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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/EP2022/076873, filed on 09/11/2025.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/28/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The abstract of the disclosure is objected to because a patent abstract must not contain legal phraseology or claim jargon (such as "means" and "said"), see use of “said” in line 2. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
See page 4: “(https://www.mirbase.org/index.shtml).”
Claim Interpretation
Claim 16 recites a method for preventing or treating cancer in a patient, comprising administering the patient with a combination of a miR-17 mimic and a miR-340 mimic. Cancer as recited is being interpreted as any cancer. Administering is being interpreted as any means/route of providing the combination therapy. The miRNAs as recited (i.e., miR-17 mimic and miR-340 mimic) are interpreted as encompassing both immature and mature forms of each miRNA as well as either strand, 3p or 5p, of the miRNAs. Similarly, dependent claims 17-18 recite the genera of miR-222 antagomiR, and miR-221 antagomiR and/or miR-551b mimic, respectively; thus, each claim is interpreted as encompassing both immature and mature forms of each miRNA as well as either strand, 3p or 5p, of the miRNAs.
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 16-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a brain tumor selected from the group consisting of astrocytomas, oligodendrogliomas, meningiomas, gliomas, and glioblastomas in a patient, comprising, administering directly to the brain tumor a combination of a miR-17-3p mimic and a miR-340-5p mimic alone, or in combination with a miR-222 antagomiR or a miR-221 antagomiR and/or a miR-551b mimic, does not reasonably provide enablement for preventing or treating any cancer with a combination of any miR-17 mimic and any miR-340 mimic administered by any means. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
An analysis of the Wands factors is addressed, and the rejection is made in view of the totality of the factors together.
(A) The breadth of the claims. The scope of independent claim 16 embraces preventing or treating any cancer by administering by any means a combination of any miR-17 mimic and any miR-340 mimic. The instant specification broadly defines “preventing” as stopping “the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof,” and “cancer” as “the growth, division, or proliferation of abnormal cells in the body,” see pg. 8 lns. 20-21 and 29-31.
(B) The nature of the invention. The invention combines miRNA gain-of-function and loss-of-function tools to regulate multiple cancer-driving pathways at once. Specifically, miR-17 and miR-340 are introduced as mimics, while miR-222 can be inhibited by an antagomiR. The application reports that this combination suppresses tumor cell survival, clonogenicity, invasion, and tumor growth across multiple GBM models. This multi-target strategy is presented as useful across GBM subtypes and potentially (emphasis added) other cancers.
(C) The state of the prior art. At the time of filing, miRNA were becoming attractive as potential diagnostic tools and therapeutic targets, especially in the context of glioblastoma. There were three main outstanding questions in the field researchers were addressing at the time of filing: “1) which miRNAs are the best candidates to become early diagnostic and prognostic circulating biomarkers” or therapeutic targets?; 2) how to deliver the therapeutic agents in the CNS to overcome the BBB?; (3) which are the best methods to restore/inhibit miRNAs?” See Petrescu GED, et al., (J Exp Clin Cancer Res. 2019 May 29;38(1):231).
(D) The level of one of ordinary skill. A PhD trained scientist with multiple years postdoctoral experience in molecular biology, mammalian models of cancer, and experimental surgical skills.
(E) The level of predictability in the art. The structure-function correlation between miRNA mimetics and/or antagomirs for the treatment of cancer generally/broadly was unpredictable as of the effective filing date. For example, antagonizing, not overexpressing/mimicking, miR-17 was known in the art to be beneficial for treating certain types of cancer:
Fontana L, et al., (PLoS ONE 3(5): e2236) shows that miR-17-5p is upregulated and oncogenic in neuroblastoma, and that antogomir-17-5p, not a mimic, abolishes tumor growth in vitro and in vivo. See abstract and introduction.
Conkrite K, et al., (Genes Dev. 2011 Aug 15;25(16):1734-45) show high expression of miR-17∼92 in human retinoblastoma, and that human retinoblastoma cells were highly sensitive to inhibition of miR-17∼92 microRNAs, providing a new therapeutic target for retinoblastoma. See abstract and introduction.
Tassone P, et al., (US20180051284A1) teach MiR-17-92 cluster gene, also known as “oncomiR-1”, encodes a polycistronic miRNA transcript (the pri-miRNA) that yields six individual miRNA components including miR-17, -18a, -19a, -20a, -19b, and -92a, and that among miRNAs significantly deregulated in human cancer, those that belong to miR-17-92 cluster retain oncogenic potential. Tassone further teaches that the upregulation of miR-17-5p was associated with poor prognosis in pancreatic cancer, and that antisense oligonucleotide against miR-17-5p induces apoptosis in lung cancer cells, see [0008][0019][0022].
Petrescu GED, et al., (J Exp Clin Cancer Res. 2019 May 29;38(1):231) teaches while miRNA therapeutics are promising and overcome many shortcomings of other therapeutic agents, “on the other hand, very little data exists regarding the passage of miRNAs from blood into the brain tissue,” and that “it is known that siRNAs, which have a molecular mass of 14 kDa, similar to the miRNAs, cannot diffuse through the BBB.” See How do miRNAs overcome the BBB?.
Thus, miRNA therapeutics are unpredictable in different cancer types, and this unpredictability is only further compounded by the approach (i.e., antagomir vs mimic), strand (i.e., 3p vs 5p), and route of administration (i.e., locoregional vs systemic).
(F) The amount of direction provided by the inventor. The specification provides direction for using the miR-17-3p mimic, miR-340-5p mimic, and miR-222 antagomiR, in cell-based assays, organoid models, xenograft models, and a doxycycline-inducible lentivector system expressing miR-17-3p mimic, miR-340-5p mimic, and miR-222 antagomiR in an orthotopic GBM model. However, the specification provided no guidance directing a skilled artisan how to practice the remainder of the claimed scope; for example, no direction is provided on selecting the 3p vs 5p strand for a given cancer type, formulating or delivering the combination to cross the blood-brain-barrier for the brain tumor embodiments claimed, and choosing dosing or regimen for a prophylactic (“preventing”) use.
(G) The existence of working examples. The specification’s working examples include: in vitro assays in GBM patient-derived cell lines and a small set of other cell lines (melanoma, breast, lung, and ependymoma). It is noted that in the art there is a poor correlation between preclinical in vitro cell line data and in vivo efficacy (especially clinical antitumor efficacy), which remains a major concern in anticancer drug screening, see Kitaeva KV, et al., (Front Bioeng Biotechnol. 2020 Apr 9;8:322). The specification also describes one subcutaneously-implanted (non-brain) GBM xenograft dosed with the miR-17-3p mimic and miR-340-5p mimic combination optionally with the miR-222 antogomiR and one orthotopic brain tumor model comprising a doxycycline-inducible lentiviral construct transduced into the tumor cells before implantation (i.e., no administration of the claimed mimic /antogomiR combination to a subject with an existing brain tumor by any of the claimed routes of administration).
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Not only is the route of administration for treating a brain tumor by crossing the blood-brain-barrier unaddressed by any working example, but the general in vitro to in vivo lack of correlation discussed above, independently means a skilled artisan would need undue experimentation even for the non-brain cancers nominally supported by the in vitro data. This is compounded by unpredictability discussed above, where a skilled artisan would need to determine, on a cancer-by-cancer basis, whether inhibiting rather than mimicking miR-17 is actually required. Furthermore, a skilled artisan would have failed practicing the full scope of the claimed invention for treating, let alone preventing, retinoblastoma and neuroblastoma (as recited in instant claim 23) by administering miR-17 mimic, as evidenced by the art cited above showing upregulation of miR-17 in retinoblastoma and neuroblastoma, such that downregulation, not mimicking/upregulation, was found therapeutically useful. Therefore, practicing the full scope of the claimed invention would require a research program and not merely routine optimization.
Claims 16-30 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.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for the following reasons.
Claims 17-30 depend either directly or indirectly from independent claim 16. Claim 16 recites a method for preventing or treating cancer in a patient comprising administering a combination of a miR-17 mimic and a miR-340 mimic. Under the broadest reasonable interpretation, claim 16 encompasses methods of preventing (emphasis added) or treating any cancer through administration of any miR-17 mimic in combination with any miR-340 mimic.
The specification describes experiments directed primarily to glioblastoma models. The disclosure demonstrates reduced cell viability and tumor-associated effects using specific miRNA combinations in GBM cell lines, orthotopic xenograft models, and selected in vitro studies involving a limited number of additional cancer cell lines. The specification further identifies particular mature miRNA species, including miR-17-3p and miR-340-5p, used in the disclosed experimental embodiments. However, the specification does not identify structural characteristics common to the entire claimed genera of miR-17 mimics and miR-340 mimics, that would permit one of ordinary skill in the art to recognize which members or common core structures of those genera possess the claimed therapeutic function of treating much less preventing any cancer.
For example, claim 16 broadly recites a “miR-17 mimic.” Under broadest reasonable interpretation, this limitation encompasses distinct mature miR-17 species, including at least miR-17-3p and miR-17-5p. These mature miRNA strands are distinct molecular species having different nucleotide sequences and different targets. Although the specification provides disclosure regarding certain specific mature miRNA species, it does not identify structural features common to the entire claimed genera or otherwise describe why all members of the claimed genera would possess the recited therapeutic function of preventing any cancer. Accordingly, the specification demonstrates possession of only a limited number of species rather than the broad functional genera recited in the claims.
The state of the art likewise does not recognize common structure-function correlations that would have permitted a person of ordinary skill in the art to conclude that the full scope of the claimed genera possessed the recited therapeutic function of preventing any cancer. Fontana et al. (PLoS ONE 3:e2236, 2008) demonstrated that miR-17-5p is upregulated and functions as an oncogenic miRNA in neuroblastoma, and that inhibition of miR-17-5p using an antagomiR, rather than administration of a miR-17 mimic, suppressed tumor growth in vitro and in vivo. Similarly, Conkrite et al. (Genes Dev. 25:1734-1745, 2011) demonstrated that retinoblastoma cells exhibit high expression of the miR-17-92 cluster and are therapeutically sensitive to inhibition of the miR-17-92 microRNAs. Tassone et al. (US 2018/0051284) likewise teaches that members of the miR-17-92 cluster, including miR-17, retain oncogenic potential in multiple human cancers and describes therapeutic inhibition of miR-17-5p in pancreatic and lung cancers. Thus, at the time of filing, the prior art recognized that the biological role and therapeutic utility of miR-17 family members depended upon the particular mature miRNA species and disease context, and did not identify common structural characteristics that would permit one of ordinary skill in the art to conclude that all members of the claimed miRNA genera would possess the claimed therapeutic function.
Accordingly, neither the specification nor the state of the art provides a representative number of species or identifies common structural features sufficient to demonstrate possession of the broad functional genera recited in claims 16-30. Therefore, the disclosure fails to reasonably convey to one of ordinary skill in the art that the inventors were in possession of the full scope of the claimed invention at the time of filing.
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 27 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 27 is indefinite because claim 16, from which claim 27 depends, requires administration of a “combination” defined by the specification as a “composition comprising a plurality of components,” while claim 27 requires the two components of that combination to be administered sequentially. It is unclear how a single composition comprising both components can be administered sequentially when the sequential administration limitation required the two components to be administered at different times.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 16-18, 23-26, and 28-30 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kokkoli E, et al., (US20240285525A1, effective filing date 06/23/2021).
Regarding claims 16-18, 23-26, and 28, Kokkoli teaches a method of treating cancer in a patient, comprising administering the patient with a combination of a miR-17mimic and a miR-340 mimic, and wherein the patient is further administered with a miR-222 antagomiR, and wherein the patient is further administered with a miR-221 antagomiR and/or a miR-551b mimic ([0014] and claim 28: “methods for treating a mammal having cancer…the methods can include, or consist essentially of, administering a composition comprising any one or more of the nanotubes described herein to a mammal having cancer;” [0015] and claims 29-30: “The mammal can be a human. The cancer can be a glioblastoma, an astrocytoma, an oligodendroglioma, an oligoastrocytoma, an ependymoma, a medulloblastoma, a meningioma, a diffuse intrinsic pontine glioma (DIPG), a breast cancer, a colon cancer, a liver cancer, a pancreatic cancer, a prostate cancer, a lung cancer, an ovarian cancer, a kidney cancer, a spleen cancer, or a gastric cancer;” [0058] and claims 13-14 and 16: “A nanostructure provided herein (e.g., a nanotube including one or more anti-cancer agents) can include any appropriate one or more (e.g., one, two, three, four, or more) anti-cancer agents. An anti-cancer agent can be any appropriate type of molecule (e.g., … nucleic acids …)…Examples of nucleic acids that can used as an anti-cancer agent and can be included in a nanostructure provided herein (e.g., a nanotube including one or more anti-cancer agents) include, without limitation, … miR-340, … miR-17-5p, … anti-miR-221, anti-miR-222…;” claim 13: “a nanotube comprising… a microRNA (miRNA), a miRNA mimic, an anti-miRNA,…”).
Regarding claims 29-30, Kokkoli teaches combination is formulated into a pharmaceutical composition ([0076]: “nanostructures provided herein (e.g., nanotubes including one or more anti-cancer agents) can be formulated into a composition (e.g., a pharmaceutically acceptable composition). For example, a composition including nanostructures provided herein can include one or more pharmaceutically acceptable carriers (additives), excipients, and/or diluents;” and that said pharmaceutical composition is administered, intravenously, orally or subcutaneously ([0087]: “a composition including nanostructures provided herein can be designed for oral or parenteral (including, without limitation, a subcutaneous, intramuscular, intracranial, intravenous, intradermal, intra-cerebral, intrathecal, or intraperitoneal injection) administration to a mammal having cancer.”).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Kokkoli E, et al., (US20240285525A1, effective filing date 06/23/2021) as applied to claims 16-18, 23-26, and 28-30 above, and further in view of Thess A, et al., (WO2021028439A1).
The teachings of Kokkoli are incorporated herein by reference to the 102 rejection above.
Kokkoli does not teach administering the miRNAs sequentially per se.
Thess teaches “administration of the combination, preferably administration of first component and the second component is sequential.” Thess further defines ““Sequential” in that context has to be understood as that administration of the first and the second component of the combination may occur in a timely staggered manner and not simultaneously.” See page 57 lines 30-39, and claim 89.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to administer the miRNAs of kokkoli sequentially. A PHOSITA would have been motivated because sequential administration is explicitly taught by Thess and could be beneficial, for example, by allowing for more flexibility during treatment. A PHOSITA would have had a reasonable expectation of success because sequential administration of therapeutic agents was routine practice frequently employed for routine optimization.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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