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 .
Claim Status
Claims 1-17 are pending.
Claims 6, 8 and 12-17 were withdrawn from further consideration (see below).
Claims 1-5, 7 and 9-11 are under consideration.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 7/30/2026 is acknowledged.
Claim(s) 12-17 were/was withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/30/2026.
Applicant’s election without traverse of species Zbtb46 mRNA nanoparticle in the reply filed on 7/30/2026 is acknowledged.
Since the elected species is free of the prior art, the search has been expanded to other species.
Claim(s) 6 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/30/2026.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at paragraph [0223] and [0224]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 recites “Zbtb46”. Abbreviation must be spelled out on its first use. Appropriate correction is required.
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 3 and 7 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 3 recites “the ICB therapy”. There is insufficient antecedent basis for this limitation in the claim. Claim 3 depends from claim 1 and claim 1 does not recite “an ICB therapy”.
Claim 7 recites “the Zbtb46 modulating agent” in line 1 and 3. There is insufficient antecedent basis for this limitation in the claim. While claim 1 recites “Zbtb46 modulation agent”, claim 1 does not recite “Zbtb46 modulating agent”.
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 1-5, 7 and 9-10 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a “written description” rejection.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Regents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to antigen, high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 (“[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims.”). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
Additionally, “An adequate written description must contain enough information about the actual makeup of the claimed products—“a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” which may be present in “functional” terminology “when the art has established a correlation between structure and function.” Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies.” Amgen Inc v. Sanofi 124 USPQ2d 1354, 1361 (Fed. Cir. 2017). “Further, the “newly characterized antigen” test flouts basic legal principles of the written description requirement. Section 112 requires a “written description of the invention.” But this test allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen. The test thus contradicts the statutory “quid pro quo” of the patent system where “one describes an invention, and, if the law's other requirements are met, one obtains a patent.” Ariad, 598 F.3d at 1345.” Amgen at 1362.
Claim Analysis
Instant claims are drawn to a method to treat a cancer in a patient, the method comprising administering a therapeutically effective amount of an immunotherapy and a therapeutically effective amount of a Zbtb46 modulation agent(s) to the patient.
Instant claim 1 recites a broad limitation “Zbtb46 modulation agent”. Instant specification disclosed that Zbtb46 expression was downregulated in the tumor-associated ECs and DCs in the wild type mice bearing 1956 sarcoma, LLC carcinoma, and breast cancer [0229]. Zbtb46 knock-out (ZKO) mice were challenged with the same tumor models to determine whether this suppression contributes to tumor outcome. Compared to their wild type counterparts, ZKO mice exhibited more robust tumor growth [0230]. Zbtb46 mRNA nanoparticle was generated using the p5RHH peptide system. The p5RHH peptide-based nanoparticle system readily formulates mRNA for systemic administration and extrahepatic nucleotide delivery and showed promise for safe and effective clinical translation. Systemic administration of Zbtb46 mRNA nanoparticle was effective in sustaining Zbtb46 expression in tumor-DCs and -ECs and resulted in the restriction of tumor growth (FIG. 11A, FIG. 11B, FIG. 11C, FIG. 11D, FIG. 11E, FIG. 11F, FIG. 11G) [0255]. The tumor growth restriction was associated with an immunostimulatory TME (FIG. 11A, FIG. 11B, FIG. 11C, FIG. 11D, FIG. 11E, FIG. 11F, FIG. 11G). Remarkably, the nanoparticles induced dramatic response in both anti-PD1-responsive (1956 sarcoma) and -refractory (PyMT-BO1) tumor models following the treatment, generating long-term complete remission of tumor mass in many of the treated animals challenged with the anti-PD1-responsive 1956 sarcoma tumor [0256]. Intriguingly, co-transplanting tumor cells with Zbtb46-overexpressed ECs also improved the anti-PD1 treatment outcome (FIG. 11I), reinforcing the importance of the EC-specific Zbtb46 expression in tumor progression [0256].
Furthermore, Kabir et al (Nature Immunology, Vol. 25, September 2024, 1546-1554; PTO-892) teaches “Here, we report that ZBTB46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs), controls both tumor angiogenesis and immunity. Zbtb46 was downregulated in both DCs and endothelial cells by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive conditions. Analysis of human cancer data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression led to TME changes to restrict tumor growth. … Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in preclinical models.” (abstract). In addition, Kabir teaches that enforced Zbtb46 expression was performed by mRNA nanoparticle (Figure 5a; reproduced below).
PNG
media_image1.png
429
1264
media_image1.png
Greyscale
Therefore, both instant specification and state of art teach combination therapy of Zbtb46 mRNA nanoparticle and anti-PD-1 immunotherapy. Instant specification did not disclose any other Zbtb46 modulation agent such as Zbtb46 mRNA, BMS493, NS398, NAC+APO, Cebpb antibody and Cebpb shRNA as claimed by instant claims. Only a single species Zbtb46 mRNA nanoparticle cannot be considered as a representative number of species falling within the scope of genus encompassing any possible Zbtb46 modulation agent. Therefore, instant specification and prior art do not provide adequate written description for broadly claimed limitation “Zbtb46 modulation agent” of instant claim 1.
The disclosure therefore does not show that applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
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.
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.
Claims 1-3, 5, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al (US2020/0264185; PTO-892) in view of Tsujii et al (Cell, vol. 93, 705-716, May 29, 1998; PTO-892).
Regarding claims 1-3, Xu teaches “Compositions and methods are disclosed for treating cancer patients and identifying patients with a malignancy that are likely to respond to treatment with anti-PD-1/PD-L1 and other anti-cancer and immune-modulating therapeutics” (abstract). Xu teaches a method of treating colon cancer by administering an anti-cancer therapy directed to PD-1 and/or PD-L1 to a subject (claims 40 and 46). Xu teaches that anti-cancer therapy is an anti-PD-1 antibody or an anti-PD-L1 antibody (claim 45).
The difference between prior art and the instant invention is that Xu does not teach combination therapy with Zbtb46 modulation agent to treat colon cancer.
Regarding claim 1 and 7, Tsujii teaches “Cyclooxygenase regulates colon carcinoma-induced angiogenesis by two mechanisms: COX-2 can modulate production of angiogenic factors by colon cancer cells, while COX-1 regulates angiogenesis in endothelial cells.” (abstract). Tsujii teaches “NSAIDs inhibit Growth of Colon Cancer Xenografts” (page 713, right column, last paragraph). Tsujii teaches “Based on the results obtained in the in vitro angiogenesis studies, we predicted that parental Caco-2 cells would grow poorly as xenografts in nude mice, while COX-2-overexpressing cells would grow well. In vivo experiments supported this hypothesis. Moreover, both indomethacin and NS-398 inhibited tumor growth effectively.” (page 713, right column, last paragraph). NS-398 is COX-2 inhibitor.
Regarding claims 5 and 9, wherein-clause of claims 5 and 9 describes the functional property of Zbtb46 modulation agent. Because Tsujii teaches same Zbtb46 modulation agent NS-398 as instant invention, NS-398 must have same functional property. Furthermore, as discussed above, COX-2 modulates production of angiogenic factors by colon cancer cells and NS-398 is COX-2 inhibitor. Therefore, NS-398 will normalize tumor blood vessels by inhibiting COX-2 from modulating production of angiogenic factors by colon cancer cells. When tumor blood vessels are normalized, it will allow access of immune cells and therefore will enhance immune response in a cancer patient’s tumor.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined anti-PD-1 antibody taught by Xu and NS-398 taught by Tsujii to treat colon cancer because Xu and Tsujii teach that these anti-cancer agents can treat same cancer of colon cancer. One of ordinary skill in the art would be motivated to combine these agents to see if the combination can treat colon cancer better. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
In re Kerkhoven affirmed that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose…the idea of combining them flows logically from their having been individually taught in the prior art”. In re Kerkhoven, 626 F .2d 846, 850, 205, USPQ 1069, 1072 (CCPA 1980).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Xu and Tsujii teach that each anti-cancer agent can treat same cancer of colon cancer and therefore one of ordinary skill in the art would be able to predict that the combination of the two will also treat same cancer of colon cancer. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Allowable Subject Matter
Claim11 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHEOM-GIL CHEONG whose telephone number is (571)272-6251. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights