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 .
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 05/15/2026 has been considered by the Examiner inasmuch as foreign documents have been submitted into the file wrapper in English.
Claim Status
The claim set and Applicant’s remarks filed May 15, 2026, as well as the supplemental amendment to the specification filed June 30, 2026 have been entered.
Claims 60, 62 and 67-68 continue to be withdrawn from further consideration as being drawn to a nonelected invention.
Claims 1-3, 5-6, 11, 13-58, 61, 63-66, 69-82 and 88 are canceled.
Claim 92 is new.
Thus, claims 4, 7-10, 12, 59, 83-87 and 89-92 as amended are examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the non-final office action on January 05, 2026:
The objection to claim 4 is withdrawn in view of Applicant’s amendment to the claim.
Response to Arguments
(I) The rejection of claims 4, 7-10, 12, 59, 83-87 and 89 under 35 U.S.C. 103 are maintained.
Applicant argues:
(A) None of the cited references, alone or in combination, teach or suggest a modified SOCS3 fusion protein comprising a single domain antibody that is cross-reactive against EGFR/EGFRvIII, see Applicant’s remarks, pg. 8, first full paragraph.
(B) Jo fails to disclosure a fusion protein of the SOCS3 protein with an antibody or fragment thereof at all, which is why the Examiner cites Choi, see Applicant’s remarks, pg. 8, second full paragraph.
(C) Applicant respectfully submits the Examiner has misinterpreted Choi, because Choi does not specify that “antibodies and antibody fragments are aMTDs for clinical applications”; contrary to the Examiner’s assertions; as Applicant argues Choi treats SOCS3 and antibodies as alternative cargos to be fused to an aMTD, not as components to be combined within the same fusion polypeptide; and therefore the combination does not teach or suggest a SOCS3 fusion protein that further comprises an sdAB, see Applicant’s remarks, pg. 8, third full paragraph.
With respect to Applicant’s arguments (A)-(C), the Examiner notes Choi teaches in paragraph [0095], when the iCP-SOCS3 recombinant protein is intended to be delivered to a particular cell, tissue, or organ, the SOCS3 protein may form a fusion product, together with an extracellular domain of a ligand capable of selectively binding to a receptor which is specifically expressed on the particular cell, tissue, or organ, or monoclonal antibody (mAb) capable of specifically binding to the receptor or the ligand and a modified form thereof".
Therefore, the Examiner notes, contrary to Applicant’s arguments, Choi does teach SOCS3 proteins may form a fusion product with a monoclonal antibody (mAb) when the iCP-SOCS3 recombinant protein is intended to be delivered to a particular cell, tissue, or organ; and thus, Choi does teach SOCS3 and antibodies are components to be combined within the same fusion polypeptide for the reason taught by Choi above.
(II) The rejection of claims 90-91 under 35 U.S.C. 103 is maintained.
Applicant argues:
(A) The Examiner’s rationale is based on the assertion that one of ordinary skill would have substituted Kim’s naringenin for Zhang’s naringenin chalcone; however, Applicant submits that the record does not support this assertion because (i) the proposed substitution is not a simple substitution and (ii) Kim’s own teachings rebut a finding of a reasonable expectation of success, see Applicant’s remarks, pg. 10, first full paragraph.
(B) The Examiner has identified no prior art teaching that naringenin chalcone and naringenin are recognized equivalents (for the treatment of glioblastoma), nor that the open-chain chalcone structure is functionally interchangeable with the closed heterocyclic ring structures of flavanones; and accordingly the Examiner’s assertion that the substitution would have “yielded predictable results” is therefore conclusory and is not sufficient to establish a prima facie case of obviousness, see pg. 10, last paragraph of the page – pg. 11, first paragraph of the page.
With respect to Applicant’s arguments (A)-(B), the Examiner notes Zhang teaches naringenin chalcone is the therapeutic agent to treat U87MG human glioblastoma cells, where a cytotoxic effect showed a sharp increase at concentrations above 50 micromolar.
Additionally, the Examiner notes Kim teaches treating the same cell-line, which is the human glioblastoma cell line (U87MG) and showed that naringenin dose-dependently inhibited the growth of said U87MG cells with an IC50 value of 133.5 micromolar, which the Examiner notes correspond to the teachings of the concentration of naringenin chalcone taught by Zhang above.
(C) Even if, arguendo, there were a presumption of similar properties between naringenin chalcone and naringenin, the teachings of Kim stand to teach away from the use of naringenin for the treatment of glioblastoma, because it functions worse than the other flavonoids apigenin and quercetin in several aspects, see Applicant’s remarks, pg. 11, last paragraph of the page.
(D) Even if, arguendo, Kim does not actually teach away, Kim’s data showing unpredictable activity among different flavonoids in the glioblastoma stem-like cell models defeats any expectation that naringenin would replicate the activity that Zhang reports for naringenin chalcone, see Applicant’s remarks, pg. 12, first full paragraph.
With respect to Applicant’s arguments (C)-(D), the Examiner reiterates their arguments above, and further notes MPEP 2143.01(I) states "The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention"; and "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed".
Accordingly, although Kim teaches lower IC50s for apigenin and quercetin; they are reasonably comparable with the inhibitory concentrations of naringenin chalcone taught by Zhang.
Also, Kim teaches naringenin partially decreases the expression levels of CD133 and Sox2 which are stemness markers which play a role in the invasiveness of GSCs, thereby reducing the invasiveness of GBM stem-like cells, see pg. 1838, right column, paragraph 1.
Kim teaches in Figures 5A, B the three flavonoids led to significant reduction of cell migration in U87MG GSCs, see pg. 1838, left column, paragraph 1; but naringenin did not induce significant delay in the migration of GBM stem-like cells at the tested concentration (25 micromolar), see pg. 1838, left column, paragraph 1.
Additionally, Kim further teaches the neurosphere formation ability was not markedly suppressed when treated with naringenin at the indicated concentration recited in Figs. 3A, B, see pg. 1837, right column, paragraph 1; wherein Figs 3. A, B teach the concentration is 25 micromolar, see pg. 1836, Figure 3.
Furthermore, the Examiner notes none of the functional aspects argued by Applicant in Applicant’s remarks on pg. 11, second to last paragraph of the page, are required within the claim; and the Examiner further notes claim 90 recites "administering a flavanone to the subject in an amount sufficient to increase the level of SOCS3 in said tumor of said subject, see claim 90, pg. 6, lines 1-2; which as the Examiner particularly notes does not exclude the amount taught by Kim as discussed above.
(E) Kim’s conclusion that only apigenin has the promise to serve as an anticancer agent clearly discredits the similarity tested naringenin for the same purpose, see Applicant’s remarks, pg. 11, last paragraph of the page – pg. 12, first paragraph of the page.
With respect to Applicant’s argument (E), the Examiner respectfully submits Applicant has misinterpreted Kim, as the Examiner respectfully notes Kim teaches "taken together, we suggest that apigenin can serve as an attractive anticancer agent against c-Met-addicted GBM", see pg. 1830, right column, paragraph 3.
Therefore, the Examiner notes Kim does not conclude only apigenin has the promise to serve as an anticancer agent as argued by Applicant.
Rather, the Examiner particularly notes the above teaching of Kim merely suggests use of apigenin as an attractive anticancer agent in treating a specific subset of glioblastoma (GBM) that relies heavily on c-Met as its mechanism of action.
Thus, Applicant’s arguments (A)-(E) have been fully considered but are not found persuasive.
New Claim Rejections
The Examiner notes the maintained 103 rejections of claims 4, 7-10, 12, 59, 83-87 and 89-91 are provided below; and that new ground rejections necessitated by Applicant's amendment, filed on May 15, 2026, where claim 92 has been newly added, is provided below.
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.
Claim 92 is 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 92 recites the limitation "The method of " in line 1. There is insufficient antecedent basis for this limitation in the claim.
The Examiner notes claim 1 is canceled as discussed above, accordingly claim 1 does not provide proper antecedence for the modified SOCS3 fusion protein recited in claim 92.
In the interest of compact prosecution, the Examiner will interpret claim 92 depends from claim 4 which first recites the modified SOCS3 fusion protein in line 3.
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.
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.
(I) Claims 4, 7-9, 59, 83-85 and 89 remain rejected under 35 U.S.C. 103 as being unpatentable over Jo et al. (Published 03 March 2016, Filed 27 August 2015, US-20160060314-A1, IDS filed 07/13/2021) in view of Choi et al. (Published 18 May 2017, US-20170137482-A1, PTO-892 mailed 07/08/2025) and Iqbal et al. (Published 24 May 2010, British Journal of Pharmacology, Vol. 160, Issue 4, pp. 1016-1028, PTO-892 mailed 01/05/2026).
Regarding claims 4, 7-9, 59, 83-85 and 89, Jo teaches improved cell-permeable SOCS3 (iCP-SOCS3) proteins, wherein SOCS3 is fused to an empirically determined advanced macromolecule transduction domain (MTD) and a customized solubilization domain (SD), wherein the macromolecular intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against various tumors such as glioblastomas, see abstract.
Jo teaches Fig. 37 shows suppression of subcutaneously implanted glioblastoma with iCP-SOCS3. Female Balb/c nu/nu mice were subcutaneously implanted with U-87 MG tumor block (1 mm3) into the left side of the back. After tumors reached a size of 50-80 mm3 (start), the mice were injected daily (I.V.) (e.g. systemic administration, required in claim 59) for 3 w with diluent alone (black) or with HS3B (blue) or HM165S3B (iCP-SOCS3, red) and observed for 2 w following the termination of the treatment. Tumor weight (left) and volume (right) were measured in the indicated day, see paragraph [0055]. Jo refers to iCP-SOCS3 as aMTD/SD-fused iCP-SOCS3 proteins, see paragraph [0011].
Jo teaches HM165S3B protein significantly suppressed the tumor growth (p<0.05) during the treatment and the effect persisted for at least 2 weeks after the treatment was terminated (65% inhibition in the gastric cancer xenograft, 79% inhibition in the colorectal cancer xenograft at day 35, 78% inhibition in the glioblastoma xenograft at day 42, respectively), see paragraph [0106]. Expression of tumor suppressors (p21, Bax, and cleaved caspase-3) was dramatically enhanced in tumor tissues treated with HM165S3B recombinant protein (FIGS. 33 and 36), suggesting that iCP-SOCS3 inhibits tumor growth by regulating tumor-specific protein expression in vivo, see paragraph [0107].
Jo teaches the levels of vascular endothelial growth factor (VEGF) and CD31, a pro-angiogenic factor, were inhibited in HM165S3B-treated tumors (FIGS. 33 and 36), see paragraph [0107], e.g. pathological blood vessel growth required in claim 4.
Jo teaches reduced or silenced SOCS3 has been found in many human types of cancer including colorectal cancer, and restoring SOCS3 expression in the cancer cells inhibits IL-6-mediated STAT3 activation, induces tumor cell apoptosis and decreases cell proliferation, see paragraph [0005] and treatment of cancer cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis of solid tumors including gastric, colorectal, breast cancer and glioblastoma and loss of cell migration/invasion potential, see abstract.
Jo teaches these in vivo results suggest that iCP-SOCS3 targets tumor cells directly and may be developed for use as novel therapy against various solid tumors including breast cancer (e.g. host tissue that is stromal tissue required in claim 9), see paragraph [0107].
Jo teaches the structure of SOCS3 recombinant proteins and HM165S3B contains SOCS3, see FIG.1. Jo teaches the amino acid sequence of human SOCS3 in SEQ ID NO: 486, see pg. 16; wherein lines 1-2 teach the three-letter amino acid sequence “Leu-Lys-Thr-Phe-Ser-Ser-Lys-Ser-Glu-Tyr-Gln-Leu” (e.g. shares 100% sequence similarity with SEQ ID NO:1, required in claim 89), see pg. 16, SEQ ID NO: 486, lines 1-2.
Although, Jo does not teach wherein the modified SOCS3 fusion protein comprises a single domain antibody (sdAb) that is cross-reactive against EGFR and EGFRvIII, required in claim 4, last two lines of the claim.
However, in the same field of endeavor of improved cell-permeable SOCS3 (iCP-SOCS3) proteins, Choi teaches improved cell-permeable (iCP)-SOCS3 recombinant protein and uses thereof. Preferably, the iCP-SOCS3 recombinant protein may be used as protein-based anti-solid tumor agent by utilizing the platform technology for macromolecule intracellular transduction. See paragraph [0001].
Choi teaches advanced macromolecule transduction domain (aMTD) / solubilization domain (SD)-fused iCP-SOCS3 recombinant proteins (iCP-SOCS3), see paragraph [0026].
Choi teaches for clinical/non-clinical application, aMTD-fused cargo materials would be biologically active molecules that could be one of the following and including antibodies and antibody fragments, see paragraph [0332].
Choi teaches solid tumors described herein include glioblastoma, see paragraph [0152].
Although, Choi does not teach the antibody is a single domain antibody (sdAb) that is cross-reactive against EGFR and EGFRvIII, required in the last two lines of instant claim 4.
However, in the same field of endeavor of targeting glioblastomas, Iqbal teaches the overexpression of epidermal growth factor receptor (EGFR) and its mutated variant EGFRvIII occurs in 50% of glioblastoma multiforme, where Iqbal developed antibody fragments against EGFR/EGFRvIII for therapeutic targeting applications, see pg. 1017, abstract, background and purpose, paragraph 1.
Iqbal exemplifies said antibody fragment when teaching EG2 an anti-EGFR/EGFRvIII single domain antibody analyzed in vitro for its binding affinities to EGFR and EGFRvIII, see pg. 1017, abstract, experimental approach, paragraph 1.
Iqbal teaches kinetic binding analyses by surface plasmon resonance revealed intrinsic affinities of 55 nM and 97 nM for the monovalent EG2 to immobilize extracellular domains of EGFR and EGFRvIII, respectively, see pg. 1017, abstract, key results, paragraph 1.
Iqbal teaches in clinical glioblastoma multiforme (GBM) a concomitant overexpression of EGFR and EGFRvIII is frequently observed, and since EG2 sdAb can recognize both EGFR and EGFRvIII it could be used for targeting GBMs and other cancers including colorectal and breast cancer, see pg. 1026, right column, paragraph 3.
With respect to the limitations “to increase the level of SOCS3 in said tumor”, required in claim 4 and claim 89; “inducing immune cell infiltration of a tumor”, required in claim 83; “decreases tumor size and tumor volume”, required in claim 84; and “wherein the immune cells are cytolytic or induce cytolysis of the tumor”, required in claim 85; are all limitations reasonably interpreted by the Examiner to be consequences of administering a modified SOCS3 fusion protein. Thus, the limitations stated above would be met as Jo teaches HM165S3B protein significantly suppresses tumor growth as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have modified the iCP-SOCS3 proteins taught by Jo to include an antibody as taught by Choi and to have specifically used EG2 taught by Iqbal above as the antibody of choice as within the scope of the artisan as combining prior art elements according to known compositions and methods to yield predictable results.
One of ordinary skill in the art would have been motivated to modify the iCP-SOCS3 proteins taught by Jo to include an antibody as taught by Choi and to have specifically chosen the single domain antibody (sdAb) known as EG2 as taught by Iqbal above as a novel protein therapy against glioblastomas as taught by Jo; as Iqbal explicitly teaches the sdAB known as EG2 has sub 100 nanomolar affinity to both EGFR and EGFRvIII and could be used to target glioblastoma multiforme (GBM); as Iqbal expressly teaches clinical GBM concomitant overexpression of EGFR and EGFRvIII is frequently observed as discussed above.
One of ordinary skill in the art would have had a reasonable expectation of success to have included the antibody of Choi and specifically the sdAb known as EG2 as taught by Iqbal above into the iCP-SOCS3 proteins taught by Jo; as both Jo and Choi are drawn to iCP-SOCS3 proteins that can be fused to an advanced macromolecule transduction domain (aMTD); Choi specifies that antibodies and antibody fragments are aMTDs for clinical applications; the iCP-SOCS3 proteins taught by Jo and Choi are antitumor agents against glioblastoma; and wherein the sdAb known as EG2 taught by Iqbal above can used to target glioblastoma multiforme as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(II) Claims 10 and 12 remain rejected under 35 U.S.C. 103 as being unpatentable over Jo et al. (Published 03 March 2016, Filed 27 August 2015, US-20160060314-A1, IDS filed 07/13/2021), Choi et al. (Published 18 May 2017, US-20170137482-A1, PTO-892 mailed 07/08/2025) and Iqbal et al. (Published 24 May 2010, British Journal of Pharmacology, Vol. 160, Issue 4, pp. 1016-1028, PTO-892 mailed 01/05/2026) as applied to claims 4, 7-9, 59, 83-85 and 89 above, and further in view of Shen et al. (Published 19 June 2015, Gene Therapy, Vol. 22, pp. 893-900, PTO-892 mailed 11/04/2024).
Jo, Choi and Iqbal address claims 4, 7-9, 59, 83-85 and 89 as written above. Jo further teaches FIG. 2 shows the construction of expression for SOCS3 recombinant proteins. These figures show the agarose gel electrophoresis analysis showing plasmid DNA fragments encoding SOCS3, aMTDs fused SOCS3 and SD cloned into the pET28 (+) vector, see paragraph [0020].
Although, Jo does not teach wherein the vector is adeno associated virus (AAV), required in claims 10 and 12.
However, in the same field of endeavor of inhibiting pathological angiogenesis, Shen teaches inhibition of pathological brain angiogenesis (e.g. the viral vector is tissue specific, required in claim 12) through systemic delivery of AAV vector expressing soluble FLT1 (e.g. the adeno associated virus (AAV), required in claim 10), see title.
Shen teaches AAV1-VEGF (Table 1 and Supplementary Figure S1) was injected into the basal ganglia of the brain to induce angiogenesis, see pg. 894, left column, results, paragraph 1. Shen teaches AAV2-sFLT02, expressing a fusion protein sFLT02 containing human FLT1 extra-cellular domain 2 and CH3 domain of IgG1, (Table 1 and Supplementary Figure S1) was stereotactically injected into the angiogenic foci at the time of (Figure 1a) or 4 weeks after (Figure 1b) angiogenic induction, see pg. 894, left column, results, paragraph 1.
Shen teaches AAV-mediated sFLT1 gene transfer could inhibit brain angiogenesis when injected into the angiogenic foci at the time of or 4 weeks after angiogenic induction, see pg. 894, left column, results, paragraph 2.
With respect to the limitation “the viral vector is tissue specific”, required in claim 12, the Examiner interprets this limitation as a physical characteristic of the viral vector, as Shen teaches AAV2 that expresses a fusion protein could inhibit brain angiogenesis. Thus, the limitation of “the viral vector is tissue specific” is met.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have substituted the pET28 (+) vector, taught by Jo, for the AAV2 vector taught by Shen as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to promote inhibition of pathological brain angiogenesis through systemic delivery of an AAV vector expressing a fusion protein as taught by Shen in order to treat the glioblastoma as taught by Jo. One of ordinary skill in the art would have had a reasonable expectation of success to have combined the AAV vector as taught by Shen, with the fusion protein HM165S3B taught by Jo above, as Shen teaches AAV2-sFLT02 can express fusion proteins, for example sFLT02 as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(III) Claims 86-87 remain rejected under 35 U.S.C. 103 as being unpatentable over Jo et al. (Published 03 March 2016, Filed 27 August 2015, US-20160060314-A1, IDS filed 07/13/2021), Choi et al. (Published 18 May 2017, US-20170137482-A1, PTO-892 mailed 07/08/2025) and Iqbal et al. (Published 24 May 2010, British Journal of Pharmacology, Vol. 160, Issue 4, pp. 1016-1028, PTO-892 mailed 01/05/2026) as applied to claims 4, 7-9, 59, 83-85 and 89 above, and further in view of Reardon et al. (Published 01 February 2016, Cancer Immunology Research, Vol. 4, Issue 2, pp. 124-135, PTO-892 mailed 11/04/2024).
Jo, Choi and Iqbal address claims 4, 7-9, 59, 83-85 and 89 as written above.
Although, Jo does not teach (a) further administering one or more checkpoint blockade immunotherapeutic agents, required in claim 86; and (b) wherein the checkpoint blockade immunotherapeutic agents are specific for the limitations recited, required in claim 87.
However, in the same field of endeavor of treating glioblastomas, Reardon teaches glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model, see title. Reardon teaches systematically evaluating the antitumor activity as measured by survival using mAbs against CTLA-4, PD-1, PD-L1, and PD-L2 as single agents and in combinatorial regimens in separate experiments, see pg. 125, right column, In vivo treatment and tumor assessment, paragraph 2.
Reardon demonstrated that systemic administration of CTLA-4, PD-L1, and PD-1 inhibitors can improve survival for intracranial glioblastoma tumors. Single-agent blockade achieved durable survival benefit in a subset of tumor-bearing animals that was most robust with PD-1 mAb therapy, but dual blockade of CTLA-4 plus PD-1 exhibited the greatest antitumor benefit, see pg. 134, left column, paragraph 1.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included limitations (a)-(b) into the treatment method of Jo as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to eradicate glioblastoma as taught by Jo following immune checkpoint blockade administration as taught by Reardon as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success to have included limitations (a)-(b) into the treatment method of Jo, as Reardon teaches dual blockade of CTLA-4 plus PD-1 exhibited the greatest antitumor benefit and wherein systemic administration of CTLA-4 and PD-1 inhibitors can improve survival for intracranial glioblastoma tumors; and wherein both Jo and Reardon are drawn to treatment of glioblastomas as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(IV) Claims 90-91 remain rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Published 12 July 2016, Bangladesh Journal of Pharmacology, Vol. 11, No. 3, pp. 684-690, PTO-892 mailed 11/04/2024) in view of Kim et al. (Published 29 July 2016, Phytotherapy Research, Vol. 30, Issue 11, pp. 1833-1840, PTO-892 mailed 01/05/2026) as evidenced by Ke et al. (Published 01 June 2000, Clinical Cancer Research, Vol. 6, Issue 6, pp. 2562-2572, PTO-892 mailed 07/08/2025).
Zhang teaches the anti-tumor effects of naringenin chalcone were examined using a nude mouse model. The U87MG human glioblastoma cells (1 x 106 cells/mouse) were subcutaneously injected into the right rear flank of each mouse (6-8 mice per group) to produce tumors in mice (e.g. a tumor in a subject, required in claim 90, lines 1-2). After tumor development, the mice were divided into 5 groups, viz., vehicle control group, naringenin chalcone-treated group with 5 mg/kg dose, naringenin chalcone-treated group with 20 mg/kg dose, naringenin chalcone-treated group with 40 mg/kg dose, and naringenin chalcone-treated group with 80 mg/kg dose (e.g. the host tissue of said subject, required in claim 90, line 3). See pg. 686, left column, Xenograft tumor model in nude mice, paragraph 1.
Zhang teaches that with increasing concentrations of the compound, the cytotoxicity effect first showed slow increase but at concentrations above 50 μM, the cytotoxic effect showed a sharp increase, see pg. 686, Results, Anti-tumor activity against U87MG human glioblastoma cells, paragraph 1. Zhang teaches in vivo results showed that both tumor volume and tumor weight were lesser in naringenin chalcone-treated groups (e.g. inhibiting the growth of said tumor in a subject, required in claim 90, lines 4-5) with its different doses than in vehicle control group, see abstract and Figure 5, pg. 689.
Zhang teaches in vivo anti-tumor activity where weight and tumor volume in nude mice decreased considerably in the naringenin chalcone-treated group with 100 mg/kg disease in contrast to the control group, see pg. 688, in vivo anti-tumor activity, paragraph 1.
Zhang teaches at the end of the experiment both tumor volume and tumor weight was measurably less as compared to Figure 5A which depicts the vehicle control group and Figure 5E, which depicts the naringenin chalcone-treated group with 80 mg/kg dose, see 689, Figure 5.
Although, Zhang does not teach wherein the flavone is naringenin as required in claim 91.
However, in the same filed of endeavor of anti-tumor activity against U87 MG cells, Kim teaches the therapeutic effect of dietary flavonoids, including naringenin, against stem cell-like phenotypes of human glioblastoma (GBM) cell lines U87MG and U373MG, see pg. 1833, abstract.
Kim teaches naringenin dose-dependently inhibited the growth of GBM stem-like cells in U97MG with an IC50 value of 133.6 µM (Fig 2B), see pg. 1837, right column, paragraph 1.
With respect to the limitation, “an amount sufficient to increase the level of SOCS3”, required in claim 90, lines 3-4, the Examiner is reasonably interpreting this limitation as a physical limitation required to inhibit the growth of the tumor. Since Zhang teaches administering naringenin chalcone to mice who developed U87MG human glioblastoma tumors as taught above, wherein the mice treated with naringenin chalcone at an 80 mg/kg dose measurably decreased both the tumor volume and tumor growth as shown in Figures 5A and 5E and Kim teaches naringenin could dose-dependently inhibit the growth of GBM stem-like cells in U87MG cells, the physical limitation of “an amount to increase the level of SOCS3” is met by the combined method taught by Zhang and Kim as discussed above.
With respect to the limitation, “pathological blood vessel growth”, required in claim 90, line 1; Zhang teaches U87MG human glioblastoma cells were injected into mice and developed into tumors and Kim tested naringenin against glioblastoma cell U87MG, wherein as evidenced by Ke, vascular endothelial growth factor (VEGF) levels in the glioma cell lines studied were shown to play an important role on angiogenesis and tumorgenicity. Ke also explicitly discloses U87MG cells secreted a significantly higher level of VEGF than other glioma cells both in vitro and in vivo; consequently, denser and larger blood vessels were formed in these tumors than in other tumors, see pg. 2570, right column, paragraph 2.
Therefore, the limitation “pathological blood vessel growth” as required in claim 90 is made obvious by the combined method of Zhang in view of Kim, as evidenced by Ke, as Ke demonstrates that U87MG cells, which are the identical cell line used by Zhang and Kim, secrete higher levels of VEGF thereby forming denser and larger blood vessels than other glioma cell lines as discussed above. Thus, the limitation “pathological blood vessel growth” is met by the combined method of Zhang and Kim.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have substituted the naringenin chalcone as the test compound as taught by Zhang for the naringenin as taught by Kim as a simple substitution of one known element for another by combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to treat the mice injected with U87MG human glioblastoma cells wherein said cells developed into tumors as taught by Zhang above. One of ordinary skill in the art would have had a reasonable expectation of success to have made the substitution as discussed above because both Zhang and Kim are drawn to methods of treating glioblastoma through the exemplification of targeting the identical glioblastoma cell line U87MG as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(V) Claim 92 is rejected under 35 U.S.C. 103 as being unpatentable over Jo et al. (Published 03 March 2016, Filed 27 August 2015, US-20160060314-A1, IDS filed 07/13/2021), Choi et al. (Published 18 May 2017, US-20170137482-A1, PTO-892 mailed 07/08/2025) and Iqbal et al. (Published 24 May 2010, British Journal of Pharmacology, Vol. 160, Issue 4, pp. 1016-1028, PTO-892 mailed 01/05/2026) as applied to claims 4, 7-9, 59, 83-85 and 89 above, and further in view of Shen et al. (Published 19 June 2015, Gene Therapy, Vol. 22, pp. 893-900, PTO-892 mailed 11/04/2024) as evidenced by Ke et al. (Published 01 June 2000, Clinical Cancer Research, Vol. 6, Issue 6, pp. 2562-2572, PTO-892 mailed 07/08/2025).
The Examiner notes Jo, Choi and Iqbal address claims 4, 7-9, 59, 83-85 and 89 as written above.
The Examiner further notes Jo and Shen teach as discussed above; and Jo further teaches aberrant expression of SOCS3 protein was observed in human solid tumors including glioblastomas, see paragraph [0003].
Jo teaches developing SOCS3 recombinant proteins fused to aMTD and solubilization domain, see pg. 14, right column, lines 1-4; as well as designing and constructing SOCS3 recombinant protein containing only solubilization domain B (SBD) (without aMTD165: HS3B), see paragraph [0096]; wherein Jo teaches aMTD165 is a domain to facilitate protein translocation across the membrane, which said differently is a cell-penetrating peptide (CPP), see paragraph [0085].
Jo also teaches STAT phosphorylation was readily detected in cells exposed to HS3, which lacks the aMTD motif required for membrane penetration (FIG. 12), indicating that HS3, which lacks an MTD sequence did not enter the cells, and thus has no biological activity, see paragraph [0099].
The Examiner notes in the preceding paragraph the teachings of Jo suggest constructing SOCS3 recombinant protein containing only solubilization domain B (SBD) does not allow said SOCS3 recombinant protein to enter the cell.
Therefore, in view of this consideration, the Examiner notes Jo does not teach where the modified SOCS3 fusion protein does not comprise a cell-penetrating peptide as recited in claim 92 for use in the method of claim 4.
However, in the same field of endeavor of inhibiting pathological angiogenesis, Shen teaches as discussed above, particularly Shen teaches inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1, see title; and a method of AAV vector construction and production, see pg. 897, right column, Materials and Methods, AAV vector construction and production.
Shen teaches AAV1-VEGF (Table 1 and Supplementary Figure S1) was injected into the basal ganglia of the brain to induce angiogenesis, see pg. 894, left column, results, paragraph 1. Shen teaches AAV2-sFLT02, expressing a fusion protein sFLT02 containing human FLT1 extra-cellular domain 2 and CH3 domain of IgG1, (Table 1 and Supplementary Figure S1) was stereotactically injected into the angiogenic foci at the time of (Figure 1a) or 4 weeks after (Figure 1b) angiogenic induction, see pg. 894, left column, results, paragraph 1.
Shen teaches AAV-mediated sFLT1 gene transfer could inhibit brain angiogenesis when injected into the angiogenic foci at the time of or 4 weeks after angiogenic induction, see pg. 894, left column, results, paragraph 2.
Moreover, as evidenced by Ke, Ke explicitly discloses U87MG cells (human glioblastoma (GBM) cell line) secreted a significantly higher level of VEGF than other glioma cells both in vitro and in vivo; consequently, denser and larger blood vessels were formed in these tumors than in other tumors, see pg. 2570, right column, paragraph 2.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have modified the SOCS3 recombinant protein containing only solubilization domain B taught by Jo with the AAV vector expressing soluble FLT1 in order to inhibit pathological angiogenesis as taught by Shen, which the Examiner notes is useful within a therapeutic context for use in glioblastomas as taught by Jo and as evidenced by Ke as discussed above, as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results.
One of ordinary skill in the art would have been particularly motivated to modify the SOCS3 recombinant protein containing only solubilization domain B taught by Jo with the AAV vector expressing soluble FLT1 as taught by Shen in order to inhibit pathological angiogenesis within glioblastomas as taught by Jo and as evidenced by Ke, as Jo explicitly teaches the SOCS3 recombinant protein containing only solubilization domain B did not enter the cells, and thus had no biological activity. One of ordinary skill in the art would have had a reasonably expectation of success to have incorporated the teachings of Shen into the teachings of Jo, because both Shen and Jo are drawn to soluble fusion proteins that inhibit pathological angiogenesis; particularly glioblastomas as taught by Jo and as evidenced by Ke; and Shen further teaches a method of AAV vector construction and production comprising said soluble fusion proteins as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
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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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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