FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed May 29, 2026 and Jun. 17, 2026.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
Claims 10-23, 26-45, 47, 48, 56, and 57 have been canceled.
Claims 1, 2, 4, 24, 25, 46, 49, 58, and 59 have been amended and incorporate no new matter.
New claims 60-61 have been added.
Thus, claims 1-9, 24, 25, 46, 49-55, and 58-61 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
The information disclosure statement (IDS) submitted on Jun. 17, 2026 was filed after the mailing date of the non-final action on Feb. 6, 2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
TERMINAL DISCLAIMER
The terminal disclaimer filed on May 29, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application Numbers 18/120,326 and 18/926,888 has been reviewed and is NOT accepted.
The terminal disclaimer does not comply with 37 CFR 1.321 because:
The person who has signed the disclaimer has not stated the extent of the applicant’s or assignee’s interest in the application/patent. See 37 CFR 1.321(b)(3).
The terminal disclaimer filed on Jun. 17, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application Numbers 18/120,311 and 18/120,318 has been reviewed and is NOT accepted.
The terminal disclaimer does not comply with 37 CFR 1.321 because: the filing date for the instant application is incorrect.
Applicant is not required to pay another disclaimer fee as set forth in 37 CFR 1.20(d) when submitting a replacement or supplemental terminal disclaimer.
MAINTAINED REJECTIONS
The following rejections are maintained from the previous Office Action dated Feb. 6, 2026, on the ground that the references cited therein continue to read on the limitations of the amended claims.
Claim Rejections – 35 U.S.C. § 103
1. Claims 1-9, 24, 25, 46, and 51-55 stand rejected under 35 U.S.C. 103 as being unpatentable over You et al. (US Pub. 2021/0139466), in view of Chen et al. (J. Med. Chem. 64, 10537-10556 (Jul. 20, 2021)) and Feng et al. (The FEBS Journal 289, 1214-1239 (Feb. 5, 2021).
You et al. claim MLL1-WDR5 protein-protein interaction inhibitors of formula (I), and methods of treating acute leukemia in a subject, such as an acute leukemia having an MLL1 gene rearrangement type, comprising administering a compound of the formula (I) or a salt thereof (claims 9-10).
In particular, You et al. exemplify the compound of Example 8,
PNG
media_image1.png
454
323
media_image1.png
Greyscale
which reads on formula (I) as recited by claims 1-9, 24, 25, and 46, wherein A is
PNG
media_image2.png
388
716
media_image2.png
Greyscale
wherein Y is -C(O)-, m is 0, and R15 is N-methylpiperazine;
L1 is -NH-C(O)-;
E is
PNG
media_image3.png
154
184
media_image3.png
Greyscale
, wherein
X6 is CR6, and R6 is halo (chlorine);
X5 is CR5, and R5 is methyl;
X7 is CR7, and R7 is halo (fluorine);
X4 is CR4, and R4 is amino (NH2); and
X3 is CR3, and R3 is hydrogen;
X1 is NR1 and R1 is methyl;
each X2 is CHR2a, and each R2a is hydrogen; and
R3a, R3b, R13a, and R13b are each hydrogen.
As evidenced by the instant specification (para. [0082]), the term “cancer” refers to any physiological condition in mammals characterized by unregulated cell growth. Cancers described herein include solid tumors and hematological (blood) cancers. A “solid tumor” or “tumor” refers to a lesion and neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues resulting in abnormal tissue growth, and thus encompasses hematological cancers such as leukemia.
Thus, You et al. disclose and claim methods of treating cancer in a subject having a tumor, comprising administering to the subject a compound of Formula I, as recited by claims 1-9, 24, 25, and 46.
You et al. further claim compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (claim 8), as recited by claim 51.
You et al. differs from the instant claims in that the reference does not disclose administering compounds of formula (I) in combination with a PD-1 inhibitor.
However, anti-PD-1 antibodies, e.g., nivolumab, were known to be effective in the treatment of cancer in combination with other therapies, as discussed below.
For example, Feng et al. review combination therapies for treating cancer, in particular the anti-PD-1 antibody nivolumab, in combination with epigenetic drugs for treating various cancers, e.g., childhood relapsed or refractory acute myeloid leukemia (AML), and hematologic malignancies (Table 2). Feng et al. note that a phase 2 study investigating azacitidine and PD-1 antibody nivolumab in AML patients reveals that the combination therapy is safe and produces encouraging objective response rate and overall survival outcomes (p. 1229, right col.).
Thus, Feng et al. establish that the elected anti-PD-1 antibody, nivolumab, was known to be effective to treat acute leukemias when administered in combination with other drugs.
It is implicit in the combination therapies disclosed by Feng et al. that nivolumab is formulated in a composition with a pharmaceutically acceptable excipient, separately from the second anti-cancer agent, as recited by claim 51.
It is further implicit in the combination therapies disclosed by Feng et al. that nivolumab is a PD-1 inhibitor, a checkpoint inhibitor, and immunotherapy, which may be administered with a second anti-cancer agent in any order, i.e., prior to or subsequent to, as recited by claims 6 and 52-55.
One of ordinary skill in the art would have been motivated to administer nivolumab in combination with the compound of Example 8 of You et al. with a reasonable expectation of success, because the prior art discloses the advantages of administering a WDR5 inhibitor in combination with a PD-1 inhibitor.
For example, Chen et al. review the various biological activities of WDR5 and the development of WDR5 inhibitors, and conclude that a synergistic combination can be achieved when WDR5-targeted inhibitors are administered in combination with other anticancer drugs. In particular, targeting the H3K4 methylation pathway regulated by MLL1 can enhance the function of PD1 antibodies. Thus, Chen et al. teach that administering a WDR5 inhibitor in combination with an anti-PD-1 antibody is an ideal choice (p. 10550, right col.).
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to treat cancer, e.g., acute leukemias, by administering the WDR5 inhibitor of Example 8 as taught by You et al., e.g., in combination with nivolumab, as taught by Feng et al., with a reasonable expectation of success, because Chen et al. teach that the combination of a WDR5-targeted inhibitor together with an anti-PD-1 antibody is synergistic; and both anti-PD-1 antibodies, such as nivolumab, and the compounds of You et al. were each separately known in the treatment of acute leukemias.
As recognized by MPEP § 2144.06, “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
The cited references do not explicitly disclose that treating cancer in a subject by administering the claimed combination results in:
increases one or more anti-tumor T cell types in a subject having a tumor, as recited by claim 2;
increases at least one anti-tumor T cell type in a tumor microenvironment of the tumor in the subject, as recited by claim 3;
induces at least a two-fold increase in expression of at least one gene associated with anti-tumor T cell infiltration, as recited by claim 4;
wherein the gene associated with an anti-tumor T cell is Batf2, Cd274 (PD-L1), Dnase1L3, Gbp2, Infg (Inf-γ), IL18 bp, IL24, Lag3, Pdcdl1g2 (PD-L2), Tgtp1, Tnfsf10, or a combination thereof, as recited by claim 5;
wherein the one or more T cell types comprise one or more of tumor-infiltrating T lymphocytes (TILs) and cytotoxic T lymphocytes (CTLs), as recited by claim 7;
wherein a ratio of tumor infiltrating leukocytes (TIL) to regulatory T cells (Tregs) in the tumor is increased, as recited by claim 8;
wherein one or more of regulatory macrophages (M2), tumor-associated myeloid cells (TAMCs), myeloid-derived suppressor cells (M-MDSCs) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are reduced in the subject, as recited by claim 9,
However, independent claims 1, 2, and 4 recite the identical active step: administering to
a subject a compound of Formula I in combination with a PD-1 inhibitor.
As evidenced by the instant specification (see Examples 1 and 2), carrying out the active method step of administering to a subject a compound of Formula I in combination with a PD-1 inhibitor achieves the claimed molecular and cellular effects. Thus, claims 2 and 4 merely recite the inherent result of carrying out the method of claim 1, even if these results were not known or appreciated.
All the molecular and cellular mechanisms by which a compound exerts its therapeutic effects are intrinsic in the methods of You et al., and occur each time the claimed combination is administered to the patient population in need of treatment for cancer, e.g., acute leukemias, regardless of whether anyone was aware of those molecular and cellular mechanisms. While the references may not explicitly recognize the claimed results, their discovery is tantamount only to finding a new property intrinsic in carrying out an old method.
Thus, claims 2-5 and 7-9 are directed to the inherent result of administering a compound of formula (I) in combination with a PD-1 inhibitor, e.g., nivolumab, to treat cancer, e.g., an acute leukemia.
For the foregoing reasons, the rejection of claims 1-9, 24, 25, 46, and 51-55 under 35 U.S.C. § 103 as obvious over You et al. in view of Feng et al. and Chen et al. is maintained.
2. Claims 1-9, 24, 25, 46, 49-55, 58, and 59 stand rejected under 35 U.S.C. 103 as being unpatentable over You et al. (US Pub. 2021/0139466), in view of Chen et al. (J. Med. Chem. 64, 10537-10556 (2021)) and Feng et al. (The FEBS Journal 289, 1214-1239 (Feb. 5, 2021), as applied to claims 1-9, 24, 25, 46, and 51-55 above.
In addition, this rejection is extended to new claims 60-61.
As discussed above, You et al., Feng et al., and Chen et al. disclose, teach, and suggest methods of treating cancer, e.g., acute leukemias, by administering a WDR5-inhibitor of formula (I) (Example 8) in combination with the PD-1 inhibitor nivolumab.
Regarding the elected species of formula (Id), as recited by dependent claims 49, 50, and 58-61, You et al. differs from the instant claims in that the compound of Example 8 lacks the fluoro and methyl substituents of the elected compound species of formula (Id), as shown below:
PNG
media_image4.png
294
788
media_image4.png
Greyscale
However, the compound of Example 8 of You et al. is disclosed as a species of general
formula (I), having the structural formula,
PNG
media_image5.png
200
400
media_image5.png
Greyscale
wherein X is hydrogen or halogen, e.g., fluoro; and R4 is N-methylpiperazine or 1,2-dimethyl-piperazine (claim 9). You et al. exemplify two species wherein X is fluoro (Examples 20-21), and one species wherein R4 is methylpiperazine substituted with a second methyl group.
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the central phenyl ring of Example 8 of You et al. by substituting a hydrogen with fluorine to arrive at the claimed compound of formula (Id) with a reasonable expectation of success, because the compounds of You et al. are disclosed to have the same mechanism of action as the claimed compounds, as MLL1-WDR5 protein-protein interaction inhibitors, and to be useful in methods of treating the same diseases.
In addition, MPEP § 2144.09 recognizes that compounds which are positional isomers (i.e., having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that they possess the same properties. This expectation is then deemed the motivation for preparing the position isomers. See In re Wilder, 563 F.2d 457 (CCPA 1977). Compounds that differ only in the placement of substituents in a ring system are not patentable absent a showing of unexpected properties. See In Re Papesch, 315 F.2d 381 (CCPA 1963); see also MPEP § 2144.09 (I).
Similarly, it would have been predictable to substitute the R4 piperazine ring with one, two, or three methyl groups, because, where a prior art compound shares the same utility as those claimed, one of ordinary skill in the art would have a reasonable expectation that modifying the compound by the interchange of hydrogen and alkyl would yield compounds having similar properties. Hydrogen and methyl substitutions are known in the art and have been held to be obvious variants of each other. See MPEP § 2144.09 and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
For the foregoing reasons, the rejection of claims 1-9, 24, 25, 46, 49-55, 58, and 59 under 35 U.S.C. § 103 as obvious over You et al. in view of Feng et al. and Chen et al. is maintained, and extended to new claims 60-61.
Double Patenting
Claims 1-9, 24, 25, 46, 49-55, 58, and 59 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-60 of copending Application No. 18/926,888 (reference application).
In addition, this rejection is extended to new claims 60-61.
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims would anticipate the examined claims.
Specifically, independent reference claim 1 is drawn to a method of treating cancer in a subject having a tumor;
independent reference claim 2 is drawn to a method of increasing one or more anti-tumor T cell types in a subject having a tumor; and
independent reference claim 4 is drawn to a method of inducing at least a two-fold increase in expression of at least one gene associated with anti-tumor T cell infiltration in a tumor in a subject having a tumor,
all three methods comprising the steps of administering to the subject a combination comprising:
(1) an MLL1-WDR5 protein-protein interaction inhibitor compound of Formula I, or a pharmaceutically acceptable salt thereof,
(2) a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, and
(3) a dose of radiation therapy,
wherein the compound of Formula I has the structure:
PNG
media_image6.png
275
186
media_image6.png
Greyscale
,
wherein variables A, X1, X2, L1, E, R3a, R3b, R13a, and R13b are defined identically to formula (I) of the examined claims.
Further, reference claims 49 and 50 recite the compound of formula (Id), which is identical to the elected formula (Id) recited by the examined claims.
Thus, the reference claims merely add a third component (a dose of radiation therapy) to the otherwise identical combination recited by the examined claims, and would anticipate the examined claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-9, 24, 25, 46, 49-55, 58, and 59 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-62 of copending Application No. 18/120,326 in view of You et al. (US Pub. 2021/0139466), Chen et al. (J. Med. Chem. 64, 10537-10556 (2021)), and Feng et al. (The FEBS Journal 289, 1214-1239 (Feb. 5, 2021).
In addition, this rejection is extended to new claims 60-61.
Reference claims 56-57 are drawn to methods for the treatment or prevention of acute leukemia with MLL1 gene rearrangement in a patient in need thereof, comprising administering to the patient a therapeutically acceptable dose of the compound of claim 1, or the pharmaceutical composition of claim 55.
Reference claim 55 is drawn to a pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
Reference claim 1 is drawn to compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, having the following structure:
PNG
media_image7.png
256
251
media_image7.png
Greyscale
which falls within the scope of formula (I) as recited by examined claim 1.
Further, reference claim 54 is drawn to compounds including, e.g.,
PNG
media_image8.png
296
488
media_image8.png
Greyscale
; and
reference claims 58-62 are drawn to compounds, or pharmaceutically acceptable salts or solvates thereof, having the following structures:
Claim 58
Claim 59
Claim 60
Claim 61
Claim 62
PNG
media_image9.png
448
330
media_image9.png
Greyscale
PNG
media_image10.png
317
257
media_image10.png
Greyscale
PNG
media_image11.png
307
248
media_image11.png
Greyscale
PNG
media_image12.png
306
251
media_image12.png
Greyscale
PNG
media_image13.png
304
251
media_image13.png
Greyscale
all of which fall within the scope of formula (I) as recited by examined claim 1.
The reference claims differ from the examined claims in that the reference claims do not recite administering compounds of formula (I) in combination with a PD-1 inhibitor. However, anti-PD-1 antibodies, e.g., nivolumab, were known to be effective in the treatment of cancer, particularly in combination with other therapies, as discussed below.
Feng et al. review combination therapies for treating cancer, in particular the anti-PD-1 antibody nivolumab, in combination with epigenetic drugs for treating various cancers, e.g., childhood relapsed or refractory acute myeloid leukemia (AML), and hematologic malignancies (Table 2). Feng et al. note that a phase 2 study investigating azacitidine and PD-1 antibody nivolumab in AML patients reveals that the combination therapy is safe and produces encouraging objective response rate and overall survival outcomes (p. 1229, right col.).
Thus, Feng et al. establish that the elected anti-PD-1 antibody, nivolumab, was known to be effective to treat acute leukemias when administered in combination with other drugs, as recited by independent examined claims 1, 2, and 4.
Chen et al. review the many biological activities of WDR5 and the development of WDR5 inhibitors, and conclude that a synergistic combination can be achieved when WDR5-targeted inhibitors are administered in combination with other anticancer drugs. In particular, targeting the H3K4 methylation pathway regulated by MLL1 can enhance the function of PD1 antibodies. Thus, Chen et al. teach that combining WDR5 inhibitors with anti-PD-1 antibodies is an ideal choice (p. 10550, right col.).
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to treat cancer, e.g., acute leukemias, by administering a compound of formula (I) as recited by the reference claims, in combination with nivolumab, as taught by Feng et al. with a reasonable expectation of success, because Chen et al. teach that a synergistic combination can be achieved when WDR5-targeted inhibitors are administered in combination with anti-PD-1 antibodies; and both anti-PD-1 antibodies, such as nivolumab, and the compounds of formula (I) were each separately known in the treatment of acute leukemias.
As recognized by MPEP § 2144.06, “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
With regard to the elected species of formula (Id), the reference claims differ from the examined claims 49, 50, and 58-61, in that formula (I) of reference claim 1, wherein R2 and R3 are limited to hydrogen, lacks the fluoro and methyl substituents of the elected compound species of formula (Id) (shown below).
Reference formula (I)
Formula (Id) – Elected compound species
PNG
media_image7.png
256
251
media_image7.png
Greyscale
PNG
media_image14.png
258
221
media_image14.png
Greyscale
However, the compound of Example 8 of You et al. is disclosed as a species of general
formula (I), having the structural formula,
You et al. formula (I)
You et al. compound of Example 8
PNG
media_image5.png
200
400
media_image5.png
Greyscale
PNG
media_image15.png
200
400
media_image15.png
Greyscale
wherein X is hydrogen or halogen, e.g., fluoro (as in Example 21); and R4 is N-methylpiperazine or 1,2-dimethylpiperazine (claim 9). You et al. exemplify two species wherein X is fluoro (Examples 20-21), and one species wherein R4 is methylpiperazine substituted with a second methyl group.
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the central phenyl ring of Example 8 of You et al. by substituting a hydrogen with fluorine to arrive at the claimed compound of formula (Id) with a reasonable expectation of success, because the compounds of You et al. are disclosed to have the same mechanism of action as the claimed compounds, as MLL1-WDR5 protein-protein interaction inhibitors, and to be useful in methods of treating the same diseases.
In addition, MPEP § 2144.09 recognizes that compounds which are positional isomers (i.e., having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that they possess the same properties. This expectation is then deemed the motivation for preparing the position isomers. See In re Wilder, 563 F.2d 457 (CCPA 1977). Compounds that differ only in the placement of substituents in a ring system are not patentable absent a showing of unexpected properties. See In Re Papesch, 315 F.2d 381 (CCPA 1963); see also MPEP § 2144.09 (I).
Similarly, it would have been predictable to substitute the R4 piperazine ring with one, two, or three methyl groups, because, where a prior art compound shares the same utility as those claimed, one of ordinary skill in the art would have a reasonable expectation that modifying the compound by the interchange of hydrogen and alkyl would yield compounds having similar properties. Hydrogen and methyl substitutions are known in the art and have been held to be obvious variants of each other. See MPEP § 2144.09 and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
RESPONSE TO ARGUMENTS
Applicant's arguments filed May 29, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that the combination of You, Chen, and Feng would not have rendered obvious the claimed methods, at least because:
The evidence does not support choosing You's compound 8 as a lead compound or why one of ordinary skill in the art would have modified compound 8 with a reasonable expectation of success;
The Office Action fails to recognize other differences between the cited references and the instant claims; thus, it fails to articulate how one of ordinary skill in the art would have combined the references to bridge the gap and produce the claimed methods; and
The Office Action fails to take into account unexpected improvements over the teaching of the references (Remarks, p. 30).
First, Applicant argues that the record evidence does not support choosing You's compound 8 as a lead compound or why one of ordinary skill in the art would have modified compound 8 with a reasonable expectation of success (Remarks, pp. 30-34).
Applicant contends that formula (I) of You does not overlap with Formula (III) in the claims. Indeed, the original claims recite no compounds that overlap with those disclosed by You. In formula (I) of You, the only variable permitted on the phenyl ring is X, which must be at the 2-position. You's broadest genus appears in claim 1, which is shown below side-by-side with Formula (III) of the instant claims:
PNG
media_image16.png
346
536
media_image16.png
Greyscale
Thus, You's formula (I) does not overlap with Formula (III) of the instant claims. Having failed to note the difference between the You reference and the compounds recited in the instant claims, the Office Action further compounds this error by failing to articulate why one of ordinary skill in the art would have chosen compound 8 as a lead compound.
Applicant further argues that You's generic teaching of substitution on the phenyl ring makes it clear that none of You's compounds can ever have a substituent at the analogous position of the phenyl ring. Thus, You expressly teaches that the only position open to substitution is the 2-position (variable "X"), and that the 5-position is always unsubstituted. Thus, the prior art teaches away from the modification of You's compound 8 to arrive at the compound of Formula (III/IIIb). Such teaching away is evidence of non-obviousness. Applicant further argues that compound 8 is not an exceptionally active MLL1-WDR5 inhibitor, compared to the other compounds taught therein. Table 3 shows that compound 8 has no better in vitro activity than any of the other MLL-1 WDR5 inhibitors prepared and tested by You. Indeed, it is less than half as active as several of the compounds tested.
Applicant argues that the lead compound analysis is not optional. Takeda, 492 F.3d at 1359; Eisai, 533 F.3d at 1359. An obviousness argument based on structural similarity, "clearly depends on a preliminary finding that one of ordinary skill in the art would have selected [the prior art compound] as a lead compound," and even post-KSR, "a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identification of a lead compound." 492 F.3d at 1359, 533 F.3d at 1359. In this case, the Examiner has presented no reasonable basis for one of ordinary skill in the art to choose You's compound 8, from among all of You's compounds, as a starting point for further development.
Applicant asserts that the Office Action fails to acknowledge the difference between compound 8 and the compounds recited in the instant claims, it clearly fails to articulate a reason why one of ordinary skill in the art would have modified compound 8. Indeed, the Office Action seems to imply that the claimed compounds are within the scope of the compounds disclosed by You, when they clearly are not. Compound 8 was not even among the compounds You tested for water solubility. One of ordinary skill in the art would have inferred from this silence that compounds having a substituent in general, and compound 8 in particular, were not particularly good candidates for further development.
Thus, Applicant argues that You teaches away from selecting compound 8 as a lead compound, and there is no reason why one of ordinary skill in the art would have and modified it to produce the compounds of Formula (III/IIIb). This teaching away from the compounds of the pending claims is further evidence of unobviousness. As the combination of references fails to teach the compounds of Formula I recited in the instant claims, the 103 rejection fails to articulate a viable prima facie case of obviousness (Remarks, pp. 30-34).
However, as recognized by MPEP § 2143, the lead compound cases do not stand for the proposition that identification of a single lead compound is necessary in every obviousness rejection of a chemical compound.
MPEP § 2144.09 recognizes situations when 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). Close structural similarity between chemical compounds (homologs, analogues, and isomers) is enough, with no need for lead compound analysis.
In addition, Applicant’s reading of You et al. is overly restrictive. Table 3 of You et al. demonstrates that the GI50 of compound 8 against leukemia cells has approximately the same micromolar potency as the other compounds tested.
As recognized by MPEP § 2123, a reference may be relied upon for all that it would have reasonably suggested to one of ordinary skill the art, including non-preferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Importantly, none of the instant claims recite compounds of formula (III) or (IIIb). Claims 1-9, 24, 25, 46, and 51-55 recite compounds of formula (I), while dependent claims 49, 50, and 58-61 recite the elected species of formula (Id).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., compounds of formula III) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As discussed in the first rejection under 35 U.S.C. § 103 set forth above, compound 8 of You et al. falls within the scope of claimed formula (I), without modification.
Thus, Applicant’s argument is applicable only to the second rejection under 35 U.S.C. § 103, which sets forth the rationale to modify compound 8 of You et al. to arrive at the elected compound of formula (Id), as recited by dependent claims 49, 50, and 58-61.
Positional isomers and the interchange of hydrogen and methyl are recognized rationales for modifying a prior art compound to arrive at a claimed compound, where, as here, they share close structural similarity, the same mechanism of action, and the same utility. See MPEP § 2144.09.
Second, Applicant argues that the Office Action fails to explain how Chen and Feng
would have led one of ordinary skill in the art to (1) choose You's compound of formula 8 as a lead compound, and (2) modify the compound of formula 8 to arrive at the compounds recited in the instant claims (Remarks, pp. 34-37).
Applicant further contends that the rejection appears to ignore clear differences between claims 1, 2 and 4, lumping them all together as if they were the same. They are not: claim 1 is
directed to a method of treating cancer; claim 2 is directed to a method of increasing one or more anti-tumor T cell types in a subject having a tumor; and claim 4 recites a method of inducing at least a two-fold increase in expression of at least one gene associated with anti-tumor T cell infiltration in a tumor in a subject having a tumor.
Applicant argues that nowhere in the rejection is it even alleged that the combination of a
compound of a WDR5 inhibitor of Formula I and a PD-1 inhibitor would increase one or more anti-tumor T cell types in a subject having a tumor (per claim 2) or induce at least a two-fold increase in at least one gene associated with anti-tumor T cell infiltration in a tumor in subject having a tumor (per claim 4), features which are not taught or suggested by Feng or Chen.
Applicant argues that Feng discloses three broad categories of epigenic target proteins, including "writers," "readers" "erasers." These regulators work coordinately to ensure the spatial and temporal regulation of gene expression, which is often dysregulated in cancer. Small molecules have been designed to target the epigenetic proteins to reverse the epigenetic reprogramming in cancer, e.g., DNMTs, HDACs, EZH2s, BETs, LSD1s, and a DOT1L. While Chen focuses on WDR5 inhibitors, Chen fails to suggest that combining a WDR5 inhibitor with a checkpoint inhibitor would be expected to be active.
Thus, Applicant argues that Feng and Chen combined show that there are many possible, divergent, avenues of exploration in this field, which is still rife with unpredictability. In fact, Feng does not list one single WDR5 inhibitor amongst the several epigenetic reprogramming compounds disclosed therein. Chen underscores unpredictability of the art, stating, "A multitude of WDR5 interaction partners and their unique role in epigenetics endow WDR5 with diverse biological functions, including reproduction, development, metabolism, immune and inflammatory reactions, and neural and humoral regulation." As the solutions suggested by the art are not finite, identified, or predictable, the combination of You, Chen, and Feng fails to render the instant claims prima facie obvious (Remarks, pp. 34-37).
To clarify, You et al. explicitly discloses methods of treating cancer by administering a compound that falls within the scope of claimed formula (I). You et al. differs from claim 1 only in that the compounds are not disclosed to be administered in combination with a PD-1 inhibitor.
Feng et al. is cited for its teaching of methods of treating cancer by administering the elected PD-1 inhibitor nivolumab in combination with other anti-cancer agents.
Chen et al. is cited for its teaching that a synergistic anti-cancer effect can be achieved by administering a WDR5 inhibitor in combination with an anti-PD-1 antibody, thus providing the motivation to combine You et al. and Feng et al.
As discussed above, the cited references differ from independent claims 2 and 4 in that they do not explicitly disclose that administering a compound of Formula I and a PD-1 inhibitor
increases one or more anti-tumor T cell types in a subject having a tumor, as recited by claim 2, and
induces at least a two-fold increase in expression of at least one gene associated with anti-tumor T cell infiltration in a tumor in a subject having a tumor, as recited by claim 4.
However, independent claims 2 and 4 each recite the same active step recited by claim 1: administering to a subject a compound of Formula I and a PD-1 inhibitor.
As evidenced by the instant specification (see Examples 1 and 2), carrying out the active method step of administering to a subject a compound of Formula I in combination with a PD-1 inhibitor achieves these biological effects. Thus, claims 2 and 4 merely recite the inherent result of carrying out the method of claim 1, even if these results were not known or appreciated. See MPEP § 2112.
Third, Applicant argues that the Office Action fails to take into account the evidence of
record, which clearly demonstrates that the claimed invention is a surprising improvement over the prior art. Specifically, Example 1 of the specification demonstrates that the in vivo efficacy of combination treatment with the claimed compound of formula (Id), HBI-2375, and anti-PD-1 antibody in syngeneic xenograft model tumors. Example 2 demonstrates that HBI-2375 and anti-PD-1 antibody inhibit CD8+ T cell infiltration and modulate gene expression in MC38 and 3LL xenografts. You, Chen, and Feng fail to suggest these unexpected results (Remarks, p. 37).
However, Chen et al. conclude that “[t]he combination of WDR5-targeted inhibitors and other anticancer drugs using WDR5 inhibitors as a synergist might be a better application direction for inhibitors targeting WDR5. It has been reported that targeting the H3K4 methylation pathway regulated by MLL1 can enhance the function of PD1 antibodies. Therefore, combining WDR5 inhibitors with PD1 antibodies or developing ADCs that link PD1 antibodies and inhibitors targeting WDR5 is an ideal choice” (p. 10550, right col.).
Thus, Chen et al. expressly suggest that the combination of an WDR5 inhibitor with an anti-PD1 antibody would have a synergistic effect. On this basis, one of ordinary skill in the art would have expected improved efficacy with the combination over each compound alone.
As recognized by MPEP § 716.02(c)(II), "[e]xpected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art).
Evidence of secondary considerations does not always overcome a prima facie case of obviousness. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics. v. Viacell, 491 F.3d 1342 at 1364 (Fed. Cir. 2007). “Even though applicant’s modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. Pfizer v. Apotex, 82 USPQ2d 1321 at 1338 (Fed. Cir. 2007, citing In re Aller, 220 F.2d at 456).
For the foregoing reasons, the rejections under 35 U.S.C. § 103 and on the grounds of obviousness-type double patenting are maintained.
CONCLUSION
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 10:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://portal.uspto.gov/external/portal. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/SARA E. TOWNSLEY/Examiner, Art Unit 1629
Prosecution Insights