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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/06/2026 has been entered.
Priority
This application is a U.S. national phase of International Application No. PCT/JP2020/039802, filed on 10/23/2020. This application claims priority to Japan patent Application No. JP2019-194717, filed 10/25/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The Amendment, filed on 02/06/2026, is acknowledged in which:
Claims 3, 14-17, 19-20, 22-23, and 39-44 are canceled.
Claims 1, 4-10, 12-13, 18, 21, 24-26, 29-35, 37-38, 45, and 48-55 were previously presented.
Claims 2, 27, and 36 are original.
Claims 57-59 are new.
Claims 1-2, 4-13, 18, 21, 24-27, 29-38, 45, and 48-59 are pending in the instant application and are examined on the merits herein.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 4-13, 18, 21, 24-27, 29-38, 45, 48-59 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/051888 A1 (herein Satoh; EN equivalent CA 2999819 A1 used for examination reference) in view of NCT03821935 (herein AbbVie; first posted 01/30/2019 with study start date 02/21/2019) and The Antibody Society (TAbS).
Regarding claims 1-2, 4-13, 18, 21, 24-27, 29-38, 45, 48-
Satoh teaches GARP is expressed on the surface of activated Tregs and has been demonstrated a necessary for TGFβ maturation and subsequent immunosuppressive activity (¶ [0002]). Satoh teaches an antibodies with specific binding to GARP (Figures 10-13) with CDRs and VH/VL sequences identical to those recited in the instant claims (see table below).
SEQ ID NO: (100% identity)
Instant
Satoh
Satoh description:
13
25
c151D heavy chain
15
27
c151D light chain
17
29
c198D heavy chain
19
31
c198D light chain
21
33
h151D-H1 heavy chain
23
35
h151D-H4 heavy chain
25
37
h151D-L1 light chain
27
39
h151D-L4 light chain
29
41
h198D-H3 heavy chain
31
43
h198D-L4 light chain
Satoh further teaches said GARP targeting antibody has inhibitory activity to immunosuppressive function of regulatory T cells (Tregs), ADCC activity, and antitumor activity in vivo (i.e. effective for cancer treatment) (claim 1; Figures 37-45). Satoh discloses that a pharmaceutical composition comprising the anti-GARP antibody may be administered in combination with at least one cancer therapeutic agent including, but not limited to immunomodulators (as defined by instant disclosure ¶ [0107]), carboplatin, cisplatin, gemcitabine, paclitaxel, sorafenib (¶ [0159]). Satoh further teaches antibody modifications identical to the instant claims (claims 28-31).
Satoh does not explicitly teach a composition of anti-GARP mediated TGFβ signaling inhibition with an immunomodulator selected from nivolumab, pembrolizumab, lambrolizumab, MK-3475, AMP-224, pidilizumab, LOPD18, atezolizumab, durvalumab, avelumab, ipilimumab or tremelimumab, or a combination thereof (i.e. PD-1, PD-L1, or CTLA-4 targeting molecules).
AbbVie teaches a treatment for advanced solid tumor cancer (e.g. subjects with triple-negative breast cancer (TNBC), pancreatic adenocarcinoma, urothelial cancer, hepatocellular carcinoma (HCC), or head and neck squamous cell carcinoma (HNSCC)) using livmoniplimab (an anti-GARP antibody) in combination with budigalimab (an anti-PD-1 antibody) (Study plan; Cohorts 2-12).
TAbS teaches PD-1 antibodies approved for cancer treatment at the time of filing to include species recited in the instant claim: nivolumab and pembrolizumab.
It would be generally understood by a skilled artisan that antibodies targeting the same antigen would reasonably function the same in inhibiting the target (i.e. art recognized suitability for an intended purpose) (See MPEP 2144.07). Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to combine an anti-GARP antibody as taught by Satoh with a PD-1 antibody as anti-GARP and anti-PD1 combination therapies were being tested in a clinical setting for the treatment of cancer as taught by AbbVie, implying a reasonable expectation of clinical benefit in dual targeting (See MPEP 2143(I)(G)). Furthermore, it would be obvious to use a PD-1 antibody known effective in a clinical setting (e.g. nivolumab and pembrolizumab) as taught by TAbS (i.e. choosing from a finite number of identified, predictable solutions with a reasonable expectation of success; see MPEP 2143(I)(E)).
Regarding claims 50-51, the combined teachings of Satoh, AbbVie, and TAbS teach claim 1 as discussed above.
However, while the combined teaching obviate a composition and method for cancer treatment using anti-GARP and an ICI antibody selected from the group consisting of species listed, none of the aforementioned reference disclose their use in a kit.
A person having ordinary skill in the art would recognize that antibodies can inherently be used in kits for binding to specific protein epitopes for detection, and that the kit itself as claimed (e.g. written instructions) does not structurally provide more to the instant invention (See MPEP 2112.01(III)). Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the composition as taught by the combined teachings of Satoh, AbbVie, and TAbS can be used within a kit.
Regarding claims 57 and 59, the combined teachings of Satoh, AbbVie, and TAbS teach claims 1 and 26 as discussed above.
Satoh further teaches that L428 cells endogenously expressing GARP were targeted by anti-GARP antibody (105F), resulting in increased antibody-dependent cellular cytotoxicity (ADCC) in an antibody dose-dependent manner (Figure 14). Satoh further teaches antibodies h151D-H1L1, h151D-H4L4 and h198D-H3L4 bound to CD4-positive FoxP3-positive cells (¶ [0242]; Figure 40).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to that the GARP antibody as taught by Satoh in monotherapy and in combination therapies would therefore also be suitable and likely to decrease any population of GARP-positive cells (e.g. CD4-positive, FoxP3-positive T cells) when in combination with PBMCs or isolated cytotoxic T cells, NK cells, or other cell types capable of ADCC (In re Soli, 317 F.2d 941, 137 USPQ 797 (CCPA 1963) and Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945); See MPEP 2144.02 and 2144.07).
Claims 56 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Satoh, AbbVie, and TAbS as applied to claim 1 and 26 above, and further in view of Xiao (Cancer Res. 2020;80(14):3023-3032).
The combined teachings of Satoh, AbbVie, and TAbS teach claims 1 and 26 as discussed above. Satoh further teaches that anti-GARP antibodies increase the cytotoxic potential of CTL cells (CD8+ cells; ¶ [0245]), indicating positive effects to T-cell activation otherwise inhibited by suppressive activity of Tregs (Figures 43 and 44).
However, none of the aforementioned references explicitly discusses changes to ICOS expressing cells.
Xiao teaches ICOS is upregulated on activated CD8 T cells in vitro (Figure 1). Xiao also teaches frequency of ICOS+ CD8+ T cells from tumor draining lymph node (TDLN) samples (in vivo cancer model) are significantly higher with PD-1 blockade compared with negative controls (Figure 2C).
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that a combination therapy as taught by the combined teachings of Satoh, AbbVie, and TAbS that activates CD8 T cells (e.g. a GARP antibody as taught by Satoh) and/or blocks PD-1 signaling (e.g. a suitable PD-1 or PD-L1 antibody as taught by TAbs) would have a reasonable expectation of increasing the ratio of ICOS+ CD8+ T cells as recited in the instant claim (In re Soli, 317 F.2d 941, 137 USPQ 797 (CCPA 1963); See MPEP 2144.02).
Response to Arguments
Applicant’s arguments with respect to claims 1-2, 4-13, 18, 21, 24-27, 29-38, 45, 48-49, and 52-55 have been considered, but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant's arguments filed 02/06/2026, in so far as the apply to the rejections discussed above, have been fully considered, but they are not persuasive.
Applicant states:
“The present application demonstrates the claimed combination of an anti-GARP antibody
and immunomodulator provides unexpected technical benefits, and MPEP § 716.02(a) instructs, "Evidence of unobvious or unexpected advantageous properties, such as superiority in a property the claimed compound shares with the prior art, can rebut prima facie obviousness .. "” (Remarks, pg 15, ¶ 1)
“…these results [Examples 1, 3, and 4] demonstrate that the combination therapy reduces T effector cell proliferation and reduces of tumor volume. Neither of these effects are taught or suggested by any of the cited prior art documents alone, or in combination.” (Remarks, pg 15, ¶ 2)
In response to applicant’s argument regarding the superiority in combination therapies (e.g. against GARP or PD-1 as taught by AbbVie) in comparison to individual therapies, evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978).
The office maintains "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). In this case, prior art teaches combination immunotherapy against GARP and PD-1 and imply a clinical benefit over monotherapies. Regarding the data disclosed within the instant application (Examples 1, 3, and 4), the combination of GARP and PD-1 targeted therapies resulted in a modest additive effect rather than a synergist effect (Figures 12 and 13). (i.e. demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e. synergism) would be evidence of nonobviousness. Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
Applicants must show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (i.e. AbbVie implicitly teaches a general expectation of an additive effect in combination immunotherapies targeting GARP and PD-1). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023) ("A difference of degree is not as persuasive as a difference in kind – i.e., if the combination produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.").
Conclusion
No claims are currently allowed.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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