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 .
Status of the Claims
Currently, claims 1, 4-5, and 12 are pending in the instant application.
Claim Rejections - 35 USC § 103 - Maintained
Claim(s) 1, 4-5 and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bai (previously referenced) in view of Lu (previously referenced).
Rejections of claims 1, 4-5, and 12:
Applicant’s arguments are not persuasive, and the rejections are hereby maintained. Applicant traverses the outstanding rejections, asserting that a skilled artisan would not arrive at the instantly claimed method in view of Bai and Lu for at least the following reasons:
The STAT3 inhibitors taught by Lu are mechanically distinct from SD-36 which is a STAT3 degrader, and there would have been no motivation to combine the teachings of Bai and Lu (Remarks pages 3-4)
There would have been no reasonable expectation of success in using the STAT3 degraders taught in Bai for the treatment of GVHD because the teachings of Bai are directed towards the treatment of cancer (Remarks page 4)
The instant method provides non-obvious advantages over the prior art by demonstrating that SD-36 can be used safely in GVHD target organs
With regards to element (i), Applicant asserts that a skilled artisan would not be motivated to combine the teachings of Bai and Lu to utilize compound SD-36 for the treatment of GVHD. Applicant supports said assertion on the basis that Lu teaches the treatment of GVHD by administering STAT3 inhibitors rather than STAT3 degraders. It is not denied that STAT3 degraders and STAT3 inhibitors have differing mechanical functions, however, Applicant’s argument largely disregards the teachings of Lu as a whole. More specifically, Lu establishes the relationship between STAT3 signaling and T-cell proliferation in GVHD wherein STAT3 signaling causes downstream alloactivation and proliferation of T-cells in GVHD (page 5254)1. As discussed in previous Office actions, Lu teaches the use of STAT3 inhibitors to prevent phosphorylation of STAT3, thereby interfering with STAT3 receptor signaling and preventing T-cell proliferation. The teachings of Lu are useful not only for teaching the use of STAT3 inhibitors for the treatment of GVHD, but for teaching the underlying mechanics of STAT3 signaling in relation to GVHD. It would flow logically from this point to receive the teachings of Bai in view of Lu because Bai teaches the mechanics of STAT3 degraders (such as SD-36). Namely, that STAT3 degrader PROTACs are capable of targeting and eliminating STAT3. While the teachings of Bai are indeed targeted towards cancers, it remains that the mechanism by which these compounds treat cancer is by interfering with STAT3 signaling by degrading STAT3, and diminishing downstream effects (page 11280)2. A person of ordinary skill in the art would immediately recognize that the compounds of Bai would have utility in the method of Lu. Accordingly, and absent evidence of the contrary, a person of ordinary skill in the art would readily be able to combine the teachings of both Bai and Lu to develop a method wherein SD-36 may be used to treat GVHD.
With regards to element (ii), Applicant asserts that there would be no reasonable expectation of success in treating GVHD using STAT3 degraders because Bai teaches the use of such STAT3 degraders in the treatment of cancers, and is silent with regards to GVHD. While it is not contested that Bai is silent with regards to GVHD, such a conclusion discounts the value of the teachings of Lu. As discussed above, the teachings of Lu elucidate the relationship between STAT3 and T-cell activation in GVHD. While the mechanics of STAT3 degraders and STAT3 inhibitors may be distinct, a person of ordinary skill in the art would readily recognize that both would diminish STAT3 signaling and any downstream effects, including the activation and proliferation of T-cells in GVHD.
With regards to element (iii), Applicant asserts that the teachings of Bai and Lu provide no reasonable expectation that the use of STAT3 degraders would be able to ameliorate GVHD because: 1) a STAT3 degrader being able to treat leukemia and lymphoma via STAT3 degradation (such as in Bai) does not provide the expectation that such a STAT3 degrader will be able to treat all other STAT3 associated diseases, and 2) the instant method provides an non-obvious advantage in that it provides safety and efficacy metrics for the treatment of GVHD. In regards to element 1), Lu ameliorates the weakness of Bai by providing an etiological link between STAT3 signaling and GVHD. As discussed above, the combination of the teachings of both Bai and Lu provide a reasonable expectation in treating GVHD with a STAT3 degrader based on the mechanics of disease being treated as disclosed by Lu. In regards to element 2), Applicant contends that the teachings of Bai and Lu provide no reasonable expectation that a STAT3 degrader could be used to treat GVHD in a safe and efficacious manner. In support of the aforementioned argument, Applicant cites Example 3 of the specification wherein SD-36 is assessed for toxicity in vitro with mouse intestinal samples. While Bai does not explicitly test for toxicity in the GI tract, toxicity testing was carried out in supplementary material (Cancer Cell 36, 498-511 November 11, 2019, page 507) as indicated in the previous Office Action. Bai’s supplementary toxicity testing of compound SD-36 revealed that the compound was well tolerated in immune competent mice and provided no significant toxic effect in spleen, kidney, liver, and heart samples. Such testing provides a reasonable expectation that SD-36 would be capable of safe and effective administration in the treatment of GVHD. Applicant has not provided any evidence as to why there would be any expectation that SD-36 may be toxic to a subject having GVHD. Furthermore, Applicant’s arguments appear to be predicated on the indication that the sole GVHD target organ is the intestines, however, Applicant’s own specification in paragraph [0002] indicates multiple target organs, including skin, liver, and gut, which have overlap with the target organs indicated in Bai’s toxicity testing.
For the reasons as iterated above, the rejections of claims 1, 4-5, and 12 are hereby maintained. Reiterations of the outstanding rejections will be provided below for the purpose of clarity.
Reiterated rejections:
Claim 1 recites a method of treating or preventing GVHD in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of Formula I:
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Bai teaches compounds as inhibitors and PROTAC degraders of STAT3 protein, one of which is the following compound SD-36:
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Bai teaches that the above compound of SD-36 has >100 fold greater selectivity over other STAT proteins, inhibits cell growth in Molm-16 leukemia and SU-DHL-1 lymphoma cell lines, and is capable of complete degradation of STAT3 in mouse spleen and Molm-16 xenograft tumor tissue (page 11290)3. Additionally SD-36 anticipates a compound of Formula I wherein:
R1a is H
R1b is H
M is CF2
A is
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, which anticipates substructure A-4 of the instant claim
E is
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wherein XA is -N(R8)CH2- and R3g is H
And wherein R8 is -L-B
And wherein L is J1-Y1-J2-Y2-J3-Z
Wherein J1, J2 and J3 are absent, Y1 is C(=O), and Y2 is C5 alkyl
And wherein Z is -C≡C-
And wherein B is
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, anticipating recited substructure B-1
QA is
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, anticipating recited substructure Q-2, wherein R12a is H and R12b is aralkyl
While Bai teaches a compound that anticipates a compound of Formula I, they do not explicitly teach a method of use in treating GVHD. However, it would be obvious to one of ordinary skill in the art to be able to develop a method of treating GVHD by administration of Bai’s compound because Lu teaches that inhibition of STAT3 attenuate T-cell activation, proliferation, and GVHD.
Lu teaches the use of small molecule STAT3 inhibitors for the treatment of GVHD. More specifically, Lu teaches the administration of cucurbitacin E and cucurbitacin I to inhibit the phosphorylation of STAT3 protein. Lu found that administration of each form of cucurbitacin provided dose dependent inhibition of T cell proliferation in allogeneic mixed leukocyte reactions. Furthermore, treatment of donor B6 splenocytes with cucurbitacin I prior to infusion in BALB/c recipient animals was found by Lu to attenuate GVHD mortality, reduce weight loss, decrease GVHD morbidity, and reduce the amount of donor CD8 T cells (page 5257, Fig 2G-2K)4.
In summary, Bai teaches a compound which anticipates Formula I of claim 1 and further teaches its properties as a STAT3 degrader, but does not explicitly teach a method of use in treating GVHD. Lu teaches the use of STAT3 inhibiting compounds in treating GVHD. While the compound of Bai and the STAT3 inhibiting compounds of Lu have different mechanical interactions with STAT3, they both disable the function of STAT3. SD-36 disables STAT3 function by degradation of the protein itself, while cucurbitacin inhibits phosphorylation activation of STAT3. It would fully be within the capabilities of one of ordinary skill in the art to recognize that the impairment of STAT3 function suppresses immune response, and that there would be a reasonable expectation that such suppression, whether by degradation or inhibition, would ameliorate GVHD. It would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to be able to develop a method of treating or preventing GVHD by administration of Bai’s compound, given the teachings of Lu, as there would have been a reasonable expectation of success in ameliorating GVHD using such a method.
Claim 4 further limits the method of claim 1 wherein the subject is human.
The compounds of Bai are directed towards the treatment of human cancers and diseases. Bai additionally teaches that STAT3 is a therapeutic target for such human diseases (page 11280)5. Accordingly, claim 4 is rejected for the same obviousness reasons as claim 1.
Claim 5 further limits the method of claim 1 wherein the GVHD is acute GVHD, late acute GVHD, chronic GVHD, or late chronic GVHD.
Acute GVHD is commonly understood as GVHD which occurs within 100 days of transplantation. Testing carried out by Lu indicates that GVHD was induced in test animals within 100 days of b6 splenocyte transplantation. Accordingly, claim 5 is rejected for the same obviousness reasons as claim 1.
Claim 12 further limits the method of claim 1 wherein a second therapeutic agent is administered.
Lu teaches the use of compound SL327 to inhibit phosphoryl activation of ERK1/2 and found a dose dependent suppression of T cell proliferation in an in vitro model of GVHD. As Lu teaches that both ERK1/2 and STAT3 inhibition can attenuate T cell proliferation in GVHD, a combination of an ERK1/2 inhibitor and STAT3 inhibitor or degrader would be obvious to a person of ordinary skill in the art, as there would be a reasonable expectation of synergistic effect in attenuation of T cell proliferation and subsequent amelioration of GVHD.
Double Patenting – Maintained
Claims 1, 4-5, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 13, 14, 22-24, 26, 34, 36, 37, 39, 41, 44 of copending Application No. 17/442/666 in view of Bai (previously referenced) and Lu (previously referenced).
Provisional Double Patenting Rejections of claims 1, 4-5, and 12 over Application 17/442,666:
Applicant’s arguments are not persuasive. Applicant has traversed the outstanding provisional double patenting rejections of the claims and asserts that a person of ordinary skill in the art would have no reason to combine the teachings of Bai and Lu for at least the same reasons as articulated in the traversal of the 103 rejections iterated above. Namely, the alleged non-obvious combination of the teachings of Bai and Lu. Likewise, the rejections are maintained in view of Bai and Lu for the reasons as articulated above with regards to outstanding 103 rejections. The relevant double patenting rejections will be iterated below for the purposes of clarity and reference.
Reiterated Rejections:
Claims 1, 4-5, 9, 12-14, 16, 30, 34, 38-46, and 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-3, 5, 13, 14, 22-24, 26, 34, 36, 37, 39, 41, 44 of copending Application No. 17/442,666 (herein the ‘666 application) in view of Bai (Cancer Cell 36, 498–511, November 11, 2019) and Lu (BLOOD, 15 DECEMBER 2008 VOLUME 112, NUMBER 13).
Claim 1 of the instant application recites a method of preventing or treating GVHD by administration of a compound of Formula (I):
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Claim 1 of copending application 17/442,666 recites a compound of Formula I:
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Formula I of the instant application and Formula I of the ‘666 application appear to be materially identical. Where the ‘666 application claims the compound itself, the instant application seeks to claim a method of use of said compound in treating or preventing GVHD. While the ‘666 application does not recite a method of use in treating or preventing GVHD, such a method of use would have been obvious to a person of ordinary skill in the art per the teachings of Bai which indicate such compounds as being STAT3 degraders, and Lu who teaches the use of STAT3 inhibitors to treat GVHD.
Bai teaches compounds as inhibitors and PROTAC degraders of STAT3 protein, one of which is the following compound SD-36:
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Bai teaches that the above compound of SD-36 has >100 fold greater selectivity over other STAT proteins, inhibits cell growth in Molm-16 leukemia and SU-DHL-1 lymphoma cell lines, and is capable of complete degradation of STAT3 in mouse spleen and Molm-16 xenograft tumor tissue (page 11290)6. Compound SD-36 anticipates a compound of Formula I as recited in the instant application as well as the ‘666 application.
While Bai teaches a compound that anticipates a compound of Formula I, they do not explicitly teach a method of use in treating GVHD. However, it would be obvious to one of ordinary skill in the art to be able to develop a method of treating GVHD by administration of Bai’s compound because Lu teaches that inhibition of STAT3 attenuate T-cell activation, proliferation, and GVHD.
Lu teaches the use of small molecule STAT3 inhibitors for the treatment of GVHD. More specifically, Lu teaches the administration of cucurbitacin E and cucurbitacin I to inhibit the phosphorylation of STAT3 protein. Lu found that administration of each form of cucurbitacin provided dose dependent inhibition of T cell proliferation in allogeneic mixed leukocyte reactions. Furthermore, treatment of donor B6 splenocytes with cucurbitacin I prior to infusion in BALB/c recipient animals was found by Lu to attenuate GVHD mortality, reduce weight loss, decrease GVHD morbidity, and reduce the amount of donor CD8 T cells (page 5257, Fig 2G-2K)7.
In summary, Bai teaches a compound which anticipates Formula I of claim 1 of both applications and further teaches its properties as a STAT3 degrader, but does not explicitly teach a method of use in treating GVHD. Lu teaches the use of STAT3 inhibiting compounds in treating GVHD. While the compound of Bai and the STAT3 inhibiting compounds of Lu have different mechanical interactions with STAT3, they both disable the function of STAT3. SD-36 disables STAT3 function by degradation of the protein itself, while cucurbitacin inhibits phosphorylation activation of STAT3. Given the teachings of Bai and Lu, one of ordinary skill in the art would understand that the compound claimed by the ‘666 application and method of use of such a compound as claimed in the instant application are obvious variants of one another.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1, 4-5, and 12 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).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “We defined a signaling profile for alloactivated T cells in vivo and identified the phosphorylation of ERK1/2 and STAT-3 as important events during T-cell (allo)activation in GVHD. We establish that interference with STAT-3 phosphorylation can inhibit T-cell activation and proliferation in vitro and GVHD in vivo.”
2 “Persistent activation of STAT3 is often associated with poor prognosis of human cancers since activated STAT3 signaling not only provides advantages of growth, survival, and metastasis to tumor cells but also suppresses the antitumor immune response.”
3 “Our efforts have yielded a series of potent STAT3degraders, with SD-36 being the best. SD-36 induces degradation of STAT3 protein in cells and demonstrates>100-fold selectivity over other STAT proteins.SD-36 potently inhibits cell growth in the Molm-16leukemia and SU-DHL-1 lymphoma cell lines. A single dose of SD-36 is capable of achieving complete degradation ofSTAT3 in native mouse spleen tissue and in the Molm-16xenograft tumor tissue with the degradation effect persisting for >2−3 days. SD-36 is capable of achieving complete and persistent tumor regression in the Molm-16 xenograft model in mice at well tolerated dose-schedules.”
4 “We preincubated B6 splenocytes with cucurbitacin E or DMSO for 1 hour, washed and infused them into BALB/c recipients. Recipient spleens were analyzed at 24 hours for donor T-cell activation. Donor CD4 and CD8 T cells that had been pretreated with cucurbitacin E displayed reduced levels of the activation marker CD25 (Figure 2E), and donor CD4 T cells also showed attenuated levels of CD69 expression, another early marker of activation (Figure 2F). T cells were not significantly apoptotic (not shown). Similar results were obtained with cucurbitacin I (not shown). Finally, we tested the importance of STAT-3 phosphorylation in GVHD. Donor B6 splenocytes were incubated for 1 hour with cucurbitacin I or DMSO, then washed and infused into irradiated BALB/c recipients with B6 TCD-BM. Recipients of cucurbitacin I– treated splenocytes had attenuated GVHD mortality (Figure 2G), less weight loss and GVHD morbidity on day 6 (Figure 2H,I), as well as decreased splenic cellularity and fewer donor CD8 T cells (Figure 2J)”
5 “Persistent activation of STAT3 is often associated with poor prognosis of human cancers since activated STAT3 signaling not only provides advantages of growth, survival, and metastasis to tumor cells but also suppresses the antitumor immune response.2,3STAT3 is an attractive therapeutic target for human cancer and other human diseases.”
6 “Our efforts have yielded a series of potent STAT3degraders, with SD-36 being the best. SD-36 induces degradation of STAT3 protein in cells and demonstrates>100-fold selectivity over other STAT proteins.SD-36 potently inhibits cell growth in the Molm-16leukemia and SU-DHL-1 lymphoma cell lines. A single dose of SD-36 is capable of achieving complete degradation ofSTAT3 in native mouse spleen tissue and in the Molm-16xenograft tumor tissue with the degradation effect persisting for >2−3 days. SD-36 is capable of achieving complete and persistent tumor regression in the Molm-16 xenograft model in mice at well tolerated dose-schedules.”
7 “We preincubated B6 splenocytes with cucurbitacin E or DMSO for 1 hour, washed and infused them into BALB/c recipients. Recipient spleens were analyzed at 24 hours for donor T-cell activation. Donor CD4 and CD8 T cells that had been pretreated with cucurbitacin E displayed reduced levels of the activation marker CD25 (Figure 2E), and donor CD4 T cells also showed attenuated levels of CD69 expression, another early marker of activation (Figure 2F). T cells were not significantly apoptotic (not shown). Similar results were obtained with cucurbitacin I (not shown). Finally, we tested the importance of STAT-3 phosphorylation in GVHD. Donor B6 splenocytes were incubated for 1 hour with cucurbitacin I or DMSO, then washed and infused into irradiated BALB/c recipients with B6 TCD-BM. Recipients of cucurbitacin I– treated splenocytes had attenuated GVHD mortality (Figure 2G), less weight loss and GVHD morbidity on day 6 (Figure 2H,I), as well as decreased splenic cellularity and fewer donor CD8 T cells (Figure 2J)”