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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 25-41, drawn to a nucleic acid carrier) in the reply filed on 28 March 2025 is acknowledged.
Claim 42 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II (claim 42, drawn to a method of manufacturing carriers), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 28 March 2025.
Accordingly, claims 25-41 are examined herein.
Priority
Acknowledgment is made of applicant’s claim for domestic priority based on US provisional application No. 62/297,194 filed on 19 February 2016.
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.
Claims 25, 28-32, and 35-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nilsen (US 6,274,723 B1; Published Date: 14 August 2001; hereinafter as Nilsen ‘723).
Regarding claim 25, Nilsen '723 teaches nucleic acid matrices (i.e., a trimer nucleic acid carrier) constructed using "monomer" (i.e., first, second, and third oligonucleotide) each comprising a first terminal arm, a central portion, and a second terminal arm (FIG. 8; Col. 2, lines 50-59). FIG. 8 from Nilsen '723 has been edited (see below) to highlight relevant for this discussion. Nilsen '723 further teaches these monomers hybridizes together to form a dendrimer wherein the first terminal arm a(+) 3' of the first oligonucleotide (highlighted, centered monomer) hybridizes with the first terminal arm a(-) 5' of the second oligonucleotide (highlighted, right monomer), wherein the second terminal arm a(+) 5' of the first oligonucleotide hybridizes with the first terminal arm a(-) 5' of the third oligonucleotide (highlighted, left monomer). Nilsen '723 further teaches the length of the monomers range from about 20 to about 200 bases (Col. 5, line 25), and have a melting temperature between 55-70°C (Col. 7, line 54).
Regarding claim 28, Nilsen '723 teaches the oligonucleotides have arms of 30 bases and waist (i.e., central portion) of 50 bases, which account for 110 bases (Col. 7, lines 38-40).
Regarding claim 29, Nilsen '723 teaches "selection of a sequence of a given length with a relatively high GC content will result in a oligomer having a relatively high melting temperature" (Col. 7, lines 21-23); therefore, if one selects a sequence of 29 to 49 bases with approximately 50% GC content, such oligomer will have a melting temperature from 65-75°C (FIGS. 3 and 4). Further, Nilsen '723
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teaches an example oligomer with a melting temperature between 55 to 70°C (Col. 7, line 54).
Regarding claims 30-32, Nilsen '723 teaches "to reinforce and help maintain the structural integrity of the assembled nucleic acid dendrimer, a plurality, and preferably all of the inter-monomer linkages…are cross-linked (Col. 9, lines 55-59)…psoralen treatment is preferred (Col. 10, line 35)". It is well-understood in the art that psoralen cross-linking is performed at 5'-TpA-3' sites. Nilsen '723 further teaches an exemplary master sequence SEQ ID NO: 1 (figure edited below to highlight relevant sections for this discussion) with multiple highlighted TpA sites distributed throughout its length. In addition, Nilsen '723 teaches "depending upon the desired result, different portions of these master sequences may be chosen as the oligomers that ultimately constitute the waist or arm sequences of the monomers" (Col. 7, lines 18-21). Thus, the entire disclosed SEQ ID NO:1 is not required to be used, but only requires oligonucleotides comprising two arms and a waist (i.e., a first and second terminal arms and a central portion). Consistent with Nilsen's teachings that arms are 30 bases and waist is 50 bases (Col. 7, lines 38-40), SEQ ID NO: 1 can be parsed into contiguous sub-regions that correspond to the arms and waist and satisfy the TpA requirements recited in the instant claims. For example, an arm may correspond to bases 81-110 with 3 TpA sites, a waist may correspond to bases 111-160 with 5 TpA sites, and another arm may correspond to bases 161-190 with 3 TpA sites. Nilsen '723 further teaches "[t]hose skilled in the art will recognize that the sequence requirements and the operating conditions vary depending on the specific cross-linking agent (Col. 10, lines 6-8). Thus, Nilsen '723 positively teaches the
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limitations in the instant claims.
Regarding claims 35-40, Nilsen '723 teaches “each polynucleotide monomer having an intermediate region comprising a linear, double stranded waist region (i.e., central portion) having a first end and a second end, said first end terminating with two single stranded hybridization regions (i.e., first and second terminal ends)…” (Col. 2, lines 50-54). The waist region is highlighted in FIG. 8 above. It is illustrated that “initial monomer” and “first layer monomer” in FIG. 8 comprise of two strands (oligonucleotides) wherein the central portion are complementary to each other, as illustrated by double arrows indicating “hybridization of these strands by necessity occurs in a 5’ to 3’ direction”. For instance, the trimer nucleic acid carrier illustrated at the bottom of FIG. 8 could be comprised of (from left to right) strand 3 (3’ b(+) w(+) a(-) 5’), strand 2 (5’ a(+) w(-) a(+) 3’), and strand 3 (5’ a(-) w(+) b(+), with the central portion underlined. Then an oligonucleotide complementary to the central portion of each strand is either w(-) or w(+). Nilsen '723 further teaches the oligonucleotides may have a wide variety of base composition and length, such that will allow for minimal non-specific homology and specific hybridization but are short enough for efficient production (Col. 5, lines 15-20), and the lengths range from about 20 to about 200 bases (Col. 5, line 26). Nilsen '723 also teaches two examples wherein the central portion comprises of 50 bases (Col. 5, line 39) and 24 bases (Col. 5, line 52), demonstrated that it only requires routine optimization and sequence designing to obtain central portions comprising of 31 bases.
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.
Claims 26, 27, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Nilsen (US 6,274,723 B1; Published Date: 14 August 2001; hereinafter as Nilsen ‘723) as applied to claim 25 above, and further in view of Nilsen (US 6,110,687; Published Date: 29 August 2000; hereinafter as Nilsen ‘687).
Regarding claims 26 and 27, The teachings of Nilsen '723 regarding the trimer nucleic acid carrier was discussed above as applied to claim 25.
However, Nilsen '723 does not teach the nucleic acid matrices further comprise one or more antibodies chemically conjugated to a fourth oligonucleotide that hybridizes or is conjugated to the second terminal arm of the second oligonucleotide.
Nilsen '687 teaches an oligonucleotide labeled antibody (i.e., an antibody that is chemically coupled to a fourth oligonucleotide) hybridized to one or more of the outer arms of a labeled dendrimer (i.e., a trimer nucleic acid carrier) Nilsen '687 teaches a labeled dendrimer (i.e., a trimer nucleic acid carrier) wherein one or more of the outer arms (the second terminal arm of the second or third oligonucleotide) is hybridized to an oligonucleotide labeled antibody (i.e., an antibody that is chemically coupled to a fourth oligonucleotide) (Abstract, FIG. 1B). Further, Nilsen '687 teaches "the outermost layer of a given DNA dendrimer has single-stranded sequences ("arms") exposed to the surface which will hybridize with a predetermined nucleic acid sequence which is complexed to the antibody…multiple labeled dendrimers, each having sequences complementary to a different sequence of the oligonucleotide arms may be hybridized to a single oligonucleotide complexed to an antibody" (Col. 6, lines 12-25), ultimately, constructing nucleic carriers comprising one more antibodies.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Nilsen '687 labeled dendrimer with the nucleic acid matrix taught by Nilsen '723 because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of using "DNA monomers that exhibit maximal self-assembly properties in that they hybridize substantially only to portions of other monomers having complementary sequences" (Nilsen '723: Abstract). One would have had a reasonable expectation of success in doing so because Nilsen '687 already teaches antibody-dendrimer conjugates.
Regarding claim 41, the teachings of Nilsen '723 regarding the trimer nucleic acid carrier is discussed above and as applied to claim 25.
However, Nilsen '723 does not teach a pharmaceutical composition comprising the trimer nucleic acid carrier of claim 25 and a pharmaceutically acceptable vehicle.
The teachings of Nilsen '687 dendrimer (i.e., trimer nucleic acid carrier) was discussed above as applied to claim 26. Nilsen '687 further teaches pharmaceutical composition comprising a dendrimer and TBS/Tween 20 (i.e., a pharmaceutically acceptable vehicle) for hybridization of complementary oligonucleotides in the dendrimer (Col. 8, lines 65).
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the composition of the trimer nucleic acid carrier of Nilsen '723 to include a pharmaceutically acceptable vehicle as taught by Nilsen '687 because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of using using a non-ionic surfactant in nucleotide hybridization to minimize non-specific binding. One would have had a reasonable expectation of success in doing so because Nilsen '687 teaches hybridization of DNA dendrimers in such pharmaceutical composition.
Claims 33 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Nilsen (US 6,274,723 B1; Published Date: 14 August 2001; hereinafter as Nilsen ‘723) as applied to claim 25 above, and further in view of Casta et al (US 2014/0017704 A1; Published Date: 16 January 2014)
Regarding claim 33, The teachings of Nilsen '723 regarding the trimer nucleic acid carrier is discussed above and as applied to claim 25.
However, Nilsen '723 does not teach wherein at least one of the first, second, and third oligonucleotides comprises nucleotides linked with a phosphorothioate nucleotide backbone.
Casta teaches DNA dendrimers (i.e., trimer nucleic acid carrier) hybridized to oligonucleotide-labeled antibodies, and their applications in lateral flow devices (Abstract and Figure 4). Casta teaches the polynucleotide (i.e., first, second, and third oligonucleotides) contains "internucleotide modifications such as…those…with negatively charged linkages (e.g., phosphorothioates)" ([0042]).
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the trimer nucleic acid carrier of Nilsen '723 with a phosphorothioate nucleotide backbone as taught by Casta because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of increasing stability and nuclease resistance. One would have had a reasonable expectation of success in doing so because Casta teaches the claimed invention can be used with "any suitable dendrimer…for example…US. Pat. 6,274,723" ([0077]), which is the cited Nilsen '723.
Regarding claim 34, the teachings of Nilsen '723 regarding the trimer nucleic acid carrier is discussed above and as applied to claim 25.
However, Nilsen '723 does not teach wherein at least one of the first, second, and third oligonucleotides comprises at least one nucleoside analog, wherein the analog increases the melting temperature of the nucleic acid carrier.
Casta teaches using "modified nucleosides…wherein one or more of the hydroxyl groups are replaced with halogen" ([0043]), which is known in the art that such modification increases the melting temperature.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the trimer nucleic acid carrier of Nilsen '723 with modified nucleosides as taught by Casta because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of designing structures with higher melting temperatures that offer enhanced stability and do not denature at relatively low temperature. One would have had a reasonable expectation of success in doing so because Casta teaches their claimed invention can be used with "any suitable dendrimer…for example…US. Pat. 6,274,723" ([0077]), which is the cited Nilsen '723.
Conclusion
No claims are allowable.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636