DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) is acknowledged. The instant application claims priority to U.S. Provisional Application No. 63/398,123, filed August 15, 2022.
Status of Claims
Claims 1-63, as amended by a Preliminary Amendment dated August 11, 2023, are pending.
Information Disclosure Statement
The Information Disclosure Statements submitted on October 3, 2025, and November 14, 2025, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 102(a)(2)
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 made in this Office action:
A person shall be entitled to a patent unless –
(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 was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 6-13, 17, 18, 20-34, 39-40, 46-56, and 58-63 are Anticipated by Compound 76 of WO’327
Claim(s) 1, 3, 6-13, 17, 18, 20-34, 39-40, 46-56, and 58-63 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Yu et al., “Kinase Inhibitors, Preparation Methods and Uses Thereof”, International Application No. PCT/CN2022/084377, effectively filed on March 31, 2022, and published as International Publication No. WO 2023/184327 A1, hereinafter “WO’327” (page numbers refer to the publication of the International Application).
Background: WO’327 and DGKs
WO’327 generally discloses compounds that are useful “in inhibiting DGKs in a cell, and/or in treating various diseases such as cancer or viral infections.” WO’327 at Abstract. DGKs are diacylglycerol kinases. DGKs are involved in intracellular checkpoints, and inhibition of certain DGKs may enhance T cell signaling pathways and T cell activation. Id. at Background. In particular, inhibition of DGK alpha and DGK zeta isoforms may restore T cell function that is suppressed by tumors. See Specification of the instant application at Background; WO’327 at Background.
Claim 1 of the instant application is generally directed to a tricyclic triazolo DGK inhibitor with the structure of the compound of Formula I, reproduced below (left panel).
[AltContent: textbox (Z)]WO’327 discloses compound 76, reproduced below, right panel (the examiner marked atoms corresponding to the variables W, X, Y, and Z of the compound of Formula I).
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Compound of Formula I of the instant application
Compound 76 of WO’327.
See WO’327 at 209-210, Table 1.
Compound 76 of WO’327 corresponds to a compound of Formula I of the instant application, wherein:
R1 is C1-6 alkyl (ethyl);
R2 is C1-6 alkyl (2S-ethyl and 5R-ethyl);
R3 is H;
W is N; R4 is not applicable;
X is CR5, R5 is CN;
Y is CR6, R6 is H;
Z is CR7, R7 is H;
n is 2;
L1 is C1-3 alkyl (CH);
Cy1 is C6-10 aryl, optionally substituted with 1 R8 unit, R8 is ORa8, Ra8 is C1-6 alkyl (methyl).
The following claims are anticipated by compound 76 of WO’327 for the reasons indicated below:
1 – see above;
3 – W is N;
6 – W is N;
7 – X is CR5;
8 – R5 is CN;
9 – R5 is CN;
10 – R5 is CN;
11 – Y is CR6;
12 – R6 is H;
13 – R6 is H;
17 – R6 is H;
18 – Z is CR7;
20 – R7 is H;
21 – R7 is H;
22 – Z is CR7 which is CH;
23 – n is 2;
24 – R2 is C1-6 alkyl (2S-ethyl and 5R-ethyl);
25 – R2 is C1-6 alkyl (2S-ethyl and 5R-ethyl);
26 – R2 is C1-6 alkyl (2S-ethyl and 5R-ethyl);
27 – R3 is H;
28 – R3 is H;
29 – R3 is H;
30 – L1 is C1-3 alkyl (CH);
31 – L1 is CH;
32 – Cy1 is C6-10 aryl, optionally substituted with 1 R8 unit (p-methoxyphenyl);
33 – Cy1 is phenyl, optionally substituted with 1 R8 unit (p-methoxyphenyl);
34 – Cy1 is phenyl, optionally substituted with 1 R8 unit (p-methoxyphenyl);
39 – R1 is C1-6 alkyl (ethyl);
40 – R1 is C1-6 alkyl (ethyl);
46 – see above;
47 – see above.
Claims 48 – 56 depend on claim 1, and recite various related generic chemical structures, reproduced below. These claims are anticipated by compound 76 of WO’327, see assignments above.
(claimed structures appear on the following page)
Claimed Structures
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Compound 76 of WO’327
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The following table provides the claim number above the claimed generic structures. The bottom right compound is compound 76 of WO’327.
Claims 58-63 are Anticipated by Disclosed Compounds of WO’327
Regarding claim 58, WO’327 states that any of the disclosed compound nos. 1-134 may be deuterated. See WO’327 at 120-121, paragraphs [0185-0186].
Regarding claim 59, WO’327 discloses pharmaceutical compositions comprising any of the disclosed compound nos. 1-134 and excipients such as carriers. See WO’327 at 106, paragraph [0154].
Regarding claim 60, WO’327 discloses methods of inhibiting the activity of diacylglycerol kinase alpha and/or zeta in a cell comprising contacting a cell with any of the disclosed compound nos. 1-134 or a pharmaceutically acceptable salt thereof. See WO’327 at 110, paragraph [0164].
Regarding claims 61 – 63, WO’327 discloses methods of treating cancers, such as melanomas, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the disclosed compound nos. 1-134. See WO’327 at 111-112, paragraph [0166].
Therefore, claims 58-63 are anticipated by WO’327.
Claims 2 and 35-38 are Anticipated by Compound 2 of WO’528
Claims 2 and 35-38 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Lu et al., “Diacylglycerol Kinase (DGK) Alpha Inhibitors and Uses Thereof”, International Application No. PCT/CN2023/079066, effectively filed on March 1, 2022, and published as International Publication No. WO 2023/165528 A1, hereinafter “WO’528” (page numbers refer to the publication of the International Application).
Claim 2 of the instant application is directed to the compound of claim 1, wherein W is CR4. R4 permits many substituents, one of which is CN.
WO’528
WO’528 discloses DGKs with the general chemical structure of Formula (I), reproduced below,
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WO’528 at 2.
One disclosed embodiment of Formula (I) of WO’528 is compound 2, reproduced below (right panel, note that the examiner marked atoms corresponding to variables W, X, Y, and Z of the compound of Formula I of the instant application).
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Compound of Formula I of the instant application.
Compound 2 of WO’528. See WO’528 at 25.
Compound 2 of WO’528 corresponds to a compound of Formula I of the instant application, wherein:
R1 is C1-6 alkyl (methyl);
R2 is not applicable, as n is 0;
R3 is H;
W is CR4; R4 is CN;
X is CR5, R5 is halo (chloro);
Y is CR6, R6 is H;
Z is CR7, R7 is H;
L1 is C1-3 alkyl (CH);
Cy1 is C6-10 aryl, optionally substituted with 1 R8 units, R8 is halo (fluoro).
Therefore, claim 2 is anticipated by compound 2 of WO’528 (i.e., W is CR4, R4 is CN).
Claims 35-38
Regarding claims 35-38, they recite the compound of Formula I, wherein Cy1 is modified by R8. In these claims, R8 have certain assignments that share overlap. For example, a compound of Formula I, wherein Cy1 is effectively fluorophenyl, would meet the limitations for claims 35-38.
As shown above with respect to claim 2, compound 2 of WO’528 bears a fluorophenyl group at Cy1.
Therefore, claims 35 – 38 are anticipated by compound 2 of WO’528.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 4 and 5 are Obvious over Compound 2 of WO’528 in view Formula (I) of WO’528
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over WO’528.
The limitations of claim 2, and the corresponding teachings of the art anticipating the genus, are described in the rejection above, and are hereby incorporated by reference.
Regarding claims 4 and 5, they recite the compound of claim 1, wherein W and R4 have certain assignments that share overlap. For example, a compound of Formula I, wherein W is effectively C–H, would meet the limitations for claims 4 and 5.
Reproduced below are the chemical structures for compound 2 (left panel) and Formula (I) (right panel) disclosed in WO’528 (note that the examiner marked the atom corresponding to the variables W of the compound of Formula I of the instant application).
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Compound 2 of WO’528. See WO’528 at 25.
Compound of Formula I of the instant application.
Formula (I) of WO’528. See WO’528 at 2.
Compound 2 of WO’528 meets all of the limitations recited in claims 4 and 5, except for the limitations recited for the variable W. For compound 2 of WO’528, W is C–CN.
However, WO’528 discloses certain substituents for the for the variable U pertaining to the general chemical structure of Formula (I), such as those wherein “U is … CRU; RU is hydrogen ….” WO’528 at 2.
WO’528 further discloses that the compounds “[d]escribed herein are DGKalpha inhibitors … and … are useful for the treatment of a disease or disorder associated with DGKalpha.” WO’528 at Abstract.
Regarding compound 2, WO’528 discloses that compound 2 inhibits DGKalpha with an IC50 of between 1 and 10 nM. WO’528 at 51.
One having ordinary skill in the art at the time of filing would be motivated to modify compound 2 of WO’528, wherein W is C–CN, to include different substitution, such as W being C–H, because 1) compound 2 exhibited strong DGKalpha inhibition, which may be tailored by further modification at the variable U (corresponding to the variable W in the Formula I of the instant application), and 2) WO’528 discloses that compounds of the invention (e.g., those encompassed by the general chemical structure of Formula (I)) are “useful for the treatment of a disease or disorder associated with DGKalpha.” WO’528 at Abstract. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the resulting compound, reproduced below (right panel), as a DGK inhibitor, because the general chemical structure of Formula (I) of WO’528 also encompasses the resulting compound.
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Compound 2 of the WO’528.
Modified compound 2 of the WO’528.
Therefore, claims 4 and 5 were obvious at the time of filing.
Claims 14-16 are Obvious over Compound 76 of WO’327 in view of Formula III-2 of WO’327
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over WO’327.
The limitations of claim 1, and the corresponding teachings of the art anticipating the genus, are described in the rejection above, and are hereby incorporated by reference.
Regarding claims 14-16, they recite the compound of claim 1, wherein R6A has certain assignments that share overlap (specifically, Y = CR6, and R6 is modified by select R6As). For example, a compound of Formula I, wherein Y is effectively C-isopropyl, would meet the limitations for claims 14-16.
As explained above in the section regarding anticipation of claim 1, WO’327 discloses compound 76 (reproduced below, left panel). Compound 76 is encompassed by the general chemical structure of Formula III-2 disclosed in WO’327 (reproduced below, right panel).
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Compound 76 of WO’327.
See WO’327 at 209-210, Table 1.
Compound of Formula I of the instant application.
Formula III-2 of WO’327.
See WO’327 at 44, paragraph [0085].
Note, for the above figure, the examiner marked variable U of Formula III-2, which corresponds to the variable Y of the compound of Formula I of the instant application.
Compound 76 of WO’327 meets all of the limitations recited in claims 14-16, except for the limitations recited for the variable Y.
However, WO’327 further discloses certain definitions for the variable U pertaining to Chemical Formula III-2. See, for example, WO’327 at paragraph [0085], reproduced below, where U in Formula III-2 is CR6, R6 is RD, wherein RD is an optionally substituted C1-4 alkyl group.
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WO’327 at 46.1
One having ordinary skill in the art at the time of filing would be motivated to modify compound 76 of WO’327, wherein Y is CH, to include different substitution, such as Y being C-isopropyl, because 1) WO’327 discloses that such modification is possible, by definitions for the variable U, and 2) WO’327 discloses that compounds of the invention (e.g., those encompassed by Formula III-2 of WO’327) are useful “in inhibiting DGKs in a cell, and/or in treating various diseases such as cancer or viral infections.” WO’327 at Abstract. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the resulting compound, reproduced below, as a DGK inhibitor, because the general Formula III-2 of WO’327 also encompasses the resulting compound.
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Compound 76 of WO’327.
Modified compound 76.
Therefore, claims 14-16 were obvious at the time of filing.
Claims 41-45 are Obvious over Compound 76 of WO’327 in view of Formula III-2 of WO’327
Claims 41-45 are rejected under 35 U.S.C. 103 as being unpatentable over WO’327.
The limitations of claim 1, and the corresponding teachings of the art anticipating the genus, are described in the rejection above, and are hereby incorporated by reference.
Regarding claims 41-45, they recite the compound of claim 1, wherein R1 and R1A have certain assignments that share overlap (specifically, R1 is modified by select R1As). For example, a compound of Formula I, wherein R1 is effectively hydroxyisopropyl, would meet the limitations for claims 41-45.
As explained above, WO’327 discloses compound 76 and Formula III-2, which are reproduced below (left and right panels, respectively).
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Compound 76 of WO’327.
See WO’327 at 209-210, Table 1.
Compound of Formula I of the instant application.
Formula III-2 of WO’327.
See WO’327 at 44, paragraph [0085].
Note, for the above figure, the examiner marked variable L2 of Formula III-2, which corresponds to the variable R1 of the compound of Formula I of the instant application.
Compound 76 of WO’327 meets all of the limitations recited in claims 41-45, except for the limitations recited for the variable R1.
However, WO’327 further discloses certain definitions for the variable L2 pertaining to Chemical Formula III-2. See, for example, WO’327 at paragraph [0085], reproduced below, where L2 in Formula III-2 is an optionally substituted C1-4 alkylene.
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WO’327 at 46-47.2
One having ordinary skill in the art at the time of filing would be motivated to modify compound 76 of WO’327, wherein R1 is ethyl, to include different substitution, such as R1 being hydroxyisopropyl, because 1) WO’327 discloses that such modification is possible, by definitions for the variable L2, and 2) WO’327 discloses that compounds of the invention (e.g., those encompassed by Formula III-2 of WO’327) are useful “in inhibiting DGKs in a cell, and/or in treating various diseases such as cancer or viral infections.” WO’327 at Abstract. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the resulting compound, reproduced below, as a DGK inhibitor, because the general Formula III-2 of WO’327 also encompasses the resulting compound.
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Compound 76 of WO’327.
Modified compound 76
Therefore, claims 41-45 were obvious at the time of filing.3
Claim 19 is Obvious over WO’327 in view of WO’650
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over WO’327 in view of Codelli et al., “Diacylglyercol Kinase Modulating Compounds”, International Application No. PCT/US2022/034270, effectively filed on June 23, 2021, and published as International Publication No. WO 2022/271650 A1, hereinafter “WO’650” (page numbers refer to the publication of the International Application).
The limitations of claim 1, and the corresponding teachings of the art anticipating the genus, are described in the rejection above, and are hereby incorporated by reference.
Claim 19 recites the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N. In cases where W is N, and X and Y are CR5 and CR6 respectively, claim 19 is generally directed to DGK inhibitor containing a [1,2,4]triazolo[4,3-a]pteridine motif, which is generally depicted below.
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[1,2,4]Triazolo[4,3-a]pteridine
WO’327 does not expressly teach DGK inhibitors that incorporate such a [1,2,4]triazolo[4,3-α]pteridine structural motif.
However, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in incorporating such a structural motif into the chemical structure of a known DGK inhibitor, such as compound 76 disclosed in WO’327, because such structural motifs were disclosed for a family of DGK modulators (WO’650).
WO’650
WO’650 discloses diacylglycerol kinase modulating compounds of the general Formula (I), and pharmaceutical compositions thereof, for treating cancer. See WO’650 at Abstract. The compound of general Formula (I) disclosed in WO’650 is reproduced below (left panel). When Z1, Z4, Z8, and Z9 are N, and Z2 and Z7 are CR2 and CR7, the compound of general Formula (I) disclosed in WO’650 incorporates a [1,2,4]triazolo[4,3-a]pteridine structural motif.
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Compound of general Formula (I) of WO’650.
See WO’650 at 2-8.
Compound of Formula I of the instant application.
Compound 76 of WO’327.
Note, for the above figure, the examiner marked atoms corresponding to the variable Z of the compound of Formula I of the instant application.
The compound of general Formula (I) of WO’650, which as explained above, may incorporate a [1,2,4]triazolo[4,3-a]pteridine structural motif, bears close structural similarity to compound 76 of WO’327, insofar as compound 76 of WO’327 instead bears a similar pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine structural motif (i.e., one ring carbon is exchanged for a ring nitrogen). Furthermore, both compounds have similar utilities, i.e., they both may be used to inhibit DGKs.
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) … and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990)….
MPEP 2144.09(I).
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of WO’650 to incorporate a [1,2,4]triazolo[4,3-a]pteridine structural motif into the structure of compound 76 of WO’327, because of the close structural similarity of the corresponding motif in compound 76 of WO’327 (i.e., a pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine structural motif). One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in inhibiting DGKs with the resulting compound, reproduced below (right panel), because both the compound of general Formula (I) disclosed in WO’650 and compound 76 of WO’327 have similar utilities with respect to inhibiting DGKs.
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Compound 76 of WO’327.
Modified compound 76.
Therefore, claim 19 was obvious at the time of filing.
Claim 57 is Obvious over WO’327 in view of WO’018
Claim 57 is rejected under 35 U.S.C. 103 as being unpatentable over WO’327 in view of Velaparthi et al., “Substituted Naphthyridinone Compounds Useful as T Cell Activators”, International Publication No. WO 2020/006018 A1, published on January 2, 2020, hereinafter “WO’018”.
The limitations of claim 1, and the corresponding teachings of the art anticipating the genus, are described in the rejection above, and are hereby incorporated by reference.
Claim 57 recites various embodiments of claim 1, one of which is the disclosed Example 5 of the instant application, reproduced below. See also Specification at 122-124 (describing the preparation of the Example 5 compound).
As explained above, WO’327 discloses compound 76, which is reproduced below, as well as a generic chemical structure that encompasses compound 76, i.e., Formula III-2 of WO’327.
However, WO’327 does not expressly disclose a species that has the di-4-fluorophenyl substituted methylene unit attached to the central 2S,5R-dialkyl substituted piperazine structural motif which is present in the chemical structure of the Example 5 compound.
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Example 3 of WO’018. See WO’018 at 128.
Compound 76 of WO’327.
WO’018
WO’018 discloses certain compounds of Formula (I) “which are useful as inhibitors of DGKα, DGKζ, or both DGKα and DGKζ.” WO’018 at 3. Compounds disclosed in WO’018 share identical core structural features with the disclosed embodiments of the instant application, such as a central 2S,5R-dialkyl substituted piperazine, wherein one nitrogen of the central piperazine is attached to a di-4-fluorophenyl substituted methylene unit. See, e.g., Example 3, WO’018 at 128, reproduced above.
Further, as seen in the above figure, the Example 3 compound of WO’018 bears close structural similarity to compound 76 of WO’327, insofar as both compounds bear a central 2S,5R-dialkyl substituted piperazine.4 Furthermore, both compounds have similar utilities, as they both may be used to inhibit DGKs.
WO’327
As discussed above, Formula III-2 of WO’327 encompasses compound 76 of WO’327. See supra sections pertaining to claims 14-16 and 41-45.
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Formula III-2 of WO’327.
See WO’327 at 44, paragraph [0085].
WO’327 discloses certain embodiments for L2 in Formula III-2, wherein L2 is
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and R13 is
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. WO’327 at 54, paragraph [0104].
WO’327 further discloses certain embodiments for R30 in Formula III-2, wherein “[m]ore preferably, R30 is a phenyl which is substituted with 1-3 (e.g., 1 or 2) R22, wherein R22 at each occurrence is independently F….” WO’327 at 56, paragraph [0108].
Claim 57 was Obvious
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of WO’018 to incorporate a di-4-fluorophenyl substituted methylene unit into the structure of compound 76 of WO’327 because of the close structural similarity of the central 2S,5R-dialkyl substituted piperazine unit. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in inhibiting DGKs with the resulting compound because 1) both Example 3 of WO’018 and compound 76 of WO’327 have similar utilities with respect to inhibiting DGKs, and 2) the general Formula III-2 of WO’327 encompasses the resulting compound, reproduced below (right panel).
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Compound 76 of WO’327.
Modified compound 76
or
Example 5 of the instant application.
Therefore, claim 57 was obvious at the time of filing.
Conclusion
No claims are allowed.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 See also, WO’327 at 121-122, paragraph [0188] (defining alkyl to include isopropyl).
2 See also, WO’327 at 121-122, paragraph [0188] (defining alkylene to include iso-butyl).
3 The examiner notes that WO’327 permits an alternative obviousness analyses of claims 41-45, wherein R1 is effectively fluorophenyl. See infra section regarding claim 57 (explaining that L2 of Formula III-2 of WO’327 may be fluorophenyl).
4 While the central piperazines differ by substitution of methyl vs. ethyl groups, WO’018 discloses examples where the central piperazine bears ethyl substitution. See, e.g., WO ’018 at 701, Table 26.