DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This application is a continuation of US application 17/376,919, filed 07/15/2021 (now US Patent No. 11,926,868), which was a continuation of US application 16/325,385, filed 02/13/2019 (now US Patent No. 11,124,824), which was the national stage of PCT/US2017/047372, filed 08/17/2017, claiming priority to US provisional application 62/376,299, filed 08/17/2016.
Election/Restrictions
Applicant's election with traverse of Group II in the reply filed on 06 January 2026 is acknowledged. The traversal is on the ground(s) that “the Office has not shown a serious burden would be required to examine all the pending claims” (Reply page 1). This is not found persuasive for the reasons stated in the Election/Restriction mailed 12 November 2025, specifically because the inventions of Groups I-II have acquired a separate status in the art in view of their different classification, and require different fields of search. It is particular noted that the probes of the products of Group II correspond to, or are defined as structurally relates to, specific SEQ ID Nos, while the methods of Group I are characterized by the performance of particular steps to achieve target detection, and do not require the specific probes of Group I.
The requirement is still deemed proper and is therefore made FINAL (however Applicant’s attention is directed to paragraph 7 of the Election/Restriction mailed 12 November 2025, which sets forth conditions for rejoinder of a elected product and withdrawn process claims).
Claims 1-4 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 09 January 2026.
Information Disclosure Statement
The information disclosure statement filed 06 February 2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. More particularly, while the majority of references were considered, several references (as indicated by strike-through on the enclosed PTO/SB/08a) were not considered, as copies of those cited documents were not found in the instant application (or its parent applications).
Claim Objections
Claims 5-15 are objected to because of the following informalities: claim 5 (from which claims 6-15 depend) recites “cell-free (cfDNA)” rather than “cell-free DNA (cfDNA)”. While this is an obvious typographical error (and the claim has been interpreted as referring to cell-free DNA (cfDNA)), appropriate correction is required.
Claim Interpretation
Regarding claim 5 and claims dependent therefrom (claims 6-15), it is noted that the claim is improperly dependent from claim 1 (see also the rejection under 35 USC 112(d) below). As the product of claim 5 cannot properly require the method of claim 1, claim 5 has been interpreted as being directed to a nucleic acid probe having the structure recited in the claim – specifically, “comprising a nucleotide sequence of at least 20-300 contiguous nucleotides complementary to SEQ ID NO: 1” – and capable of use in “detecting an Alu sequence(s) in cell free (cfDNA) [sic]”. While the structure of the recited “nucleotide sequence” is indefinite for the reasons given below, as any nucleotide sequence of “at least 20” contiguous nucleotides complementary to SEQ ID NO: 1 could be employed in some manner in ‘detecting an Alu sequence(s)’” in cfDNA, the preamble recitation “for detecting….” has also been interpreted as an intended use of the claimed product that is not further limiting of its structure.
Regarding the limitations “a nucleotide sequence of at least ___-___ contiguous nucleotides complementary to SEQ ID NO: 1” in claims 5 (at least 20-300) and 11-15 (at least 20-292, 20-180, 50-150, 70-100, and 80-90, respectively), it is noted that this language is interpreted as setting forth “at least __” (the first recited number) as a minimum/lower boundary and the second recited number as an upper limit/boundary. See also the rejection under 35 USC 112(b) set forth below regarding upper limits/boundaries that exceed the length of SEQ ID NO: 1 (which is only 290 nucleotides in length).
Regarding dependent claims 6-9, as well as claim 16 and claims dependent therefrom (claims 17-20), it is noted that the term “detectable moiety” - which appears throughout the claims, with the probes of the claims recited as being “covalently linked” to such a moiety/moieties (see text of claims 6-7 and 17-18) - has been interpreted as equivalent to the term “detectable label” (which appears in independent claim 16, reciting a requirement for a sequence “covalently linked to” a detectable label). The term “moiety” appears in, e.g., paragraph 73 of the specification in relation to elements of signal producing agents, which are also disclosed in that paragraph as being employable as labels. However, it is clear from, e.g., dependent claims 8-9 and 19-20 that the claims are not further limited to such specific moieties (as, e.g., claims 8 and 19 explicitly recites biotin as a preferred “detectable moiety”). Thus, the broadest reasonable interpretation of the term “detectable moiety” that is consistent with the claim language and disclosure - particularly as both the “detectable label” and detectable moiety/moieties of the claims must be covalently linked to the recited nucleic acid/nucleotide sequence - is that it is equivalent to “detectable label” (and it is further noted that this term is not employed in the disclosure such a way that one of ordinary skill in the art would reasonably interpret the claims as encompassing, e.g., the use of additional/other naturally occurring nucleotides as a “detectable” label or moiety).
Regarding dependent claims 7-9, it is noted that the limitation “wherein the 3’ or the 5’ ends are covalently linked to a detectable moiety” in claim 7 is interpreted as requiring that either the 3’ end or the 5’ end be “covalently linked to a detectable moiety”.
Similarly, regarding dependent claims 18-19, the limitation “wherein the 3’ or the 5’ ends are covalently linked to a detectable moiety” in claim 18 is interpreted as requiring that either the 3’ end or the 5’ end be “covalently linked to a detectable moiety”.
Claim Rejections - 35 USC § 112(d)/fourth paragraph
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 5-15 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 5 (from which claims 6-15 depend) is drawn to a “nucleic acid probe for detecting an Alu sequence(s) in cell-free (cfDNA) [sic] according to claim 1…”. As the claim clearly does not require performance of the steps/actions recited in claim 1, the claim fails to include all limitations of the claim from which it depends, and also fails to further limit the subject matter of claim 1. 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.
Claims 11-15 are additionally 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 10 (which is dependent from claim 5, and from which claims 11-15 depend), is drawn to a nucleic acid probe “complementary to exactly 81 nucleotides of SEQ ID NO: 1”. However, claims 11-15 each recite probes that are of a broader scope than those of claim 10, such that the claims are not further limiting of claim 10, and also fail to include all the limitations of claim 10. 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 § 112(b)/second paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5-9, 11, 17, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 5-9 and 11 are indefinite over the recitation in claim 5 of the limitation “at least 20-300 contiguous nucleotides complementary to SEQ ID NO: 1”, and with further regard to claim 11, the limitation “at least 20-292 contiguous nucleotides complementary to SEQ ID NO: 1”. As SEQ ID NO: 1 is only 290 nucleotides in length, it is unclear what sequences may meet the requirements of the claims with regard to those embodiments involving nucleotide sequence lengths longer than 290 nucleotides (given what is required by the present claim language). Accordingly, further clarification is required.
(It is noted that those claims dependent from claim 5 reciting exact lengths or upper limits lesser than the length of SEQ ID NO: 1 were deliberately excluded from this rejection as these claims are sufficiently clear and definite; this includes claim 10 as well as [improperly dependent] claims12-15).
Claim 6 is indefinite over the recitation of the limitation “wherein the 3’ and the 5’ ends are covalently linked to at least three detectable moieties”, because it is unclear whether this claim language imparts a collective requirement for “at least three detectable moieties” (i.e., a total number of moieties of “at least three”), or whether this language requires that each of “the 3’ and the 5’ ends” are covalently linked to at least three detectable moieties. As there are multiple reasonable interpretations of the claim language that have different meanings and boundaries, clarification is required.
Claim 17 is also indefinite over the recitation of the limitation “wherein the 3’ and the 5’ ends are covalently linked to at least three detectable moieties”, because it is unclear whether this claim language imparts a collective requirement for “at least three detectable moieties” (i.e., a total number of moieties of “at least three”), or whether this language requires that each of “the 3’ and the 5’ ends” are covalently linked to at least three detectable moieties. As there are multiple reasonable interpretations of the claim language that have different meanings and boundaries, clarification is required.
Claim 20 is indefinite over the recitation of the limitation “wherein the detectable moiety is a fluorescent molecule”. While it is reiterated that the terms “detectable label” and “detectable moiety” as employed in the claims have been interpreted as indicated above, the reference to “the detectable moiety” in claim 20 is confusing given that claim 16 (from which the claim depends) employs the term “label” rather than “moiety”, while other dependent claims actually employ the term “detectable moiety”. This change in terminology in claim 20 creates confusion as to whether the claim is in fact referencing the “detectable label” of claim 16, or whether the claim may have been intended to depend from, e.g., claim 18, which actual employs the exact term “detectable moiety”. Further clarification is therefore required to ensure that the meaning and boundaries of what is claimed are clear.
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.
Claim(s) 5 and 11-13 are rejected under 35 U.S.C. 102(a)(1) and 35 USC 102(a)(2) as being anticipated by Hoon et al (John Wayne Cancer Institute, WO 2006/128192 A2 [30 Nov 2006]; cited in IDS).
With regard to claims 11-13, it is reiterated that these claims do not properly depend from claim 10 (as the claims as written clearly are clearly broader in scope than claim 10). Given that the claims are improperly dependent, they are included in the present rejection in the interest of compact prosecution.
Hoon et al teach methods comprising detection of “free circulating” DNA (a.k.a. cell-free DNA) in body fluids, which methods include targeting Alu sequences in the cfDNA to determine the amount thereof (see entire reference, particularly the Summary at page 1-4). Instant SEQ ID NO: 1 shares 100% identity with the consensus human Alu sequence of Hoon et al, as depicted below (see also Figures 1, 6A and 11A of Hoon et al):
Query Match 100.0%; Score 290; Length 290;
Best Local Similarity 100.0%;
Matches 290; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGA 60
Qy 61 TCACCTGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TCACCTGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACT 120
Qy 121 AAAAATACAAAAATTAGCCGGGCGTGGTGGCGCGCGCCTGTAATCCCAGCTACTCGGGAG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AAAAATACAAAAATTAGCCGGGCGTGGTGGCGCGCGCCTGTAATCCCAGCTACTCGGGAG 180
Qy 181 GCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCGGAGGTTGCAGTGAGCCGAGATCGCG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCGGAGGTTGCAGTGAGCCGAGATCGCG 240
Qy 241 CCACTGCACTCCAGCCTGGGCGACAGAGCGAGACTCCGTCTCAAAAAAAA 290
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CCACTGCACTCCAGCCTGGGCGACAGAGCGAGACTCCGTCTCAAAAAAAA 290
With regard to nucleic acid probes meeting the requirements of the instant claims, Hoon et al disclose methods comprising obtaining any body fluid sample (see, e.g., page 3 at line 19; page 11 at line 15), and detecting and quantitating the cfDNA therein via the use of microarrays, “probes by blotting”, etc., with a preferred method being qPCR, particularly employing fluorogenic probes detectably labeled with a fluorophore and quencher (see entire reference, particularly, e.g., pages 11-12). Among the preferred nucleic acid amplification products taught by Hoon et al are ALU247 and ALU115 PCR products (see, e.g., pages 15-17, the Examples, and Figures 6A and 11A), which products are produced via amplification using primer pairs depicted on pages 22 (regarding the 115 base pair amplicon ALU115) and 29 (regarding both the 115 base pair amplicon ALU115 and the 247 base pair amplicon ALU247). The reverse ALU115 primer disclosed by Hoon et al is 20 nucleotides in length and complementary to instant SEQ ID NO: 1, and thus meets the requirements of instant claims 5 and 11-12; additionally both PCR products disclosed by Hoon et al inherently include nucleic acid probes complementary to instant SEQ ID NO: 1, and thus also meet the requirements of claims 5 and 11, with the ALU115 product also including a complement meeting the requirements of claims 12-13. Furthermore, given the methods disclosed by Hoon et al and their teaching that their disclosed target sequence in Figures 1, 6A, and 11A is a human Alu sequence, Hoon et al also clearly disclose nucleic acids/probes meeting the requirement of “for detecting an Alu sequence” in cfDNA.
Hoon et al thus anticipate claims 5 and 11-13.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 7, 9-10, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Hoon et al (John Wayne Cancer Institute, WO 2006/128192 A2 [30 Nov 2006]; cited in IDS) in view of the Plant-Microbe Genomics Facility (PMGF) at The Ohio State University (hereinafter “OSU”) (“Procedures and Recommendations for Quantitative PCR”, version 1.2 [April 2003]; cited herein).
With regard to claims 14-15, it is reiterated that these claims do not properly depend from claim 10 (as the claims as written clearly are clearly broader in scope than claim 10).
Hoon et al teach methods comprising detection of “free circulating” DNA (a.k.a. cell-free DNA) in body fluids, which methods include targeting Alu sequences in the cfDNA to determine the amount thereof (see entire reference, particularly the Summary at page 1-4). Instant SEQ ID NO: 1 shares 100% identity with the consensus human Alu sequence of Hoon et al, as depicted below (see also Figures 1, 6A and 11A of Hoon et al):
Query Match 100.0%; Score 290; Length 290;
Best Local Similarity 100.0%;
Matches 290; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGA 60
Qy 61 TCACCTGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TCACCTGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACT 120
Qy 121 AAAAATACAAAAATTAGCCGGGCGTGGTGGCGCGCGCCTGTAATCCCAGCTACTCGGGAG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AAAAATACAAAAATTAGCCGGGCGTGGTGGCGCGCGCCTGTAATCCCAGCTACTCGGGAG 180
Qy 181 GCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCGGAGGTTGCAGTGAGCCGAGATCGCG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCGGAGGTTGCAGTGAGCCGAGATCGCG 240
Qy 241 CCACTGCACTCCAGCCTGGGCGACAGAGCGAGACTCCGTCTCAAAAAAAA 290
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CCACTGCACTCCAGCCTGGGCGACAGAGCGAGACTCCGTCTCAAAAAAAA 290
With regard to nucleic acid probes encompassed by claim 5 (from which the claims rejected herein depend), Hoon et al disclose methods comprising obtaining any body fluid sample (see, e.g., page 3 at line 19; page 11 at line 15), and detecting and quantitating the cfDNA therein via the use of microarrays, “probes by blotting”, etc., with a preferred method being qPCR, particularly employing fluorogenic probes detectably labeled with a fluorophore and quencher (see entire reference, particularly, e.g., pages 11-12). Among the preferred nucleic acid amplification products taught by Hoon et al are ALU247 and ALU115 PCR products (see, e.g., pages 15-17, the Examples, and Figures 6A and 11A), which products are produced via amplification using primer pairs depicted on pages 22 (regarding the 115 base pair amplicon ALU115) and 29 (regarding both the 115 base pair amplicon ALU115 and the 247 base pair amplicon ALU247). The reverse ALU115 primer disclosed by Hoon et al is 20 nucleotides in length and complementary to instant SEQ ID NO: 1, and thus meets the requirements of instant claim 5; additionally both PCR products disclosed by Hoon et al inherently include nucleic acid probes complementary to instant SEQ ID NO: 1, and thus also meet the requirements of claims 5 (with the ALU115 product also including a complement meeting the length requirements of claims 12-13 [see the rejection under 35 USC 102 above], but too long in length to meet the requirements of claims 10, 14, and 15. Given the methods disclosed by Hoon et al and their teaching that their disclosed target sequence in Figures 1, 6A, and 11A is a human Alu sequence, Hoon et al also clearly disclose nucleic acids/probes meeting the requirement of “for detecting an Alu sequence” in cfDNA.
Hoon et al, while teaching a preferred method of qPCR, particularly employing fluorogenic probes detectably labeled with a fluorophore and quencher (see entire reference, particularly, e.g., page 12), as well as primers meeting the length requirements of claim 5 (as noted above), fail to explicitly teach probes labeled “wherein the 3’ or the 5’ ends are covalently linked to a detectable moiety”, as required by claim 7 (as well as claim 9). Additionally, Hoon et al do not teach Alu amplification products meeting the length requirements of claims 10, 14, and 15 (which products would inherently include a type of probe meeting the requirements of these claims), and do not otherwise teach probes meeting the length requirements of claim 10, 14, and 15.
OSU provides detailed guidance regarding the performance of quantitative PCR (i.e., the preferred methodology of Hoon et al noted above) to achieve quantitation of a target sequence of interest (see entire reference, particularly pages 1-4). OSU teaches that in qPCR as recited by Hoon et al - which is taught by Hoon et al as employing a fluorogenic probe that “is an oligonucleotide with both a reporter fluorescent dye and a quencher dye attached” in a method in which during “the extension phase of PCR….the probe anneals downstream from one of the primer sites and is cleaved by the 5’ nuclease of Taq DNA polymerases” resulting in separation of reporter dye from quencher (Hoon et al p. 12) – the probes “have a dye at each end of the oligonucleotide” (i.e., a dye at the 5’ end and at the 3’ end) (see in particular pages 2-3 of OSU).OSU further teach that in such qPCR the target amplicon size is 75-150 bases (see pages 3-4).
In view of the teachings of OSU, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have employed in qPCR as taught by Hoon et al a fluorogenic probe in which the fluorophore and quencher were covalently linked to the 5’ and 3’ ends of the probe. Given the lack of specific guidance provided by Hoon et al, an ordinary artisan would have looked to the teachings of the prior art – such as OSU - for additional guidance needed to successfully implement the methods of Hoon et al, and as a result of modifying Hoon et al in view of OSU, would have prepared probes labeled in the manner required by the claims. An ordinary artisan would have taken this approach simply for the advantage of efficiency and convenience in implementing the teachings of Hoon et al (as compared to experimenting to identify appropriate types/manner of labeling, etc.) Additionally, given the detailed guidance provided by OSU, an ordinary artisan would have had a reasonable expectation of success in preparing such labeled probes. With further regard to claim 9, it is noted that both Hoon et al and OSU teach the use of fluorescent molecules as labels in such methods.
With further regard to claims 10, 14, and 15, it also would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have - when performing/implementing a qPCR targeting the Alu sequence disclosed by Hoon et al in the manner suggested by the teachings of Hoon et al in view of OSU, as indicated above – designed primers and a probe for amplification and detection of an amplicon 75-150 base pairs in length, simply because this is the preferred amplicon size taught by OSU for such methods (see again page 3 bridging to page 4). Again, one of ordinary skill in the art would have recognized a benefit in the efficiency and convenience provided by following specific prior art teachings regarding implementation of qPCR regarding a target of interest, and would have had a reasonable expectation of success in implementing such a modification given the detailed guidance provided by OSU. The teachings of Hoon et al in view of OSU suggest any of a range of different amplicons 75-150 base pairs in length – meeting the length requirements of claims 10, 14, and 15 – any of which would have contained a nucleic acid functional as a probe complementary to instant SEQ ID NO: 1, and thus meeting the requirements of the claims. While each of claims 10, 14, and 15 recites a narrower range of lengths falling within the range suggested by the cited art (with claim 10 reciting a specific length within this range), it is noted that - as discussed in MPEP 2144.05(I) – where a claimed range overlaps or lies inside a range disclosed by the prior art, a prima facie case of obviousness exists. Thus, absent, e.g., a showing of unexpected results, the probes of the claims are obvious over the teachings of Hoon et al in view of OSU (see MPEP 2144.05(III)).
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over Hoon et al in view of OSU as applied to claims 7 and 9, above, and further in view of Ryazantsev et al (Analyst 139:2867 [2014]; cited herein).
The teachings of Hoon et al and OSU are set forth above. While Hoon et al in view of OSU suggest ‘fluorogenic” probes labeled 5’ and 3’, neither Hoon et al nor OSU teaches probes “covalently linked to at least three detectable moieties”, as required by claim 6. Ryazantsev et al teach an alternative types of fluorogenic probes usable in qPCR, molecular beacons, and teach a variety of different labeling schemes suitable for qPCR (see entire reference, particularly the Abstract, Table 1, and Figure 2). Among the alternatives taught by Ryazantsev et al are probes including three total detectable moieties at the 3’ and 5’ ends (meeting the requirements of claim 6); see, e.g., MB13 and MB14 as depicted in Fig 2 (and see also Table 1). Ryazantsev et al teach that MB14 “has a very high signal/background ratio in fluorescent melting” and “allows maximizing the fluorogenic effect in real-time PCR” (see “Conclusion”, page 2872, left column). In view of the teachings of Ryazantsev et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods suggested by Hoon et al in view of OSU so as to have prepared and employed a probe labeled in the manner taught by Ryazantsev et al, and thereby to have prepared a probe meeting the requirements of claim 6. An ordinary artisan would have been motivated to have made such a modification for the benefits taught by Ryazantsev et al of superior signal/background ratio and “maximizing the fluorogenic effect” when performing qPCR. Further, an ordinary artisan would have had a reasonable expectation of success in making such a modification given the teachings and guidance provided by Hoon et al, OSU, and (with particular regard to a labeling scheme as required by the claim) Ryazantsev et al.
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Hoon et al in view of OSU as applied to claims 7 and 9, above, and further in view of Reischl et al (Molecular Biotechnology 3:55 [1995]; cited herein).
The teachings of Hoon et al and OSU are set forth above. While Hoon et al in view of OSU suggest the use of probes labeled 5’ and 3’ in qPCR, neither Hoon et al nor OSU teaches probes in which a detectable moiety is biotin, as required by claim 8.
Reischl et al provide an overview of qPCR (see entire reference), including teachings related to various known and usable labeling procedures (see in particular section 3.1 at pages 60-61). Reischl et al teach that while radioactive labels were initially commonly employed in PCR, “a variety of highly sensitive nonradioactive indicator systems” were developed due to the difficulties presented in handling radioactive labels (page 60, right column). Among the alternative label types taught by Reischl et al is biotin (page 60, right column), and Reischl et al teach that biotin may be incorporated into PCR products in multiple different ways, including via the end labeling (page 60, right column). Reischl et al also teach that PCR products may be “double labeled” with biotin and other labels, with the presence of biotin allowing capture via streptavidin (see section 3.2.3 “Solid-Phase Assays”, pages 62-63). In view of the teachings of Reischl et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods suggested by Hoon et al in view of OSU so as to have prepared and employed a probe end-labeled with biotin (including in combination with other labels, as required by the claims). An ordinary artisan would have been motivated to have made such a modification for the benefit of facilitating capture/detection of nucleic acids/amplicons via streptavidin, as taught by Reischl et al. Additionally and/or alternative, an ordinary artisan would have recognized such a modification as the simple substitution of one known, prior art label type for another, facilitating the predictable result of detecting a qPCR product (via any preferred method of qPCR; while it is noted that the claims recite a ”nucleic acid probe”, primers as taught by the cited art are also types of probes that function in both amplification and detection of target sequences of interest). Further, an ordinary artisan would have had a reasonable expectation of success in making such a modification given the teachings and guidance provided by Hoon et al, OSU, and (with particular regard to a labeling scheme as required by the claim) Reischl et al.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 5 and 10-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon/law of nature without significantly more.
The specification teaches that SEQ ID NO: 1 “represents an exemplary human Alu repeat”, stating that Alu elements “are the most abundant repetitive elements in the human genome” (see paragraph 37, page 9 of the specification). It is noted that the specification also describes employing probes as set forth in the claims in targeting SEQ ID NO: 1 present in human biofluid samples for detection (see, e.g., paragraph 51, page 12, as well as discussion of “THE NUCLEIC ACID PROBE” on pages 14-15); the teachings of the specification make clear that probes of the invention may be composed of naturally occurring nucleotides, and that only some embodiments include “modified” nucleotides and/or conjugated labels (see again pages 14-15). Thus, the present claims (unlike, e.g., dependent claims 6-9, which require (a) covalently linked detectable moiety/moieties) encompass nucleotide sequences corresponding to fragments of naturally occurring nucleic acids (as each of claims 5 and 10-15 embraces complements [of various required minimum lengths] of a DNA sequence as defined by SEQ ID NO: 1, embracing fragments of naturally occurring complements of this human Alu repeat). Such nucleic acid fragments are products of nature that are analyzed for patent eligibility using the “markedly different characteristics” analysis (see MPEP 2106.04(c)), and in the present case, none of the nucleic acids of claims 5 and 10-15 as claimed is markedly different from naturally occurring Alu nucleic acid counterparts. Furthermore, there are no additional elements recited in the claims that might potentially integrate the claimed products into a practical application, or add something “significantly more” that a judicial exception (as again, the claims as written embrace naturally occurring nucleic acid fragments, and the products as claimed require nothing more than this). It is also noted that even to the extent that the claims may embrace, e.g., embodiments that are markedly different from naturally occurring nucleic acids – as is the case with the probes set forth in claims 6-9, which depend from claim 5 – “A claim whose BRI (broadest reasonable interpretation) covers both statutory and non-statutory embodiments embraces subject matter that is not eligible for patent protection and therefore is directed to non-statutory subject matter” (MPEP 2106.03(II)).
Thus, none of claims 5 and 10-15 is directed to patent eligible subject matter.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 16 and 20 are rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1 and 5, respectively, of prior U.S. Patent No. 11,926,868 (cited in IDS). This is a statutory double patenting rejection.
Instant claim 16 is drawn to a “nucleic acid probe for detecting Alu copy number in a nucleic acid from a biofluidic sample, comprising the nucleic acid sequence of SEQ ID NO: 2 covalently linked to a detectable label”, while its dependent claim 20 further requires that “the detectable moiety is a fluorescent molecule”. It is reiterated that (as discussed above) the terms “detectable label” and “detectable moiety” have been interpreted as equivalent to one another.
‘868 claim 1 is drawn to a “nucleic acid probe for detecting an Alu nucleic acid sequence in a nucleic acid from a biofluidic sample, comprising the nucleic acid sequence of SEQ ID NO: 2 covalently linked to a detectable moiety”, while its dependent claim 5 further requires that “the detectable moiety is a fluorescent molecule”. It is noted that SEQ ID NO: 2 of the ’868 patent (which issued from the parent application of the instant application) is identical to instant SEQ ID NO: 2, such that the instant claims and the ‘868 claims are directed to nucleic acid probes identical in structure to one another (and this applies both with regard to instant claim 16 as compared to ‘868 claim 1, and instant claim 20 as compared to ‘868 claim 5). While the instant claims and the ‘868 claims contain slightly different preamble wording, the intended uses of the claimed probes (both of which are recited as targeting Alu nucleic acids in nucleic acid from a biofluidic sample) do not impart any further structural requirements on the claimed products, which are defined via the recitation of specific sequences (SEQ ID NO: 2) and a required covalently linked detectable label/moiety (which is the case of the dependent claims must be a “fluorescent molecule”). Thus, instant claims 16 and 20 claim the same invention as ‘868 claims 1 and 5, respectively.
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 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,926,868 (cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. (Please see also the statutory double patenting rejection above that applies to instant claims 16 and 20; those claims are also included herein as they are also not patentably distinct from the other claims of the ‘868 patent).
Regarding instant claims 16-20, claim 16 (from which claims 17-20 depend) is drawn to a “nucleic acid probe for detecting Alu copy number in a nucleic acid from a biofluidic sample, comprising the nucleic acid sequence of SEQ ID NO: 2 covalently linked to a detectable label”. ‘868 claim 1 is drawn to a “nucleic acid probe for detecting an Alu nucleic acid sequence in a nucleic acid from a biofluidic sample, comprising the nucleic acid sequence of SEQ ID NO: 2 covalently linked to a detectable moiety”, while its dependent claim 5 further requires that “the detectable moiety is a fluorescent molecule”. It is again noted that SEQ ID NO: 2 of the ’868 patent (which issued from the parent application of the instant application) is identical to instant SEQ ID NO: 2. Thus, the sequence/structure of the nucleic acid of the instant claims is identical to that of the ‘868 claims, with the instant claims merely reciting different labeling schemes as compared to the ‘868 claims (such that the claimed inventions are not identical, other than instant claim 16 and ‘868 claim 1, and instant claim 20 and ‘868 claim 5). Given that the ‘868 claims recite both 3’ and 5’ labeling with a “detectable moiety” as well as multiple such moieties, and further recite the same preferred such moieties as the instant claims (biotin and a “fluorescent molecule), the instant claims are not patentably distinct from the ‘868 claims. In some cases the ‘868 claims anticipate the instant claims (for example, ‘868 claims 2-3 are preferred embodiment embraced by instant claim 18, with ‘858 claims 4 and 6 also anticipating instant claims 18-19), and those claims that are not anticipated by the ‘868 claims are clearly obvious over the ‘868 claims (as those claims recite probes covalently linked to one or more of the same preferred types of detectable moieties).
Claims 5, 7-8, 10-16, and 18-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,124,824 (cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
The ‘824 patent claims methods in which probes meeting the requirements of the present claims are either employed (such that the products of the instant claims are anticipated by the ‘824 claims), or clearly suggested by the products employed in the methods of the ‘824 claims. More particularly, probes meeting the requirements of claims 5, 7-8, and 10-15, are recited in, e.g., ‘824 claims 1-2, 11-15, and 18 (with claim 15 specifying a biotin label as required by claim 8). With regard to claim 16 and claims dependent therefrom (claims 18-19), while the ‘824 claims do not recite a probe comprising SEQ ID NO: 2, the ‘824 claims do recite probes “complementary to at least 50 contiguous nucleotides of SEQ ID NO: 2” (see claim 2), which would have suggested to one of ordinary skill in the art Alu probes including SEQ ID NO: 2; such an artisan
would have readily recognized that either strand of such a (specifically recited, preferred) nucleic acid could be successfully employed as a probe. Further, labeling as specified in claims 18-19 is suggested by, e.g., ‘824 claims 1 and 12-15. Thus, the instant claims are not patentably distinct from the ‘824 claims.
Claims 6, 9, 17, and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,124,824 in view of Hoon et al.
As discussed above, instant claim 5 (from which claims 6 and 9 depend) and instant claim 16 (from which 17 and 20 depend) are not patentably distinct from the ‘824 claims. The ‘824 claims recite probes covalently linked to a detectable label at the 3’ or 5’ end, and do not encompass probes including multiple labels (as required by claims 6 and 17), or probes including a fluorescent molecule (as required by claims 9 and 20).
Hoon et al teach methods comprising detection of “free circulating” DNA (a.k.a. cell-free DNA) in body fluids, which methods – like those of the ‘824 claims - include targeting Alu sequences in the cfDNA (see entire reference, particularly the Summary at page 1-4). More particularly, Hoon et al disclose methods comprising obtaining any body fluid sample (including a urine sample; see, e.g., page 3 at line 19; page 11 at line 15), and detecting and quantitating the cfDNA therein, with a preferred method being qPCR employing fluorogenic probes detectably labeled with a fluorophore and quencher (see entire reference, particularly, e.g., pages 11-12).
In view of the teachings of Hoon et al, it would have been prima facie obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to have labeled probes as set forth in the ‘824 claims in the manner taught by Hoon et al, i.e., to have included multiple labels/moieties including “a fluorescent molecule”. An ordinary artisan would have been motivated to have made such a modification for the benefit of preparing alternative probes labeled for successful use in the preferred methods taught by Hoon et al. With further regard to claim 6 and 17, and particularly given that Hoon et al disclose that multiple moieties on a single probe are employed in some types of detection methods/assays, while the claims in view of Hoon et al do not explicitly suggest the use of “at least three detectable moieties”, an ordinary artisan would have considered the addition of further moieties as routine optimization, and would have been motivated to have included additional moieties as needed depending upon the manner in which a probe was to be used. Thus, claims 6, 9, 17, and 20 are not patentably distinct from the ‘824 claims in view of Hoon et al.
Claims 5-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,505,822 (cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Regarding claims 5-15, the ‘822 claims anticipate the instant claims. More particularly, the ‘822 claims recite mixtures including Alu sequence targeting probes (particularly targeting at least 70 consecutive nucleotides of ‘822 SEQ ID NO: 1, which is identical to instant SEQ ID NO: 1), which probes are 3’ and/or 5’ labeled with detectable moieties that may include biotin (see, e.g., claim 3) or a fluorescent molecule (see, e.g., claims 2 and 6); the ‘822 claims also encompass probes attached to multiple moieties (see claims 8-11). Thus, the instant claims are not patentably distinct from the ‘823 claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DIANA B JOHANNSEN whose telephone number is (571)272-0744. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682