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`COPYOFPAPERS
`ORIGINALLY FLLED
`
`
`RECED/ED
`2 82002
`
`K’)
`
`
`Doc
`
`/GJG
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`Applicants:
`
`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—E‘.TI-IYNYLPHENYL) -6, 7-
`BIS (2-METHOXYETHOXY)-4-QUINAZOLINAMINE
`HYDROCHLORIDE, METHODS OF PRODUCTION, AND
`
`PHARMACEUTICAL USES THEREOF
`
`A
`
`/
`
`1185 Avenue of the Americas
`New York, New York
`10036
`June 13, 2002
`
`Assistant Commissioner for Patents
`
`Washington, D.C.
`
`20231
`
`SIR:
`
`AMENDMENT IN RESPONSE TO DECER 13, 2001 OFFICE
`*
`ACTION AND PETITIQN FOR A THREE-‘MONTH EXTENSION OF TIME
`
`is submitted in response to the Office Action:
`I »~ . This Amendment
`issued December 13,
`-2001 by the U.S. Patent and ‘Trademark
`
`Office in connection with the above—identified application.
`
`A.
`
`response to the December 13,
`
`2001 Office Action was due
`
`March
`
`13,
`
`2002.
`
`Applicants hereby request
`
`a
`
`three—month
`
`extension of time from March 13, 2002 to June 13, 2002.
`
`The
`
`fee for a three~month extension of time is $920.00 and a check
`including this amount is enclosed. Accordingly, a response to
`the December 13, 2001 Office Action is now due June 13, 2002
`
`and this Amendment is being timely filed.
`
`Please amend the subject application as follows:
`
`-
`
`In the Title of the Invention
`
`Please change the title to:
`
`&
`
`STABLE POLYMORPH ON N-_(3-ETHYNYLPHEINYL)-6,7-BIS (2-
`
`METHOXYETHOXY)-4—QOINAZOLINAMINE
`cs/25/2902 unnmum ooooooee 097112724
`-
`A
`*3
`“6
`'
`‘
`‘92o.oo on
`
`-
`
`‘
`
`-
`
`
`
`~
`
`-
`
`'
`
`-
`
`-
`
`.: -'
`
`.v:>-.~f-;HHm.pvr.n“"'
`
`
`HYDROCHLORIDE,
`p
`
`-
`
`.
`
`'
`
`.
`
`In-'»te$.~::§-<§~‘.i.-""".'
`
`‘
`
`‘"'I"’_§,W'=A.-rvr=,o,~ .fI~~v‘'‘P'.--— « --
`
`“
`
`Q
`
`
`
`
`
`i.«_ A
`
`‘I-:5:
`
`-41.5‘ _ re.’ V-.f'~4'-\I
`
`APOTEX EX. 1003-001
`
`3
`
`'
`
`5
`
`.
`
`‘
`
`K
`
`A
`
`,
`
`

`
`lApplicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`2
`
`METHODS
`
`OF
`
`PRODUCTION,
`
`AND
`
`PHARMACEUTICAL
`
`USES
`
`THEREOF
`
`The difference
`
`between
`
`the
`
`new Title and
`
`the previously
`
`pending Title is shown in the marked-up copy of
`
`the Title
`
`attached hereto.
`
`In the Claims
`
`Please amend claims 5, 14, 23 and 50 and add new claims 55-72
`
`under the provisions of 37 C.F.R. §1.l21(c).
`
`The amended set
`
`of claims is presented below and the amendments to the claims
`
`are indicated in the marked—up set of claims attached hereto.
`
`
`5.
`
`(Amended)
`
`A
`
`composition
`
`comprising
`
`a substantially
`
`homogeneous crystalline polymorph of
`
`salt
`
`of N-
`
`
`
`the hydrochloride
`
`12.48, 13.39,
`
`
`
`16.96,
`and, 26.91, and a carrier.
`
`20.20,
`
`21.10, 22.98, 24.46,
`
`25.14
`
`(Amended) A meth
`mammal which compr
`es administering to said mammal
`
`therapeutically effect've
`claim 1.
`
`amount
`
`of
`
`the
`
`polymorph of
`
`a
`
`
`
`of treating abnormal cell growth in a
`
`Sub
`
`S-ut”
`CL{
`
`
`
`23.
`
`(Amended)
`
`A
`
`the treatment of abnormal cell
`
`1 which comprises administering to said
`
`ically
`
`polymorph of claim 1
`combination with an anti—tumor
`
`agent selected from the
`roup consisting of
`a mitotic
`
`effective
`
`amount
`
`of
`
`the
`
`APOTEX EX. 1003-002
`
`
`ethod for
`
`therape
`
`growth in a ma
`
`mammal
`
`a
`
`(/b
`
`0
`
`9 C
`
`

`
`V
`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`3
`
`q;L}b
`(:Q
`
`.
`
`cell
`
`cycle
`
`inhibitor,
`
`inhibitor,
`
`intercalating a tibiotic,
`
`inhib' or,
`
`a biologic
`hormone, and an anti—androgen.
`
`n alkylating agent,
`
`an anti—metabolite,
`
`an
`
`a growth factor
`
`enzyme,
`
`a
`
`inhibitor,
`
`a
`
`topoisomerase
`
`an
`
`response modifier,
`
`an
`
`anti-
`
`
`
`method
`
`for
`
`prophylaxis
`
`against
`
`the
`
`50.
`
`(Amended)
`
`risk
`
`to
`
`said
`
`said method
`
`comprising
`
`squamous cell carcinoma of
`
`the
`
`in persons of high
`
`development of basal or
`
`skin in areas ex
`sed to the sun or
`ca cinoma,
`administering to said
`
`rsons a therapeutically effective
`
`a pharmaceuti
`N—(
`least
`one
`of
`acceptable salts thereof in anh
`
`amount
`
`of"
`
`1 composition comprised of’ at
`
`methoxyethoxy)-4—quinazolinami e,
`
`—ethynylphenyl)—6,7-bis(2-
`
`and
`
`pharmaceutically
`
`rous and hydrate forms,
`
`
`/j$}{/
`
`S
`
`éj 3
`
`so
`
`as
`
`to thereby result
`
`in pr hylaxis
`
`against
`
`the
`
`development of basal or
` —
`skin.
`
`squamous
`
`c
`
`l carcinoma of
`
`the
`
`_______fl____________n_;______.____________._____.~___—~
`
`
`
`Please add new claims 55-72 as follows:
`
`
`
`55.
`
`(New) A cosposition comprising a crystalline polymorph of
`
`the hydrochl~ride salt of N-(3—ethynylphenyl)-6,7—bis(2-
`
`methoxyethoxy) 4—quinazolinamine
`
`designated
`
`the
`
`B
`
`polymorph
`that
`e hibits
`an X-ray
`powder diffraction
`pattern having c:£La teristic peaks expressed in degrees
`
`2—theta
`
`at
`
`approxi-ately 6.26,
`
`12.48,
`
`13.39,
`
`16.96,
`
`20.20, 21.10, 22.98,
`
`..46, 25.14 and, 26.91 in a weight
`
`% of the B polymorph relative to the A polymorph which is .
`
`.
`
`at least 70%.
`
`
`
`J
`
`APOTEX EX. 1003-003
`
`

`
`
`
`
`
`
`
`
`O
`
`O
`
`r
`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page:
`
`4
`
`composition
`
`of
`
`claim 55, wherein
`
`the
`
`B
`
`of
`
`the
`
`hydrochloride
`
`salt
`
`of
`
`N-(3-
`
`X~ray
`
`powder diffraction pattern having
`
`56.
`
`(N\\
`
`The
`
`polymo ph
`
`
`
`characterist'c peaks
`
`expressed in degrees 2-theta at
`
`approximately:
`
`
`
`
`
`EMIIIIMIIIEIIIIEII
`ellflflfii
`3 IQRIE
`
`I IESIE
`IEEI‘:'!!;!-EIEIEI
`3
`
`I EEK
`
`I $&FlEE
`‘
`
`
`
`2.9MI
`I@$I.-E
`
`
`composition of claim \g5, wherein the N—(3—
`
`ethynylphenyl)-6,7—bis(2~methoxyethoxy)—1—quinazolinamine
`
`(New)
`
`The
`
`57.
`
`hydrochloride in the polymorph B form is c aracterized by
`
`
`the X-ray powder diffraction pattern shown in Figure 3.
`§:L/L)
`E58.
`(New)
`A pharmaceut'cal
`composition which
`comprises
`a
`)@
`thera£Jeutically effec ive
`amount
`of
`the
`polymorph of
`claim 1 and a pharmaceut'cally acceptable carrier.
`
`
`
`aceutical composition of claim 5
`
`, wherein
`
`q
`
`l‘a’fi6.
`
`:y7
`.
`fa
`iE\,
`
`
`(New) The pha
`said composition
`(New) The pharmaceutica
`
`‘s adapted for oral administration.
`
`
`the pharmaceutical
`
`tablet.
`
`
`compo
`
`
`composition of claim , wherein
`
`is
`
`in the
`
`form of
`
`a
`
` ‘tion
`
`47
`
`(9
`
`APOTEX EX. 1003-004
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`
`1.
`
`pol morph
`
`of
`
`the
`
`hydrochloride
`
`salt
`
`of
`
`N—(3-
`
`ethy‘ylphenyl)-6,7-bis(2—methoxyethoxy)-4-quinazolinamine
`
`design-ted
`
`the
`
`B
`
`polymorph
`
`by
`
`recrystallization
`
`compris‘ng the steps of:
`
`a)
`
`heat ng
`
`to
`
`reflux
`
`alcohol,
`
`water
`
`and
`
`the
`
`hydrochloride salt of N—(3-ethynylphenyl)-6,7—bis(2—
`
`xa
`methox rthoxy ~4—quinazolinamine
`
`so
`
`as
`
`to form a
`
`solution-
`
`b)
`
`c)
`
`d)
`
`cooling t e solution to between about 65 and 70
`
`‘C;
`
`clarifying the solution; and
`
`precipitati g polymorph B
`
`by
`
`further cooling the
`
`clarified so ution.
`
`62.
`
`(New)
`
`A 0 composition
`
`comprising
`
`a
`
`substantially
`
`homogeneous crystalli e polymorph of N—(3—ethynylphenyl)—
`I
`0‘ 3-‘ U)
`
`(2-methoxyethox~)~4~quinazolinamine
`
`hydrochloride
`
`ON
`
`\I
`
`in the form of polymorpx B, which is characterized by the
`
`following peaks:
`
`Po!
`
`0 h B
`
`Anode: Cu - Wavelenth 1 1.54056 Wavelenth 2: 1. 439 Re! Intensi
`
`:0.500
`
`Range # 1 - Coupled 3.000 to. 40.040 Stepsize: 0.040 tepTime 1.00
`
`Smoothing Width: 0.300 Threshold: 1.0
`
`MEI
`IEEEIIIIEH
`IE
`EM‘
`
`14.4 III'I—E
`$IEKE
`
`4-7
`2.9
`EIEEIIEEIE
`
`or,
`
`APOTEX EX. 1003-005
`
`5 6
`
`(N~w)
`
`A method
`
`for
`
`the production of
`
`a crystalline
`
`

`
`-
`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`6
`
`PoumoQhB
`Ano 2 Cu — Wavelenth 1 1.54056 Wavelenth 2: 1.54439 Rel Intensi
`
`:0.50O
`
`Range#
`
`- Coupled: 3.000 to 40.040 StepSize 0.040 StepTime: 1.00
`
`Smothing
`
`th:O.300 Threshold: 1.0
`
`Ea?-IIREII
`@ @
`EEIE
`El‘
`IIEIEIHIE
`|‘..1!EEI—E-
`EEEVEZIIEKEZ
`EIEEIE
`
`Q (/ Em!%—lH
`‘
`) ImE$$EI 1.7
`
`C
`
`3.
`
`(New) A method of ind cing differentiation of tumor cells
`
`I;
`
`in a
`
`tumor
`
`comprisino
`
`contacting the cells with an
`
`effective amount
`
`of
`
`‘the
`
`compound
`
`of
`
`claim 1,
`
`or
`
`a
`
`composition
`
`of
`
`claims
`
`or
`
`6
`
`so
`
`as
`
`to
`
`thereby
`
`differentiate the tumor cells.
`
`(New) A method for the treatment 0' NSCLC (non small cell
`
`lung cancer), pediatric malignancie
`
`cervical and other
`
`tumors caused or promoted by human pap lloma virus (HPV),
`
`melanoma, Barrett's esophagus
`
`(pre—maliqnant
`
`syndrome),
`
`adrenal
`
`and skin cancers
`
`and
`
`auto immune, neoplastic
`
`cutaneous
`
`diseases
`
`and
`
`atherosclerosis
`
`in
`
`a mammal
`
`comprising
`
`administering
`
`to
`
`said
`
`ma
`
`al
`
`a
`
`therapeutically effective
`
`amount
`
`of
`
`a
`
`pharmaceutical
`
`composition
`
`comprised
`
`of
`
`at
`
`least
`
`one
`
`of
`
`N—(3-
`
`ethynylphenyl)—6,7~bis(2-methoxyethoxy -4-
`
`quinazolinamine,
`
`and pharmaceutically acceptable s:lts
`
`thereof in anhydrous and hydrate forms.
`
`. 4
`
`
`
`/
`
`9'
`
`Q)
`
`S; U
`
`The metho of
`(New)
`further comprises
`a
`monotherapy.
`
`treatment
`claim %, wherein the
`pa liative or neo—adjuvant/adjuvant
`
`53
`
`APOTEX EX. 1003-006
`
`

`
`-
`
`' Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page:
`
`7
`
`(New)
`
`The method of
`
`claim.1§fl{ wherein the treatment
`
`further
`
`comprises
`
`blocking
`
`epidermal
`
`growth
`
`factor
`
`eceptors (EGFR).
`
`V1
`The method. of clain1i§4,
`
`for‘ use in treatment of
`
`
`
`(New)
`
`3ft 3%;
`
`155K
`Q7
`9
`firlfl
`
`J
`
`EEQ
`
`3°
`Tfli
`
`that express EGFRVIII.
`
`method of
`
`claim\\;AC wherein the
`
`treatment
`
`further co prises a combination with any of chemotherapy
`
`and immunoth rapy,
`
`further comprises
`
`treatment with either or both anti-
`
`, wherein the treatment
`
`claim
`The meth d of
`(New)
`EGFR and anti—EGF a tibodies.
`off
`
`(New)
`The method of
`\\J
`laim jflc wherein the treatment
`further comprises a furth r administration to said mammal
`
`of a member of the group co sisting of inhibitors of MMP
`
`(matrix—metallo—proteinase), VEGFR
`
`esyl
`fa
`
`.(cytotoxic T—lymphocyte antigen 4)
`rhuMAb—VEGF, erbB2 MAb and a b3 Mab.
`
`growth
`
`factor
`
`receptor),
`
`transferase,
`
`CTLA4
`
`and erbB2, MAb
`
`to
`
`(vascular endothelial
`
`VEGFr,
`
`N
`/51'
`
`7\\k (New) The method of claim fflf wherein
`
`he pharmaceutical
`radiation sensit zers
`
`compounds are used as
`
`for cancer
`
`fl
`
`4;
`‘%
`
`'?K
`
`treatment or in combination with anti-horm nal therapies.
`"~"
`(New) The method of claim 4, wherein the pha aceutical
`
`compounds are used for the inhibition of tumor g owth in
`
`
`humans in a regimen with radiation treatment.
`
`
`057
`
`6
`
`APOTEX EX. 1003-007
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`8
`
`REMLRKS
`
`Claims 1-7, 14-32,
`
`50 and 52-54 were pending in the subject
`
`application.
`
`Applicants have hereinabove amended claims 5,
`
`14, 23 and 50, and added new claim 55-72. Accordingly, claims
`
`1-7, 14-32,
`
`50 and 52-72 are currently pending in the subject
`
`application.
`
`Information Disclosure Statement
`
`In Section 2 of
`
`the December 13,
`
`2001 Office Action,
`
`the
`
`Examiner noted that an IDS was
`
`filed on June 29, 2001, but
`
`indicated that
`
`the form PTO—1449 or
`
`the references could not
`
`be found.
`
`In response, applicants submit as Exhibit 1 a copy of the form
`
`PTO-1449
`
`and as Exhibit
`
`2
`
`a
`
`copy of
`
`the stamped postcard
`
`receipt
`
`indicating that
`
`the U.S. Patent Office received the
`
`Information Disclosure Statement,
`
`including form PTO—1449 and
`
`87 references on June 29, 2001.
`
`The form PTO—1449 and each of
`
`the
`
`references were
`
`clearly marked with
`
`the
`
`subject
`
`application's Serial No.
`
`and filing date.
`
`If the references
`
`received by the U.S. Patent Office on June 29, 2001 have not
`
`yet been forwarded to the Examiner by the Office personnel,
`
`applicants
`
`request
`
`that
`
`the Examiner notify applicants’
`
`attorney by telephone call at
`
`the number provided below and
`
`applicants’ will be happy to hand deliver a courtesy copy of
`
`the references directly to the Examiner.
`
`Objection to Claims
`
`The Examiner
`
`objected
`
`to
`
`claims
`
`2-4
`
`alleging they
`
`are
`
`substantial duplicates of claim 1, and also objected to claims
`
`6 and 7 alleging they are substantial duplicates of claim 5.
`
`The Examiner did not see a distinction between the limitations
`
`{/5
`
`APOTEX EX. 1003-008
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`9
`
`“substantially free of
`
`the A polymorph”
`
`and “substantially
`
`homogeneous”.
`
`In response,
`
`applicants
`
`respectfully point out
`
`that being
`
`“substantially free of
`
`the A polymorph”
`
`is not necessarily
`
`synonymous with being “substantially homogeneous”. Applicants
`
`respectfully request
`
`that
`
`the Examiner
`
`reconsider
`
`these term
`
`and withdraw the objection.
`
`Rejection under 35 U.S.C. § 112, second paragraph
`- claims 5-7
`
`In Section 5 of
`
`the December
`
`13,
`
`2001 Office Action the
`
`Examiner
`
`rejected claims
`
`5-7
`
`under
`
`35 U.S.C.
`
`112,
`
`second
`
`paragraph, as allegedly indefinite for failing to particularly
`
`point out
`and distinctly claim the
`subject matter which
`applicant regards as the invention.
`The three rejected claims
`
`are
`
`compositions
`
`containing polymorph
`
`B
`
`and all
`
`lack a
`
`carrier.
`
`In response, applicants have amended claims 5-7 to recite a
`
`carrier
`
`as
`
`suggested by
`
`the Examiner.
`
`Accordingly,
`
`the
`
`rejection under 35 U.S.C. § 112, second paragraph is moot.
`
`Rejection under 35 U.S.C. § 112, second paragraph
`- claims 14 and 17-23
`
`In Section 6 of
`
`the December
`
`13,
`
`2001 Office Action the
`
`Examiner
`
`rejected claims
`
`14
`
`and 17-23 under
`
`35 U.S.C.
`
`112,
`
`second paragraph,
`
`as
`
`allegedly indefinite
`
`for
`
`failing to
`
`particularly point out and distinctly claim the subject matter
`
`which applicants
`
`regard as
`
`the
`
`invention.
`
`The Examiner
`
`alleged that
`
`the phrase “a hyperproliferative disorder” is
`
`indefinite, noting, however,
`
`that
`
`from the dependent claims,
`
`it
`
`is clear
`
`that
`
`this disorder
`
`includes solid tumors.
`
`The
`
`I5
`
`APOTEX EX. 1003-009
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 10
`
`Examiner
`
`questioned whether
`\\
`
`leukemias
`
`are
`
`also
`
`covered,
`
`whether psoriasis
`
`is
`
`a hyperproliferative disorder”,
`
`and
`
`whether hirsutism be covered.
`
`In response,
`
`applicants
`
`respectfully submit
`
`that
`
`the
`
`term
`
`“hyperproliferative disorder” would be readily understood by
`
`one of skill
`
`in the art.
`
`For example, “proliferation” is
`
`defined by Stedman’s Medical Dictionary, 27“ Edition,
`
`to mean
`
`“growth
`
`and
`
`reproduction of
`
`similar cells.”
`
`The prefix
`
`“hyper—”
`
`is
`
`defined
`
`by
`
`the
`
`same dictionary as meaning
`
`“excessive, above normal.”
`
`A copy of the relevant portions of
`
`the dictionary are attached is Exhibit 3.
`
`Thus,
`
`the "term
`
`“hyperproliferative disorder” would be readily understood by
`
`one of skill
`
`in the art
`
`to mean a disorder where there is
`
`abnormal cell growth.
`
`To advance prosecution of the subject
`
`application,
`
`applicants
`
`have
`
`amended
`
`the
`
`claims
`
`to recite
`
`“abnormal
`
`cell
`
`growth”
`
`instead
`
`of
`
`“hyperproliferative
`
`disorder”, which
`
`terms
`
`applicants
`
`contend are
`
`synonymous.
`
`Applicants will use the term “abnormal cell growth” because
`
`this term is explicitly defined in the subject application on
`
`page
`
`23,
`
`line
`
`25
`
`to page
`
`24,
`
`line
`
`7,
`
`and
`
`exemplified
`
`throughout the subject specification.
`
`Accordingly,
`
`applicants
`
`respectfully request
`
`reconsideration
`
`and withdrawal of the rejection under 35 U.S.C.
`
`§ 112,
`
`second
`
`paragraph.
`
`Rejection under 35 U.S.C. § 112, first paragraph
`- claims 14 and 16-22
`
`In Section 7 of
`
`the December
`
`13,
`
`2001 Office Action,
`
`the
`
`Examiner rejected claims 14 and 16-22 under 35 U.S.C.
`
`§ 112,
`
`first paragraph, as allegedly containing subject matter which
`
`APOTEX EX. 1003-010
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 11
`
`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
`
`applicants
`
`are
`
`not
`
`enabled
`
`for
`
`treatment
`
`of
`
`that
`\\
`
`a
`
`hyperproliferative disorder” generally.
`
`The Examiner cited In
`
`re Buting 163 USPQ 689,
`
`for
`
`the preposition that evidence
`
`involving a single compound and two type of cancer was not
`
`found
`
`sufficient
`
`to
`
`establish the
`
`enablement
`
`of
`
`claims
`
`directed to a method of
`
`treating seven types of cancer with
`
`members of a class of several compounds.
`
`The Examiner also
`
`cited Draetta
`
`(Ann. Reports Med. Chem.),. final
`
`sentence on
`
`page 246,
`
`for
`
`the quote,
`
`“[A)lthough many still think about
`
`the need for a magic bullet as a cure for all cancers, our
`
`knowledge of
`
`the molecular mechanism underlying this disease
`
`make
`
`the prospect of developing such a universal cure very
`
`unlikely.”
`
`The Examiner did acknowledge
`
`that advances
`
`in
`
`chemotherapy have seen the development of specific compounds
`
`to treat specific types of cancer.
`
`In response, applicants point out
`
`that
`
`the rejected claims 14
`
`and 16-22 are all directed to a specific compound for
`
`the
`
`treatment
`
`of
`
`specific
`
`types
`
`of
`
`cancer.
`
`The Examiner's
`
`citation of
`
`In
`
`re Buting 163
`
`USPQ
`
`689
`
`and Draetta
`
`is
`
`misplaced,
`
`therefore. Applicants specification,
`
`on the very
`
`first page, states that
`
`the specific compound,
`
`a polymorph of
`
`which applicants are now claiming,
`
`is known to be an inhibitor
`
`of
`
`the erbB family of oncogenic and protooncogenic protein
`
`tyrosine kinases,
`
`such as epidermal growth factor
`
`receptor
`
`(EGFR),
`
`and
`
`is
`
`therefore
`
`useful
`
`for
`
`the
`
`treatment
`
`of
`
`associated diseases.
`
`The diseases which are known to fall
`
`APOTEX EX. 1003-011
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 12
`
`within this class are described,
`
`for example, on pages 24-29
`
`on the subject specification.
`
`Importantly, Phase I and II 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.
`
`Of note
`
`is
`
`that
`
`the
`
`Examiner has
`
`rejected claim 16, which recites this group of
`
`cancers.
`
`This rejection of claim 16, applicants contend,
`
`is
`
`clearly improper.
`
`All of
`
`the cancers of
`
`the Clinical Trials are EGFR positive
`
`tumor
`
`types.
`
`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. Therefore, applicants have enabled the treatment of
`
`any disease by the inhibition of the erbB family of oncogenic
`
`and protooncogenic protein tyrosine kinases, such as epidermal
`
`growth factor receptor (EGFR).
`
`Accordingly, applicants respectfully request that the Examiner
`
`reconsider and withdraw the rejection under 35 U.S.C.
`
`§ 112,
`
`first paragraph.
`
`Rejection under 35 U.S.C. 112, first paragraph — claim 50
`
`In Section 8 of
`
`the December
`
`13,
`
`2001 Office Action,
`
`the
`
`Examiner
`
`rejected claim 50
`
`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 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
`
`despite
`
`intensive
`
`efforts,
`
`.3
`
`APOTEX EX. 1003-012
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 13
`
`pharmaceutical
`
`science has
`
`been unable
`
`to find a 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, Genentech vs Novo Nordisk,
`
`42 USPQ 2“ 1001, 1006.
`
`In
`
`response,
`
`applicants
`
`have
`
`amended
`
`claim 50
`
`to recite
`
`prophylaxis against
`
`the development of basal or squamous cell
`
`carcinoma of
`
`the skin.
`
`Prophylaxis against
`
`the development
`
`can be readily practiced by anyone skilled in the art and does
`
`not
`
`require prevention.
`
`As
`
`the Examiner will appreciate,
`
`because the recited compound is known
`
`to inhibit EGFR,
`
`and
`
`basal and squamous cell carcinomas are EGFR positive,
`
`it
`
`is
`
`reasonable
`
`to expect
`
`a prophylactic effect
`
`against
`
`these
`
`carcinomas during early stages.
`
`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 under 35 U.S.C. 1021a)
`
`In Section 9 of
`
`the December 13,
`
`2001 Office Action,
`
`the
`
`Examiner
`
`rejected claims 1-7, 14-23,
`
`50,
`
`and 52—54 under 35
`
`U.S.C.
`
`102(e)
`
`as allegedly anticipated by U.S. Patent No.
`
`5,747,498
`
`to Schnur
`
`(“the
`
`‘498 patent”).
`
`The
`
`Examiner
`
`alleged
`
`that
`
`the
`
`reference
`
`teaches
`
`the
`
`synthesis
`
`and
`
`0
`
`APOTEX EX. 1003-013
`
`

`
`‘Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 14
`
`crystallization
`
`of
`
`N-(3-ethynylphenyl)—6,7—bis(2-
`
`methoxyethoxy)—4—quinazolinamine, monohydrochloride in Example
`
`20,
`
`lines 30-49,
`
`column 22.
`
`The Examiner acknowledged that
`
`applicants have
`
`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 that polymorph B
`
`is the
`
`more stable form.
`
`The Examiner question whether the material
`
`made by Schnur
`
`(‘498)
`
`is polymorph A, whether earlier workers
`
`also found the more stable form,
`
`and whether
`
`the material
`
`prepared by Schnur
`
`(‘498)
`
`could contain some or substantial
`
`amounts of polymorph B.
`
`In
`
`response,
`
`applicants
`
`respectfully submit
`
`that
`
`it
`
`is
`
`improper
`
`to base an anticipation rejection on what
`
`someone
`
`could have possibly prepared.
`
`The word “polymorph” does not
`
`appear
`
`in the ‘498 patent.
`
`The process of Example 20 of the
`
`‘498 patent
`
`is not
`
`the same as the process described by the
`
`subject application for preparing claimed polymorph B.
`
`Therefore,
`
`the anticipation rejection is
`
`improper at
`
`least
`
`because all of the recited elements of applicants’ claims are
`
`not
`
`found in the ‘498 patent.
`
`Assuming,
`
`arguendo,
`
`that
`
`the
`
`Examiner
`
`is
`
`relying
`
`on
`
`an
`
`inherency
`
`theory,
`
`applicants
`
`respectfully point out
`
`that
`
`inherency cannot be predicated on
`
`mere possibilities.
`
`Accordingly,
`
`the rejection under
`
`35 U.S.C.
`
`§
`
`102
`
`should be
`
`withdrawn.
`
`Rejection under 35 U.S.C. 103(3)
`
`In Section 10 of
`
`the December 13,
`
`2001 Office Action,
`
`the
`
`15
`
`APOTEX EX. 1003-014
`
`

`
`:App1icant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 15
`
`Examiner
`
`rejected claims 24~32 under
`
`35 U.S.C.
`
`§ 103(a)
`
`as
`
`allegedly unpatentable
`over Schnur
`(‘498).
`The Examiner
`alleged that
`the reference teaches crystallization of N-(3-
`
`ethynylphenyl)-6,7—bis(2—methoxyethoxy)—4~quinazolinamine,
`
`monohydrochloride from chloroform and ether.
`
`The Applicants
`
`claim crystallization from water and alcohol.
`
`The Examiner
`
`alleged that
`
`the difference between the claimed and taught
`
`processes is the solvent employed,
`
`and changes in solvent are
`
`a matter of
`
`routine experimentation to the process chemist
`
`trying safer and less flammable solvents for the pilot plant.
`
`The
`
`Examiner
`
`quoted
`
`the
`
`Board
`
`of
`
`Patent Appeals
`
`and
`
`Interferences in Ex parte Goldschmidt,
`
`123 USPQ 41 “It
`
`is our
`
`opinion that
`
`is does not amount
`
`to invention for the skilled
`
`chemist...to determine...which specific organic
`
`solvent
`
`is
`
`most suitable”.
`
`In
`
`response,
`
`applicants
`
`respectfully point
`
`out
`
`that
`
`the
`
`rejection fails to explain how, merely from the disclosure of
`
`the ‘498 patent, one would be motivated to 1)
`
`try the specific
`
`combination of" water
`
`and alcohol,
`
`and 2)
`
`have a
`
`reasonable
`
`expectation of the success of this combination.
`
`In fact,
`
`the
`
`rejection even fails to point out where in the ‘498 patent a
`
`combination of solvents of water and alcohol are taught or
`
`suggested.
`
`Even if all of these shortcomings of the rejection
`\\
`
`could be addressed by the proffered
`
`routine experimentation”
`
`theory,
`
`how one would arrive at
`
`a process
`
`for preparing
`
`polymorph B, as recited in claims 24-32,
`
`is also not explained
`
`in the rejection.
`
`Accordingly,
`
`the rejection under
`
`35 U.S.C.
`
`§ 103 should be
`
`withdrawn.
`
`1%
`
`APOTEX EX. 1003-015
`
`

`
`v-Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 16
`
`Conclusion
`
`In view of the amendments and remarks hereinabove, applicants
`
`maintain that
`
`the cited reference does not
`
`teach or suggest
`
`‘applicants’
`
`claimed
`
`invention.
`
`Accordingly,
`
`applicants
`
`respectfully request
`
`that
`
`the Examiner reconsider and withdraw
`
`the rejections and objection set
`
`forth in the December 13,
`
`2001 Office Action and earnestly solicit allowance of
`
`the
`
`pending claims.
`
`No fee, other than the enclosed $920.00 fee for a three-month
`
`extension of time,
`
`is deemed necessary in connection with the
`
`filing of
`
`this Amendment.
`
`However,
`
`if any additional
`
`fee is
`
`required, authorization is hereby given to charge the amount
`
`of any such fee to Deposit Account No. 03-3125.
`
`Respectfully submitted,
`
`this
`that
`certify
`hereby
`I
`is
`being
`deposited
`correspondence
`this
`date with
`the U.S.
`Postal
`Service with sufficient postage as
`first
`class mail
`in an
`envelope
`““m3“dt°*
`Assistant Commissioner
`Washington, D.C. 20231 .
`
`for Patents
`
`Reg. No. 39,992
`
`Gary J. Gershik
`
`
`
`-
`
`I
`28 678
`
`‘ John p_ White
`Registration NO
`,
`Gary J- Gershlk
`Registration NO. 39,992
`Attorneys for Applicants
`cooper & Dunham LLP
`1185 Avenue of the Americas
`
`New York, New York 10036
`(212) 278~O400
`
`(5
`
`APOTEX EX. 1003-016
`
`

`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 17
`
`TITLE WITH REVISION SHOWN
`
`STABLE POLYMORPH ON N-(3-ETHYNYLPHENYLAMffi6)-6,7*BIS (2-
`
`METHOXYETHOXY)-4-QUINAZOLINAMINE HYDROCHLORIDE, METHODS OF
`
`PRODUCTION, AND PHARMACEUTICAL USES THEREOF
`
`0
`
`APOTEX EX. 1003-017
`
`

`
`. Applicant: Timothy Norris et a1.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page:
`18
`
`CLAIM SET WITH REVISION SHOWN
`
`1.
`
`A substantially homogeneous crystalline polymorph of the
`
`hydrochloride
`
`salt
`
`of
`
`N—(3—ethynylphenyl)—6,7-bis(2-
`
`methoxyethoxy)—4—quinazolinamine
`
`designated
`
`the
`
`B
`
`polymorph
`
`that
`
`exhibits
`
`an X—ray
`
`powder diffraction
`
`pattern having characteristic peaks expressed in degrees
`
`2—theta
`
`at
`
`approximately
`
`6.26,
`
`12.48,
`
`13.39,
`
`16.96,
`
`20.20, 21.10, 22.98, 24.46, 25.14, and 26.91.
`
`2.
`
`The polymorph of claim 1,
`
`characterized by the X—ray
`
`powder diffraction pattern shown in Figure 3.
`
`3.
`
`A crystalline polymorph of
`
`the hydrochloride salt of N-
`
`(3—ethyny1phenyl)—6,7—bis(2-methoxyethoxy)-4-
`
`quinazolinamine designated the B polymorph that exhibits
`
`an X—ray powder diffraction pattern having characteristic
`
`peaks expressed in degrees 2—theta at approximately 6.26,
`
`12.48,
`
`13.39, 16.96, 20.20, 21.10, 22.98, 24.46,
`
`25.14
`
`and,
`
`26.91, which
`
`is
`
`substantially free
`
`of
`
`the
`
`A
`
`polymorph.
`
`4.
`
`The polymorph of claim 3,
`
`characterized by the X—ray
`
`powder diffraction pattern shown in Figure 3.
`
`5.
`
`(Amended)
`
`A
`
`composition
`
`comprising
`
`a
`
`substantially
`
`homogeneous crystalline polymorph of
`
`the hydrochloride
`
`salt
`
`of N—(3—ethynylpheny1)—6,7—bis(2—methoxyethoxy)-4-
`
`quinazolinamine designated the B polymorph that exhibits
`
`an X—ray powder diffraction pattern having characteristic
`
`peaks expressed in degrees 2—theta at approximately 6.26,
`
`12.48,
`
`13.39, 16.96, 20.20, 21.10,
`
`22.98, 24.46, 25.14
`
`/b’
`
`APOTEX EX. 1003-018
`
`

`
`.Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 19
`
`and, 26.91, and a carrier.
`
`6.
`
`The
`
`composition of claim 5, wherein the hydrochloride
`
`salt
`
`of N-(3—ethynylphenyl)-6,7—bis(2—methoxyethoXy)-4-
`
`quinazolinamine
`
`exhibits
`
`an X—ray
`
`powder diffraction
`
`pattern having characteristic peaks expressed in degrees
`
`2-theta at approximately:
`
`
`
`2-Theta
`2-Theta
`Irel
`2—Theta
`lrel
`elmmfllm
`
`IE 3
`.
`3.9KB
`IEEIIIIIE
`EIEIEZIIII
`EIKIEIII
`EIIEIIII
`
`
`IE
`
`
`
`
`
`
`
`7.
`
`The
`
`composition
`
`of
`
`claim 5,
`
`wherein
`
`the
`
`N—(3—
`
`ethynylphenyl)~6,7-bis(2—methoxyethoxy)—4—quinazolinamine
`
`hydrochloride in the polymorph B form is characterized by
`
`the X-ray powder diffraction pattern shown in Figure 3.
`
`14.
`
`(Amended)
`
`A method
`
`of
`
`treating a-hyperproffferative
`
`disorder abnormal cell growth in a mammal which comprises
`
`administering to said mammal a therapeutically effective
`
`amount of the polymorph of claim 1.
`
`15.
`
`The method of claim 14, wherein the method is for
`
`the
`
`treatment of a cancer selected from brain,
`
`squamous cell,
`
`bladder,
`
`gastric,
`
`pancreatic,
`
`breast,
`
`head,
`
`neck,
`
`oesophageal, prostate, colorectal,
`
`lung,
`
`renal,
`
`kidney,
`
`ovarian, gynecological and thyroid cancer.
`
`1/5’
`
`APOTEX EX. 1003-019
`
`

`
`. Applicant:
`Serial No:
`
`Timothy Norris et al.
`09/711,272
`2000
`Filed: November 9,
`20
`Page:
`
`16.
`
`The method of claim 14,
`
`wherein the znethod of
`
`for
`
`the
`
`treatment of
`
`a cancer selected from non—small cell
`
`lung
`
`cancer
`
`(NSCLC),
`
`refractory ovarian cancer, head and neck
`
`cancer, colorectal cancer and renal cancer.
`
`17.
`
`18.
`
`The method of
`
`claim 14, wherein
`
`the
`
`therapeutically
`
`effective
`
`amount
`
`is
`
`from about
`
`0.001
`
`to about
`
`100
`
`mg/kg/day.
`
`The method of
`
`claim 14, wherein
`
`the
`
`therapeutically
`
`effective amount
`
`is from about
`
`1 to about 35 mg/kg/day.
`
`19.
`
`The method of
`
`claim 14, wherein
`
`the
`
`therapeutically
`
`effective amount
`
`is from about
`
`1 to about 7000 mg/day.
`
`20.
`
`The method
`
`of
`
`claim 19, wherein
`
`the
`
`therapeutically
`
`effective amount
`
`is from about 5 to about 2500 mg/day.
`
`The method
`
`21.
`
`of
`
`claim 20, wherein
`
`the
`
`therapeutically
`
`effective amount
`
`is from about 5 to about 200 mg/day.
`
`22.
`
`The method of
`
`claim 21, wherein
`
`the
`
`therapeutically
`
`effective amount
`
`is from about 25 to about 200 mg/day.
`
`23.
`
`(Amended)
`
`A
`
`method
`
`for
`
`the
`
`treatment
`
`of
`
`a
`
`hyperproliferative-disorder abnormal cell growth in a
`
`mammal which comprises
`
`administering to
`
`said mammal
`
`a
`
`therapeutically
`
`effective amount
`
`of
`
`the
`
`polymorph
`
`of
`
`claim 1
`
`in combination with an anti—tumor agent selected
`
`from the group consisting of
`
`a mitotic inhibitor,
`
`an
`
`alkylating agent,
`
`an anti—metabolite,
`
`an
`
`intercalating
`
`antibiotic,
`
`a
`
`growth
`
`factor
`
`inhibitor,
`
`a cell
`
`cycle
`
`fl
`
`APOTEX EX. 1003-020
`
`

`
`y Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 21
`
`inhibitor,
`
`an
`
`enzyme,
`
`a
`
`topoisomerase
`
`inhibitor,
`
`a
`
`biological
`
`response modifier,
`
`an
`
`anti—hormone,
`
`and an
`
`anti—androgen.
`
`24.
`
`A method of preparing a crystalline polymorph of N—(3—
`
`ethynylphenyl)—6,7—bis(2—methoxyethoxy)—4—quinazolinamine
`
`hydrochloride designated the B polymorph which comprises
`
`the step of recrystallizing -(3-ethynylphenyl)-6,7-bis(2-
`
`methoxyethoxy)—4—quinazolinamine
`
`hydrochloride
`
`in
`
`a
`
`solvent comprising alcohol.
`
`25.
`
`The method of
`
`claim 24, wherein the
`
`solvent
`
`further
`
`comprises water.
`
`26.
`
`The method of claim 24, wherein N-(3-ethynylphenyl)-6,7-
`
`bis(2—methoxyethoxy)—4—quinazolinamine
`
`hydrochloride
`
`is
`
`prepared by coupling a compound of formula 6
`
`with
`
`a
`
`compound
`
`of
`
`NH2
`
`formula 4
`
`1%
`
`APOTEX EX. 1003-021
`
`

`
`‘I-‘-4-4...;-Ir-cad
`
`Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 22
`
`27.
`
`The method of claim 26, wherein said compound of
`
`formula
`
`6 is prepared by reacting a compound of formula 5
`
`CH3
`
`CH3
`
`% OH
`
`NH2
`
`in a suspension of metal alkali and solvent and with heating.
`
`28.
`
`The method of claim 26, wherein said compound of
`
`formula
`
`4
`
`is prepared by chlorinating a compound of formula 3
`
`H3C\0NO
`
`H3c/O\/\o
`
`OH
`
`\\N
`J
`N/
`
`.
`
`3
`
`29.
`
`A method for the production of
`
`the polymorph B of claim
`
`1 comprising the steps of:
`
`a)
`
`substitution chlorination of starting quinazolinamine
`
`compound of formula 3
`
`on
`
`\N
`
`/1
`
`N
`
`3
`
`/O%
`
`o
`
`H3C
`
`having an hydroxyl group,
`
`to provide a compound of formula 4
`
`0
`
`APOTEX EX. 1003-022
`
`

`
`«Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`Page: 23
`
`0
`I'I3C/ X/\O
`
`Cl
`
`2
`
`N
`
`4
`
`by
`
`reaction thereof
`
`in a
`
`solvent mixture of
`
`thionyl
`
`chloride, methylene chloride and dimethylformamide,
`
`b) preparation of a compound of formula 6
`
`%
`
`NH2
`
`in situ from starting material of compound of formula 5
`
`CH3
`
`CH3
`
`% OH
`
`NH2
`
`by reaction of the latter in a suspension of metal alkali and
`
`solvent and with heating;
`
`c)
`
`reaction of the compound of formula 6
`
`in situ with the
`
`compound of
`
`formula
`
`4 wherein the
`
`compound of
`
`formula
`
`6
`
`replaces the chlorine in the compound of formula 4
`
`to give the
`
`N—(3—ethynylphenyl)-6,7—bis(2—methoxyethoxy)-4-quinazolinamine
`
`hydrochloride;
`
`13
`
`APOTEX EX. 1003-023
`
`

`
`1 Applicant: Timothy Norris et al.
`Serial No: 09/711,272
`Filed: November 9, 2000
`
`Page: 24
`
`d)
`
`recrystallizing
`
`the Ne(3—ethynylphenyl)—