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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 7, 2025 has been entered.
Claim Rejections - 35 USC § 103
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The 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 353, 355, 359-361, 363, and 365 are rejected under 35 U.S.C. 103 as being unpatentable over Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018).
Llado et al. teaches that PKCζ is a negative regulator of tumorigenesis in intestinal cancers and that PKCζ deficiency results in increased stem cell activity and increased tumorigenic and regenerative activity; see Summary.
Regarding PKCλ/ι, Nakanishi et al. teaches that PKCλ/ι is a negative regulator of intestinal inflammation and cancer. Inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, regarding claim 355, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn’s disease and Kaplan-Meier survival analysis of CRC patients revealed that low PRKCI levels, the gene which encodes for PKCλ/ι, are correlated with significantly worse patient survival; see Summary.
Neither Llado et al. nor Nakanishi et al. teach treating with a PD-L1 inhibitor.
Regarding the method of treating in claims 353 and 363, Zhou et al. teaches treating a subject having cancer, including colon cancer, or an autoimmune or inflammatory disease, including intestinal mucosal inflammation, wasting disease associated with colitis, Crohn's disease, and inflammatory bowel disease, by administering a human antibody targeting PD-L1; see claims 1, 9, 12, and 13.
Neither Llado et al., Nakanishi et al., nor Zhou teach treating serrated polyps or serrated adenocarcinoma.
Hagedorn et al. teaches that large, right-sided sessile serrated adenomas/polyps have a significant risk of developing into adenocarcinoma, and that such polyps probably account for 20-30% of colon cancers; see paragraph 0004. Hagedorn et al. teaches a method wherein the expression levels of genes are measured in a biological sample and compared to a control.
Given that Llado et al. and Nakanishi et al. teach that loss of PKCζ and PKCλ/ι is associated with increased tumorigenesis of intestinal tumors, Zhou et al. teaches treating colon cancer with a PD-L1 antibody, it would have been obvious to treat any colon cancer patients with a PD-L1 antibody, including those with serrated polyps, such as those taught by Hagedorn et al. Thus, since 20-30% of colon cancer patients have serrated polyps or serrated adenocarcinoma, then it would have been obvious to one of ordinary skill and one would have had a reasonable expectation of success to treat patients having serrated polyps or serrated adenocarcinoma with the anti-PD-L1 antibody.
Regarding claims 361 and 365, given that Llado et al. and Nakanishi et al. demonstrate that PKCζ and PKCλ/ι expression can be assessed by immunohistochemistry or RT-PCR of tissue samples and compared to healthy controls and that loss of PKCζ and PKCλ/ι is associated with increased tumorigenesis of intestinal tumors (see Llado et al. Figures 3F and G and Nakanishi et al. Figures 7A, B, and F), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to screen a tissue sample from a patient having, suspected of having, or at risk of developing an intestinal cancer, such as colon cancer, by IHC or RT-PCR for PKCζ and PKCλ/ι wherein a decreased level of PKCζ and PKCλ/ι compared to a healthy control or non-diseased individual is suggestive of tumorigenesis or a more aggressive malignancy.
Further, in cases of inflammatory bowel diseases, Nakanishi et al. teaches that patients having IBD are at risk of developing colon cancer; see page 2, last paragraph. Taken together, it would have been obvious to one of ordinary skill in the art and with a reasonable expectation of success to screen patients who have IBD and are at risk to develop colon cancer for expression of PKCζ and PKCλ/ι a decreased level of PKCζ and PKCλ/ι compared to a healthy control or non-diseased individual is suggestive of tumorigenesis and a more aggressive malignancy.
Given that Zhou teaches that a PD-1/PD-L1 inhibitor, specifically an anti-PD-L1 antibody, can be use to treat either colon cancer or IBD, it would have been obvious and one would have had a reasonable expectation of success in treating a subject identified as having colon cancer or having IBD and, therefore being at risk of developing colon cancer, to treat the subject with a PD-L1 inhibitor.
Moreover, Inaguma et al. teaches that PD-L1 positivity is associated with CRC arising via the serrated neoplasia pathway; see Abstract and page 284 left column. Additionally, Inaguma et al. teaches that PD-L1 immunohistochemistry is a potential biomarker for treatment response to PD-L1 or PD-1 immune checkpoint inhibitors; see page 284 left column. Furthermore, Jesudoss reports treating a patient having a sessile serrated polyp of the colon with pembrolizumab, an anti-PD-1 agent. Given the elevated expression of PD-L1 in serrated CRC and the teaching a subject matter expert treating a patient with serrated disease with an agent antagonizing the interaction between PD-L1 and PD-1, it would have been obvious and one would have had a reasonable expectation of success to treat serrated polyps of the intestine or serrated adenocarcinoma with a PD-L1 inhibitor.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 354, 362, and 364 are rejected under 35 U.S.C. 103 as being unpatentable over Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018)as applied to claims 353, 355, 359-361, 363, and 365 above, and further in view of Rosengren et al. (US 2018/0044419 A9; Published: Feb 15, 2018).
The teachings of Llado et al., Nakanishi et al., Zhou, Hagedorn et al., Inaguma et al., and Jesudoss as related to claims 353, 355, 359-361, 363, and 365, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach a method further comprising measuring the level of hyaluronan and treating with an inhibitor when the expression is elevated.
Regarding claim 354, Rosengren et al. teaches a method of treating cancer wherein the cancer is a solid tumor, including colon cancer, and is determined to have moderate to high or high hyaluronan content; see claims 1 and 7-9. Rosengren et al. teaches that hyaluronan content can be measured in body fluids, such as blood, urine, saliva and serum, and/or in the tumorous tissue or cell and the level can be compared to a standard or other suitable control, such as a comparable sample from a subject who does not have the HA-associated disease; see paragraph 0266. Regarding claim 362, suitable assays for assessing hyaluronan content include: immunohistochemistry, immunofluorescence, western blot, PCR, RT-PCR, or ELISA; see paragraphs 0724-0728.
Further, regarding claim 364, Rosengren et al. teaches that a hyaluronan-degrading enzyme, including recombinant or exogenous hyaluronidase said be administered in combination with an immune checkpoint inhibitor, such as an anti-PD-1 or anti-PD-L1 antibody; see claims 1, 4, and 21 and paragraph 0012.
Given that Rosengren et al. teaches that this method of treating cancer by measuring hyaluronan and administering hyaluronidase and an anti-PD-1 or anti-PD-L1 antibody when hyaluronan content is elevated is appropriate for the treatment of colon cancer, it would have been obvious to one of ordinary skill in the art to combine it with the teachings of of Llado et al., Nakanishi et al., Zhou, Hagedorn et al., Inaguma et al., and Jesudoss wherein hyaluronan is measured and a hyaluronan inhibitor is administered in addition to the PD-1/ PD-L1 inhibitor when hyaluronan level is elevated. Given the Rosengren et al. teaches the combination of hyaluronidase and an anti-PD-1 or anti-PD-L1 antibody for treating colon cancer, one of ordinary skill in the art would have had a reasonable expectation of success in adding the hyaluronan content assessment and hyaluronidase as taught be Rosengren et al. to the method of treating taught by Llado et al., Nakanishi et al., and Zhou.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 366-369 are rejected under 35 U.S.C. 103 as being unpatentable over Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018) as applied to claims 353, 355, 359-361, 363, and 365 above, and further in view of Holmgaard et al. (Journal for ImmunoTherapy of Cancer. 6:477; Published: Jun 4, 2018).
The teachings of Llado et al., Nakanishi et al., Zhou, Hagedorn et al., Inaguma et al., and Jesudoss as related to claims 353, 355, 359-361, 363, and 365, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach administering a TGF-β1 inhibitor in addition to the PD-L1 inhibitor.
Regarding claims 366-369, Holmgaard et al. teaches administering the TGF-β1 small molecule inhibitor, galunisertib, in combination with a PD-1/PD-L1 pathway inhibitor, specifically an anti-PD-L1 antibody, in a mouse model of colon cancer; see Abstract and In Vivo Studies. The combination of anti-PD-L1 and galunisertib therapy resulted in significant antitumor benefit compared to monotherapy with a marked enhancement of response (9/14 CRs) and all animals responding to treatment; see page 9, right column and Fig. 5. Further, Holmgaard et al. teaches that inhibiting immune suppression with galunisertib may accelerate the biological activity of anti-PD-L1; see page 11, left column.
Given that Llado et al., Nakanishi et al., and Zhou provide support for the treatment of colon cancer or IBD, which may develop into colon cancer, with decreased expression of PKCζ and PKCλ/ι with a PD-1/PD-L1 inhibitor and Holmgaard et al. teaches the antitumor benefit of combining the TGF-β1 small molecule inhibitor, galunisertib, with a PD-1/PD-L1 pathway inhibitor to treat colon cancer, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to combine the method taught by of Llado et al., Nakanishi et al., Zhou, Hagedorn et al., Inaguma et al., and Jesudoss with the addition of the TGF-β1 small molecule inhibitor, galunisertib, as supported by the favorable anti-tumor effect of the combination regimen taught by Holmgaard et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 370-373 are rejected under 35 U.S.C. 103 as being unpatentable over Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018) as applied to claims 353, 355, 359-361, 363, and 365 above, and further in view of Wang et al. (BMC Cancer. 12: 418; Published: Sept 21, 2012) and Le et al. (NEJM. 372: 2509-2520; Published: Jun 25, 2015).
The teachings of Llado et al., Nakanishi et al., Zhou, Hagedorn et al., Inaguma et al., and Jesudoss as related to claims 353, 355, 359-361, 363, and 365, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach determining an immunosuppressive environment in a biological sample by measuring CD8+ T cell infiltration or the presence of IL-17A-producing CD4+ T cells.
Regarding claim 370, Wang et al. teaches assessing the presence of Th17 cells and Treg cells, which are suggested to inhibit anti-tumor immune response, using flow cytometry in the circulation of colorectal adenoma (CRA) and colorectal carcinoma (CRC) patients and healthy controls and quantifying cytokine expression (IL-1β, IL-6, IL-17A, IL-21, IL-23 or TGF-β) by ELISA in sera and supernatants from both normal and tumor tissues cultured ex vivo; see Abstract and page 2, first sentence. Regarding claims 372 and 373, Wang et al. demonstrates that the percentage of CD4+ Th17 T cells (IL-17a expressing cells) was elevated in samples from patients with CRC compared to health controls; see Figure 1B and 1C. Additionally, Wang et al. teaches that IL-17a is elevated in the serum of CRC patients compared to healthy controls; see Figure 3C.
Wang et al. does not teach detecting CD8+ T cell infiltration into tumor tissue.
Regarding claim 371, Le et al. teaches measuring CD8+ T cell infiltration into tumor tissue by immunohistochemistry; see Supplementary Appendix page 8. Figure S6 shows a similar level of CD8+ T cells in MMR-deficient CRC tumors compared to normal tissue with the greatest concentration of CD8+ T cells along the invasive front and a decreased expression of CD8+ T cells in the tumor tissue of MMR-proficient CRC tumors compared to normal tissue; see Figure S6. Le et al. teaches that greater intratumoral CD8+ T cell density was significantly associated with a favorable objective response to anti-PD-1 antibody treatment; see Figure S8.
Given that the presence of an immunosuppressive tumor microenvironment is associated with the progression of colon cancer and the worsening response to anti-PD-1 antibody treatment in CRC, it would have been obvious to one of ordinary skill in the art to combine the teachings of assessing IL-17a producing CD4+ T cells and/or CD8+ T cell infiltration by Wang et al. and Le et al. with the method taught by of Llado et al., Nakanishi et al., Zhou, Hagedorn et al., Inaguma et al., and Jesudoss. The assays (flow cytometry and IHC) taught by Wang et al. and Le et al. for determining an immunosuppressive environment are common practice in the art and were conducted in the context of colorectal cancer, thus, one of ordinary skill would have had a reasonable expectation of success in conducting the assays and interpreting their clinical significance for a patient with CRC.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
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.
Claims 353-355, 359-365, and 374-376 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 11, 14, 20-23, 25, 27, 28, 32, 34, and 35 of copending Application No. 17/906,818 in view of Rosengren et al. (US 2018/0044419 A9; Published: Feb 15, 2018), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018).
Regarding instant claims 353, 354, 362, and 364, copending claims 1-5, 8, 11, 14, 22, 23, 25, 27, 28, 32, and 34 teach a method of treating a serrated tumor in a subject comprising administering an inhibitor of hyaluronan, optionally the small molecule PVHA, wherein subject has lower expression levels of PKCζ and PKCλ/ι compared to an individual without a serrated tumor. Regarding the subtype of disease, serrated tumors are a subtype of cancer. Regarding instant claim 365, copending claims 20, 21, and 35 teach that the sample can be blood, blood plasma, sera, or a tissue biopsy and that low levels of PKCζ and PKCλ/ι comprises low transcription, translation, or activity.
The copending claims do not teach a method which further comprises measuring hyaluronan content.
Regarding instant claim 354, Rosengren et al. teaches a method of treating cancer wherein the cancer is a solid tumor, including colon cancer, and is determined to have moderate to high or high hyaluronan content; see claims 1 and 7-9. Rosengren et al. teaches that hyaluronan content can be measured in body fluids, such as blood, urine, saliva and serum, and/or in the tumorous tissue or cell and the level can be compared to a standard or other suitable control, such as a comparable sample from a subject who does not have the HA-associated disease; see paragraph 0266. Regarding instant claims 362, suitable assays for assessing hyaluronan content include: immunohistochemistry, immunofluorescence, western blot, PCR, RT-PCR, or ELISA; see paragraphs 0724-0728.
Further, regarding instant claim 364, Rosengren et al. teaches that a hyaluronan-degrading enzyme, including recombinant or exogenous hyaluronidase said be administered in combination with an immune checkpoint inhibitor, such as an anti-PD-1 or anti-PD-L1 antibody; see claims 1, 4, and 21 and paragraph 0012.
The copending claims do not teach administering a PD-L1 inhibitor when the expression level of PKCζ and PKCλ/ι is low.
Regarding the use of a PD-L1 inhibitor in instant claims 353 and 363, Zhou et al. teaches treating a subject having cancer, including colon cancer, or an autoimmune or inflammatory disease, including intestinal mucosal inflammation, wasting disease associated with colitis, Crohn's disease, and inflammatory bowel disease, by administering a human antibody targeting PD-L1; see claims 1, 9, 12, and 13.
Neither of the methods taught by the copending claims nor Zhou teach measuring PKCζ and/or PKCλ/ι in colorectal cancer (CRC), specifically.
Llado et al. teaches that PKCζ is a negative regulator of tumorigenesis in intestinal cancers and that PKCζ deficiency results in increased stem cell activity and increased tumorigenic and regenerative activity; see Summary.
Regarding PKCλ/ι, Nakanishi et al. teaches that PKCλ/ι negative regulator of intestinal inflammation and cancer. Inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, regarding instant claim 355, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn’s disease and Kaplan-Meier survival analysis of CRC patients revealed that low PRKCI levels, the gene which encodes for PKCλ/ι, are correlated with significantly worse patient survival; see Summary.
While the copending claims teach a method of treating serrated tumors, they do not teach a method comprising determining the likelihood of a subtype of CRC characterized by serrated epithelial changes such as sessile serrated adenomas/polyps or serrated adenocarcinoma.
Hagedorn et al. teaches that large, right-sided sessile serrated adenomas/polyps have a significant risk of developing into adenocarcinoma, and that such polyps probably account for 20-30% of colon cancers; see paragraph 0004. Hagedorn et al. teaches a method wherein the expression levels of genes are measured in a biological sample and compared to a control. Hagedorn et al. teaches that the biological sample is obtained from a colorectal polyp and the method further comprises predicting the likelihood that the colorectal polyp will develop into colorectal cancer based on the relative difference between the expression level and the control value associated with each gene; see claims 1 and 3.
However, Hagedorn et al. does not provide support to assessing the risk of serrated colorectal cancer in patients with IBD.
Regarding instant claims 361 and 365, given that Llado et al. and Nakanishi et al. demonstrate that PKCζ and PKCλ/ι expression can be assessed by immunohistochemistry or RT-PCR of tissue samples and compared to healthy controls and that loss of PKCζ and PKCλ/ι is associated with increased tumorigenesis of intestinal tumors (see Llado et al. Figures 3F and G and Nakanishi et al. Figures 7A, B, and F), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to screen a tissue sample from a patient having, suspected of having, or at risk of developing an intestinal cancer, such as colon cancer, by IHC or RT-PCR for PKCζ and PKCλ/ι wherein a decreased level of PKCζ and PKCλ/ι compared to a healthy control or non-diseased individual is suggestive of tumorigenesis or a more aggressive malignancy.
Given that the copending claims teach treating a serrated tumor comprising administering a hyaluronan inhibitor when a subject has lower levels of PKCζ and PKCλ/ι compared to an individual without a serrated tumor, that Rosengren et al. teaches a similar method of treating cancer by measuring hyaluronan and administering hyaluronidase and an anti-PD-1 or anti-PD-L1 antibody when hyaluronan content is elevated is appropriate for the treatment of colon cancer, that Zhou teaches treating colon cancer or IBD with an anti-PD-L1 antibody, and that Llado et al. and Nakanishi et al. teach that loss of PKCζ and PKCλ/ι is associated with increased tumorigenesis of intestinal tumors, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to screen a patient having or suspected of having an intestinal cancer, such as colon cancer, for PKCζ and PKCλ/ι and to treat said patient with a PD-1/ PD-L1 inhibitor when the level of PKCζ and PKCλ/ι is decreased or suggestive of a more aggressive disease.
Moreover, Inaguma et al. teaches that PD-L1 positivity is associated with CRC arising via the serrated neoplasia pathway; see Abstract and page 284 left column. Additionally, Inaguma et al. teaches that PD-L1 immunohistochemistry is a potential biomarker for treatment response to PD-L1 or PD-1 immune checkpoint inhibitors; see page 284 left column. Furthermore, Jesudoss reports treating a patient having a sessile serrated polyp of the colon with pembrolizumab, an anti-PD-1 agent. Given the elevated expression of PD-L1 in serrated CRC and the teaching a subject matter expert treating a patient with serrated disease with an agent antagonizing the interaction between PD-L1 and PD-1, it would have been obvious and one would have had a reasonable expectation of success to treat serrated polyps of the intestine or serrated adenocarcinoma with a PD-L1 inhibitor.
Further, it would have been obvious to measure the level of hyaluronan and administer a hyaluronan inhibitor in addition to the PD-1/ PD-L1 inhibitor when hyaluronan level is elevated. Given that Rosengren et al. teaches the combination of hyaluronidase and an anti-PD-1 or anti-PD-L1 antibody for treating colon cancer, one of ordinary skill in the art would have had a reasonable expectation of success in adding the hyaluronan content assessment and a hyaluronan inhibitor as taught be Rosengren et al. to the method of treating taught by the claims of the copending application, in view of Zhou, Llado et al., and Nakanishi et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 366-369, 381, and 386 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 11, 14, 20-23, 25, 27, 28, 32, 34, and 35 of copending Application No. 17/906,818 in view of Rosengren et al. (US 2018/0044419 A9; Published: Feb 15, 2018), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018) as applied to claims 353-355, 359-365, and 374-376 above, and further in view of Holmgaard et al. (Journal for ImmunoTherapy of Cancer. 6:477; Published: Jun 4, 2018).
The teachings of the claims of copending Application No. 17/906,818 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss as related to claims 353-355, 359-365, and 374-376, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach administering a TGF-β1 inhibitor in addition to the PD-L1 inhibitor.
Regarding instant claims 366-369, Holmgaard et al. teaches administering the TGF-β1 small molecule inhibitor, galunisertib, in combination with a PD-1/PD-L1 pathway inhibitor, an anti-PD-L1 antibody, in a mouse model of colon cancer; see Abstract and In Vivo Studies. The combination of anti-PD-L1 and galunisertib therapy resulted in significant antitumor benefit compared to monotherapy with a marked enhancement of response (9/14 CRs) and all animals responding to treatment; see page 9, right column and Fig. 5. Further, Holmgaard et al. teaches that inhibiting immune suppression with galunisertib may accelerate the biological activity of anti-PD-L1; see page 11, left column.
Given that the claims of copending Application No. 17/906,818 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss provide support for the treatment of colon cancer or IBD, which may develop into colon cancer, with decreased expression of PKCζ and PKCλ/ι with a PD-1/PD-L1 inhibitor and Holmgaard et al. teaches the antitumor benefit of combining the TGF-β1 small molecule inhibitor, galunisertib, with a PD-1/PD-L1 pathway inhibitor to treat colon cancer, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to combine the method taught by the claims of copending Application No. 17/906,818 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss with the addition of the TGF-β1 small molecule inhibitor, galunisertib, as supported by the favorable anti-tumor effect of galunisertib and PD-1/PD-L1 pathway inhibitor in colon cancer as taught by Holmgaard et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 370-373 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 11, 14, 20-23, 25, 27, 28, 32, 34, and 35 of copending Application No. 17/906,818 in view of Rosengren et al. (US 2018/0044419 A9; Published: Feb 15, 2018), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018) as applied to claims 353-355, 359-365, and 374-376 above, and further in view of Wang et al. (BMC Cancer. 12: 418; Published: Sept 21, 2012) and Le et al. (NEJM. 372: 2509-2520; Published: Jun 25, 2015).
The teachings of the claims of copending Application No. 17/906,818 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss as related to claims 353-355, 359-365, and 374-376, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach determining an immunosuppressive environment in a biological sample by measuring CD8+ T cell infiltration or the presence of IL-17A-producing CD4+ T cells.
Regarding instant claim 370, Wang et al. teaches assessing the presence of Th17 cells and Treg cells, which are suggested to inhibit anti-tumor immune response, using flow cytometry in the circulation of colorectal adenoma (CRA) and colorectal carcinoma (CRC) patients and healthy controls and quantifying cytokine expression (IL-1β, IL-6, IL-17A, IL-21, IL-23 or TGF-β) by ELISA in sera and supernatants from both normal and tumor tissues cultured ex vivo; see Abstract and page 2, first sentence. Regarding instant claims 372 and 373, Wang et al. demonstrates that the percentage of CD4+ Th17 T cells (IL-17a expressing cells) was elevated in samples from patients with CRC compared to health controls; see Figure 1B and 1C. Additionally, Wang et al. teaches that IL-17a is elevated in the serum of CRC patients compared to healthy controls; see Figure 3C.
Wang et al. does not teach detecting CD8+ T cell infiltration into tumor tissue.
Regarding instant claim 371, Le et al. teaches measuring CD8+ T cell infiltration into tumor tissue by immunohistochemistry; see Supplementary Appendix page 8. Figure S6 shows a similar level of CD8+ T cells in MMR-deficient CRC tumors compared to normal tissue with the greatest concentration of CD8+ T cells along the invasive front and a decreased expression of CD8+ T cells in the tumor tissue of MMR-proficient CRC tumors compared to normal tissue; see Figure S6. Le et al. teaches that greater intratumoral CD8+ T cell density was significantly associated with a favorable objective response to anti-PD-1 antibody treatment; see Figure S8.
Given that the presence of an immunosuppressive tumor microenvironment is associated with the progression of colon cancer and the worsening response to anti-PD-1 antibody treatment in CRC, it would have been obvious to one of ordinary skill in the art to combine the teachings of assessing IL-17a producing CD4+ T cells and CD8+ T cell infiltration by Wang et al. and Le et al. with the method taught by the claims of copending Application No. 17/906,818 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss. The assays (flow cytometry and IHC) taught by Wang et al. and Le et al. for determining an immunosuppressive environment are common practice in the art and were conducted in the context of colorectal cancer, thus, one of ordinary skill would have had a reasonable expectation of success in conducting the assays and interpreting their clinical significance for a patient with CRC.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 353-355, 359-365, and 374-376 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 23, 24, 47, and 69 of copending Application No. 18/692,253 in view of Rosengren et al. (US 2018/0044419 A9; Published: Feb 15, 2018), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018).
Regarding instant claims 353, 354, 362, and 364, copending claims 1, 4-9, 23, 24, 47, and 69 teach a method of treating a subject having colorectal cancer or a subject suspected of having or having a subtype of colorectal cancer comprising administering an inhibitor of hyaluronan, optionally the small molecule PVHA, wherein subject has lower expression levels of PKCζ and PKCλ/ι compared to an individual without colorectal cancer or the subtype of colorectal cancer. The copending specification does not provide a definition for subtype, but of diagnosis the specification teaches that it refers to a classification of a particular subtype of cancer, e.g., by histopathological criteria or by molecular features; see page 30. In the absence of a limiting definition for subtype, serrated tumors are interpreted as a subtype of colorectal cancer. Regarding instant claim 365, copending claims 1, 9, 23, 24, and 69 teach assaying expression from a biological sample. The copending specification defines sample to include whole blood, blood plasma, sera, or tissue , including tumor tissue; see page 28.
Copending claim 8 teaches assays for measuring hyaluronan and the aPKCs, but do not teach all the assays of claim 362.
Regarding instant claim 354, Rosengren et al. teaches a method of treating cancer wherein the cancer is a solid tumor, including colon cancer, and is determined to have moderate to high or high hyaluronan content; see claims 1 and 7-9. Rosengren et al. teaches that hyaluronan content can be measured in body fluids, such as blood, urine, saliva and serum, and/or in the tumorous tissue or cell and the level can be compared to a standard or other suitable control, such as a comparable sample from a subject who does not have the HA-associated disease; see paragraph 0266. Regarding instant claims 362, suitable assays for assessing hyaluronan content include: immunohistochemistry, immunofluorescence, western blot, PCR, RT-PCR, or ELISA; see paragraphs 0724-0728.
Further, regarding instant claim 364, Rosengren et al. teaches that a hyaluronan-degrading enzyme, including recombinant or exogenous hyaluronidase said be administered in combination with an immune checkpoint inhibitor, such as an anti-PD-1 or anti-PD-L1 antibody; see claims 1, 4, and 21 and paragraph 0012.
The copending claims do not teach administering a PD-L1 inhibitor.
Regarding the use of a PD-L1 inhibitor in instant claims 353 and 363, Zhou et al. teaches treating a subject having cancer, including colon cancer, or an autoimmune or inflammatory disease, including intestinal mucosal inflammation, wasting disease associated with colitis, Crohn's disease, and inflammatory bowel disease, by administering a human antibody targeting PD-L1; see claims 1, 9, 12, and 13.
Neither of the methods taught by the copending claims nor Zhou teach PKCζ and/or PKCλ/ι having reduced expression in colorectal cancer (CRC), broadly.
Llado et al. teaches that PKCζ is a negative regulator of tumorigenesis in intestinal cancers and that PKCζ deficiency results in increased stem cell activity and increased tumorigenic and regenerative activity; see Summary.
Regarding PKCλ/ι, Nakanishi et al. teaches that PKCλ/ι negative regulator of intestinal inflammation and cancer. Inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, regarding instant claim 355, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn’s disease and Kaplan-Meier survival analysis of CRC patients revealed that low PRKCI levels, the gene which encodes for PKCλ/ι, are correlated with significantly worse patient survival; see Summary.
While the copending claims teach a method of treating a subtype of colorectal cancer, including serrated tumors, they do not teach a method comprising determining the likelihood of a subtype of CRC characterized by serrated epithelial changes such as sessile serrated adenomas/polyps or serrated adenocarcinoma.
Hagedorn et al. teaches that large, right-sided sessile serrated adenomas/polyps have a significant risk of developing into adenocarcinoma, and that such polyps probably account for 20-30% of colon cancers; see paragraph 0004. Hagedorn et al. teaches a method wherein the expression levels of genes are measured in a biological sample and compared to a control. Hagedorn et al. teaches that the biological sample is obtained from a colorectal polyp and the method further comprises predicting the likelihood that the colorectal polyp will develop into colorectal cancer based on the relative difference between the expression level and the control value associated with each gene; see claims 1 and 3.
However, Hagedorn et al. does not provide support to assessing the risk of serrated colorectal cancer in patients with IBD.
Regarding instant claims 361 and 365, given that Llado et al. and Nakanishi et al. demonstrate that PKCζ and PKCλ/ι expression can be assessed by immunohistochemistry or RT-PCR of tissue samples and compared to healthy controls and that loss of PKCζ and PKCλ/ι is associated with increased tumorigenesis of intestinal tumors (see Llado et al. Figures 3F and G and Nakanishi et al. Figures 7A, B, and F), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to screen a tissue sample from a patient having, suspected of having, or at risk of developing an intestinal cancer, such as colon cancer, by IHC or RT-PCR for PKCζ and PKCλ/ι wherein a decreased level of PKCζ and PKCλ/ι compared to a healthy control or non-diseased individual is suggestive of tumorigenesis or a more aggressive malignancy.
Given that the copending claims teach treating a serrated tumor comprising administering a hyaluronan inhibitor when a subject has lower levels of PKCζ and PKCλ/ι compared to an individual without a serrated tumor, that Rosengren et al. teaches a similar method of treating cancer by measuring hyaluronan and administering hyaluronidase and an anti-PD-1 or anti-PD-L1 antibody when hyaluronan content is elevated is appropriate for the treatment of colon cancer, that Zhou teaches treating colon cancer or IBD with an anti-PD-L1 antibody, and that Llado et al. and Nakanishi et al. teach that loss of PKCζ and PKCλ/ι is associated with increased tumorigenesis of intestinal tumors, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to screen a patient having or suspected of having an intestinal cancer, such as colon cancer, for PKCζ and PKCλ/ι and to treat said patient with a PD-1/ PD-L1 inhibitor when the level of PKCζ and PKCλ/ι is decreased or suggestive of a more aggressive disease.
Moreover, Inaguma et al. teaches that PD-L1 positivity is associated with CRC arising via the serrated neoplasia pathway; see Abstract and page 284 left column. Additionally, Inaguma et al. teaches that PD-L1 immunohistochemistry is a potential biomarker for treatment response to PD-L1 or PD-1 immune checkpoint inhibitors; see page 284 left column. Furthermore, Jesudoss reports treating a patient having a sessile serrated polyp of the colon with pembrolizumab, an anti-PD-1 agent. Given the elevated expression of PD-L1 in serrated CRC and the teaching a subject matter expert treating a patient with serrated disease with an agent antagonizing the interaction between PD-L1 and PD-1, it would have been obvious and one would have had a reasonable expectation of success to treat serrated polyps of the intestine or serrated adenocarcinoma with a PD-L1 inhibitor.
Further, it would have been obvious to measure the level of hyaluronan and administer a hyaluronan inhibitor in addition to the PD-1/ PD-L1 inhibitor when hyaluronan level is elevated. Given that Rosengren et al. teaches the combination of hyaluronidase and an anti-PD-1 or anti-PD-L1 antibody for treating colon cancer, one of ordinary skill in the art would have had a reasonable expectation of success in adding the hyaluronan content assessment and a hyaluronan inhibitor as taught be Rosengren et al. to the method of treating taught by the claims of the copending application, in view of Zhou, Llado et al., and Nakanishi et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 366-369, 381, and 386 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 23, 24, 47, and 69 of copending Application No. 18/692,253 in view of Rosengren et al. (US 2018/0044419 A9; Published: Feb 15, 2018), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018) as applied to claims 353-355, 359-365, and 374-376 above, and further in view of Holmgaard et al. (Journal for ImmunoTherapy of Cancer. 6:477; Published: Jun 4, 2018).
The teachings of the claims of copending Application No. 18/692,253 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss as related to claims 353-355, 359-365, and 374-376, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach administering a TGF-β1 inhibitor in addition to the PD-L1 inhibitor.
Regarding instant claims 366-369, Holmgaard et al. teaches administering the TGF-β1 small molecule inhibitor, galunisertib, in combination with a PD-1/PD-L1 pathway inhibitor, an anti-PD-L1 antibody, in a mouse model of colon cancer; see Abstract and In Vivo Studies. The combination of anti-PD-L1 and galunisertib therapy resulted in significant antitumor benefit compared to monotherapy with a marked enhancement of response (9/14 CRs) and all animals responding to treatment; see page 9, right column and Fig. 5. Further, Holmgaard et al. teaches that inhibiting immune suppression with galunisertib may accelerate the biological activity of anti-PD-L1; see page 11, left column.
Given that the claims of copending Application No. 18/692,253 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss provide support for the treatment of colon cancer or IBD, which may develop into colon cancer, with decreased expression of PKCζ and PKCλ/ι with a PD-1/PD-L1 inhibitor and Holmgaard et al. teaches the antitumor benefit of combining the TGF-β1 small molecule inhibitor, galunisertib, with a PD-1/PD-L1 pathway inhibitor to treat colon cancer, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to combine the method taught by the claims of copending Application No. 18/692,253 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss with the addition of the TGF-β1 small molecule inhibitor, galunisertib, as supported by the favorable anti-tumor effect of galunisertib and PD-1/PD-L1 pathway inhibitor in colon cancer as taught by Holmgaard et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 370-373 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 23, 24, 47, and 69 of copending Application No. 18/692,253 in view of Rosengren et al. (US 2018/0044419 A9; Published: Feb 15, 2018), Zhou (US 2017/0218066 A1; Published: Aug 3, 2017), Llado et al. (Cell Reports. 10(5): 740-754; Published: Feb 10, 2015), Nakanishi et al. (Cell Reports. 16(12): 3297-3310; Published: Sept 20, 2016), Hagedorn et al. (WO 2014/062845 A1; Published: Apr 24, 2014), Inaguma et al. (Modern Pathology. 30: 278-285; Published Online: November 4, 2016), and Jesudoss (American Journal of Gastroenterology, 113: p S836; Published: October 2018) as applied to claims 353-355, 359-365, and 374-376 above, and further in view of Wang et al. (BMC Cancer. 12: 418; Published: Sept 21, 2012) and Le et al. (NEJM. 372: 2509-2520; Published: Jun 25, 2015).
The teachings of the claims of copending Application No. 18/692,253 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., Inaguma et al., and Jesudoss as related to claims 353-355, 359-365, and 374-376, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach determining an immunosuppressive environment in a biological sample by measuring CD8+ T cell infiltration or the presence of IL-17A-producing CD4+ T cells.
Regarding instant claim 370, Wang et al. teaches assessing the presence of Th17 cells and Treg cells, which are suggested to inhibit anti-tumor immune response, using flow cytometry in the circulation of colorectal adenoma (CRA) and colorectal carcinoma (CRC) patients and healthy controls and quantifying cytokine expression (IL-1β, IL-6, IL-17A, IL-21, IL-23 or TGF-β) by ELISA in sera and supernatants from both normal and tumor tissues cultured ex vivo; see Abstract and page 2, first sentence. Regarding instant claims 372 and 373, Wang et al. demonstrates that the percentage of CD4+ Th17 T cells (IL-17a expressing cells) was elevated in samples from patients with CRC compared to health controls; see Figure 1B and 1C. Additionally, Wang et al. teaches that IL-17a is elevated in the serum of CRC patients compared to healthy controls; see Figure 3C.
Wang et al. does not teach detecting CD8+ T cell infiltration into tumor tissue.
Regarding instant claim 371, Le et al. teaches measuring CD8+ T cell infiltration into tumor tissue by immunohistochemistry; see Supplementary Appendix page 8. Figure S6 shows a similar level of CD8+ T cells in MMR-deficient CRC tumors compared to normal tissue with the greatest concentration of CD8+ T cells along the invasive front and a decreased expression of CD8+ T cells in the tumor tissue of MMR-proficient CRC tumors compared to normal tissue; see Figure S6. Le et al. teaches that greater intratumoral CD8+ T cell density was significantly associated with a favorable objective response to anti-PD-1 antibody treatment; see Figure S8.
Given that the presence of an immunosuppressive tumor microenvironment is associated with the progression of colon cancer and the worsening response to anti-PD-1 antibody treatment in CRC, it would have been obvious to one of ordinary skill in the art to combine the teachings of assessing IL-17a producing CD4+ T cells and CD8+ T cell infiltration by Wang et al. and Le et al. with the method taught by the claims of copending Application No. 18/692,253 in view of Rosengren et al., Zhou, Llado et al., Nakanishi et al., Hagedorn et al., and Inaguma et al., and Jesudoss. The assays (flow cytometry and IHC) taught by Wang et al. and Le et al. for determining an immunosuppressive environment are common practice in the art and were conducted in the context of colorectal cancer, thus, one of ordinary skill would have had a reasonable expectation of success in conducting the assays and interpreting their clinical significance for a patient with CRC.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s amendments filed October 7, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
Regarding the rejection under U.S.C. 103, Applicant argues that the art does not provide a connection between the expression of PKCζ and PKCλ/ι and serrated polyps in an intestine or serrated adenocarcinoma or the use of a PD-L1 inhibitor and, thus, there is no motivation to combine the references.
As stated previously, the claimed method does not require measuring PKCζ and PKCλ/ι in order to diagnose serrated polyps or serrated adenocarcinoma. The method does require treating one subject having a disease or condition characterized by serrated polyps or serrated adenocarcinoma, determining that a subject has reduced expression of PKCζ and PKCλ/ι by any type of biological sample, and administering a PD-L1 / PD-1 inhibitor. As above, given that Llado et al. and Nakanishi et al. teach decreased PKCζ and PKCλ/ι is associated with more tumorigenic colon cancer and Zhou teaches treating colon cancer with a PD-L1 antibody, it would have been obvious to one of ordinary skill in the art to treat colon cancer, including colon cancer having decreased PKCζ and PKCλ/ι, with a PD-L1 antibody.
Restated more directly, the claimed method does not require diagnosing the subject as having serrated polyps or serrated adenocarcinoma based on reduced expression of PKCζ and PKCλ/ι. Additionally, the step of determining in the claimed method does not guide treatment.
The rejection has been modified to provide stronger rationale for the treatment of serrated polyps or serrated adenocarcinoma with a PD-L1 inhibitor.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Ma et al. (Cell. 152(3): 599-611; Published: Jan 31, 2013) teaches that the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and low expression of PKCζ is associated with poor prognosis in patients. Zheng et al. (WO 2017/127282 A1; Published: Jul 27, 2017) teaches a method of selecting a treatment based on the expression of biomarkers in a sample, wherein patients with decreased expression are treated with a PD-1/PD-L1 inhibitor.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 7:30am - 5:00pm.
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, Janet Epps-Smith can be reached on (571)272-0757. 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.
/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682