Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Specification
The disclosure is objected to because of the following informalities: In paragraph 0001 on page 1 of the specification, (Cross-Reference to Related Applications), the phrase –now U.S. Patent no. 11,718,870—should be inserted after the phrase “U.S. Patent application 16/445,635, filed June 19, 2019” so as to update the status of the parent application.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 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.
On lines 4-5 of claim 1, the phrase “a template parent strand” is indefinite since it is not clear what this refers to. Does the template parent strand comprise a strand of nucleotides? See this same problem with the phrase “a nascent strand” on line 5 of claim 1. Does the nascent strand comprise a strand of nucleotides? On line 10 of claim 1, the phrase “a moiety” is indefinite since it is not clear what types of molecules or compounds can constitute the “moiety”. Without knowing what the “moiety” can be in this phrase, one of ordinary skill in the art would not know whether they are infringing on the system or not. On lines 16-17 of claim 1, the phrase “measure the value of the characteristic through the first conductor and the second conductor” should be changed to -- measure the value of the characteristic through the first conductor and the second conductor via the moiety—so as to recite the same terminology as recited on lines 11-12 of claim 1. This phrase is also indefinite since it is not clear whether the value of the characteristic is measured when the set of nucleotides is contacted with the tunneling junction. On line 18 of claim 1, the “reference value” is indefinite since it is not clear what this reference value represents. Is the reference value a value of an electrical or magnetic characteristic of the tunneling junction through the first and second conductors via the moiety when the tunneling junction is not contacted with the set of nucleotides?
Inventorship
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 Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-9 and 16-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oldham et al (WO 2017/189930, submitted in the IDs filed on June 26, 2023).
With regards to claim 1, Oldham et al teach of a system for analyzing nucleic acid molecules (see paragraph 0005 in Oldham et al where it states “Some aspects of the present disclosure provide systems for sequencing polynucleotide molecules such as DNA”) comprising: a tunneling junction comprising a first conductor and a second conductor separated by an insulating layer (see paragraph 0005 in Oldham et al where it states “The systems may comprise two electrodes disposed on a substrate separated by a non-conductive gap”, wherein the two electrodes constitutes a first conductor and a second conductor, and paragraph 0189 in Oldham et al where it states “In some cases, a target complex may be bound to a dielectric which may comprise a material used to form a gap between electrodes of an electrode pair, which may be silicon nitride, silicon oxide… or other standard semiconductor dielectric materials”, wherein the dielectric material forming the non-conductive gap between the electrodes of the tunneling junction constitutes an insulating layer), a polymerase attached to the tunneling junction and connected to a template parent strand, the polymerase configured to elongate a nascent strand that is hybridized to the template parent strand (see paragraph 0006 in Oldham et al where it states “The electrodes and the gap may be configured to accommodate a polymerase in the vicinity of the two electrodes. The electrodes and the gap may be adapted for detecting an electron or hole tunneling current during incorporation and or binding of a nucleotide into a polynucleotide in the presence of the polymerase. The nucleotide may comprise a tunneling label. The nucleotide may be incorporated into or bound to a single stranded portion of the polynucleotide”, and paragraph 0200 in Oldham et al where it states “A polymerase may be provided with a primed target nucleic acid strand, wherein a single stranded portion may provide a template for incorporation (addition) of complementary nucleotides, which may be nucleotides with tunneling labels), a power supply in electrical communication with at least one of the first conductor and the second conductor (i.e. the first and second electrodes) (see Figures 2B-2D in Oldham et al which depict a power supply in electrical communication with the first electrode 202A of the tunneling junction on the left-hand side of the tunneling junction), a set of nucleotides, each nucleotide of the set of nucleotides attached to a label compound comprising a moiety (see paragraph 0006 in Oldham et al where it states “The electrodes and the gap may be adapted for detecting an electron or hole tunneling current during incorporation and or binding of a nucleotide into a polynucleotide in the presence of the polymerase. The nucleotide may comprise a tunneling label.”, paragraph 0201 in Oldham et al where it states “an enzyme or polymerase may be considered to be in a vicinity of a gap between two electrodes when a labeled moiety bound by an enzyme or polymerase may be able to bind or interact with both electrodes such that a measurable tunneling current may be detected as a result of an interaction of the label bound to a labeled moiety with both electrodes.”, and paragraph 0202 in Oldham et al where it states “Incorporation or binding of a base with a tunneling label may cause an increase in tunneling current going from one electrode to another.”), a meter device configured to measure a value of a characteristic through the first conductor and the second conductor via the moiety, wherein the characteristic is an electrical characteristic (see Figures 2B-2D in Oldham et al which depict a meter A in communication with the second electrode 202B of the tunneling junction on the right-hand side of the tunneling junction, and see paragraphs 0201-0202 in Oldham et al), and a non-transitory computer readable medium storing a plurality of instructions that when executed by a processor, cause the processor to perform the steps of the method to measure a value of the electrical characteristic through the first and second electrodes when the labeled moiety on a nucleotide of the set of nucleotides binds to a complementary nucleotide on the template parent polynucleotide strand attached to the polymerase on the tunneling junction, and measure a background value of the electrical characteristic of the tunneling junction when no labeled nucleotide from the set of nucleotides is bound to the polymerase and template parent strand as a baseline “no-current” reference value (see paragraph 0021 in Oldham et al where it states “Another aspect of the present disclosure provides a non-transitory computer-readable medium comprising machine-readable code that, upon execution by one or more computer processors, implements a method for sequencing a nucleic acid molecule…”, paragraph 0205 in Oldham et al where it states “During this time wherein no nucleotide and associated label 205 may be bound by a polymerase or other enzyme 206, essentially no current may flow between electrodes 202A and 202B.”, and paragraph 0330 where it states “A background signal may be determined from sensors which may not have bound enzymes, and may thus not have signals.”). See Figures 2B-2D, and paragraphs 0004-0015, 0020, 0024, 0189, 0200-0205, 0314 and 0330 in Oldham et al.
Oldham et al fail to teach that the instructions provided by the non-transitory computer readable medium cause the processor to compare the value of the electrical characteristic when a labeled nucleotide is contacted with the polymerase and template parent polynucleotide strand on the tunneling junction with the reference value of the electrical characteristic of the tunneling junction when no labeled nucleotide from the set of nucleotides is bound to the polymerase and template parent strand (“no current”), and upon determining that the electrical characteristic measured in the presence of the labeled nucleotide exceeds the reference value, detecting that the labeled nucleotide has become hybridized to the template parent polynucleotide strand. However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include instructions in the non-transitory computer readable medium in the system taught by Oldham et al for causing the processor to perform such comparison and detection steps because Oldham et al teach of measuring an electrical characteristic of the tunneling junction both in the presence and in the absence of a labeled nucleotide, wherein the absence of a labeled nucleotide provides a reference “no current” value and the presence of a labeled nucleotide hybridized to a complementary nucleotide on the template parent strand produces a positive electrical characteristic value, thus allowing a determination of a labeled nucleotide being hybridized to the template parent strand when the electrical characteristic measured in the presence of the labeled nucleotide differs from the reference “no current” value.
With regards to claim 2, Oldham et al teach that the system further comprises a set of fluidic channels that are used to distribute reagents, polymerases, etc. to an electrode pair disposed on a substrate, wherein the fluidic channels serve as reservoirs in fluid communication with the tunneling junction (see paragraph 0313 in Oldham et al). Oldham et al also teach that the tunneling junction may be provided on a substrate of a chip, wherein the chip has multiple input ports for introducing different fluids into the chip from multiple reservoirs (see paragraphs 0343 and 0345 in Oldham et al), and that a pump or other source of positive or negative pressure (i.e. an injection system) may be used to deliver a liquid from a reservoir to the tunneling junction (see paragraph 0377 in Oldham et al).
With regards to claim 3, Oldham et al teach that the system comprises a plurality of tunneling junctions, and the power supply is in electrical communication with the plurality of tunneling junctions (see paragraphs 0308-0309 in Oldham et al which teach that many tunneling junction sensors may be placed on a single chip so that many samples may be analyzed at the same time in parallel).
With regards to claim 4, Oldham et al teach that the first and second conductors are electrodes, that the tunneling junction is provided on a surface of a substrate, that the insulating layer (i.e. the dielectric layer) has a surface parallel to the surface of the substrate, and the characteristic measured by the meter device is an electrical characteristic. See paragraphs 0005-0006, 0009 and 0189 in Oldham et al.
With regards to claim 5, Oldham et al teach that the polymerase is attached to the tunneling junction at the insulating layer at the surface parallel to the substrate. See paragraph 0006 in Oldham et al where it states “The electrodes and the gap may be configured to accommodate a polymerase in the vicinity of the two electrodes.”, also see paragraph 0015 in Oldham et al where it states “In some embodiments, a polymerase may be disposed on a dielectric between at least two electrodes”.
With regards to claim 6, Oldham et al teach that the insulating layer comprises silicon nitride or silicon oxide. See paragraph 0189 in Oldham et al where it states “In some cases, a target complex may be bound to a dielectric which may comprise a material used to form a gap between electrodes of an electrode pair, which may be silicon nitride, silicon oxide… or other standard semiconductor dielectric materials”.
With regards to claim 7, Oldham et al teach that the first electrode comprises gold, silver, platinum or palladium. See paragraph 0166 in Oldham et al.
With regards to claim 8, Oldham et al teach that the electrical characteristic is current. See paragraph 0006 in Oldham et al where it states “The electrodes and the gap may be configured to accommodate a polymerase in the vicinity of the two electrodes. The electrodes and the gap may be adapted for detecting an electron or hole tunneling current during incorporation and or binding of a nucleotide into a polynucleotide in the presence of the polymerase”. Also see paragraph 0202 in Oldham et al where it states “Incorporation or binding of a base with a tunneling label may cause an increase in tunneling current going from one electrode to another.”
With regards to claim 9, Oldham et al teach that the insulating layer has a thickness greater than 2 nm. See paragraphs 0312 and 0329 in Oldham et al which describes the gap forming the insulating layer of the tunneling junction as having a thickness of “larger or wider than about 2-3 nm”, or “greater than or equal to about 5, 6, 7, 8,9, 10… or more nm”.
With regards to claims 16-17, Oldham et al teach that each nucleotide of the set of nucleotides is attached to a cleavable linker by being directly bonded to the cleavable linker, and the cleavable linker is attached to the moiety or label. See paragraph 0106 in Oldham et al where it states “A label may be bound through a cleavable linker, which may be a photocleavable or a chemically cleavable linker. A cleavable linker may leave a label bound to an enzyme complex until a label may be intentionally removed”. Also see paragraph 0107 in Oldham et al where it states “A nucleobase may be incorporated and a linker may thus be cleaved between a nucleobase and its associated label”.
With regards to claims 17-20, Oldham et al teach that the moiety or label attached to each nucleotide of the set of nucleotides can comprise an organometallic group such as ferrocene (see paragraph 0083 in Oldham et al), or can comprise a metal nanoparticle such as gold, silver, platinum, magnesium, or titanium nitride (see paragraph 0084 in Oldham et al).
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oldham et al (WO 2017/189930, submitted in the IDs filed on June 26, 2023) in view of Lindsay et al (article from Nanotechnology, vol. 21, 262001, pages 1-12, 2010, submitted in the IDS filed on June 26, 2023). For a teaching of Oldham et al, see previous paragraphs in this Office action.
With regards to claim 15, Oldham et al fail to specifically teach that the thickness of the insulating layer in the tunneling junction is greater than the size of each moiety or label of each nucleotide in the set of nucleotides.
Lindsay et al teach of using recognition tunneling for nucleic acid sequencing (see abstract), and also teach of various design considerations for a tunnel junction used for the sequencing. Specifically, Lindsay et al teach that the gap size (i.e. the space between the electrodes in the tunnel junction) is “critical” and can affect the movement of the molecule through the tunnel gap, the conformation of the molecule, the stability of the gap, and noise in the junction (see the abstract and page 9, section 7 of Lindsay et al). While Lindsay et al do not teach the same recited thickness of the insulating layer in the tunneling gap as recited in instant claim 15, one of ordinary skill in the art would understand from Lindsay et al that the thickness of the insulating layer and the gap size in a tunneling junction used to sequence nucleic acids are result effective variables. Thus, it would have been obvious to one ordinary skill in the art before the effective filing date of the claimed invention to adjust the thickness of the insulating layer in the tunneling junction taught by Oldham et al to be greater than the size of each moiety of each nucleotide of the set of nucleotides because Lindsay et al teach that the thickness of an insulating layer in a tunneling junction used to sequence nucleic acids is a result effective variable that can be optimized using routine experimentation in order to produce desired results in a sequencing procedure such as optimal movement of a molecule through the tunnel gap, an optimal conformation of the molecule, optimal stability of the gap, and optimal noise in the junction.
Claim(s) 10-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oldham et al (WO 2017/189930, submitted in the IDs filed on June 26, 2023) in view of Mandell et al (WO 2017/030999, submitted in the IDS filed on June 26, 2023). For a teaching of Oldham et al, see previous paragraphs in this Office action.
With regards to claims 10-11, Oldham et al fail to teach that the first and second conductors (i.e. electrodes) in the tunneling junction of the system used to sequence nucleic acids can be made of different ferromagnetic materials, and that a change in an electrical characteristic caused by magnetic properties of magnetic particles used to label the nucleotides is measured using the tunneling junction.
Mandell et al teach of a system for sequencing nucleic acids by synthesis using a detection system that includes an array of magnetically-responsive sensors. Each of the magnetically-responsive sensors is located proximate to a designated space to detect a magnetic property therefrom. The detection system also comprises a plurality of nucleic acid template strands located within corresponding designated spaces. The method of using the detection system comprises adding labeled nucleotides to the array of magnetically-responsive sensors to grow strands of nucleic acids that are complementary to the template strands located within designated spaces of the sensors by incorporating complementary nucleotides along each template strand. The labeled nucleotides added to the sensors are labeled with magnetic particles having respective magnetic properties. Each binding event between the labeled nucleotides and the template strands in each of the designated spaces of the magnetically-responsive sensors is detected by detecting changes in electrical resistance (i.e. an electrical characteristic) at the sensors caused by the respective magnetic properties of the magnetic particles used to label the nucleotides. Mandell et al teach that each of the magnetically-responsive sensors in the detection system comprise at least two ferromagnetic layers and a non-magnetic layer that separates the two ferromagnetic layers so as to form a tunnel magnetoresistance (TMR) sensor. See the abstract, pages 1-2 and 6-7 of the specification, and the claims in Mandell et al.
Based upon a combination of Oldham et al and Mandell et al, it would have been obvious to one ordinary skill in the art before the effective filing date of the claimed invention to use electrodes made of one of the common ferromagnetic materials recited in instant claim 11 as the first and second conductors in the tunneling junction taught by Oldham et al, to label the nucleotides in the set of nucleotides added to the tunneling junction with a magnetic particle, and to measure a change in an electrical characteristic of the tunneling junction caused by magnetic properties of the magnetic particles when a labeled nucleotide binds to a complementary template strand because Oldham et al teach of sequencing nucleic acids during their synthesis using a tunneling junction by detecting a change in an electrical characteristic in the junction when a labeled nucleotide binds to a template strand of nucleotides located at the junction along with a polymerase, and Mandell et al teach that one way to perform such a sequencing method using a tunneling junction is to employ a tunnel magnetoresistance (TMR) sensor that comprises two ferromagnetic layers and a non-magnetic layer separating the two ferromagnetic layers as the tunneling junction, and to detect binding events between magnetically-labeled nucleotides and a template strand located at the tunneling junction by detecting changes in electrical resistance (i.e. an electrical characteristic) at the junction caused by the respective magnetic properties of the magnetic particles used to label the nucleotides.
With regards to claim 12, Oldham et al teach that the moiety or label used to label the nucleotides in the system can be a polymer having a terminus bound to a magnetic or paramagnetic bead or particle. See paragraph 0195 in Oldham et al.
With regards to claim 13, Oldham et al teach that the polymerase is attached to the tunneling junction at the insulating layer. See paragraph 0006 in Oldham et al where it states “The electrodes and the gap may be configured to accommodate a polymerase in the vicinity of the two electrodes.”, also see paragraph 0015 in Oldham et al where it states “In some embodiments, a polymerase may be disposed on a dielectric between at least two electrodes”.
With regards to claim 14, Oldham et al teach that the characteristic measured by the meter device in the system is an electrical characteristic comprising current. See paragraphs 0005-0006 and 0009 in Oldham et al.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Please make note of: Astier et al (US 12,313,584) who teach of a method and a device for analyzing molecules and sequencing nucleic acids using a tunneling junction; Astier (US 2020/0040389) who teach of a method for nucleic acid sequencing using nanotransistors; Turner et al (US 2016/0083798) who teach of a method for nucleic acid sequencing using nanoscale electrode pairs separated by an insulating layer; and Astier et al (US 11,718,870) which corresponds to the parent application of this application.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN M WALLENHORST whose telephone number is (571)272-1266. The examiner can normally be reached on Monday-Thursday from 6:30 AM to 4:30 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander, can be reached at telephone number 571-272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MAUREEN WALLENHORST/Primary Examiner, Art Unit 1797 February 19, 2026