Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 2
`
`Notice of Pre-AIA or ATA Status
`
`The present application is being examined underthe pre-AJAfirst to invent provisions.
`
`DETAILED ACTION
`
`Claims 1-18 are currently pending in the instant application.
`
`Election/Restrictions
`
`The Markush group set forth in the claims includes both independent and distinct
`
`inventions, and patentable distinct compounds (or species) within each invention. However, this
`
`application discloses and claims a plurality of patentable distinct inventions far too numerous to
`
`list individually. Moreover, each of these inventions contains a plurality of patentable distinct
`
`methods, also far too numerous to list
`
`individually. For these reasons provided below,
`
`restriction to one of the following Groups is required under 35 U.S.C. 121, wherein a Groupis
`
`a set of patentable distinct inventions of a broad statutory category (e.g. compounds, methods of
`
`use, methods of making, etc.):
`
`I
`
`Claims 1-11 drawn to a methodof treating a Bruton’s Tyrosine Kinase mediated
`
`disorder in a subject comprising administering a therapeutically effective amount
`
`of a compound of Formula (I) classified in AG1K 31/4985.
`
`I
`
`Claims 12-18 drawn to a combination of a compound of Formula (I) classified in
`
`C07D 487/04.
`
`Rationale Establishing Patentable Distinctiveness Within Each Group
`
`Each Group listed above are recognized in the art as being distinct from one another
`
`because of their diverse chemical structure, their different chemical properties, modes of action,
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 622 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 622 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 3
`
`different effects and reactive conditions (MPEP 806.04, MPEP 808.01). Additionally, the level
`
`of skill in the art is not such that one invention would be obvious over the other invention
`
`(Group), ie. they are patentable over each other. Chemical structures, which are similar, are
`
`presumedto function similarly, whereas chemical structures that are not similar are not presumed
`
`to function similarly. The presumption even for similar chemical structures though is not
`
`irrefutable, but may be overcomebyscientific reasoning or evidence showing that the structure
`
`of the prior art would not have been expected to function as the structure of the claimed
`
`invention. Note that in accordance with the holding of Application of Papesch, 50 CCPA 1084,
`
`315 F.2d 381, 137 USPQ 43 (CCPA 1963) and In re Lalu, 223 USPQ 1257 (Fed. Cir. 1984),
`
`chemical structures are patentably distinct where the structures are either not structurally similar,
`
`or the prior art fails to suggest a function of a claimed compound would have been expected
`
`from a similarstructure.
`
`In accordance with the decisions in In_re Harnisch, 631 F.2d 716, 206 USPQ 300
`
`(CCPA 1980); and Ex parte Hozumi, 3 USPQ 2d 1059 (Bd. Pat. App. & Int. 1984), restriction of
`
`a Markush group is proper where the compounds within the group either (1) do not share a
`
`common utility, or (2) do not share a substantial structural feature disclosed as being essential to
`
`that utility. In addition, a Markush group may encompassa plurality of independent and distinct
`
`inventions where two or more members are so unrelated and diverse that a prior art reference
`
`anticipating the claim with respect to one of the members would not render the other member(s)
`
`obvious under 35 U.S.C. 103.
`
`The above groups represent general areas wherein the inventions are independent and
`
`distinct, each from the other because of the following reasons:
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 623 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 623 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 4
`
`Inventions I-IT are related as products and their method of uses. The inventions can be
`
`shownto be distinct if either or both of the following can be shown: (1) the process for using the
`
`product as claimed can be practiced with another materially different product or (2) the product
`
`as claimed can be used in a materially different process of using that product (MPEP §
`
`$06.05(h)). In the instant case, the product as claimed could be used in materially different
`
`processes of using that product as demonstrated throughout the specification and in claims 1-11
`
`for example, which are specifically directed to different method of using the products. Therefore,
`
`a separate search considerations are involved, which would impose a burden if unrestricted.
`
`Also, the fields of search are not coextensive. Additionally, besides performing a class/subclass
`
`search, the Examiner performs a commercial data base search and an automated patent system
`
`(text) search.
`
`The products of GroupsI-II differ materially in structure and in element. The invention
`
`Groups I-II outlined above relates to compoundsand their methods of uses, which do not possess
`
`a substantial common core wherein a reference anticipating one would not necessarily render the
`
`other obvious and to search all the above groups in a single application would be an undue
`
`burden on the Examiner. In addition, because of the several classes and subclasses in each of the
`
`Group, a serious burden is imposed on the examiner to perform a complete search of the defined
`
`areas. Therefore, because of the reasons given above,the restriction set forth is proper and not to
`
`restrict would impose a serious burden in the examination of this application.
`
`Where an election of any one of Group I-II is made, an election of a single
`
`compoundis further required including an exact definition of each substitution on the base
`
`molecule, wherein a single member at each substituent group or moiety is selected. Upon the
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 624 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 624 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 5
`
`election of a single disclosed compound (e.g. Example, page numberandstructural depiction),
`
`the scope of invention, inclusive of the elected compound,will be identified by the Examiner for
`
`examination along with the elected species. Moreover, whatever specific compoundis ultimately
`
`elected, applicants are required to list all claims readable thereon. In the instant case, upon
`
`election of a single compound, the Office will review the claims and disclosure to determine the
`
`scope of the independent invention encompassing the elected compound (compounds which are
`
`so similar thereto as to be within the same inventive concept and reduction to practice). The
`
`scope of an independent invention will encompass all compounds within the scope of the claim,
`
`which fall into the same class and subclass as the elected compound, but may also include
`
`additional compounds, which fall in related subclasses. Examination will then proceed on the
`
`elected compound ANDthe entire scope of the invention encompassing the elected compound
`
`will be determined. A clear statement of the examined invention, defined by those class (es) and
`
`subclass (es) will be set forth in the first action on the merits. Note that
`
`the restriction
`
`requirement will not be made final until such time as applicant is informed of the full scope of
`
`compounds along with (if appropriate) the process of using or making said compound under
`
`examination. This will be set forth by reference to specific class(es) and subclass(es) examined.
`
`Should applicant traverse on the ground that the compound are not patentably distinct, applicant
`
`should submit evidence or identify such evidence now of record showing the compound to be
`
`obvious variants or clearly admit on the record that this is the case. In either instance, if the
`
`examiner finds one of the inventions unpatentable over the prior art, the evidence or admission
`
`may be usedin a rejection under 35 U.S.C. 103(a) of the other invention.
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 625 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 625 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 6
`
`All compoundsfalling outside the class(es) and subclass(es) of the selected compound
`
`and any other subclass encompassed by the election above will be directed to nonelected subject
`
`matter and will be withdrawn from consideration under 35 U.S.C. 121 and 37 C.F.R. 1.142(b).
`
`Applicant may reserve the right to file divisional applications on the remaining subject matter.
`
`(The provisions of 35 U.S.C. 121 applies with regard to double patenting covering divisional
`
`applications.)
`
`If desired upon election of a single compound, applicants can review the claims and
`
`disclosure to determine the scope of the invention and can set forth a group of compounds,
`
`which are so similar within the same inventive concept and reduction to practice. Markush
`
`claims must be provided with support in the disclosure for each memberof the Markush group.
`
`See MPEP 608.01(p). Applicant should exercise caution in making a selection of a single
`
`member for each substituent group on the base molecule to be consistent with the written
`
`description.
`
`Applicant is reminded that upon cancellation of claims to a nonelected invention, the
`
`inventions must be amended in compliance with 37 C.F.R. 1.48(b) if one of the currently named
`
`inventors is no longer an inventor of at least one claim remaining in the application. Any
`
`amendmentof inventorship must be accompanied by a petition under 37 C.F.R. 1.48(b) and by
`
`the fee required under 37 C.F.R. 1.17().
`
`Because these inventions are distinct for the reasons given above and have acquired a
`
`separate status in the art as shown by their different classification (subclasses), restriction for
`
`examination purposeas indicated is proper.
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 626 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 626 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 7
`
`Because these inventions are distinct for the reasons given above and have acquired a
`
`separate status in the art because of their recognized divergent subject matter, restriction for
`
`examination purposeas indicated is proper.
`
`Applicants preserve their rightto file a divisional on the non-elected subject matter.
`
`Advisory of Rejoinder
`
`The followingis a recitation of M.P.E.P. 821.04, Rejoinder:
`
`Where product and process claims drawn to independent and distinct inventions are presented in
`the same application, applicant may be called upon under 35 U.S.C. 121 to elect claims to either the
`product or process. See MPEP § 806.05(f) and § 806.05(h). The claimsto the nonelected invention will
`be withdrawnfromfurther consideration under 37 CFR 1.142. See MPEP § 809.02(c) and § 821 through §
`821.03. However, if applicant elects claims directed to the product, and a product claim is subsequently
`found allowable, withdrawn process claims, which depend from or otherwise includeall the limitations of
`the allowable product claim will be rejoined.
`
`Where the application as originally filed discloses the product and the process for making and/or
`using the product, and only claims directed to the product are presented for examination, when a product
`claim is found allowable, applicant may prescnt claims dirceted to the proccss of making and/or using the
`patentable product by way of amendment pursuant to 37 CFR 1.121. In view of the rejoinder procedure,
`and in order to expedite prosecution, applicants are encouraged to present such process claims, preferably
`as dependentclaims, in the application at an early stage of prosecution. Process claims, which depend from
`or otherwise includeall the limitations of the patentable product, will be entered as a matterof right if the
`amendmentis presented prior to final rejection or allowance. Amendments submitted after final rejections
`are governed by 37 CFR 1.116. Process claims, which do not depend from or otherwise include the
`limitations of the patentable product, will be withdrawn fromconsideration, via an election by original
`presentation (see MPEP § 821.03). Amendments submitted after allowance is governed by 37 CFR 1.312.
`Process claims which depend from or otherwise include all the limitations of an allowed product claim and
`which meetthe requirements of 35 U.S.C. 101, 102, 103, and 112 maybe entered.
`
`Where product and process claims are presented in a single application and that application
`qualifies under the transitional restriction practice pursuant to 37 CFR 1.129(b), applicant mayeither: (A)
`clect the invention to be scarched and cxamined and pay the fee sct forth in 37 CFR 1.17(s) and have the
`additional inventions searched and examined under 37 CFR 1.129(b)(2); or (B) elect the invention to be
`searched and examined and not paythe additional fee (37 CFR 1.129(b)(3)). Where no additional fee is
`paid,
`if the clected invention is directed to the product and the claims directed to the product arc
`subsequently found patentable, process claims which either depend from or include all the limitations of the
`allowable product will be rejoined. If applicant chooses to pay the fees to have the additional inventions
`searched and examined pursuant to 37 CFR 1.129(b)(2) even if the product is found allowable, applicant
`would not be entitled to a refund of the fees paid under 37 CFR 1.129(b) by arguing that the process claims
`could have been rejoined. 37 CFR 1.26(a) states that “[T] he Commissioner may refund any fee paid by
`mistake or in excess of that required. A change of purpose after the payment of a fee...will not entitle a
`party to a refund of such fee...” In this case, the fees paid under 37 CFR 1.129(b) were not paid by mistake
`nor paid in excess, therefore, applicant would not be entitled to a refund.
`In the event of rejoinder, the
`rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to
`be allowable, the rejoined claims must meetall criteria for patentability including the requirements of 35
`U.S.C. 101,102, 103, and 112. If the application containing the rejoined claims is not in condition for
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 627 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 627 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 8
`
`allowance, the subsequent Office action may be madefinal, or, if the application was already underfinal
`rejection, the next Office action may be an advisory action. Form paragraphs 8.42 through 8.44 should be
`used to notify applicant of the rejoinder of process claims, which depend from or otherwise includeall the
`limitations of an allowable product claim.
`
`In the event of rejoinder, the rejoined process claims will be fully examined for patentability in
`accordance with 37 CFR 1.104 - 1.106. Thus, to be allowable, the rejoined claims must meetall criteria for
`patentability including the requirements of 35 U.S.C. 101, 102, 103, and 112. If the application containing
`the rejoined claimsis not in condition for allowance, the subsequent Office action may be madefinal,or,if
`the application was alrcady under final rejection, the next Office action may be an advisory action.
`
`“Guidance on Treatment of Product and
`The following is a recitation from paragraph five,
`Process Claimsin light of In re Ochiai, In re Brower and 35 U.S.C. §103(b)” (1184 TMOG 86(March 26,
`1996)):
`
`“However, 1n the case of an elected product claim, rejoinder will be permitted when a product
`claim is found allowable and the withdrawn process claim depends from or otherwise includes all the
`limitations of an allowed product claim. Withdrawn proccss claims not commensurate in scope with an
`allowed product claim will not be rejoined.” (Emphasis added)
`
`Therefore, in accordance with M.P.EP 821.04 and In re Ochiai, 71 F.3d 1565, 37 USPQ
`
`1127 (Fed. Cir. 1995), rejoinder of product claims with process claims commensurate in scope
`
`with the allowed product claims will occur following a finding that the product claims are
`
`allowable. Until, such time, a restriction between product claims and process claims is deemed
`
`proper. Additionally, in order to retain the right to rejoinder in accordance with the above policy,
`
`Applicant is advised that the process claims should be amended during prosecution to maintain
`
`either dependency on the product claims or to otherwise include the limitations of the product
`
`claims. Failure to do so may result in a loss of the right to rejoinder.
`
`Applicant is advised that the reply to this requirement to be complete must include an
`
`election of the invention to be examined even though the requirementis traversed (37 CFR 1.143).
`
`Telephone Inquiry
`
`Any inquiry concerning this communication or earlier communications from the
`
`examiner should be directed to Golam Shameem, Ph.D., whose telephone number is (571) 272-
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 628 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 628 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 9
`
`0706. The examiner can normally be reached on Monday-Thursday from 7:30 AM - 6:00 PM.
`
`If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor,
`
`Joseph McKane, can be reached at (571) 272-0699. The Unofficial fax phone numberfor this
`
`Group is (703) 308-7922. The Official fax phone numbers for this Group are (571) 273-8300.
`
`Whenfiling a FAX in Technology Center 1600, please indicate in the Header (upperright)
`
`“Official” for papers that are to be entered into the file, and “Unofficial” for draft documents and
`
`other communications with the PTO that are not for entry into the file of the application. This
`
`will expedite processing of your papers.
`
`Communications via Internet e-mail regarding this application, other than those under 35
`
`U.S.C. 132 or which otherwise require a signature, may be used by the applicant and should be
`
`addressed to [joseph.mckane@uspto.gov]. All Internet e-mail communications will be made of
`
`record in the application file. PTO employees will not communicate with applicant via Internet
`
`e-mail where sensitive data will be exchanged or where there exists a possibility that sensitive
`
`data could be identified unless there is of record an express waiver of the confidentiality
`
`requirements under 35 U.S.C. 122 by the applicant. See the Interim Internet Usage Policy
`
`published by the Patent and Trademark Office Official Gazette on February 25, 1997 at 1195 OG
`
`89,
`
`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 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.
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 629 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 629 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 10
`
`Any inquiry of a general nature or relating to the status of this application should be
`
`directed to the Group receptionist, whose telephone numberis (571) 272-1600.
`
`/Golam M. M. Shameem/
`Primary Examiner
`Art Unit 1626
`Technology Center 1600
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 630 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 630 of 891
`
`

`

`Application/Control Number: 15/019,543
`Art Unit: 1626
`
`Page 11
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`SANDOZINC.
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`IPR2023-00478
`
`Ex. 1023, p. 631 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 631 of 891
`
`

`

`
`
`UNITED StaTreS PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and ‘Trademark Office
`Address: COMMTSSIONER, FOR PATENTS
`PC. Box 1450
`Alexandria, Virgnia 22313-1450
`Wwww.uspto.gov
` APPLICATION NUMBER
`FIRST NAMED APPLICANT
`FILING OR 371(C) DATE
`ATTY. DOCKET NO/TTILE
`15/019,543
`02/09/2016
`‘Tjeerd A. Barf
`015332.1182-US02
`CONFIRMATION NO. 1984
`PUBLICATION NOTICE
`
`26853
`COVINGTON & BURLING, LLP
`
`Attn: Patent Docketing
`
`One CityCenter
`850 Tenth Street, NW
`Washington, DC 20001-4956
`
`ATA
`
`Title:4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK
`INHIBITORS
`
`Publication No.US-2016-0151364-A1
`Publication Date:06/02/2016
`
`NOTICE OF PUBLICATION OF APPLICATION
`
`The above-identified application will be electronically published as a patent application publication pursuant to 37
`CFR 1.211, et seq. The patent application publication number and publication date are set forth above.
`
`The publication may be accessed through the USPTO's publically available Searchable Databases via the
`Internet at www.uspto.gov. The direct link to access the publication is currently http:/Awww.uspto.gov/pattt/.
`
`The publication process established by the Office does not provide for mailing a copy of the publication to
`applicant. A copy of the publication may be obtained from the Office upon paymentof the appropriate fee set forth
`in 37 CFR 1.19(a)(1). Orders for copies of patent application publications are handled by the USPTO's Office of
`Public Records. The Office of Public Records can be reachedby telephone at (703) 308-9726 or (800) 972-6382,
`by facsimile at (703) 305-8759, by mail addressed to the United States Patent and TrademarkOffice, Office of
`Public Records, Alexandria, VA 22313-1450 or via the Internet.
`
`In addition, information on the status of the application, including the mailing date of Office actions and the
`dates of receipt of correspondencefiled in the Office, may also be accessed via the Internet through the Patent
`Electronic Business Center at www.uspto.gov using the public side of the Patent Application Information and
`Retrieval (PAIR) system. The direct link to access this status information is currently http://pair.uspto.gov/. Prior to
`publication, such status information is confidential and may only be obtained by applicant using the private side of
`PAIR.
`
`Further assistance in electronically accessing the publication, or about PAIR, is available by calling the Patent
`Electronic Business Center at 1-866-217-9197.
`
`
`
`Office of Data Managment, Application Assistance Unit (571) 272-4000, or (571) 272-4200, or 1-888-786-0101
`
`page 1 of 1
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 632 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 632 of 891
`
`

`

`des brevets
`
`Europaisches
`Patentamt
`P'
`Patent Office
`Office européen
`
`Bescheinigung
`
`Certificate
`
`Attestation
`
`Die angehefteten
`Unterlagen stimmen mit der
`als urspruinglich eingereicht
`geltenden Fassung der auf
`dem nachsten Blatt
`bezeichneten europaischen
`Patentanmeldung Uberein.
`
`The attached documents are
`exact copies of the text in
`which the European patent
`application described on the
`following page is deemedto
`have been filed.
`
`Les documentsjoints a la
`présente attestation sont
`conformes au texte,
`considéré comme
`initialement déposé, de la
`demandede brevet
`européen qui est spécifiée a
`la page suivante.
`
`PatentanmeldungNr.
`
`Patent application No.
`
`Demande de brevet n°
`
`11174578 .2 /EP11174578
`
`The organization code and number of your priority application, to be used for filing abroad under the Paris
`Convention, is EP11174578.
`
`Der Prasident des Europaischen Patentamts;
`Im Auftrag
`For the President of the European Patent Office
`Le President de I'Office européen des brevets
`p.o.
`
`A ot
`
`R.G. van Dijk
`
`EPA/EPO/OEB Form 1014=12.08
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 633 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 633 of 891
`
`

`

`
`
`Anmeldung Nr:
`Application no.:
`Demande no :
`
`11174578.2
`
`Anmelder / Applicant(s) / Demandeur(s):
`
`N.V. Organon
`Kloosterstraat 6
`5349 AB Oss/NL
`
`Anmeldetag:
`Dateoffiling:
`Date de dépét:
`
`19.07.11
`
`Bezeichnung der Erfindung / Title of the invention / Titre de I'invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben ist, siehe Beschreibung.
`If no title is shown please refer to the description.
`Si aucun titre n'est indiqué se référer ala description.)
`
`BTK inhibitors
`
`In Anspruch genommenePrioritat(en) / Priority(Priorities) claimed / Priorité(s) revendiquée(s)
`Staat/Tag/Aktenzeichen / State/Date/File no. / Pays/Date/Numéro de dépét:
`
`Internationale Patentklassifikation / International Patent Classification / Classification internationale de brevets:
`
`C07D487/00
`
`Am Anmeldetag benannte Vertragstaaten / Contracting States designated at date offiling / Etats contractants désignéeslors
`du dépot:
`
`AL AT BE BG CH GY CZ DE DK EE ESFI FR GB GR HR HU IE IS IT LILT LU LV MG MK MT NL NO PL
`PT RO RS SE SI SK SM TR
`
`
`
`EPA/EPO/OEB Form 1014=12.08 2
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 634 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 634 of 891
`
`

`

`BTKinhibitors
`
`Field of the invention
`
`5
`
`10
`
`The present
`
`invention relates
`
`to 6-5 membered fused pyridine
`
`ring compounds,
`
`pharmaceutical compositions comprising these compounds and to their use in therapy.
`
`to
`
`In
`
`particular,
`
`the present
`
`invention relates to the use of 6-5 membered fused pyridine ring
`
`compounds in the treatment of Bruton’s Tyrosine Kinase (Btk) mediated disorders.
`
`Backgroundof the invention
`
`B lymphocyte activation is key in the generation of adaptive immune responses. Derailed B
`
`lymphocyte activation is a hallmark of many autoimmune diseases and modulation of this
`
`15.
`
`immune response is therefore of therapeutic interest. Recently the success of B cell therapies
`
`in autoimmune diseases has been established. Treatment of rheumatoid arthritis (RA) patients
`
`with Rituximab (anti-CD20 therapy) is an accepted clinical therapy by now. More recentclinical
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`trial studies show that
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`treatment with Rituximab also ameliorates disease symptoms in
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`relapsing remitting multiple sclerosis (RRMS) and systemic lupus erythematosus (SLE)
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`20+patients. This success supports the potential for future therapies in autoimmune diseases
`
`targeting B cell immunity.
`
`Bruton tyrosine kinase (Btk) is a Tec family non-receptor protein kinase, expressed in B cells
`
`and myeloid cells. The function of Btk in signaling pathways activated by the engagement of
`
`the B cell receptor (BCR) and FceR1 on mastcells is well established.
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`In addition, a function
`
`25
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`for Btk as a downstream target in Toll
`
`like receptor signaling was suggested. Functional
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`mutations in Btk in human results in the primary immunodeficiency disease called XLA whichis
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`characterized by a defect in B cell development with a block between pro- and pre-B cell stage.
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`This results in an almost complete absence of B lymphocytes in human causing a pronounced
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`reduction of serum immunoglobulin of all classes. These finding support the key role for Btk in
`
`30
`
`the regulation of the production of auto-antibodies in autoimmune diseases.
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`In addition,
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`regulation of Btk may affect BCR-induced production of pro-inflammatory cytokines and
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`chemokines byBcells, indicating a broad potential for Btk in the treatment of autoimmune
`diseases.
`
`With the regulatory role reported for Btk in FceR-mediated mast cell activation, Btk inhibitors
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`35. may also show potential in the treatment of allergic responses [Gilfillan et al, Immunological
`
`Reviews 288 (2009) pp149-169].
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 635 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 635 of 891
`
`

`

`-2.
`
`Furthermore, Btk is also reported to be implicated in RANKL-induced osteoclast differentiation
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`[Shinohara et al, Cell 132 (2008) pp794-806] and therefore may also be ofinterest for the
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`treatment of bone resorption disorders.
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`§ Other diseases with an important role for dysfunctional B cells are B cell malignancies. Indeed
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`anti-CD20 therapy is used effectively in the clinic for the treatment of follicular lymphoma,
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`diffuse large B-cell lymphoma and chronic lymphocytic leukemia [Lim et al, Haematologica, 95
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`(2010) pp135-143]. The reported role for Btk in the regulation of proliferation and apoptosis of
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`B cells indicates there is potential for Btk inhibitors in the treatment of B cell lymphomas as
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`10
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`~——-well. Inhibition of Btk seems to be relevant in particular for B cell lymphomas due to chronic
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`active BCR signaling [Davis et al, Nature, 463 (2010) pp8&8-94].
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`Some classes of 6-5 membered fused pyridine ring compounds have been described as kinase
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`inhibitors e.g. Imidazo[1 ,5-f][1,2,4]triazine compounds have been described in WO2005097800
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`15
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`and W0O2007064993;.
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`Imidazo[1,5-aJpyrazineé
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`compounds
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`have
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`been
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`described
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`in
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`W02005037836 and WO2001019828 as IGF-1R enzyme inhibitors.
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`Someof the Btk inhibitors reported are not selective over Src-family kinases. With dramatic
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`adverse effects reported for knockouts of Src-family kinases, especially for double and triple
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`20
`
`knockouts, this is seen as prohibitive for the developmentof Btk inhibitors that are not selective
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`over the Src-family kinases.
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`Both Lyn-deficient and Fyn-deficient mice exhibit autoimmunity mimicking the phenotype of
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`human lupus nephritis.
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`In addition, Fyn-deficient mice also show pronounced neurological
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`defects. Lyn knockout mice also show an allergic-like phenotype,
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`indicating Lyn as a broad
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`25
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`negative
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`regulator of
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`the
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`IgE-mediated
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`allergic
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`response
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`by
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`controlling mast
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`cell
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`responsiveness and allergy-associated traits [Odom et al, J. Exp. Med., 199 (2004) pp1491-
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`1502]. Furthermore, aged Lyn knock-out mice develop severe splenomegaly (myeloid
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`expansion) and disseminated monocyte/macrophage tumors [Harder et al, Immunity, 15 (2001)
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`pp603-615]. These observations are in line with hyperresponsive B cells, mast cells and
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`30 myeloid cells, and increased lg levels observed in Lyn-deficient mice.
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`Female Src knockout mice are infertile due to reduced follicle development and ovulation
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`[Roby et al, Endocrine, 26 (2005) pp169-1 76].
`The double knockouts Src’Fyn” and Src’Yes” show a severe phenotype with effects on
`movement and breathing. The triple Knockouts Src’Fyn”Yes”die at day 9.5 [Klinghoffer et al,
`EMBO J., 18 (1999) pp2459-2471]. For the double knockout Src’Hck”, two thirds of the mice
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`35
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`die at birth, with surviving mice developing osteopetrosis, extramedullary hematopoiseis,
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`anemia, leukopenia [Lowell et al, Blood, 87 (1996) pp1 780-1792].
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`Hence, an inhibitor that inhibits multiple or all Kinases of the Src-family kinases simultaneously
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`may cause serious adverse effects.
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`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 636 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 636 of 891
`
`

`

`Detailed description of the invention
`
`The object of the present invention is to provide 6-5 membered fused pyridine ring compounds,
`
`§
`
`to pharmaceutical compositions comprising these compounds and to their use in therapy.
`
`In
`
`particular,
`
`the present
`
`invention relates to the use of 6-5 membered fused pyridine ring
`
`compounds in the treatment of Bruton’s Tyrosine Kinase (Btk) mediated disorders.
`
`More specifically, the present invention provides 6-5 membered fused pyridine ring compounds
`
`10
`
`according to formula | or pharmaceutically acceptable salts thereof.
`
`R5
`
`YNOI
`0NH
`
`x
`
`N
`
`Bi
`
`Ph
`
`/
`==B,
`
`NH,
`
`A
`
`Ni
`
`——
`
`Lon 4
`R4
`R3
`
`N
`
`RI
`
`Nn”
`\R2
`
`Formula |
`
`In this formula the substituents are defined as
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`X is CH, N, OQ ors;
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`15 Yis C(R6),N, Oors;
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`zis CH, N or bond;
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`Ais CHorN;
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`B1 is N or C(R7);
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`B2 is N or C(R8);
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`20
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`B3is N or C(RQ);
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`B4 is N or C(R10);
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`R1 is R11C(O), R12S(O), R13S0,or (1-6C)alkyl optionally substituted with R14:
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`R2 is H, (1-3C)alkyl or (3-7C)cycloalkyl;
`
`25
`
` R3is H, (1-6C)alkyl or (38-7C)cycloalkyl); or
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`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 637 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 637 of 891
`
`

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`-4.
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`R2 and R3 form, together with the N and C atom theyare attached to, a (3-7C)heterocycloalkyl
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`optionally substituted with one or morefluorine, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo;
`
`R4is H or (1-3C)alkyl;
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`R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, (3-6C)cycloalkyl; all alkyl groups of R5 are
`
`§
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`optionally substituted with one or more halogen; or R& is (6-10C)aryl or (2-6C)heterocycloalkyl;
`
`R6 is H or (1-3C)alkyl; or
`
`R5 and Ré6
`
`together may form a (3-7C)cycloalkenyl, or
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`(2-6C)heterocycloalkenyl, each
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`optionally substituted with (1-3C)alkyl, or one or more halogen;
`
`R7 is H, halogen or (1-3C)alkoxy;
`
`10
`
`R8 is Hor (1-3C)alkyl; or
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`R7 and R8 form, together with the carbon atom they are attached to a (-10C)aryl or (1-
`
`9C)heteroaryl;
`
`Rg is H, halogen or (1-3C)alkoxy;
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`R10 is H, halogen, or (1-3C)alkoxy;
`
`15.
`
`_-R11
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`is independently selected from a group consisting of (1-6C)alkyl, (2-6C)alkenyl and (2-
`
`6C)alkynyl each alkyl, alkenyl or alkynyl optionally substituted with one or more groups
`
`selected from hydroxyl, (1-4C)alkyl, (8-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkylJamino,
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`(1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl or (3-7C)heterocycloalkyl; or
`
`R11 is (1-3C)alkyl-C