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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/18/2025 has been entered.
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 08/18/2025 is acknowledged. Claim 59 was cancelled. Claim 25 was amended. Claims 25,50-55 and 60-67 are pending and under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 25,50-55 and 60-67 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 25,50-55 and 60-66 encompass a method of treating a large genus of cancers in a subject in need thereof, comprising administering to the subject having a genus of cancers a genus of therapeutically effective amounts of a genus of pathogen-associated molecular pattern (PAMP)-containing nucleic acid molecules sufficient to induce TRIM16 mediated apoptotic activity in the cancer cell, and wherein the therapeutically effective amount is sufficient to activate RIG-I, thereby inducing RIG-I mediated apoptosis in the cancer cell. Claims 65-66 specify the PAMP-containing nucleic acid molecule comprises or consists of SEQ ID NO:2, and therefor recites a specific species of PAMP-containing nucleic acid molecules, but still encompasses treating a genus of cancers with this specific PAMP-containing nucleic acid molecule. Claim 62 recites the cancer is a hematological cancer and claim 67 recites a specific species of cancer, hepatocellular cancer, however both claims encompass administering a genus of PAMP-containing nucleic acid molecules.
The state of the art is silent as to treating cancer in a subject by administering a PAMP-containing nucleic acid molecule in an amount sufficient to induce TRIM16 mediated apoptotic activity in a cancer cell, and wherein the therapeutically effective amount is sufficient to activate RIG-I, thereby inducing RIG-I mediated apoptosis in the cancer cell.
Gale et al. (US 20150017207, Published 15 January 2015), cited on an IDS dated 07/31/2020, teach a PAMP molecule comprising a 5’-arm region, a poly-uracil core, and a 3’arm region (page 1, paragraph [0008]), the 5’-arm region comprising a terminal triphosphate and the 5’-arm region further comprises one or more nucleic acid residues disposed between the terminal triphosphate and the poly-uracil core (page 1, paragraph [0009]), the poly-uracil core comprises at least 8 contiguous uracil residues and consists of between 8 and 30 uracil residues (page 1, paragraph [0010]) and the 3’-arm region is not a uracil and is at least 30% uracil residues (page 1, paragraph [0011].
Gale et al. teach the nucleic acid PAMP is capable of inducing RIG-I-like receptor activation [0013], and teaches a method of treating a viral, bacterial, protozoal, fungal or helminth infection in a subject and a method of inducing an innate immune response in a subject by administering an effective amount of a pharmaceutical composition comprising the synthetic nucleic acid PAMP (paragraphs [0017] and [0018]). Gale et al. does not teach that the PAMP-nucleic acid is capable of treating cancer or that it induces TRIM16 mediated apoptotic activity in a cancer cell, or the amount of the PAMP-nucleic acid that is required to induce apoptosis in a genus of cancer cells in a subject.
Zips et al. (In vivo 19:1-8 (2005), Review: “New Anticancer Agents: In Vitro and In Vivo Evaluation), teach that not all tumor cell lines show the same magnitude of response to anticancer agents (right column, page 2). Zips et al. teach that cells in culture are an artificial and simplified system, however tumors are complex consisting of interacting malignant and non-malignant cells, and vascularization, perfusion and drug access to the tumor cells are not evenly distributed which consists of an important source of heterogeneity in tumor response to drugs that do not exist in vitro (Right column, page 3). Zips et al. teach that prediction of drug effects solely on in vitro data is not reliable and further evaluation in animal antitumor systems is essential (Right column, page 3). Zips et al. advocate in vitro and in vivo experiments with at least two or three different tumor cell lines, applying functional non-clonogenic and if applicable clonogenic assays for evaluation of new anticancer agents (Right column, page 6).
Kim et al. (Apoptosis, Published 13 Feb 2013, 18: 639-651), cited on an IDS, teach TRIM16 induces apoptosis in breast and lung cancer cells, by unknown mechanisms, and that overexpression of TRIM16 induces apoptosis in human breast cancer and neuroblastoma cells, by directly modulating caspase-2 activity (Abstract). Kim et al. teach enforced overexpression of TRIM16 induces apoptosis in MB-MDA-231 breast and SK-MES-1 lung cancer cells, however, the exact mechanisms of TRIM16 involvement in the regulation of apoptosis remains unclear (page 640, left column). Therefore, while Kim et al. teach that TRIM16 can induce apoptosis in certain types of cancer cells (breast, lung, neuroblastoma cancer cells), the mechanisms by which it does so are not clear, and Kim et al. do not describe the relationship of TRIM16 with RIG-I or PAMP-containing nucleic acids.
Post-filing art Zhang et al. (Journal for Immunotherapy of Cancer, 2023) teach retinoic acid-inducible gene-I (RIG-I) is a crucial component in innate antiviral immunity, but its role in antitumor immunity remains unclear (Abstract). Zhang et al. teach silencing RIG-I decreased resistance to tumor cells killed by T cells and attenuated colon tumor growth in mice, while overexpressing RIG-I promoted tumor progression, and that RIG-I influenced PD-L1 expression to promote colon cancer immune evasion (Abstract). Zhang et al. teach their previous study also has shown that RIG-I can serve as a binding protein to regulate the PTMs of other proteins, confers resistance to IFN-α-induced apoptosis in melanoma (page 1, right column). Therefore, even post-filing, the state of the art teaches that the role of RIG-I in antitumor immunity is not clear, and RIG-I has been shown to promote colon cancer progression and immune evasion, and resistance to apoptosis in melanoma.
When claims 25,50-55 and 60-67 are analyzed in light of the specification, the instant invention encompasses treating hepatocellular carcinoma cells in vitro comprising administering 50ng, 100ng and 200ng of PAMP-containing nucleic acid molecules as described in PMID: 18548002. The as-filed specification defines the term “therapeutically effective” as an amount of the composition that results in a therapeutic effect and can be readily determined (page 19, lines 4-6). However, this definition is very broad and does not specify a particular range or amount of the PAMP-containing nucleic acid that is sufficient to induce TRIM16 mediated apoptotic activity in a cancer cell, or sufficient to activate RIG-I thereby inducing RIG-I mediated apoptosis in a cancer cell. The description of Figures 1A-1D on page 5 describes that Figure 1A shows a western blot showing dose-dependent activation of innate immune signaling in human hepatocellular carcinoma cells at all doses of HCV PAMP RNA and dose-dependent induction of apoptosis, and Figure 1D illustrates cell death analysis that shows a dose-dependent increase in cell death induction up to a threshold of 200ng. The description of Figures 7A and 7B on page 7 and page 28 shows that PAMP RNA treatment includes oncolytic destruction of HepG2 and Huh7 hepatocellular carcinoma cells but not normal, noncancerous cells, and shows the amounts 50ng, 100ng and 200ng as the amounts of PAMP administered to the cells (Fig 7A and 7B) but does not show the structure of the PAMP-containing nucleic acid molecule. Additionally, these figures only show the results in HepG2 and Huh7 hepatocellular carcinoma cells, and not in any other type of cancer cell. The therapeutically effective amount could be different depending on the type of cancer being treated. Page 26, lines 10-17 contemplate that 100ng/mL is the minimal concentration of PAMP-RNA-induced cell death and that 200ng/mL induced the highest level of cell death in Huh7 cells. Page 28 contemplates that TRIM16 but not TRIM25 is involved in RIG-I mediated apoptosis, and that PAMP-RNA specifically signals RIG-I mediated apoptosis cell death through the novel RIG-I binding partner TRIM16.
Additionally, the examples starting on page 30 disclose human Huh7 hepatocellular carcinoma cells as treated with a PAMP-containing nucleic acid molecule, but do not show the method being carried out in a subject in vivo, or for any other types of cancers other than in hepatocellular carcinoma cells. Page 32 of the examples describes transfecting cells with a PAMP-containing nucleic acid and refers to PMID:18548002 which is a PubMed identification number for a research article that specifically disclosed instant SEQ ID NO: 2 and experimental results thereof (See Saito T. et al. Nature, 2008). However this article by Saito et al. does not reference cancer at all, much less that the recited genus of PAMP-containing nucleic acids are capable of carrying out the recited function of treating a genus of cancers. The working examples on pages 30-34 do not disclose that TRIM16 mediated apoptotic activity or RIG-I mediated apoptosis in cancer cells occurred as a result of administering the PAMP-containing nucleic acid molecule.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, while the specification discloses transfecting HepG2 and Huh7 hepatocellular carcinoma cells with a PAMP-containing nucleic acid according to PMID:18548002, the specification does not disclose any other complete structures of the PAMP-containing nucleic acid molecules with the recited function of inducing TRIM16 mediated apoptotic activity and activating RIG-1, thereby inducing RIG-I mediated apoptosis in a genus of cancer cells and which results in treating a genus of cancers in a subject. The specification discloses 50ng, 100ng and 200ng as the amounts of a PAMP-containing nucleic acid molecule administered to Huh7 cells (Fig 7A and 7B), but that 100ng/mL is the minimal concentration of PAMP-RNA-induced cell death and that 200ng/mL induced the highest level of cell death in Huh7 cells. In addition, the specification only discloses carrying out the method in vitro in hepatocellular carcinoma cells cancer cells and not in vivo in a subject with cancer, as well as the method only being carried out in Huh7 hepatocellular carcinoma cells but not in other types of cancer cells. There is no written support for the genus of therapeutically effective amounts or the genus of PAMP-containing nucleic acid molecules that would be sufficient to result in the induction of TRIM16 mediated apoptotic activity and activation of RIG-I, thereby inducing RIG-I mediated apoptosis in a genus of cancer cells in a subject in vivo. As evidenced by Zips et al., prediction of drug effects solely on in vitro data is not reliable, and further evaluation in animal antitumor systems is essential (Right column, page 3), and the specification does not show what the therapeutically effective amount of the PAMP-containing nucleic acid molecule is sufficient to induce TRIM16 mediated apoptotic activity and activation of RIG-I, thereby inducing RIG-I mediated apoptosis in a genus of cancer cells that can be extrapolated to occurring in vivo in a subject and in any type of cancer cell. The amount of PAMP-containing nucleic acid molecule that is sufficient to induce TRIM16 mediated apoptotic activity and activation of RIG-I, thereby inducing RIG-I mediated apoptosis in a cancer cell in a subject in vivo to treat cancer may be different than the amount of PAMP-containing nucleic acid molecule that successfully induces TRIM16 mediated apoptotic activity and activation of RIG-I, thereby inducing RIG-I mediated apoptosis in a cancer cell in vitro. The specification only provides written support for the in vitro treatment of Huh7 hepatocellular carcinoma cells with the PAMP-containing nucleic acid of instant SEQ ID NO: 2 at a minimal concentration of 100ng/mL and 200ng/mL of as the concentration inducing the highest level of Huh7 cell death.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicant’s disclosure of the in vitro treatment of Huh7 hepatocellular carcinoma cells with 100ng and 200ng of a PAMP-containing nucleic acid molecule of instant SEQ ID NO: 2 is not deemed sufficient to reasonably convey to one skilled in the art that the instant disclosure was in possession of the claimed broad genus at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Response to Arguments
Applicant's arguments filed 08/18/2025 have been fully considered but they are not persuasive.
Applicant summarizes the written description rejection on pages 5-6 of the response filed 08/18/2025, and that to advance prosecution, claim 25 has been amended to recite in part, “wherein the therapeutically effective amount is sufficient to activate retinoic acid-inducible gene I (RIG-I), thereby inducing RIG-I mediated apoptosis in the cancer cell”, and new claim 67 is directed to when the cancer is hepatocellular cancer. Applicant cites In re Herschler on pages 6-7, and that the instant applicant meets the written description requirement in a manner that can be correlated with Herschler (page 7). Applicant argues on page 7 of response that that is literal written description for the claims in the original specification (p. 7, lines 20-23) but also reduction to practice (see Figs. 1A-1D and 7A-7B), and that the application provides the novel and nonobvious breakthrough discovery that PAMP-containing nucleic acid meeting the specific structural features of the claims activates RIG-1 signaling, thereby inducing programmed cell death in cancer cells, and relates to the discovery that the compositions of Gale, Jr. et al. (US 20150017207) have a surprisingly advantageous impact for treatment of cancer. Applicant argues Gale is incorporated by reference into the instant application and that the PAMPs and PAMP-containing nucleic acid molecules thereof address PAMP induction of innate immune response signaling, and Tables 1 and 2 of Gale describe multiple PAMP-containing nucleic acid molecules tested for the ability to induce RIG-I mediated innate immune response in vivo and in vitro.
This is not found persuasive. The amendment to claim 25 “wherein the therapeutically effective amount is sufficient to activate retinoic acid-inducible gene I (RIG-I), thereby inducing RIG-I mediated apoptosis in the cancer cell”, and new claim 67 directed to when the cancer is hepatocellular cancer does not address the written description rejection regarding treating a genus of cancers, or the issues of in vitro to in vivo correlation, or the structure of the genus of PAMP-containing nucleic acid molecules with the recited functions, as explained in the written description rejection. Regarding Applicants argument that the instant applicant meets the written description requirement in a manner that can be correlated with Herschler (page 7), this is not found persuasive. Applicant cites that the CCPA reasoned that the physiologically active steroidal agents were known to those of ordinary skill in the art, and “were this application drawn to novel ‘steroidal agents’, a different question would be posed”. This is not the case with the instant application, because while PAMP-containing nucleic acids were known in the art for inducing RIG-I-like receptor activation and treating a viral, bacterial, protozoal, fungal or helminth infection in a subject and inducing an innate immune response, the state of the art does not recognize that the PAMP-containing nucleic acid molecules were known to induce TRIM16 mediated apoptotic activity in cancer cells, or activate RIG-I to induce RIG-I mediated apoptosis in a cancer cell which results in treating cancer. Therefore, it cannot be said that the instant PAMP-containing nucleic acid molecules are well known, or the required amount to achieve the recited effect is well known.
Instant claims 25,50-55,60-64 and 67 only require that the PAMP-containing nucleic acid molecule comprise a 5’ arm region comprising a terminal triphosphate, a poly-uracil core comprising at least 8 contiguous uracil residues, and a 3’ arm region comprising at least 8 nucleic acid residues, wherein the 5’-most nucleic acid residue of the 3’-arm region is not a uracil and wherein the 3’-arm region is at least 30% uracil residues and also requires that administering to a subject having a genus of cancers a therapeutically effective amount of this PAMP-containing nucleic acid has the recited function of inducing TRIM16 mediated apoptotic activity in a genus of cancer cells and the function of activating RIG-I thereby inducing RIG-I mediated apoptosis in a genus of cancer cells and resulting in treating a genus of cancers in the subject. There is no structure-function correlation described in the prior art or the instant specification. Gale et al. (US 20150017207) may disclose PAMP-containing nucleic acid structures and their use for inducing RIG-I-like receptor activation and treating a viral, bacterial, protozoal, fungal or helminth infection in a subject and inducing an innate immune response, however, Gale et al. does not pertain to treating cancer or to inducing TRIM16 mediated apoptotic activity or RIG-I mediated apoptosis in cancer cells. Therefore, Gale et al. cannot be relied on for the required structure necessary for having the recited functions of the instant claims (inducing TRIM16 mediated apoptotic activity in a cancer cell, inducing RIG-I mediated apoptosis in a cancer cell, and resulting in treating cancer in a subject). While page 14 of the instant specification discloses that non-limiting examples of nucleic acid sequences of PAMPs encompassed by the disclosed PAMP-containing nucleic acids are disclosed in US 2015/0017207 and US 2018/0104325 which are incorporated herein by reference and set forth herein as SEQ ID NOs: 2-92, there is no support that the effect described in the instant examples is produced by the sequences disclosed above or SEQ ID NO: 2 as recited in claims 65-66, or that these sequences would have the recited function in a genus of cancers in vivo.
Applicant cites MPEP 2163(II)(3)(a)(ii) and MPEP 2163(I)(B) regarding the therapeutically effective amount on pages 7-8. Applicant points to Example 1, providing objective data supporting inference of SEQ ID NO: 2 having antitumor effects, and which is PAMP-RNA of PMID: 18548002 which is a PubMed identification number for a research article that specifically disclosed instant SEQ ID NO: 2 and experimental results thereof (See Saito T. et al. Nature, 2008). Applicant argues that the office acknowledges that the instant application shows that RIG-I activation causes cell death in cancer cells over a 0.1 ng to 500 ng dosing range of PAMP-containing nucleic acid molecules (Office Action page 5, lines 8-17), and that the office action acknowledged that the application as filed shows oncolytic destruction of HepG2 and Huh7 hepatocellular carcinoma cells but not normal, noncancerous cells across the 50-200 ng dose range of PAMP-containing nucleic acid molecule.
This is not found persuasive. Applicant does not show what the therapeutically effective amount of the PAMP-nucleic acid molecule is for administration to a subject in need thereof, and only discloses amounts that are used in vitro in Huh7 and HepG2 cells. Even if Gale et al. shows that the PAMP-containing nucleic acid molecules induce RIG-I-like receptor activation and induce an innate immune response, this data does not show that this response is sufficient to induce apoptosis and to treat all types of cancer as required by the claims (i.e., is a therapeutically effective amount). To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention", and the examiner maintains that the patent specification does not describe the claimed invention in sufficient detail such that one skilled in the art could conclude that the inventor had possession of the claimed invention. See Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Applicant argues on page 8 that a person having ordinary skill in the art would have immediately recognized their ability to determine an effective dose of a PAMP-containing nucleic acid molecule required for inducing RIG-I in vivo upon a review of the instant disclosure and that person’s knowledge of their own field, at the very least, with additional (undue) experimentation.
This is not found persuasive. Applicant’s argument regarding additional, undue experimentation pertains to enablement, rather than written description. MPEP 2163(I) states that the written description requirement is separate and distinct from the enablement requirement. See In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). Therefore, while experimentation regarding the effective dose of the PAMP-containing nucleic acid would not be undue, this does not mean that there is adequate written description of the required structure and amount of the PAMP-containing nucleic acid to result in the claimed function (induce TRIM16 mediated apoptotic activity in a cancer cell, activating RIG-I, thereby inducing RIG-I mediated apoptosis in the cancer cell and resulting in treating cancer in a subject). Applicant fails to respond to the examiner’s argument regarding claims 25,50-55 and 60-67 reciting treating a genus of cancers and the in vitro vs in vivo correlation, when the examples only pertain to hepatocellular carcinoma cells in vitro.
In conclusion, the examiner is maintaining the written description rejection based on the reasons and responses set forth above, regarding the lack of structure-function correlation of the therapeutically effective amount of a PAMP-containing nucleic acid molecule that has the function of inducing TRIM16 mediated apoptotic activity in a cancer cell, thereby treating cancer in a subject.
Conclusion
Claims 25,50-55 and 60-67 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/ Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636