`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES 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.
`
`14/523,650
`
`10/24/2014
`
`John C. BYRD
`
`PIR-88501
`
`1095
`
`FOLEY HOAG, LLP (W/PIR) a|
`
`FOL
`
`a
`
`wee
`
`PATENT GROUP,Seaport West
`155 SEAPOR'T BLVD
`BOSTON, Ma 02210
`
`TRAN, MY CHAU T
`
`1629
`
`NOUIFICATION DATE
`
`DELIVERY MODE
`
`04/22/2016
`
`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):
`
`Patent @foleyhoag.com
`pair_foleyhoag @ firsttofile.com
`ABBVIE_PATENTS_ABT_PRK @abbvie.com
`
`PTOL-90A (Rev. 04/07)
`
`SAN EX 1021, Page 1
`
`SAN EX 1021, Page 1
`
`

`

`A SHORTENED STATUTORY PERIOD FOR REPLYIS SET TO EXPIRE 3MONTHS FROM THE MAILING DATE OF
`THIS COMMUNICATION.
`- Extensions of time may be available underthe provisions of 37 CFR 1.136{a).
`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 monthsafter the mailing date of this communication, evenif timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`
`In no event, however, may a reply be timelyfiled
`
`-
`-
`
`Status
`1)X] Responsive to communication(s)filed on 03/08/2016.
`L] A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filedon__
`2a)L] This action is FINAL.
`2b)X] This action is non-final.
`3)0 An election was made by the applicant in responseto a restriction requirement set forth during the interview on
`; the restriction requirement and election have been incorporated into this action.
`4\L] Since this application is in condition for allowance exceptfor formal matters, prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`Disposition of Claims*
`5) Claim(s) 1-20 is/are pending in the application.
`5a) Of the above claim(s) 79 and 20 is/are withdrawn from consideration.
`
`6)L] Claim(s)
`is/are allowed.
`7)K] Claim(s) 1-18 is/are rejected.
`8)L] Claim(s)__ is/are objected to.
`
`3)[] Claim(s)
`are subject to restriction and/or election requirement.
`* IF any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program ata
`participating intellectual property office for the corresponding application. For more information, please see
`
`hite
`/Avww.usoto.gov/patents/init events/ooh/index.jso or send an inquiry to PPHieedback@uspto.dov.
`
`Application Papers
`10)Z The specification is objected to by the Examiner.
`11)X] The drawing(s)filed on 10/24/2014 is/are: a)[X] accepted or b)[_] abjected 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).
`
` Attachment(s)
`
`
`Application No.
`Applicant(s)
`14/523,650
`BYRD ETAL.
`
`Office Action Summary
`Examiner
`Art Unit
`AIA (FirstInventorto File)
`
`
`1629MY-CHAU T. TRAN vese
`-- The MAILING DATEof this communication appears on the cover sheet with the correspondenceaddress--
`Period for Reply
`
`Priority under 35 U.S.C. § 119
`12)L] Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or(f).
`Certified copies:
`a)DAll bj) Some** c) None ofthe:
`1.[] Certified copies of the priority documents have beenreceived.
`2..] Certified copies of the priority documents have been received in Application No.
`3...) Copies ofthe certified copies of the priority documents have been received in this National Stage
`application from the International Bureau (PCT Rule 17.2(a)).
`“ See the attached detailed Office action foralist of the certified copies not received.
`
`1) Xx Notice of References Cited (PTO-892)
`;
`:
`2) Xx Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mail Date 03/08/2016.
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`3) | Interview Summary (PTO-413)
`Paper No(s)/Mail Date.
`4 oO Other:
`ther: __.
`)
`
`.
`
`Part of Paper No./Mail Date 20160416
`
`SAN EX 1021, Page 2
`
`
`
`SAN EX 1021, Page 2
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 2
`
`DETAILED ACTION
`
`Application and Claims Status
`
`1.
`
`Applicant’s response filed on 02/02/2016 is acknowledged and entered.
`
`2.
`
`Claims 1-20 were pending. No claims were amended, added, and/orcancelled.
`
`Therefore, claims 1-20 are currently pending.
`
`3.
`
`The present application, filed on or after March 16, 2013, is being examined under the
`
`first inventor to file provisions of the AIA.
`
`Election/Restrictions
`
`4.
`
`Applicant’s election without traverse of a species for a pharmaceutical composition in the
`
`reply filed on 02/02/2016 is acknowledged. The elected species is as follows: “Applicant
`
`respectfully elects without traverse claims drawnto (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-
`
`pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-one, also knownas ibrutinib,
`
`
`
`represented by the structuralformula
`
`frutinit
`
`5.
`
`Claims 19 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b)
`
`as being drawn to nonelected species, there being no allowable generic or linking claim.
`
`SAN EX 1021, Page 3
`
`SAN EX 1021, Page 3
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 3
`
`Election was made without traverse in the reply filed on 02/02/2016. Accordingly, claims 1-18
`
`are under consideration in this Office Action.
`
`Priority
`
`6.
`
`This instant application claims for domestic priority under 35 U.S.C. 119(e) to four
`
`provisional applications. They are as follows: 61/895,981 that wasfiled on 10/25/2013;
`
`61/910,945 that was filed on 12/02/2013; 61/973,173 that was filed on 03/31/2014; and
`
`61/973,176 that wasfiled on 03/31/2014. Thus,the effective filing date of this instant application
`
`is 10/25/2013.
`
`Information Disclosure Statement
`
`7.
`
`The information disclosure statement (IDS) that was filed on 03/18/2016 has been
`
`reviewed, and the references that have been consideredare initialed as recorded in PTO-1449
`
`forms,
`
`Claim Rejections - 35 USC § 112
`
`8.
`
`The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
`
`Thespecification shall contain a written description of the invention,
`(a) INGENERAL.
`and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to
`enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to
`make and use the same, and shall set forth the best mode contemplated by the inventoror joint inventor
`ofcarrying out the invention.
`
`The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
`
`The specification shall contain a written description ofthe invention, and of the manner and
`process of making and usingit, in such full, clear, concise, and exact terms as to enable any person
`
`SAN EX 1021, Page 4
`
`SAN EX 1021, Page 4
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 4
`
`skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the
`same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
`
`9.
`
`Claims | and 3-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-ATA), first
`
`paragraph,as failing to comply with the enablement requirement. The claim(s) contains subject
`
`matter which wasnot described in the specification in such a way as to enable one skilled in the
`
`art to which it pertains, or with which it is most nearly connected, to make and/or use the
`
`invention. This is a scope of enablementrejection.
`
`First, claim | recites “A method ofpreventing the occurrence ofgraft versus host disease
`
`(GVHD) or reducing the severity of GVHD occurrencein a patient requiring cell
`
`transplantation, comprising administering to the patient a therapeutically effective amount of a
`
`compound of Formula (A) having the structure:
`
`Rn oe
`
`Noe
`bo an
`Se “N
`Ry
`Formula (4%
`
`wherein: A is N; R; is phenyl-O-
`
`phenyl or phenyl-S-phenyl; Ro and R3 are independently H; Rg is L3-X-L4-G, wherein, L; is
`
`optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally
`
`substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally
`
`substituted or unsubstituted alkynyl; X is optional, and when present is a bond, -O-, -C(=O)-, -S-
`
`, -S(=O)-, -S(=O)2-, -NH-, -NRo-, -NHC(Q)-, -C(O)NH-, -NRoC(Q)-, -C(O)NRo-, -S(=O)2NH-, -
`
`NHS(=O)s-, -S(=O)J2NRo-, -NRoS(=O)2-, -OC(OJNH-, -NHC(O)O-, -OC(OJNRo-, -NRoC(Q)O-, -
`
`CH=NO.-, -ON=CH-, -NRj9C(O)N Rjo-, heteroaryl-, aryl-, -N RygC(=NR1,)N Ryo-, -N
`
`RiyoC(=NR11)-, -C(=NR1)NRyo-, -OC(=NRj1)-, or -C(=NR11)O-; La is optional, and whenpresent
`
`is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
`
`SAN EX 1021, Page 5
`
`SAN EX 1021, Page 5
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 5
`
`or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl,
`
`substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle; or L3, X and
`
`[4 taken togetherform a nitrogen containing heterocyclic ring; G is
`
` , wherein, Re, R7 and Rs are
`
`independently selectedfrom among H, halogen, CN, OH, substituted or unsubstituted alkyl or
`
`substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl, substituted or
`
`unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted
`
`heteroaryl; each Ro is independently selected from among H, substituted or unsubstituted lower
`
`alkyl, and substituted or unsubstituted lower cycloalkyl; each Rio is independently H, substituted
`
`or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or two Rio groups
`
`can togetherform a 5-, 6-, 7-, or 8-memberedheterocyclic ring; or Rio and Ri; can together
`
`form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or each Ri; is independently selectedfrom H
`
`or substituted or unsubstituted alkyl; or a pharmaceutically acceptable salt thereof, thereby
`
`preventing the occurrence ofgraft versus host disease (GVHD) or reducing the severity of
`
`GVADoccurrence in the patient’.
`
`It is interpreted that the instant claimed method encompasses
`
`both (a) a treatment method(i.e.) and (b) a method of prevention,i.e. “protecting” of any
`
`destruction prior to the onset“the occurrence of graft versus host disease (GVHD)”. Moreover,
`
`since the instant specification disclosures (see instant specification sections [0022]-[0033]) is
`
`silent regarding the definition of the term “prevention”, this interpretation would be encompass
`
`by the definition (i.e. the plain meaning) for the term ‘prevention’.
`
`SAN EX 1021, Page 6
`
`SAN EX 1021, Page 6
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 6
`
`Here, claims 1 and 3-18 are rejected under 35 U.S.C. 112,first paragraph, because the
`
`specification, while being enabling for only a treatment methodfor ‘reducing the severity of
`
`GVADoccurrence in the patient’ (see instant specification sections: [0033] and [00173]-
`
`[00264]), does not reasonably provide enablement for a method of preventing “the occurrence of
`
`graft versus host disease (GVHD)’. The specification does not enable any person skilled in the
`
`art to which it pertains, or with which it is most nearly connected, to make and use the invention
`
`commensurate in scope with these claims.
`
`There are manyfactors to consider when determining whetherthere is sufficient evidence
`
`to support a determination that a disclosure doesnotsatisfy the enablement requirement and
`
`whether any experimentation is “undue”. These factors include, but are not limited to: 1) The
`
`breadth of the claims; 2) The nature of the invention; 3) The state of the prior art; 4) The level of
`
`one of ordinary skill; 5) The level of predictability in the art; 6) The amountof direction
`
`provided by the inventor; 7) The presence or absence of working examples; and 8) The quantity
`
`of experimentation necessary needed to make oruse the invention based on the disclosure. See
`
`In re Wands USPQ 2d 1400 (CAFC 1988).
`
`(1-2) The breadth of the claims and the nature of the invention:
`
`Theclaimsare directed to the method for the prevention of ‘the occurrence of graft
`
`versus host disease (GVHD) using any of the compounds claimed by instant claim 1.
`
`The claims are broad enough to encompass both “protecting” of any destruction prior to
`
`any disease or disorder onset (e.g. PREVENTION) and during/subsequent to any disease or
`
`disorder onset (e.g. TREATMENT) wherein the disease or disorderis ‘graft versus host disease
`
`(GVHD).
`
`SAN EX 1021, Page 7
`
`SAN EX 1021, Page 7
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 7
`
`Consequently, the nature of the invention cannot be fully determined because the
`
`invention has not been defined with particularity.
`
`(3 and 5) The state of the prior art and the level ofpredictability in the art:
`
`Claims drawn to pharmaceuticals and methods of treatment generally require supporting
`
`data because of the unpredictability in biological responses to therapeutic treatments. This is
`
`especially true for a preventive method, which meets with stricter scrutiny than treatments, since
`
`additional controls and testing must be performed to insure prevention. The burden of enabling
`
`the prevention of a disease or disorder; or its symptoms(i.e. the need for additional testing)
`
`would be greater than that of enabling a treatment due to the need to screen those mammals (e.g.
`
`humans) susceptible to such diseases or disorders. And the difficulty of proofthat the
`
`administration of the drug composition wasthe agent that acted to prevent ‘graft versus host
`
`disease (GVHD). The specification does not provide guidance as to how oneskilled in the art
`
`would go about screening those mammals susceptible to ‘graft versus host disease (GVHD)’.
`
`Noris guidance provided in the specification as to a specific protocol to be utilized in orderto
`
`prove the efficacy of the presently claimed compound/composition, i.e. any of the compounds
`
`claimed by instant claims | and 3-6. Accordingly, undue experimentation is necessary to
`
`determine screening and testing protocols to demonstrate the efficacy of the presently claimed
`
`invention. Moreover, Magenauetal. disclose that there are many attempts to treat GVHD that
`
`have not been proven successful and that further is require in order to provide prevention and
`
`immunity to GVHD(see e.g. pg. 200, right col., lines 22-38; British Journal of Haematology,
`
`April 2016, Vol. 173, Issue 2, pp. 190-205).
`
`SAN EX 1021, Page 8
`
`SAN EX 1021, Page 8
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 8
`
`For, the efficacy of a drug treatment in vivo faces unfavorable obstacles not present in
`
`vitro models. As such, in vivo utility necessarily involves unpredictability with respect to
`
`physiological activity of an asserted process in humans. See discussion in Ex parte Kranz, 19
`
`USPQ2d 1216,1218-1219 (6/90). For example, drug delivery to the targeted area must survive
`
`the acidic environmentof the stomach if administered orally. Additionally, the delivery of the
`
`drug across necessary cell surfaces in amounts neededto be efficacious, but not lethal to the
`
`organism, necessitates sensitive testing in order to adequately determine the proper human
`
`dosage. Additionally, there are no specific mammalian (e.g. human) genetic markers to enable
`
`screening of those mammals genetically predisposed toward ‘graft versus host disease (GVHD)’.
`
`Accordingly, undue experimentation is necessary to determine screening andtesting
`
`protocols to demonstrate the efficacy of the presently claimed invention.
`
`(4) The level of one of ordinary skill in the art:
`
`Thelevel of skill would be high, mostlikely at the Ph.D. level.
`
`(6-7) The amount of direction provided by the inventor and the existence of working examples:
`
`The specification only provides support (i.e. examples) for the treatment methodsfor
`
`“reducing the severity of GVHD occurrenceinthe patient’ (see instant specification sections:
`
`[0033] and [00173]-[00264]). However, these examples would not be deemed by one of
`
`ordinary skill in the art to correlate or extrapolate toward the PREVENTIONofthe onset of
`
`‘graft versus host disease (GVHD).
`
`(8) The quantity of experimentation needed to make or use the invention based onthe content of
`
`the disclosure:
`
`SAN EX 1021, Page 9
`
`SAN EX 1021, Page 9
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 9
`
`As a result of the broad and unpredictable nature of the invention and the lack of specific
`
`guidance from the specification, the Examiner contends that the quantity of experimentation
`
`needed to make and or use the invention would be great. Note that there must be sufficient
`
`disclosure, either through illustrative examples or terminology, to teach those of ordinary skill
`
`how to makeand use the invention as broadly as it is claimed. In re Vaeck, 947 F.2d 488,496 &
`
`n.23, 20 USPQ2d 1438, 1445 * n.23 (Fed. Cir. 1991). In this case, Applicants have not provided
`
`any working examples that would teach this enormous genusthatfalls within a highly
`
`unpredictable art area. Therefore, it is deemed that further research of an unpredictable nature
`
`would be necessary to make or use the invention as claimed. Thus, due to the inadequacies of
`
`the instant disclosure one of ordinary skill would not have a reasonable expectation of success
`
`and the practice of the full scope of the invention would require undue experimentation.
`
`Therefore based on the evidences as a whole regarding each of the above factors (e.g.
`
`factors 1-8), the specification, at the time the application wasfiled, does not satisfy the
`
`enablement requirementfor the instant claimed method of claims | and 3-18.
`
`Claim Rejections - 35 USC § 102
`
`10,
`
`In the event the determination ofthe status of the application as subject to ATA 35 U.S.C.
`
`102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the
`
`statutory basis for the rejection will not be considered a new ground of rejection if the prior art
`
`relied upon, and the rationale supporting the rejection, would be the same undereitherstatus.
`
`SAN EX 1021, Page 10
`
`SAN EX 1021, Page 10
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 10
`
`11.
`
`The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the
`
`basis for the rejections under this section madein this Office action:
`
`A person shall be entitled to a patent unless —
`
`(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or
`otherwise available to the public before the eftective filing date ofthe claimed invention.
`
`(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for
`patent published or deemed published under section 122(b), in which the patent or application, as the
`case may be, names another inventor and waseffectively filed before the effective filing date of the
`claimed invention.
`
`12,
`
`Claims 1, 3-6, 11, 12, and 18 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being
`
`anticipated by Izumi et al. (US Patent Application Publication US 2015/0086507 A1; Effective
`
`Filing Date of 04/11/2012).
`
`For claims I, 3-6, 11, 12, and 18, Yzumiet al. disclose pyrimidine-based inhibitors of
`
`Bruton’s tyrosine kinase (Btk) and methodsoftheir use (see e.g. Abstract; sections: [0001],
`
`[0006]-[0007], [0009]-[0022], and [0065]-[0077]). In one embodiment, the pyrimidine-based
`
`inhibitor (Btk inhibitor) is a compoundofstructural FormulaIIL:
`
`
`
`* , wherein: La
`
`is O; Aris an unsubstituted phenyl; Y isa 6-membered monocyclic nitrogen containing
`
`heterocyclic ring; Z is C(=O); Rg is H; Ry is H; and Rgis H (see e.g. sections: [0066]-[0077] and
`
`[0086]-[0094]). The compound can be in a form suitable fororal use (see e.g. sections: [0110],
`
`[0117]-[0118], and [0122]-[0126]). This compound read on the elected species and instant
`
`claims 1, 3-6, and 18. In one embodiment, the method of administering the Btk inhibitor and
`
`SAN EX 1021, Page 11
`
`SAN EX 1021, Page 11
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 11
`
`hematopoietic stem and/or progenitor cell transplantation to a subject in order to enhance the
`
`success of bone marrow transplantation, and/or to aid in restoration of damaged organtissue (see
`
`e.g. sections: [0007], [0009], [0129], [0131], and [0157]-[0172]). Although Izumiet al. do not
`
`disclose treating the condition of ‘graft versus host disease (GVHD)’, this conditionis art
`
`recognized to be directly associated with haematopoietic stem cell transplantation as evident by
`
`Magenauetal. (see e.g. pg. 190, left col., lines 1-19; British Journal of Haematology, April
`
`2016, Vol. 173, Issue 2, pp. 190-205) and Min(see e.g. pg. 80; THE KOREAN JOURNAL OF
`
`HEMATOLOGY,June 2011, Vol. 46, No. 2, pp. 80-87). These disclosure would read on the
`
`instant claimed method of claims 1, 11, 12, and 18.
`
`Therefore, the compound and methodof Izumiet al. do anticipate the instant claimed
`
`invention.
`
`13.
`
`Claims 1-18 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as anticipated by or, in the
`
`alternative, under 35 U.S.C. 103 as obvious over Izumiet al. (US Patent Application Publication
`
`US 2015/0086507 Al; Effective Filing Date of 04/11/2012).
`
`Forclaims 1, 3-6, 11, 12, and 18, Izumi et al. disclose pyrimidine-based inhibitors of
`
`Bruton’s tyrosine kinase (Btk) and methods of their use (see e.g. Abstract; sections: [0001],
`
`[0006]-[0007], [0009]-[0022], and [0065]-[0077]). In one embodiment, the pyrimidine-based
`
`SAN EX 1021, Page 12
`
`SAN EX 1021, Page 12
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 12
`
`
`
`inhibitor (Btk inhibitor) is a compoundofstructural Formula TIT:
`
`
`* | wherein: La
`
`is O; Ar is an unsubstituted phenyl; Y is a 6-membered monocyclic nitrogen containing
`
`heterocyclic ring; Z is C(=O); Rs is H; R7 is H; and Reis H (see e.g. sections: [0066]-[0077] and
`
`[0086]-[0094]). The compound can be in a form suitable for oral use (see e.g. sections: [0110],
`
`[0117]-[0118], and [0122]-[0126]). This compound read on the elected species and instant
`
`claims 1, 3-6, and 18. In one embodiment, the method of administering the Btk inhibitor and
`
`hematopoietic stem and/or progenitorcell transplantation to a subject in order to enhance the
`
`success of bone marrow transplantation, and/or to aid in restoration of damaged organ tissue (see
`
`e.g. sections: [0007], [0009], [0129], [0131], and [0157]-[0172]). Although Izumiet al. do not
`
`disclose treating the condition of ‘graft versus host disease (GVHD)’, this condition is art
`
`recognized to be directly associated with haematopoietic stem cell transplantation as evident by
`
`Magenauetal. (see e.g. pg. 190, left col., lines 1-19; British Journal of Haematology, April
`
`2016, Vol. 173, Issue 2, pp. 190-205) and Min (see e.g. pg. 80; THE KOREAN JOURNAL OF
`
`HEMATOLOGY,Jane 2011, Vol. 46, No. 2, pp. 80-87). These disclosure would read on the
`
`instant claimed method of claims 1, 11, 12, and 18.
`
`Forclaim 2, Izumi etal. disclose pyrimidine-based inhibitors of Bruton’s tyrosine kinase
`
`(Btk) and methodsof their use (see e.g. Abstract; sections: [0001], [0006]-[0007], [0009]-[0022],
`
`and [0065]-[0077]). In one embodiment, the pyrimidine-based inhibitor (Btk inhibitor) is a
`
`SAN EX 1021, Page 13
`
`SAN EX 1021, Page 13
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 13
`
`
`
`*s , wherein: La is O; Ar is an unsubstituted
`
`compoundofstructural FormulaTIT:
`
`phenyl; Y is a 6-membered monocyclic nitrogen containing heterocyclic ring; Z is C(=O); Rg is
`
`H; Rz is H; and Re is H (see e.g. sections: [0066]-[0077] and [0086]-[0094]). This compound
`
`read on the elected species and the compound ofinstant claim 2. In one embodiment, the
`
`method of administering the Btk inhibitor to a subject in order to enhance the success of bone
`
`matrow transplantation, and/or to aid in restoration of damaged organ tissue (see e.g. sections:
`
`[0007], [0009], [0129], [0131], and [0157]-[0172]). Although Izumiet al. do not disclose
`
`treating the condition of ‘graft versus host disease (GVHD)’, this condition is art recognized to
`
`be directly associated with haematopoietic stem cell transplantation as evident by Magenauetal.
`
`(see e.g. pg. 190, left col., lines 1-19; British Journal of Haematology, April 2016, Vol. 173,
`
`Issue 2, pp. 190-205) and Min (see e.g. pg. 80; THE KOREAN JOURNAL OF HEMATOLOGY,
`
`June 2011, Vol. 46, No. 2, pp. 80-87). These disclosure would read on the instant claimed
`
`method of claim 2.
`
`Alternatively, the claimed invention furtherdiffers from the prior art teachings only by the
`
`recitation of:
`
`Forclaims 2, 7-10 and 13-17, the claimed limitations of claims 2 and 7-10 (.e. the
`
`specific type of GVHD conditions and disease of claim 10) and the claimed limitations of claims
`
`13-17 (ie. the specific type of dosage and/or dosing regimens) are interpreted as the functional
`
`SAN EX 1021, Page 14
`
`SAN EX 1021, Page 14
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 14
`
`limitation for the instantly compound. The claimed invention appears to be the same or obvious
`
`variations of the reference teachings, absent a showing of unobvious differences. The office
`
`does not have the facilities and resources to provide the factual evidence needed in orderto
`
`determine and/or compare the specific activities of the instant claimed compound versus the
`
`reference compound. In the absence of evidence to the contrary, the burden is upon the applicant
`
`to prove that the claimed compoundis different from the one taught by prior art and to establish
`
`the patentable differences, See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex
`
`parte Gray 10 USPQ2d 1922(PTO Bd. Pat. App. & Int. 1989). As a result, the method of Izumi
`
`et al. wouldstill anticipate the presently claimed method since it meetsall the structural
`
`limitation ofthe claimed compoundofclaims 1-6.
`
`Therefore, the compound and method of Izumiet al. do anticipate the instant claimed
`
`invention.
`
`Double Patenting
`
`14.
`
`The nonstatutory double patenting rejection is based on a judicially created doctrine
`
`groundedin public policy (a policy reflected in the statute) so as to prevent the unjustified or
`
`impropertimewise extension ofthe “right to exclude” granted by a patent and to prevent possible
`
`harassment by multiple assignees, A nonstatutory double patenting rejection is appropriate
`
`where the claimsat issue are not identical, but at least one examined application claim is not
`
`patentably distinct from the reference claim(s) because the examined application claim is either
`
`anticipated by, or would have been obviousover, the reference claim(s). See, e.g., /n re Berg,
`
`140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d
`
`SAN EX 1021, Page 15
`
`SAN EX 1021, Page 15
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 15
`
`2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van
`
`Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619
`
`(CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
`
`A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may
`
`be used to overcome an actual or provisional rejection based on a nonstatutory double patenting
`
`ground provided the reference application or patent either is shown to be commonly owned with
`
`this application, or claims an invention made as a result of activities undertaken within the scope
`
`of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR
`
`1.321(b).
`
`The USPTOinternet Website contains terminal disclaimer forms which may be used.
`
`form should be used. A web-based eTerminal Disclaimer may be filled out completely online
`
`using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and
`
`approved immediately upon submission. For more information about eTerminal Disclaimers,
`
`15.
`
`Claims 1, 3-6, 12, and 15-18 are provisionally rejected on the ground of nonstatutory
`
`double patenting as being unpatentable over claims 1-5, 11, and 16-19 of copending Application
`
`No. 14/558,297 (US Patent Application Publication US 2015/0157634 A1; hereinafter refers to
`
`as Blazaret al.). Although the conflicting claims are not identical, they are not patentably
`
`distinct from each other because both the methodofthe instant claims 1, 3-6, and 15-18, and the
`
`SAN EX 1021, Page 16
`
`SAN EX 1021, Page 16
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`Page 16
`
`method of claims 1-5, 11, and 16-19 of Blazar et al. used a compound with similar structural
`
`features.
`
`substituted or unsubstituted 14/558,297
`
`14/523,650
`
`1. A method of preventing the occurrence of
`graft versus host disease (GVHD) or
`reducing the severity of GVHD occurrence
`in a patient requiring cell transplantation,
`comprising administering to the patient a
`therapeutically effective amountof a
`compound of Formula (A) having the
`Lf
`Nok,
`inna stn s
`Ry
`.
`.
`.
`clemnisia TAI
`structure; F°™'8> Wherein: A is N; Ry is
`phenyl-O-phenyl or phenyl-S-phenyl;
`R» and R; are independently H; Ry is L3-X-
`L4-G, wherein, L3 is optional, and when
`present is a bond, optionally substituted or
`unsubstituted alkyl, optionally substituted or
`unsubstituted cycloalkyl, optionally
`substituted or unsubstituted
`alkenyl, optionally substituted or
`unsubstituted alkynyl; X is optional, and
`whenpresent is a bond, -O-, -C(=O)-, -S-, -
`S(=O)-, -S(=O)2-, -NH-, -NRo-, -NHC(O)-,-
`C(O)NH-, -NRoC(O)-, -C(O)NRo-, -
`S(=O)2NH-, -NHS(=0O),-, -S(=O),NRo-, -
`NRoS(=0)2-, -OC(O)NH-, -NHC(O)O-,-
`OC(O)NRo-, -NRoC(O)O-, -CH=NO-,-
`ON=CH-, -NRioC(O)N Rio-, heteroaryl-,
`aryl-, -N RipCENRi)N Ryo, -N
`RioC(=NRi1)-, -C(=]NRi)NRio-,-
`OC(=NR}1)-, or -C(=NR,,)O-; Ly is
`optional, and when presentis a bond,
`substituted or unsubstituted alkyl,
`substituted or unsubstituted cycloalkyl,
`substituted. or unsubstituted alkenyl,
`
`1. A methodoftreating alloantibody driven
`chronic graft versus host disease (CGVHD)
`in a patient, comprising administering
`to a patient in need thereof a
`therapeutically effective amount of a
`compoundof Formula (A) having the
`
`eS
`Rg
`
`.
`.
`Permianla TAY
`we" wherein: A is N;
`structure:
`R, is phenyl-O-phenyl or phenyl-S-phenyl;
`R; and R; are independently H; Ry is L3-X-
`L4-G, wherein, L3 is optional, and when
`present is a bond, optionally substituted or
`unsubstituted alkyl, optionally substituted
`or unsubstituted cycloalkyl, optionally
`substituted or unsubstituted
`alkenyl, optionally substituted or
`unsubstituted alkynyl; X is optional, and
`when presentis a bond, -O-, -C(=0Q)-, -S-, -
`S(=O)-, -S(=O)2-, -NH-, -NRo-, -NHC(O)-,
`-C(O)NH-, -NRoC(O)-, -C(O)NRo-, -
`S(=O)2NH-, -NHS(=O)2-, -S(=O)2NRo-, -
`NRoS(=O)-, -OC(O)NH-, -NHC(O)O-, -
`OC(O)NRo-, -NRoC(Q)O-, -CH=NO-, -
`ON=CH-, -NRioC(OYN Rio-, heteroaryl-,
`aryl-, -N RioC(=NRi)N Rio-, -N
`RyoC(=NR11)-, -C(=NRi1)NRio-, -
`OC(=NR11)-, or -C(=]NR11)O-; Ly is
`optional, and when presentis a bond,
`substituted or unsubstituted alkyl,
`substituted or unsubstituted cycloalkyl,
`substituted or unsubstituted alkenyl,
`
`SAN EX 1021, Page 17
`
`SAN EX 1021, Page 17
`
`

`

`Application/Control Number: 14/523,650
`Art Unit: 1629
`
`
`Page 17
`
`alkynyl, substituted or unsubstituted aryl,
`substituted or unsubstituted heteroaryl,
`substituted or unsubstituted heterocycle; or
`L;, X and L4 taken together form a nitrogen
`containing heterocyclic ring; G is
`
`
`
`
`
`substituted or unsubstituted
`alkynyl, substituted or unsubstituted aryl,
`substituted or unsubstituted heteroaryl,
`substituted or unsubstituted heterocycle; or
`Ls, X and L4 taken together form a
`nitrogen containing heterocyclic ring; G is
`
`
`0 w
`
`herein, Re, R7 and Rg are independently
`selected from among H, halogen, CN, OH,
`substituted or unsubstituted alkyl or
`substituted or unsubstituted heteroalkyl or
`substituted or unsubstituted cycloalkyl,
`substitut