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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/26/2025 has been entered.
Status of the Claims
Claims 235 – 249 were pending. Claim 250 has been newly added. No claim has been amended or canceled. Claims 235 – 250 are currently pending and are the subject of this Office Action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/26/2025 is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Previous rejection, witdrawn: claims 235 – 238 and 246 – 249 were rejected under 35 U.S.C. 103 as being unpatentable over UNDERWOOD (WO 2015/184099 A1, published 12/03/2015; see PTO-892: Notice of References Cited of 11/19/2024) in view of LUBRANO DI RICCO (Lubrano di Ricco, M. et al. “Tumor Necrosis Factor Receptor Family Costimulation Increases Regulatory T‐cell Activation and Function via NF‐κB.” European Journal of Immunology 50.7 (2020): 972–985; see PTO-892 of 11/19/2024).
After further consideration, this rejection is withdrawn.
Previous rejection, withdrawn:: claim 239 is rejected under 35 U.S.C. 103 as being unpatentable over UNDERWOOD in view of LUBRANO DI RICCO as applied to claims 235 – 238 and 246 – 250 and further in view of FAUSTMAN (WO 2020/102739 A1, published 05/22/2020; see PTO-892 of 11/19/2024).
After further consideration, this rejection is withdrawn.
New rejection: claims 235 – 250 are rejected under 35 U.S.C. 103 as being unpatentable over UNDERWOOD in view of FAUSTMAN and SILVA (Silva JP, et al. The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation. J Biol Chem. 2015 Feb 27;290(9):5462-9; see PTO-892 submitted with this Office Action).
The present application is directed to a modified antibody or antigen-binding fragment thereof that specifically binds tumor necrosis factor receptor 2 (TNFR2), wherein the modified antibody or antigen-binding fragment thereof comprises a heavy chain variable region, a light chain variable region, and a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P, and wherein the amino acid position is numbered according to the EU index.
UNDERWOOD is directed to antibodies that specifically bind to human glucocorticoid-induced TNFR family related receptor (GITR, which, like TNFR2, is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and compositions comprising such antibodies and to methods for treating disorders, such as cancer and infectious diseases, by administering an antibody that specifically binds to human GITR and modulates GITR activity. See abstract. According to UNDERWOOD, treating animals with GITR-Fc fusion protein ameliorates autoimmune/inflammatory diseases while GITR triggering is effective in treating viral, bacterial, and parasitic infections, as well in boosting immune response against tumors, which is due to several concurrent mechanisms including: co-activation of effector T-cells, inhibition of regulatory T (Treg) cells. See paragraph [0003]. UNDERWOOD further teaches that the antibody is an IgG4 which comprises a S228P mutation (see p. 17, paragraph 0020).
FAUSTMAN is directed to agonistic TNFR2 polypeptides, such as antibodies and antigen-binding fragments thereof, and the use of these polypeptides to stimulate the proliferation of regulatory T cells (Treg cells) and/or myeloid-derived suppressor cells (MDSCs), as well as to inhibit the function of, reduce the proliferation of, and/or directly kill, T effector cells, such as CD8+ T effector cells. FAUSTMAN teaches that the TNFR2 polypeptides, such as antibodies and antigen-binding fragments thereof, can be used, for example, to suppress autoimmunity and inflammation, as well as to promote the protection, healing, preservation, and/or regeneration of a wide variety of tissues and organs, such as tissues and organs containing TNFR2+ cells, See abstract.
SILVA is directed to how the S228P mutation prevents in Vivo and in Vitro IgG4 Fab-arm Exchange. SILVA teaches that human immunoglobulin G isotype 4 (IgG4) antibodies (Abs) are potential candidates for immunotherapy when reduced effector functions are desirable; however, IgG4 Abs are dynamic molecules able to undergo a process known as Fab arm exchange (FAE), which results in functionally monovalent, bispecific antibodies (bsAbs) with unknown specificity and hence, potentially, reduced therapeutic efficacy. SILVA further teaches that a serine 228 to proline (S228P) IgG4 Fc stabilizes the core-hinge and can prevent IgG4 FAE to undetectable levels both in vitro and in vivo. See abstract. Thus, SILVA teaches the advantages of an IgG4 Fc domain with a S228P mutation.
Regarding claims 235 – 238, UNDERWOOD discloses an antibody with a heavy chain variable region and a light chain variable region that binds human GITR (see claim 1) and which has a modified human IgG4 constant region with the sequence of SEQ ID NO: 1547. UNDERWOOD’s SEQ ID NO: 562 is identical to present SEQ ID NO: 1547 (of present claims 235, 238, and 244). See Appendix. Furthermore, UNDERWOOD discloses that the antibody has an IgG4 Fc region with an amino acid substitution of S228P. See claim 76. UNDERWOOD discloses that mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region. See paragraph [00244].
Because UNDERWOOD discloses an anti-GITR antibody with a modified human IgG4 constant region (having a sequence identical to present SEQ ID NO: 1547 and with the amino acid substitution of S228P) that is effective in the treatment of cancer and/or immune disorders, FAUSTMAN teaches an anti-TNFR2 antibody for the suppression of immune disorders, and SILVA teaches that a IgG4 with an S228P mutation stabilizes the antibody for immunotherapy, it would have been obvious to one having ordinary skill in the art to modify UNDERWOOD’s antibody to target TNFR2 instead of GITR, thereby arriving to the inventions of claims 235 – 238. There would have been a reasonable expectation of success considering that an anti-GITR antibody with an IgG4 Fc region having an S228P substitution and an anti-TNFR2 antibody are successful at treating cancer and infectious diseases and that TNFRSF members GITR and TNFR2 both enhance Treg activation and function, as evidenced by the applied art.
Regarding claim 239, FAUSTMAN discloses CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1413, 1414 or 1420, 1415, 1416, 1417, and 1418, respectively. FAUSTMAN’s SEQ ID NO: 15 discloses SEQ ID NOs: 1413, 1414 or 1420, 1415 with 100% identity, and FAUSTMAN’s SEQ ID NO: 42 discloses SEQ ID NOs: 1416, 1417, and 1418 with 100% identity. See Appendix.
Regarding claim 246 and 247, UNDERWOOD discloses that the antibody is a humanized monoclonal antibody. See paragraph [0058], last sentence.
Regarding claim 248, UNDERWOOD discloses that the antibody or antigen-binding fragment thereof is agonistic. See paragraph [0010], last sentence.
Regarding claim 249, UNDERWOOD discloses that parenteral administration is characterized by either subcutaneous, intramuscular or intravenous injection. See paragraph [00393].
Regarding claim 250, according to the present specification, “[t]he loss of agonism caused by ADCC for an IgG1 antibody, which has a functionally intact Fc domain that promotes ADCC, was demonstrated by the well-known bimodal response curve of the IgG1 antibody (FIG. 4A). This bimodal response curve was eliminated with the modified IgG4 antibody, which retained high potency (as demonstrated by the enhancement of Treg proliferation) at very high doses” (p. 210, lines 13 – 16). Thus, the property “wherein the modified antibody or antigen-binding fragment thereof lacks a bimodal response curve as determined using a Treg cell proliferation assay” of present claim 250 is directly attributed to the modified IgG4 Fc domain. While UNDERWOOD does not expressly state that the modified antibody lacks a bimodal response curve as determined using a Treg cell proliferation assay, UNDERWOOD discloses an antibody having an IgG4 Fc domain with the same structure as that recited in present claim 235, and thus UNDERWOOD’s antibody would inherently lack a bimodal response curve as determined using a Treg cell proliferation assay.
Response to Arguments
Applicant’s arguments, including the Declaration by Dr. Denise L. Faustman, are insufficient to overcome the rejections of claims 235 – 239 and 246 – 250 based upon 35 U.S.C. 103 for the following reasons.
On page 6, second paragraph, of the reply of 09/26/2025, Applicant argues that “Underwood, in one example, describes an anti-GITR antibody with an IgG4 heavy chain constant region and an S228P mutation, nowhere does Underwood teach or suggest that these modifications to an anti-GITR antibody promote any improvement in activity. Consequently, and contrary to the Examiner's conclusion, Underwood fails to provide any motivation to incorporate these changes in an entirely different antibody, such as an anti-TNFR2 antibody.”
Applicant’s argument is not found persuasive because UNDERWOOD teaches that “mutations (e.g., amino acid substitutions) are introduced into the Fc region of an antibody described herein or a fragment thereof (e.g., CH2 domain (residues 231-340 of human IgG1) and/or CH3 domain (residues 341-447 of human IgG1) and/or the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and/or antigen-dependent cellular cytotoxicity.” See paragraph 00243. Thus, UNDERWOOD suggests that the amino acid mutations improve the function of the antibodies.
Furthermore, SILVA teaches that IgG4 antibodies are potential candidates for immunotherapy but may undergo FAE, which can result in reduced therapeutic efficacy in WT IgG4. SILVA teaches that the S228P mutation can mitigate this issue and provide stability for the IgG4 antibody. See abstract. Thus, SILVA teaches the advantages of an IgG4 Fc domain with a S228P mutation on a therapeutic antibody.
On page 6, second to last paragraph – p. 7, of the reply, Applicant argues that “Underwood, whether considered singly or in combination with Lubrano di Ricco, provides no reason to expect that an anti-TNFR2 antibody according to the present claims would exhibit the absence of a bimodal dose response curve, e.g., as determined using a cellular or cell signalling assay”.
Applicant’s argument has been considered but not found persuasive because, as discussed above, the absence of the bimodal dose response curve is attributed to the IgG4 Fc domain of the present claims. Thus, because UNDERWOOD discloses an antibody with the claimed IgG4 Fc domain, UNDERWOOD’s antibody would also inherently lack a bimodal dose response curve. As Applicant mentions, UNDERWOOD’s FIG 18A discloses an IgG1 anti-GITR, not an IgG4 anti-GITR antibody, and thus does not represent the behavior of UNDERWOOD’s IgG4 antibody. Although a dose response curve may not be provided in UNDERWOOD, UNDERWOOD still teaches an antibody with an IgG4 Fc domain as presently claimed (discussed under the 103 rejection above) and thus renders the modified IgG4 Fc of the present claims obvious.
“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). See MPEP 2112.
On page 8 of the reply, Applicant argues that the claimed antibody or an antigen-binding fragment thereof exhibits an unexpected technical effect and points to Example 8 which describes the how the modified IgG4 antibody eliminates the bi-modal curve of agonism. However, as discussed above, UNDERWOOD specifically teaches the presently claimed modified IgG4 antibody and thus renders the elimination of the bi-modal curve obvious.
According to the present specification, “[t]he loss of agonism caused by ADCC for an IgG1 antibody, which has a functionally intact Fc domain that promotes ADCC, was demonstrated by the well-known bimodal response curve of the IgG1 antibody (FIG. 4A). This bimodal response curve was eliminated with the modified IgG4 antibody, which retained high potency (as demonstrated by the enhancement of Treg proliferation) at very high doses” (p. 210, lines 13 – 16). Thus, the property “wherein the modified antibody or antigen-binding fragment thereof lacks a bimodal response curve as determined using a Treg cell proliferation assay” of present claim 250 is directly attributed to the modified IgG4 Fc domain. While UNDERWOOD does not expressly state that the modified antibody lacks a bimodal response curve as determined using a Treg cell proliferation assay, UNDERWOOD discloses an antibody having an IgG4 Fc domain with the same structure as that recited in present claim 235, and thus UNDERWOOD’s antibody would inherently lack a bimodal response curve as determined using a Treg cell proliferation assay.
The Faustman Declaration does not address the teachings of the combination of the references currently cited in the present rejection as applied to the present claims. Points 3 – 7 of the Faustman Declaration state how the replacement of IgG1 antibodies with the presently claimed IgG4 antibodies unexpectedly leads to elimination of the bimodal response curve. However, as discussed above, UNDERWOOD teaches the replacement of the IgG1 antibody with the claimed modified IgG4 antibody as discussed above.
As discussed during the interview of 07/08/2025, the application comprises allowable subject matter that may overcome the cited references for the reasons discussed below.
Allowable Subject Matter
Claim 240 – 245 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Independent claim 235, which claims 240 – 245 depend from either directly or indirectly, is rendered obvious by the references cited under the 103 rejections above. However, none of the cited references discloses the sequences of claims 240 – 245, and SEQ ID NOs: 1488, 1495, 1501, and 1508 are free of the art.
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.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 15 of U.S. Patent No. 10,906,982 in view of UNDERWOOD, FAUSTMAN and SILVA.
The patented claims recite a humanized, human, or chimeric antibody or antigen-binding fragment thereof capable of specifically binding human TNFR2.
The main difference between the present claims and the patented claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the patented claims recite a humanized, human, or chimeric antibody or antigen-binding fragment thereof capable of specifically binding human TNFR2 and UNDERWOOD discloses a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the patented claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody, thereby arriving to the anti-TNFR2 antibody of the present claims.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 9 of U.S. Patent No. 11,859,002 in view of UNDERWOOD, FAUSTMAN and SILVA.
Patented claim 1 recite a humanized or chimeric antibody or antigen-binding fragment thereof . . . wherein each X is independently leucine or isoleucine; and wherein the antibody or antigen-binding fragment thereof specifically binds human tumor necrosis factor receptor 2 (TNFR2) and inhibits TNFR2 signaling.
The main difference between the present claims and the patented claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the patented claims recites a humanized or chimeric antibody or antigen-binding fragment thereof . . . wherein each X is independently leucine or isoleucine; and wherein the antibody or antigen-binding fragment thereof specifically binds human tumor necrosis factor receptor 2 (TNFR2) and inhibits TNFR2 signaling and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the patented claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody, thereby arriving to the anti-TNFR2 antibody of the present claims.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 22 of U.S. Patent No. 9,821,010 in view of UNDERWOOD, FAUSTMAN and SILVA.
Patented claim 1 recites an isolated, human, humanized, or chimeric antibody or antigen-binding fragment thereof that selectively binds to an epitope of TNFR2.
The main difference between the present claims and the patented claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the patented claims recite an isolated, human, humanized, or chimeric antibody or antigen-binding fragment thereof that selectively binds to an epitope of TNFR2 and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the patented claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody, thereby arriving to the anti-TNFR2 antibody of the present claims.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 2, 26, 29, 32, 36, 84, 87, 185 – 188, 219, 374, and 377 – 380 of copending Application No. 17/294,008 in view of UNDERWOOD, FAUSTMAN and SILVA.
Copending claim 1 recites an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2).
The main difference between the present claims and the copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2) and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the copending claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody, thereby arriving to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Previous rejections, withdrawn or maintained-in-modified-form below: claims 235 – 238 and 246 – 249 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims listed in the table below of copending U.S. Application No. listed in the table below in view of UNDERWOOD and LUBRANO DI RICCO.
U.S. App. No.
Claim No(s)
1
17/269,315
1, 3, 21, 34, 38, 65, 91 – 92, 212 – 215, 225 – 227, 232, 237, and 245
2
17/561,448
134 – 136, 138 – 144, 147
3
17/924,455
240 – 258
4
18/334,574
1 – 17
5
18/540,207
91 – 104
6
18/928,513
1 – 19
This is a provisional nonstatutory double patenting rejection.
The previous rejection over claims 1 – 17 of copending application 18/334,574 has been withdrawn in view of the abandonment of 18/334,574.
The previous rejections over copending applications 17/269,315, 17/561,448, 17/924,455, 18/540,207, and 18/928,513 are maintained in separate rejections below.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 258 and 260 – 323 of copending U.S. Application No. 17/269,315 in view of UNDERWOOD, FAUSTMAN and SILVA.
Copending claim 1 recites a humanized antibody or antigen-binding fragment thereof that specifically binds human TNFR2.
The main difference between the present claims and copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2) and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the copending claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody to arrive to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 134 – 136, 138 – 144, 147 of copending U.S. Application No. 17/561,448 in view of UNDERWOOD, FAUSTMAN and SILVA.
Copending claim 134 recites an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2).
The main difference between the present claims and copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2) and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the copending claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody to arrive to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims listed in the table below of copending U.S. Application No. 17/924,455 in view of UNDERWOOD, FAUSTMAN and SILVA.
Copending claim 240 recites an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2).
The main difference between the present claims and copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2) and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the copending claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody to arrive to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims listed in the table below of copending U.S. Application No. 18/540,207 in view of UNDERWOOD, FAUSTMAN and SILVA.
Copending claim 91 recites an isolated human, humanized or chimeric antibody or antigen-binding fragment thereof that selectively binds to an epitope of tumor necrosis-factor receptor 2 (TNFR2).
The main difference between the present claims and copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2) and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the copending claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody to arrive to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims listed in the table below of copending U.S. Application No. 18/928,513 in view of UNDERWOOD, FAUSTMAN, and SILVA.
Copending claim 1 recites a humanized or chimeric antibody or antigen-binding fragment thereof capable of specifically binding human tumor necrosis factor receptor 2 (TNFR2).
The main difference between the present claims and copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite an antibody or antigen-binding fragment thereof that specifically binds human tumor necrosis factor receptor 2 (TNFR2) and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in the treatment of cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the copending claims with the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody to arrive to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 2, 26, 29, 32, 36, 84, 87, 185 – 188, 219, 374, and 130 – 131, 188, and 190 – 198 of copending Application No. 17/150,686 in view of UNDERWOOD, FAUSTMAN, and SILVA.
The copending claims recite method of ameliorating a cancer in a human with the cancer, said method comprising administering to the human an antagonistic antibody or antigen-binding fragment thereof capable of specifically binding human TNFR2.
The main difference between the present claims and the copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite a method of ameliorating a cancer in a human with the cancer, said method comprising administering to the human an antagonistic antibody or antigen-binding fragment thereof capable of specifically binding human TNFR2 and UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in a method of treating cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the method of the copending claims with an anti-TNFR2 antibody having the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody, thereby arriving to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Previous rejection, maintained in modified form: claims 235 – 239 and 246 – 250 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 194 – 203 of copending Application No. 18/399,071 in view of UNDERWOOD, FAUSTMAN, and SILVA.
The copending claims recite a method of slowing progression of a cancer in a human that is undergoing treatment with an anti-cancer agent, said method comprising administering to the human an antibody or antigen-binding fragment thereof capable of specifically binding human tumor necrosis factor receptor 2 (TNFR2).
The main difference between the present claims and the copending claims is that the present claims further recite that the anti-TNFR2 antibody or antigen-binding fragment thereof includes a modified human IgG4 constant region comprising a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human IgG4 Fc hinge region comprises the amino acid substitution of S228P. However, UNDERWOOD and SILVA render these limitations obvious. The teachings of UNDERWOOD, FAUSTMAN, and SILVA, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 103 above.
Because the copending claims recite a method of slowing progression of a cancer in a human that is undergoing treatment with an anti-cancer agent, said method comprising administering to the human an antibody or antigen-binding fragment thereof capable of specifically binding human tumor necrosis factor receptor 2 (TNFR2), UNDERWOOD discloses an anti-GITR antibody that has a modified human IgG4 Fc hinge region, wherein the modified human IgG4 constant region with the amino acid sequence of SEQ ID NO: 1547 and the amino acid substitution of S228P (which helps stabilizes the antibody, according to SILVA) that is effective in a method of treating cancer and/or immune disorders, it would have been obvious to one having ordinary skill in the art to modify the anti-TNFR2 antibody of the method of the copending claims with an anti-TNFR2 antibody having the IgG4 Fc region of UNDERWOOD’s anti-GITR antibody, thereby arriving to the anti-TNFR2 antibody of the present claims.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
On page 11, second paragraph under “Nonstatutory Double Patenting Rejections”, Applicant argues that “[a]s is discussed above, Underwood and Lubrano di Ricco fail to teach, suggest, or motivate a skilled artisan to make the claimed antibody or antigen-binding fragment thereof. Similarly, the claims of the cited patents and applications also do not teach, suggest, or motivate a skilled artisan to make the claimed antibody or antigen-binding fragment thereof.”
Applicant’s arguments are not persuasive, and the maintained double patenting rejections are discussed above.
Conclusion
Claims 235 – 239 and 246 -250 are rejected, and claims 240 – 245 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ESTELLA M. GUSTILO whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:00 AM - 5:00 PM.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
APPENDIX
Alignment with SEQ ID NO: 1547
BCI62642
ID BCI62642 standard; protein; 327 AA.
XX
AC BCI62642;
XX
DT 26-JAN-2017 (revised)
DT 28-JAN-2016 (first entry)
XX
DE Human IgG4 heavy chain constant region mutant (S228P), SEQ ID 562.
XX
KW Immunoglobulin G4; Immunoglobulin gamma 4; antibody identification;
KW antibody production; antibody therapy; cancer; cell differentiation;
KW cytostatic; heavy chain constant region; immune modulation; mutein;
KW prophylactic to disease; protein interaction; t-lymphocyte; therapeutic;
KW viral infection; virucide.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Misc-difference 209
FT /note= "Wild-type Ser substituted by Pro"
XX
CC PN WO2015184099-A1.
XX
CC PD 03-DEC-2015.
XX
CC PF 28-MAY-2015; 2015WO-US032895.
XX
PR 28-MAY-2014; 2014US-0004071P.
PR 13-MAY-2015; 2015US-0161250P.
XX
CC PA (FOUR-) 4 ANTIBODY AG.
CC PA (LICR ) LUDWIG INST CANCER RES LTD.
CC PA (SLOK ) SLOAN KETTERING INST CANCER RES.
CC PA (UNDE/) UNDERWOOD D J.
XX
CC PI Gonzalez AM, Leger O, Merghoub T, Ritter G, Schaer D, Siebert V;
CC PI Tsuji T, Underwood DJ, Van Dijk M, Wilson NS, Wolchok JD;
CC PI Zappasodi R;
XX
DR WPI; 2015-835393/04.
XX
CC PT New isolated antibody capable of binding to human glucocorticoid-induced
CC PT TNF-receptor family related gene, useful in pharmaceutical composition
CC PT for e.g. modulating immune response, treating cancer, and enhancing
CC PT expansion of T cells.
XX
CC PS Claim 78; SEQ ID NO 562; 370pp; English.
XX
CC The present invention relates to a novel isolated antibody that
CC specifically binds to a human glucocorticoid-induced TNFR-related protein
CC (GITR). The anti-GITR antibody partially inhibits a human GITR ligand
CC (GITRL) from binding to the human GITR. Also described are: (1) an
CC isolated nucleic acid molecule encoding a heavy chain variable region or
CC a light chain variable region; (2) an isolated vector comprising the
CC nucleic acid molecule; (3) a host cell comprising the nucleic acid
CC molecule; (4) a method for producing the anti-GITR antibody; (5) a
CC pharmaceutical composition comprising the anti-GITR antibody and a
CC pharmaceutically carrier or excipient; (6) a method for modulating an
CC immune response in a subject; (7) a method for enhancing the expansion of
CC T cells and T cell effector function; (8) a method for enhancing the
CC expansion of CD8+ T cells; (9) a method for activating T cells
CC independent of TCR triggering; (10) a method for inducing, activating or
CC enhancing the activity of NF-kappa B independent of TCR triggering; (11)
CC a method for increasing the percentage of polyfunctional T cells; (12) a
CC method for inc