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 .
DETAILED ACTION
1. Applicant’s election without traverse of Group I claims in the reply filed on August 11, 2025 is acknowledged. Applicant’s election of SEQ ID NO. 9 with traverse is acknowledged. The traversal is based on no search burden examining all the sequences together. The arguments were found unpersuasive. As discussed in the previous office action, each sequence is structurally different with different sequence of nucleotides and have different function and searching all the sequences together would be a serious search burden. For all the above the restriction to elect a single sequence for examination is proper.
Status of the Application
2. Claims 1-5, 8-11, 15-16, 21, 24-25, 27-28, 30, 33-34, 36, 38-39, 42, 46, 104-105,108-109 and 117 along with the elected SEQ ID NO. 9 are considered for examination. Claims 47 and 115 were withdrawn as being drawn to nonelected group. Claims 6-7, 12-14, 17-20, 22-23, 26, 29, 31-32, 35, 37, 40-41, 42-45, 48-103, 106-107, 110-114, 116 and 118-126 were canceled.
Priority
3. This application is a 371 of PCT/US2020/014570 filed on 1/22/2020, which claims priority benefit of US 62/958,510 filed on1/08/2020 and US 62/897,561 filed on 09/09/2019.
Nucleotide and/or Amino Acid Sequence Disclosures
4. This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
(i) the specification discloses sequences in para 0045-0049, 0056-0059, 00136-0137, 00336-00339, 0416-0418, 423, 426, 430-434, 437,442 and claim 117, that fail to comply with the requirements of 37 CFR 1.821-1.825. No sequence listing and CRF is noted.
(ii) Sequences appearing in the drawings (Fig. 29A- Fig. 29B) are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Further, no sequence listing of the sequences in the drawings and CRF of the sequences is noted.
Applicant must provide:
1) A "Sequence Listing" part of the disclosure; together with a) An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2); b) A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and c) A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
2) If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, a) A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and b) A statement according to item 2) a) or b) above.
Appropriate correction is required.
Informalities
5. The following informalities are noted:
(i) claim 117 recites a sequence comprising ‘+’ signs. Amending the claim to indicate what the ‘+’ means, is suggested. Appropriate correction is required.
Claim Rejections - 35 USC § 112
6. 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.
A. Claim 21 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 21 recites ‘a capture nucleic acid with a length of from 9 to 30 oligonucleotides’. The limitation ‘length of from 9 to 30 oligonucleotides’ is unclear and indefinite because it is not clear how a length of a capture nucleic acid length encompasses 9 to 30 oligonucleotides. The specification on para 00316 discloses a capture nucleic as a single oligonucleotide. It is not clear if the limitation is referring to nucleotides in length or a plurality of 9 to 30 oligonucleotides.
B. Claim 36 is 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. The claim 36 is dependent on a canceled claim 35. The limitations in claim 36 are unclear and indefinite because it is not clear what the limitations are referring to.
C. Claim 108 is 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. The claim 108 recites ‘each genetic variant that is detected distinguishes the presence of one organism from another in the sample’. The limitations in the claim are unclear and indefinite because the claim 108 is dependent on claim 30 which is dependent on claim 2 which is dependent on claim 1, wherein the claim 1 is detecting a first genetic variant. The recitation of each genetic variant distinguishes one organism from another organism is unclear and indefinite because claim 1 requires detection of a single genetic variant and claim 30 do not require a sample comprising organisms.
Claim Rejections - 35 USC § 103
7. 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.
A. Claims 1-5, 8-10, 16, 21, 25, 28, 30, 33-34, 36, 39, 42, 46, 104-105 and 108-109 are rejected under 35 U.S.C. 103 as being unpatentable over Hellyer et al. (US 2014/0193819) in view of Hassibi et al. (US 2018/0251828).
Hellyer et al. teach a method of claim 1, detecting the presence of a first genetic variant in a target nucleic acid in a sample comprising: (a) contacting the target nucleic acid with (i) a first primer, (ii) a second primer (iii) a polymerase and (iv) a blocking oligonucleotide, wherein the blocking oligonucleotide comprises a sequence complementary to a second genetic variant of the target nucleic acid, and the first and second primers are configured for amplification of the target nucleic acid (para 0015-0017: indicating a forward primer and a reverse primer as a first and second primers to amplify a target nucleic acid, a modulator oligonucleotide as a blocking oligonucleotide hybridizes to a second variant,);
(b) amplifying the target nucleic acid thereby providing amplicons of the target nucleic acid (para 0015-0017); (c) contacting the amplicons with a capture nucleic acid, wherein the capture nucleic acid comprises a sequence complementary to the first genetic variant of the target sequence, thereby providing captured amplicons (para 0015-0018: indicating a reporter probe detectable labeled to capture first variant); (d) contacting the captured amplicons with a detectable label (para 0015-0018); and (e) detecting a presence, absence, amount, or change thereof of a detectable label (para 0015-0018: indicating detection of the detectable label wherein para 0085-0086 indicates detectable label).
With reference to claim 8-9, Hellyer et al. teach that the detecting of (e) comprises detecting binding of one or more amplicons that bind to the capture nucleic acid and amount of amplicons (para 0016).
With reference to claim 16, Hellyer et al. teach that the blocking oligonucleotide is selected from the group consisting of: a blocking oligonucleotide which, when hybridized to the second genetic variant, substantially prevents amplification of the target nucleic acid; a blocking oligonucleotide with a melting temperature of at least 75 °C; or a blocking oligonucleotide with a length of from 9 to 20 oligonucleotides and a blocking oligonucleotide comprising at least 3 locked nucleotides (para 0069-0082, 0020).
With reference to claim 21, Hellyer et al. teach that the capture nucleic acid (reporter probe) having a length of 9-30 nucleotides (para 0020, claim 23).
With reference to claim 28, Hellyer et al. teach that the amplifying comprises polymerase chain reaction (para 0017).
With reference to claims 30, 39, 105, 108-109, Hellyer et al. teach that the first genetic variant is at least one or more SNP, deletion, insertions or mutation, wherein first and second genetic variants comprise allelic variants in a sample from a subject and distinguishes different organisms (para 0041, 0048, 0052, 0012-0014, 0139-0144).
With reference to claim 42, Hellyer et al. teach that the captured amplicons are in fluid contact with a buffer prior to or during the detection, a concentration of positively charged cations in the buffer is decreased by at least 50% (para 0065).
However, Hellyer et al. did not teach a primer comprising a first member of the binding pair and contacting captured amplicons with a first detectable label comprising a second member of the binding pair.
Hassibi et al. teach a method of 1-5, 8-10, 16, 21, 25, 28, 30, 34-35, 36, 39, 42, 46, 104-105 and 108-109 for solid phase Q-PCR or real-time microarray based PCR for detecting multiple analytes in a sample wherein the method comprises addressable array comprising probes and PCR amplification comprises a primer labeled with one member of a binding pair (quencher label), produces a labeled amplicon and probes comprise a second member of the binding pair (fluorescent label) wherein the probes capture the labeled amplicon (para 0021-0026, 0050, 0088-0091) and capture probes are attached to magnetic beads (magnetic sensor) (para 0124, 0157-0158, 0203, 0217, 0237, 0242). Hassibi et al. teach use of a microfluidic device comprising addressable array comprising capture probes (para 0035, 0227-0231); nucleic acid purification (para 0119-0121) and use of a blocker sequence to detect single nucleotide polymorphism (SNP or genetic variants) (para 0084)
It would have been prima facie obvious an ordinary person skilled in the art before the effective filling date of the invention to modify the method as taught by Hellyer et al. and with a primer labeled with a first member of the binding pair and capturing with a second member of the biding pair as taught by Hassibi et al. to improve the sensitivity of the method. The ordinary person skilled in the art would have motivated to combine the teachings of Hellyer et al. with the first and second member of the binding pair and capturing amplicons on to a magnetic bead (sensor) as taught by Hassibi et al. and have a reasonable expectation of success that the combination would improve the sensitivity of detecting and target genetic variants because Hassibi et al. explicitly taught FRET binding pair based Q-PCR method comprising a labeled primer comprising a first member of the binding pair and capturing the labeled amplicons on to a magnetic bead comprising labeled capturing probes comprising a second member of the binding pair, which improves the sensitivity of the detecting genetic variants (para 0124, 0021-0024) and such a modification of the method is considered obvious over the cited prior art. Further it would be obvious to further modify the method of Hellyer et al. with microfluidic based processing of nucleic acids as taught by Hassibi et al. to achieve automated method for processing the nucleic acids in a sample.
B. Claims 11, 15, 24 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Hellyer et al. (US 2014/0193819) in view Hassibi et al. (US 2018/0251828) as applied to claims 1-5, 8-10, 16, 21, 25, 28, 30, 36, 39, 42, 46, 104-105 and 108-109 above, and further in view of Rothmann et al. (US 2012/0107818).
Hellyer et al. in view of Hassibi et al. teach a method of detecting the presence of a first genetic variant in a target nucleic acid as discussed above.
Hellyer et al. and Hassibi et al. did not specifically teach measuring a change in magneto resistance and the sensor comprising a giant magnetoresistance sensor.
Rothmann et al. teach a method for detecting genetic variants (alleles) using a microfluidic cartridge comprising amplification reaction chambers, wherein the amplification and detection of target nucleic acids using locus specific primer is performed in said cartridge, wherein the cartridge is fluidically connected to a microfluidic device that allows amplification and detection to occur at defined reaction chamber, wherein the detection comprises use of giant magneto resistance (GMR) for measuring changes in dielectric properties of the target nucleic acids (para 0009-0011, 0038-0040, 0077-0085).
It would have been prima facie obvious an ordinary person skilled in the art before the effective filling date of the invention to modify the method as taught by Hellyer et al. and Hassibi et al. with GMR sensor based detection of a target nucleic acid as taught by Rothmann et al.to improve the sensitivity of the method. The ordinary person skilled in the art would have motivated to combine the teachings of Hellyer et al. and Hassibi et al. with the GMR sensor as taught by Rothmann et al. and have a reasonable expectation of success that the combination would improve the sensitivity of detecting and target genetic variants because Rothmann et al. explicitly taught detecting magnetic bead bound target nucleic acid with GMR, that measures a change in the dielectric properties (para 0077) and such a modification of the method is considered obvious over the cited prior art.
C. Claims 27 and 117 are rejected under 35 U.S.C. 103 as being unpatentable over Hellyer et al. (US 2014/0193819) in view of Hassibi et al. (US 2018/0251828) as applied to claims above, and further in view of Chiari et al. (WO 2018/178943).
Hellyer et al. and Hassibi et al. did not specifically teach biotinylated primer comprising biotin as the first member of the binding pair and streptavidin as a second member of the binding pair bound a probe and a blocking oligonucleotide sequence of SEQ ID No. 9.
Chiari et al. teach a method for detecting genetic variants (alleles), wherein the method comprises contacting a genomic DNA sample with a biotin (first member of the binding pair) labeled primer and a tagged primer, extending the primers to form a primer extension product and capturing primer extension products onto streptavidin (second member of the binding pair) coated magnetic beads (magnetic sensor) (page 35, paragraph under section 1.1) (with reference to claims 1, 27). Chiari et al. also teach that method comprises an allele-specific blocking oligonucleotide wherein the blocking oligonucleotide comprises the sequence of SEQ ID NO:9 (page 54-58, indicating the use of oligo 3- Wt: DBCO probe sequence comprising the sequence of SEQ ID NO: 9 (with reference to claim 117).
It would have been prima facie obvious an ordinary person skilled in the art before the effective filling date of the invention to modify the method as taught by Hellyer et al. and Hassibi et al. with a biotin- streptavidin binding pair and an allele-specific competitive blocking oligonucleotide sequence comprising SEQ ID NO: 9 as taught by Chiari et al.to improve the sensitivity of the method. The ordinary person skilled in the art would have motivated to combine the teachings of Hellyer et al. and Hassibi with biotinylated primer and capture probe comprising streptavidin to capture the amplicon and the allele-specific blocking oligonucleotide comprising the sequence of SEQ ID NO: 9 as taught by Chiari et al. and have a reasonable expectation of success that the combination would improve the sensitivity of detecting and target genetic variants because Chiari et al. explicitly taught detecting genetic variants or alleles using biotin and streptavidin based capture of amplicons and allele-specific blocking oligonucleotide targeted to one allele (wt allele) improves the detection another genetic variant (allele) (page 54, line 17 to page 58, line 20) and such a modification of the method is considered obvious over the cited prior art.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SURYAPRABHA CHUNDURU whose telephone number is (571)272-0783. The examiner can normally be reached 8.00am-4.30pm.
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Suryaprabha Chunduru
Primary Examiner
Art Unit 1681
/SURYAPRABHA CHUNDURU/Primary Examiner, Art Unit 1681