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
Applicant’s response filed June 25, 2026 is acknowledged. Claims 1-20 are pending.
Restriction/Election
Applicant’s election without traverse of Invention I (claims 1-14) in the response filed on June 25, 2026 is acknowledged. Claims 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Claims 1-14 are under consideration hereinafter.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/385,258, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, Application No. 63/385,258 generically discloses “microRNA200c,” and “miR 200c-3p” (e.g., [0012], Fig. 3) which could be from any species, for example, with any sequence corresponding thereto. Application No. 63/385,258 does not disclose the specific microRNA sequence set forth in SEQ ID NO: 1. The first disclosure of the specific microRNA sequence set forth in SEQ ID NO: 1 is in the instant application. The effective filing date of claims 3 and 11, therefore, is November 6, 2023. The remaining claims find support in Application No. 63/385,258 and, therefore, the effective filing date of claims 1-2, 4-10, and 12-14 is November 29, 2022.
Drawings
The drawings are objected to because of the following informalities:
The view numbers are preceded by the term “Figure.” 37 C.F.R. 1.84(u)(1) states that “view numbers must be preceded by the abbreviation "FIG."
Appropriate correction is required.
Claim Objections
Claims 4, 6, and 9 are objected to because of the following informalities:
Claim 4, 6, and 9 recite “an amino terminus of the dodecylamine.” It is clear that the term “amino terminus” refers to the previously recited “amino group” of the dodecylamine based on the meaning and structure of “dodecylamine” set forth in the specification (“the term “dodecylamine” refers to an organic compound having… the following chemical structure… characterized by a primary amine functional group… the amino group of the dodecylamine is located at a twelfth carbon of the dodecylamine,” [0054]). It would be preferable to amend each instance of “an amino terminus” to recite “the amino group,” so that the claim terminology is consistent.
Claim 6 recites the phrase “a peptide linker conjugated to the dodecylamine at an amino terminus of the dodecylamine amino terminus of the dodecylamine and a PEG conjugated to the peptide linker at an amino terminus of the peptide linker.” This phrase is redundant. To improve the flow of the claim, and in view of the objection above regarding the phrase “amino terminus,” claim 6 should be amended to recite the following: “a peptide linker conjugated to the amino group of the dodecylamine
Claim 9 recites the phrase “the peptide linker is conjugated to the dodecylamine at an amino terminus of the dodecylamine amino terminus of the dodecylamine, and the PEG is conjugated to the peptide linker at an amino terminus of the peptide linker.” This phrase is redundant. To improve the flow of the claim, and in view of the objection above regarding the phrase “amino terminus,” claim 9 should be amended to recite the following: “the peptide linker is conjugated to the amino group of the dodecylamine
Appropriate correction is required.
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 1-14 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 “an oligonucleotide.” The specification states that the term oligonucleotide “refers to a short DNA or RNA molecules, which usually has 13-25 nucleotides long. The maximum length of oligonucleotides is around 200 nucleotide residues” ([0057]). The definition of “oligonucleotide” includes relative terminology (“short,” “usually,” “around”). The specification does not provide a reasonable metric for ascertaining the degree of “short,” because it uses the term “usually” to precede a range of nucleotides, and then, provides a different, greater number of nucleotides, preceded the term “around,” which is also not defined. The scope of oligonucleotides encompassed by claim 1 is unclear, therefore, because the skilled artisan would not know whether, for example, an oligonucleotide 4 nts, 10 nts, or 215 nts in length is within the scope of oligonucleotides because these values are less than 200, or could be considered “around” 200, but are not in the recited “usual” range, for example.
Claims 2-14 are rejected for depending from claim 1 and failing to remedy the indefiniteness. In the interest of compact prosecution, the term “oligonucleotide” will be interpreted as a nucleotide sequence less than 200 nucleotides in length hereinafter.
Claims 6 and 9 recite “a peptide linker.” The specification states that the term peptide linker “refers to a short chain of amino acids…” ([0062]). The definition of “peptide linker” includes relative terminology (“short”). The specification does not provide a reasonable metric for ascertaining the degree of “short,” and therefore, the scope of peptide linkers encompassed by the claims is unclear.
Claims 7-8, and 10-13 are rejected for depending from claims 6 or 9 and failing to remedy the indefiniteness. In the interest of compact prosecution, the term “peptide linker” will be interpreted as an amino acid sequence with the intended use of linking elements hereinafter.
Claim Rejections - 35 USC § 112(a) – Written Description
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 1-14 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 the following:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.”
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Species Encompassed
Claim 1 is directed to an “oligonucleotide therapeutic” comprising an oligonucleotide and a dodecylamine. The term “therapeutic” is interpreted as an intended use for the oligonucleotide which does not impose any further structural limitations on the oligonucleotide, because the claim body recites a structurally complete invention. The term “oligonucleotide” is interpreted as a nucleotide sequence less than 200 nucleotides in length in view of the indefiniteness described above. The term “dodecylamine” is interpreted as the compound set forth in [0054]. The phrase “an amino group of the dodecylamine is located at a twelfth carbon of the dodecylamine” is interpreted as a phrase which describes a structure inherent to the dodecylamine, and which imposes numbering on the dodecylamine carbons. Accordingly, the phrase “a first carbon of the dodecylamine is conjugated to the oligonucleotide at a 5’ end of the oligonucleotide” is interpreted as requiring that the 5’ end of oligonucleotide is conjugated to the “first” carbon of the dodecylamine, i.e., the carbon furthest from the amino group-carbon.
Claims 4-9, and 12-13 encompass oligonucleotide therapeutics further comprising a polyethylene glycol (PEG), e.g., PEG 500, PEG 1000, or PEG 2000, conjugated to the amino group of the dodecylamine, as well as oligonucleotide therapeutics further comprising a peptide linker conjugated to the amino group of the dodecylamine, and a polyethylene glycol (PEG) conjugated to the amino terminus of the peptide linker. The term “peptide linker” is interpreted as an amino acid sequence with the intended use of linking elements in view of the indefiniteness described above. The peptide linker may “consist[] of a sequence of SEQ ID NO: 2,” which is interpreted as a peptide linker consisting of any two or more consecutive amino acids of SEQ ID NO: 2. Finally, claims 2-3, and 10-11 encompass oligonucleotide therapeutics wherein the oligonucleotide is a “microRNA,” which is interpreted as a single-stranded RNA sequence consisting of 18-22 nucleotides, which leads to translational inhibition, degradation of target genes, and/or regulation of mRNA molecules ([0058]). The oligonucleotide may consist of a sequence of SEQ ID NO: 1, i.e., any two or more consecutive nucleotides of SEQ ID NO: 1, which corresponds to a mature miR-200c-3p sequence ([0059]).
Claims 1-13 are, therefore, directed to a genus of oligonucleotides therapeutics, comprising an oligonucleotide which may have virtually any sequence less than 200 nucleotides as interpreted herein, including partial sequences of known mature microRNA sequences. The oligonucleotide is conjugated to a dodecylamine, a dodecylamine-PEG, or a dodecylamine-peptide linker-PEG, wherein the peptide linker may have virtually any sequence, including partial sequences of the sequence of SEQ ID NO: 2. The claims encompass oligonucleotides which are microRNAs, which function to inhibit translation, degrade target genes, and/or regulate mRNA molecules ([0058]). As will be further described below, the specification has not sufficiently described the genus of oligonucleotide therapeutics which have microRNA function.
Species Described in the Specification
The specification describes five species in the claimed genus: an oligonucleotide consisting of instant SEQ ID NO: 1, wherein SEQ ID NO: 1 is modified at the 5’ end with a dodecylamine (“C12-miR,” [0091]), oligonucleotides consisting of instant SEQ ID NO: 1, wherein SEQ ID NO: 1 is modified at the 5’ end with a dodecylamine, and further conjugated to 0.5, 1, or 2kDa PEG at the amino group of the dodecylamine (“P.5-C12-miR, P1-C12-miR, and P2-C12-miR,” [0092]), and an oligonucleotide consisting of instant SEQ ID NO: 1, wherein SEQ ID NO: 1 is modified at the 5’ end with a dodecylamine, wherein the amino group of the dodecylamine is modified with the peptide linker consisting of SEQ ID NO: 2, and further conjugated to 0.5kDa PEG at the amino terminus of the peptide linker (“P.5-L-C12-miR,” [0093]). The species are depicted in Fig. 1. The specification teaches that the species increase expression of PD-L1 in cells in some contexts ([0104]; [0111]; Figs. 3-4). The specification reports that the results are “completely opposite to the downregulating effects of microRNA 200c-3p mimic or microRNA 200c-3p expression vector on PD-L1 expression” reported in the prior art ([0104]).
The specification does not describe any other species in the genus of oligonucleotide therapeutics which are microRNAs, and which function to inhibit translation, degrade target genes, and/or regulate mRNA molecules. The results in the specification also strongly suggest that the function of the oligonucleotide therapeutics is unpredictable, even when the oligonucleotide therapeutic comprises a known microRNA sequence. The specification does not provide any rationale to understand why the known microRNA sequence, when coupled to dodecylamine, peptide linker, and/or PEG, has the opposite function to the function described in the prior art. Absent such guidance, the skilled artisan cannot reasonably predict the function of undisclosed variants of the disclosed species, e.g., oligonucleotide therapeutics comprising only a partial sequence of SEQ ID NO: 1 (i.e., “a sequence of SEQ ID NO: 1”), or a partial sequence of SEQ ID NO: 2 (i.e., “a sequence of SEQ ID NO: 2”), or which comprise additional elements, e.g., multiple PEG moieties, or a different arrangement of components. The skilled artisan also cannot reasonably predict the function of the many species of oligonucleotide therapeutics comprising different, known microRNA sequences, or variants, or partial sequences thereof, given the apparent unpredictable function of conjugated forms of microRNA sequences.
Guidance in the Prior Art
The prior art describes one species in the claimed genus, i.e., the oligonucleotide therapeutic of Mirkin, which is further described below. However, Mirkin’s oligonucleotide therapeutic does not comprise a microRNA sequence, and a thorough search of the prior art failed to uncover any oligonucleotide therapeutics in the claimed genus which comprise a microRNA sequence, or which comprise the additional elements (i.e., peptide linker and PEG), in the instantly claimed arrangements, coupled with any oligonucleotide.
The prior art was searched for general guidance regarding coupling an oligonucleotide, and more specifically, an oligonucleotide which functions through RNAi (e.g., microRNA, siRNA), to lipids, PEG, and/or peptide linkers. With respect to lipid conjugation to RNAi oligonucleotides, Kubo (Kubo et al., 21 December 2020, ACS Chemical Biology, 2021, 16, pg. 150-164) demonstrates that an siRNA conjugated to C12 was less effective in gene silencing compared to other siRNA-lipid conjugates (Fig. 3). Kubo also teaches that the siRNA conjugated to C12 did not exhibit high membrane permeability (pg. 160), which is the primary intent of lipid-oligonucleotide conjugation (pg. 150-151). The skilled artisan would predict based on structural similarity to C12, that dodecylamine may confer similarly less effective gene silencing, and lower membrane permeability. Although the function of some microRNA sequences has been documented, the skilled artisan would, therefore, be unable to predict the function of an oligonucleotide therapeutic comprising dodecylamine based on the function of the oligonucleotide element’s unconjugated form.
Hatakeyama (Hatakeyama, 2009, Journal of Controlled Release, (2009), pg. 127-132) appears to be the closest prior art to an oligonucleotide therapeutic comprising an oligonucleotide conjugated to dodecylamine, a peptide linker, and PEG. Importantly, in contrast to the instantly claimed oligonucleotide therapeutics, Hatakeyama discloses a separate oligonucleotide (“siRNA”), and a separate lipid-peptide-PEG conjugate (“PPD”), which are prepared as a nanoparticle (Abstract; Introduction; Preparation of MENDs, pg. 127-128). The lipid of Hatakeyama is not conjugated to the oligonucleotide at a 5’ end of the oligonucleotide, and is a different lipid species (“DOPE”), the peptide linker of Hatakeyama is also distinct from the instantly claimed peptide linker of SEQ ID NO: 2. Neither Hatakeyama nor the remaining prior art reviewed during examination suggest modifying Hatakeyama’s nanoparticle so as to arrive at the instantly claimed oligonucleotide therapeutics, and doing so would require modification of virtually every component of Hatakeyama’s nanoparticle. A search of the prior art also did not uncover any oligonucleotide therapeutics which comprise the peptide linker set forth in SEQ ID NO: 2, any PEG or dodecylamine conjugates with the peptide linker set forth in SEQ ID NO: 2, or any suggestion to use the sequence of SEQ ID NO: 2 as instantly claimed.
Taken together, the prior art fails to provide any additional species in the genus which are microRNAs, and which function to inhibit translation, degrade target genes, and/or regulate mRNA molecules. The prior art provides additional unpredictability regarding the function of known microRNA sequences, when conjugated to dodecylamine as instantly claimed. The prior art also does not appear to provide any guidance which would allow the skilled artisan to reasonably predict the function of oligonucleotide therapeutics comprising only a partial sequence of SEQ ID NO: 1 (i.e., “a sequence of SEQ ID NO: 1”), or a partial sequence of SEQ ID NO: 2 (i.e., “a sequence of SEQ ID NO: 2”), or which comprise additional elements, e.g., multiple PEG moieties, or a different arrangement of components, or comprise different, known microRNA sequences, or variants, or partial sequences thereof.
Conclusion
Considering the large variation in the genus, the small percentage of species described in the specification (i.e., five species with substantially identical structure), and the lack of predictability provided by the specification and prior art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Additional Dependent Claims
Claim 14 does not further limit the genus of oligonucleotide therapeutics so as to resolve the issues above, and is therefore not sufficiently described for at least the reasons above.
Claim Rejections - 35 USC § 102 - Mirkin
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 1 and 14 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Mirkin (Mirkin et al., US 2012/0244230 A1, published 27 September 2012).
The interpretation of claim 1 is described above and applied hereinafter.
Regarding claim 1, Mirkin teaches an oligonucleotide, which is intended to be used as a therapeutic, and wherein the oligonucleotide comprises a dodecylamine conjugated at the 5’ end of the oligonucleotide (“5’ dodecylamine TAG CTG CAC GCT GCC GTC-((CH2CH2O)6PO3)2-propylthiol 3' (SEQ ID NO: 1),” [0125]). As shown in Scheme 1 ([0048]), the amino group of the dodecylamine is exposed (“amine terminated polynucleotide,” [0125]). Mirkin’s oligonucleotide, therefore, meets the structural limitations of instant claim 1, wherein a first carbon of dodecylamine is conjugated to the 5’ end of the oligonucleotide.
Regarding claim 14, Mirkin teaches compositions comprising the oligonucleotide and a pharmaceutically acceptable carrier or excipient ([0118]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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