IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Docket No.: PIR-88501
`
`(PATENT)
`
`In re Patent Application of:
`John C. Byrd, er a].
`
`Application No.: 14/523,650
`
`Confirmation No.: 1095
`
`Filed: October 24, 2014
`
`Art Unit: 1629
`
`For: METHODS OF TREATING AND
`PREVENTING GRAFT VERSUS HOST
`
`Examiner: TRAN, My Chau T.
`
`DISEASE
`
`AMENDMENT AND RESPONSE
`
`MS Amendment
`
`Commissioner for Patents
`
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`Dear Sir:
`
`In response to the pending Office Action, dated April 22, 2016,
`
`in connection with the
`
`above-referenced application, Applicant submits this Response. Please amend the application as
`
`follows.
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`Amendments to the Claims begin on page 2.
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`Remarks begin on page 6.
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`Application No. 14/523,650
`Amendment and Response
`
`IN THE CLAIMS:
`
`2
`
`Docket No.: FIR-88501
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`1.
`
`(Currently amended) A method of treating preventing—the—Geeurrenee—etlgraft versus
`
`host disease (GVHD); or reducing the severity of GVHD occurrence; in a patient having chronic
`
`GVHD {Well—transplantation; comprising administering to the patient a therapeutically
`
`effective amount of a compound of Formula (A) having the structure:
`
`R3\
`
`R2
`
`N
`
`N
`
`N \15$
`
`R1
`
`N
`R4
`
`Formula (A);
`
`wherein:
`
`Ais N;
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`R1 is phenyl-O-phenyl or phenyl-S-phenyl;
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`R2 and R3 are independently H;
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`R4 is L3-X-L4-G; wherein;
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`L3 is optional; and when present is a bond; optionally substituted or unsubstituted alkyl;
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`optionally substituted or unsubstituted cycloalkyl; optionally substituted or unsubstituted alkenyl;
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`optionally substituted or unsubstituted alkynyl;
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`X is optional; and when present is a bond; -O-; -C(=O)-; -S-; -S(=O)-; -S(=O)2-; -NH-;
`
`
`
`«R93 -NHC(O)-; -C(O)NH-; -NR9C(O)-; -C(O)NR9-; -S(=O)2NH-; -NHS(=O)2-; -S(=O)2NR9-;
`
`’R98(=O)2-; -OC(O)NH-, -NHC(O)O-, -OC(O)NR9-; -NR9C(O)O-; -CH=NO-; -ON=CH-;
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`VR10C(O)NR10-; heteroaryl-; aryl-; -NR10C(=NR11)NR10-; -NR10C(=NR11)-; -C(=NR11)NR10-;
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`-OC(=NR11)-; or -C(=NR11)O-;
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`L4 is optional; and when present is a bond; substituted or unsubstituted alkyl; substituted or
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`unsubstituted cycloalkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl;
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`Application No. 14/523,650
`Amendment and Response
`
`3
`
`Docket No.: FIR-88501
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`substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
`
`heterocycle;
`
`or L3, X and L4 taken together form a nitrogen containing heterocyclic ring;
`
`OQS/IO R6
`0
`R6
`0
`. EMR7 53% I771
`
`G 1s
`
`R8
`
`7
`
`R
`
`7
`
`6
`
`R8
`
`7
`
`7
`
`I771
`
`lcl)
`
`R6
`
`R8
`
`Icl)
`§
`RZC’)
`
`R7
`
`7
`
`or
`
`R5
`
`R7
`
`R8
`
`.
`, wherem,
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`R6, R7 and R3 are independently selected from 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 R9 is independently selected from among H, substituted or unsubstituted lower alkyl,
`
`and substituted or unsubstituted lower cycloalkyl;
`
`each R10 is independently H, substituted or unsubstituted lower alkyl, or substituted or
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`unsubstituted lower cycloalkyl; or
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`two R10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
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`R10 and R11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
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`each R11 is independently selected from H or substituted or unsubstituted alkyl; or a
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`pharmaceutically acceptable salt thereof,
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`thereby treating thepreyenti-ng—the—eeeurrenee—ef graft versus host disease (GVHD) or
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`reducing the severity of GVHD occurrence in the patient.
`
`2.
`
`3.
`
`(Canceled)
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`(Original) The method of claim 1, wherein L3, X and L4 taken together form a nitrogen
`
`containing heterocyclic ring.
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`4.
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`(Original) The method of claim 3, wherein the nitrogen containing heterocyclic ring is
`
`a piperidine group.
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`Application No. 14/523,650
`Amendment and Response
`
`4
`
`Docket No.: FIR-88501
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`5.
`
`6.
`
`(Original) The method of claim 1, wherein G is
`
`R8
`
`or
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`(Original) The method of claim 1, wherein the compound of Formula (A) is l-[(3R)-3-
`
`[4-amino-3 -(4-phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin- l -yl]piperidin- l -yl]prop-2-en- 1 -one.
`
`7.
`
`
`(Currently amended) The method of claim 1, wherein the chronic GVHD is
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`sclerodermatous GVHD, steroid resistant GVHD, cyclosporin-resistant GVHD, refractory GVHD,
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`oral GVHD, ehrenie oral GVHD, reticular oral GVHD, erosive GVHD, or ulcerative oral GVHD.
`
`8.
`
`
`(Currently amended) The method of claim 1, wherein the chronic GVHD is
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`sclerodermatous GVHD.
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`9.
`
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`(Currently amended) The method of claim 1, wherein the chronic GVHD is steroid
`
`resistant GVHD.
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`10.
`
`(Original) The method of claim 1, wherein the patient has chronic lymphocytic
`
`leukemia (CLL).
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`11.
`
`(Currently amended) The method of claim 1, wherein the patient had eel-l
`
`transplantation—is a hematopoietic cell transplantation.
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`12.
`
`(Canceled)
`
`l3.
`
`(Canceled)
`
`l4.
`
`(Canceled)
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`15.
`
`(Original) The method of claim 1, wherein the compound of Formula (A) is
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`administered at a dosage of between about 0.1 mg/kg per day to about 100 mg/kg per day.
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`16.
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`(Currently amended) The method of claim 1, wherein the amount of the compound of
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`Formula (A) administered is about 40 mg/day, about 140 mg/day, about 280 mg/day: about
`
`420 mg/day, about 560 mg/day, or about 840 mg/day.
`
`l7.
`
`(Canceled)
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`Application No. 14/523,650
`Amendment and Response
`
`5
`
`Docket No.: FIR-88501
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`18.
`
`(Original) The method of claim 1, wherein the compound of Formula (A) is
`
`administered orally.
`
`l9.
`
`(Withdrawn) The method of claim 1, wherein the compound of Formula (A) is
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`administered in combination with one or more additional therapeutic agents.
`
`20.
`
`(Withdrawn) The method of claim 19, wherein the additional therapeutic agent is a
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`corticosteroid, cyclosporine (CSA), mycophenolate mofetil (MMF), or a combination thereof.
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`21.
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`(New) A method of treating chronic graft versus host disease (GVHD) comprising
`
`administering to a patient having chronic GVHD a therapeutically effective amount of a compound
`
`of the structure:
`
`cc
`
`NH2
`
`N
`
`N k
`
`\ \
`/
`/N
`
`Nb
`
`“?
`
`o
`
`,
`
`or a pharmaceutically acceptable salt thereof.
`
`22.
`
`(New) The method of claim 21, wherein the patient has classic chronic GVHD.
`
`23.
`
`(New) The method of claim 21, wherein the patient has overlap chronic GVHD.
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`24.
`
`(New) The method of claim 21, wherein the patient has steroid-dependent/refractory
`
`chronic GVHD.
`
`25.
`
`(New) The method of claim 21, wherein the therapeutically effective amount of the
`
`compound is about 40 mg/day, about 140 mg/day, about 280 mg/day, about 420 mg/day, about
`
`560 mg/day, or about 840 mg/day.
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`Application No. 14/523,650
`Amendment and Response
`
`6
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`Docket No.: FIR-88501
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`REMARKS
`
`Claims 1-20 were pending. Please enter the amendments and arguments submitted herewith.
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`By this Amendment, claims 1, 7-9, 11, and 16 have been amended, claims 2, 12-14, and 17 have
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`been canceled, and new claims 21-25 have been added. Support for the claim amendments and the
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`new claims can be found in the specification and claims as filed. For example, support for new
`
`claims 22 and 23 may be found at least in paragraph [00216] of the specification as filed, and
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`support for new claim 24 may be found at least in paragraph [00202] of the specification as filed.
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`Therefore, no new matter has been added.
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`Amendment or cancellation of claims should in no way be construed as an acquiescence to a
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`rejection, or surrender of any subject matter. Amendments or cancellations have been made not only
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`to claim with particularity the invention for which protection is sought, but also to expedite
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`prosecution of the present application. Applicant reserves the option to prosecute the originally filed
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`claims, or similar ones, in the instant or subsequently filed patent applications.
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`Response to Rejections Under 35 U.S.C. § 1121 First Paragraph
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`Claims 1 and 3-18 stand rejected under 35 U.S.C. § 112, first paragraph, because the
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`specification allegedly does not reasonably provide enablement for a method of preventing the
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`occurrence of graft versus host disease (GVHD). 4/22/16 Office Action, page 6. $01er to expedite
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`prosecution, independent claim 1 has been amended to recite: “A method of treating graft versus
`
`host disease (GVHD) or reducing the severity of GVHD occurrence in a patient having chronic
`
`GVHD.” As a result of this amendment, reconsideration and withdrawal of the claim rejections
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`under 35 U.S.C. § 112, first paragraph, are respectfully requested.
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`Response to Rejections Under 35 U.S.C. § 102
`
`Legal Slandard
`
`“A claim is anticipated only if each and every element as set forth in the claim is found,
`
`either expressly or inherently described, in a single prior art reference.” Verdegaal Bros. v. Union
`
`011 C0. ofCalz'fornia, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987).
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`Application No. 14/523,650
`Amendment and Response
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`7
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`Docket No.: FIR-88501
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`“In relying upon the theory of inherency, the examiner must provide a basis in fact and/or
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`technical reasoning to reasonably support the determination that the allegedly inherent characteristic
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`necessarily flows from the teachings of the applied prior art.” Ex parte Levy, 17 USPQ2d 1461,
`
`1464 (Bd. Pat. App. & Inter. 1990).
`
`Regarding Izumi as evidenced by Magenau andMin
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`Claims 1-18, in particular, claims 1, 3-6, 11, 12, and 18, stand rejected under 35 U.S.C.
`
`§§102(a)(1) and 102(a)(2) as allegedly being anticipated by Izumi
`
`(US 2015/0086507), as
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`evidenced by Magenau (Brit. J. Haematology 2016, 173(2), 190-205) and Min (Kor. J. Hematology
`
`2011, 46(2), 80-87). Applicant respectfully traverses.
`
`Importantly,
`
`in most circumstances, “only one reference should be used in making a
`
`rejection under 35 U.S.C. 102.” MPEP § 2131.01. There are only three specific instances when a
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`multiple-reference novelty rejection is appropriate:
`
`(A) to show that the primary reference contains
`
`an enabled disclosure, (B) to explain the meaning of a term in the primary reference, or (C) to show
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`that a characteristic not disclosed in the primary reference is inherent. MPEP § 2131.01.
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`The Office has relied upon multiple references to support its rejection under 35 U.S.C.
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`§ 102. Specifically, the Office concedes that Izumi fails to teach methods of treating GVHD, but
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`introduces Magenau and Min as allegedly showing that “this condition is art recognized to be
`
`directly associated with haematopoietic stem cell transplantation.” 4/22/ 16 Office Action, page 11.
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`However, the Office’s position does not fall within one of the three specific instances when a
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`multiple-reference rejection under 35 U.S.C. § 102 is appropriate. For example, Min discloses that
`
`the incidence of chronic GVHD following hematopoietic stem cell transplantation ranges from 25%
`
`to 80% (Min, page 80, left column). In other words, a patient receiving hematopoietic stem cell
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`transplantation does not necessarily have GVHD. So, the secondary references demonstrate that
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`Izumi fails to inherently teach or suggest the claimed invention ((C), above). See MPEP §2112 IV (a
`
`pertinent excerpt is reproduced immediately below).
`
`The fact that a certain result or characteristic may occur or be present in the prior art
`is not sufficient to establish the inherency of that result or characteristic. In re
`Rijckaert, 9 F.3d 1531, 1534, 28 USPQ2d 1955, 1957 (Fed. Cir. 1993) (reversed
`rejection because inherency was based on what would result due to optimization of
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`Application No. 14/523,650
`Amendment and Response
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`8
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`Docket No.: PIR-88501
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`conditions, not what was necessarily present in the prior art), In re Oelrz'ch, 666 F.2d
`578, 581-82, 212 USPQ 323, 326 (CCPA 1981). “To establish inherency,
`the
`extrinsic evidence ‘must make clear that the missing descriptive matter is necessarily
`present in the thing described in the reference, and that it would be so recognized by
`persons of ordinary skill.
`Inherency, however, may not be established by
`probabilities or possibilities. The mere fact that a certain thing may result from a
`given set of circumstances is not sufficient.”’ In re Robertson, 169 F.3d 743, 745, 49
`USPQ2d 1949, 1950-51 (Fed. Cir. 1999) (citations omitted) (The claims were drawn
`to a disposable diaper having three fastening elements. The reference disclosed two
`fastening elements that could perform the same function as the three fastening
`elements in the claims. The court construed the claims to require three separate
`elements and held that the reference did not disclose a separate third fastening
`element, either expressly or inherently.)
`
`Furthermore, for the same reason, the secondary references do not show that Izumi is enabled (A),
`
`nor do the secondary references provide an adequate definition of a term in Izumi (B).
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`So, the Office has not met its burden of establishing that the claimed methods necessarily
`
`flow from Izumi. Therefore, Applicant respectfully requests reconsideration and withdrawal of the
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`claim rejections under 35 U.S.C. § 102 based on the combination of Izumi, Magenau, and Min.
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`Response to Rejections Under 35 U.S.C. § 103
`
`Legal Slandard
`
`To establish a prima facie case of obviousness, a number of criteria must be met. For
`
`example, all of the limitations of a rejected claim must be taught or suggested by the combination of
`
`references relied upon by the Examiner. Moreover, one of ordinary skill in the relevant art must
`
`have a reasonable expectation of success in light of the cited references. Importantly, the reasonable
`
`expectation of success must be found in the prior art, and may not be based on the Applicant’s
`
`disclosure. In re Vaeck, 947 F.2d 488, 20 U.S.PQ. 2d 1438 (Fed. Cir. 1991), see MPEP § 2143 - §
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`2143.03 for decisions pertinent to each of these criteria.
`
`Regarding Izumi as evidenced by Magenau andMin
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`Claims 1-18 stand rejected under 35 U.S.C. §103 as allegedly being obvious in view of
`
`Izumi as evidenced by Magenau and Min. Applicant respectfully traverses.
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`Application No. 14/523,650
`Amendment and Response
`
`9
`
`Docket No.: FIR-88501
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`As an initial matter, it is worth noting that Magenau was published on March 27, 2016.
`
`Therefore, based on its publication date, Magenau does not qualify as prior art under any section of
`
`35 U.S.C. § 102. Importantly, in order for a reference to qualify as prior art under 35 U.S.C. § 103,
`
`it must first qualify under one or more sections of 35 U.S.C. § 102.
`
`Applicant respectfully submits that the Examiner has not established a prima facie case of
`
`obviousness with respect to amended claim 1 because the combination of references advanced by
`
`the Examiner does not teach or suggest every element of the now-claimed invention, nor would one
`
`of ordinary skill have had a reasonable expectation of success in developing the now-claimed
`
`invention based on the cited combination of references.
`
`Izumi relates to methods of mobilizing hematopoietic stem cells and progenitor cells to the
`
`peripheral blood of a subject by administering a Btk inhibitor. Izumi, paragraph [0005]. It does not
`
`teach or suggest treating GVHD.
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`Further, based on the disclosures of the cited references, one of ordinary skill in the art
`
`would not have reasonably expected that compounds that mobilize hematopoietic stem cells and
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`progenitor cells to the peripheral blood of a subject would be effective treatments of GVHD.
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`Accordingly, reconsideration and withdrawal of the claim rejections under 35 U.S.C. § 103
`
`based on Izumi, Magenau, and Min are respectfully requested.
`
`Response to Rejections based on the Judicially Created Doctrine of
`
`Obviousness-Type Double Patenting
`
`Claims 1-6, 12, and 15-18 stand rejected on the grounds of nonstatutory obviousness-type
`
`double patenting as allegedly being unpatentable over claims 1-5, 11, and 16-19 of US. Patent
`
`Appl. No. 14/558,297 (Blazar).
`
`Blazar was filed on December 2, 2014. The instant application was filed on October 24,
`
`2014. So, because the instant application has an earlier filing date,
`
`it
`
`is the “earlier-filed”
`
`application. Importantly:
`
`If a “provisional” nonstatutory double patenting rejection is the only rejection
`remaining in an application having the earliest effective U.S. filing date (including
`any benefit claimed under 35 U.S.C. 120, 121, 365(c), or 386(c)) compared to the
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`Application No. 14/523,650
`Amendment and Response
`
`10
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`Docket No.: FIR-88501
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`should withdraw the rejection in the
`the examiner
`reference application(s),
`application having the earliest effective U.S. filing date and permit that application to
`issue as a patent, thereby converting the “provisional” nonstatutory double patenting
`rejection in the other application(s) into a nonstatutory double patenting rejection
`when the application with the earliest U.S. effective filing date issues as a patent.
`MPEP 804(I)(B)(1).
`
`Therefore, because Applicant believes that the other pending rejections are overcome by this
`
`Amendment, Applicant respectfully requests withdrawal of the rejections based on obviousness-
`
`type double patenting in view of Blazar.
`
`Conclusion
`
`The Applicant believes that no fees are due in connection with the filing of this paper.
`
`Nevertheless, the Director is hereby authorized to charge any and all required fees to our Deposit
`
`Account No. 06-1448, reference FIR-885.01. If a telephone conversation with Applicant’s Attorney
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`would expedite prosecution of the application, the Examiner is urged to contact the undersigned.
`
`Dated: July 22, 2016
`
`Respectfully submitted,
`
`/Janine S. Ladislaw/
`By:
`Janine S. Ladislaw, PhD.
`Registration No: 64,000
`FOLEY HOAG LLP
`
`155 Seaport Blvd
`Boston, Massachusetts 02210
`(617) 832-1000
`Attorney For Applicant
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