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 .
Application Status
Claims 12-30 are pending and under examination.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure. A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art. Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length. See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The disclosure is also objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 36. 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 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 12-30 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.
Claims 12, 27 and 30 recite “HRD cancer and BRCA-associated cancer”. The Specification discloses “HRD cancer” is “homologous recombination deficiency cancer” and refers to cancer displaying defective homologous recombination (HRD)-mediated DNA repair. Also, “HRD cancer” includes but is not limited to BRCA-associated cancer (page 7, lines 13-17). The Specification then defines “BRCA-associated cancer” as referring to “cancer associated with BRCA mutation or BRCA expression deficiency” and indicates that it includes, but is not limited to cancer associated with BRCA1 and/or BRCA2 mutation, inactivation, expression deficiency, HRD cancer and/or BRCA0deficiency cancer (such as basal-like, luminal and HER2-overexpression carcinomas, breast, ovarian, and prostate tumors harboring BRCA1/2 mutations and other cancers). From this description, it is not clear what cancers are encompassed by HRD cancer and BRCA-associated cancer. For instance, it is not clear if a cancer that has a copy number variation with BRCA1 but is still HR-competent is included. Additionally, there is a term in the art “BRCAness” that refers to a functional BRCA1/2 HR pathway, but deficient in other HR pathways such that the cancer has many phenotypes that are similar to a BRCA1-/- and BRCA2-/- cancer. See e.g., Lord and Ashworth, Nature Reviews Cancer (2016), 16:110-116. It is not clear if those BRCAness cancers are encompassed in the claim.
Claims 13-26 and 28-29 are rejected for depending from claims 12 or 27 and not remedying the indefiniteness.
It is suggested that the claims recite specific cancers that comprise a mutation causing the inactivation of the BRCA1 and BRCA2 genes.
Claim 14 recites “wherein the cancer is PARPi resistant BRCA-associated cancer or cisplatin resistant BRCA-associated cancer, including those with somatic reversion of the BRCA mutation and HR restoration. It is not clear how a cancer can be “HR deficient” but then have HR restoration or have a BRCA-associated mutation but then have the mutation revert back to wild type. As such it is not clear what cancers are included in the methods of treatment.
Claims 18, 22, 26 and 30 recite “such as novobiocin", which renders the claim indefinite because it is unclear whether the limitation following the phrase (i.e., novobiocin) is part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(a)
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 12-30 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.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species' means that the species which are adequately described are representative of the entire 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.”
Claims 12, 27 and 30 recite “an NMNAT1 inhibitor”. The Specification indicates that an inhibitor is referring to any compound that binds to NMNAT1 as a potent antagonist or inactivates NMNAT1, and also includes small organic molecules, polypeptides, aptamers, antibodies or oligonucleotides such as siRNA, DNA, and shRNA. Thus, an NMNAT1 inhibitor can be virtually any organic molecule, which represents at vast and diverse genus of molecules, and is only defined by their function of inhibiting NMNAT1 activity of expression.
Regarding nucleic acid-based inhibitors, the genomic and expressed transcript sequences of NMNAT1 are well known and can be targeted with antisense oligonucleotides (See e.g., Kiss et al., Cancers (2020), 12: 1180, pages 1-21). Because there is a known correlation between the structure of antisense molecules and their inhibitory function, one skilled in the art could have predicted the structure of antisense oligonucleotides such as siRNA, shRNA and ASOs that have the claimed inhibitor function. However, for the reasons described below, Applicants have not sufficiently described the genus of NMNAT1 antibodies, generic polypeptides, aptamers, or small molecules that have the claimed NMNAT1 inhibitory function such that one skilled in the art could have reasonably concluded applicants had possession of the genus as claimed.
The claims recite an antibody, polypeptide, aptamer and small molecule that inhibits NMNAT1 and therefore only identify the genus molecules by function. A definition by function does not suffice to define the genus because it is only an indication of what the antibody/polypeptide/aptamer/small molecule does, rather than what it is. To provide adequate written description and evidence of possession of the claimed inhibitor genus, the instant specification in view of the art must structurally describe representative molecules that function as an inhibitor or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
No anti-NMNAT1 antibody or NMNAT1-binding aptamer, peptide or small molecule structure is recited in the claims or in the Specification that correlates to the claimed function of inhibiting NMNAT1.
A few NMNAT1 antibodies are commercially available that can be used to detect NMNAT1 by western blot, immunofluorescence or immune-histochemistry (e.g., sold by ThermoFisher). However, the companies do not provide the structure of the NMNAT1 antibodies. Additionally, none of the commercially available NMNAT1 antibodies are disclosed as capable of entering cells to inhibit the function of NMNAT1 in the cell nucleus, which would need to occur for the antibody to function in the therapeutic method. A thorough search of the prior and contemporary art found no disclosure of a DNA aptamer, RNA aptamer or peptide/polynucleotide capable of binding to NMNAT1 and/or inhibiting its function.
Although Applicants may argue that it is possible to screen for NMNAT1 antibodies, peptides or aptamers that function as claimed, the court found in that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future NMNAT1-binding antibody, aptamer or peptide yet to be discovered that may function as an NMNAT1 inhibitor as claimed.
A diligent search of the prior and contemporaneous art found only a few small molecule inhibitors (Fortunato et al., IUBMB Life (2022), 74: 562-575). Gallotannin inhibits all three NMNAT isoforms, however, NMNAT3 the most sensitive (page 569, ¶3). Additionally, nucleotide polyphosphates only showed inhibition in the micromolar range (page 569, ¶3). Very recently the PRMT1 inhibitor, AMT-1, was shown to specifically inhibit NMNAT1 (Lansiquot et al., bioRxiv, posted April 8, 2026, doi.org/10.64898/2026.04.07.716846). However, as this study was published over 4 years after the effective filing date of the claimed invention, it was not available to the skilled artisan at the time the application was filed. Therefore, as of the effective filing date, only 2 small molecules of NMNAT1 were known, one of which was non-selective, and one which was a very week inhibitor.
Around the time of the filing date, skilled artisans understood that discovering inhibitors of proteins generally was unpredictable. Wu observes that although computer-aided protein-inhibitor discovery technology was available, there is insufficient data to predict inhibitors of many proteins (Wu et al., Molecules (2019), 24: 4428, pages 1-14). Wu writes: [U]nder many circumstances, it is hard to find a [compound] library with functionally and structurally diverse molecules with quantitative activity data for a given protein. More importantly, the lack of publications with negative results hinders the identification of inactive molecules, resulting often in the development of qualitative common feature pharmacophores only from active compounds. Finally, as LBVS applications are generally based on the properties of the known ligands, the diversity of the hits discovered are generally limited. (Page 3 of 14, second paragraph.) Wu supports a finding that skilled artisans expected genera of inhibitors of a given protein to be diverse and that as of the effective filing date, they would not have concluded that applicants possessed a representative number of species of small molecule inhibitors of NMNAT1.
Given the lack of representative examples to support the full scope of the NMNAT1 inhibitors encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown sequences of NMNAT1 antibodies, polypeptides, aptamers and small molecules that provide can inhibit NMNAT1 function, the specification does not provide an adequate written description of molecules that inhibit NMNAT1 function that is required to practice the claimed invention.
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.
Claims 12-30 are rejected under 35 U.S.C. 103 as being unpatentable over Kiss (Kiss et al., Cancers (2020), 12: 1180, pages 1-21) in view of Engert (Engert et al., Oncotarget (2017), 30: 48794-48806), Kovac (Kovac et al., Nature Communications (2015), 6:8940, pages 1-9) and Lilienthal (Lilienthal and Herold, International Journal of Medical Sciences (2020), 21:6885, pages 1-55).
Regarding claims 12, 15 and 16, Kiss teaches treating SAOS-2 osteosarcoma cells with an siRNA (i.e., an oligonucleotide) targeted to NMNAT1 which reduced NMNAT1 expression by 70% (i.e., an NMNAT1 siRNA inhibitor) (FIG 7). Kiss teaches NMNAT1 siRNA-treated SAOS-2 cells had reduced viability (Fig 7A-D).
Kiss does not teach whether osteosarcoma cancer or SAOS-2 cells were HR-deficient. Kiss does not teach treating a subject with cancer with the NMNAT1 siRNA.
Engert teaches that SAOS-2 cells harbor losses in CHEK2 and TP53 and display BRCAness, characterized by deficiency in HR (page 48795, ¶6). Engert also teaches that the vast majority of primary osteosarcomas have mutation signatures reminiscent of BRCA deficiency (Abstract). Kovac teaches that “over 80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.” (Abstract). Therefore, the skilled artisan would have predicted that osteosarcoma and the SAOS-2 cells of Kiss are an HRD cancer.
Lilienthal teaches the current state of the art for osteosarcoma treatment and future strategies (Title). Lilienthal teaches siRNAs targeting APE1, PARP1 or ERRa could (re)sensitize osteosarcoma cells to chemotherapeutic agents in xenograft models or in cell lines (page 26, ¶4; page 27, ¶1; page 31, ¶2).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the NMNAT1-targeting siRNA in Kiss to treat HR-deficient osteosarcomas in a subject. It would have amounted to using a known siRNA by known means to yield predictable results. The skilled artisan would have predicted that the NMNAT1 siRNA could be administered to a subject having osteosarcoma because Lilienthal teaches siRNAs have been used previously in clinical trials and provided to mouse models. The skilled artisan would have been motivated to use the NMNAT1 siRNA because Kiss teaches that it reduces the viability of osteosarcoma cells in vitro.
Regarding claims 13-14, Lilienthal teaches osteosarcoma is chemo-resistant (page 1, ¶1), including resistant to cisplatin (page 26, ¶3; page 31, ¶2). Engert teaches SAOS-2 cells are resistant to cisplatin (Fig 2).
Regarding claim 17, Lilienthal teaches due to their vast genomic instability, heterogenicity, and metastatic proficiency, treatment of osteosarcomas requires a highly intensive combination of therapies (page 7, ¶6). Lilienthal teaches treating SAOS-2 cells with the PARP1 inhibitor olaparib induced cell death (page 16, ¶2). Lilienthal also teaches cotreatment with olaparib had synergistic effects with other chemotherapy agents (page 27, ¶1). Kiss teaches “PARP1 activation acts as a survival factor via assisting DNA repair, in line with our current understanding of the role of PARylation in the repair of cisplatin-induced DNA” (page 13, ¶3). Kiss teaches that “potent” NMNAT1 inhibitors are not yet clinically available (page 13, ¶3).
It also would have been obvious to treat the subject with olaparib in combination with the NMNAT1 siRNA because Lilienthal teaches that the PARP inhibitor is synergistic with other agents. The skilled artisan would have been motivated to have combined with Kiss’s NMNAT1 siRNA because the siRNA did not fully eliminate NMNAT1 expression. Kiss teaches PARP inhibition can act in the same pathway as NMNAT1 to promote DNA repair. As such, the skilled artisan would have predicted that inhibiting both NMNAT1 and PARP would eliminate DNA repair, thereby reducing osteosarcoma cell survival.
Regarding claim 18, Kiss teaches NMNAT1 is induced by cisplatin, a DNA damaging agent (page 12, ¶3). Kiss teaches inhibiting NMNAT1 expression increases the cell-killing effect of cisplatin in both U-2OS cells and SAOS-2 cells (Fig 7).
Regarding claims 19-26, the limitations of each of the claims and the obviousness of using the NMNAT-1 siRNA of Kiss in osteosarcoma (i.e., a cisplatin-resistant HR-deficient cancer) are addressed above for claims 12-18.
Regarding claim 27-29, the teachings of Kiss, Engert, Kovac and Lilienthal and the obviousness of using the Kiss’s NMNAT1 siRNA in combination with the PARP inhibitor olaparib are recited above as applied to claims 12 and 15-17.
Regarding claim 30, the teachings of Kiss, Engert, Kovac and Lilienthal and the obviousness of using the Kiss’s NMNAT1 siRNA in combination with cisplatin are recited above as applied to claims 12 and 22.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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