Status of the Claims
Claims 1-2, 7, 10, 12-13, 15, 23, 26, 29, 36-37, 41-43, 45, 47-48, and 50-51 are pending and examined herein.
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 .
Specification
The disclosure is objected to because of the following informalities:
On page 38, line 7, Figure 2C is referenced. However, only Figure 2 was supplied as part of the disclosure. It appears that this was meant to reference Figure 8C instead.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 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. Specifically, claim 45 recites the limitation “in order” in referring to oligos positioned along the length of the complex. It is unclear what “order” the oligos should be positioned in, outside of the optional limitation that follows. To overcome this rejection, the claim could be amended to make the explicitly recited order non-optional, or the indefinite “in order” limitation could be removed. Other solutions are possible. For the purposes of examination, the limitation will be interpreted to encompass any order of positioning the oligonucleotides.
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.
Heyduk et al.
Claims 36, 1, 13, 41, 2, 15, 37, 10, and 12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Heyduk et al. (US Pat No: 9,618,505).
Regarding claim 36, Heyduk discloses a system (Fig. 45A; col. 13, lines 37-41: formula (I)) comprising a first member of a binding pair (p53-antibody conjugate = R1) conjugated to a first oligonucleotide (R3) that is further conjugated to a fluorophore (fluorescein = R4) and second member of the binding pair (dsDNA comprising p53 binding site = R5) conjugated to a second oligonucleotide (R7) (col. 67, lines 19-25).
Heyduk does not explicitly disclose the dissociation constant of the binding members. However, it is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). In the instant case there is evidence to suggest that the first and second members (p53 and dsDNA comprising the p53 binding sequence) bind to each other with a dissociation constant of about 7.7 nM, as evidenced by Petty et al. (EMBO J. (2011), 30(11): 2167-2176).
Furthermore, while Heyduk does not provide the dissociation constant for the oligonucleotides, it does teach preferred ΔG values for association of the oligonucleotides, including 8.0 kcal/mol (col. 15, lines 24-26). As a free energy for association of 8.0 kcal/mol at 21°C (room temperature) corresponds to a KD of 1.12 μM, the provided ΔG value fulfills the limitation of “about” 1 μM.
Regarding claim 1, Heyduk further discloses that the fluorophore conjugated to the first oligonucleotide is a FRET donor (fluorescein) and the second oligonucleotide is further conjugated to a FRET acceptor fluorophore (Cy5) (col. 65, lines 24-27; col. 15, lines 34-36).
Regarding claims 13 and 41, Heyduk discloses a method wherein the components are provided at a concentration of 10 nM (col. 67, lines 25-26), which is lower than the oligonucleotide dissociation constant and within the range of 100 pM to 100 nM. Heyduk further discloses combining the first and second members with a sample, measuring test fluorescence, and identifying the sample as containing an agent that decreases binding of the first member to the second member as fluorescence decreased in the presence of the sample (Fig 45B; col. 67, lines 31-34: specific competitor).
Regarding claims 2, 15, and 37, Heyduk discloses the limitations of claims 36, 1, and 13 as discussed above. Additionally, Heyduk further discloses that the first/second members are conjugated to the first/second oligonucleotides using a linker comprising four adjacent 18-atom hexa-ethyleneglycol spacers (R2 and R6; col.14-15, lines 65-1: Spacer 18).
Regarding claim 10, Heyduk further discloses that when the first and second oligonucleotides are hybridized, the donor and acceptor FRET fluorophores are spaced apart by 1 base pair (Fig 45A).
Regarding claim 12, Heyduk further discloses that the first member is a protein (col. 67, lines 19-25: p53 and anti-p53 antibody conjugate).
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.
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.
Heyduk et al.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Heyduk et al. As discussed previously, Heyduk teaches all limitations of claim 13 upon which claim 29 is dependent . However, Heyduk does not teach providing the binding members at concentrations lower than the member KD. Despite this, the limitation recited in claim 29 of members being provided at concentrations lower than their KD is obvious because finding the optimal working ranges of concentrations is considered routine experimentation. In particular, determining the binding member concentrations that will produce the greatest change in FRET signal upon binding and/or interaction with a modulator would be considered standard optimization by one of ordinary skill in the art. See MPEP § 2144.05(II)(A).
Heyduk et al. and Hanson et al.
Claims 7 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Heyduk et al. in view of Hanson et al. (biorxiv (2020), doi: 10.1101/2020.06.16.154708).
Regarding claim 7, Heyduk teaches all limitations of claim 1 as discussed previously. However, Heyduk does not disclose that the first member is a viral component nor that the second member is a mammalian cell. Hanson teaches a proximity assay for the high-throughput investigation of binding modulators of the ACE2-RBD interaction. Hanson discloses that the first member is a viral component, specifically the SARS-CoV-2 receptor binding domain, and that the second member is a mammalian component is receptor ACE2 (Figure 1; p. 5, 2nd ¶). Additionally, Hanson teaches that the ACE2-RBD interaction is the first step in SARS-CoV-2 infection and is therefore a high-priority target to find small molecule inhibitors of (p. 3, 2nd ¶). Therefore, it would have been obvious to one of ordinary skill in the art to combine the binding members of Hanson with the binding assay system of Heyduk to investigate potential small molecule inhibitors. Furthermore, there would have been a reasonable expectation of success considering the modular nature of the FRET system and the previous success by the orthogonal method of Hanson, rendering claim 7 obvious.
Regarding claim 23, Heyduk discloses all limitations of claim 13 as previously discussed. By the same reasoning as with claim 7 above, combination of the binding members of Hanson with the binding assay system of Heyduk renders claim 23 obvious.
Heyduk et al., Hanson et al., and Hansen et al.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Heyduk et al. in view of Hanson et al. as applied to claim 23 above, and further in view of Hansen et al. (Science (2020), 369: 1010-1014). Heyduk and Hanson do not disclose that the agent is an antibody nor that the sample is a blood or serum sample. Hansen teaches a method of screening convalescent patient sera (p.1, col. 3, top) for antibodies that have the ability to block the binding interaction of ACE2 and the SARS-CoV-2 RBD (p. 1, col. 3, middle). Hansen further discloses that antibodies identified as viral inhibitors have the ability to be developed into antiviral therapies, which were highly sought after at the time of the instant application (p. 1, col. 1, top; col. 2, top: “yielded a single-therapeutic antibody treatment”). One of ordinary skill in the art would have a reasonable expectation of success in applying the sample and agent of Hansen to the member binding assay system of Heyduk and Hanson because binding of an antibody could reasonably disrupt the binding of ACE2 and RBD, thereby eliminating the measurable FRET response. Additionally, Heyduk discloses that the binding assay system can be used to assay plasma samples (col. 55, lines 25-26). Therefore, it would have been obvious to one of ordinary skill in the art to apply the agent and sample of Hansen to the ACE2-RBD binding assay method of Heyduk and Hanson to screen for a potential antiviral therapy.
Wong et al. and Heyduk et al.
Claims 42-43, 45, 47-48, and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (US Pat No: 9,914,958) in view of Heyduk et al.
Regarding claim 42, Wong discloses a system (Fig. 2A; “nucleic acid complex”) comprising first and second members of a binding pair (col. 20, lines 13-15) and a complex/polymer comprising a ssDNA scaffold hybridized to a plurality of single-stranded oligonucleotides (col. 16, 31-33), wherein the first and second members are linked to first and second oligonucleotides (col. 18, lines 25-29), and that the complex/polymer adopts a looped conformation when the members bind to each other (col. 20, lines 17-19). Wong does not disclose that the members have a KD of 100 pM to 100 μM, nor does Wong disclose first and second FRET oligonucleotides conjugated to first and second FRET fluorophores and further conjugated to the complex.
As discussed previously, Heyduk discloses binding members that have a KD of 7.7 nM. It would have been obvious to incorporate the binding partners of Heyduk into the nucleic acid complex of Wong because this would constitute a simple substitution of one known element for another to obtain predictable results. The complex of Wong is highly modular (col. 2, lines 32-34) and can accommodate many different types of binding partners (col. 3, lines 33-55). Additionally, the antibody-p53 conjugate and dsDNA binding members were known to have affinity for one another (Petty et al.) and would have been compatible with the complex of Wong, including being able to be linked to single-stranded oligonucleotides as evidenced by Heyduk (Fig. 45A). Therefore, it would have been obvious to one of ordinary skill in the art to substitute the generic binding members of Wong with the antibody-p53 conjugate and dsDNA binding members of Heyduk.
Heyduk also disclosed first and second FRET oligonucleotides conjugated to first and second FRET fluorophores and further conjugated to the molecular beacon complexes, as discussed above. Additionally, Heyduk discloses that FRET oligonucleotides are important for increasing the stability of the complex when binding partners and oligonucleotides are bound, thereby increasing the sensitivity and specificity of the assay employing the molecular beacons (col. 54, lines 1-3). This provides motivation for combining the FRET oligonucleotides of Heyduk with the nucleic acid complex of Wong.
Furthermore, Wong discloses the possibility of multiple binding pairs conjugated to the complex (col. 20, lines 31-33), demonstrating that the combination would have a reasonable expectation of success. Additionally, further feasibility is provided by Wong, which states that “Change in binding including presence or absence of binding, in any of the aspects and embodiments of the invention, may be detected using any suitable methodology including… single-molecule fluorescence” (col. 9, lines 10-17).
Therefore, it would have been obvious to one of ordinary skill in the art by the effective filing date of the application to combine the FRET oligonucleotides of Heyduk with the nucleic acid complex of Wong in order to increase the sensitivity and specificity of the complex. There would have also been a reasonable expectation of success because of the acknowledged possibility of incorporating additional binding pairs into the complex, as well as the feasibility of using single-molecule fluorescence to detect conformational changes in the nucleic acid complex.
Regarding claim 43, Wong further discloses that the polymer comprises a nucleic acid scaffold (col. 16, lines 31-33).
Regarding claim 45, Heyduk discloses that the FRET oligonucleotides are conjugated to the complex using a linker comprising a one or more 18-atom hexa-ethyleneglycol spacers (col.14-15, lines 65-1: Spacer 18). Additionally, Wong discloses that the oligonucleotides are positioned along the length of the complex in an order, specifically as the first oligonucleotide (A1), the first FRET oligonucleotide (B1), the second FRET oligonucleotide (B2), and the second oligonucleotide (A2) (col. 20, lines 39-44).
Regarding claim 47, Heyduk further discloses that the first and second oligonucleotides of the complex bind to each other only upon binding of the first and second members to each other (col. 15, lines 6-10).
Regarding claim 48, Wong discloses that binding partners are between 40-100 base pairs apart in the complex. However, Wong does not specifically disclose that the first oligonucleotide and first FRET oligonucleotide are 30 base pairs apart. Wong does state that “Suitable distances will vary based on the application and will depend on the size of the binding partners, the degree of single- and double- strandedness of the looped region, the use of linkers to attach the binding partners to oligonucleotides within the complex, and the like” (col. 25, lines 13-17). Therefore, it would have been obvious to one of ordinary skill in the art to arrive at an optimum number of base pairs separating the first oligonucleotide and the first FRET oligonucleotide by routine experimentation.
Regarding claim 50, Wong discloses that the nucleic acid complex can comprise more than two linked binding partners, specifically that the number may be more than 4 (col. 20, lines 31-33). Wong elaborates that the nucleic acid complex can accommodate a plurality of binding partners in multiple types of arrangements, including two terminal binding partners (binding members) and one internal binding partner (FRET oligonucleotides) (col. 4, lines 35-37).
Regarding claim 51, Wong discloses a method of combining the nucleic acid complex with a sample (col. 8, line 40: excess soluble forms), under conditions that allow for binding and detection of a change in binding between a first binding partner and a second binding partners (col. 7-8, lines 66-5), as well as identifying the sample as containing an agent that decreases binding of the first member to the second member (col. 8, lines 38-43).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Patent No: 9,914,958
Claims 42, 43, 45, and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 15, 19, 25, and 29 of U.S. Patent No. 9,914,958 in view of Heyduk et al.
Claims 1, 15, and 25 of the reference patent each teach a complex comprising a single-stranded scaffold nucleic acid hybridized to a plurality of single-stranded oligonucleotides, wherein first and second binding members that have affinity for each other are conjugated to single-stranded oligonucleotides, and the complex adopts a looped conformation upon binding of the binding members. Patent 9,914,958 does not teach that the binding members have a dissociation constant of about 100 pM to 100 μM, nor does it teach FRET oligonucleotides.
However, as noted in the current rejections, combination of these features, as taught by Heyduk et al., with the disclosed nucleic acid complex would have been obvious to a person of ordinary skill in the art by the effective filing date based on the motivation provided by Heyduk to increase the sensitivity and specificity of the complex, rendering claims 42, 43, 45, and 47 obvious.
Patent No: 11,198,900
Claims 42, 43, 45, and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,198,900 in view of Heyduk et al.
Claim 1 of the reference patent discloses a complex comprising a single-stranded nucleic acid which is capable of hybridizing to a plurality of single-stranded oligonucleotides, wherein first and second binding members that have affinity for each other are conjugated to single-stranded oligonucleotides, and the complex adopts a looped conformation upon binding of the binding members. Patent 11,198,900 does not teach that the binding members have a dissociation constant of about 100 pM to 100 μM, nor does it teach FRET oligonucleotides.
However, as noted in the current rejections, combination of these features, as taught by Heyduk et al., with the disclosed nucleic acid complex would have been obvious to a person of ordinary skill in the art by the effective filing date based on the motivation provided by Heyduk to increase the sensitivity and specificity of the complex, rendering claims 42, 43, 45, and 47 obvious.
Patent No: 12,077,807
Claims 42, 43, 45, and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,077,807 in view of Heyduk et al.
Claim 1 of the reference patent discloses a nanoswitch comprising a single-stranded nucleic acid hybridized to a plurality of single-stranded oligonucleotides, wherein first and second binding members that have affinity for each other are conjugated to single-stranded oligonucleotides, and that the complex adopts a looped conformation upon binding of the binding members. Patent 11,198,900 does not teach that the binding members have a dissociation constant of about 100 pM to 100 μM, nor does it teach FRET oligonucleotides. Additionally, the reference patent also discloses stabilization of the looped conformation via base pairing that occurs only upon binding of the binding members, but this stabilization occurs via a “latch” nucleic acid, not FRET oligonucleotides.
As noted in the current rejections, addition of the undisclosed binding KD as well as replacement of the latch nucleic acid with FRET oligonucleotides as taught by Heyduk et al., would have been obvious to a person of ordinary skill in the art by the effective filing date based on the motivation provided by Heyduk to increase the sensitivity and specificity of the complex, rendering claims 42, 43, 45, and 47 obvious.
This is a provisional nonstatutory double patenting rejection.
Application 18/751,136
Claims 42, 43, 45, 47, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 4, 27, and 30 of copending Application No. 18/751,136 in view of Heyduk et al.
Claims 3, 4, 27, and 30 of the reference application disclose a nucleic acid complex comprising a single-stranded scaffold nucleic acid hybridized to a plurality of single-stranded oligonucleotides, wherein a first and second binding partner that have affinity for each other and are linked to single-stranded oligonucleotides hybridized to the complex, and that the complex adopts a looped conformation upon interaction of the two binding members. The reference application does not teach that the binding members have a dissociation constant of about 100 pM to 100 μM, nor does it teach FRET oligonucleotides.
However, as noted in the current rejections, the combination of these features as taught by Heyduk et al. with the disclosed nucleic acid complex would have been obvious to a person of ordinary skill in the art by the effective filing date based on the motivation provided by Heyduk to increase the sensitivity and specificity of the complex, rendering claims 42, 43, 45, and 47 obvious.
Additionally, claims 3, 27, and 30 disclose a method for detecting an agent comprising combining the nucleic acid complex with a sample, detecting binding, and identifying the sample as containing an agent that increases or decreases binding of the binding members, rendering obvious claim 51.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon (Frato et al.) is considered pertinent to applicant's disclosure because it is prior art that is highly similar to the subject matter of claim 36 and its dependent claims.
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/ALEXANDRA OLSON/
Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684