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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/06/2026 has been entered.
Claim Status
No new amendments have been filed. Claims 2-13, 15-25, 27-28, 31-38, 41-15, 57-122, and 127-128 were previously cancelled. Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are pending in the instant application.
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 have an effective filing date of April 17, 2019, corresponding to PRO 62/835,488.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/06/2026 and 04/06/2026 are is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The information disclosure statements filed 04/06/2026 and 04/06/2026 fail to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein struckthrough, listed below, has not been considered.
LUNDQVIST et al. “31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (STIC 2016): part two” J Immunother Cancer (2016) 4 (Suppl 1): 82.
JP 2014522846 A.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 stand as rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) in view of non-patent literature by Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; previously cited on PTO-892; herein after referred to as "Li").
Response to Arguments - 35 USC § 103
Applicant's arguments filed 04/06/2026 (herein after referred to as “Remarks”) have been fully considered but they are not persuasive. With regard to the above-listed claim rejection under 35 U.S.C. 103 over Swanson and Li, Applicant argues the following on Pages 6-7 of Remarks:
Example 15 and Figures 14A and 14B of the instant specification, describing a dose ranging study of a variant ICOSL IgV-Fc molecule containing the N52H/N57Y/Q100R mutation, in a mouse model of GVHD. The activity of the ICOSL variant is compared to belatacept (CTLA-4-Fcl 104E/A29Y). The tested variant ICOSL IgV-Fc (N52H/N57Y/Q100R) at all dose levels tested significantly enhanced survival (FIG. 14A) and reduced disease scores (FIG. 14B) compared to mice treated with belatacept (i.e. 100% vs. 40% survival at Day 42, respectively; p<0.01 by Mantel-Cox log rank test). Notably, single dose (100μg) administration of variant ICOSL IgV-Fc (N52H/N57Y/Q100R) resulted in similar protection from disease as repeat dosing of 100μg belatacept.
Paragraphs [0490]-[0493] of the instant specification describe the observation that the variant ICOSL IgV-Fc (N52H/N57Y/Q100R) function as a dual antagonist, and thus exhibit superior control of ICOS+ T cells, which may escape ICOS or CD28 pathway blockade, such as with the CD28 pathway antagonist belatacept.
The combination of potent dual antagonist activity and superior activity of a single dose as compared to belatacept could not have been predicted in view of the teachings of Swanson or Li, alone or in combination. Thus, none of the references alone or in combination render the instant claims obvious.
With regard to the argument that the tested variant ICOSL IgV-Fc (N52H/N57Y/Q100R) at all dose levels tested significantly enhanced survival (FIG. 14A) and reduced disease scores (FIG. 14B) compared to mice treated with belatacept, it is specifically noted that Swanson exemplifies successfully treating GVHD in a mouse model and demonstrates that, for example, variant N52H/N57Y/Q100P (which meets the limitations of instant claim 1) had improved survival rates comparable to the clinical benchmark belatacept, and demonstrates variant N52H/N57Y/Q100P significantly increased survival and disease control compared to saline (see Example 17, Figures 7A-7D). Specifically, FIG. 7A shows survival curves of the treated animals. Aggressive disease course and subsequent mortality was observed in the saline control animals, with similar survival observed in the animals treated with wild-type ICOSL-Fc, as well as the N52H/I143T ICOSL variant, variant N52H/N57Y/Q100P had improved survival rates comparable to the clinical benchmark belatacept; FIG. 7B shows similar trends in body weight loss, with ICOSL variant N52H/N57Y/Q100P demonstrating similar weight maintenance as animals treated with belatacept, even though all other groups experienced rapid weight loss; FIG. 7C shows clinical scores from standardized GVHD Disease Activity Index (DAI) observations, again showing lower scores in animals treated with the ICOSL variant N52H/N57Y/Q100P that are comparable to the clinical benchmark belatacept while the other groups of animals experienced higher DAI scores; FIG. 7D depicts a flow cytometric measurement of CD4 and CD8 percentages in blood from experimental animals measured on day 14, the percentage of CD8 cells between experimental groups was largely the same, however, animals treated with ICOSL variant N52H/N57Y/Q100P and belatacept have lower percentages of CD4 cells compared to the other experimental groups (Paragraph 0066, emphasis added). Swanson successfully demonstrates treating GVHD in a mouse model and demonstrates ICOSL IgV-Fc (N52H/N57Y/Q100P) had improved survival rates comparable to the clinical benchmark belatacept; demonstrates ICOSL IgV-Fc (N52H/N57Y/Q100P) significantly increased survival compared to saline control; demonstrates ICOSL IgV-Fc (N52H/N57Y/Q100P) and belatacept had similar disease control; and demonstrates ICOSL IgV-Fc (N52H/N57Y/Q100P) showed significantly different levels of CD4+ T cells compared to saline treatment group (Figures 7A-D). Swanson concludes: “This study demonstrates the therapeutic effect of the variant ICOSL Fc variant protein on human primary T cells and GVHD during in vivo modeling” (Paragraph 0527). Therefore, Swanson provides both motivation and reasonable expectation of success to treat GVHD by administering the same claimed ICOSL IgV-Fc (N52H/N57Y/Q100P). Furthermore, with regard to the specific ICOSL variant comprising N52H/N57Y/Q100R mutations (corresponding to instant SEQ ID NO: 36 of claim 52), it is noted that Figures 4B and 5 of Swanson further indicate that similar effects to those of N52H/N57Y/Q100P would reasonably be expected. Figure 4B generally demonstrates via proliferation, the costimulatory capacity of wild-type (WT) or variant ICOSL when coimmobilized with anti-CD3, and more specifically shows the percent of total pan T-cell proliferation following 10 nM ICOSL costimulation (Paragraph 0063; see also Example 14). Figure 5 depicts ICOSL vIgD candidate function in a human Mixed-Lymphocyte-Reation (MLR); the majority of ICOSL variant candidates show superior antagonistic activity at all three concentrations tested compared to belatacept (both N52H/N57Y/Q100P and N52H/N57Y/Q100R both demonstrate superior antagonistic activity) as reflected by the lower concentration of IFN-gamma in those cultures (Paragraph 0064; see also Example 15). Thus, although Applicants argue successful and superior treatment results for ICOSL IgV-Fc (N52H/N57Y/Q100R) in the GVHD mouse model disclosed at Example 15, these results are expected and not surprising based on the successful and superior treatment results for ICOSL IgV-Fc (N52H/N57Y/Q100P) in the GVHD mouse model disclosed by Swanson and similar properties obtained for the N52H/N57Y/Q100R mutant. Swanson teaches and/or suggests administering the same claimed ICOSL IgV-Fc (N52H/N57Y/Q100P and/or N52H/N57Y/Q100R) to treat GVHD. Li is solely relied upon for the suggestion that ICOS/ICOS-L blockade might be an especially attractive target for downregulating T-cell responses in GVHD once it has been initiated, such as cases of aGVHD, including Grades II-IV, wherein said aGVHD is refractory to corticosteroids.
Additionally, although Applicants argue that they determined ICOSL IgV-Fc?? (N52H/N57Y/Q100R) functions as a dual antagonist and demonstrates such activity with superior control of ICOS+ T cells compared to belatacept, Swanson teaches administering the same claimed ICOSL IgV-Fc (N52H/N57Y/Q100R) to treat GVHD, therefore the ICOSL IgV-Fc (N52H/N57Y/Q100R) taught by Swanson inherently possesses the same claimed functions argued by Applicants. Although Applicants argue ICOSL IgV-Fc (N52H/N57Y/Q100R) has superior control of ICOS+ T cells compared to belatacept, instant Figure 14A demonstrates that a single 100 ug dose of ICOSL IgV-Fc (N52H/N57Y/Q100R) was slightly less effective than belatacept in increasing survival relative to saline control in methods of treating GVHD, and instant Figure 14B demonstrates that single dose ICOSL IgV-Fc (N52H/N57Y/Q100R) had a slightly higher mean DAI score than belatacept in methods of treating GVHD. Swanson also demonstrates belatacept had improved survival and similar DAI compared to ICOSL IgV-Fc (N52H/N57Y/Q100P). Therefore, the dual antagonist properties argued by Applicants as superior and unexpected do not translate to superior or unexpected methods of treating GVHD over what is taught and expected by the prior art.
Further in response to Applicant's argument that that the variant ICOSL IgV-Fc (N52H/N57Y/Q100R) function, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention."). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by Applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991) (Appellant argued that the presence of DEHP as the plasticizer in a blood collection bag unexpectedly suppressed hemolysis and therefore rebutted any prima facie showing of obviousness. However, the closest prior art utilizing a DEHP plasticized blood collection bag inherently achieved same result, although this fact was unknown in the prior art.). In the instant case Swanson exemplifies successfully treating GVHD in a mouse model and demonstrates that, for example, variant N52H/N57Y/Q100P (which meets the limitations of instant claim 1) had improved survival rates comparable to the clinical benchmark belatacept, and demonstrates variant N52H/N57Y/Q100P significantly increased survival and disease control compared to saline (see Example 17, Figures 7A-7D). Thus, Swanson provides both motivation and reasonable expectation of success to treat GVHD by administering the same claimed ICOSL IgV-Fc (N52H/N57Y/Q100P). Furthermore, with regard to the specific ICOSL variant comprising N52H/N57Y/Q100R mutations (corresponding to instant SEQ ID NO: 36 of claim 52), it is noted that Figures 4B and 5 of Swanson further indicate that similar effects to those of N52H/N57Y/Q100P would reasonably be expected. Swanson teaches and/or suggests administering the same claimed ICOSL IgV-Fc (N52H/N57Y/Q100P and/or N52H/N57Y/Q100R) to treat GVHD, and the results argued by Applicant would inherently be possessed by the instantly claimed ICOSL IgV-Fc variants, which are explicitly disclosed by Swanson.
As such, the above-listed claim rejection under 35 U.S.C. 103 over Swanson and Li is deemed proper and is maintained.
Double Patenting - Maintained
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 19-22, 25-26, and 29-30 of copending Application No. 18/172,258 (herein after referred to as “’258”) in view of WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) and Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; herein after referred to as "Li").
Claims 1, 7, 13-15, 18, 26, 29-30, 39-41, 51-56, and 123-128 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-9, 12-13, and 16-19 of copending Application No. 18/821,680 (herein after referred to as “’680”) in view of WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) and Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; herein after referred to as "Li").
Similarly, claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the U.S. Patents listed in the table below in view of WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) and Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; herein after referred to as "Li"):
Patent Number
Brief Description of the Invention
Pertinent Claims
10882914
Variant ICOSL Polypeptides and Fusion Proteins Thereof
1-8, 12-15, 17-27, 30-36, 39-45
11613566
Variant ICOSL-Fc Fusion Protein and Pharmaceutical Composition Thereof
1-4
12110339
Variant ICOSL Polypeptides, Fusion Proteins, Pharmaceutical Compositions, Methods of Modulating Immune Responses, and Methods of Treatment Thereof
1-3, 5-8, 10-21
Response to Arguments - Double Patenting
Applicant's arguments filed 04/06/2026 (herein after referred to as “Remarks”) have been fully considered but they are not persuasive. With regard to the above-listed claim rejections under nonstatutory double patenting over the above cited reference applications and reference patents in view of Swanson and Li, Applicant argues the following on Pages 7-8 of Remarks:
The ‘258 application in view of Swanson and Li could not have predicted the combination of potent dual antagonist activity and superior activity of a single dose of the claimed variants as compared to belatacept and argued in the 103 section above, and thus the cited references do not render the instant claims obvious.
The ‘680 application in view of Swanson and Li could not have predicted the combination of potent dual antagonist activity and superior activity of a single dose of the claimed variants as compared to belatacept and argued in the 103 section above, and thus the cited references do not render the instant claims obvious.
The reference patents in view of Swanson and Li could not have predicted the combination of potent dual antagonist activity and superior activity of a single dose of the claimed variants as compared to belatacept and argued in the 103 section above, and thus the cited references do not render the instant claims obvious.
The arguments as pertain to the teachings of Swanson and Li, as provided specifically above in the 103 section, have been thoroughly addressed and have been deemed not persuasive. As such, the addition of the claimed subject matter in the reference applications and reference patents, generally drawn to variant ICOSL fusion proteins (e.g., ICOSL-Fc fusion proteins), compositions thereof, and uses thereof only further supports obviousness.
As such, the above-listed claim rejections under nonstatutory double patenting are deemed proper and are maintained.
Conclusion
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are pending. Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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, Samira Jean-Louis can be reached at (571)270-3503. 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.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
Prosecution Insights