Notice of Allowability
`
`Application No.
`11/576,178
`Examiner
`DIANA JOHANNSEN
`
`Applicant(s)
`WOLFGANG ET AL.
`AlA (First Inventor to
`Art Unit
`File) Status
`1634
`No
`
`-- The MAILING DATE of this communication appears on the cover sheet with the correspondence address-(cid:173)
`All claims being allowable, PROSECUTION ON THE MERITS IS (OR REMAINS) CLOSED in this application. If not included
`herewith (or previously mailed), a Notice of Allowance (PTOL-85) or other appropriate communication will be mailed in due course. THIS
`NOTICE OF ALLOW ABILITY IS NOT A GRANT OF PATENT RIGHTS. This application is subject to withdrawal from issue at the initiative
`of the Office or upon petition by the applicant. See 37 CFR 1.313 and MPEP 1308.
`
`1. [gl This communication is responsive to the Supplemental Amendment filed 6/10/13 and interview of 7119/13.
`D A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on ___ .
`2. D An election was made by the applicant in response to a restriction requirement set forth during the interview on __ ; the restriction
`requirement and election have been incorporated into this action.
`
`3. [gl The allowed claim(s) is/are 63-73.76-79 and 82. As a result of the allowed claim(s), you may be eligible to benefit from the Patent
`Prosecution Highway program at a participating intellectual property office for the corresponding application. For more information,
`please see ~;t!;Q:i/www.us_Qto.gov/gatents/init events/QQhiindexjs.Q or send an inquiry to PPHfeedback@'uS(Qto.aov .
`4. D Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
`*c) D None of the:
`a) D All
`b) D Some
`1. D Certified copies of the priority documents have been received.
`2. D Certified copies of the priority documents have been received in Application No. __ .
`3. D 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(a)).
`* Certified copies not received: __ .
`
`Applicant has THREE MONTHS FROM THE "MAILING DATE" of this communication to file a reply complying with the requirements
`noted below. Failure to timely comply will result in ABANDONMENT of this application.
`THIS THREE-MONTH PERIOD IS NOT EXTENDABLE.
`5. D CORRECTED DRAWINGS (as "replacement sheets") must be submitted.
`D including changes required by the attached Examiner's Amendment I Comment or in the Office action of
`Paper No./Mail Date __ .
`Identifying indicia such as the application number {see 37 CFR 1.84{c)) should be written on the drawings in the front {not the back) of
`each sheet. Replacement sheet{s) should be labeled as such in the header according to 37 CFR 1.121 {d).
`6. 0 DEPOSIT OF and/or INFORMATION about the deposit of BIOLOGICAL MATERIAL must be submitted. Note the
`attached Examiner's comment regarding REQUIREMENT FOR THE DEPOSIT OF BIOLOGICAL MATERIAL.
`
`Attachment(s)
`1. D Notice of References Cited (PT0-892)
`2. [gilnformation Disclosure Statements (PTO/SB/08),
`Paper No./Mail Date 0313; 0613; 0713
`3. D Examiner's Comment Regarding Requirement for Deposit
`of Biological Material
`4. [gilnterview Summary (PT0-413),
`Paper No./Mail Date part of 20130718.
`
`/Diana B. Johannsen/
`Primary Examiner, Art Unit 1634
`
`5. [gl Examiner's Amendment/Comment
`6. [gl Examiner's Statement of Reasons for Allowance
`7. D Other __ .
`
`U.S. Patent and Trademark Off1ce
`PTOL-37 (Rev. 05-13)
`
`Notice of Allowability
`
`Part of Paper No./Mail Date 20130718
`
`Vanda Exhibit 2017 - Page 1
`
`

`
`Examiner-Initiated Interview Summary
`
`Application No.
`
`Applicant(s)
`
`11/576,178
`
`Examiner
`
`WOLFGANG ET AL.
`
`Art Unit
`
`DIANA JOHANNSEN
`
`1634
`
`All participants (applicant, applicant's representative, PTO personnel):
`
`(1) Diana Johannsen.
`
`(2) Javme Torelli.
`
`(3) __ .
`
`(4) __ .
`
`Type:
`
`Date of Interview: 19 Julv 2013.
`[8J Telephonic 0 Video Conference
`0 Personal [copy given to: 0 applicant
`Exhibit shown or demonstration conducted: 0 Yes
`If Yes, brief description: __ .
`
`0 applicant's representative]
`1Z1 No.
`
`[8J112 0102 0103 OOthers
`Issues Discussed 0101
`(For each of the checked box( es) above, please describe below the issue and detailed description of the discussion)
`
`Claim(s) discussed: 64 and 79.
`
`Identification of prior art discussed: NA.
`
`Substance of Interview
`(For each issue discussed, provide a detailed description and indicate if agreement was reached. Some topics may include: identification or clarification of a
`reference or a portion thereof, claim interpretation, proposed amendments, arguments of any applied references etc ... )
`
`The examiner contacted applicant's representative on 7/18/13 to discuss minor clarifvinq amendments to claims 64
`and 79. Agreement was reached and an examiner's amendment was authorized on 7/19/13 ..
`
`Applicant recordation instructions: It is not necessary for applicant to provide a separate record of the substance of interview.
`
`Examiner recordation instructions: Examiners must summarize the substance of any interview of record. A complete and proper recordation of
`the substance of an interview should include the items listed in MPEP 713.04 for complete and proper recordation including the identification of the
`general thrust of each argument or issue discussed, a general indication of any other pertinent matters discussed regarding patentability and the
`general results or outcome of the interview, to include an indication as to whether or not agreement was reached on the issues raised.
`0 Attachment
`/Diana B. Johannsen/
`Primary Examiner, Art Unit 1634
`
`U.S. Patent and Trademark Off1ce
`PTOL·413B (Rev. 8/11/2010)
`
`Interview Summary
`
`Paper No. 20130718
`
`Vanda Exhibit 2017 - Page 2
`
`

`
`Application/Control Number: 11/576,178
`Art Unit: 1634
`
`Page 2
`
`EXAMINER'S AMENDMENT
`
`1.
`
`This action is responsive to the amendment filed June 10, 2013 and the interview
`
`concluding July 19, 2013. Claims 63-73, 76-79, and 82 are now allowed, subject to the
`
`examiner's amendment set forth below. In accordance with 37 CFR 1.126, claims 63-
`
`73, 76-79, and 82 will be renumbered as claims 1-16 in the issued patent; original claim
`
`numbering is employed in the examiner's amendment.
`
`2.
`
`An examiner's amendment to the record appears below. Should the changes
`
`and/or additions be unacceptable to applicant, an amendment may be filed as provided
`
`by 37 CFR 1.312. To ensure consideration of such an amendment, it MUST be
`
`submitted no later than the payment of the issue fee.
`
`Authorization for this examiner's amendment was given in a telephone interview
`
`with Jayme M. Torelli on July 19, 2013.
`
`Vanda Exhibit 2017 - Page 3
`
`

`
`Application/Control Number: 11/576,178
`Art Unit: 1634
`
`3.
`
`The application has been amended as follows:
`
`Page 3
`
`In claim 64, at line 7, after "extracted genomic DNA" insert-or mRNA--.
`
`In claim 64, at line 9, after "having sequenced the" delete "amplified CYP2D6
`
`DNA" and insert therefore-DNA sample--.
`
`In claim 64, at line 10, delete "amplified DNA" and insert therefore-DNA
`
`sample--.
`
`In claim 79, at line 2, after "metabolizer'' delete", therefore".
`
`Vanda Exhibit 2017 - Page 4
`
`

`
`Application/Control Number: 11/576,178
`Art Unit: 1634
`
`Page 4
`
`4.
`
`The following is an examiner's statement of reasons for allowance. All of
`
`the claims as amended June 10, 2013 now require steps in which the CYP2D6
`
`genotype of a particular type of patient is assayed or has been assayed in a biological
`
`sample from the patient, and in which particular dosages of iloperidone are internally
`
`administered based on the genotype determined. As noted in the interview summary
`
`mailed April 17, 2013, applicant's arguments of March 20, 2013 were found persuasive
`
`with respect to the fact that prior art did not teach or suggest methods in which the
`
`dosages specified in the claims are administered based on a determination of the
`
`presence or absence of a CYP2D6 poor metabolizer genotype. Particularly, the
`
`teachings of the prior art are not sufficient to suggest that which is claimed in view of:
`
`(a) the teachings of the prior art as exemplified by Bertilsson et al (Br. J. Clin.
`
`Pharmacal. 53:111 [2002]; cited in IDS) regarding the need to establish for each type of
`
`substrate the effect of CYP2D6 genotype on drug metabolism, and the fact that the
`
`actual effect of a CYP2D6 poor metabolizer genotype on iloperidone metabolism was
`
`unknown at the time the invention was made; and (b) the unexpected benefit of
`
`reducing the risk of QTc prolongation by administering the specified reduced dosages of
`
`iloperidone to those with a CYP2D6 poor metabolizer genotype (as disclosed in the
`
`specification and discussed in the arguments of March 13, 2013).
`
`Any comments considered necessary by applicant must be submitted no later
`
`than the payment of the issue fee and, to avoid processing delays, should preferably
`
`accompany the issue fee. Such submissions should be clearly labeled "Comments on
`
`Statement of Reasons for Allowance."
`
`Vanda Exhibit 2017 - Page 5
`
`

`
`Application/Control Number: 11/576,178
`Art Unit: 1634
`
`Page 5
`
`Conclusion
`
`5.
`
`Claim 63, which is generic with respect to the species of previously withdrawn
`
`claims 67-68, has been allowed. The species election requirement of December 30,
`
`2009 has therefore been withdrawn with respect to the multiple species of CYP2D6
`
`poor metabolizer genotype embraced by elected Group I. Claims 67-68 are no longer
`
`withdrawn from consideration because the claim(s) requires all the limitations of an
`
`allowable claim, and claims 67-68 have also been allowed. In view of the above noted
`
`withdrawal of the species election requirement, applicant is advised that if any claim
`
`presented in a continuation or divisional application is anticipated by, or includes all the
`
`limitations of, a claim that is allowable in the present application, such claim may be
`
`subject to provisional statutory and/or nonstatutory double patenting rejections over the
`
`claims of the instant application.
`
`Once a restriction requirement is withdrawn, the provisions of 35 U.S. C. 121 are
`
`no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32
`
`(CCPA 1971 ). See also MPEP § 804.01.
`
`6.
`
`Any inquiry concerning this communication or earlier communications from the
`
`examiner should be directed to DIANA JOHANNSEN whose telephone number is
`
`(571 )272-0744. The examiner can normally be reached on Monday-Friday, 8:30am-
`
`2:30pm.
`
`If attempts to reach the examiner by telephone are unsuccessful, the examiner's
`
`supervisor, Dave Nguyen can be reached at 571/272-0731. The fax phone number for
`
`the organization where this application or proceeding is assigned is 571-273-8300.
`
`Vanda Exhibit 2017 - Page 6
`
`

`
`Application/Control Number: 11/576,178
`Art Unit: 1634
`
`Page 6
`
`Information regarding the status of an application may be obtained from the
`
`Patent Application Information Retrieval (PAIR) system. Status information for
`
`published applications may be obtained from either Private PAIR or Public PAIR.
`
`Status information for unpublished applications is available through Private PAIR only.
`
`For more information about the PAIR system, see http://pair-direct.uspto.gov. Should
`
`you have questions on access to the Private PAIR system, contact the Electronic
`
`Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a
`
`USPTO Customer Service Representative or access to the automated information
`
`system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
`
`/Diana B. Johannsen/
`Primary Examiner, Art Unit 1634
`
`Vanda Exhibit 2017 - Page 7
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicants( s):
`
`Curt D. Wolfgang, et al.
`
`Conf. No.:
`
`7411
`
`Serial No.:
`
`11/576,178
`
`Art Unit:
`
`1634
`
`Filed:
`
`March 28, 2007
`
`Examiner:
`
`Diana B. Johannsen
`
`Examiner: V AND-0002-US
`
`Title:
`
`Methods for the Administration of Iloperidone
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-14 50
`
`AMENDMENT TO NON-FINAL REJECTION
`
`Sir:
`
`I.
`
`INTRODUCTORY COMMENTS
`
`This paper is in response to the non-final Office Action dated December 20, 2012. Please
`
`amend the above-referenced patent application as follows:
`
`The Amendments to the Claims are reflected in the listing of the claims that begins on
`
`page 2 of this paper.
`
`Remarks begin on page 7 of this paper.
`
`The Conclusion appears on page 18 of this paper.
`
`Serial No. 11/576,178
`March 20,2013
`
`1/18
`
`Vanda Exhibit 2017 - Page 8
`
`

`
`II.
`
`AMENDMENTS TO THE CLAIMS
`
`The following listing of claims replaces any previous and prior listings of the claims:
`
`1-62. (Cancelled)
`
`63. (Currently amended) A method for treating a patient with iloperidone, wherein the patient is
`
`suffering from schizophrenia, the method comprising the steps of:
`
`determining whether the patient is a CYP2D6 poor metabolizer by:
`
`obtaining a biological sample from the patient;
`
`extracting genomic DNA or mRNA from the biological sample; and
`
`sequencing CYP2D6 DNA derived from the extracted genomic DNA or from the
`
`extracted mRNA to determine if the patient has a CYP2D6 poor metabolizer genotype;
`
`and
`
`if the patient has a CYP2D6 poor metabolizer genotype, then internally administering
`
`iloperidone to the patient in an amount of 12 mg/day or less, and
`
`if the patient has a CYP2D6 normal metabolizer genotype or a CYP2D6 extensive
`
`metabolizer genotype, then internally administering iloperidone to the patient in an amount that
`
`is greater than 12 mg/day, up to 24 mg/day,
`
`wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer
`
`genotype is lower following the internal administration of 12 mg/day or less than it would be if
`
`the iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/day.
`
`Serial No. 11/576,178
`March 20,2013
`
`2/18
`
`Vanda Exhibit 2017 - Page 9
`
`

`
`64. (Previously presented) The method of claim 63, wherein the extracting step comprises
`
`extracting genomic DNA from the biological sample, and
`
`wherein the sequencing step further comprises: amplifying a CYP2D6 region in the
`
`extracted genomic DNA to prepare a DNA sample enriched in DNA from the CYP2D6 gene
`
`region; and
`
`sequencing the amplified CYP2D6 DNA by hybridizing the amplified DNA to
`
`nucleic acid probes to determine if the patient has a CYP2D6 poor metabolizer genotype; and
`
`wherein the CYP2D6 poor metabolizer genotype is one of the CYP2D6G 1846A
`
`genotype or the CYP2D6C 1 OOT genotype.
`
`65. (Previously presented) The method of claim 64, wherein the CYP2D6 poor metabolizer
`
`genotype is one of the CYP2D6G 1846A (AA) genotype or the CYP2D6G 1846A (AG) genotype.
`
`66. (Previously presented) The method of claim 65, wherein the CYP2D6 poor metabolizer
`
`genotype is the CYP2D6G 1846A (AA) genotype.
`
`67. (Withdrawn) The method of claim 64, wherein the CYP2D6 poor metabolizer genotype is
`
`one of the CYP2D6C100T (TT) genotype or the CYP2D6C100T (CT) genotype.
`
`68. (Withdrawn) The method of claim 67, wherein the CYP2D6 poor metabolizer genotype is the
`
`CYP2D6C 1 OOT (TT) genotype.
`
`Serial No. 11/576,178
`March 20,2013
`
`3/18
`
`Vanda Exhibit 2017 - Page 10
`
`

`
`69 0 (Previously presented) The method of claim 63, wherein the step of internally administering
`
`iloperidone to the patient in an amount of 12 mg/day or less comprises internally administering
`
`iloperidone to the patient in an amount of 6 mg or less b.iodo
`
`700 (Previously presented) The method of claim 64, wherein, if the patient has a CYP2D6 poor
`
`metabolizer genotype, then internally administering iloperidone to the patient in an amount of 6
`
`mg b.iodo
`
`710 (Previously presented) A method of treating a patient who is suffering from a psychotic
`
`disorder and who is a CYP2D6 poor metabolizer, the method comprising:
`
`internally administering iloperidone to the patient in an amount of up to 12 mg/dayo
`
`720 (Previously presented) The method of claim 71, wherein the patient is at risk for a prolonged
`
`QT interval.
`
`73 0 (Previously presented) The method of claim 71, wherein the patient has a CYP2D6 genotype
`
`of one of:
`
`CYP2D6G 1846A (AA), CYP2D6G 1846A (AG), CYP2D6C 1 OOT (TT), or
`
`CYP2D6C100T (CT)o
`
`740 (Previously presented) The method of claim 71, wherein the psychotic disorder comprises at
`
`least one of: schizophrenia, schizoaffective disorder, a delusional disorder, or schizophreniform
`
`Serial No. 11/576,178
`March 20,2013
`
`4/18
`
`Vanda Exhibit 2017 - Page 11
`
`

`
`disorder.
`
`75. (Currently amended) The method of claim 71, wherein the patient is suffering from at least
`
`one of cardiac arrythmia, Tourette~ [[,s]] Syndrome, bipolar mania/depression, or depression.
`
`76. (Previously presented) The method of claim 71, wherein the method comprises: internally
`
`administering the iloperidone to the patient in an amount of 6 mg b.i.d.
`
`77. (Previously presented) A method of treating a patient who is suffering from a psychotic
`
`disorder and who is at risk for iloperidone-induced QTc prolongation, the method comprising:
`
`internally administering iloperidone to the patient in an amount of up to 12 mg/day.
`
`78. (Previously presented) The method of claim 77, wherein the patient is a CYP2D6 poor
`
`metabolizer.
`
`79. (Previously presented) The method of claim 78, wherein the patient has a CYP2D6 genotype
`
`of one of: CYP2D6G1846A (AA), CYP2D6G1846A (AG), CYP2D6C100T (TT), or
`
`CYP2D6C100T (CT).
`
`80. (Previously presented) The method of claim 77, wherein the psychotic disorder comprises at
`
`least one of: schizophrenia, schizoaffective disorder, a delusional disorder, or schizophreniform
`
`disorder.
`
`Serial No. 11/576,178
`March 20,2013
`
`5/18
`
`Vanda Exhibit 2017 - Page 12
`
`

`
`81. (Currently amended) The method of claim 77, wherein the patient is suffering from at least
`
`one of cardiac arrythmia, Tourette~ [[,s]] Syndrome, bipolar mania/depression, or depression.
`
`82. (Previously presented) The method of claim 77, wherein the method comprises: internally
`
`administering the iloperidone to the patient in an amount of 6 mg b.i.d.
`
`Serial No. 11/576,178
`March 20,2013
`
`6/18
`
`Vanda Exhibit 2017 - Page 13
`
`

`
`III.
`
`REMARKS
`
`Claims 63-82 are pending in this application. By this Amendment, claims 63, 75, and 81
`
`are amended. Claims 1-62 have been cancelled previously. Claims 67 and 68 were previously
`
`withdrawn from consideration. Applicants are not conceding in this application that any claims
`
`are not patentable over the art cited by the Examiner. Applicants respectfully reserve the right to
`
`pursue these and other claims in one or more continuation and/or divisional patent applications.
`
`Reconsideration in view of the following remarks is respectfully requested.
`
`Claim Objections
`
`In the Office Action, the Examiner raises an objection to the spelling of"Tourette's
`
`Syndrome" (claims 75 and 81), apparently based on an incorrect punctuation mark. Applicants
`
`have amended each of claims 75 and 81 to correct the punctuation mark.
`
`Rejections under 35 U.S.C. § 112, 2nd paragraph
`
`In the Office Action, claims 63-66 and 69-70 are rejected under 35 U.S.C. § 112(b) or 35
`
`U.S.C. § 112 (pre-AlA), second paragraph, as being indefinite for failing to particularly point out
`
`and distinctly claim the subject matter which the inventors, or for pre-AlA the Applicant, regards
`
`as the invention.
`
`In particular, the Examiner alleges that claims 63-66 and 69-70 are unclear as to whether
`
`a step of administering iloperidone to a patient is required. Applicants have amended claim 63
`
`herein to recite "determining whether the patient is a CYP2D6 poor metabolizer," and "if the
`
`patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to
`
`the patient in an amount of 12 mg/day or less, and if the patient has a CYP2D6 normal
`
`metabolizer genotype or a CYP2D6 extensive metabolizer genotype, then internally
`
`Serial No. 11/576,178
`March 20,2013
`
`7118
`
`Vanda Exhibit 2017 - Page 14
`
`

`
`administering iloperidone to the patient in an amount that is greater than 12 mg/ day, up to 24
`
`mg/day" (claim 63). Applicants respectfully submit that as claimed herein, claim 63 is clear as
`
`to its metes and bounds, and further, that claims 64-66 and 69-70 are clear by virtue of their
`
`dependency on claim 63.
`
`Rejections under 35 U.S.C. § 103(a)
`
`In the Office Action, claims 71-72, 74-78 and 80-82 are rejected under§ 103(a) as being
`
`unpatentable over Obach (previously cited) in view of Jain (previously cited), and with regard to
`
`claims 72, 77-78 and 80-82, as evidenced by Woosley (previously cited). Claims 63-66, 69-70,
`
`73 and 79 are rejected under 35 USC§ 103(a) as being unpatentable over Obach in view of Jain,
`
`as evidenced by Woosley as applied to claims 71-72, 7 4-78 and 80-82, above, and further in
`
`view ofNeville et al. (previously cited).
`
`The foregoing§ 103(a) rejections represent combinations of references which are
`
`previously of record and previously relied upon by the Examiner for substantially the same
`
`reasons as presently asserted. In the Office Action, the Examiner indicates that "Applicant's
`
`arguments regarding the rejections previously of record have been reviewed and considered, and
`
`the claims now under consideration are rejected on the new grounds set forth below." (Office
`
`Action, pp. 2-3.) The "new grounds" substantially re-assert the Examiner's previous position.
`
`Nowhere in the Office Action does the Examiner appear to engage with the arguments presented
`
`in Applicants' submission dated October 19, 2012, nor is there any indication as to why or what
`
`portions of Applicants' arguments the Examiner finds unpersuasive.
`
`As noted in MPEP § 707.07(£), "where the applicant traverses any rejection, the examiner
`
`should, if he or she repeats the rejection, take note of the applicant's argument and answer the
`
`Serial No. 11/576,178
`March 20,2013
`
`8/18
`
`Vanda Exhibit 2017 - Page 15
`
`

`
`substance of it." Additionally, "[i]fa rejection ofrecord is to be applied to a new or amended
`
`claim, specific identification of that ground of rejection, as by citation of the paragraph in the
`
`former Office letter in which the rejection was originally stated, should be given." Applicants
`
`respectfully request that, should the present response fail to place the application in condition for
`
`allowance for any reason, that a detailed and non-final action be provided, "provid[ing]
`
`explanation as to non-persuasiveness." (MPEP § 7.07(f), Form Paragraph 7.37, Examiner Note
`
`2.)
`
`Applicants respectfully submit that the claims of record define a non-obvious invention
`
`for the reasons and evidence presented in Applicants' reply dated October 19, 2012. Not
`
`knowing why this previous submission was deemed unpersuasive, Applicants expressly
`
`incorporate the remarks presented in pages 10-24 ("Rejections under 35 U.S.C. §§ 102(b) and
`
`103(a)") of the October 19, 2012 reply, which are already of record. In addition, Applicants
`
`enter additional remarks, as follows.
`
`With respect to claim 63, Applicants submit that the proposed combination of Obach,
`
`Jain, Woosley, and Neville fails to disclose, and further does not suggest the claimed method
`
`including, inter alia, "determining whether the patient is a CYP2D6 poor metabolizer ... [and] if
`
`the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone
`
`to the patient in an amount of 12 mg/day or less, and if the patient has a CYP2D6 normal
`
`metabolizer genotype or a CYP2D6 extensive metabolizer genotype, then internally
`
`administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24
`
`mg/day" (claim 63). Similarly, with respect to claims 71 and 77, Applicants submit that the
`
`proposed combination ofObach, Jain, and Woosley fails to disclose a "method of treating a
`
`Serial No. 11/576,178
`March 20,2013
`
`9/18
`
`Vanda Exhibit 2017 - Page 16
`
`

`
`patient who is suffering from a psychotic disorder and who is a CYP2D6 poor metabolizer, the
`
`method comprising: internally administering iloperidone to the patient in an amount of up to 12
`
`mg/day" (claim 71) or "method of treating a patient who is suffering from a psychotic disorder
`
`and who is at risk for iloperidone-induced QTc prolongation, the method comprising: internally
`
`administering iloperidone to the patient in an amount ofup to 12 mg/day" (claim 77).
`
`A. Selective reduction of dosage of any drug whose metabolism is CYP2D6-
`mediated based on a patient's CYP2D6 genotype is not taught by the art of
`record.
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`Applicants respectfully submit that the proposed combination of references, and
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`particularly Obach and Jain, fail to expressly or inherently describe administering iloperidone to
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`a patient having normal CYP2D6 enzyme expression in an amount that is greater than 12
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`mg/day, and administering 12 mg/day or less of iloperidone to a patient who is determined based
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`on CYP2D6 genotype to be a CYP2D6 poor metabolizer as claimed herein.
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`As discussed in the response dated October 19, 2012, Obach teaches co-administration of
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`a drug cleared by a CYP2D6-mediated pathway with a CYP2D6 inhibitor (claims 1, 14; see also,
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`Office Action, p. 6). Applicants respectfully submit that this method (Obach, claim 1) and
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`combination pharmaceutical composition (Obach, claim 14) not only fails to disclose the
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`selective adjustment of dosage of a therapeutic agent based on CYP2D6 genotype as claimed
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`herein, but it also fails to credibly teach any particular reduction for poor metabolizers. In a
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`passage cited in the Office Action (pp. 6-7), Obach teaches that in the described co-
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`administration method,
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`"the Therapeutic Drug will be administered in an amount ranging
`from one order of magnitude less than the amount that is known to be
`efficacious and therapeutically acceptable for use of the Therapeutic
`Drug alone (i.e., as a single active agent) to the amount that is known
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`to be efficacious and therapeutically acceptable for use ofthe
`Therapeutic Drug alone." ... "In some instances, dosage levels
`below the lower limit of the aforesaid range may be more than
`adequate, while in other cases still larger doses may be employed
`without causing any harmful side effect." (Obach, [0053].)
`
`Applicants respectfully disagree with the Examiner's characterization that this passage
`
`provides "general guidance" (Office Action, p. 6) with respect to dosage of a drug cleared by
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`CYP2D6-mediated pathways. The administration of 10% (or less) to 100% (or more) of a
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`therapeutic dose to poor metabolizers (whether by virtue of genotype or by administration of a
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`CYP2D6 inhibitor) represents a range so broad as to fail to credibly teach any reduction at all. In
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`fact, it teaches that in some instances, dosages increased to larger than 100% of a therapeutic
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`dose may be administered to CYP2D6 poor metabolizers, which teaches away from the claimed
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`methods.
`
`Applicants further submit that Obach's broadening statements, such as that "[t]he
`
`appropriate dose regimen, the amount of each dose administered, and specific intervals between
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`doses of each active agent will depend on the patient being treated, and the source and severity of
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`the condition" (Obach, [0053]) further fail to provide guidance with respect to dosage of drugs
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`cleared by CYP2D6-mediated pathways. Rather, they introduce additional variables in
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`determining an appropriate dosage for a patient. How, specifically, these variables impact
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`dosage determination is not addressed in the rejection.
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`B. Reduction of dosage of iloperidone in particular is not taught or suggested by the
`art of record.
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`In particular, Applicants submit that reduction of dosage of iloperidone for CYP2D6 poor
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`metabolizers is not obvious based on Obach's, Jain's, Woosley's, and Neville's teachings.
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`In the Office Action, the Examiner asserts that even if Obach does not explicitly teach the
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`administration of iloperidone to a patient at a dosage determined based on genotype, "it would
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`have been prima facie obvious to one of ordinary skill ... to have determined a subject[']s status
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`with respect to CYP2D6 metabolism ... prior to iloperidone administration, and to have
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`employed dosages at the low end of the effective range taught by Jain in such subjects." (Office
`
`Action, p. 7.) Applicants respectfully disagree with this assertion. Given Obach's comments
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`discussed above, which indicate that "in some instances," a CYP2D6-cleared drug may be
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`administered at up to 100% or more of the therapeutic dose, and the lack of teachings specific to
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`iloperidone, Applicants submit that the Examiner's assertion employs impermissible hindsight
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`bias.
`
`At paragraphs [0028]-[0029], Obach provides "examples of other drugs for which the
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`major clearance mechanism in humans is CYP2D6 mediated oxidative biotransformation," one
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`of which is the atypical antipsychotic iloperidone. Risperidone is the only other atypical
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`antipsychotic drug included in Obach's list (0028]-[0029]), and is the most closely related listed
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`drug to iloperidone. The US FDA-approved full prescribing information for Risperdal®
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`risperidone as of the September 30, 2004 priority date of the instant application included the
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`following passage:
`
`CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for
`metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other
`drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of
`Caucasians, and a very low percentage of Asians, have little or no activity and
`are "poor metabolizers") and to inhibition by a variety of substrates and some
`non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert
`risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6
`metabolizers convert it much more slowly. Although extensive metabolizers
`have lower risperidone and higher 9-hydroxyrisperidone concentrations than
`poor metabolizers, the pharmacokinetics of the active moiety, after single and
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`multiple doses, are similar in extensive and poor metabolizers.
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`Risperidone could be subject to two kinds of drug-drug interactions (see Drug
`Interactions under PRECAUTIONS). First, inhibitors of CYP 2D6 interfere with
`conversion of risperidone to 9-hydroxyrisperidone. This occurs with quinidine,
`giving essentially all recipients a risperidone pharmacokinetic profile typical of
`poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
`patients receiving quinidine have not been evaluated, but observations in a
`modest number (n•70) of poor metabolizers given risperidone do not suggest
`important differences between poor and extensive metabolizers. 1
`
`The December 2003 Label for Risperdal® risperidone goes on to state that:
`
`Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that
`is polymorphic in the population and that can be inhibited by a variety of
`psychotropic and other drugs (see CLINICAL PHARMACOLOGY). Drug
`interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone
`would increase the plasma concentrations of risperidone and lower the
`concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
`modest number of poor metabolizers (n•70) does not suggest that poor and
`extensive metabolizers have different rates of adverse effects. No comparison of
`effectiveness in the two groups has been made. 2
`
`This passage appears in the September 2011 revision of the Risperdal® label as wele,
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`and can be contrasted with the full prescribing information for Fanapt® iloperidone. The
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`prescribing information for Fanapt® iloperidone specifically indicates that "PMs [poor
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`metabolizers] of CYP2D6 have higher exposure to iloperidone compared with EMs [extensive
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`metabolizers] and PMs should have their dose reduced by one-half. Laboratory tests are available
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`to identify CYP2D6 PMs,"4 which is consistent with the method of the instant claims.
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`Thus, the prescribing information for Risperdal® risperidone as of the priority date of the
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`1 Janssen Pharmaceutic a Products, L.P., Risperdal® (Risperidone) tablets/oral solution; Risperdal® M- TAB™
`(Risperidone) Orally Disintegrating Tablets December 2003 Label, available at
`2 /dhttp:ltitv\Hl.accessdata.fda.go