DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is a 371 National Stage Entry of PCT/GB2021/050360 filed on February 12, 2021 which claims priority to foreign application No. GB2001980.8 filed on February 13, 2020.
Status of Claims
Acknowledgement is made of previously presented (2, 8-9, 11-12, 16-18, 26, 33, 35, 44), amended (5-7, 13, 19, 21, 28), cancelled (1, 3-4, 10, 14-15, 20, 22-25, 27, 29-32, 34, 36-43), and new (45) claims filed July 9, 2026. Claims 2, 5-9, 11-13, 16-19, 21, 26, 28, 33, 35, 44-45 are pending in instant application.
Response to Arguments
Applicant’s amendments filed July 9, 2026 have overcome the following:
the 35 U.S.C. 112(b) rejection of claims 5-7, 13, 16, 19, 21, 23, 28
the 35 U.S.C. 112(d) rejection of claim 23
The above have been withdrawn.
Applicant's arguments filed July 9, 2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments of synergy (see 7/9/26 Remarks at p. 2), It is the Examiner’s understanding that Applicant repeatedly alleges the existence of unexpected results commensurate in scope with the requirements of MPEP §716, §716.01, and §716.02, wherein such results are sufficient to rebut prima facie obviousness (see, e.g., Reply filed 7/9/26 at p. 2 ¶3).
However, to establish unexpected results, the evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP § 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)).
If Applicant means to allege the existence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 based upon instant 1.8 (see, e.g., Reply filed 7/9/26 at p. 2 ¶4 and Figure 39A) this is also not persuasive because the requirements of MPEP § 716.02 have not been satisfied. Specifically, MPEP § 716.02(b) is not satisfied because no evidence of statistical significance has been placed on record. Additionally, MPEP § 716.02(d) is not satisfied because such proffered evidence is not commensurate in scope with the instant claims with respect to USP7 inhibitor or immune checkpoint inhibitor concentration (see, e.g., instant claim 2, no concentration specified or required; see also MPEP § 716.02(d)(I)-(II)); rather the one example is highly limited and only tested a single concentration of ADC-159 and a single unspecified anti-PD-L1 or a single unspecified anti-CTLA-4 (see Figure 39A) and fails to establish that the observed results persist within the full scope and ranges of compositions presently claimed (any USP7 inhibitor, any immune checkpoint inhibitor, any concentration, see, e.g., MPEP § 716.02(d)). Accordingly, for at least these reasons, the proffered data at Example 1.8 is insufficient to establish unexpected results commensurate in scope with the requirements of MPEP § 716.02. Accordingly, zero evidence of any unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record at this time.
In regards to Applicant’s response to the use of Fu (see 7/9/26 Remarks at pp. 2-3), Applicant argues Fu discusses IL-10 undermines PD-1 therapy for ovarian cancer, and that it cannot be concluded from Fu that colon cancers adapt to PD-1 blockade by increasing IL-10 levels such that the efficacy of the anti-PD-1 therapy is reduced. The above are not claimed limitations. The instant limitations relevant to the teachings of Fu in the WO’602 or US’717 rejection are i) combining a USP7 inhibitor with an anti-PD-1 inhibitor (instant claim 2, 44) and ii) administering to a patient previously administered a therapy (instant claim 26). Fu addresses both of these; i) Fu suggests combining USP7 inhibitors with anti-PD-1 antibodies to help improve the effect of anti-PD-1 therapies (see Fu at p. 616 left col. ¶3, “USP7 inhibitors may be a new option for colon cancer combination therapy such as combination with anti-PD-1”) and ii) Fu teaches resistance to existing colorectal cancer therapies is a known challenge (see Fu at p. 609 ¶1, “clinical chemotherapeutic drugs… showed promising cancer treatment efficiency, but…the development of resistance limit their long-term utility”), and proposes USP7 inhibitors with anti-PD-1 therapies as a new combination therapy strategy for colorectal cancer (see Fu at p. 616 left col. ¶3).
New claim 45 is rejected in view of new reference Fiegle.
Modified/Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 2, 5-8, 11-13, 16-19, 26, 33, 35, 44 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/073602 A11 in view of Fu et. al.2 as evidenced by American Cancer Society3.
Regarding claim 2 and treating colon cancer with a USP7 inhibitor/immune checkpoint inhibitor combination, WO’602 discloses USP7 inhibitors (see WO’602 at Title). WO’602 teaches a method of treating cancer comprising administering a compound of Formula I (see WO’602 claim 29). WO'602 teaches the cancer may be colon cancer (see WO'602 at p. 44 line 35, p. 46 line 6, p. 47 line 12). WO’602 discloses combination therapies with second drugs in combination or separate administration (see WO’602 at p. 44 lines 20-21). WO’602 teaches the USP7 inhibitor may be used in combination with an immune-modulatory (see WO'602 at p. 45 lines 8-12).
Regarding claim 33 wherein the USP7 inhibitor is a compound of instant Formula I, WO’602 discloses USP7 inhibitors of Formula I (see WO’602 claim 1), which have the same substituent limitations as instant claim 33.
WO’602 Claim 1 Formula I
Instant Claim 33 Formula I
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Regarding claims 23 and cancer types, the American Cancer Society explains that colon cancer is a solid cancer (see American Cancer Society at p. 23).
Regarding claims 5-8 and VEGF and HIF1α, claim 19 and angiogenesis, claim 11 and inhibiting USP7 and TILs, claim 12 and inhibiting USP7 and decreased proportion of Treg cells relative to CD8+ T cells, claim 13 and ECM remodeling and claim 17 MMP secretion, claim 16 and EMT and claim 18 and inhibiting fibroblast invasion, The claims are drawn to effects of the active step of administering a USP7 inhibitor of Formula I. Per MPEP § 2112.01(II), “Products of identical chemical composition cannot have mutually exclusive properties.” Therefore, because the prior art teaches the identically claimed chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F. 2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
The prior art differs from the claims as follows: While WO’602 teaches treating colon cancer with USP7 inhibitors, WO’602 does not specify: i) an embodiment of the USP7 inhibitor of instant claim 35, ii) a subject who has previously been administered an initial therapeutic agent, iii) that the immune-modulatory agent is an immune checkpoint inhibitor.
However,
Regarding claims 2, 44 and USP7 inhibitor in combination with an anti-PD-1 inhibitor for treating colon cancer, Fu teaches a selective USP7 inhibitor P5091 was found to inhibit CT26 xenografts (colon cancer model, see Fu at p. 610 right col par 2) growth in mice, which is comparable to the effect of a current colon cancer treatment, an anti-PD-1 antibody (see Fu at Abstract, p. 609 ¶1, p. 612 left col. ¶1). Fu suggests combining USP7 inhibitors with anti-PD-1 antibodies to help improve the effect of anti-PD-1 therapies (see Fu at p. 616 left col. ¶3).
Regarding claim 26 and a previously administered therapy, Fu teaches studies on USP7 show that it has been closely implicated in tumorigenesis, cancer metastasis, and HIV progression (see Fu at p. 608 left col. ¶2). Fu teaches anti-PD-1 inhibitors face the challenge of resistance mechanisms (see Fu at p. 616 left col ¶3). Fu teaches resistance to existing colorectal cancer therapies is a known challenge (see Fu at p. 609 ¶1, “clinical chemotherapeutic drugs… showed promising cancer treatment efficiency, but…the development of resistance limit their long-term utility”).
Regarding a species of claim 35, WO’602 teaches USP7 inhibitor Example 202, 7-(Benzo[d][1,3]dioxol-5-yl)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-3H-pvrrolo[2,3-d]pyrimidin-4(7H)-one, CAS# 2222784-58-7 (see WO’602 at Table 1 p.24 and p. 212 and claim 23 p. 287), the same as instantly disclosed Example 5 (see instant specification at p. 54). CAS# 2222784-58-7 differs from the instantly claimed compound only in fused ring identity, dioxolane O vs tetrahydrofuran CH2. WO’602 also claims Q may be
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(see WO’602 claim 7) and discloses R9b may be an optionally substituted C3-C8 heteroaryl (see WO’602 at p. 22 lines 12-13), which may be 2 fused rings (see WO’602 at p. 13 line 28) one which may be saturated and the other unsaturated (see WO’602 at p. 14 lines 1-2) which encompasses the instant dihydrobenzofuran.
WO’602
CAS# 2222784-58-7
Instant Claim 35
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Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding a combination, per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to one skilled in the art to administer a known USP7 cancer treatment (as taught by WO’602) with an anti-PD-1 antibody to a colon cancer patient with a reasonable expectation of success because the prior art teaches USP7 is implicated in cancer metastasis and that USP7 inhibitors and anti-PD-1 antibodies are known colon cancer treatments (as taught by Fu). In addition or in the alternative, per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine an USP7 inhibitor taught by WO’602 in combination with an anti-PD-1 antibody because the prior art suggests combining a USP7 inhibitor with an immune-modulatory agent (as taught by WO’602), and both USP7 inhibitors and anti-PD-1 antibodies (immune checkpoint inhibitor, see instant claim 44) are known to treat colon cancer and each composition would be performing the same purpose separately as they would be together (treating colon cancer, as taught by Fu).
Moreover, the prior art suggests the expectation of synergy for combining USP7 inhibitors and anti-PD-1 therapies (as taught by Fu) (see also MPEP § 2143(I)(C)).
Regarding claim 26 and a previously administered therapy, it would be obvious to administer a combination of a USP7 inhibitor and an anti-PD-1 antibody to a patient who has previously received a therapy such as an anti-PD-1 antibody or other known colorectal cancer treatment because the prior art teaches cancers can develop resistance to colorectal cancer treatments, and proposes USP7 inhibitors can improve the efficacy of anti-PD-1 (as taught by Fu). Accordingly, an artisan would be motivated to try a USP7 inhibitor/anti-PD-1 combination therapy to a patient who has developed resistance to a prior colorectal cancer therapy (see MPEP §2143(I)(G)).
Regarding a species of claim 35, per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. In addition or in the alternative, per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled in the art to arrive at the instant compound because WO’602 teaches the core structure of instant compound and discloses variation that encompasses the claimed substituent.
Furthermore, it is well-within the ordinary skill in art to: i) administer a known USP7 inhibitor cancer treatment for use in treating a metastatic colon cancer as taught by the prior art, ii) select suggested substituents for use in a known core structure for the same purpose as taught by the prior art, iii) incorporate a tetrahydrofuran in lieu of a dioxolane, and iv) combine two known colon cancer treatments to treat colon cancer.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claims 2, 9, 23, 26, 44 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 9,717,717 B14 in view of Fu as evidenced by American Cancer Society.
Regarding claim 2 and treating colon cancer with a USP7 inhibitor in combination with an immune checkpoint inhibitor, US’717 teaches a method of treating cancer by modulating immune system activity comprising administering a USP7 inhibitor of Formula II (see US'717 at Title and claim 1). US’717 teaches the disclosed compounds can be used for treating colorectal cancer (see US’717 at col. 15 lines 17-28). US’717 further claims administering an additional therapy such as an anti-cancer immunomodulatory agent (see US’717 claim 4).
US’717 Claim 1 Formula II
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Regarding claims 23 and cancer types, The American Cancer Society explains that colon cancer is a solid cancer (see American Cancer Society at p. 23).
Regarding claim 9 and modulating the tumor microenvironment, US'717 teaches USP7 inhibitors have both anti-cancer activity (increasing apoptosis) and an effect on the anti-cancer immune response (increasing effector T cells), these effects impact the tumor microenvironment (see US'717 at Fig. 1, copied below).
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The prior art differs from the claims as follows: While US’717 teaches treating colon cancer with USP7 inhibitors, US’717 does not specify i) in combination with an immune checkpoint inhibitor, or ii) to a subject previously administered a therapy.
However,
Regarding claims 2, 44 and a combination of USP7 inhibitor with an immune checkpoint inhibitor and colon cancer, Fu teaches studies on USP7 show that it has been closely implicated in tumorigenesis, cancer metastasis, and HIV progression (see Fu at p. 608 left col ¶2). Fu teaches a selective USP7 inhibitor P5091 was found to inhibit CT26 xenografts (colon cancer model, see Fu at p. 610 right col ¶2) growth in mice, which is comparable to the effect of a current colon cancer treatment, an anti-PD-1 antibody (see Fu at Abstract, p. 609 par 1, p. 612 left col. ¶1). Fu suggests combining USP7 inhibitors with anti-PD-1 antibodies to help improve the effect of anti-PD-1 therapies (see Fu at p. 616 left col. ¶3).
Regarding claim 26 and a previously administered therapy, Fu teaches studies on USP7 show that it has been closely implicated in tumorigenesis, cancer metastasis, and HIV progression (see Fu at p. 608 left col. ¶2). Fu teaches anti-PD-1 inhibitors face the challenge of resistance mechanisms (see Fu at p. 616 left col ¶3). Fu teaches resistance to existing colorectal cancer therapies is a known challenge (see Fu at p. 609 ¶1, “clinical chemotherapeutic drugs… showed promising cancer treatment efficiency, but…the development of resistance limit their long-term utility”),
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding a combination and colon cancer, per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to one skilled in the art to administer a known USP7 cancer treatment (as taught by US’717) with an anti-PD-1 antibody to a colon cancer patient with a reasonable expectation of success because the prior art teaches USP7 is implicated in cancer metastasis and that USP7 inhibitors and anti-PD-1 antibodies are known colon cancer treatments (as taught by Fu). In addition or in the alternative, per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine an USP7 inhibitor taught by US’717 in combination with an anti-PD-1 antibody because the prior art teaches both USP7 inhibitors and anti-PD-1 antibodies are known to treat colon cancer and each composition would be performing the same purpose separately as they would be together (as taught by Fu).
Moreover, the prior art suggests the expectation of synergy for combining USP7 inhibitors and anti-PD-1 therapies (as taught by Fu) (see also MPEP § 2143(I)(C)).
Regarding claim 26 and a previously administered therapy, it would be obvious to administer a combination of a USP7 inhibitor and an anti-PD-1 antibody to a patient who has previously received a therapy such as an anti-PD-1 antibody or other known colorectal cancer treatment because the prior art teaches cancers can develop resistance to colorectal cancer treatments, and proposes USP7 inhibitors can improve the efficacy of anti-PD-1 (as taught by Fu). Accordingly, an artisan would be motivated to try a USP7 inhibitor/anti-PD-1 combination therapy to a patient who has developed resistance to a prior colorectal cancer therapy (see MPEP §2143(I)(G)).
Furthermore, it is well-within the ordinary skill in art to: i) administer a known USP7 inhibitor cancer treatment for use in treating a colon cancer as taught by the prior art and ii) combine two known colon cancer treatments to treat colon cancer.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claims 2, 5-8, 11-13, 16-19, 23, 26, 33, 44 are rejected under 35 U.S.C. 103 as being unpatentable over O’Dowd et. al.5 in view of Fu as evidenced by Elemam et. al.6 and American Cancer Society.
Regarding instant claim 2 and a method of treating colon cancer with a USP7 inhibitor, O'Dowd teaches selective USP7 inhibitors for treating cancer (see O'Dowd at Abstract), including in vitro testing in HCT116 cells (see O'Dowd at p. 241 Figure 4) and pharmacokinetic profiling in mice (see O'Dowd at p. 242 Table 6). Elemam explains HCT-116 cells are colorectal cancer cells (see Elemam at Title and p. 884 right col. ¶3).
Regarding claim 23 and cancer types, The American Cancer Society explains that colon cancer is a solid cancer (see American Cancer Society at p. 23).
Regarding instant claim 33 and a USP7 inhibitor of Formula I, O’Dowd teaches many USP7 inhibitors that read on instant Formula I such as thiophenylpyrimidinones (see O'Dowd at p. 239 Table 1)
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, N-methyl pyrazolopyrimidinones (see O'Dowd at p. 240 Table 3)
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, and monocyclic pyrimidinones (see O'Dowd at p. 240 Table 4)
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.
Regarding claims 5-8 and VEGF and HIF1α, claim 19 and angiogenesis, claim 11 and inhibiting USP7 and TILs, claim 12 and inhibiting USP7 and decreased proportion of Treg cells relative to CD8+ T cells, claim 13 and ECM remodeling and claim 17 MMP secretion, claim 16 and EMT and claim 18 and inhibiting fibroblast invasion, The claims are drawn to effects of the active step of administering a USP7 inhibitor of Formula I. Per MPEP § 2112.01(II), “Products of identical chemical composition cannot have mutually exclusive properties.” Therefore, because the prior art teaches the identically claimed chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F. 2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
The prior art differs from the claims as follows: While O’Dowd teaches treating colon cancer with USP7 inhibitors, O’Dowd does not specify i) a combination with an immune checkpoint inhibitor, ii) or a subject previously administered a therapy.
However,
Regarding claims 2, 44 and immune checkpoint inhibitors and colon cancer, Fu teaches studies on USP7 show that it has been closely implicated in tumorigenesis, cancer metastasis, and HIV progression (see Fu at p. 608 left col ¶2). Fu teaches a selective USP7 inhibitor P5091 was found to inhibit CT26 xenografts (colon cancer model, see Fu at p. 610 right col ¶2) growth in mice, which is comparable to the effect of a current colon cancer treatment, an anti-PD-1 antibody (see Fu at Abstract, p. 609 par 1, p. 612 left col. ¶1). Fu suggests combining USP7 inhibitors with anti-PD-1 antibodies to help improve the effect of anti-PD-1 therapies (see Fu at p. 616 left col. ¶3).
Regarding claim 26 and a previously administered therapy, Fu teaches anti-PD-1 inhibitors face the challenge of resistance mechanisms (see Fu at p. 616 left col ¶3). Fu teaches resistance to existing colorectal cancer therapies is a known challenge (see Fu at p. 609 ¶1, “clinical chemotherapeutic drugs… showed promising cancer treatment efficiency, but…the development of resistance limit their long-term utility”).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to one skilled in the art to administer a known USP7 colon cancer treatment (as taught by O’Dowd) with an anti-PD-1 antibody to a colon cancer patient with a reasonable expectation of success because the prior art teaches USP7 is implicated in cancer metastasis and that USP7 inhibitors and anti-PD-1 antibodies are known colon cancer treatments (as taught by Fu). In addition or in the alternative, per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine an USP7 inhibitor taught by O’Dowd in combination with an anti-PD-1 antibody because the prior art teaches both USP7 inhibitors and anti-PD-1 antibodies are known to treat colon cancer and each composition would be performing the same purpose separately as they would be together (as taught by Fu).
It would be obvious to administer a combination of a USP7 inhibitor and an anti-PD-1 antibody to a patient who has previously received a therapy such as an anti-PD-1 antibody or other known colorectal cancer treatment because the prior art teaches cancers can develop resistance to colorectal cancer treatments, and proposes USP7 inhibitors can improve the efficacy of anti-PD-1 (as taught by Fu). Accordingly, an artisan would be motivated to try a USP7 inhibitor/anti-PD-1 combination therapy to a patient who has developed resistance to a prior colorectal cancer therapy (see MPEP §2143(I)(G)).
Moreover, the prior art suggests the expectation of synergy for combining USP7 inhibitors and anti-PD-1 therapies (as taught by Fu) (see also MPEP § 2143(I)(C)).
Furthermore, it is well-within the ordinary skill in art to: i) administer a known USP7 inhibitor cancer treatment for use in treating a metastatic colon cancer as taught by the prior art and ii) combine two known colon cancer treatments to treat colon cancer.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claims 2, 5-8, 11-13, 16-18, 23, 24, 26, 33, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/105963 A17 in view of Fu as evidenced by American Cancer Society.
Regarding claim 2 and administering a USP7 inhibitor in combination with an immune checkpoint inhibitor to treat colon cancer, WO’963 teaches USP7 inhibitors (see WO’963 at Title) for treating cancer (see WO’963 at p. 2 lines 13-16). WO’963 claims wherein the cancer may be a cancer of the colon (WO’963 claim 19). WO’963 claims where the USP7 inhibitor may be in combination with an additional agent such as an immunomodulator (see WO’963 at claim 21).
Regarding claims 23 and cancer types, The American Cancer Society explains that colon cancer is a solid cancer (see American Cancer Society at p. 23).
Regarding claim 33 wherein the USP7 inhibitor is of instant Formula I, WO’963 teaches USP7 inhibitors of Formula I, the limitations encompassing those of instant claim 33. Furthermore WO’963 discloses Example 21 (see WO’963 at pp.48-49), which also reads on the limitations of instant claim 33 when Q is an optionally substituted nitrogen containing heterocycle, specifically
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, R1 is H, and R2 is an optionally substituted C3-C6 cycloalkyl, specifically
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WO’963 Claim 1 Formula I
Instant Claim 33 Formula I
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WO’963 Example 21 CAS#2432611-15-6
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Regarding claims 5-8 and VEGF and HIF1α, claim 19 and angiogenesis, claim 11 and inhibiting USP7 and TILs, claim 12 and inhibiting USP7 and decreased proportion of Treg cells relative to CD8+ T cells, claim 13 and ECM remodeling and claim 17 MMP secretion, claim 16 and EMT and claim 18 and inhibiting fibroblast invasion, The claims are drawn to effects of the active step of administering a USP7 inhibitor of Formula I. Per MPEP § 2112.01(II), “Products of identical chemical composition cannot have mutually exclusive properties.” Therefore, because the prior art teaches the identically claimed chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F. 2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
The prior art differs from the claims as follows: While WO’963 teaches treating colon cancer with USP7 inhibitors, WO’963 does not specify i) a combination with an immune checkpoint inhibitor, ii) a subject previously administered a therapy.
However,
Regarding claims 2, 44 and USP7 inhibitor in combination with an anti-PD-1 inhibitor for treating colon cancer, Fu teaches studies on USP7 show that it has been closely implicated in tumorigenesis, cancer metastasis, and HIV progression (see Fu at p. 608 left col ¶2). Fu teaches a selective USP7 inhibitor P5091 was found to inhibit CT26 xenografts (colon cancer model, see Fu at p. 610 right col par 2) growth in mice, which is comparable to the effect of a current colon cancer treatment, an anti-PD-1 antibody (see Fu at Abstract, p. 609 ¶1, p. 612 left col. ¶1).
Regarding claim 26 and a previously administered therapy, Fu teaches anti-PD-1 inhibitors face the challenge of resistance mechanisms (see Fu at p. 616 left col ¶3). Fu teaches resistance to existing colorectal cancer therapies is a known challenge (see Fu at p. 609 ¶1, “clinical chemotherapeutic drugs… showed promising cancer treatment efficiency, but…the development of resistance limit their long-term utility”).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding a combination and metastatic colon cancer, per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to one skilled in the art to administer a known USP7 colon cancer treatment (as taught by WO’963) with an anti-PD-1 antibody to a colon cancer patient with a reasonable expectation of success because the prior art teaches USP7 is implicated in cancer metastasis and that USP7 inhibitors and anti-PD-1 antibodies are known colon cancer treatments (as taught by Fu). In addition or in the alternative, per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine an USP7 inhibitor taught by WO’963 in combination with an anti-PD-1 antibody because the prior art teaches both USP7 inhibitors and anti-PD-1 antibodies are known to treat colon cancer and each composition would be performing the same purpose separately as they would be together (as taught by Fu).
Moreover, the prior art suggests the expectation of synergy for combining USP7 inhibitors and anti-PD-1 therapies (as taught by Fu) (see also MPEP § 2143(I)(C)).
Regarding claim 26 and a previously administered therapy, it would be obvious to administer a combination of a USP7 inhibitor and an anti-PD-1 antibody to a patient who has previously received a therapy such as an anti-PD-1 antibody or other known colorectal cancer treatment because the prior art teaches cancers can develop resistance to colorectal cancer treatments, and proposes USP7 inhibitors can improve the efficacy of anti-PD-1 (as taught by Fu). Accordingly, an artisan would be motivated to try a USP7 inhibitor/anti-PD-1 combination therapy to a patient who has developed resistance to a prior colorectal cancer therapy (see MPEP §2143(I)(G)).
Furthermore, it is well-within the ordinary skill in art to: i) administer a known USP7 inhibitor cancer treatment for use in treating a colon cancer as taught by the prior art and ii) combine two known colon cancer treatments to treat colon cancer.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claims 21 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over WO’602 in view of Fu as evidenced by American Cancer Society as applied to claims 2, 5-8, 11-13, 16-19, 26, 33, 35, 44 above, and in further view of Rigatti et. al.8, Michaelis et. al.9, and Desidero et. al.10
The prior art differs from the claim as follows: While WO’602 and Fu teach treating colon cancer with a combination USP7 inhibitor/immune checkpoint inhibitor therapies and to patients previously administered initial therapeutic agent, the prior art does discuss if an initial agent was an inhibitor of an MDM2 pathway or if the cells are resistant to inhibitors of an MDM2 pathway.
However,
Rigatti teaches MDM2 inhibitors are a known colon cancer treatment (see Rigatti at Title and Abstract). Michaelis teaches MDM2 inhibitor drug resistance is a concern for cancer treatment (see Michaelis at Abstract). Desidero teaches that changing the colon cancer treatment (e.g. changing the drug or drug combination) after a first line treatment results in tumor relapse (tumor progresses again) is a known colon cancer treatment strategy to elicit a new tumor response (see Desidero at Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to one skilled in the art to switch from treating colon cancer with an MDM2 inhibitor (as taught by Rigatti) a patient is no longer responding to (as taught by Michaelis) a different known colon cancer treatment combination such as a USP7 inhibitor/immune checkpoint inhibitor combination (taught by WO’602 and Bunnett) with an expectation of success because the prior art teaches switching colon cancer treatments after relapse is a known strategy for treating colon cancer (as taught by Desidero).
Furthermore, it is well-within the ordinary skill in art to apply a known cancer treatment strategy for treating cancer with known cancer therapies.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
New Rejection(s)
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over WO’602 in view of Fu as evidenced by American Cancer Society as applied to claims 2, 5-8, 11-13, 16-19, 26, 33, 35, 44 above and in further view of Fiegle et. al.11
The prior art differs from the claims as follows: While WO’602 and Fu teach treating colon cancer with a combination of USP7 inhibitors and an immune checkpoint inhibitor such as an anti-PD-1, the prior art does not specify wherein the immune checkpoint inhibitor is an anti-CTLA4 antibody.
However,
Regarding claim 45 and USP7 inhibitor in combination with an anti-CTLA4 antibody for treating colon cancer, Fiegle teaches dual CTLA-4 and PD-L1 blockade exerts synergistic inhibitory effects on growth and metastasis of colon tumors (see Fiegle at p. 942 right col. ¶2 and at p. 941 Figure 6). Fiegle teaches CTLA-4 or PD-L1 inhibition alone decreased colon tumor volume (see Fiegle at p. 935 Figure 1).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding a combination, per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to one skilled in the art to administer a known USP7 cancer treatment (as taught by WO’602) with an anti-PD-L1 and/or CTLA-4 inhibitor (as taught by Fiegle) because the prior art teaches inhibition of PD-L1 and/or CTLA-4 decreases colon tumor size, and dual PD-L1/CTLA-4 inhibition for colon cancer is synergistic (as taught by Fiegle). In addition or in the alternative, per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine an USP7 inhibitor taught by WO’602 in combination with an anti-PD-L1 antibody and CTLA-4 antibody (as taught by Fiegle) because both are known to treat colon cancer and each composition would be performing the same purpose separately as they would be together (treating colon cancer).
Furthermore, it is well-within the ordinary skill in art to combine two known colon cancer treatments to treat colon cancer.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Conclusion
Claims 2, 5-9, 11-13, 16-19, 21, 26, 28, 33, 35, 44-45 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/S.R./ Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
1 Filed October 20, 2017 and published April 26, 2018. Cite No. 1 in the IDS filed 8/8/22. Hereinafter WO’602. Later patented as U.S. Patent No. 10,766,903 B2. Cited in previous Office Action.
2 Fu et. al. "Pharmacological inhibition of USP7 promotes antitumor immunity and contributes to colon cancer therapy" OncoTargets and Therapy 2019, 12, 609-617. DOI: 10.2147/OTT.S182806. Hereinafter Fu.
3 American Cancer Society. "Colorectal Cancer Facts & Figures 2017-2019."
Atlanta: American Cancer Society; 2017. Hereinafter American Cancer Society.
4 Patented August 1, 2017. Cite No. 1 in the IDS filed 8/8/22. Hereinafter US’717. Cited in previous Office Action.
5 O'Dowd et. al. "Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors" ACS Med. Chem. Lett. 2018, 9, 238-243. DOI: 10.1021/acsmedchemlett.7b00512. Published February 21, 2018. Cited in previous Office Action.
6 Elemam et. al. "HCT-116 colorectal cancer cells secrete chemokines which induce chemoattraction and intracellular calcium mobilization in NK92 cells" Cancer Immunol Immunother, 2019, 68, 6, 883–895. DOI: 10.1007/s00262-019-02319-7. Hereinafter Elemam.
7 Filed November 28, 2018 and published June 6, 2019. Hereinafter WO’963.
8 Rigatti et. al. "Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells" Mol Carcinog 2011, 51, 5, 363-378. DOI: 10.1002/mc.20795. Hereinafter Rigatti.
9 Michaelis et. al. "Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells" Cell Death & Disease, 2011, 2, e243. DOI: 10.1038/cddis.2011.129. Hereinafter Michaelis.
10 Desidero et. al. "Chemotherapeutic and antiangiogenic drugs beyond tumor progression in colon cancer: Evaluation of the effects of switched schedules and related pharmacodynamics" Biochemical Pharmacology 2019, 164, 94-105. DOI: 10.1016/j.bcp.2019.04.001. Hereinafter Desidero.
11 Fiegle et. al. "Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer" Neoplasia 2019, 21, 9, 932-944. DOI: 10.1016/j.neo.2019.07.006. Hereinafter Fiegle.
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