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 .
Alternative Names
Dipeptidyl peptidase4 is also referred to as DPP4, DPPIV, DPP IV and CD26 here and in the literature. (See also paragraph [0004] of the specification.)
Specification
The paragraph numbering in reference to the specification is to the new clean substitute specification filed 2/22/2026.
Prior Art Cited on the Previous PTO-892 Form
The Examiner regrets that Metzemaekers et al., Int. J. Mol. Sci. 18:1513, 2017, cited on the PTO-892 mailed 09/30/2025 had not been included with the Office action. It is attached as an Appendix to this action.
Response to Amendment
The rejection of claims 9, 12 and 20 under 35 U.S.C. 112(b) is withdrawn in view of the cancelation of claim 9 and amendment to claims 12 and 20 specifying potentiating activity of CD8+ T cells; however, claims 12 and 20 remain rejected as dependent on claim 1 (still rejected). The rejection of claim 1 due to recitation of “a corresponding wild type CXCL9” and “N-terminus” is withdrawn in view of the deletion of references thereto. However, a new rejection of claim 1 is set forth below.
The rejection of claims 1,3,6-9,12, 23 and 25 under 35 U.S.C. 112(a) for lacking written description is withdrawn in view of the cancelation of claim 9 and amendment to claim 1 wherein there is a single insertion of an additional amino acid immediately following the signal peptide. This means that whether the wild-type CXCL9 polypeptide is full-length or the mature form lacking the signal peptide, the single insertion is placed immediately following where the signal peptide is or was, i.e., for the full-length CXCL9 that is after the signal peptide (after amino acid 22 of SEQ ID NO:8 for the human sequence) and for the mature CXCL9 at the N-terminus.
The rejection of claim 25 under 35 U.S.C. 112(a), enablement, is withdrawn in view of the amendment to claim 1 wherein there is a single insertion of an additional amino acid immediately following the signal peptide.
The rejection of claims 1, 3, 6, 8, 12, 14, 17, 20 and 23 under 35 U.S.C. 102(a)(2) as being anticipated by US 2022/0017585 A1 (Yamamoto) is withdrawn in view of the requirement that the modified CXCL9 polypeptide comprise an IgG1-Fc of SEQ ID NO:5, which is not taught by Yamamoto.
The rejection of claim(s) 14-17 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zohar et al. (J. Con. Invest. 124(5):2009-2022, 2014, cited in the IDS filed 6/20/25) in view of Karin et al. (Cytokine, 109:24-28, 2018) is withdrawn in view of the cancelation of claim 15 and amendment to independent claim 14 requiring conjugation of the CXCL9 polypeptide to an IgG-c which is hinge-ch2-ch3 as set forth in SEQ ID NO:5. However, a new rejection appears below.
Declaration
The Declaration by Dr. Karin under 37 CFR 1.132 filed 02/22/2026 is insufficient to overcome the rejection of claims 1, 3, 6, 8, 12, 14, 17, 10 and 23 based upon lack of novelty over US 2022/0017585 A1 (Yamamoto) as set forth in the last Office action (see paragraph 8 of Declaration) because: Dr. Karin argues it would not have been obvious to modify the CXCL9 polypeptide by linkage to an IgG-Fc as taught generally by US 7,083,784 to increase half-life, including a human Fc sequence to reduce the chance of a negative immunogenic reaction when administered to a human (paragraph 8). Paragraph 9 goes on to state that claim 1 has been amended to specify the sequence of the IgG-Fc has the sequence of SEQ ID NO:5. Paragraph 10 and Fig. 1 shows the activity of Q-CXCL9-Fc with and without DDP4 was similar to non-modified CXCL9-Fc in the absence of DDP4 in CHO-Ki cells overexpressing human CXCR3A. The “modified CXCL9-Fc fusion is distinct, unexpected and different from any of the cited prior art.” (Paragraph 11) Some of these statements are directed toward anticipation, which is not at issue, the rejection under 35 USC 102 having been withdrawn. SEQ ID NO:5 is not novel, but is a human IgG-Fc sequence taught in the prior art. As the statements relate to the current rejections under 35 USC 103, it is not agreed the modified fusion protein is nonobvious in view of the prior art as set forth in the rejection below. As to the argument that adding a Fc region for the purpose of increasing half-life would not have been obvious because there would not have been motivation to do so, the prior art supports the motivation of fusing the Fc region for increasing stabilization/half-life of the fusion and made similar constructs with that expectation, but also or alternatively for the purpose of purification of the fusion by binding to protein A (see Yamamoto and US 7,083,784). As stated in Yamamoto: “[0190] FIG. 1A shows a schematic diagram of an hCXCL10 variant Fc fusion.” “[0195] FIG. 4A shows a schematic diagram of an hCXCL11 or hITIP variant Fc fusion.” And in [0365], “A fusion protein comprising a CXCR3 ligand can be purified using a substance that binds to the fusion protein. For example, when fused with an antibody Fc region, adsorption onto immobilized protein A can be used to recover the CXCR3 ligand.” Additionally, for the reasons set forth in the rejection, it is not unexpected that a modified CXCL9 in which there is an insertion of an amino acid immediately after the signal peptide is resistant to DPP4 cleavage or that a fusion of the modified CXCL9 with IgG-Fc is also DPP4-resistant. It is maintained that the instant invention is obvious in view of the prior art of record.
Claim Rejections - 35 USC § 112(b)
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 1 and dependent claims 3, 8, 12, 23 and 25 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 1 recites the limitation "the signal peptide" in line 3. There is insufficient antecedent basis for this limitation in the claim. “A wild-type CXCL9 polypeptide” does not necessarily comprise a signal peptide. According to the specification ([0008]), a “wild type” CXCL9 includes “full-length” CXCL9. “Includes” is not the same as “is” or “means”, for example. Instead, it is open language encompassing “full-length” CXCL9 but not limited to it. This is supported by the specification in [0009], which states the amino acid insertion is “at the N-terminus of a corresponding wild type CXCL9”, which in line with the disclosure means at the N-terminus of the mature CXCL9 natural protein. Without specifying that the CXCL9 is a full-length protein or has a specific full-length sequence, such as SEQ ID NO:8, there is no antecedent basis for “the signal peptide”. Human CXCL9 has the sequence of SEQ ID NO:8 ([0043]), which includes a 22 amino acid signal sequence.
Claim 1 is also confusing as amended because of the word “comprising” before “a single insertion”. This allows for multiple insertions, but the word is followed by a single insertion. It there is only a single insertion then clarity could be added by using wording such as ‘…: a wild-type CXCL9 polypeptide wherein a single additional amino acid is inserted immediately following the signal-peptide of the full-length CXCL9 polypeptide.’
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120. The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. US 63/041,940, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. This application does not disclose insertion of an additional amino acid at the N-terminus of a wild type CXCL9. Therefore, the benefit of priority for claims 1, 3 and 5-9, 12, 23 and 25 is extended only to US 63/150,629 (filed 2/18/2021).
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.
Claim Rejections - 35 USC § 103
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.
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.
Claim(s) 1, 3, 5, 8, 12, 14, 16-17, 20, 23 and 25 remain rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0017585 A1 (Yamamoto) as applied to claims 1, 3, 6, 8, 12, 14, 17, 20 and 23 above, and further in view of Metzemaekers et al. (Int. J. Mol. Sci. 18:1513, 2017), Bronger et al. (Canc. Metast. Rev. 38:417-430, Sept. 2019, cited in the IDS filed 6/30/2023), Karin et al. (Cytokine, 109:24-28, 2018), US 7,083,784 (US ‘784) and GenBank Database, Accession No. NP_002407 (version NP_0024071, C-X-C motif chemokine 9 precursor [Homo sapiens], 30 Dec. 2018) as recast here to address the amendment to the claims.
Yamamoto teaches CXCR3 ligand variants having resistance to DPPIV (DPP4) and activity to cause migration of cells expressing CXCR3 (claims 1-2). CXCR3 chemokine ligands are CXCL9, CXCL10 and CXCL11 ([0002]). The N-terminus of each ligand is known to be cleaved by dipeptidyl peptidase-4 (DPPIV or DPP4, [0005]-[0007]). Claim 16 teaches a method of conferring resistance to DPPIV on a parent CXCR3 ligand in which the 2nd amino acid from the N-terminus is P, wherein the method comprises further adding Q, E, D or P to the N-terminus. The CXCR3 ligand that is made to have resistance to DPPIV is a CXCL9 variant ([0328], [0334] and [0337]). Figure 1B shows insertion of an amino acid (b) to disrupt the DPPIV cleavage site of CXCL10. Fig. 4B shows insertion of an amino acid (b) to disrupt the DPPIV cleavage site of CXCL11. Both these sites are at the N-terminus of the mature protein, i.e., immediately after the signal peptide sequence of the full-length protein. Yamamoto also teaches wherein the CXCR3 ligand is fused to an antibody Fc region via a linker, as well as a pharmaceutical composition of the modified ligand ([0120]). “A fusion protein comprising a CXCR3 ligand can be purified using a substance that binds to the fusion protein. For example, when fused with an antibody Fc region, adsorption onto immobilized protein A can be used to recover the CXCR3 ligand.“ ([0365]) In Example 1, human CXCL10 (hCXCL10) was fused to a human IgG1 Fc domain ([0426]). Likewise, Example 4 uses a hCXCL11 variant fused to a hIgG1 Fc ([0532]). Example 5 teaches fusion of hIgG1 Fc to a chimeric of hCXCL10-hCXCL11 variants ([0536]). In all cases (see above three Examples, same paragraphs) it is stated that the fusion constructs were expressed “by a method known to those skilled in the art and purified by a method known to those skilled in the art using protein A.” Yamamoto does not teach insertion of an amino acid at the N-terminus of CXCL9 resulting in an amino acid sequence of one of SEQ ID NO:1-4 or wherein the modified CXCL9 polypeptide is linked to an IgG-Fc molecule. An activity of a modified CXCL9 binding CXCR3 and/or inducing CD8+ T cells is not explicitly taught. Yamamoto does not teach treatment of cancer by administration of the modified CXCL9 polypeptide.
Metzemaekers et al. teaches CXCR3 is strongly expressed by Th1 helper CD4+ T cells, effector CD8+ T cells and natural killer (NK) cells, and its chemokine ligands have chemotactic effects and angiostatic properties (p. 2/4, first paragraph). It is stated on p. 3, second paragraph:
An enzyme that has been shown to provoke NH2-terminal processing of various chemokines including CXCL9, CXCL10 and CXCL11 is dipeptidyl peptidase IV or CD26 [50,52,53]. In addition to its enzymatic activity as a serine protease, the multifunctional or “moonlighting” protein CD26 functions as a receptor, costimulator for T cell activation, adhesion molecule and has been associated with apoptosis [54–57]. The membrane-bound enzyme is expressed on cells of different origins, including certain immune cells, whereas soluble proteolytically active CD26 exists in several body fluids such as plasma and seminal fluid. CD26 preferentially removes the two most NH2-terminal amino acids from substrates whose penultimate position is occupied by a (hydroxy) proline or alanine residue. Pro is present at this position in a number of chemokine sequences. The NH2-terminal chemokine domain is responsible for GPCR binding and activation and, consequently, limited proteolysis by CD26 (but also by other enzymes) may have drastic effects on the biological functioning of a chemokine [50–52]. It turned out that the biological effect of CD26-mediated cleavage is highly complex and depends on the chemokine ligand involved. For all three CXCR3 agonists, it was previously demonstrated that processing by CD26 results in drastic loss of receptor signaling and impaired capacity to direct lymphocyte chemotaxis, while leaving the angiostatic properties of these chemokines unaffected [53]. For human CXCL10 and CXCL11, the corresponding CD26-truncated isoforms CXCL10 (3–77) and CXCL11 (3–73) were previously isolated from natural sources, including conditioned medium from MG-63-osteosarcoma cells, fibroblasts and keratinocytes [22,58–61].
Bronger et al. taught that the CXCR3 and CXCR1 ligands, CXCL9-11 and CX3CL1, respectively, are mainly responsible for tumor-suppressive lymphocyte (TIL) infiltration into the tumor microenvironment (second paragraph of Abstract). CXCR3-expressing cells include Tregs, CD4+ and CD8+ T cells, dendritic cells NK and NKT cells (p. 419, col. 2, second paragraph). “Raising the intratumoral concentration of intact and functional CXCR3 chemokines, e.g., by inhibition of their proteolytic inactivation, might thus kill two birds with one stone: tumor-suppressive immune cells would be attracted to the tumor site, and CXCR3-positive tumor cells would be chemotactically prevented from escaping the primary cancer. This idea is supported by both preclinical and clinical findings…. Moreover, in human cancers, overexpression of CXCL9 and CXCL10 is associated with a higher number of tumor-infiltrating lymphocyte and improved survival, e.g., in breast, ovarian, colon, lung, and several other cancers [67, 76-83].” (p. 421, col. 1, second paragraph) CXCR3 chemokines also contribute to antitumor activity of multiple current therapeutics such as immune checkpoint inhibitors of the PD-1/PD-L1 axis, as well as CDK4/6 inhibitors and poly[ADP-ribose] polymerase 1 inhibitors (p. 421, paragraph bridging cols. 1-2). CXCR3 chemokine inactivation presents a cancer treatment resistance mechanism, “which renders inhibitors of CXCR3-chemokine cleaving proteases feasible adjuvants to all these therapies.” (p. 421, col. 2, end of first paragraph) In line with this, dipeptidyl peptidase 4 (DPP4) removes N-terminal amino acids from CXCR3 chemokines (p. 423, last paragraph). It has already been shown that (p. 425, col. 1, last paragraph), “In syngeneic models of melanoma and colorectal cancer (B16F10 and CT26 models, respectively), inhibition of DPP4 by sitagliptin or DPP4 knockout led to enhanced T cell infiltration, impaired tumor growth and less metastatic spread [19].” Also, in a xenograft and fully immunocompetent model of hepatocellular carcinoma, inhibition of DPP4 impaired tumor growth through enhanced CXCR3-mediated NK and T cell infiltration (p. 425, col. 1, last paragraph). It is concluded that, “proteolytic cleavage of the tumor-suppressive CXCR3 and CX3CR1 chemokines impairs their functions and, on top of this, in feedback loops, the chemokines may even lead to increased expression of the proteases targeting themselves.”
Karin et al. teaches that chemokine receptor CXCR3-A binds CXCL9, CXCL10 and CXCL11 and is expressed primarily on activated T lymphocytes and NK cells (p. 25, col. 2, second and start of third paragraph). CXCL11 binds a different site on CXCR3 than do CXCL9 and CXCL10 (p. 25, col.2, third paragraph). It is further taught (paragraph bridging pp. 25-26) that chemokines have very short in vivo half-lifes and as a result need to be stabilized for effective therapeutic use. To accomplish this chemokine-Ig based fusion proteins were made. The researchers had already shown that generation of an Ig based fusion protein of chemokine CCL1 (CCL1-Ig) increased in vivo half-life time [32]. This has also been shown for an Ig stabilized cytokine, IL-31 [64]. “We therefor suggest using CXCL10-Ig for cancer therapy.” The reasoning was that CXCL10 induced effector Th1 cells and has been associated with recruitment of CXCR3+ CD8+ T cells to a tumor site and Granzyme B production by these T cells, leading to potentiation of antitumor activity (Fig. 1 and p. 26, col. 2, first full paragraph). Further, CXCL10-Ig had been shown in mice engrafted with myeloma tumor cells to increase effector CD4, CD8 and NK cells at the tumor site, reduce Tregs and “significantly reduce accumulation of myeloma [65]”. Separately it has been shown that inhibition of DPP4 increased CXCL10 levels and suppressed experimental melanoma (p.26, col. 2, first full paragraph).
US 7,083,784 teaches IgG hinge-Fc regions from human having the amino acid sequence of SEQ ID NO:83 (col. 6, lines 61-63, and Fig. 2; which is identical to instant SEQ ID NO:5). The prior art discloses fusion with the IgG hinge-Fc increased in vivo half-life of the non-IgG Fc protein of the fusion (col. 3, lines 6-11). Additionally, modified IgG-Fc fusions are taught with increased in vivo half-lives (e.g., col. 31, lines 56-64, and claims 1-4) and wherein the IgG-Fc is linked to the bioactive protein, which linkage may be by a linker sequence (col. 34, lines 59-67, and col. 37, lines 10-14). The Fc-containing fusion proteins may be purified by methods well known to those skilled in the art. IgGs were purified from conditioned media with protein A columns according to the manufacturer’s instructions (col. 67, lines 51-56, and col. 68, lines 38-41).
GenBank Database, Accession No. NP_002407 teaches the sequence of C-X-C motif chemokine 9 precursor from human, also known as CXCL9, Humig and MIG (CDS section). The signal peptide is amino acids 1-22 (sig_peptide).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention wherein CXCL9 had a human sequence as shown in GenBank Database Accession No. NP_002407 because of the role the chemokine plays in T and NK cell activity and/or migration and their relationship to human cancers (e.g., Bronger et al. and Karin et al.). As taught by Yamamoto, inserting an amino acid in the N-terminus of the mature CXCR3 ligands results in resistance to peptidase DPPIV, thereby maintaining CXCR3 activity. As Yamamoto also taught wherein the inserted amino acid may be glutamine, asparagine or proline (see claims), modified human CXCL9 polypeptides would have the sequence of one of instant SEQ ID NO:1-4. The use of such a modified CXCL9 polypeptide in a pharmaceutical composition for the treatment of cancer would have been obvious because activation of CXCR3 is needed for such treatment based on administration of its ligand(s). The prior art supports the negative effect of DPPIV by cleavage of CXCR3 ligands, resulting in inactive ligands; therefore, use of the modified, DPPIV-noncleavable ligand(s) would allow treatment of cancer. There would have been a reasonable expectation of success in view of the teachings of Bronger et al. that in human cancers, overexpression of CXCL9 and CXCL10 is associated with a higher number of tumor-infiltrating lymphocytes and improved survival, e.g., in breast ovarian, colon, lung, and several other cancers. It further would have been obvious wherein the modified CXCL9 polypeptide was linked to an IgG-Fc as taught generally by US ‘784 to increase the half-life of the CXCL9 or facilitate purification by protein A (Yamamoto and US ’784), including wherein the IgG-Fc was the human hinge-CH2-CH3 sequence of SEQ ID NO:83 of US ‘784 so as to reduce the chance of a negative immunogenic reaction if administered in a human or for purification of the in vitro expressed CXCR3 ligand. A CXCL9-Ig fusion is supported by Karin et al., which taught the advantages of having a CCL1-Ig with increased in vivo half-life time and which suggested treatment of cancer with a CXCL10-Ig fusion and pointed to the prior art results showing CXCL10-Ig increased effector CD4, CD8 and NK cells at the tumor site in mice engrafted with myeloma tumor cells. Use of CXCL9 in this context would have been obvious and desirable because of the teachings of Bronger et al. that CXCR3 and CXCR1 ligands, CXCL9-11 and CX3CL1, respectively, are mainly responsible for tumor-suppressive lymphocyte (TIL) infiltration into the tumor microenvironment and that CXCR3-expressing cells include Tregs, CD4+ and CD8+ T cells, dendritic cells, NK and NKT cells (p. 419, col. 2, second paragraph). This is also obvious in view of the suggestion by Bronger et al. (p. 421, col. 1, second paragraph) of “Raising the intratumoral concentration of intact and functional CXCR3 chemokines, e.g., by inhibition of their proteolytic inactivation, might thus kill two birds with one stone: tumor-suppressive immune cells would be attracted to the tumor site, and CXCR3-positive tumor cells would be chemotactically prevented from escaping the primary cancer. This idea is supported by both preclinical and clinical findings….” Also as taught by US ‘784, it would have been obvious wherein the linkage between the Ig-Fc and bioactive protein (CXCL9 in this case) was a linker sequence. Increase in half-life would reasonably have been expected to enhance the positive antitumor effects of CXCR3 because Karin et al. and Bronger et al. respectively suggested increased activation of CXCR3 by a CXCL-Ig fusion and inhibition of DPPIV, both of which function to increase time that the CXCR3 ligand can bind and activate its receptor, for treatment of cancers.
Applicant argues in the REMARKS filed 2/22/2026 (p. 9, last paragraph, and p. 10, first paragraph) that because resistance to DPP4 significantly increases activity of CXCL10 (Yamamoto), “probably also the activity of CXCL9. In view of this, it is not clear a person skilled in the art would be motivated to further increase stability of CXCL9 by fusion to an Fc region, when activity is already increased by the DPP4 resistance.” Also, because the prior art does not disclose a modified CXCL9 fusion, an unmodified CXCL9, a modified CXCR3 ligand or a modified cytokine fused to SEQ ID NO:5, the invention is not obvious and there would have been no expectation for both the DPP4 protection and the Fc region to function together to enhance activity and stability (or efficacy). The argument has been fully considered but is not persuasive. First, all the references besides US ‘784 disclose CXCL9. Yamamoto contemplates modification of CXCR3 ligands to introduce DPP4-cleavage resistance, thereby maintaining chemokine activity of the ligand, which the prior art supports as beneficial for antitutmor activity through effector cells (T and NK cells). Further, it was common in the prior art to increase half-life of a variety of proteins by addition of an Fc region (e.g., Strohl, BioDrugs, 29:215-239, 2015, p. 220, first paragraph, and p. 235, third paragraph, where it is stated, “One of the major problems today with the use of fusion proteins such as Fc, IgG, or albumin to generate a biobetter by extending the half-life of a biologically active, commercially available peptide or protein… is that it is now an obvious approach to take. This obviousness has made it much more difficult to obtain patent protection for constructs of these types [125].”) However, the fusion of an IgG-Fc region has the added advantage of allowing purification of the fusion protein by its binding to protein A, which may be immobilized on a column or used for immunoprecipitation (Yamamoto and US ‘784, see also, e.g., Zettlitz, Chapter 34: Protein A/G Chromatography, Antibody Engineering. Springer Protocols Handbooks. Springer, Berlin, Heidelberg. Vol. 1, pp. 531-535, 2010, p. 531, first sentence, “Protein A or G affinity chromatography is a well established and reliable method for purifying whole antibodies, Fc-fusion proteins and Fab-fragments from serum or cell culture supernatant.”)
Applicant argues (p. 10, second paragraph) that a CXCL9 polypeptide modified by both the addition of an amino acid (Glu as represented in Fig. 1 of the Declaration) and also of an IgG-Fc of SEQ ID NO:5 in the presence of DPP4 showed activity similar to unmodified CXCL9 in the absence of DPP4. Therefore, the claims are not obvious. The argument has been fully considered but is not persuasive. For the reasons set forth in the rejection, particularly in view of Yamamoto showing that both variant CXCL10-Fc and CXCL11-Fc still have similar migration-inducing activity of cells expressing CXCR3 (Figs. 3A-3B and 6-1, 6-2 and 6-3; without the Fc see [0473] and note Fig. 5 hCXCL10R75A.0028 (Table 2-1 for sequence) showing the same activity in the presence and absence of DPPIV), the activity of the modified CXCL9-Fc of the Declaration is not surprising. Based on the prior art, the artisan of ordinary skill would have had a reasonable expectation that the CXCL9 variant fused to a hIgG-Fc of SEQ ID NO:5 would have activity comparable to without the Fc region. It is maintained that the invention is obvious.
Claim(s) 14-17 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zohar et al. (J. Con. Invest. 124(5):2009-2022, 2014, cited in the IDS filed 6/20/25) in view of Karin et al. (Cytokine, 109:24-28, 2018) and US Patent 7,083,784 B2 (US ‘784).
Zohar et al. teaches (p. 2009, col. 1, second paragraph and col. 2, first full paragraph) the G protein-coupled receptor (GPCR) CXCR3 binds ligands CXCL9, -10 and -11. CXCL11 binds to CXCR3 at a different site than CXCL9 and -10. It was shown that CXCL11 and CXCL10 have different effects, with CXCL10 polarizing effector Th1 immune cells and CXCL11 polarizing native T cells into IL-10hi Tregs (p. 2009, col. 2, end). Zohar et al. made fusion proteins of murine CXCL11 or CXCL10 linked to murine IgG1 Fc (hinge-CH2-CH3; CXCL11-ig and CXCL10-Ig), which preserved the biological properties of each chemokine, stabilized and prolonged in vivo half-life (p. 2014, col. 2, first full paragraph, and p. 2020, col. 1, last paragraph). Each fusion maintained CXCR3 binding and the ability to attract CXCR3+ T cells, while anti-cytokine specific antibodies inhibited this migration (p. 2014, col. 2, first full paragraph). The fusions were tested on an EAE murine model of inflammatory autoimmune disease (p. 2014, last paragraph through p. 2018, col. 1, second paragraph). Different activities of different ligands on the same receptor are discussed (p. 2018, col. 1, third paragraph, and col. 2, fourth paragraph), with the conclusion that, “Whereas CXCL10 (and possibly CXCL9) drives Th1/Th17 polarization by signaling via STAT4 (and perhaps STAT5), CXCL11 not only competes with these proinflammatory activities, but can directly activate, via STAT3, mTOR, and STAT6 pathways, leading to enhanced polarization of FOXP3–IL-10hi- and IL-4hi-producing Tregs.” The advantage of using a cytokine-Ig fusion is described as likely extending in vivo half-life while maintaining biological activity, as well as being able to use low doses due to the extended half-life (p. 2019, col. 1, last paragraph). It is concluded (p. 2019, col. 2, end of first full paragraph), “Whether these findings with CXCR3 and its distinct ligands can be extended to other different autoimmune diseases, as well as to other chronic inflammatory processes, remains to be investigated.” Zohar et al. does not teach a CXCL9-immunoglobulin conjugate.
Karin et al. teaches that chemokine receptor CXCR3-A binds CXCL9, CXCL10 and CXCL11 and is expressed primarily on activated T lymphocytes and NK cells (p. 25, col. 2, second and start of third paragraph). CXCL11 binds a different site on CXCR3 than do CXCL9 and CXCL10 (p. 25, col.2, third paragraph). It is further taught (paragraph bridging pp. 25-26) that chemokines have very short in vivo half-lifes and as a result need to be stabilized for effective therapeutic use. To accomplish this chemokine-Ig based fusion proteins were made. The researchers had already shown that generation of an Ig based fusion protein of chemokine CCL1 (CCL1-Ig) increased in vivo half-life time [32]. This has also been shown for an Ig stabilized cytokine, IL-31 [64]. “We therefor suggest using CXCL10-Ig for cancer therapy.” The reasoning was that CXCL10 induced effector Th1 cells and has been associated with recruitment of CXCR3+ CD8+ T cells to a tumor site and Granzyme B production by these T cells, leading to potentiation of antitumor activity (Fig. 1 and p. 26, col. 2, first full paragraph). Further, CXCL10-Ig had been shown in mice engrafted with myeloma tumor cells to increase effector CD4, CD8 and NK cells at the tumor site, reduce Tregs and “significantly reduce accumulation of myeloma [65]”. Separately it has been shown that inhibition of DPP4 increased CXCL10 levels and suppressed experimental melanoma (p.26, col. 2, first full paragraph).
US 7,083,784 teaches IgG hinge-Fc regions from human having the amino acid sequence of SEQ ID NO:83 (col. 6, lines 61-63, and Fig. 2; which is identical to instant SEQ ID NO:5). The prior art discloses fusion with the IgG hinge-Fc increased in vivo half-life of the non-IgG Fc protein of the fusion (col. 3, lines 6-11). Additionally, modified IgG-Fc fusions are taught with increased in vivo half-lives (e.g., col. 31, lines 56-64, and claims 1-4) and wherein the IgG-Fc is linked to the bioactive protein, which linkage may be by a linker sequence (col. 34, lines 59-67, and col. 37, lines 10-14). The Fc-containing fusion proteins maybe purified by methods well known to those skilled in the art. IgGs were purified from conditioned media with protein A columns according to the manufacturer’s instructions (col. 67, lines 51-56, and col. 68, lines 38-41).
It would have been obvious to have a fusion protein comprising CXCL9 conjugated to an immunoglobulin molecule Fc region because both Zohar et al. and Karin et al. taught functional Ig fusion of cytokines and of chemokines that had longer half-lives. It would have been obvious to substitute one known element for another, e.g., one CXCL for another (especially one CXCR3 ligand for another) and, for example, mouse IgG-Fc for human IgG-Fc of US ‘784. As stated above, Zohar et al. acknowledges that further investigation is necessary to determine if their findings with CXCR3 and its distinct ligands can be applied to other autoimmune diseases. Further, Karin et al. suggest CXCL10-Ig may be used for treatment of cancers. The prior art provides motivation to make and use a CXCL9-Ig fusion for investigation of these therapeutic treatments. Further, because ultimately most therapeutics are designed for human use, it would have been obvious wherein the Ig- Fc, e.g., hinge-CH2-CH3, were of human origin to reduce the chance of undesirable immune response in humans. It further would have been desirable to have a linker between the chemokine and Ig-Fc, such as a glycine- and serine-containing linker, in order to increase flexibility between the two components to reduce the chance of steric hindrance during receptor binding. Because the experiments of Zohar et al. and Karin et al. support CXCR3 binding by the CXCL11-Ig and CXCL10-Ig fusion, one of ordinary skill in the art would reasonably have expected a CXCL9-Ig fusion to also bind CXCR3.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US 8,541,564 B2 is drawn to chemokine-immunoglobulin fusion polypeptides, wherein the chemokine can be CXCL9 and Ig can be human IgG1 (e.g., col. 2, lines 33-49). It teaches SEQ ID NO:39, which is identical to the human CXCL9 (see Table 1 of patent). It also teaches a hCXCL11-hIgG1-Fc fusion of SEQ ID NO:67, as well as fusion of variants hCXCL11 to hIgG-Fc of hinge-ch2-ch3, wherein the Fc region has a sequence highly similar to instant SEQ ID NO:5. The prior art is cited to show the concept of a fusion protein comprising a CXCL9 polypeptide conjugated to an IgG-Fc was known in the art before Zohar et al. relied upon above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
May 22, 2026
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