Attorney Docket No.: APX0125-201-US
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In Re Application of
`
`Thomas Gant
`
`Confirmation No. 4598
`
`U.S. Patent Application No. 12/562,621
`
`Group Art Unit: 1625
`
`Filed: September 18,2009
`
`Examiner: Desai, Rita J.
`
`BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE
`TITLE:
`TRANSPORTER 2
`
`REPLY TO REQUIREMENT FOR RESTICTION AND ELECTION OF SPECIES
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`This is in response to the Office Action dated February 3, 2012, having a
`
`shortened statutory period for reply which expired on March 3, 2012.
`
`Authorization is hereby given to treat this and any future reply, which requires or
`
`might require a petition for an extension of time under 37 CFR § 1.136(a) for its timely
`
`submission or payment of fee, as incorporating a petition for extension of time for the
`
`appropriate length of time and an authorization to pay any required fees from Deposit
`
`Account No. 50-4296.
`
`Claim amendments are presented on page 2 of this paper.
`
`Remarks are presented on page 4 of this paper.
`
`- 1 -
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`001
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`Apotex Ex. 1027
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`Apotex v. Auspex
`IPR2021-01507
`
`

`

`Attorney Docket No.: APX0125-201-US
`
`Amendments to the Claims
`
`This listing of claims will replace all prior versions, and listings, of claims in the
`
`application:
`
`Listing of Claims:
`
`What is claimed is:
`(Currently Amended) A compound et having the structural !<formula~ I
`0
`
`1.
`
`or a salt thereof, \vherein:
`R+~ are independently selected from the group consisting of hydrogen and
`
`deuterium; and
`
`at least one of R+~is deuterium.
`
`8.
`
`2-7. (Canceled)
`(Currently Amended) The compound as recited in Claim':/- l wherein each position
`represented as D has deuterium enrichment of no less than about 10%.
`(Currently Amended) The compound as recited in Claim':/- l wherein each position
`represented as D has deuterium enrichment of no less than about 50%.
`
`9.
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`- 2 -
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`Attorney Docket No.: APX0125-201-US
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`10. (Currently Amended) The compound as recited in Claim':/- l wherein each position
`represented as D has deuterium enrichment of no less than about 90%.
`11. (Currently Amended) The compound as recited in Claim ':/- 1 wherein each position
`represented as D has deuterium enrichment of no less than about 98%.
`
`12-14. (Canceled)
`
`15. (Original) A pharmaceutical composition comprising a compound as recited in Claim
`
`1 together with a pharmaceutically acceptable carrier.
`
`16-33. (Canceled)
`
`- 3 -
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`Attorney Docket No.: APX0125-201-US
`
`Remarks
`
`Claim Amendment
`
`Claims 1 and 8-11 are currently amended. Claim 15 is as originally presented.
`
`Claims 2-7, 12-14, and 16-33 are canceled. No new matter has been added. After entry of
`
`the above amendment, claims 1, 8-11, and 15 are pending.
`
`Requirement for Restriction
`
`This action requires restriction under 35 U.S.C. 121 among Groups I and II.
`
`Applicant respectfully elects, with traverse, Group I.
`
`Applicant traverses the restriction requirement because there would be no serious
`
`burden on the examiner if restriction between Groups I and II is not required. MPEP 808.02.
`
`Although Groups I and II may be separately classified as compounds and compositions and
`
`methods of use, the method claims of Group II recite methods of using the compounds and
`
`compositions of Group I. Accordingly, any search which would identify compounds and
`
`compositions of Group I would also identify any methods of use thereof, such compounds,
`
`compositions, and methods being disclosed in the same references
`
`Election of Species
`
`In response to the election of species requirement under 35 U.S.C. 121, applicant
`
`provisionally elects, for search purposes only, the compound of Example 2, page 32, 3-
`
`Isobutyl-9, 10-d6-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2, l-a]isoquinolin-2(11 bH)-one
`
`( d6-tetrabenazine ), the structure of which is:
`
`Claims 1, 8-11, and 15 read upon the elected species and compositions thereof.
`
`- 4 -
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`Attorney Docket No.: APX0125-201-US
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`It is respectfully submitted that the claims have been put in condition for
`
`allowance. Notification to this effect is earnestly solicited. The Examiner is invited to
`
`contact the undersigned attorney at the telephone number provided below if such would
`
`advance the prosecution of the case.
`
`Respectfully submitted,
`
`March 26, 2012
`
`Date
`
`Global Patent Group, LLC
`
`1005 North Warson Rd., Suite 201
`
`St. Louis, MO 63132
`
`TELE: 314-812-8020
`
`/Dennis A. Bennett/
`
`Dennis A. Bennett, Reg. No. 34,547
`
`Attorney for Applicants
`
`- 5 -
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`UNITED STA IBS p A IBNT AND TRADEMARK OFFICE
`
`UNITED STA TES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria., Virginia 22313-1450
`www.uspto.gov
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`12/562,621
`
`09/18/2009
`
`Thomas G. Gant
`
`APX0125-201-US
`
`4598
`
`04/10/2012
`7590
`69495
`GLOBAL PATENT GROUP - APX
`1005 North Warson Road
`Suite 201
`ST. LOUIS, MO 63132
`
`EXAMINER
`
`DESAI, RITA J
`
`ART UNIT
`
`PAPER NUMBER
`
`1625
`
`NOTIFICATION DATE
`
`DELIVERY MODE
`
`04/10/2012
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
`following e-mail address(es):
`lhall@globalpatentgroup.com
`knhall@globalpatentgroup.com
`vmclaurin@globalpatentgroup.com
`
`PTOL-90A (Rev. 04/07)
`
`006
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`Office Action Summary
`
`Application No.
`
`12/562,621
`
`Examiner
`
`Applicant(s)
`
`GANT ET AL.
`
`Art Unit
`
`1625
`RITA DESAI
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address -(cid:173)
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE ;J. MONTH(S) OR THIRTY (30) DAYS,
`WHICHEVER IS LONGER, FROM THE MAILING DATE OF THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a). In no event, however, may a reply be timely filed
`after SIX (6) MONTHS from the mailing date of this communication.
`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
`
`1 )IZI Responsive to communication(s) filed on 26 March 2012.
`2a)O This action is FINAL.
`2b)IZI This action is non-final.
`3)0 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.
`4)0 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 G.D. 11, 453 O.G. 213.
`
`Disposition of Claims
`
`5)1Zl Claim(s) 1.8-11 and 15 is/are pending in the application.
`5a) Of the above claim(s) __ is/are withdrawn from consideration.
`6)0 Claim(s) __ is/are allowed.
`7)1Zl Claim(s) 1. 8-11 and 15 is/are rejected.
`8)0 Claim(s) __ is/are objected to.
`9)0 Claim(s) __ are subject to restriction and/or election requirement.
`
`Application Papers
`
`10)0 The specification is objected to by the Examiner.
`11 )0 The drawing(s) filed on __ is/are: a)O accepted or b)O objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
`12)0 The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152.
`
`Priority under 35 U.S.C. § 119
`
`13)0 Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`a)O All b)O Some * c)O None of:
`1.0 Certified copies of the priority documents have been received.
`2.0 Certified copies of the priority documents have been received in Application No. __ .
`3.0 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)).
`*Seethe attached detailed Office action for a list of the certified copies not received.
`
`Attachment{s)
`1) [8J Notice of References Cited (PTO-892)
`2) 0 Notice of Draftsperson's Patent Drawing Review (PTO-948)
`3) [8J Information Disclosure Statement(s) (PTO/SB/08)
`Paper No(s)/Mail Date 3/27112.
`
`4) 0 Interview Summary (PTO-413)
`Paper No(s)/Mail Date. __ .
`5) 0 Notice of Informal Patent Application
`6) 0 Other: __ .
`
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 03-11)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20120402
`
`007
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`Application/Control Number: 12/562,621
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`Page 2
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`Art Unit: 1625
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`DETAILED ACTION
`
`Priority
`
`This application claims priority to US provisional application 61097896 filed 9/18/2008.
`
`Applicants claims are drawn to a deuterated tetrabenazine.
`
`Claims 1, 8-11, and 15 are pending.
`
`Applicant's election of Group I of the restriction is acknowledged. The argument that it would
`
`not be a serious burden is not found to be convincing.
`
`The inventions are are independent and distinct especially since tetrabenazine is a well known
`
`pharmaceutical.
`
`Claim Rejections - 35 USC§ 103
`
`The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness
`
`rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described as
`
`set forth in section 102 of this title, if the differences between the subject matter sought to be
`
`patented and the prior art are such that the subject matter as a whole would have been obvious at
`
`the time the invention was made to a person having ordinary skill in the art to which said subject
`
`matter pertains. Patentability shall not be negatived by the manner in which the invention was
`
`made.
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`Application/Control Number: 12/562,621
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`Page 3
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`Art Unit: 1625
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`Claims 1, 8-11 and 15 are rejected under 35 U.S.C. 103(a) as being unpatentable over Robert
`
`Foster WO 95/26325, (in IDS) WO 2007 /130365 Kung Hank F. (in IDS). WO 2005/077946
`
`Clarke et al. ( in IDS)., Zhang et al., ( in IDS), Schwartz et al., Biochem. Pharmacol., 1966, 15,
`
`645-655 ( in IDS), Alan Foster (in IDS), Paleacu et al ( IDS), Kenney and Jankovic, Kushner
`
`DJ, ( in IDS) Helfenbein et al.( in IDS) Dyck et. al. Journal of Neurochemistry 1986, 46, 399 -
`
`404, (IDS) Wolen et. al. Journal of Clinical Pharmacology 1986; 26: 419-424(1DS), U.S.
`
`6,440,710 ( in IDS), Lance Pohl et al ( in the IDS).
`
`Applicants claims are drawn to a deuterated form of tetrabenazine.
`
`:-,..-·
`,,-
`
`,-. ,,.
`
`0
`
`Scope & Content of Prior Art MPEP 2141.01
`
`WO 95/26325 Foster clearly teaches deuteration of drugs to enhance efficacy.
`
`WO 2007 /130365 Kung Hank F teaches the radiolabelled dihydrotetrabenazine as 1miagmg
`
`agents.
`
`Tetrabenazine is known drug for the treatment of Hyperkinesias. See Kenney and Jankovic
`
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`Page 4
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`Art Unit: 1625
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`Deuterium is an isotope of H, it is heavier as it has an extra neutron. The properties are the same
`
`as those of H as it has the same number of electrons and protons. F and H which are different
`
`atoms are also considered to be bioisosters and have similar properties. H and 2H ( D) are the
`
`same elecment and hence would be expected to have similar properties.
`
`The structure is very similar. Thus compounds would be expected to have similar activity.
`
`Alan Foster, 2003 discusses the effect of deuterated drugs on the pathways.
`
`Kushner DJ. In 1999, discusses the effect of deuteurated compounds in whole animals, animal
`
`cells and microorganisms. " some deuterated drugs transport prossess. Most are more restant to
`
`metabolic
`
`Deuteration
`
`change
`
`the
`
`F
`
`____ See, __ e.g.,
`
`In re
`
`--------7 __ 1_ 2 __ " _______ 1 7__ 7 --17 ::
`
`"
`
`!
`
`of
`
`drug __ ___________ __ ! ____ ' ___________________ , ___ ($ ______
`
`_ ___ 7 __ ) ___________________ (__ __ ( " ____ ( # ____ s ____ _
`
`metabolism.
`
`11
`
`I
`
`changes.
`
`may also
`
`pathway
`
`Changed
`
`metabolism may lead to increased duration of action and lower toxicity. It may also lead to a
`
`lower activity if the drug is normally changed to the active form in-vivo.
`
`Helfenbein et al teaches a study of propofol.
`
`The deuteration of drugs is a well known technique to obtain enhanced pharmaceutical
`
`properties. See Dyck et. al. Journal of Neurochemistry 1986, 46, 399 - 404 states, "Thus,
`
`deuterium substitution seems to be a useful strategy to enhance the pharmacological effects of a
`
`compound without significantly altering its basic chemical structure.
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`Page 5
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`Art Unit: 1625
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`Wolen et. al. Journal of Clinical Pharmacology 1986; 26: 419-424, notes that the lack of
`
`toxicity for deuterium makes it "ideally suited for human studies" (abstract) concludes that "the
`
`application of stable isotope methodology to the problems of bioavailability and bioequivalence
`
`have proved extremely versatile and useful. The technique is simple and powerful and results in
`
`extremely low risk to the subject." (page 423)
`
`Browne et. al. Journal of Clinical Pharmacology 1998, 38, 213-220 quantifies the advantage of
`
`using stable isotope labeled drugs to, for example, identify metabolites, to evaluate drug
`
`interactions, and to measure absolute bioavailability. Compared with standard methods which do
`
`not use isotopically labeled drugs, there is a cost reduction of 23% and a reduction in 36% in
`
`terms of the number of subjected needed. This again provides a strong motivation, to obtain
`
`these advantages.
`
`U.S. 6,440,710 on pagel, lines 22-27. "Deuterium- and tritium-labeled organic compounds have
`
`become increasingly important for the role they play in structure determination, mechanistic
`
`studies, elucidation ofbiosynthetic pathways and in biochemical studies."
`
`Lance Pohl et al. shows a study which teaches which group to deuterate to reduce the side effects
`
`of the metabolites. ( see whole document) .
`
`n vivo, tetrabenazine is rapidly and extensively metabolized to its reduced form, 3-isobutyl-9,10-
`
`dimethoxy- 1,3,4,6,7,1
`
`lb-hexahydro-2H-pyrido[2,1 a]isoquinolin-2-ol, which
`
`then binds
`
`specifically toVMAT2 (Zhang et al., AAPS Journal, 2006, 8(4), E682-692). Additional
`
`metabolic pathways involve 0- demethylation of the methoxy groups, as well as hydroxylation
`
`of the isobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15, 645-655). Adverse effects
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`Art Unit: 1625
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`associated with
`
`the
`
`administration of
`
`tetrabenazine
`
`include neuroleptic malignant
`
`syndrome,
`
`drowsiness,
`
`fatigue,
`
`nervousness,
`
`anxiety,
`
`.
`.
`msomma,
`
`agitation,
`
`confusion,
`
`orthostatic
`
`hypotension,
`
`nausea,
`
`dizziness,
`
`depression,
`
`and
`
`Parkinsonism.
`
`Difference between Prior Art and the claims MPEP 2141.02
`
`The specific deuterated tetrabenazine is not disclosed.
`
`Prima Facie Obviousness, Rational and Motivation MPEP 2142-2413
`
`One of skill in the drug design with the knowledge of the all the prior art given above would be
`
`motivated to make the deuterated compound of the known drug as it has the same structure and
`
`would be expected to have the same properties.
`
`WO 95/26325 clearly teaches enhancing the activity of the drug by its deuteration. See
`
`background of the invention, Page 1.
`
`Zang and Swartz teach that the methoxy group is in the metabolite. It also teaches that the
`
`tetrabenazine has several side effects.
`
`From the reference given above, it is well known that deuterated compounds and have certain
`
`better effects such as lowering some side effects, increasing the bioavailability, increasing the
`
`time of activity as it stays longer in the system and so on, would be obviously motivated to make
`
`the deuterated compound to make different compounds and expect the properties to be the same.
`
`Polh et al. teaches a techniques of using deuterated drugs to modify the activity on the basis of
`
`the toxic metabolites. This would motivate a person to replace specific H's with deuterium to
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`Page 7
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`Art Unit: 1625
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`see if it had any effect on toxicity, lipophilic effect or in general improve or change the activity
`
`of the compound.
`
`In the absence of a showing of unexpected results it cannot be seen how the claims can be
`
`patentable.
`
`The specification in paragraph 00110 page 45, recites that "the changes in the metabolic activity
`
`can be shown by the assays. Compounds listed above which have not yet been made or tested are
`
`predicted to have a changed metabolic properties. "
`
`There is thus no showing of any unexpected or surprising results.
`
`From all the above reference it is expected that there some change can be expected, however that
`
`much change is to be expected and hence obvious.
`
`The examiner has used several reference to show the preponderance of evidence.
`
`Zhang and Swartzboth show that the compounds have metabolite with the methoxy group.
`
`Polh shows how the metabolites can be modified to decrease the toxic effects.
`
`Many references teach deuteration of known pharmaceutical drugs.
`
`Thus with all this knowledge in the prior art ,one of skill in the art of drug design would have
`
`been motivated to do this because the compounds would be expected to have similar properties.
`
`A reference is good not only for what it teaches by direct anticipation but also for what one of
`
`ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d
`
`1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing
`
`discussion, the Examiner concludes that the subject matter defined by the instant claims would
`
`have been obvious within the meaning of 35 USC 103(a). From the teachings of the references,
`
`it is apparent that one of ordinary skill in the art would have had a reasonable expectation of
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`Application/Control Number: 12/562,621
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`Page 8
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`Art Unit: 1625
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`success in producing the claimed invention. Therefore, the invention as a whole was prima facie
`
`obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by
`
`the references, especially in the absence of evidence to the contrary.
`
`In re Grabiak 226 USPQ 870, "[w]hen chemical compounds have "very close" structural
`
`similarities and similar utilities, without more a prima facie case may be made. In this case the
`
`difference is a neutron.
`
`In re Papesch, 315 F.2d 381, 386 (C.C.P.A. 1961) ( holding that structural similarity between
`
`the prior art and the claimed compound supports a prima facie case of obviousness, which is
`
`rebuttable by evidence that the claimed compound exhibits unexpected or surprising properties
`
`that the prior art does not possess.) The Papasch court further explained that a chemical
`
`compound and its properties are in separable because the formula drawn in the patent merely
`
`identifies the compound being patented and is not the invention.
`
`Conclusion
`
`Claims 1, 8-11 and 15 are rejected.
`
`Any inquiry concerning this communication or earlier communications from the exammer
`
`should be directed to RITA DESAI whose telephone number is (571)272-0684. The examiner
`
`can normally be reached on Maxi- flex time ..
`
`If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Janet
`
`Andres can be reached on 571-272-0867. The fax phone number for the organization where this
`
`application or proceeding is assigned is 571-273-8300.
`
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`Application/Control Number: 12/562,621
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`Page 9
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`Art Unit: 1625
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`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.
`
`/Rita J. Desai/
`
`Primary Examiner, Art Unit 1625
`
`April 2, 2012.
`
`015
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`Attorney Docket No.: APX0125-201-US
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In Re Application of
`
`Thomas Gant
`
`Confirmation No. 4598
`
`U.S. Patent Application No. 12/562,621
`
`Group Art Unit: 1625
`
`Filed: September 18, 2009
`
`Examiner: Desai, Rita J.
`
`BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE
`TITLE:
`TRANSPORTER 2
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`RESPONSE TO NON-FINAL REJECTION
`
`Sir:
`
`This is in response to the Office Action dated April 10, 2012, having a shortened
`
`statutory period for reply which expired on July 10, 2012.
`
`Authorization is hereby given to treat this and any future reply, which requires or
`
`might require a petition for an extension of time under 37 CPR § 1.136(a) for its timely
`
`submission or payment of fee, as incorporating a petition for extension of time for the
`
`appropriate length of time and an authorization to pay any required fees from Deposit
`
`Account No. 50-4296.
`
`An Information Disclosure Statement is submitted herewith.
`
`Remarks are presented on page 2 of this paper.
`
`- 1 -
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`Attorney Docket No.: APX0125-201-US
`
`Remarks
`
`Claims
`
`Claims 1, 8-11, and 15 are pending. No new matter is added.
`
`Requirement for Restriction
`
`Applicant acknowledges that the restriction has been made final.
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`The Bradbury Declaration
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`Applicants present herewith a Declaration under 37 CPR 1.132 of Dr. Margaret
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`Bradbury (the "Bradbury Declaration). Dr. Bradbury is the Senior Director of Research
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`and Development at Auspex Pharmaceuticals, Inc. ("Auspex"), the assignee of the
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`present application. d6-Tetrabenazine (a deuterated analog of tetrabenazine) as recited in
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`the instantly pending claims (the "Claimed Compound") was tested either by Dr.
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`Bradbury or by or for Auspex in a human liver microsome ("HLM") assay, human S9
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`liver fraction assay, rat, mouse, dog and monkey liver microsome assays, and in a Phase
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`1 clinical trial in healthy human volunteers (Bradbury Declaration, Exhibits 1-4).
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`The Claimed Compound exhibited increased overall stability in the HLM and dog
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`liver microsome assay. Results in the rat liver microsome assay was mixed, and testing in
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`mouse and monkey liver microsomes showed decreased metabolic stability. The degree
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`of increased stability in human liver microsomes for the Claimed Compound ranged from
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`48.5% to 139% relative to tetrabenazine in results obtained from 8 experiments
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`(Bradbury Declaration, paragraph 8(a)(i)).
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`In human liver microsomes, the maJor metabolites of deuterated and non(cid:173)
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`deuterated a-HTBZ and ~-HTBZ, a pair of mono-O-desmethyl metabolites of each
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`HTBZ metabolite (d3 or d0-9-O-desmethyl-a-HTBZ, d3 or d0-9-O-desmethyl-~-HTBZ, d3
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`or d0-10-O-desmethyl-a-HTBZ, d3 or d0-10-O-desmethyl-~-HTBZ), were measured after
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`digestion of deuterated and non-deuterated a-HTBZ and ~-HTBZ in human liver
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`microsomes. The O-desmethyl HTBZ metabolites produced by digestion d6-a-HTBZ and
`of d6-~-HTBZ were reduced by at least 50% compared to their non-deuterated forms
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`(Bradbury Declaration, paragraph 8(a)(ii)).
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`Attorney Docket No.: APX0125-201-US
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`The Claimed Compound exhibited increased overall stability in healthy human
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`volunteers. In a randomized, double-blind, 2-way crossover study of single dose
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`administration of 25 mg of d6-tetrabenazine (SD-809) or tetrabenazine, deuterium
`substitution approximately doubled systemic exposure to d6-a-HTBZ, d6-~-HTBZ with
`associated near doubling of half-lives (Bradbury Declaration, paragraph 8b).
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`Applicants have amended the claims to recite the tested d6-tetrabenazine
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`compound. As explained below, there could not have been a reasonable expectation that
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`the Claimed Compound demonstrate increased overall metabolic stability as compared to
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`tetrabenazine.
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`Rejection Under 35 USC 103
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`Claims 1, 8-11, and 15 were rejected under 35 USC§ 103(a) as obvious over WO
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`95/26325, WO 2007130365, WO 2005077946, Zheng et al., The AAPS Journal, 2006,
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`8(4), Art. 78, Schwartz et al., Biochem. Pharmacol., 1966, 15, 645-655, Foster, Alan,
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`Trends in Pharmacological Sciences, December 1984, 524-527, Paleacu et al., Clin.
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`Neuropharmacol., 2004, 27, 230-233, Kenney et al., Exp. Rev. Neurother., 2006, 6(1), 7-
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`17, Kushner, Can. J. Physiol. Pharmacol., 1999, 77, 79-88, Helfenbein et al., J. Med.
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`Chem., 2002, 45, 5806-5808, Dyck et al., J. Neurochem., 1986, 46(2), 399-404, Wolen et
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`al., J. Clin. Pharmacol., 1986, 26, 419-424, US 6,440,710, Pohl et al., Drug Metab. Rev.,
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`1985, 1335, and Browne et al., J. Clin. Pharmacol., 1998, 38, 213-220.
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`Discussing the various teachings of these references, the Office Action concluded
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`that it would have been obvious to one of ordinary skill in the art to deuterate
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`tetrabenazine in order to either (1) prepare a compound with improved pharmacokinetic
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`properties or (2) perform studies related to the metabolism of the non-deuterated drug.
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`The Prior Art as a Whole Does Not Teach or Suggest that Deuteration Will Generally
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`Improve Overall Metabolic Stability
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`Describing the teachings of the cited references, the Office Action states that "it is
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`well known that deuterated compounds have certain better effects such as lowering some
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`side effects, increasing the bioavailability, increasing the time of activity as it stays in the
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`system and so on, would be obviously motivated to make the deuterated compound."
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`Attorney Docket No.: APX0125-201-US
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`(Action, p6). The Office Action also stated that change in drug properties "is to be
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`expected and hence obvious." (Action, p7). The examiner's assertion of a reasonable
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`expectation of success is not supported when viewed in light of the prior art as a whole.
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`As of the filing date, the state of the art clearly showed that although, as the Kushner
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`reference cited by the examiner states, deuteration may increase metabolic stability in
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`some cases, a) the effect of deuteration of a drug on its overall metabolic stability was
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`unpredictable; and b) in most cases, deuteration did not significant! y affect overall
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`metabolic stability.
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`According to several review articles published over the last three decades,
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`substitution of deuterium for hydrogen at or near a site of metabolism of a compound
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`might alter the rate of metabolism at that particular site. For example, Foster, A.B., Adv.
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`Drug Res., Academic Press, London, GB, Vol 14, 1 January 1985, pages 1-40 ("Foster,"
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`submitted in an Information Disclosure Statement attached herewith), reviews the
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`experimental results from numerous research groups on deuterated versions of drugs and
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`other compounds. In many of the reviewed studies involving a cytochrome P450-
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`catalyzed (CYP) reaction, a deuterium isotope effect (DIE) was observed at the site of
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`metabolism near the deuterium substitution. However, those studies provided almost no
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`information on the effect of deuteration on the overall (net) stability of the compound.
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`The DIEs reported in Foster refer to the effect of deuteration on one (or in some cases
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`more than one) sites of metabolism in a compound. They do not refer to the effect of
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`deuteration on the overall stability of the compound. One must keep this distinction in
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`mind when evaluating the prior art.
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`The fact that a DIE is observed in a compound cannot be extrapolated to a
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`conclusion that the deuterated version of the compound will demonstrate increased net
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`stability. This is due in large part to the phenomenon of metabolic switching, which
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`compensates for a reduced rate of metabolism at one site in a molecule by increasing the
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`rate of metabolism at a different site (see Foster at pp. 6-8). Metabolic switching typically
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`results in no significant net effect on the overall metabolism of a compound. Foster states
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`that "[i]t is now becoming clear that the scope for using DIEs effectively in drug design
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`to block adverse metabolism or to deflect metabolism away from toxic products
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`(metabolic switching) is very limited ... " Foster, 1985 at p. 35.
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`Attorney Docket No.: APX0125-201-US
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`Fisher MB et al., Current Opinion in Drug Discovery & Development 9:101-09
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`(2006) ("Fisher"; previously submitted in an invention disclosure statement) explains the
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`kinetic mechanism of CYP-mediated metabolism and its inherent complexities. Fisher
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`teaches that for compounds having multiple potential sites of metabolism (like
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`tetrabenazine), while it may be possible that deuteration would cause a DIE effecting the
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`distribution of metabolites for CYP-mediated reactions, an overall change in metabolic
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`stability would not be expected:
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`"In Equation 4, PI and P2 represent different metabolites. If the alternative
`pathway is simply a result of metabolism at another position, there will be
`an isotope effect on the distribution of metabolites (i.e., PI decreases and
`P2 increases upon deuteration), but the overall rate of metabolism will
`likely be unchanged (i.e., PI + P2 is unchanged)." (Fisher at p 103, right
`column) (emphasis added).
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`According to Fisher, the only cases in which a change in overall rate of
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`metabolism would occur are those where the iron oxene species present in activated
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`CYPs is reduced to form water, since in such cases metabolism shifts to production of
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`water rather than formation of an alternative metabolite (Fisher p. 103, right-hand column
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`and equation 5). But whether such a reaction could occur at all, and even if so, to what
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`extent cannot be reasonably predicted:
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`"The only situation in which blocking a site of metabolism via deuterium
`substitution will result in decreased substrate clearance is when metabolite
`P2 (Equations 4 and 6) is actually a reduction of oxene to water [citation
`omitted]. While it is impossible to measure the proportion of enzyme
`turnover that occurs through this pathway relative to metabolite formation
`in vivo, several in vitro studies have attempted this measurement. In some
`cases, water can be a major 'metabolite', although in one side-by-side
`comparison of various isoforms and substrates it appeared that water
`formation was not a major pathway in most cases." (Fisher, p 104, right
`column).
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`In light of the above, one of skill in the art would not be able to predict whether
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`deuteration at any particular site in a molecule would cause a net increase in metabolic
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`stability of that molecule. This conclusion is further supported by the Bradbury
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`Attorney Docket No.: APX0125-201-US
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`Declaration, which states that "the effect of deuterium substitution on the in vitro or the
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`in vivo stability of compounds cannot be reasonably predicted based on the structure of
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`the compound, the site at which deuterium is installed, or prior knowledge of the
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`metabolic pathways of the compound" (Bradbury Declaration, paragraph 6). This
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`unpredictability is observed in the case of tetrabenazine, where deuteration at the
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`methoxy groups results in opposite effects on in vitro metabolic stability depending on
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`which species is being examined (Bradbury Declaration, Exhibit 2, Table 3, showing that
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`d6-tetrabenazine is less stable than n