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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 19, 2026 has been entered.
DETAILED ACTION
The amendment filed March 19, 2026 in response to the Office Action of November 19, 2025 is acknowledged and has been entered.
Claims 1, 9, and 15 have been amended.
Claim 61 has been added.
Claims 1, 2, 9, 15, 16, 18, 27-30, 34, 37-39, 45, 46, 48, 51, 60 and 61 are pending.
It is noted that Applicant elected immunomodulatory moiety comprises SEQ ID NO: 17 in the Remarks of August 20, 2025. However, the amended claim 15 changed the structure of immunomodulatory moiety of the fusion protein from a sequence of TGF-β receptor II to a TGF-β-specific antigen binding fragment comprising a fresolimumab VH domain and VL domain. Amended claim 15 is drawn to a fusion protein with different structure (non-overlapping structure) compared with the fusion protein of previous claim 15 or amended claim 1. Thus, claims 15, 16 and 18 are withdrawn from examination.
Claims 15, 16, 18, 30, 34, 38, 39, 45, 46, 48, 51, 60, and 61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 2, 9, 27-29 and 37 are currently under consideration as drawn to the elected invention.
MAINTAINED/MODIFIED REJECTION
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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 9, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Bedi (Bedi et al., WO 2011/109789 A2, Publication Date: 09/09/2011, cited in IDS of 12/18/2023, of record), and in view of Chu (Chu et al., US 2014/0294759 A1, Publication Date: 10/02/2014, of record).
Bedi teaches a molecule including a targeting moiety fused with an immunomodulatory moiety. The targeting moiety specifically binds a target molecule, and the immunomodulatory moiety specifically binds a molecule, such as TGF-β ([0004]).
Bedi teaches in one aspect, the targeting moiety specifically binds a component of a regulatory T cell, such as CD4 ([0006]). In one aspect, the targeting moiety includes an antibody that specifically binds to CD4 ([0009]).
Bedi teaches in one aspect, the immunomodulatory moiety includes a molecule that binds TGF-β, such as an extracellular ligand binding domain of Transforming growth factor-beta receptor TGF-βRII, which inhibits the activity or function of TGF-β ([0007], [0112]).
Bedi teaches an exemplary extracellular domain (SEQ ID NO: 89) of TGF-βRII that binds TGF-β (see v of Fig. 1B). As shown below, SEQ ID NO: 89 comprises SEQ ID NO: 17 of the instant application (the elected species):
CC PN WO2011109789-A2.
XX
CC PS Example 1; SEQ ID NO 89; 154pp; English.
XX
SQ Sequence 112 AA;
Query Match 100.0%; Score 570; Length 112;
Best Local Similarity 100.0%;
Matches 101; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 QLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPY 61
Qy 61 HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIF 101
|||||||||||||||||||||||||||||||||||||||||
Db 62 HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIF 102
Bedi teaches fusion proteins comprising full length anti-CD4 antibody (full length heavy chain and light chain) and TGF-βRII extracellular domain (ECD), wherein the TGF-βRII extracellular domain is fused to the C-terminus of the heavy chain of anti-CD4 antibody, with a linker (GGGGS)3 (Fig. 9). The TGF-βRII extracellular domain (ECD) shown in Fig. 9 comprises SEQ ID NO: 17 of the instant application (the elected species) as shown below:
WO2011109789
Query Match 100.0%; Score 570; DB 1; Length 137;
Best Local Similarity 100.0%;
Matches 101; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 27 QLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPY 86
Qy 61 HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIF 101
|||||||||||||||||||||||||||||||||||||||||
Db 87 HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIF 127
Bedi teaches the fusion protein can be used to counteract immune tolerance in the tumor microenvironment and promote T cell-mediated adaptive antitumor immunity ([0103]).
Thus, Bedi teaches a fusion protein comprises a full length anti-CD4 antibody with a TGF-βRII extracellular domain (ECD) (SEQ ID NO: 17 of instant claim) fused at the C-terminus of heavy chain of the anti-CD4 antibody. However, Bedi does not teach the anti-CD4 antibody with the recited sequences of instant claim 1, or that the fusion protein does not deplete CD4+ regulatory T cells (Tregs), or that the fusion protein enhances differentiation and tumor infiltration of CD4+ helper T (TH) cells compared to a fusion protein that comprises the immunomodulatory moiety but not the CD4 targeting moiety.
Chu teaches that T cells express CD4 on their surface ([0006]).
Chu teaches specific anti-CD4 antibody ibalizumab and sequences of ibalizumab (Fig. 30C, CDRs are underlined).
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226
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As shown below, SEQ ID NO: 10 comprises SEQ ID NOs: 6-7-8 of the instant application:
ALIGNMENT:
Query Match 89.4%; Score 207.4; Length 452;
Best Local Similarity 46.5%;
Matches 40; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GYTFTSYVIH--------------YINPYNDGTDYDEKFKG------------------- 27
|||||||||| |||||||||||||||||
Db 26 GYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSS 85
Qy 28 -------------EKDNYATGAWFAY 40
|||||||||||||
Db 86 LRSEDTAVYYCAREKDNYATGAWFAY 111
As shown below, SEQ ID NO: 10 comprises a sequence which is identical to SEQ ID NO: 5 of the instant application:
Query Match 100.0%; Score 657; DB 1; Length 452;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDY 60
Qy 61 DEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTV 120
Qy 121 SS 122
||
Db 121 SS 122
As shown below, SEQ ID NO: 10 is 99% identical to SEQ ID NO: 26 of the instant application:
ALIGNMENT:
Query Match 99.0%; Score 2394; Length 452;
Best Local Similarity 98.9%;
Matches 446; Conservative 2; Mismatches 3; Indels 0; Gaps 0;
Qy 1 QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDY 60
Qy 61 DEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTV 120
Qy 121 SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 180
Qy 181 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL 240
Qy 241 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 300
Qy 301 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSR 360
||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||
Db 301 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 360
Qy 361 DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 420
:|:|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 420
Qy 421 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 451
|||||||||||||||||||||||||||||||
Db 421 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 451
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132
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As shown below, SEQ ID NO: 11 comprises SEQ ID NOs: 2-3-4 of the instant application:
Query Match 85.1%; Score 141.3; Length 219;
Best Local Similarity 40.5%;
Matches 32; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KSSQSLLYSTNQKNYLA---------------WASTRES--------------------- 24
||||||||||||||||| |||||||
Db 24 KSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISS 83
Qy 25 -----------QQYYSYRT 32
||||||||
Db 84 VQAEDVAVYYCQQYYSYRT 102
As shown below, SEQ ID NO: 11 comprises a sequence identical to SEQ ID NO: 1 of the instant application:
Query Match 100.0%; Score 585; DB 1; Length 219;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTR 60
Qy 61 ESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIK 112
As shown below: SEQ ID NO: 11 is also 100% identical to SEQ ID NO: 27 of the instant application:
ALIGNMENT:
Query Match 100.0%; Score 1138; Length 219;
Best Local Similarity 100.0%;
Matches 219; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTR 60
Qy 61 ESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKRTVAAPSV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKRTVAAPSV 120
Qy 121 FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 180
Qy 181 SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 219
|||||||||||||||||||||||||||||||||||||||
Db 181 SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 219
Thus, Ibalizumab reads on the anti-CD4 targeting moiety for claims 1 and 2.
Chu teaches specific anti-CD4 antibody: ibalizumab binds CD4+ T cells ([0093] and Fig. 10).
Chu teaches various fusion proteins comprising anti-CD4 antibody, for example a peptide fused at the C-terminus of anti-CD4 antibody heavy chain (see 13035, 13038 format on Fig. 25, and Example 6).
Chu teaches the composition can be used for treating disease affected by T cells, such as cancers ([0145])
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to make a fusion protein comprising a full length anti-CD4 antibody with a TGF-βRII extracellular domain (ECD) (comprising SEQ ID NO: 17 of instant claim) fused at the C-terminus of heavy chain of the anti-CD4 antibody for cancer treatment, as taught by Bedi, and to use ibalizumab as the anti-CD4 antibody in the fusion protein, because Bedi teaches bispecific molecule targeting both CD4 and TGF-β signaling can reduce immunosuppression by T cells and treat cancers, Chu teaches ibalizumab, an anti-CD4 antibody which bind T-cells, can be used in compositions for cancer treatment. One of ordinary skill in the art would have expected that a fusion protein of ibalizumab and a TGF-βRII extracellular domain (ECD) (comprising SEQ ID NO: 17 of instant claim, which is also an inhibitor of TGF-β signaling) would be able to bind CD4 expressing T cell and inhibit TGF-β signaling, to reduce immunosuppression in tumor microenvironment and to enhance anti-tumor therapeutic activity. The motivation would have been to expand the options of fusion proteins and to produce a better fusion protein for cancer therapy. With regarding to the limitation “wherein the fusion protein does not deplete CD4+ regulatory T cells (Tregs); wherein the fusion protein enhances differentiation and tumor infiltration of CD4+ helper T (TH) cells compared to a fusion protein that comprises the immunomodulatory moiety but not the CD4 targeting moiety”, because Bedi and Chu teach a fusion protein with the same structure as the 4T-Trap used in the Examples of the instant specification – Fig. 74: a TGF-βRII extracellular domain (ECD) (comprising SEQ ID NO: 17 of instant claim) fused at the C-terminus of heavy chain of ibalizumab. Thus the fusion protein would have the same functions and properties as 4T-Trap, as evidenced by the instant specification (Figs. 52, 76, and 78).
Regarding claim 9, as set forth above, Bedi teaches TGF-βRII extracellular domain (ECD), wherein the TGF-βRII extracellular domain is fused to the C-terminus of the heavy chain of anti-CD4 antibody, with a linker (GGGGS)3 (Fig. 9).
Regarding claims 27 and 28, Bedi teaches that the fusion proteins of the invention can be synthesized using recombination DNA technology well known in the art where the coding sequences of various portions of the fusion proteins can be linked together at the nucleic acid level. Subsequently, the fusion proteins of the invention can be produced using a host cell well-known in the art ([0211]).
Regarding claim 29, Bedi teaches pharmaceutical composition comprising the invention and that pharmaceutically acceptable carrier in the formulation ([0196]-[0198]. Chu also teaches composition comprising antibody and a pharmaceutically acceptable carrier ([0390]).
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Bedi (Bedi et al., WO 2011/109789 A2, Publication Date: 09/09/2011, cited in IDS of 12/18/2023, of record) and Chu (Chu et al., US 2014/0294759 A1, Publication Date: 10/02/2014, of record), as applied to claims 1, 2, 9, and 27-29 above, and further in view of Hu (Hu et al., US 2003/0228635 A1, Publication Date: 12/11/2003, of record)
Bedi and Chu teach the fusion protein of claim 1 as set forth above. However, Bedi and Chu do not explicitly teach a kit comprising the fusion protein of claim 1 and instructions for use.
Hu teaches that in performing assays, it is convenient to use a kit with all necessary reagents, media, buffers ([0058]). Hu teaches kit comprising antibody, buffers and instructions for use (claim 22).
Therefore, it would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to the fusion protein of claim 1 as taught by Bedi and Chu. In light of the teachings of Hu as well as the well-known advantages of providing reagents in kit form for commercial sale, one would be motivated to combine together the fusion protein and instructions in a kit.
Response to Arguments
For the rejection under 35 U.S.C. 103, Applicant argues:
Bedi expressly teaches that the anti-CD4-TGF-βRII ECD fusion proteins disclosed herein "provide the ability to bind a targeted molecule expressed by Tregs . .. while concurrently sequestering and inhibiting one or more immunosuppressive molecule [e.g., TGF-β] that promotes their development, survival or function" and "directly deplete the number of Tregs." Bedi at paragraph [0105]. Bedi discloses a single fusion protein comprising a TGF-βRII ECD fused to the VH and VL domains of the CE9. l anti-CD4 antibody, and merely speculates that the disclosed CE9 .1-TGF-βRII ECD fusion protein negatively impacts Treg function. Moreover, neither Bedi nor Chu teach or suggest any anti-CD4-TGF-βRII ECD fusion protein that enhances differentiation and tumor infiltration of CD4+ helper T (TH) cells, a class of CD4+ CD45+ Foxp3- T cells that are separate and distinct from Tregs (CD4+ CD45+ Foxp3+).
In the present case, Bedi and Chu fails to provide the skilled artisan with a reason to expect that all anti-CD4-TGFβRII ECD fusion proteins would categorically promote differentiation and tumor infiltration of CD4+ helper T (TH) cells. As an initial matter, neither Bedi and Chu teach or suggest that the TGF-βRII ECD portion in the anti-CD4-TGF-βRII ECD fusion protein would enhance differentiation and tumor infiltration of CD4+ helper T cells. Moreover, with respect to the antiCD4 portion of the anti-CD4-TGF-βRII ECD fusion protein, the skilled artisan at the time of filing would have appreciated that not all anti-CD4 antibodies promote T helper function. For example, Schulze-Koops et al., J Rheumatol 25(1 I):2065-76 (1998) demonstrates that a humanized non-depleting anti-CD4 monoclonal antibody (ORTHOCLONE OKTcdr4a) reduced the activity of THI cells.3 See also Wang et al., Clin Exp Immunol I994; 95:128-134 (demonstrating that two different anti-CD4 antibodies (MAX.16H5, and TIS I) inhibited helper T cell functions). Taken together, the skilled artisan would have been unable to reasonably predict which, if any, anti-CD4 antibody sequences would yield anti-CD4-TGF-βRII ECD fusion proteins that unequivocally enhance differentiation and tumor infiltration of CD4+ helper T cells in view of teachings of Bedi and Chu.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Bedi explicitly teaches fusion proteins comprising full length anti-CD4 antibody (full length heavy chain and light chain) and TGF-βRII extracellular domain (ECD), wherein the TGF-βRII extracellular domain is fused to the C-terminus of the heavy chain of anti-CD4 antibody, with a linker (GGGGS)3 (Fig. 9). In addition, as evidenced by claim 4 of Bedi, the anti-CD4 antibody is not limited to CE9.1. Bedi teaches the fusion protein can be used to counteract immune tolerance in the tumor microenvironment and promote T cell-mediated adaptive antitumor immunity ([0103]). One of ordinary skill in the art would have reasonable expectation of success and motivation to use anti-CD4 antibody ibalizumab (taught by Chu) for the fusion protein, because Chu teaches ibalizumab, an anti-CD4 antibody which bind T-cells, can be used in compositions for cancer treatment.
Applicant also argues that Bedi and Chu do not teach/suggest any anti-CD4-TGFβRII ECD fusion would have claimed properties; and not all anti-CD4 antibodies (such as OKTcdr4a and MAX.16H5) promote T helper function. It is noted that Bedi and Chu combined teach a specific fusion antibody (not any fusion protein). Bedi and Chu teach a fusion protein with the same structure as the 4T-Trap used in the Examples of the instant specification – Fig. 74: a TGF-βRII extracellular domain (ECD) (comprising SEQ ID NO: 17 of instant claim) fused at the C-terminus of heavy chain of ibalizumab. Thus, the fusion protein would have the same functions and properties as 4T-Trap, as evidenced by the instant specification (Figs. 52, 76, and 78).
Applicant further argues:
In contrast, the present specification demonstrates that unlike the anti-CD4-TGF-βRII ECD fusion proteins disclosed in Bedi, the claimed anti-CD4-TGF-βRII ECD fusion proteins (e.g., 4T-Trap) do NOT deplete CD4+ regulatory T cells (Tregs). As shown in FIG. 52 and FIG. 78 (reproduced below), the Treg levels in subjects treated with the claimed anti-CD4-TGF-βRII ECD fusion proteins (e.g., 4T-Trap) were comparable to those treated with the negative mG053 control, which lacks both the anti-CD4 antibody and the TGF-βRII ECD.
Moreover, the claimed anti-CD4-TGF-βRII ECD fusion proteins (e.g., 4T-Trap) unexpectedly enhances differentiation and tumor infiltration of CD4+ helper T (TH) cells (e.g., IFN-γ-positive THI and IL-4-positive TH2 cells) compared to a fusion protein that comprises the immunomodulatory moiety but not the CD4 targeting moiety (e.g., TGF-β-Trap) or ibalizumab (e.g., anti-CD4) control antibody. See FIG. 76 and FIG. 78 (reproduced in part below).
As set forth above, Bedi and Chu combined teach a specific fusion protein with the same structure as the 4T-Trap used in the Examples of the instant specification – Fig. 74: a TGF-βRII extracellular domain (ECD) (comprising SEQ ID NO: 17 of instant claim) fused at the C-terminus of heavy chain of ibalizumab. Thus, the fusion protein would have the same functions and properties as 4T-Trap, as evidenced by the instant specification (Figs. 52, 76, and 78).
In addition, the claimed properties: “wherein the fusion protein does not deplete CD4+ regulatory T cells (Tregs); wherein the fusion protein enhances differentiation and tumor infiltration of CD4+ helper T (TH) cells compared to a fusion protein that comprises the immunomodulatory moiety but not the CD4 targeting moiety” were observed in only one specific fusion protein 4T-Trap in a specific tumor model (MMTV-PyMT (PyMT)). The rejected claims encompass other fusion proteins which may or may not have the claimed properties. For example, SEQ ID NO: 11 and SEQ ID NO: 12 represent full-length TGF-βRII, but SEQ ID NO: 17 represents TGF-βRII extracellular domain (ECD). Thus, the fusion proteins encompassed by the instant claims may have opposite effects on CD4+ T cells. Thus, the examples are not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Therefore, the rejection is maintained for the reasons of record.
NEW REJECTION
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation "the antigen binding fragment" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 2 recites the limitation "the antibody" in line 4. There is insufficient antecedent basis for this limitation in the claim.
Claim 29 recites the limitation “wherein the fusion protein is optionally conjugated…” which renders the claim indefinite. A wherein clause is to recite a specific structure. Consequently, the use of the term “wherein” implies that this structure is there. However, adding the word “optionally” implies a total absence of the specific structure, thus, the claim is indefinite.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 9, 27-29 and 37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Claim 1 amended after the filing date. The limitation of “wherein the fusion protein does not deplete CD4+ regulatory T cells (Tregs); wherein the fusion protein enhances differentiation and tumor infiltration of CD4+ helper T (TH) cells compared to a fusion protein that comprises the immunomodulatory moiety but not the CD4 targeting moiety” in claim 1 has no clear support in the specification as originally filed. Applicant argues that support for the limitation can be found in the originally filed claims and at paragraphs [0107], [0109], [0162], [0415], [0419], [0423] and [0425] and FIGs. 52, 76, 78, 91 and 95 of the specification. However, upon careful examination, the paragraphs do not support the new limitation, as shown below:
[0107] FIG. 76 shows representative flow cytometry plots of IFN-γ and IL-4 expression in conventional CD4+Foxp3− T cells from the tumor-draining lymph nodes of hCD4PyMT mice treated with 4T-Trap, αCD4, TGF-β-Trap or mGO53 antibodies as well as statistical analyses of the gated populations (n=3 for each group). All statistical data are shown as mean±SEM. **: P<0.01; and ns: not significant.
Paragraph [0107] describes the effects of hCD4PyMT mice treated with 4T-Trap on IFN-γ and IL-4 expression in CD4+Foxp3- T cells.
[0109] FIG. 78 shows representative flow cytometry plots of TCRβ, NK1.1, CD4, CD8, and Foxp3 expression in tumor-infiltrating leukocytes from hCD4PyMT mice treated with 4T-Trap, αCD4, TGF-β-Trap or mGO53 antibodies as well as statistical analyses of the gated populations. All statistical data are shown as mean±SEM. **: P<0.01; and ns: not significant.
Paragraph [0109] describes the effects of hCD4PyMT mice treated with 4T-Trap on expression of various marker genes.
[0162]. As used herein, the term “CD4+ helper T cells” refer to CD4 expressing T cells that recognize an MHC class II-antigenic peptide complex that is expressed on antigen presenting cells (APCs) such as dendritic cells, B-cells, macrophages etc., and release effector T cell cytokines. Examples of CD4+ helper T cells include T H1 and T H2 cells, but exclude Tregs.
Paragraph [0162] is a general description/definition of CD4+ helper T cells.
[0415] To investigate whether blockade of TGF-β signaling in helper T cells with biologics could be a viable therapeutic approach, protein-engineering techniques were employed to generate bispecific antibodies, one specific for CD4 and one for TGF-β. Ibalizumab, an anti-human CD4 (αCD4) that recognizes an epitope in the C2 domain of CD4 distinct from its major histocompatibility complex class II binding site, was used to achieve CD4+ T cell targeting (FIG. 46). (See Burkly, L. C. et al., Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody. Dissecting the basis for its inhibitory effect on HIV-induced cell fusion, J. Immunol. 149, 1779-1787 (1992); Song, R. et al., Epitope mapping of ibalizumab, a humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients, J. Virol. 84, 6935-6942, doi:10.1128/JVI.00453-10 (2010).) To block TGF-β signaling, the TGF-βRII ECD was utilized, as it would not be immunogenic and its binding to TGF-β could exert a dominant negative function by recruiting endogenous TGF-β receptor I (TGF-βRI) (FIG. 47).
Paragraph [0415] does not describe results related to the claimed fusion protein. In fact, this paragraph indicates that the TGF-βRII ECD exert a dominant negative function. Thus, the full length TGF-βRII (SEQ ID NO: 11 and SEQ ID NO: 12, as evidenced by Fig. 98 of the specification) could have different function compared to TGF-βRII ECD (SEQ ID NO: 17).
[0419] The human CD4 epitope recognized by ibalizumab is not conserved in mice. (See Burkly et al., supra.) To test the therapeutic efficacy of 4T-Trap in vivo, a strain of human CD4 transgenic (hCD4) mice was generated using a bacterial artificial chromosome harboring the human CD4 locus with the proximal enhancer region replaced by the murine equivalent to augment its expression (FIG. 62). Flow cytometry experiments revealed exclusive expression of human CD4 on mouse CD4+ T cells at a level comparable to that on human CD4+ T cells (FIG. 63 and data not shown).
Paragraph [0419] describes that 4T-Trap confers good expression on mouse CD4+ T cells in vivo.
[0423] 4T-Trap inhibition of tumor progression was associated with enhanced differentiation of IFN-γ-producing Th1 and IL-4-producing Th2 cells, as well as increased tumor infiltration of conventional CD4+Foxp3− T cells at the expense of CD8+ T cells (FIGS. 76 and 78). 4T-Trap, but not αCD4, TGF-β-Trap or mGO53, blocks TGF-β signaling in tumor-draining lymph node CD4+ T cells, and induces enhanced effector/memory CD4+ T cell differentiation (FIGS. 77A-77C). In particular, neutralization of IL-4, but not IFN-γ, reversed the tumor suppression phenotype (FIGS. 79 and 80), which was associated with attenuated vessel organization, diminished hypoxia, and reduced tumor cell death (FIG. 81). Thus, as in the genetic model of TGF-βRII ablation (see Examples 1-6), it is type 2 immunity that mediates the 4T-Trap-induced anti-tumor immune response..
Paragraph [0423] describes that the specific fusion protein 4T-Trap can induce enhanced effector/memory CD4+ T cell differentiation, in MMTV-PyMT (PyMT) transgenic model of murine breast cancer (as evidenced by [0411] and Example 8).
FIGs. 52, 76, and 78 described the results of the specific fusion protein 4T-Trap. FIGs. 91 and 95 described the anti-CD4/anti-TGFβ bispecific antibody which does not have the structure of amended claim 1.
Taken together, the claims and specification as originally filed provide support for only one specific fusion protein with claimed structure (4T-Trap, also see Fig. 52, [0416]) which does not deplete CD4+ regulatory T cells (Tregs), and enhances differentiation and tumor infiltration of CD4+ helper T (TH) cells compared to a fusion protein that comprises the immunomodulatory moiety but not the CD4 targeting moiety in a specific tumor model: MMTV-PyMT (PyMT). Thus, the claims and specification as originally filed do not provide support for the amended claim 1 which encompasses a broad genus of fusion proteins and a broad genus of tumors.
The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See MPEP 2163.05 (II). See also In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (“Whatever may be the viability of an inductive-deductive approach to arriving at a claimed subgenus, it cannot be said that such a subgenus is necessarily described by a genus encompassing it and a species upon which it reads.”) Thus the limitation of amended claim 1 and its dependent claims is new matter because it is not supported by the as-filed disclosure.
Thus, the subject matters claimed in the rejected claims broaden the scope of the invention as originally disclosed in the specification and claims from what was originally disclosed in the specification and claims as filed.
Claims 2, 9, 27-29 and 37 are also rejected because these claims encompass new matter encompassed by the rejected claim above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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/CHENG LU/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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