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 1-19) in the reply filed on 12 June 2026 is acknowledged.
Claims 20-44 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 June 2026.
Applicant’s election without traverse of a species of the composition wherein the sequence of the first fractional initiator is SEQ ID NO: 1, the sequence of the second fractional initiator is SEQ ID NO 2, and the sequence of the proximity probe is SEQ ID NO: 3 in the reply filed on 12 June 2026 is acknowledged. Due to the search not uncovering said species as anticipated or obvious, the search was expanded to all species of the composition with the potential sequences enumerated in claim 15. Therefore, the requirement of Species Election 1 of the Requirement for Restriction mailed 30 April 2026 is withdrawn.
Applicant’s election without traverse of a species of the composition wherein the reporter is a fluorophore in the reply filed on 12 June 2026 is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) filed 19 July 2024 (9 IDS filed on this date), 23 October 2025, and 9 March 2026 are considered, initialed, and attached hereto.
On the IDS filed 19 July 2024 where the first Non-Patent Literature Document is by Clay, H et al., the Non-Patent Literature Document Cite No 21 for the reference by Dicarlo, J et al. is lined through and not considered because it was not provided with the IDS.
On the IDS filed 19 July 2024 where the first Non-Patent Literature Document is by Ferre, F., the Non-Patent Literature Document Cite No 1 for the reference by Ferre F. is lined through and not considered because it was not provided with the IDS.
On the IDS filed 19 July 2024 where the first Non-Patent Literature Document is by Peng et al., the Non-Patent Literature Document Cite No 47 for the reference by Seeman et al., Nucleic Acid Nanostructures: Bottom Up Control of Geometry on the Nanoscale, is lined through and not considered because it was not provided with the IDS.
On the IDS filed 19 July 2024 where the first Non-Patent Literature Document is by Willis, M.C., et al., the Non-Patent Literature Document Cite No 3 for the reference by Winfree, E. “On the computational power of DNA annealing and ligation.”, is lined through and not considered because it was not provided with the IDS.
On the IDS filed 19 July 2024 where the first Non-Patent Literature Document is by Peng et al., the Non-Patent Literature Document Cite No 8 for the reference by Player, “An Enhanced-Sensitivity Branched-DNA Assay for Quantification of Human Immunodeficiency Virus Type 1 RNA in Plasma” appears to be misattributed to Player and to be identical to the correctly attributed reference by Kern et al. (Non-Patent Literature Document Cite No 14 on the IDS filed 19 July 2024 where the first Non-Patent Literature Document is by Jhaveri et al.), so this reference has been considered only insofar as the Kern et al. reference has been considered.
Examiner notes that though on the IDS filed 19 July 2024 that includes cited U.S. Patents the Non-Patent Literature Document Cite No 32 for the reference by Bushnell et al. was not provided with the IDS and on the IDS filed 19 July 2024 where the first Non-Patent Literature Document is by Clay, H et al., the Non-Patent Literature Document Cite No 6 for the reference by Collins et al., “A branched DNA signal amplification assay for quantification of nucleic acid targets below 100 molecules/ml”, was not provided with the IDS, these references were provided with the IDS filed 23 October 2025 and are therefore considered.
The listing of references in the specification (on pages 61-68 of the specification filed 29 February 2024) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or in a proper IDS, they have not been considered.
Claim Status
Claims 1-44 are pending.
Claims 20-44 are withdrawn.
Claims 1-19 are under examination.
Specification
The abstract of the disclosure filed 29 February 2024 is objected to because it contains a second paragraph reciting “58253530”. 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 on page 65 reciting a website with the prefix https://. 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.
The use of terms including, but not limited to, Tween and Triton-X, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they 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 Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9 and 11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 depends upon claim 1 and further recites “wherein the colocalized full initiator is used to mediate generation of a signal directly or indirectly”. Firstly, this is a statement of an intended use of the colocalized full initiator that the claimed composition is capable of forming, which does not structurally limit the claimed composition and therefore is not interpreted as limiting (see MPEP §2111.02 regarding Intended Use). Secondly, even if the intended use were interpreted as limiting the structure, claim 1 already recites the colocalized full initiator mediating generation of a signal in lines 20-22 and mediation of the generation of a signal can only occur directly or indirectly (there is no third option), so the use that the composition of claim 9 must be capable of fulfilling fails to further the signal generation of claim 1 upon which claim 9 depends.
Claim 11 depends upon claim 1 and further recites “wherein the first target and second target are selected from protein, RNA, DNA, or other molecules” (emphasis added). As ‘other molecules’ encompasses all possible targets of the probes, claim 11 fails to further limit claim 1 upon which claim 11 depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1-6, 8-13, and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al. (Foreign Patent Document Cite No 9 in the IDS filed 19 July 2024 wherein the first Foreign Patent Document is WO 2017/0189525)(WO 2021/221789, published 4 November 2021), herein Pierce, in view of Fredriksson et al. (“Protein detection using proximity-dependent DNA ligation assays” Nat Biotechnol 20(5), pages 473-477 (2002)), herein Fredriksson.
Regarding claim 1, Pierce teaches a composition ([0266]; FIG. 4A) comprising:
a first fractional-initiator probe comprising:
a first target-binding domain configured to bind directly or indirectly a first target (“the first fractional initiator probe (1190) further comprises a first target binding section (1141) […] wherein the first target binding section (1141) is configured to bind to a first target section (1100)” [0266]; FIG. 4A, 1141),
a first fractional initiator (“a first fractional initiator probe (1190) that comprises a first fractional initiator (1151)” [0266]; FIG. 4A, 1151),
a second fractional initiator probe comprising:
a second target-binding domain configured to bind directly or indirectly a first target (“the second fractional initiator probe (1290) further comprises a second target binding section (1241)” [0266]; FIG. 4A 1241),
a second fractional initiator (“a second fractional initiator probe (1290) that comprises a second fractional initiator (1251), wherein […] the second target binding section (1241) is configured to bind to a second target section (1200)” [0266]; FIG. 4A, 1251),
a hybridization chain reaction (HCR) amplifier comprising two or more HCR hairpin monomers at least one of which comprises a reporter (“a composition is provided comprising a first hairpin monomer (1510), a second hairpin monomer (1610), a first fractional initiator probe (1190) comprising a first fractional initiator (1151), and a second fractional initiator probe (1290) comprising a second fractional initiator (1251)” [0267]; “one or more of the hairpin monomers can include a reporter molecule” [0269]); and
wherein when the first fractional-initiator probe is bound to the first target and the second fractional-initiator probe is bound to the second target, the first fractional initiator and the second fractional initiator colocalize to form a full initiator that is configured to initiate HCR signal amplification whereupon the HCR hairpin monomers self-assemble into a tethered HCR amplification polymer thereby generating a signal (“when both fractional initiator probes are bound to both targets, the first and second fractional initiators (within the fractional initiator probes) are close enough to form a full initiator (1050), from which HCR can occur” [0266]; “the first and second fractional initiators (1151, 1251) together form a full initiator (1050), from which HCR can progress, via the first and second hairpin monomers (1510, 1610)” [0267]; “polymerization of the hairpin monomers (first and second, and optionally more), will result in a signaling event that is detectable” [0269]).
Additionally, Pierce teaches that the first initiator and second initiator probes will not cause significant polymerization of the HCR hairpin monomers via HCR in the absence of the target(s) needed to colocalize the first and second initiators into a full initiator by using a target mRNA that brings the first and second initiators into close contact when both are bound to the target mRNA ([0581], FIG. 7A-B, note lack of HCR polymer band in FIG. 7B lane 6 having probes P1 and P2 but not the target, compared to lane 3 having probes P1 and P2 and the target). One of ordinary skill in the art would understand this to teach the importance of the fractional initiators being brought together to form the full initiator in FIG. 7A to initiate HCR, which notably is apparently held together as tightly in FIG. 4A with longer flexible segments between the respective target-binding domain and fractional initiator of each probe.
However, Pierce does not teach that the first fractional-initiator probe comprises a first proximity domain, that the second fractional-initiator probe comprises a second proximity domain, that the composition further comprises a proximity probe configured to bind the first proximity domain and the second proximity domain. This deficiency is made up for in the teachings of Fredriksson.
Regarding claim 1, Fredriksson teaches an assay wherein two probes (“two aptamer-based proximity probes, A1 and A2” Figure 1 page 474) are brought together in proximity when their targets are sufficiently close to each other (Figure 1 page 474). These probes each contain oligonucleotide ends not involved target binding that, when ligated together, serve as the basis for signal production that indicates the targets being in close proximity (Figure 1 page 474). Fredriksson further teaches the inclusion of a connector oligonucleotide (equivalent to the claimed proximity probe), that hybridizes to a domain of each of the two probes (Figure 1 page 474), which provides the advantage of decreasing the time necessary for the oligonucleotide ends to be ligated and increases the signal obtained for a given ligation time (Figure 2A, note that as the concentration of the connector increases even the shortest ligation time yields significant amounts of signal; see also page 473 right column paragraph 2 through page 474 left column paragraph 1). One of ordinary skill in the art would recognize that this advantage is not limited to strictly to increasing the rate of a ligation reaction of the 5’ and 3’ ends of oligonucleotides together, but that the connector oligonucleotide would advantageously increase the rate of any reaction that requires the colocalization of the two oligonucleotides that it binds to, such as the formation of a full initiator from the fractional initiators and initiation of HCR by the full initiator as taught by Pierce. This would be particularly advantageous for situations like in Pierce’s FIG. 4A where there fractional initiators are colocalized to the same area by the targets they’re bound to but are not held directly adjacent like in FIG. 7A, since the connector oligonucleotide would, like the mRNA in FIG. 7A, bring the portions with the fractional-initiators more closely together to form a full initiator.
Regarding claim 2, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition wherein at least one of the HCR hairpin monomers comprises an input domain and wherein the first fractional initiator and second fractional initiator together form a full initiator configured to hybridize to the input domain (“In some embodiments, each HCR hairpin comprises an input domain […] if the fractional initiator probes within a probe unit bind to their adjacent cognate binding sites on the target to colocalize a full HCR initiator, the full HCR initiator initiates a chain reaction of polymerization steps in which the full initiator hybridizes to the input domain of a first HCR hairpin” [0406]).
Regarding claim 3, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition further comprising a third fractional-initiator probe comprising a third target-binding domain configured to bind directly or indirectly to a third target and a third fractional initiator (“In some embodiments, an HCR initiator (II or 12) is split between three fractional initiator probes (fraction fl for probe PI, fraction f2 for probe P2, fraction f3 for probe 3 such that fl + f2 + f3 = 1); in this case, a probe unit consists of three fractional initiator probes” [0123]; “a fractional initiator probe comprises one or more target-binding domains and one or more fractional initiator domains” [0168]). In this embodiment, one of ordinary skill in the art would be motivated by the teachings of Fredriksson to modify the connector oligonucleotide and third fractional-initiator probe so that the connector oligonucleotide further binds a domain on the third fractional-initiator probe so that the connector oligonucleotide would be able to retain in this 3 fractional initiator embodiment the ability to colocalize all 3 fractional initiators necessary to form the full initiator.
Regarding claim 4, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition wherein the first target is a protein, a nucleic acid, or a combination thereof, and wherein the second target is a protein, a nucleic acid, or a combination thereof (“A probe unit can detect a target comprising: 1. any molecule including but not limited to an RNA molecule (for example, mRNA, rRNA, IncRNA, siRNA, shRNA, microRNA, non-coding RNA, synthetic RNA, or modified RNA), a DNA molecule, a non-natural nucleic acid molecule, a protein molecule” [0154]; FIG. 4B and 4C as examples of each target).
Regarding claim 5, the combination of Pierce and Fredriksson teach the composition of Claim 4 (see 35 U.S.C. 103 rejection of claim 4 above), and Pierce further teaches the composition wherein the first target and the second target are bound to each other (“A probe unit can detect a target comprising: […] 3. any collection of proximal molecules or complexes such that the fractional initiators in the probe unit can colocalize to form a full HCR initiator when the fractional initiator probes comprising the probe unit are bound to their respective targets within the collection of proximal molecules or complexes” [0154]; see FIG. 5A).
Regarding claim 6, the combination of Pierce and Fredriksson teach the composition of Claim 4 (see 35 U.S.C. 103 rejection of claim 4 above), and Pierce further teaches the composition wherein the first target and the second target are the same molecule (“A probe unit can detect a target comprising: 1. any molecule” [0154]; see FIG. 4A).
Regarding claim 8, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition where the first fractional-initiator probe and/or the second fractional-initiator probe comprises an antibody, a nanobody, and/or an oligonucleotide (“a fractional initiator probe may comprise one or more fractional initiator domains made of DNA and a target-binding domain made of amino acids (for example, an antibody or a nanobody or an antibody fragment)” [0168]).
Regarding claim 9, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above). As discussed in the rejection of claim 9 under 35 U.S.C. 112(d) above, claim 9 recites an intended use and fails to further limit claim 1 upon which it depends, so by teaching claim 1 the combination of Pierce and Fredriksson teach the claimed subject matter of claim 9. Furthermore, Pierce teaches the composition wherein the colocalized initiator is used to mediate generation of a signal directly or indirectly (“the first and second fractional initiators (1151, 1251) together form a full initiator (1050), from which HCR can progress, via the first and second hairpin monomers (1510, 1610)” [0267]; “polymerization of the hairpin monomers (first and second, and optionally more), will result in a signaling event that is detectable” [0269]).
Regarding claim 10, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition wherein the colocalized full initiator triggers assembly of metastable fluorophore-labeled HCR hairpins into a tethered fluorescent amplification polymer to generate an amplified signal at the site of the targets (“the reporter molecule comprises a fluorescent molecule such as a fluorophore” [0276]; “Metastable fluorescent hairpins self-assemble into fluorescent amplification polymers upon detection of a cognate initiator” [0322].
Regarding claim 11, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above). As discussed in the rejection of claim 11 under 35 U.S.C. 112(d) above, claim 11 fails to further limit claim 1 upon which it depends, so by teaching claim 1 the combination of Pierce and Fredriksson teach the claimed subject matter of claim 11. Furthermore, Pierce teaches the composition wherein the first target and second target are any of protein, RNA, or DNA (“A probe unit can detect a target comprising: 1. any molecule including but not limited to an RNA molecule (for example, mRNA, rRNA, IncRNA, siRNA, shRNA, microRNA, non-coding RNA, synthetic RNA, or modified RNA), a DNA molecule, a non-natural nucleic acid molecule, a protein molecule” [0154]).
Regarding claim 12, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition wherein the first target and the second target form a complex (“A probe unit can detect a target comprising: […] 3. any collection of proximal molecules or complexes such that the fractional initiators in the probe unit can colocalize to form a full HCR initiator when the fractional initiator probes comprising the probe unit are bound to their respective targets within the collection of proximal molecules or complexes” [0154]; see FIG. 5A).
Regarding claim 13, the combination of Pierce and Fredriksson teach the composition of Claim 12 (see 35 U.S.C. 103 rejection of claim 12 above), and Pierce further teaches the composition wherein the composition comprises additional fractional initiators for each of N target complexes to be detected in a sample (“Consider a sample containing some or all of N target types of interest as well as zero, one, or more additional off- target species that are not of interest. Each target can be detected using a probe set comprising one or more probe units (each comprising two or more fractional initiator probes) that selectively bind the cognate target so that each bound probe unit colocalizes a full HCR initiator” [0187]).
Regarding claims 16 and 18, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition wherein the at least one reporter comprises a fluorophore, the elected species of reporter to which the search of claims 16 and 18 has been restricted (“the reporter molecule comprises a fluorescent molecule such as a fluorophore” [0276]).
Regarding claim 17, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition wherein the at least one reporter mediates generation of the signal directly or indirectly (“one or more of the hairpin monomers can include a reporter molecule, such that polymerization of the hairpin monomers (first and second, and optionally more), will result in a signaling event that is detectable” [0269]). Note that claim 17, unlike claim 9, is interpreted as further limiting the claim upon which it depends because it connects the generation of the signal to the reporter.
Regarding claim 19, the combination of Pierce and Fredriksson teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above), and Pierce further teaches the composition wherein the HCR amplification polymer mediates catalytic reporter deposition (CARD) (“In some embodiments, the reporter molecule comprises an enzyme or is enzymatic, and/or can mediate enzymatic signaling after HCR polymerization. In some embodiments, reporting is achieved by catalyzed reporter deposition (“CARD”)” [0277]).
In view of the teachings of Fredriksson that the inclusion of a connector oligonucleotide provides the advantage of increasing the rate of reactions that require the colocalization of the nucleic acids that the connector oligonucleotide binds to, one of ordinary skill in the art would modify the composition of Pierce to include a connector oligonucleotide that binds to a domain on each of the fractional-initiator probes. One of ordinary skill in the art would have a reasonable expectation of success in this combination because both Pierce and Fredriksson are concerned with assays involving the colocalization of oligonucleotide ends of probes and the inclusion of a connector oligonucleotide that binds to a domain on each of the fractional-initiator probes would not be expected to prevent the composition of Pierce from retaining its function of detecting the proximity of the first and second targets (and actually improving it with the advantage discussed above). Therefore, the invention as a whole of claims 1-6, 8-13, and 16-19 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
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.
Claims 1, 4, 8-9, 11, 17, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 26 of copending Application No. 18/764,002, herein ‘002. Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Note that a one-way test of distinctness (whether the invention claimed in the application would have been anticipated by, or an obvious variation of, the invention claimed in the reference application) has been used to determine the provisional double patenting rejection due to the “absence of a finding: (A) that "the PTO is solely responsible for any delays" in prosecution of that application (In re Hubbell, 709 F.3d 1140, 1150, 106 USPQ2d 1032, 1039 (Fed. Cir. 2013)); and (B) that the applicant could not have filed the conflicting claims in a single (i.e., the earlier-filed) application ( In re Kaplan, 789 F.2d 1574, 229 USPQ 678 (Fed. Cir. 1986))” (see MPEP §804(II)(B)(4)).
Regarding instant claim 1, claim 26 of ‘002, which depends on claim 25 of ‘002, itself depending on claim 24 of ‘002, itself depending on claim 18 of ‘002, recites via claim 18 of ‘002 a method comprising providing a probe set comprising a probe unit comprising two or more HCR fractional-initiator probes, wherein an HCR fractional-initiator probe comprises a target-binding domain and an HCR fractional initiator, and providing a reporter-labeled first HCR amplifier wherein an HCR amplifier comprises two or more HCR hairpins, and that the colocalized full initiator comprising two or more HCR fractional-initiators initiates HCR signal amplification whereupon the HCR hairpins self-assemble into a tethered reporter-decorated HCR amplification polymer thereby generating the signal. Claim 24 of ‘002 further recites that the probe unit further comprises one or more proximity probes, claim 25 of ‘002 further recites that each HCR fractional-initiator probe within a probe unit further comprises a proximity domain, and claim 26 of ‘002 further recites that the one or more proximity probes bind to the proximity domains within a probe unit to colocalize a full HCR initiator capable of triggering HCR signal amplification. As the method of claim 26 of ‘002 thus includes a composition meeting all limitations of instant claim 1, instant claim 1 is not patentably distinct from claim 26 of ‘002.
Regarding instant claim 8, claim 18 of ‘002 on which claim 26 of ‘002 depends recites that the fractional-initiator probes comprise a barcode oligonucleotide, so a composition used in the method of claim 26 of ‘002 anticipates instant claim 8. Therefore, instant claim 8 is not patentably distinct from claim 26 of ‘002.
Regarding instant claim 9, claim 18 of ‘002 on which claim 26 of ‘002 depends recites that the colocalized full initiator initiates signal amplification thereby generating the signal, so a composition used in the method of claim 26 of ‘002 anticipates instant claim 9. Therefore, instant claim 9 is not patentably distinct from claim 26 of ‘002.
Regarding instant claim 17, claim 18 of ‘002 on which claim 26 of ‘002 depends recites generating a signal, directly or indirectly, from one or more reporter-decorated HCR amplification polymers, so a composition used in the method of claim 26 of ‘002 anticipates instant claim 17. Therefore, instant claim 17 is not patentably distinct from claim 26 of ‘002.
Regarding instant claims 4 and 11, claim 23 of ‘002 recites the target comprising a protein or a nucleic acid along with other possible options. It would be obvious to combine claim 26 of ‘002 as discussed above with the specific targets recited in claim 23 of ‘002 because both depend from claim 18 of ‘002 and the choice of target would not prevent the functioning of the invention of claim 23 of ‘002. As instant claims 4 and 11 are thus obvious variations of the composition used in the method of claim 26 of ‘002, instant claims 4 and 11 are not patentably distinct from claim 26 of ‘002.
Regarding instant claim 19, claim 22 of ‘002 recites the reporters on the reporter-decorated amplification polymer mediating CARD. It would be obvious to combine claim 26 of ‘002 as discussed above with the specific reporters that mediate CARD recited in claim 22 of ‘002 because both depend from claim 18 of ‘002 and the choice of the specific reporter and signal would not prevent the functioning of the invention of claim 23 of ‘002. As instant claim 19 is thus an obvious variation of the composition used in the method of claim 26 of ‘002, instant claim 19 is not patentably distinct from claim 26 of ‘002.
Claims 2-3, 5-6, 10, 12-13, 16, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 26 of copending Application No. 18/764,002, herein ‘002, as applied to claims 1, 4, 8-9, 11, 17, and 19 above, and further in view of Pierce et al. (Foreign Patent Document Cite No 9 in the IDS filed 19 July 2024 wherein the first Foreign Patent Document is WO 2017/0189525)(WO 2021/221789, published 4 November 2021), herein Pierce.
This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 2, though claim 26 of ‘002 via its dependency on claim 18 of ‘002 recites that the HCR hairpins comprise an input domain, it does not recite that the full initiator is configured to hybridize to the input domain. This deficiency is made up for in the teachings of Pierce, as discussed with regard to instant claim 2 in the 35 U.S.C. 103 rejection of instant claim 2 above, which teaches a similar composition comprising fractional-initiator probes. Similarly, regarding instant claims 3, 5-6, 10, 12-13, 16, and 18, Pierce teaches the limitations of these claims as discussed in the 35 U.S.C. 103 rejections of the respective claims above. With regard to instant claim 3, the same reasoning used in the 35 U.S.C. 103 rejection of instant claim 3 for why one of ordinary skill in the art would be motivated to modify the proximity probe/connector oligonucleotide of Fredicksson and the third fractional-initiator probe so that the connector oligonucleotide further binds a domain on the third fractional-initiator probe applies to the proximity probe recited by claim 26 of ‘002.
Though claim 26 of ‘002 and Pierce do not individually teach each element of the claimed composition of instant claims 2-3, 5-6, 10, 12-13, 16, and 18, each of these elements is taught in either claim 26 of ‘002 or by Pierce and one of ordinary skill in the art could have combined the elements as claimed by known methods such that each element merely performs the same function as it does in the references separately (MPEP §2143(I)(A)). One of ordinary skill in the art would have a reasonable expectation of success because claim 26 of ‘002 and Pierce both teach very similar compositions involving sets of fractional-initiator probes for initiating HCR. Therefore, instant claims 2-3, 5-6, 10, 12-13, 16, and 18 are not patentably distinct from claim 26 of ‘002 in view of the teachings of Pierce.
Claims 1, 4, 9-11, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5 of copending Application No. 19/055,411, herein ‘411. Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Note that a one-way test of distinctness (whether the invention claimed in the application would have been anticipated by, or an obvious variation of, the invention claimed in the reference application) has been used to determine the provisional double patenting rejection due to the “absence of a finding: (A) that "the PTO is solely responsible for any delays" in prosecution of that application (In re Hubbell, 709 F.3d 1140, 1150, 106 USPQ2d 1032, 1039 (Fed. Cir. 2013)); and (B) that the applicant could not have filed the conflicting claims in a single (i.e., the earlier-filed) application ( In re Kaplan, 789 F.2d 1574, 229 USPQ 678 (Fed. Cir. 1986))” (see MPEP §804(II)(B)(4)).
Regarding instant claim 1, claim 5 of ‘411, which depends on claim 4 of ‘411, itself depending on claim 1 of ‘411, recites via claims 1 and 4 of ‘411 a composition comprising a first HCR initiator wherein the first HCR initiator is a colocalized full first initiator formed when two or more fractional-initiator probes are bound specifically to their cognate binding sites on two targets that are complexed or are in proximity (implying that the fractional-initiator probes comprise target binding domains and fractional initiators) and a HCR amplifier comprising two or more HCR hairpins, at least one of which comprises a reporter, wherein the first HCR initiator is configured trigger the HCR hairpins of the first HCR hairpin amplifier to grow a reporter-decorated HCR amplification polymer tethered to the first HCR initiator when one or more targets are present. Claim 5 further recites the composition additionally comprising one or more proximity probes configured to bind to the two or more fractional-initiator probes (implying that the fractional-initiator probes comprise proximity domains that the proximity probe binds to). As the composition of claim 5 of ‘411 meets all limitations of instant claim 1, instant claim 1 is not patentably distinct from claim 5 of ‘411.
Regarding instant claims 9 and 17, claim 1 of ‘411 recites the composition wherein the first HCR initiator (as discussed regarding claim 5 of ‘411 above, the first HCR initiator is the colocalized full initiator) is configured to trigger the HCR hairpins of the first HCR amplifier to grow a reporter-decorated first HCR amplification polymer and wherein the reporters are configured to directly or indirectly mediate generation of an amplified signal. As the composition of claim 5 of ‘411 meets all limitations of instant claims 9 and 17, instant claims 9 and 17 are not patentably distinct from claim 5 of ‘411.
Regarding instant claims 4 and 11, claim 13 of ‘411 recites the composition wherein the target comprises a RNA molecule, a DNA molecule, or a protein, along with other possible options. It would be obvious to combine claim 5 of ‘411 as discussed above with the specific targets recited in claim 13 of ‘411 because both depend from claim 1 of ‘411 and the choice of target would not prevent the functioning of the invention of claim 5 of ‘411. As instant claims 4 and 11 are thus obvious variations of the composition used in the method of claim 5 of ‘411, instant claims 4 and 11 are not patentably distinct from claim 5 of ‘411.
Regarding instant claims 10, 16, and 18, claim 8 of ‘411 recites the composition wherein, in a specifically recited embodiment, the reporter comprises a fluorophore. It would be obvious to combine claim 5 of ‘411 as discussed above with the specific reporter recited in claim 8 of ‘411 because both depend from claim 1 of ‘411 and the choice of reporter would not prevent the functioning of the invention of claim 5 of ‘411. As instant claims 10, 16, and 18 are thus obvious variations of the composition used in the method of claim 5 of ‘411, instant claims 10, 16, and 18 are not patentably distinct from claim 5 of ‘411.
Claims 2-3, 5-6, 8, 12-13, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5 of copending Application No. 19/055,411, herein ‘411, as applied to claims 1, 4, 9-11, and 16-18 above, and further in view of Pierce et al. (Foreign Patent Document Cite No 9 in the IDS filed 19 July 2024 wherein the first Foreign Patent Document is WO 2017/0189525)(WO 2021/221789, published 4 November 2021), herein Pierce.
This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 2, claim 5 of ‘411 does not recite that at least one of the HCR hairpins comprise an input domain and that the full initiator is configured to hybridize to the input domain. This deficiency is made up for in the teachings of Pierce, as discussed with regard to instant claim 2 in the 35 U.S.C. 103 rejection of instant claim 2 above, which teaches a similar composition comprising fractional-initiator probes. Similarly, regarding instant claims 3, 5-6, 8, 12-13, and 19, Pierce teaches the limitations of these claims as discussed in the 35 U.S.C. 103 rejections of the respective claims above. With regard to instant claim 3, the same reasoning used in the 35 U.S.C. 103 rejection of instant claim 3 for why one of ordinary skill in the art would be motivated to modify the proximity probe/connector oligonucleotide of Fredriksson and the third fractional-initiator probe so that the connector oligonucleotide further binds a domain on the third fractional-initiator probe applies to the proximity probe recited by claim 5 of ‘411.
Though claim 5 of ‘411 and Pierce do not individually teach each element of the claimed composition of instant claims 3, 5-6, 8, 12-13, and 19, each of these elements is taught in either claim 5 of ‘411 or by Pierce and one of ordinary skill in the art could have combined the elements as claimed by known methods such that each element merely performs the same function as it does in the references separately (MPEP §2143(I)(A)). One of ordinary skill in the art would have a reasonable expectation of success because claim 5 of ‘411 and Pierce both teach very similar compositions involving sets of fractional-initiator probes for initiating HCR. Therefore, instant claims 3, 5-6, 8, 12-13, and 19 are not patentably distinct from claim 5 of ‘411 in view of the teachings of Pierce.
Allowable Subject Matter
Claims 7 and 14-15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claim 7, the nearest prior art is the combination of Pierce and Fredriksson, which teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above). However, neither Pierce nor Fredriksson teach a proximity probe/connector (or splint) oligonucleotide that contains one or more clamp domains configured to bind to some or all of the first fractional initiator and/or the second fractional initiator if one target is not proximal (this claim is illustrated in Figure 24 of the instant drawings). The clamp appears to serve the purpose of a blocking oligonucleotide, restricting the ability for the fractional initiator to bind to HCR hairpin monomers and initiate HCR amplification in the absence of colocalization with the other fractional initiator. While blocking oligonucleotides to prevent undesirable binding are well known in the art, one of ordinary skill in the art would (1) not be motivated to combine them with the fractional initiator composition because fractional initiators already have the advantage of automatic background suppression (“separating the initiator into two or more fractional initiators, which only effectively co-localize in the presence of a target, provides for automatic background suppression during the detection step” Pierce [0008]) and (2) even if one were motivated to include a blocking oligonucleotide for redundancy of background suppression, one of ordinary skill in the art would have no motivation to include the blocking sequence on the proximity probe/connector oligonucleotide. Therefore, claim 7 is free of the prior art.
Regarding claim 14¸ the nearest prior art is the combination of Pierce and Fredriksson, which teach the composition of Claim 13 (see 35 U.S.C. 103 rejection of claim 13 above), and Pierce further teaches the composition wherein the N target complexes are each detected in the same sample using a different pair of fractional-initiator probes and HCR amplifier for each target complex (“In some embodiments, the probe set for each of N target types colocalizes full HCR initiators for a different HCR amplifier. For example, Target 1 can be detected with Probe Set 1 that colocalizes one or more full HCR initiators for HCR Amplifier 1, Target 2 can be detected with Probe Set 2 that colocalizes one or more full HCR initiators for HCR Amplifier 2, and so on, with Probe Set N colocalizing one or more full HCR initiators for HCR Amplifier N” [0187]). However, neither Pierce nor Fredriksson suggest using a different proximity probe/connector oligonucleotide for each target complex of the N target complexes (note that claim 14 is interpreted as requiring a different pair of fractional-initiator probes, a different proximity probe, and a different HCR amplifier for each target complex).
Though the prior art teachings multiplex assays that use an analogous proximity probe/connector oligonucleotide (such as proximity ligation assays), nothing suggests to use a different proximity probe/collector oligonucleotide for each target complex, but rather teach using a single connector oligonucleotide that binds to the various pairs in the multiplexed assay, see Fredriksson et al. #2 (“Multiplexed protein detection by proximity ligation for cancer biomarker validation” Nat Methods 4(4), pages 327-329 (2007)) teaching a method using a connector oligonucleotide (Figure 1 page 327) and proximity probe cares with ligation sites on the connector sequence (page 328 left column paragraph 2), Lundberg et al. (“Multiplexed homogeneous proximity ligation assays for high-throughput protein biomarker research in serological material” Mol Cel Proteomics 10(4): M110.004978 (2011)) teaching a method using a universal connector (FIG. 1 panel 2 page 4), and Darmanis et al. (“ProteinSeq: High-Performance Proteomic Analyses by Proximity Ligation and Next Generation Sequencing” PLoS One 6(9): e25583 (2011)) teaching the ligation of 36 different oligonucleotide pairs using a single oligonucleotide connector referred to as a ligation template (page 7 right column paragraph 1). Therefore, claim 14 is free of the prior art.
Regarding claim 15, the nearest prior art is the combination of Pierce and Fredriksson, which teach the composition of Claim 1 (see 35 U.S.C. 103 rejection of claim 1 above). However, neither Pierce nor Fredriksson teach fractional initiators or proximity probes wherein their sequence is any of the sequences recited in claim 15. As oligonucleotides with the exact sequences of SEQ ID NOs: 1-9 are not found in the prior art, claim 15 is free of the prior art.
Regarding claim 15, Examiner notes regarding the interpretation that the recitation “wherein the sequence of [X] is selected from [SEQ ID NOs]” requires the exact sequence of a recited SEQ ID NO. Examiner also notes that [0208] and Table 1 on page 52 of the specification filed29 February 2024 recites each of SEQ ID NOs 1-2, 4-5, and 7-8 as being the combined sequence of a fractional initiator and a proximity domain (along with a nucleotides not assigned to a domain), which is different from claim 15 reciting these SEQ ID NOs as being either “the first fractional initiator” or “the second fractional initiator”. Because the above portions of the specification are not specifically limiting, claim 15 is interpreted based only off of the claim language, and therefore requires that the respective fractional initiator of a fractional-initiator probe has the claimed sequence.
Conclusion
Claims 1-6, 8-13, and 16-19 are rejected. Claims 20-44 are withdrawn. Claims 7 and 14-15 are objected to.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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