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 Claims
Applicant’s amendment filed on 11/04/2025 is acknowledged. Following the amendment, claim 153 is cancelled. Claims 152, 154, and 156 are amended. Claims 152, 154-160, and 162-171 are currently pending and under examination.
Claim Rejections - 35 USC § 103
Applicant’s arguments that cited references do not teach or suggest the features of the amended claims nor would they guide a person of skill in the art to the methods of the amended claims with any reasonable expectation of success, see pgs. 6-7, filed 11/04/2025, with respect to the rejection of claims 152-171 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Applicant’s amendment and newly found prior art reference.
Claims 152, 154-160, and 162-171 are rejected as being unpatentable over Freeman et al. (WO2016094273, cited on pg. 1 of IDS filed 09/23/2021) in view of Derosa et al. (Annals of Oncology, 2018, 29(6):1437-1444).
As described in the previous office action dated 08/05/2025, Freeman teaches the co-administration of an anti-RGMB monoclonal antibody together with an anti-PD-1 or anti-PD-L1 agent to increase efficacy of cancer therapy in colorectal cancer (CRC) subjects where anti PD-1 therapy alone was insufficient (lines 30-33, pg. 7; lines 27-31, pg. 121). Freeman discloses that many microsatellite-stable CRC patients are poor responders to antibody blockade of the PD-1 pathway and demonstrate that the combination of anti-PD-1/anti-PD-L1 antibody with anti-RGMb antibody administration produces markedly superior tumor regression and long-term survival in murine models compared with anti-PD-1 monotherapy alone. Freeman further teaches that the combination therapy is expected to enhance survival “especially [in] those poor responders to immunotherapy targeting the PD-1 pathway” (lines 30-31, pg. 121). Therefore, Freeman accounts for (i) the non-responder patient population, (ii) the use of anti-RGMb plus PD-1/PD-L1 blockade, and (iii) the resulting conversion of poor responders into responders.
While Freeman teaches the efficacy of combination anti PD-1/PD-L1 and anti-RGMb antibody therapy for poor responders, Freeman does not directly teach the dysbiosis related limitations of amended claim 152.
Derosa (cited above) addresses these deficiencies. Derosa examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-PD-L1 monotherapy or combination therapy (Patients and Methods). In addition, Derosa studied patients receiving antibiotic therapy within 30 days of beginning anti-PD-L1 therapy compared with those who did not (Patients and Methods). Derosa teaches that antibiotic therapy compared with no antibiotic therapy was associated with increased risk of primary progressive disease and shorter overall survival in NSLC and RCC patients and that in multivariate analyses, the impact of antibiotic therapy remained significant for lower progression-free survival and overall survival in NSLC (Results). They suggest that modulation of antibiotic related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with anti-PD-L1 therapy (Conclusion).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of anti-PD-1/PD-L2 antibody treatment with anti-RGMb antibody as taught by Freeman to address the problem of checkpoint-blockade failure in patients rendered dysbiotic by antibiotic therapy as taught by Derosa. One would be motivated to do so, because Freeman’s animal data demonstrates that anti-RGMb antibody combination is effective even when anti-PD-1 antibody treatment alone is inadequate. There would have been a reasonable expectation of success that the same combination regimen would convert the antibiotic-exposed, non-responders of anti-PD-L1 therapy of Derosa into responders. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant’s argument that the working examples show unexpected results of the pending claims have been fully considered but they are not persuasive. Figure 2 of the instant application confirms a known observation that broad-spectrum antibiotics blunt the efficacy of anti-PD-L1 therapy without actually testing the claimed solution of combining an anti-RGMb antibody. In addition, while Figures 8 and 9 do add anti-RGMb, these results merely confirm what a person of ordinary skill would have reasonably expected from the combined teachings of the prior art as discussed above. Derosa identifies patients rendered non-responsive to anti-PD-L1 antibody therapy by antibiotic exposure. Freeman teaches that adding anti-RGMb antibody converts “poor responders” to responders in conventional mice and expressly proposes this combination for clinical poor responders. Therefore, since the prior art already points to using anti-RGMb to rescue anti-PD-1 checkpoint non responders, demonstration of that rescue in an antibiotic setting does not rise to an unexpected result. Furthermore, Applicant claims encompass multiple solid-tumor types, a variety of dysbiosis inducing conditions, and a three-month antibiotic window. However, Applicant’s data is limited to a single murine colon-cancer line under laboratory conditions with no time-based antibiotic parameter. Such narrowly drawn experiments cannot negate the obviousness for claims of far broader therapeutic scope. Therefore, the results as presented are not commensurate in scope and fail to demonstrate a non-obvious advantage over the prior art.
Double Patenting
1. Applicant’s arguments, see pgs. 9-11, filed 11/04/2025, with respect to the provisional rejection of claims 152-160, and 162-171 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/702,439 (‘439) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Applicant’s amendment to claims filed on 11/04/2025.
Claims 152, 154-160, and 162-171 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/702,439 (‘439) in view of Freeman et al. (cited above). While the claims of application ‘439 recite a method of using anti-PD-L2 antibody therapy with anti-PD-1/PD-L1 antibodies to convert non- responders to responders for cancer therapy, application ‘439 claims are silent in regards to direct use of anti-RGMb antibodies with anti-PD-1/PD-L1 antibodies for conversion of non-responders to responders as recited in the instant application claims. Freeman addresses these limitations. As discussed previously, Freeman teaches a method of selectively inhibiting or blocking the expression of RGMb and PD-1 with antibodies thereby upregulating immune response to treat conditions such as infections and colorectal cancer that would benefit from upregulating the immune response (Summary, lines 1-5). Although the claims at issue are not identical, they are not patentably distinct from each other because as disclosed in the specification of the instant application, RGMb interacts with PD-L2 and disrupting the PD-L2/RGMb interaction enhances the efficacy of PD-1 or PD-L1 blockade (Summary, pg. 1). Therefore, it would have been obvious to the person of ordinary skill in the art to substitute the PD- L2 antibodies disclosed in application ‘439 with anti-RGMb antibodies as taught by Freeman to treat anti-PD-1/anti-PD-L1 non-responders and better improve immunotherapy in cancer patients. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
2. Applicant’s arguments, see pgs. 9-11, filed 11/04/2025, with respect to the provisional rejection of claims 152-160, and 162-171 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 10, 14, 15, 20, 22, 27, 31, 39, 41, 43, 45, 128- 129, 132, 135, 138, 142, 146, 151, 156, and 158 of co-pending Application No. 18/026,746 (‘746) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Applicant’s amendment to claims filed on 11/04/2025.
Claims 152, 154-160, and 162-171 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 10, 14, 15, 20, 22, 27, 31, 39, 41, 43, 45, 128- 129, 132, 135, 138, 142, 146, 151, 156, and 158 of copending Application No. 18/026,746 (‘746) in view of Derosa et al. (cited above).
Claims 1-3, 10, 14, 15, 20, 22, 27, 31, 39, 41, 43, 45, 128-129, 132, 135, 138, 142, 146, 151, 156, and 158 of application ‘746 are directed to a method of treating cancer that has failed a prior anti-PD1/PD-L1 therapy and involves administering a first agent that blocks PD-L2, RGMb, or a combination thereof, and a second agent that blocks PD-L1, PD-1, or a combination thereof. Although the claims at issue are not identical, they are not patentably distinct from each other because they both recite the use of combined anti-PD1/anti RGMb therapy in subjects that are non-responders to traditional anti-PD1 therapy alone.
While application ‘746 teaches the efficacy of combination anti PD-1/PD-L1 and anti-RGMb antibody therapy for poor responders, application ‘439 does not directly teach the dysbiosis related limitations of amended claim 152. As discussed previously, Derosa addresses these limitations.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of anti-PD-1/PD-L2 antibody treatment with anti-RGMb antibody as taught by application ‘439 to address the problem of checkpoint-blockade failure in patients rendered dysiotic antibiotic therapy as taught by Derosa. One would be motivated to do so, because application ‘746 data demonstrates that anti-RGMb antibody combination is effective even when anti-PD-1 antibody treatment alone is inadequate. There would have been a reasonable expectation of success that the same combination regimen would convert the antibiotic-exposed, non-responders of anti-PD-1 therapy of Derosa into responders. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowable.
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/DENNIS GEORGE/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645