alleged that
`
`the claims are drawn to the same
`
`substance with the same purity limitation.
`
`that claim l has been amended
`Initially, applicants point out
`to recite “A homogeneous crystalline polymorph ... B,” claim
`
`3 has been amended to recite the “B polymorph ... which is
`
`free of
`
`the 23 polymorph,” and claim:
`
`5 has been amended to
`
`recite a composition which “is free of the A polymorph.”
`
`In response to the objection,
`
`applicants respectfully point
`
`that being “free of
`out
`with being “homogeneous”.
`
`synonymous
`the IX polymorph” is not
`For
`example,
`a’ composition of
`
`matter that.is free of A, may not necessarily be substantially
`
`free of X.
`
`A homogenous composition of matter would be the
`
`same material at every point
`
`throughout
`
`the composition of
`
`matter,
`
`Therefore,
`
`the
`
`terms
`
`are
`
`not
`
`synonymous,
`
`and
`
`applicants respectfully request
`
`that
`
`the Examiner
`
`reconsider
`
`these terms and withdraw the objection.
`
`Regarding the
`
`similar objection to claims
`
`2,
`
`4,
`
`6
`
`and 7,
`
`applicants
`
`submit
`
`that
`
`these
`
`claims
`
`are proper dependent
`
`claims because each further
`
`limits the claim fronx which it
`
`depends by reciting additional data points.
`Each of claims 1,
`3 and 5 recites ten (10) data points. Claim 6 recites 45 data
`
`points,
`
`i.e.
`
`an additional
`
`35 data points more
`
`than its
`
`CL
`
`APOTEX EX. 1005-016
`
`

`
`U
`2
`
`.‘
`1
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 16
`
`respective claim from which it depends. Claim 2,
`
`4 and 7 each
`
`recites a continuum of data points,
`
`i.e.
`
`the full diffraction
`
`pattern in graph form,
`
`adding a continuum of.data points to
`
`its respective claim from which it depends.
`
`Because claim 2,
`
`4,
`
`6
`
`and
`
`7
`
`each
`
`further
`
`limits
`
`the
`
`claim from which
`
`it
`
`depends, each of these claims is a proper dependent claim.
`
`The sections cited by the Examiner, namely 37 C.F.R.
`
`§ 1.75
`
`and M.P.E.P.
`
`§
`
`706.03(k)
`
`do not prohibit
`
`applicants
`
`from‘
`
`defining their invention by using any and all of,
`
`a continuum
`
`In fact,
`10 data point.
`45 data point or
`of‘ data point,
`“court
`M.P.E.P.
`§
`706.03(k)
`specifically V states ‘
`that,
`decisions have confirmed applicant's right
`to restate (i.e.,
`
`by plural claiming)
`
`the invention in a
`
`reasonable number of
`
`ways.
`
`Indeed,
`
`a mere difference in scope between claims has
`
`-E.a_¢h. 9? Claims 2%
`lbeerz hs_l.dfi2<>__1?e: efiosgh-” _<EmPhasi.S addsw-t
`4,
`6 and 7 certainly recites a different scope. Accordingly,
`
`the objections to claims 2-4,
`
`6 and 7 are improper and should
`
`be withdrawn.
`
`Claims
`
`55~57
`
`have
`
`been
`
`canceled
`
`without
`
`prejudice.
`
`Accordingly,
`
`the objection to claims 56 and 57 under 37 C.F.R.
`
`1.75 as being a substantial duplicate of claim 55,
`
`is moot.
`
`In Section 7
`
`of
`
`the August
`
`30,
`
`2002 Office Action,‘ the
`
`Examiner
`
`objected to
`
`claim 58
`
`under
`
`37 C.F.R.
`
`1.75
`
`as_
`
`allegedly a substantial duplicate of claim 5.
`
`The Examiner
`
`stated that it is not
`
`logical
`
`that a composition intended for
`
`is claim 5, would not contain a
`as
`therapy,
`effective amount of the compound of claim 1.
`
`therapeutically
`
`In response, applicants respectfully note that while claim 58
`
`Q
`
`APOTEX EX. 1005-017
`
`

`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`.Filed: November 9, 2000
`
`Page: 17
`
`is directed to a pharmaceutical
`
`composition,
`
`claim 5
`
`broader
`
`to cover,
`
`for
`
`example,
`
`bulk form compositions
`
`is
`
`in
`
`transit.
`
`Therefore,
`
`claim 58 is not
`
`a substantial duplicate
`
`of claim 5, and the objection to claim 58 should be withdrawn...
`
`In 'Section 8
`
`of
`
`the August
`
`30,
`
`2002 Office Action,
`
`the
`
`,Examiner
`
`objected
`
`to claim 62
`
`under
`
`37 C.F.R.
`
`1.75
`
`as
`
`allegedly a substantial duplicate of claim 5.
`The Examiner
`stated that applicants have chosen a different and ultimately
`
`equivalent way of expressing the X-ray data, and that both are
`
`compositions of the identical substance.
`
`In response, applicants respectfully direct
`
`the Examiner
`
`to
`
`their
`
`remarks
`
`above because similart
`
`remarks are appropriate
`
`Applicants have
`for claim 62.
`amended claim 62
`to recite
`awhile
`..,“ho_mogen.e<$u§,"
`claim 5_ ‘recites
`“free of
`‘the
`A
`polymorph.” Consequently,
`the objection to claim 62 should be“
`withdrawn.
`
`Rejection under 35 U.S.C. § 112, first paragraph
`- claims 14 and 17-22
`
`In Section 9
`
`of
`
`the August
`
`30,
`
`2002 Office Action,
`
`the
`
`Examiner rejected claims 14 and 17-22 under 35 U.S.C.
`
`§ 112,
`
`first paragraph, as allegedly containing subject matter which
`
`was not described in the specification in such a way as
`
`to
`
`reasonably enable one skilled in the relevant art to which it
`
`pertains, or with which it is most nearly connected,
`
`to make
`
`and/or
`
`use
`
`the
`
`invention.
`
`The
`
`Examiner
`
`alleged
`
`that
`
`applicants are not enabled for
`
`treatment of
`
`“abnormal cell
`
`growth” generally.
`
`The Examiner cited In re Buting 163 USPQ
`
`689,
`
`for
`
`the preposition that
`
`evidence
`
`involving a
`
`single
`
`compound and two types of cancer was not
`
`found sufficient
`
`to
`
`APOTEX EX. 1005-018
`
`

`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`"Page: 18
`
`establish the enablement of claims directed to a
`
`Inethod of
`
`treating seven types of
`
`cancer‘ with members of
`
`a class of
`
`several
`compounds.
`The Examiner noted applicants’
`argument
`that
`claim 14
`is drawn to the treatment of specific cancers,
`and noted the clinical data presented on the pages
`spanning
`50-53.
`However,
`the Examiner
`alleged
`that
`applicants’
`argument
`is not persuasive because claim I4 is not
`limited to
`
`specific cancers.
`
`In
`
`response,
`
`applicants
`
`have
`
`amended
`
`claim 14
`
`to recite
`
`abnormal cell growth of a cell expressing the epidermal growth
`
`factor receptor
`
`(EGFR).
`
`As noted by the Examiner, Phase I and
`
`III Clinical Studies are described on pages
`
`50
`
`to 53 of
`
`the
`
`subject specification for non—small cell
`
`lung cancer, head and
`
`neck cancer,
`
`refractory ovarian cancer,
`
`colorectal
`
`cancer,
`
`renal carcinoma_.vAll_of the cancersmof
`
`the clinical
`
`trials
`
`are EGFR positive tumor
`
`types.
`
`Furthermore, as noted in the
`
`description of
`
`the clinical
`
`trials on page 52,
`
`lines 32-35,
`
`other EGFR positive tumor
`
`types have ‘been documented to be
`
`affected by the specific compound. Also, on page I of their
`specification, applicants disclose that
`the specific compound
`
`is known to be an inhibitor of
`
`the epidermal growth factor
`
`receptor
`
`(EGFR), and is therefore useful for the treatment of
`
`associated diseases.
`
`The diseases which
`
`fall within this
`
`class
`
`are described,
`
`for
`
`example,
`
`on pages
`
`24~29 of. the
`
`subject specification. Therefore, applicants have enabled the
`
`treatment of any disease by the inhibition of
`
`the epidermal
`
`growth factor receptor (EGFR).
`
`Accordingly, applicants respectfully request that
`
`the Examiner
`
`reconsider and withdraw the rejection of claim 14 and 17~22,
`
`as amended, under 35 U.S.C.
`
`§ 112, first paragraph.
`
`O
`
`APOTEX EX. 1005-019
`
`

`
`-
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 19
`
`
`
`firstRe ection under 35 U.S.C. 112 ara ra h - claim 50
`
`
`
`In Section 10 of
`
`the August
`
`30,
`
`2002 Office Action,
`
`the
`
`Examiner
`paragraph,
`
`rejected claim 50
`under
`35 U.S.C.
`112,
`first
`as allegedly. containing subject matter which was
`
`not described in the specification in such a way as to enable
`
`one skilled in the art to which it pertains, or with which it
`
`is most nearly connected,
`to make and/or use the invention.
`The Examiner
`alleged that applicants
`are not
`enabled ‘for
`
`preventing basal or
`also alleged that
`
`squamous cell carcinoma.
`The Examiner
`the
`only
`established‘ prophylactics
`are
`
`vaccines not
`
`the N~(3~ethynylphenyl)-6,7—bis(2—methoxyethoxy)-
`
`4—quinazolinamine salt
`
`such as present here.
`
`The Examiner
`
`alleged that despite intensive efforts, pharmaceutical science
`
`has been unable to find 21 way of getting a
`
`compound to be
`
`effective
`
`for
`
`the
`
`prevention
`
`of proliferative
`
`diseases
`
`generally. »The Examiner stated that under such circumstances,
`it
`is proper
`for
`’the
`PTO to require evidence that
`such an
`
`unprecedented
`
`feat
`
`has
`
`actually ‘been
`
`accomplished,
`
`In
`
`re
`
`Ferens,
`
`163 USPQ 609,
`
`and no such evidence has been presented
`
`in this case.
`
`The Examiner further alleged that
`
`the failure
`
`of
`
`skilled scientists
`
`to achieve
`
`a
`
`goal
`
`is
`
`substantial
`
`evidence that achieving such a goal
`
`is beyond the skill of
`
`practitioners in that art, citing Genentech vs Novo Nordisk,
`
`42 USPQ 2“ 1001, 1006.
`
`In response, applicants have amended claim 50 to clarify that
`administering the recited compound inhibits the development of
`
`basal or
`
`squamous cell
`
`carcinoma of
`
`the
`
`skin.
`
`Carcinoma
`
`develops after the first cancerous cell is formed.
`
`Inhibiting
`
`the proliferation of
`
`this first cancerous cell will
`
`inhibit
`
`development
`
`of
`
`the
`
`carcinoma.
`
`The
`
`recited compound
`
`is
`
`Q 0
`
`1
`
`APOTEX EX. 1005-020
`
`

`
`.\
`
`.
`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 20
`
`reasonably expected to inhibit. proliferation of
`
`a cancerous
`
`basal or
`
`squamous cell because such cell
`
`is EGFR positive.
`
`Thus,
`
`it
`
`is
`
`reasonable to expect
`
`the
`
`recited —compound
`
`to
`
`inhibit proliferation of
`such
`first
`cancerous cell,
`and,
`hence,
`to inhibit
`the development of basal or
`squamous cell
`
`carcinoma of the skin.
`
`Accordingly, applicants respectfully request that
`
`the Examiner
`
`reconsider and withdraw the rejection of claim 50, as amended,
`
`under 35.U.S.C.
`
`§ 112, first paragraph.
`
`Rejection of claim 63 under 35 U.S.C. § 112,
`first and second paragraphs
`
`In Section 11 of
`
`the August 30,
`
`2002 Final Office Action the
`
`Examiner
`
`rejected claims
`
`63
`
`under
`
`35 U.S.C.4
`
`112,
`
`second
`
`paragraph, as allegedly indefinite for failing to particularly
`
`‘point
`
`‘cut
`
`and distinctly‘ claim‘
`
`the "subject matter —which
`
`applicant
`
`regards
`
`as
`
`the invention.
`
`I The Examiner
`
`inquired
`
`whether
`
`this claim is restricted to cancer therapy or whether
`
`there are additional
`
`reasons for “inducing differentiation of
`
`tumor cells”.
`
`In Section 12
`
`of
`
`the August
`
`30,‘ 2002 Office Action,
`
`the
`
`Examiner
`
`rejected ‘claim 63
`
`under
`
`35 U.S.C.
`
`112,
`
`first
`
`paragraph, while being enabling for treating specific tumors,
`
`allegedly does not
`
`reasonably provide enablement
`
`for cancer
`
`treatment
`
`generally
`
`of
`
`for
`
`other
`
`uses
`
`of
`
`tumor
`
`cell
`
`differentiation which are not therapeutic.
`
`In
`
`response,
`
`applicants
`
`have
`
`amended
`
`claim 63
`
`to recite
`
`treating a subject with a tumor by inducing differentiation of
`
`tumor cells expressing an epidermal growth factor
`
`receptor
`
`APOTEX EX. 1005-021
`
`

`
`.\
`
`.
`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`’
`Filed: November 9, 2000
`Page: 21
`
`V
`
`.
`
`(EGFR)
`
`in the tumor.
`
`Amended claim 63 recites treatment of a
`
`specific type of
`
`tumors, which the Examiner
`
`indicated to be
`
`enabled.
`
`Accordingly,
`
`applicants
`
`respectfully request
`
`that
`
`the Examiner reconsider and withdraw the rejections under 35
`
`U.S.C.
`
`§ 112,
`
`first
`
`and _second paragraphs,
`
`of’ clain1 63,
`
`as
`
`amended.
`
`Re‘ection under 35 U.S.C. 102 e
`
`- claims 1-7
`
`14-23 and 52-54
`
`"In Section 13 of
`
`the August
`
`30,
`
`2002 Office Action,
`
`the
`
`Examiner rejected claims 1-7, 14-23, and 52-54 under 35 U.S.C.
`102(e)
`as allegedly anticipated by U.S. Patent No. 5,747,§98
`to Schnur et.al.
`(“the ‘498 patentT).
`The
`Examiner alleged
`
`that
`of
`
`the reference teaches the synthesis and crystallization
`N- (3-ethynylphenyl)-6, 7—bis (2—methoxyethoxy) -4-
`
`quinazolinamine,-monohydrochloride in Example 20,
`
`lines 30-49,
`
`acgnowledged that‘ applicants have
`“column. 22.f._The _Examiner
`amply characterized their claimed material, polymorph B, but
`
`alleged that
`
`there
`
`is
`
`no
`
`side—by-side
`
`comparison
`
`to the
`
`material
`
`taught by the reference.
`
`The Examiner‘ noted that
`
`applicants state in lines 15-19, page 16
`
`[that]
`
`the material
`
`made
`by
`polymorph
`
`the
`B,
`
`‘498 patent
`but
`that
`
`is
`there
`
`a mixture of polymorph A and
`is
`no data provided in the
`
`specification as to.the ratio~A and B in the prior art.
`
`The
`
`Examiner questioned could the material prepared by the
`
`‘498
`
`patent contain substantial
`
`amounts of polymorph B,
`
`e.g,
`
`as
`
`high as 70%, or might it be 90%.
`
`The Examiner noted that on
`
`line 2, page 5 applicants disclose “substantially homogeneous”
`
`polymorph B, but questioned what
`
`that means,
`
`i.e. whether it
`2
`
`is 99.9% polymorph B,
`
`90%, or 51%.
`
`The Examiner also noted that
`
`the treatment of
`
`lung, ovarian,
`
`head, neck, colorectal, and renal cancer is taught
`
`in lines 8-
`
`CL
`
`APOTEX EX. 1005-022
`
`

`
`A
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page:-22
`
`ll, column_14 of the ‘498 patent.
`
`In response, applicants have clarified their claims to recite
`
`jeither “homogenous” B, or B “free of A”.
`
`The amended claims
`
`clarify thati applicants’
`
`claimed subject matter
`
`is distinct
`
`from mixtures that have detectable amounts of
`
`the A polymorph
`
`using x—ray diffraction. Accordingly, applicants respectfully
`
`request
`
`that
`
`the
`
`Examiner
`
`reconsider
`
`and withdraw the
`
`rejection under 35 U§S.C.
`
`lO2(e) of claims