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
The present application claims priority to the following applications: PCT/CN2021/109547 and PCT/CN2022/108923, with effective filing dates of 30 July 2021 and 29 July 202, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction filed, 8 May 2026.
Applicant’s election without traverse of Group I (claims 1, 3-6, 9, 11-18, 26, 28, 31, 35, and 36) and species of Compound 6 (
PNG
media_image1.png
149
310
media_image1.png
Greyscale
) in the reply filed 8 May 2026 is acknowledged.
Claim 38 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group (Group II: claim 38), there being no allowable generic or linking claim.
Claims 3-4 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claim 3 specifies a degron selected from:
PNG
media_image2.png
186
664
media_image2.png
Greyscale
, which does not read on the elected species. Claim 4 specifies a degron selected from
PNG
media_image3.png
222
628
media_image3.png
Greyscale
, which does not read on the elected species.
Claims 1, 5-6, 9, 11-18, 26, 28, 31, and 35-36 are pending and under examination in the instant office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
1. Claims 1, 5-6, 9, 11-18, 26, 28, 31, and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “…R4 is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl…” and the claim also recites “…preferably R4 is selected from -CH3, -OCH3, -NHCH3, -CHF2, and -C(CH3)2OH…”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Dependent claims 5-6, 9, 11-18, 26, 28, 31, and 36 are included for depending on a rejected claim and not reciting limitations that resolve the ambiguity.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 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 (i.e., changing from AIA to pre-AIA ) 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 under either status.
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.
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.
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.
2. Claim(s) 1, 5-6, 9, 11-18, 26, 28, 31, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Zhong (WO 2021/000935, filed 3 July 2020) in view of Linney (Exp. Opin. Therap. Patents¸ 2021, 31(10), 893-910), Vara (ACS Med. Chem. Lett., 2021, 12, 653-661), Jin (WO 2020/227325, published 5 May 2020, see IDS filed 21 May 2024), and Mainolfi (WO 2019/140387, published 14 Jan 2019).
Zhong teaches HPK1 inhibitors having general structures:
PNG
media_image4.png
113
126
media_image4.png
Greyscale
and
PNG
media_image5.png
89
164
media_image5.png
Greyscale
(abstract). Zhong teaches that HPK1 (also known as MAP4K1) is a protein kinase that is predominantly expressed in lymphoid organs/tissues and in all cell types in the hematopoietic compartment (page 1, paragraph 2). Zhong teaches that the ATP-binding site of HPK1 includes Lys-46 and that mutation of Lys-46 to methionine abolishes catalytic activation of HPK1 (page 1, paragraph 5). Zhong teaches that HPK1 plays dual and opposite roles in JNK activation and TCR signaling (page 3, paragraph 3). Zhong teaches that HPK1 can also control antitumor immunity via T- and B-lymphocyte-dependent mechanisms and that adoptive transfer of HPK1 deficient T cells were more effective in controlling tumor growth and metastasis than wild-type T cells (page 5, paragraph 3). Zhong teaches that bone marrow-derived dendritic cells from HPK1 knockout mice were more efficient to mount a T cell response to eradicate Lewis lung carcinoma as compared to wild-type bone marrow-derived dendritic cells (page 5, paragraph 3). Zhong specifically teaches
PNG
media_image6.png
106
203
media_image6.png
Greyscale
(Example 38, page 233) and
PNG
media_image7.png
67
129
media_image7.png
Greyscale
(Example 50, page 242).
Regarding claim 1, Zhong fails to teach an HPK1 degrader.
Linney teaches HPK1 inhibitors in the recent patent literature (abstract). Linney teaches that HPK1 is a negative regulator of T-cell function and that inhibition of HPK1 leads to increased T-cell proliferation and cytokine production and thus is an attractive approach for the immunotherapy of cancer (page 893, column 2, paragraph 2; page 894, column 1, paragraph 1). Linney teaches the importance of the hinge binding to Cys91 and Glu93 residues in the binding of HPK1 ligand/inhibitor to HPK1 (page 895, column 1, paragraph 2; Figure 2). Linney specifically teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
(Figure 8, page 899), wherein the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent (figure 8, page 899).
Vara teaches HPK1 inhibitors and structure-activity-relationships (SAR) around an inhibitor scaffold (abstract). Vara teaches that HPK1 inhibition is able to circumvent potential immune-evasive events via potentiation of T cell-mediated killing of tumor cells (page 653, column 1, paragraph 1; page 653, column 2, paragraph 1). Vara teaches the generic formula modeled in a schematic of the binding pocket:
PNG
media_image9.png
137
180
media_image9.png
Greyscale
(Figure 2) as well as crystal structures of compounds of interest in the binding pocket of HPK1 (Figure 3). Vara investigates the SAR surrounding the ortho-substitution of the phenyl ring in the eastern fragment (Tables 2 and 4). Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions (Figure 2, page 655; Figure 6, page 658).
Jin teaches HPK1 degraders and that the HPK1 degraders therein are expected to overcome resistance that is inherent to HPK1 inhibitors regardless of whether the resistance is due to drugs used in prior treatments or whether acquired resistance was caused by gene mutation, amplification, or otherwise (page 1, lines 5-8; page 1, lines 18-21). Jin specifically teaches the degraders,
PNG
media_image10.png
102
297
media_image10.png
Greyscale
(Example 181, page 381) and
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(Example 188, page 382). Jin specifically teaches that Example 188 (HC90-50) was selected as a lead due to activity (Example 351, page 413). While Jin teaches that the piperazine is adjacent to the POI ligand instead of the cereblon (E3 ligase) ligand, Jin contemplates the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357) and that the HC58 series of HPK1 degraders were able to reduce the expression level of HPK1 protein in Jurkat T cell line by approximately 75% (Example 348, page 412; Figure 1A).
Mainolfi teaches ligands for binding and modulating the activity of cereblon ([0001]). Mainolfi teaches that many diseases are associated with abnormal ubiquitin-proteasome pathway , which plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basis cellular processes ([0002]-[0003]). Mainolfi teaches that aberrations in the process are implicated in the pathogenesis of several diseases (both inherited and acquired) and that cereblon interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 such that proteins recognized by cereblon are ubiquitinated and degraded by proteasomes [0004]; [0005]). Mainolfi teaches that thalidomide and lenalidomide, cereblon binders, are associated with teratogenicity and cytotoxicity, respectively ([0006]) and thus new cereblon ligands are needed ([0007]). Mainolfi specifically teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]), which has activity of 10-100 uM (page 224).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the POI ligand (
PNG
media_image6.png
106
203
media_image6.png
Greyscale
) of Zhong to (1) be an 7-azaindole core as taught by both Zhong (
PNG
media_image7.png
67
129
media_image7.png
Greyscale
) and Linney (
PNG
media_image8.png
117
159
media_image8.png
Greyscale
) to optimize potency; (2) to utilize the fused phenyl-piperidine of Zhong as the exit vector as taught by Vara (
PNG
media_image9.png
137
180
media_image9.png
Greyscale
); (3) to optimize the potency of the POI ligand by capitalizing on hydrophobic interactions by moving the di-substituted amide of
PNG
media_image6.png
106
203
media_image6.png
Greyscale
from the ortho-position of the phenyl to the para-position; (4) to include a linker as taught by Jin (
PNG
media_image11.png
105
288
media_image11.png
Greyscale
) and orient the piperazine toward the E3 ligase ligand instead of the POI ligand as taught by Jin (with Compound 18); and (5) to incorporate a minimalist cereblon linker that lacks teratogenic effects as taught by Mainolfi (
PNG
media_image13.png
96
131
media_image13.png
Greyscale
) to arrive at Compound 6:
PNG
media_image14.png
149
310
media_image14.png
Greyscale
(a compound of Formula (I)). One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Zhong teaches HPK1 inhibitors having general structures:
PNG
media_image4.png
113
126
media_image4.png
Greyscale
and
PNG
media_image5.png
89
164
media_image5.png
Greyscale
,
-Zhong teaches that HPK1 (also known as MAP4K1) is a protein kinase that is predominantly expressed in lymphoid organs/tissues and in all cell types in the hematopoietic compartment,
-Zhong teaches that the ATP-binding site of HPK1 includes Lys-46 and that mutation of Lys-46 to methionine abolishes catalytic activation of HPK1,
-Zhong teaches that HPK1 plays dual and opposite roles in JNK activation and TCR signaling,
-Zhong teaches that HPK1 can also control antitumor immunity via T- and B-lymphocyte-dependent mechanisms and that adoptive transfer of HPK1 deficient T cells were more effective in controlling tumor growth and metastasis than wild-type T cells,
-Zhong teaches that bone marrow-derived dendritic cells from HPK1 knockout mice were more efficient to mount a T cell response to eradicate Lewis lung carcinoma as compared to wild-type bone marrow-derived dendritic cells,
-Zhong teaches Example 38:
PNG
media_image6.png
106
203
media_image6.png
Greyscale
and Example 50:
PNG
media_image7.png
67
129
media_image7.png
Greyscale
,
-Linney teaches HPK1 inhibitors in the recent patent literature,
-Linney teaches that HPK1 is a negative regulator of T-cell function and that inhibition of HPK1 leads to increased T-cell proliferation and cytokine production and thus is an attractive approach for the immunotherapy of cancer,
-Linney teaches the importance of the hinge binding to Cys91 and Glu93 residues in the binding of HPK1 ligand/inhibitor to HPK1,
-Linney teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
, which the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent,
-Vara teaches HPK1 inhibitors and structure-activity-relationships (SAR) around an inhibitor scaffold,
-Vara teaches that HPK1 inhibition is able to circumvent potential immune-evasive events via potentiation of T cell-mediated killing of tumor cells,
-Vara teaches the generic formula modeled in a schematic of the binding pocket:
PNG
media_image9.png
137
180
media_image9.png
Greyscale
(Figure 2) as well as crystal structures of compounds of interest in the binding pocket of HPK1 (Figure 3),
-Vara investigates the SAR surrounding the ortho-substitution of the phenyl ring in the eastern fragment,
-Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions,
-Jin teaches HPK1 degraders and that the HPK1 degraders therein are expected to overcome resistance that is inherent to HPK1 inhibitors regardless of whether the resistance is due to drugs used in prior treatments or whether acquired resistance was caused by gene mutation, amplification, or otherwise,
-Jin teaches specifically teaches the degraders,
PNG
media_image10.png
102
297
media_image10.png
Greyscale
(Example 181) and
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(Example 188),
-Jin teaches Example 188 (HC90-50) was selected as a lead due to activity,
-While Jin teaches that the piperazine is adjacent to the POI ligand instead of the cereblon (E3 ligase) ligand, Jin contemplates the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
; HC58-35) and that the HC58 series of HPK1 degraders were able to reduce the expression level of HPK1 protein in Jurkat T cell line by approximately 75%,
-Mainolfi teaches ligands for binding and modulating the activity of cereblon,
-Mainolfi teaches that many diseases are associated with abnormal ubiquitin-proteasome pathway , which plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basis cellular processes,
-Mainolfi teaches that aberrations in the process are implicated in the pathogenesis of several diseases (both inherited and acquired) and that cereblon interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 such that proteins recognized by cereblon are ubiquitinated and degraded by proteasomes,
-Mainolfi teaches that thalidomide and lenalidomide, cereblon binders, are associated with teratogenicity and cytotoxicity, respectively and thus new cereblon ligands are needed, and
-Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20), which has activity of 10-100 uM.
Further, structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved
properties. See, e.g., Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Deuel, 51 F.3d 1552, 1558, 34 USPQ2d 1210, 1214 (Fed. Cir. 1995). Additionally, structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093- 95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the compound of Zhong, Linney, and Vara differs from the elected species of the claimed invention via a methyl, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Thus, the combination of Zhong, Linney, and Vara teaches the inhibitor,
PNG
media_image15.png
120
168
media_image15.png
Greyscale
.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element for another to predictably arrive at a compound of Formula (I):
PNG
media_image14.png
149
310
media_image14.png
Greyscale
.
Regarding claim 5, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]).
Regarding claim 6, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]).
Regarding claim 9, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]), wherein R8 is hydrogen.
Regarding claim 11, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L1 is *L1-C2H4C(O)-**L1.
Regarding claim 12, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L1 is *L1-C2H4C(O)-**L1.
Regarding claim 13, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L2 is a single bond.
Regarding claim 14, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L2 is a single bond.
Regarding claim 15, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L3 is a single bond.
Regarding claim 16, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L3 is a single bond.
Regarding claim 17, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that
PNG
media_image16.png
51
121
media_image16.png
Greyscale
is a piperazine.
Regarding claim 18, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that the linker is
PNG
media_image17.png
87
179
media_image17.png
Greyscale
.
Regarding claim 26, Zhong specifically teaches
PNG
media_image6.png
106
203
media_image6.png
Greyscale
(Example 38, page 233). Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions (Figure 2, page 655; Figure 6, page 658). Thus, the combination of Zhong and Vara teaches
PNG
media_image18.png
129
93
media_image18.png
Greyscale
.
Regarding claim 28, Zhong teaches
PNG
media_image6.png
106
203
media_image6.png
Greyscale
(Example 38, page 233) and
PNG
media_image7.png
67
129
media_image7.png
Greyscale
(Example 50, page 242), wherein R5 and R6 are hydrogen.
Regarding claim 31, Zhong teaches
PNG
media_image6.png
106
203
media_image6.png
Greyscale
(Example 38, page 233) and
PNG
media_image7.png
67
129
media_image7.png
Greyscale
(Example 50, page 242), wherein X1 is -CH2- and X2 is -CH2CH2-.
Regarding claim 35, Zhong teaches
PNG
media_image6.png
106
203
media_image6.png
Greyscale
(Example 38, page 233) and
PNG
media_image7.png
67
129
media_image7.png
Greyscale
(Example 50, page 242). Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions (Figure 2, page 655; Figure 6, page 658). Thus, the combination of Zhong and Vara teaches
PNG
media_image18.png
129
93
media_image18.png
Greyscale
. Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that the linker is
PNG
media_image17.png
87
179
media_image17.png
Greyscale
. Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]). Thus, the combination of Zhong, Linney, Vara, Jin, and Mianolfi teaches Compound 6:
PNG
media_image19.png
124
283
media_image19.png
Greyscale
.
Regarding claim 36, Zhong teaches compositions of the compounds therein (page 9, paragraph 7). Additionally, Jin teaches compositions of the degraders therein (page 1, lines 5-9), and Mainolfi teaches compositions thereof (abstract).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims 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 obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
3. Claim 1, 5-6, 9, 11-18, 26, 28, 31, and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 16, and 25 of U.S. Patent No. 12,454,534 in view of Linney (Exp. Opin. Therap. Patents¸ 2021, 31(10), 893-910), Vara (ACS Med. Chem. Lett., 2021, 12, 653-661), Jin (WO 2020/227325, published 5 May 2020, see IDS filed 21 May 2024), and Mainolfi (WO2019/140387, published 14 Jan 2019).
U.S. Patent No. 12,454,534 teaches compounds of Formula (I):
PNG
media_image20.png
119
219
media_image20.png
Greyscale
and specifically teaches the compound,
PNG
media_image21.png
150
202
media_image21.png
Greyscale
(claims 1, 16, and 25).
Regarding claim 1, ‘534 fails to teach an HPK1 degrader.
Linney teaches HPK1 inhibitors in the recent patent literature (abstract). Linney teaches that HPK1 is a negative regulator of T-cell function and that inhibition of HPK1 leads to increased T-cell proliferation and cytokine production and thus is an attractive approach for the immunotherapy of cancer (page 893, column 2, paragraph 2; page 894, column 1, paragraph 1). Linney teaches the importance of the hinge binding to Cys91 and Glu93 residues in the binding of HPK1 ligand/inhibitor to HPK1 (page 895, column 1, paragraph 2; Figure 2). Linney specifically teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
(Figure 8, page 899), wherein the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent (figure 8, page 899).
Vara teaches HPK1 inhibitors and structure-activity-relationships (SAR) around an inhibitor scaffold (abstract). Vara teaches that HPK1 inhibition is able to circumvent potential immune-evasive events via potentiation of T cell-mediated killing of tumor cells (page 653, column 1, paragraph 1; page 653, column 2, paragraph 1). Vara teaches the generic formula modeled in a schematic of the binding pocket:
PNG
media_image9.png
137
180
media_image9.png
Greyscale
(Figure 2) as well as crystal structures of compounds of interest in the binding pocket of HPK1 (Figure 3). Vara investigates the SAR surrounding the ortho-substitution of the phenyl ring in the eastern fragment (Tables 2 and 4). Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions (Figure 2, page 655; Figure 6, page 658).
Jin teaches HPK1 degraders and that the HPK1 degraders therein are expected to overcome resistance that is inherent to HPK1 inhibitors regardless of whether the resistance is due to drugs used in prior treatments or whether acquired resistance was caused by gene mutation, amplification, or otherwise (page 1, lines 5-8; page 1, lines 18-21). Jin specifically teaches the degraders,
PNG
media_image10.png
102
297
media_image10.png
Greyscale
(Example 181, page 381) and
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(Example 188, page 382). Jin specifically teaches that Example 188 (HC90-50) was selected as a lead due to activity (Example 351, page 413). While Jin teaches that the piperazine is adjacent to the POI ligand instead of the cereblon (E3 ligase) ligand, Jin contemplates the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357) and that the HC58 series of HPK1 degraders were able to reduce the expression level of HPK1 protein in Jurkat T cell line by approximately 75% (Example 348, page 412; Figure 1A).
Mainolfi teaches ligands for binding and modulating the activity of cereblon ([0001]). Mainolfi teaches that many diseases are associated with abnormal ubiquitin-proteasome pathway , which plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basis cellular processes ([0002]-[0003]). Mainolfi teaches that aberrations in the process are implicated in the pathogenesis of several diseases (both inherited and acquired) and that cereblon interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 such that proteins recognized by cereblon are ubiquitinated and degraded by proteasomes [0004]; [0005]). Mainolfi teaches that thalidomide and lenalidomide, cereblon binders, are associated with teratogenicity and cytotoxicity, respectively ([0006]) and thus new cereblon ligands are needed ([0007]). Mainolfi specifically teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]), which has activity of 10-100 uM (page 224).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the POI ligand (
PNG
media_image21.png
150
202
media_image21.png
Greyscale
) of ‘534 to (1) be an 7-azaindole core as taught by ‘ Linney (
PNG
media_image8.png
117
159
media_image8.png
Greyscale
) to optimize potency; (2) to utilize the fused phenyl-piperidine of ‘534 as the exit vector as taught by Vara (
PNG
media_image9.png
137
180
media_image9.png
Greyscale
); (3) to include a linker as taught by Jin (
PNG
media_image11.png
105
288
media_image11.png
Greyscale
) and orient the piperazine toward the E3 ligase ligand instead of the POI ligand as taught by Jin (with Compound 18); and (4) to incorporate a minimalist cereblon linker that lacks teratogenic effects as taught by Mainolfi (
PNG
media_image13.png
96
131
media_image13.png
Greyscale
) to arrive at Compound 6:
PNG
media_image14.png
149
310
media_image14.png
Greyscale
(a compound of Formula (I)). One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘534 teaches compounds of Formula (I):
PNG
media_image20.png
119
219
media_image20.png
Greyscale
,
-‘534 teaches the compound,
PNG
media_image21.png
150
202
media_image21.png
Greyscale
,
-Linney teaches HPK1 inhibitors in the recent patent literature,
-Linney teaches that HPK1 is a negative regulator of T-cell function and that inhibition of HPK1 leads to increased T-cell proliferation and cytokine production and thus is an attractive approach for the immunotherapy of cancer,
-Linney teaches the importance of the hinge binding to Cys91 and Glu93 residues in the binding of HPK1 ligand/inhibitor to HPK1,
-Linney teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
, which the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent,
-Vara teaches HPK1 inhibitors and structure-activity-relationships (SAR) around an inhibitor scaffold,
-Vara teaches that HPK1 inhibition is able to circumvent potential immune-evasive events via potentiation of T cell-mediated killing of tumor cells,
-Vara teaches the generic formula modeled in a schematic of the binding pocket:
PNG
media_image9.png
137
180
media_image9.png
Greyscale
(Figure 2) as well as crystal structures of compounds of interest in the binding pocket of HPK1 (Figure 3),
-Vara investigates the SAR surrounding the ortho-substitution of the phenyl ring in the eastern fragment,
-Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions,
-Jin teaches HPK1 degraders and that the HPK1 degraders therein are expected to overcome resistance that is inherent to HPK1 inhibitors regardless of whether the resistance is due to drugs used in prior treatments or whether acquired resistance was caused by gene mutation, amplification, or otherwise,
-Jin teaches specifically teaches the degraders,
PNG
media_image10.png
102
297
media_image10.png
Greyscale
(Example 181) and
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(Example 188),
-Jin teaches Example 188 (HC90-50) was selected as a lead due to activity,
-While Jin teaches that the piperazine is adjacent to the POI ligand instead of the cereblon (E3 ligase) ligand, Jin contemplates the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
; HC58-35) and that the HC58 series of HPK1 degraders were able to reduce the expression level of HPK1 protein in Jurkat T cell line by approximately 75%,
-Mainolfi teaches ligands for binding and modulating the activity of cereblon,
-Mainolfi teaches that many diseases are associated with abnormal ubiquitin-proteasome pathway , which plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basis cellular processes,
-Mainolfi teaches that aberrations in the process are implicated in the pathogenesis of several diseases (both inherited and acquired) and that cereblon interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 such that proteins recognized by cereblon are ubiquitinated and degraded by proteasomes,
-Mainolfi teaches that thalidomide and lenalidomide, cereblon binders, are associated with teratogenicity and cytotoxicity, respectively and thus new cereblon ligands are needed, and
-Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20), which has activity of 10-100 mM.
Further, structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved
properties. See, e.g., Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Deuel, 51 F.3d 1552, 1558, 34 USPQ2d 1210, 1214 (Fed. Cir. 1995). Additionally, structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093- 95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the compound of ‘534, Linney, and Vara differs from the elected species of the claimed invention via a methyl, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Thus, the combination of ‘534, Linney, and Vara teaches the inhibitor,
PNG
media_image15.png
120
168
media_image15.png
Greyscale
.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element for another to predictably arrive at a compound of Formula (I):
PNG
media_image14.png
149
310
media_image14.png
Greyscale
.
Regarding claim 5, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]).
Regarding claim 6, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]).
Regarding claim 9, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]), wherein R8 is hydrogen.
Regarding claim 11, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L1 is *L1-C2H4C(O)-**L1.
Regarding claim 12, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L1 is *L1-C2H4C(O)-**L1.
Regarding claim 13, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L2 is a single bond.
Regarding claim 14, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L2 is a single bond.
Regarding claim 15, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L3 is a single bond.
Regarding claim 16, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L3 is a single bond.
Regarding claim 17, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that
PNG
media_image16.png
51
121
media_image16.png
Greyscale
is a piperazine.
Regarding claim 18, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that the linker is
PNG
media_image17.png
87
179
media_image17.png
Greyscale
.
Regarding claim 26, ‘534 teaches the compound,
PNG
media_image21.png
150
202
media_image21.png
Greyscale
(claims 1, 16, and 25), which teaches
PNG
media_image18.png
129
93
media_image18.png
Greyscale
.
Regarding claim 28, ‘534 teaches the compound,
PNG
media_image21.png
150
202
media_image21.png
Greyscale
(claims 1, 16, and 25), wherein R5 and R6 are hydrogen.
Regarding claim 31, ‘534 teaches the compound,
PNG
media_image21.png
150
202
media_image21.png
Greyscale
(claims 1, 16, and 25), wherein X1 is -CH2- and X2 is -CH2CH2-.
Regarding claim 35, ‘534 teaches the compound,
PNG
media_image21.png
150
202
media_image21.png
Greyscale
(claims 1, 16, and 25). Linney specifically teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
(Figure 8, page 899), wherein the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent (figure 8, page 899). Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that the linker is
PNG
media_image17.png
87
179
media_image17.png
Greyscale
. Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]). Thus, the combination of ‘534, Linney, Vara, Jin, and Mianolfi teaches Compound 6:
PNG
media_image19.png
124
283
media_image19.png
Greyscale
.
4. Claim 1, 5-6, 9, 11-18, 26, 28, 31, and 35-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 4, and 12 of U.S. Application No. 18/924,058 in view of Linney (Exp. Opin. Therap. Patents¸ 2021, 31(10), 893-910), Vara (ACS Med. Chem. Lett., 2021, 12, 653-661), Jin (WO 2020/227325, published 5 May 2020, see IDS filed 21 May 2024), and Mainolfi (WO2019/140387, published 14 Jan 2019).
U.S. Application No. 18/924,058 teaches compounds of Formula (I):
PNG
media_image22.png
154
193
media_image22.png
Greyscale
and compositions thereof (claims 1, 4, and 12).
Regarding claim 1, ‘058 fails to teach an HPK1 degrader.
Linney teaches HPK1 inhibitors in the recent patent literature (abstract). Linney teaches that HPK1 is a negative regulator of T-cell function and that inhibition of HPK1 leads to increased T-cell proliferation and cytokine production and thus is an attractive approach for the immunotherapy of cancer (page 893, column 2, paragraph 2; page 894, column 1, paragraph 1). Linney teaches the importance of the hinge binding to Cys91 and Glu93 residues in the binding of HPK1 ligand/inhibitor to HPK1 (page 895, column 1, paragraph 2; Figure 2). Linney specifically teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
(Figure 8, page 899), wherein the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent (figure 8, page 899).
Vara teaches HPK1 inhibitors and structure-activity-relationships (SAR) around an inhibitor scaffold (abstract). Vara teaches that HPK1 inhibition is able to circumvent potential immune-evasive events via potentiation of T cell-mediated killing of tumor cells (page 653, column 1, paragraph 1; page 653, column 2, paragraph 1). Vara teaches the generic formula modeled in a schematic of the binding pocket:
PNG
media_image9.png
137
180
media_image9.png
Greyscale
(Figure 2) as well as crystal structures of compounds of interest in the binding pocket of HPK1 (Figure 3). Vara investigates the SAR surrounding the ortho-substitution of the phenyl ring in the eastern fragment (Tables 2 and 4). Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions (Figure 2, page 655; Figure 6, page 658).
Jin teaches HPK1 degraders and that the HPK1 degraders therein are expected to overcome resistance that is inherent to HPK1 inhibitors regardless of whether the resistance is due to drugs used in prior treatments or whether acquired resistance was caused by gene mutation, amplification, or otherwise (page 1, lines 5-8; page 1, lines 18-21). Jin specifically teaches the degraders,
PNG
media_image10.png
102
297
media_image10.png
Greyscale
(Example 181, page 381) and
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(Example 188, page 382). Jin specifically teaches that Example 188 (HC90-50) was selected as a lead due to activity (Example 351, page 413). While Jin teaches that the piperazine is adjacent to the POI ligand instead of the cereblon (E3 ligase) ligand, Jin contemplates the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357) and that the HC58 series of HPK1 degraders were able to reduce the expression level of HPK1 protein in Jurkat T cell line by approximately 75% (Example 348, page 412; Figure 1A).
Mainolfi teaches ligands for binding and modulating the activity of cereblon ([0001]). Mainolfi teaches that many diseases are associated with abnormal ubiquitin-proteasome pathway , which plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basis cellular processes ([0002]-[0003]). Mainolfi teaches that aberrations in the process are implicated in the pathogenesis of several diseases (both inherited and acquired) and that cereblon interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 such that proteins recognized by cereblon are ubiquitinated and degraded by proteasomes [0004]; [0005]). Mainolfi teaches that thalidomide and lenalidomide, cereblon binders, are associated with teratogenicity and cytotoxicity, respectively ([0006]) and thus new cereblon ligands are needed ([0007]). Mainolfi specifically teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]), which has activity of 10-100 uM (page 224).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the POI ligand (
PNG
media_image22.png
154
193
media_image22.png
Greyscale
) of ‘058 to (1) be an 7-azaindole core as taught by Linney (
PNG
media_image8.png
117
159
media_image8.png
Greyscale
) to optimize potency; (2) to utilize the fused phenyl-piperidine of ‘058 as the exit vector as taught by Vara (
PNG
media_image9.png
137
180
media_image9.png
Greyscale
); (3) to include a linker as taught by Jin (
PNG
media_image11.png
105
288
media_image11.png
Greyscale
) and orient the piperazine toward the E3 ligase ligand instead of the POI ligand as taught by Jin (with Compound 18); and (4) to incorporate a minimalist cereblon linker that lacks teratogenic effects as taught by Mainolfi (
PNG
media_image13.png
96
131
media_image13.png
Greyscale
) to arrive at Compound 6:
PNG
media_image14.png
149
310
media_image14.png
Greyscale
(a compound of Formula (I)). One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘058 teaches compounds of Formula (I):
PNG
media_image22.png
154
193
media_image22.png
Greyscale
and compositions thereof,
-Linney teaches HPK1 inhibitors in the recent patent literature,
-Linney teaches that HPK1 is a negative regulator of T-cell function and that inhibition of HPK1 leads to increased T-cell proliferation and cytokine production and thus is an attractive approach for the immunotherapy of cancer,
-Linney teaches the importance of the hinge binding to Cys91 and Glu93 residues in the binding of HPK1 ligand/inhibitor to HPK1,
-Linney teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
, which the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent,
-Vara teaches HPK1 inhibitors and structure-activity-relationships (SAR) around an inhibitor scaffold,
-Vara teaches that HPK1 inhibition is able to circumvent potential immune-evasive events via potentiation of T cell-mediated killing of tumor cells,
-Vara teaches the generic formula modeled in a schematic of the binding pocket:
PNG
media_image9.png
137
180
media_image9.png
Greyscale
(Figure 2) as well as crystal structures of compounds of interest in the binding pocket of HPK1 (Figure 3),
-Vara investigates the SAR surrounding the ortho-substitution of the phenyl ring in the eastern fragment,
-Vara teaches Compound 27 in the binding pocket and shows that there is room for substitution at the para-position of the phenyl ring to capitalize on hydrophobic interactions,
-Jin teaches HPK1 degraders and that the HPK1 degraders therein are expected to overcome resistance that is inherent to HPK1 inhibitors regardless of whether the resistance is due to drugs used in prior treatments or whether acquired resistance was caused by gene mutation, amplification, or otherwise,
-Jin teaches specifically teaches the degraders,
PNG
media_image10.png
102
297
media_image10.png
Greyscale
(Example 181) and
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(Example 188),
-Jin teaches Example 188 (HC90-50) was selected as a lead due to activity,
-While Jin teaches that the piperazine is adjacent to the POI ligand instead of the cereblon (E3 ligase) ligand, Jin contemplates the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
; HC58-35) and that the HC58 series of HPK1 degraders were able to reduce the expression level of HPK1 protein in Jurkat T cell line by approximately 75%,
-Mainolfi teaches ligands for binding and modulating the activity of cereblon,
-Mainolfi teaches that many diseases are associated with abnormal ubiquitin-proteasome pathway , which plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basis cellular processes,
-Mainolfi teaches that aberrations in the process are implicated in the pathogenesis of several diseases (both inherited and acquired) and that cereblon interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 such that proteins recognized by cereblon are ubiquitinated and degraded by proteasomes,
-Mainolfi teaches that thalidomide and lenalidomide, cereblon binders, are associated with teratogenicity and cytotoxicity, respectively and thus new cereblon ligands are needed, and
-Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20), which has activity of 10-100 uM.
Further, structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved
properties. See, e.g., Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Deuel, 51 F.3d 1552, 1558, 34 USPQ2d 1210, 1214 (Fed. Cir. 1995). Additionally, structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093- 95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the compound of ‘058, Linney, and Vara differs from the elected species of the claimed invention via a methyl, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Thus, the combination of ‘058, Linney, and Vara teaches the inhibitor,
PNG
media_image15.png
120
168
media_image15.png
Greyscale
.
As such, an artisan having ordinary skill in the art would have been motivated to substitute one known element for another to predictably arrive at a compound of Formula (I):
PNG
media_image14.png
149
310
media_image14.png
Greyscale
.
Regarding claim 5, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]).
Regarding claim 6, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]).
Regarding claim 9, Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]), wherein R8 is hydrogen.
Regarding claim 11, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L1 is *L1-C2H4C(O)-**L1.
Regarding claim 12, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L1 is *L1-C2H4C(O)-**L1.
Regarding claim 13, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L2 is a single bond.
Regarding claim 14, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L2 is a single bond.
Regarding claim 15, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L3 is a single bond.
Regarding claim 16, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that L3 is a single bond.
Regarding claim 17, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that
PNG
media_image16.png
51
121
media_image16.png
Greyscale
is a piperazine.
Regarding claim 18, Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that the linker is
PNG
media_image17.png
87
179
media_image17.png
Greyscale
.
Regarding claim 26, ‘058 teaches the compound,
PNG
media_image22.png
154
193
media_image22.png
Greyscale
(claims 1 and 4), which teaches
PNG
media_image18.png
129
93
media_image18.png
Greyscale
.
Regarding claim 28, ‘058 teaches the compound,
PNG
media_image22.png
154
193
media_image22.png
Greyscale
(claims 1 and 4), wherein R5 and R6 are hydrogen.
Regarding claim 31, ‘058 teaches the compound,
PNG
media_image22.png
154
193
media_image22.png
Greyscale
(claims 1 and 4), wherein X1 is -CH2- and X2 is -CH2CH2-.
Regarding claim 35, ‘058 teaches the compound,
PNG
media_image22.png
154
193
media_image22.png
Greyscale
(claims 1 and 4). Linney specifically teaches Compound 37:
PNG
media_image8.png
117
159
media_image8.png
Greyscale
(Figure 8, page 899), wherein the red atoms are the putative hinge binder, the amide (western fragment) comprises the proposed substituents toward the P loop, and the phenyl fragment (eastern fragment) comprises the proposed substituents toward the solvent (figure 8, page 899). Jin teaches Example 188:
PNG
media_image11.png
105
288
media_image11.png
Greyscale
(page 382). Additionally, Jin teaches the piperazine adjacent to the E3 ligase ligand in other compounds, such as Compound 18 (
PNG
media_image12.png
113
312
media_image12.png
Greyscale
, HC58-35; page 357), which showed good activity in Jurkats (Example 348, page 412; Figure 1A). Accordingly, Jin teaches that the linker is
PNG
media_image17.png
87
179
media_image17.png
Greyscale
. Mainolfi teaches the cereblon binder,
PNG
media_image13.png
96
131
media_image13.png
Greyscale
(I-20, Example 8, [00383]). Thus, the combination of ‘058, Linney, Vara, Jin, and Mianolfi teaches Compound 6:
PNG
media_image19.png
124
283
media_image19.png
Greyscale
.
Regarding claim 36, ‘058 teaches a composition of the compound,
PNG
media_image22.png
154
193
media_image22.png
Greyscale
(claims 1, 4, and 12).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
Prosecution Insights