.
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`UNITED STATES PATENT AND 'Il2ADE:MARx OFFICE
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`.
`
`
`
`UNITED S'l'ATF£'I DEPAKTDIHVT OF COMMERCE
`United States Patent. and Trndernnrk Office
`‘
`Address: COMMISSIONER OF PATENTS AND TRADEMARKS
`Washington. DC. 20231
`www.u.apuJ.gvv
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION N0.
`
`09/7 I 1,272
`
`l I/09/2000
`
`Timothy Norris
`
`628l4—A/JPW/GIG
`
`6700
`
`7590
`
`03/30/2002
`
`J°h“P“’hi*e
`Cooper & Dunham LLP
`ll85 Avenue of the Americas
`New York, NY 10036
`
`MCKENZIE’ THOMAS C
`
`1524
`DATE MAILED: 08/30/2002
`
`(7
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`PTO-90C (Rev. 07-01)
`
`APOTEX EX. 1004-001
`
`

`
`Office Action Summary
`
`Application No.
`
`Applicant(s)
`
`09/711,272
`
`Examine,
`
`Thomas McKenzie Ph.D.
`
`NORRIS ET AL.
`
`Ar, Unit
`
`1624
`
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE §3_ MONTH(S) FROM
`THE MAILING DATE OF THIS COMMUNICATION.
`— Extensions of time may be available under the provisions of 37 CFR 1.136(a).
`after SIX (6) MONTHS from the mailing date of this communication.
`It the period for reply specified above is less than thirty (30) days, a reply within the statutory minimum of thirty (30) days will be considered timely.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this'communication.
`Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`Status
`
`In no event, however, may a reply be timely filed
`
`1)lZ Responsive to communication(s) filed on 19 June 2002 .
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`2a)IZI
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`This action is FINAL.
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`2b)[:j This action is non-final.
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`3):]
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`Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11, 453 O.G. 213.
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`Disposition of Claims
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`4)IZ| Claim(s) 1-7 14-32 50 and 52-72 is/are pending in the application.
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`4a) Of the above c|aim(s) _: is/are withdrawn from consideration.
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`5)XI Claim(s)§1is/are allowed.
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`6)IZ Claim(s) 1-7 14-32 50 52-60 and 62-68 is/are rejected.
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`7)IZI Claim(s) §§_-_7_2 is/are objected to.
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`8)[:l Claim(s)
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`are subject to restriction and/or election requirement.
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`Application Papers
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`9)[:] The specification is objected to by the Examiner.
`
`10)[:j The drawing(s) filed on _ is/are: a)[:] accepted or b)C] objected to by the Examiner.
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`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`
`11)[:] The proposed drawing correction filed on __ is: a)E] approved b)[:] disapproved by the Examiner.
`if approved, corrected drawings are required in reply to this Office action.
`
`12)I:] The oath or declaration is objected to by the Examiner.
`
`Priority under 35 U.S.C. §§ 119 and 120
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`13)[:] Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or ( ).
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`a)D All b)|:l Some * c)[:l None of:
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`1.D Certified copies of the priority documents have been received.
`
`2.[j Certified copies of the priority documents have been received in Appiication No.
`
`3.[] Copies of the certified copies of the priority documents have been received in this National Stage
`application from the International Bureau (PCT Rule 17.2( )).
`" See the attached detailed Office action for a list of the certified copies not received.
`
`14)[] Acknowledgment is made of a claim for domestic priority under 35 U.S.C. § 119(e) (to a provisional application).
`
`a) E] The translation of the foreign language provisional application has been received.
`‘l5)lj Acknowledgment is made of a claim for domestic priority under 35 U.S.C. §§ 120 and/or 121.
`Attachment(s)
`
`1) [:1 Notice of References Cited (PTO-892)
`2) D Notice of Draftsperson’s Patent Drawing Review (PTO-948)
`3) D lnforrnation Disclosure Statement(s) (PTO-1449) Paper No(s)
`U.S. Patent and Trademark Office
`PTO-326 (Rev. 04-01)
`
`Office Action summary
`
`4) [3 interview Summary (PTO-413) Paper No(s).
`5) [3 Notice of lnforrnal Patent Application (PTO-152)
`6) [3 Other:
`
`.
`
`.
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`Part of Paper No. 9
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`APOTEX EX. 1004-002
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`

`
`Application/Control Number: 09/711,272
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`Page 2
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`Art Unit: 1624
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`1.
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`This action is in response to amendments filed on 6/19/02. Applicants have
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`DETAILED ACTION
`
`.
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`amended claims 5, 14, 23, and 50. Claims 55-72 are new. There are forty-eight
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`claims pending and under consideration. Claims 1-4 are compound claims.
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`Claims 5-7, 55-60, and 62 are composition claims. Claims 14-23, 50, and 63-72
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`are use claims. Claims 24-32, 52-54, and 61 are method of making claims. This is
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`the second action on the merits. The application concerns a specific crystal form
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`of N-(3-efliynylphenyl}6,7-bis(2-rriethoxyethoxy)-4-quinazolinamine hydrochloride, which has
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`Chemical Abstracts registry number 183319-69-9.
`
`Response to Amendment
`Applicants’ addition of a carrier to composition claim 5 overcomes the
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`2.
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`indefiniteness
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`rejection made
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`in
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`point
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`#5.
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`Applicants
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`replaced
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`“a
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`hyperproliferative disorder” with “abnormal cell growt ” in claim 14 and point the
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`paragraph spanning pages 23 to 24 as indicating what they intend. Thus, the
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`indefiniteness rejection made in point #6 is withdrawn.. Applicants point to the
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`phase II studies in the passage spanning line 19, page 51 to line 35, page 52 as
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`enabling their claims to treating specific cancers. This is persuasive, and the
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`enablement rejection to claim 16 is withdrawn. Claim 50 is an independent claim,
`
`not limited to the polymorph of claim 1. In lines 9-10, column 14 of Schnur (‘498)
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`treatment
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`of
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`hepatic
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`carcinoma
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`with
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`N-(3-ethynylpheny1)-6,7-bis(2-
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`APOTEX EX. 1004-003
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`

`
`Application/Control Number: 09/711,272
`Art Unit: 1624
`
`Page 3
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`methoxyethoxy)-4-quinazolinarnine in taught. Prophylaxis is taught in lines 7 and
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`8, column 14. However, prophylaxis against basal cell carcinoma is nowhere
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`taught
`
`in the reference.
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`Thus,
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`the anticipation rejection against claim 50 is
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`withdrawn.
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`Information Disclosure Statement
`The copy of PTO-1449 and the post card receipt supplied by Applicants is
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`3.
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`acknowledged. The Examiner cannot find any references in the file and a search
`
`has been started.
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`Claim Objections
`Objection remains to claims 2-4 under 37 CFR 1.75 as being a substantial
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`4.
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`duplicate of claim 1. When two claims in an application are duplicates or else are
`
`so close in content that they both cover the same thing, despite a slight difference
`in wording, it is proper after allowing one claim to object to the otheras being a
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`substantial duplicate of the allowed claim. See MPEP §706.03(k). The four
`
`claims
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`concern
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`the
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`B
`
`polymorph
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`of N-(3-ethynylphenyl)-6,7—bis(2-
`
`methoxyethoxy)-4-quinazolinarnine, monohydrochloride. There Applicants state
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`that only two polymorphs are known, A and B. There are only two purity
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`limitations in the four objected claims, “substantially homogeneous” in claim 1 and
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`“substantially free of the A polymorph” in claim 3. A substance, which exhibits x-
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`ray diffraction peaks, must be crystalline. The Examiner can see no difference in
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`APOTEX EX. 1004-004
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`

`
`Application/Control Number: 09/711,272
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`Page 4
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`Art Unit: 1624
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`these limitations. Thus, all four claims are to the same substance with the same
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`purity limitation.
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`5.
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`Objection remains to claims 6 and 7 under 37 CFR 1.75 as being a
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`substantial duplicate of claim 5, for reasons cited previously.
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`6.
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`Objection is made to claims 56 and 57 under 37 CFR 1.75 as being a
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`substantial duplicate of claim 55, for reasons cited above.
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`7.
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`Objection is made to claim 58 underi37 CFR 1.75 as being a substantial
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`duplicate of claim 5.
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`It is not logical that a composition intended for therapy, as is
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`claim 5, would not contain a therapeutically effective amount of the compound of
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`claim 1.
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`8.
`
`Objection is made to claim 62 under 37 CFR 1.75 as being a substantial
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`duplicate of claim 5. Applicants have chosen a different and ultimately equivalent
`
`way of expressing the X-ray data. Both are compositions of the identical
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`substance.
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`Applicants argue that claim 3 differs from claim 1 because “substantially
`
`homogeneous” is not necessarily “substantially free of the A polymorph”. This is
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`not persuasive. Neither phrase is defined in the specification and any homogenous
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`substance must be free of other substances. Applicants made no argument
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`concerning the objection to claims 2, 4, and 6.
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`APOTEX EX. 1004-005
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`

`
`Application/Control Number: 09/711,272
`Art Unit: 1624
`
`Page 5
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`_
`Claim Rejections - 35 USC § 112
`The text of those sections of Title 35, U.S. Code not included in this action
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`9.
`
`can be found in a prior Office action. Claims 14 and 17-22 remain rejected under
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`35 U.S.C. 112,
`
`first paragraph, as containing subject matter which was not
`
`described in the specification in such a way as to enable one skilled in the art to
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`which it pertains, or with which it is most nearly connected, to make and/or use the
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`invention. Applicants are not enabled for treatment of “abnormal cell growth”
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`generally. Evidence involving a single compound and two types of cancer was not
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`found sufficient to establish the enablement of claims directed to a method of
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`treating seven types of cancer with members of a class of several compounds In re
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`Buting 163 USPQ 689.
`
`Applicants argue that claim 14 is drawn to the treatment of specific cancers.
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`They also point to the clinical data presented on the pages spanning 50-53 as
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`enabling their claim. This is not persuasive. Lines 29-30, page 23 says among
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`other diseases that “tumor cells (tumors) both benign and malignant, expressing an
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`activated Ras oncogene” are to be treated. Thus, Applicants’ claim is not limited
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`to the specific tumors of claim 17.
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`10.
`
`Claim 50 is rejected under 35 U.S.C. 112, first paragraph, as containing
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`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
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`APOTEX EX. 1004-006
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`

`
`Application/Control Number: 09/711,272
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`Page 6
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`Art Unit: 1624
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`connected, to use the invention. Applicants are not enabled for preventing basal or
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`squamous cell carcinoma. The only established prophylactics are vaccines not the
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`N—(3-ethynylphenyl)—6,7-bis(2—methoxyethoxy)-4-quinazolinamine
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`salt
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`such as
`
`present here. Despite intensive efforts, pharmaceutical science has been unable to
`
`find a way of getting a compound to be effective for the prevention of proliferative
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`diseases generally. Under such circumstances, it is proper for the PTO to require
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`evidence that such an unprecedented feat has actually been accomplished, In re
`
`Ferens, 163 USPQ 609. No such evidence has been presented in this case. The
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`failure of skilled scientists to achieve a goal is substantial evidence that achieving
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`such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo
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`Nordisk, 42 USPQ2nd 1001, 1006.
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`Applicants have replaced “chemoprevention” with “prophylaxis against”.
`
`The Examiner can see no difference in meaning.
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`11.
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`Claim 63 is rejected under 35 U.S.C. 112, second paragraph, as being
`
`indefinite for failing to particularly point out and distinctly claim the subject matter
`
`which applicant regards as the invention. Is this claim restricted to cancer therapy?
`
`Are there additional
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`reasons for “inducing differentiation of tumor cells”?
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`Clarification is requested.
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`APOTEX EX. 1004-007
`
`

`
`Application/Control Number: O9/711,272
`Art Unit: 1624
`
`Page 7
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`12.
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`Claim 63 is rejected under 35 U.S.C.112, first paragraph, because the
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`specification, while being enabling for
`
`treating specific tumors, does not
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`reasonably provide enablement for cancer treatment generally or for other uses of
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`tumor cell differentiation which are not therapeutic. The specification does not
`
`enable any person skilled in the art to which it pertains, or with which it is most
`
`nearly connected, to use the invention commensurate in scope with these claims.
`
`The issue of general tumor treatment is discussed above. Beyond the passage in
`
`lines 29-31, page 13 Applicants provide no explanation of why one would want to
`
`do this.
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`Claim Rejections - 35 USC § 102
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`13.
`
`Claims 1-7, 14-23, and 52-54 remain rejected under 35 U.S.C. l02(e) as
`
`being anticipated by Schnur (‘498).
`
`‘The reference teaches the synthesis and
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`crystallization
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`of
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`N—(3—ethynylphenyl)-6,7-bis(2—methoxyethoxy)-4-quinazolinamine,
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`monohydrochloride in Example 20, lines 30-49, column 22. Applicants have
`
`amply characterized their material, polymorph B but there is no side-by-side
`
`comparison to the material taught by the reference. Applicants state in lines 15-19,
`
`page 16 the material made by Schnur (‘498) is a mixture of polymorph A and
`
`polymorph B. There is no data provided in the specification as to the ratio A and B
`
`in the prior art. Could the material prepared by Schnur (‘498) contain substantial
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`APOTEX EX. 1004-008
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`

`
`Application/Control Number: 09/71 1,272
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`Page 8
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`Art Unit: 1624
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`amounts of polymorph B? Could it be as high as 70%? Might it be 90%?
`Applicants provide no data as to the numeric ratio of A to B in their material. Line
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`2, page 5 says that it is “substantially homogeneous” polymorph B. What does this
`
`mean? Must it be 99.9% polymorph B? Could it be 90%? Could it be 51%?
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`Treatment of lung, ovarian, head, neck, colorectal, and renal cancer is taught
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`in lines 8-11, column 14 of the reference.
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`Applicants make two arguments, firstly, that Schnur (‘498) does not use the
`
`word polymorph. Secondly, that Applicants’ process used to produce the crystal
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`form of claim 1 differs from that of the reference used to produce their crystalline
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`material. Neither argument is persuasive. Applicants’ claim 1
`
`is for a specific
`
`crystal form of a known compound salt. Patentability of Applicants’ crystal form
`
`derives from the structure of that crystal, specifically the internal arrangement of
`
`the molecule within the crystal lattice and the form of the crystal lattice itself.
`
`In
`
`re Spada 15 USPQ2d 1655 (new property of previously known composition does
`
`not impart patentability to the composition). The relevance to patentability of the
`
`x-ray characteristics exhibited by Applicants’ compound is limited to assessing the
`
`significance of their crystal structure over the prior art. When the Examiner shows
`
`sound basis for believing that the products of the applicant and the prior art are the
`
`same, the applicant has the burden of showing that they are not.
`
`In re King 231
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`APOTEX EX. 1004-009
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`

`
`Application/Control Number: 09/711,272
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`Page 9
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`Art Unit: 1624
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`USPQ 136; In re Ludtke 169 USPQ 563. The inherency case of anticipation can be
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`rebutted by evidence showing that the prior art products do not necessarily possess I
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`the characteristics of the claimed product.
`
`In re Best 195 USPQ 430 (prior art
`
`zeolite with same SiO2/Al2O3and Na2O/A1203 molar ratios but not specifically
`
`disclosing x-ray powder data either anticipates based on "inherency" under 35 USC
`
`102, on "prima facie obviousness" under 35 USC 103, jointly or alternatively).
`
`Secondly, the patentability of a new chemical structure is independent of
`
`how it is made, In re Hoeksema 141 USPQ 733 (product patentable even though
`
`the process was obvious).
`
`14.
`
`Claims 55-60 are rejected under 35 U.S.C. l02(e) as being anticipated by
`
`Schnur (‘498). Compositions are taught in the reference in the passage spanning
`
`line 63, column 15 to line 45, column 16. Tablets are specifically mention in line
`
`64. Applicants admit that polymorph B is taught by the reference. The silence of
`
`the reference as to the amount of polymorph B present does not make Applicants
`
`claims patentable for the reasons cited above.
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`15.
`
`Claims 62-68 are rejected under 35 U.S.C. 102(e) as being anticipated by
`
`Schnur (‘498). Applicants admit that the prior art material and the composition
`
`made from it contain polymorph B. The prior art and Applicants’ silence as to the
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`ratios do not make their claims patentable for reasons cited above. Cancer therapy
`
`APOTEX EX. 1004-010
`
`

`
`Application/Control Number: 09/711,272
`
`Page 10
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`Art Unit: 1624
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`broadly in found in claim 28 of the reference. Applicants’ claim 64 is an
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`independent claim with no limitation as to crystal form. Treatment of lung cancer,
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`leukemia, and cervical tumors is taught in lines 6-16, column 14.
`
`treatment of
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`"immunological disorders" is taught in 28, column 14.
`
`treatment t of skin cancer is
`
`taught in claim 29. The concept of additional anti-tumor agents is taught in lines
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`46-51, column 16.
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`Claim Rejections - 35 USC § 103
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`16.
`
`Claims 24-32 remain rejected under 35 U.S.C. l03(a) as being unpatentable
`
`over Schnur (‘498). The reference teaches crystallization of N-(3-ethynylphenyl)-6, —
`bis(2-methoxyeflioxy)-4-quinazolinamine, monohydrochloride
`from chloroform and
`
`ether.
`
`The Applicants claim crystallization from water and alcohol.
`
`The
`
`difference between the claimed and taught processes is the solvent employed.
`
`Changes in solvent are amatter of routine experimentation to the process chemist
`trying safer and less flammable solvents for the pilot plant. No more than routine
`
`skill is required.for the process chemist to optimize the solvent choice. To quote
`
`the Board of Patent Appeals and Interferences Ex parte Goldschmidt, 123 USPQ
`
`41 “It is our opinion that it does not amount to invention for the skilled chemist
`
`to determine which specific organic solvent is most suitable”.
`
`Applicants make two arguments. Firstly, that they were not told where in
`
`the reference to find the teaching of solvent. Secondly, that the prior art reference
`
`made no suggestion to change solvent or which other solvent to choose. The
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`solvent teaching is in lines 45-48, column 22. The Examiner pointed to this
`
`APOTEX EX. 1004-011
`
`

`
`Application/Control Number: O9/711,272
`
`Page 11
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`Art Unit: 1624
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`passage in the anticipation rejection, using the same reference, in point #9 of the
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`previous office action .
`
`Secondly, the Examiner did not use the primary reference for a suggestion to
`
`change solvent. The economic and safety motivation was suggested above.
`
`In
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`addition, routine experimentation does not require a specific teaching. Of course,
`
`if Applicants’ can establish to novelty of their crystal form, then their process
`
`would be non—obvious, In re Ochiai 37 USPQ2d 1127.
`Allowable Subject Matter
`
`17.
`
`Claim 61 is allowed. The prior art does not suggest any clarifying step in
`
`their process.
`
`18.
`
`Claim 69-72 are objected to as being dependent upon a rejected base claim,
`
`but would be allowable if rewritten in independent form including all of the
`
`limitations of the base claim and any intervening claims. The following is a
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`statement of reasons for the indication of allowable subject matter: The prior art
`
`does not teach treatment using the specific additional antibodies, MMP inhibitors,
`
`or radiation treatment required by these claims.
`
`Conclusion
`
`19. Applicant's amendment necessitated the new ground(s) of rejection
`
`presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL.
`
`See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as
`
`set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final
`
`action is set to expire THREE MONTHS from the mailing date of this action.
`
`In
`
`the event a first reply is filed within TWO MONTHS of the mailing date of this
`
`final action andthe advisory action is not mailed until after the end of the THREE-
`
`APOTEX EX. 1004-012
`
`

`
`Application/Control Number: 09/711,272
`Art Unit: 1624
`
`Page 12
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`MONTH shortened statutory period, then the shortened statutory period will expire
`
`on the date the advisory action is mailed, and any extension fee pursuant to 37
`
`CFR 1.l36(a) will be calculated from the mailing date of the advisory action.
`
`In
`
`no event, however, will
`
`the statutory period for reply expire later than SIX
`
`MONTHS from the date of this final action.
`
`20.
`
`Please direct any inquiry concerning this communication or earlier
`
`communications from the Examiner to Thomas C McKenzie, Ph. D. whose
`
`telephone number is (703) 308-9806. The FAX number for after final amendments
`
`is (703) 872-9307. The Examiner is available from 8:30 to 5:30, Monday through
`
`Friday.
`
`If attempts to reach the Examiner by telephone are unsuccessful,
`
`the
`
`Examiner’s supervisor, Mukund Shah can be reached on (703) 308-4716. Please
`
`direct general inquiries or any inquiry relating to the status of this application to
`
`the receptionist whose telephone number is (703) 308-1235.
`
`J JLJ’
`Mukund Shah
`
`August 28, 2002
`
`TCMcK
`
`Supervisory Patent Examiner
`Art Unit 1624
`
`APOTEX EX. 1004-013