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 1-41 are pending and under examination.
Drawings
The drawings are objected to for two reasons.
First, the text is very blurry and/or of low resolution in FIGs. 1-3, 5A-C, 7A, 8A-D, 10A, 11A-B, 12, 13A-D. Rule 37 C.F.R. 1.84(l) requires that “all drawings be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”
Second, the figures are referred to as “Figure” in the drawings. MPEP §608.02.V states that according to 37 C.F.R. 1.84(u)(1) “View numbers must be preceded by the abbreviation "FIG.".
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term Fluor-Jade C®, HiLyteTM, Huygens®, SpectraMx i3x®, pHrodo®, and DQTM, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 6-41 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, claims 6-41 have not been further treated on the merits.
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 1-5 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 1 recites “wherein the active agent inhibits the transcription or translation of a human miR17-92 cluster.” The Specification discloses that the miR17-92 cluster is a gene that encodes a cluster of microRNAs (miR or miRNA), which are known in the art to be noncoding RNAs (ncRNAs) and do not encode a protein (Fig 1; page 15, last ¶). Including “inhibits… translation of a human miR17-92 cluster” is confusing because miRNAs are never translated so there is nothing to inhibit. The Specification describes FIG 1, panel B as “translational regulation” (page 3), which shows the miRNAs inhibiting the translation of their gene targets. However, this is not the same as inhibiting the translation of miR17-92 cluster.
Claims 2-5 are rejected for depending from claim 1 and not remedying the indefiniteness.
To overcome this rejection, it is suggested that the claim recite: “wherein the active agent inhibits the transcription or function of a human miR17-92 cluster.” See page 15, last ¶ for support.
Claim Interpretation
For the purpose of examination, the claims are interpreted as the active agent inhibits transcription of the miR17-92 cluster or miRNAs or inhibits the function of the miRNAs. Additionally, it appears Applicant is using the term “antagomir” as a short single stranded nucleic acid that hybridizes to a miRNA. Although in the art antagomirs typically have non-natural nucleic acids (i.e., 2’-modifications and phosphorothioate linkages) and are conjugated to cholesterol, Applicant appears to use the term more broadly. None of the sequences or SEQ ID NOs in the table on pages 14-15 are denoted with specific substitutions. Additionally, the specification describes an antagomir as also binding to a miRNA through non-canonical base pairing (page 13, line 30). Therefore, “antagomir” in claims 3-5 is interpreted as a short, single stranded nucleic acid, including DNA or RNA, that can bind to a miRNA through direct hybridization with canonical or non-canonical base pairing.
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 1-3 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.”
Claim 1 recites an active agent that inhibits the transcription [or function] of a human miR17-92 cluster, which represents a genus of molecules that are defined by their function rather than their structure. The Specification does not define or otherwise limit the scope of “agent”. Therefore an “agent” is interpreted as encompassing a large genus of molecules that includes antibodies, other proteins, peptides, small molecules, nucleic acid aptamers, or antisense nucleic acids. Additionally, there is no requirement for the “inhibitor” to act directly on the miR17-92 cluster; therefore, the genus also includes molecules that act upstream of the miR17-19 expression. Because there is a known correlation between the structure of antisense molecules and their inhibitory function to a specific genomic sequence, one skilled in the art could have predicted the structure of antisense molecules that directly hybridize to the intended target that have the claimed inhibitor function. However, for the reasons described below, Applicants have not sufficiently described the genus of antibodies, small molecules, nucleic acid aptamers, or nucleic acids that indirectly inhibit transcription of the human miR17-92 cluster, such that one skilled in the art could have reasonably concluded applicants had possession of the genus as claimed.
Regarding antibodies, small molecules, peptides and nucleic acid aptamers, 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 agents 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.). In this case, the Specification only describes nucleic acid-based inhibitors, specifically antagomirs, that are complementary to the miR17-92 cluster (pages 14-15). The Specification is completely silent as the to the structure of proteins, antibodies, small molecules and aptamers that can directly bind and/or inhibit the transcription or function of miR17-92. Additionally, the Specification does not provide guidance on what other genes/proteins could be targeted to disrupt the transcription of the miR17-92 cluster.
A thorough search of the prior and contemporary prior art discovered no evidence of an antibody, aptamer, polypeptide or small molecule that can directly bind to a miRNA to inhibit its function of inhibiting translation of another protein. Additionally, except for known small molecules and aptamers that inhibit the basal transcriptional machinery and inhibit the transcription of all genes, polypeptides, small molecules, and aptamers that specifically inhibit miR17-92 transcription have not been discovered.
Although Applicants may argue that it is possible to screen for antibodies, aptamers, polypeptides or small molecules 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 antibody, aptamer, polypeptide or small molecule yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the antibody, aptamer, polypeptide or small molecule inhibitor agents encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown structures of antibody, aptamer, polypeptide or small molecules that can inhibit miR17-92 transcription or function, the specification does not provide an adequate written description of molecules that inhibit miR17-92 transcription or function that is required to practice the claimed invention.
Regarding claim 2, the genus of active agents is limited to nucleic acids. However, nucleic acids include aptamers, which bind to proteins based on shape and not on complementary base pairing. Applicant has not disclosed the structure of any aptamers that can inhibit the transcription of miR17-22 or its function.
Regarding claim 3, the genus of active agents is limited to antagomirs. Antagomirs are nucleic acids that “interact with a target nucleic acid molecule through either canonical or non-canonical base pairing” (page 13, last ¶). The Speciation discloses antagomir sequences (page 14-15), which are all complementary to the sequence of the miR17-92 cluster. Thus, each of the disclosed sequences would interact with the miR17-92 nucleic acids through “canonical base pairing”. The Specification does not provide any example of nucleic acid sequences, or specifically antagomirs, that bind through non-canonical base pairing. Additionally, the genus of agents also encompasses antagomirs that do not directly bind to the miR17-92 cluster, and instead could inhibit other genes/miRNAs that promote miR17-92 cluster transcription. The Specification does not disclose any antagomir sequences that inhibit miR17-92 transcription or function indirectly.
Note that claims 4-5 are not rejected for lack of sufficient written description because the genus of agents is limited to antagomirs (nucleic acids) that hybridize to the miR17-92 cluster.
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.
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.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Xiao (Xiao et al., RSC Advances (2021), 11: 32549-32558; published October 4, 2021), evidenced by Xiao2 (Xiao et al., ACS Appl. Mater. Interfaces (2016), 8: 7638−7645) and in view of Estfanous (Estfanous et al., Frontiers in Immunology (2021), 12: 705581, pages 1-17; published July 27, 2021) and Mendell (Joshua Mendell, Cell (2008), 133: 217-222). Claims 4-5 are evidenced by ThermoFisher (mirVana™ miRNA Inhibitor, 5 nmol – FAQs, https://www.thermofisher.com/order/catalog/product/4464084/faqs, [retrieved September 16, 2026]).
Regarding claims 1-3, Xiao teaches mannose-functionalized D-DoGo lipid nanoparticles comprising an siRNA (i.e., a short RNA sequence that binds to its target through direct hybridization) for direct delivery to microglia (page 32549, ¶3). Xiao teaches lipid nanoparticles (LNPs) comprising (1) D-DvMa, (2) D-DoGo2, (3) DOPE (i.e., a neutral lipid), and (4) siRNA (page 32554; ¶2). Regarding (1), Xiao teaches that D-DvMa is a lipid conjugated to mannose (Scheme 2), which targets the LNP to microglial cells (i.e., D-DvMa is a lipid comprising the microglial targeting agent) (page 32549, ¶3). Regarding (2), although Xiao teaches that D-DoGo2 interacts electrostatically with negatively charged siRNA, Xiao is silent as to whether D-DoGo2 comprises a cationic lipid. However, Xiao2 teaches that DoGo2 is an ionizable and cationic lipid (Figure 1). Regarding (4), Xiao teaches the siRNA consists of a double stranded RNA 21-mer (page 32553, ¶2). Xiao teaches that mannose-LNPs had limited cytotoxicity (Fig 4), were taken up by microglia (Table 2; Fig 5), and the siRNA cargo was functional to reduce expression of the target mRNA (Fig 7). Therefore, Xiao inherently teaches a composition comprising an LNP comprising a lipid with a microglial targeting agent, a cationic lipid, a neutral lipid and an active agent that binds to and inhibits the function of a cellular RNA that can deliver the functional siRNA cargo to microglial cells.
Xiao does not teach the active agent inhibits human miR17-29.
Estfanous teaches that microglia in a mouse AD model cannot degrade Ab deposits (¶ spanning pages 5-6) because autophagy proteins are poorly expressed in the microglia (page 6, ¶3). Estfanous teaches the miR17-92 cluster is upregulated in microglia in human Alzheimer’s Disease (AD) in areas with Ab deposits (Fig 5). Estfanous teaches inhibiting upregulated miR-17 in the microglia from AD mice restored the ability of microglia to degrade Ab deposits (page 8, ¶3 – page 9, ¶3). Estfanous teaches delivering an antagomir of miR-17 (i.e., an agent that inhibits the function of miR17) to microglia in culture (Figure 6C-D). Estfanous teaches injecting the miR-17 antagomir into the intracisternal magna of mice (page 9, ¶4).
Mendell teaches the sequences of the mature miRNAs in the miR-17-92 cluster are highly conserved in all vertebrates, and classifies the miRNA sequence conservation as “extreme” (page 217, ¶2).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have incorporated Estfanous’s miR-17 antagomir into the microglial-targeting LNPs developed by Xiao for the purpose of delivery to microglial cells of humans. It would have amounted to the simple substitution of one inhibitor RNA for another by known means to yield predictable results. The skilled artisan would have predicted that Xiao’s LNP could be used to encapsulate Estfanous’s miR-17 antagomir since the two cargo molecules are both short negatively charged RNAs. As such, the cationic lipid of Xiao’s LNP would predictably interact with the antagomir electrostatically. It also would have been entirely predictable that Estfanous’s miR-17 antagomir could target the human miR17-92 cluster based on the extreme conservation of sequence between the human and mouse miR17-92 clusters. The skilled artisan would have been motivated to use Xiao’s LNP to deliver the antagomir because Xiao teaches successful delivery of the antisense cargo to microglia with limited cell toxicity, which would selectively target the antagomir to microglia in the CNS.
Regarding claims 4-5, Estfanous teaches the miR-17 antagomir was purchased from ThermoFisher, product 4464084 (page 4, ¶5). Estfanous is silent as to whether the miR-17 antagomir binds to human miR-17 under moderate or high stringency.
However, ThermoFisher teaches their miRNA inhibitors are designed to “specifically bind and inhibit endogenous microRNAs” (page 6). Because Estfanous teaches the antagomir purchased from ThermoFisher targets miR-17 in mouse cells, and Mendell teaches the mouse and human miR-17 sequence is highly conserved, the skilled artisan would have predicted that Estfanous’s miR-17 antagomir would hybridize to the human miR-17 under both moderate and high stringent conditions.
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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