DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-15 are currently pending and under examination herein.
Claims 1-15 are rejected.
Claims 14-15 are objected to.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 filed on 01/18/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/12/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. A signed copy of a list of references cited from each IDS is included in this Office Action.
The Examiner notes that although Ouldali et al. was filed in the IDS on 7/12/2023, there are additional figures not included in the filed prior art listing and therefore, an alternative prior art document has been attached to this Office Action for the following prior art rejections below.
Drawings
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 5 is objected to because of the following informalities: The claims require an “and” between steps ii) and iii). Appropriate correction is required.
Claims 14-15 is objected to because of the following informalities: The claims require a comma after “in any case,”. 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 3, 5-6, 10, and 13-15 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.
With respect to claims 3, 5, 10, and 13-15, it is unclear if the claim is limited to what is recited in the “in particular” or if the art on the broader meaning of the terms can be applied. Appropriate correction is required.
Regarding claim 10, “e.g.” is exemplary claim language and it is not clear whether the claimed narrower range is a limitation (see MPEP 2173.05(d)). Appropriate correction is required.
Claim 12 recites a use claim which attempts to claim a process without setting forth any steps involved in the process and is therefore indefinite (see MPEP 2173.05(q)).
The term “sufficiently” in claims 14-15 is a relative term which renders the claim indefinite. The term “sufficiently” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the representative set of residual current values describing heteropolymer sequences for structure or elucidation prediction are rendered indefinite from the use of the term “sufficiently”. Appropriate correction is required.
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 12 and 14 are rejected under 35 U.S.C 101 the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because:
Claim 12 recites a non-statutory use claim as "use" claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101. (see MPEP 2173.05(q) and In re Moreton, 288 F.2d 708, 709, 129 USPQ 227, 228 (CCPA 1961) ("one cannot claim a new use per se, because it is not among the categories of patentable inventions specified in 35 U.S.C. § 101 ").
Claim 14 is non-statutory as it recites "computer program code". The claims as instantly
recited read on carrier waves, which are transitory propagating signals and therefore are not proper
patentable subject matter because they do not fit within any of the four statutory categories of
invention (In re Nuijten, Federal Circuit, 2007). It is noted that the recitation of a "non-transitory
computer readable medium" would overcome the rejection with respect to claim 14 reading on signals.
However, the amendment to only "non-transitory computer readable medium" would not overcome
the rejection under 35 U.S.C. 101 since the claims would still be directed to a judicial exception without significantly more (see below).
Claims 1-11 and 13-15 are rejected under 35 U.S.C 101 because the claimed invention is directed to an abstract idea and/or a natural phenomenon without significantly more.
In accordance with MPEP 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature, or natural phenomenon (Step 2A, Prong 1). Although claim 14 does not recite a statutory category of invention, subsequent analysis will continue in the interest of compact prosecution.
Claim 1 recites a method for identifying a sequence of monomer building blocks of a biological or synthetic heteropolymer, performing an evaluation method in which a sequence of monomer building blocks of the heteropolymer is determined from the representative set of characteristic current signals.
Claim 5 recites a method comprising: determining the primary structure of a macromolecule formed at least from heteropolymers, in particular a protein; using of the method according to claim 1 for determining a sequence of monomer building blocks, in particular amino acids, of at least one, in particular each, of the heteropolymers; and performing a macromolecule recognition method in which the primary structure of the macromolecule is determined from a sequence listing of the at least one heteropolymer.
Claim 13 recites statistically determining of a representative set of characteristic residual current values from the residual current values, a characteristic residual current value describing in each case one fragment type, in particular fragment size, of the number n of fragment types of a fragment mixture formed from the heteropolymer, the representative set uniquely describing the heteropolymer sequence, sorting the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence; and assigning the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types.
Claim 14 and 15 recite statistically determining of a representative set of characteristic residual current values from the residual current values, a characteristic residual current value describing in each case one fragment type, in particular fragment size, of the number n of fragment types of a fragment mixture formed from the heteropolymer, the representative set uniquely describing the heteropolymer sequence unambiguously, but in any case sufficiently for a desired structure elucidation or structure prediction, sorting the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence; and assigning the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types.
The limitations of identifying a sequence of monomer building blocks of a biological or synthetic heteropolymer, performing an evaluation method in which a sequence of monomer building blocks of the heteropolymer is determined from the representative set of characteristic current signals, determining the primary structure of a macromolecule formed at least from heteropolymers, in particular a protein; using of the method according to claim 1 for determining a sequence of monomer building blocks, in particular amino acids, of at least one, in particular each, of the heteropolymers; performing a macromolecule recognition method in which the primary structure of the macromolecule is determined from a sequence listing of the at least one heteropolymer, sorting the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence; assigning the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types and assigning the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types fall under the “mental process” grouping of ideas. Identification, evaluation, sorting, and assigning based on data can be practically performed in the human mind or with a pen and paper and is therefore a mental process. The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (See, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674 and Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016).
The limitations of statistically determining of a representative set of characteristic residual current values from the residual current values, a characteristic residual current value describing in each case one fragment type, in particular fragment size, of the number n of fragment types of a fragment mixture formed from the heteropolymer, the representative set uniquely describing the heteropolymer sequence and determining of a representative set of characteristic residual current values from the residual current values, a characteristic residual current value describing in each case one fragment type, in particular fragment size, of the number n of fragment types of a fragment mixture formed from the heteropolymer, the representative set uniquely describing the heteropolymer sequence unambiguously, but in any case sufficiently for a desired structure elucidation or structure prediction, sorting the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence are all verbal equivalents of a mathematical calculation and fall under the “mathematical concept” grouping of ideas. Of note, the transformation of residual current values into a set of characteristic residual values is merely a mathematical computation and therefore is grouped into the mathematical concept category. As such, claims 1-15 recite abstract ideas.
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflects an improvement to technology or applies or uses the recited judicial exception in some other meaningful way. Rather, the instant claims recite additional elements that amount to mere instructions to implement the abstract idea in a generic computing environment. Specifically, the claims recite the following additional elements:
Claim 1 recites performing a fragmentation method in which the heteropolymer is broken down into fragments, thereby obtaining a fragment mixture whose fragments are molecules having different sequence segments of the heteropolymer and performing a current measurement method in which current signals of a current through the channel of a nanopore are detected, wherein each current signal is based on the interaction of a fragment of the fragment mixture with the channel of the nanopore, wherein the current signals are characteristic of the different fragments such that a representative set of characteristic current signals representing the fragment mixture is determinable.
Claim 2 recites the method according to claim 1, wherein the fragments of the fragment mixture are obtained by enzymatic, chemical and/or physical methods and/or are obtained by successive degradation of the heteropolymer.
Claim 3 recites the method according to claim 2, wherein the successive degradation of the heteropolymer provides that the heteropolymer is chain-like and, starting from one end of its chain, is stepwise shortened by one monomer building block to obtain length fragments, in particular substantially all length fragments n-(n-1), n-(n-2).... to n-(n-n), of a heteropolymer consisting of n monomer building blocks.
Claim 4 recites the method according to claim 1, wherein the heteropolymer is a peptide and the fragmentation method is or includes Edman degradation
Claim 5 recites cleavage of the macromolecule, in particular by enzymatic and/or chemical and/or physical cleavage, to obtain heteropolymers, in particular peptides, as cleavage products of the macromolecule and optionally: obtaining the heteropolymers by chromatographic or electrophoretic separation of a heteropolymer mixture obtained by the cleavage.
Claim 7 recites the method according to claim 1, wherein the nanopore is a solid-state nanopore or a hybrid of solid-state and biological components.
Claim 8 recites the method according to claim 1, wherein the fragmentation of the heteropolymer is carried out by enzymes.
Claim 9 recites the method according to claim 1. wherein the fragmentation of the heteropolymer is carried out chemically and non-enzymatically.
Claim 10 recites the method according to claim 1, wherein the fragmentation of the heteropolymer is carried out physically, e.g. by exposure to heat, cold, sound waves, electromagnetic radiation, in particular infrared, ultraviolet or X-ray radiation, microwaves or visible light.
Claim 11 recites the method according to claim 1, wherein the nanopore is aerolysin, alpha-hemolysin, VDAC, or other protein of the beta-barrel protein family.
Claim 13 recites a computer-implemented method.
Claim 14 recites a computer program code.
Claim 15 recites a data processing system.
The limitations of performing a fragmentation method in which the heteropolymer is broken down into fragments, thereby obtaining a fragment mixture whose fragments are molecules having different sequence segments of the heteropolymer and performing a current measurement method in which current signals of a current through the channel of a nanopore are detected, wherein each current signal is based on the interaction of a fragment of the fragment mixture with the channel of the nanopore, wherein the current signals are characteristic of the different fragments such that a representative set of characteristic current signals representing the fragment mixture is determinable; the cleavage of the macromolecule, in particular by enzymatic and/or chemical and/or physical cleavage, to obtain heteropolymers, in particular peptides, as cleavage products of the macromolecule and optionally: obtaining the heteropolymers by chromatographic or electrophoretic separation of a heteropolymer mixture obtained by the cleavage amount to insignificant data gathering as performing a fragmentation method to obtain a fragment mixture, obtaining current measurements of current signals, and obtaining heteropolymers via a variety of methods merely serve to collect measurements and other materials for subsequent analysis.
The limitations of the fragments of the fragment mixture being obtained by enzymatic, chemical and/or physical methods and/or being obtained by successive degradation of the heteropolymer; the successive degradation of the heteropolymer provides that the heteropolymer is chain-like and, starting from one end of its chain, is stepwise shortened by one monomer building block to obtain length fragments, in particular substantially all length fragments n-(n-1), n-(n-2).... to n-(n-n), of a heteropolymer consisting of n monomer building blocks; the heteropolymer is a peptide and the fragmentation method is or includes Edman degradation; the nanopore is a solid-state nanopore or a hybrid of solid-state and biological components; the fragmentation of the heteropolymer is carried out by enzymes; the fragmentation of the heteropolymer is carried out chemically and non-enzymatically; the fragmentation of the heteropolymer is carried out physically, e.g. by exposure to heat, cold, sound waves, electromagnetic radiation, in particular infrared, ultraviolet or X-ray radiation, microwaves or visible light; the nanopore is aerolysin, alpha-hemolysin, VDAC, or other protein of the beta-barrel protein family; the use of a nanopore for performing the method for identifying a sequence of monomer building blocks of a biological or synthetic heteropolymer according to claim 1 are serve to merely further limit the fragmentation step which is insignificant extra-solution activity. Therefore, the claim limitations do not integrate the additional elements into a practical application.
Furthermore, regarding the claim limitations of claim 13-15, there are no limitations that indicate that the claimed computer, processor, input device or computer-readable medium require anything other than generic computing systems. As such, these limitations equate to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. As such, claims 1-11 and 13-15 do not integrate the judicial exceptions into a practical application.
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that amount to mere instructions to implement the abstract idea in a generic field-of-use and/or technological environment. The instant claims recite the following additional elements:
Claim 1 recites performing a fragmentation method in which the heteropolymer is broken down into fragments, thereby obtaining a fragment mixture whose fragments are molecules having different sequence segments of the heteropolymer and performing a current measurement method in which current signals of a current through the channel of a nanopore are detected, wherein each current signal is based on the interaction of a fragment of the fragment mixture with the channel of the nanopore, wherein the current signals are characteristic of the different fragments such that a representative set of characteristic current signals representing the fragment mixture is determinable.
Claim 2 recites the method according to claim 1, wherein the fragments of the fragment mixture are obtained by enzymatic, chemical and/or physical methods and/or are obtained by successive degradation of the heteropolymer.
Claim 3 recites the method according to claim 2, wherein the successive degradation of the heteropolymer provides that the heteropolymer is chain-like and, starting from one end of its chain, is stepwise shortened by one monomer building block to obtain length fragments, in particular substantially all length fragments n-(n-1), n-(n-2).... to n-(n-n), of a heteropolymer consisting of n monomer building blocks.
Claim 4 recites the method according to claim 1, wherein the heteropolymer is a peptide and the fragmentation method is or includes Edman degradation.
Claim 5 recites cleavage of the macromolecule, in particular by enzymatic and/or chemical and/or physical cleavage, to obtain heteropolymers, in particular peptides, as cleavage products of the macromolecule and optionally: obtaining the heteropolymers by chromatographic or electrophoretic separation of a heteropolymer mixture obtained by the cleavage.
Claim 7 recites the method according to claim 1, wherein the nanopore is a solid-state nanopore or a hybrid of solid-state and biological components.
Claim 8 recites the method according to claim 1, wherein the fragmentation of the heteropolymer is carried out by enzymes.
Claim 9 recites the method according to claim 1. wherein the fragmentation of the heteropolymer is carried out chemically and non-enzymatically.
Claim 10 recites the method according to claim 1, wherein the fragmentation of the heteropolymer is carried out physically, e.g. by exposure to heat, cold, sound waves, electromagnetic radiation, in particular infrared, ultraviolet or X-ray radiation, microwaves or visible light.
Claim 11 recites the method according to claim 1, wherein the nanopore is aerolysin, alpha-hemolysin, VDAC, or other protein of the beta-barrel protein family.
Claim 13 recites a computer-implemented method.
Claim 14 recites a computer program code.
Claim 15 recites a data processing system.
The limitations of performing a fragmentation method in which the heteropolymer is broken down into fragments, thereby obtaining a fragment mixture whose fragments are molecules having different sequence segments of the heteropolymer and the fragmentation of the heteropolymer being carried out by enzymes; and the cleavage of the macromolecule, in particular by enzymatic and/or chemical and/or physical cleavage, to obtain heteropolymers, in particular peptides, as cleavage products of the macromolecule and optionally: obtaining the heteropolymers by chromatographic or electrophoretic separation of a heteropolymer mixture obtained by the cleavage is a well-understood, routine, conventional step as disclosed by the applicant’s specification (page 2 lines 11-24) as a standard method of identifying proteins includes tryptic digestion into peptide fragments. In addition, the limitations of the method for identifying a sequence of monomer building blocks of a biological or synthetic heteropolymer according to claim 1 is a well-understood, routine, conventional step as disclosed by the applicant’s specification (page 2 lines 4-10). Furthermore, the limitations of the nanopore being aerolysin, alpha-hemolysin, VDAC, or other protein of the beta-barrel protein family is a well-understood, routine, conventional activity as evidenced by the applicant’s specification (page 5 lines 9-13).
The limitations of performing a current measurement method in which current signals of a current through the channel of a nanopore are detected, wherein each current signal is based on the interaction of a fragment of the fragment mixture with the channel of the nanopore, wherein the current signals are characteristic of the different fragments such that a representative set of characteristic current signals representing the fragment mixture is determinable is a well-understood, routine, conventional activity as various methods including nanopore ionic current measurement are disclosed by Ouldali et al. (Ouldali, H., Sarthak, K., Ensslen, T. et al. Electrical recognition of the twenty proteinogenic amino acids using an aerolysin nanopore. Nat Biotechnol 38, 176–181 (2020); explicitly stated that a method of amino acid sequence identification includes that of nanopore ionic currents; see second paragraph in page 176 in “Main”).
The limitations of the fragments of the fragment mixture are obtained by enzymatic, chemical and/or physical methods and/or are obtained by successive degradation of the heteropolymer; the successive degradation of the heteropolymer provides that the heteropolymer is chain-like and, starting from one end of its chain, is stepwise shortened by one monomer building block to obtain length fragments, in particular substantially all length fragments n-(n-1), n-(n-2).... to n-(n-n), of a heteropolymer consisting of n monomer building blocks; and the heteropolymer is a peptide and the fragmentation method is or includes Edman degradation is a well-understood, routine, conventional activity as all of these limitations describes the Edman degradation step as disclosed by Chait et al. (US6271037B1; see Col 1. Lines 52-56) as the state-of-the-art method for amino acid sequence determination.
The limitations of the nanopore being a solid-state nanopore or a hybrid of solid-state and biological components family is a well-understood, routine, conventional activity as evidenced by Nandivada (Nandivada, S. (2017). Characterization of Nanoparticles Using Solid State Nanopores. Graduate Theses and Dissertations; see “Abstract” wherein solid state nanopores are widely used in detection of highly charged biomolecules like DNA and proteins).
The limitations of the fragmentation of the heteropolymer being carried out chemically and non-enzymatically; the fragmentation of the heteropolymer is carried out physically, e.g. by exposure to heat, cold, sound waves, electromagnetic radiation, in particular infrared, ultraviolet or X-ray radiation, microwaves or visible light is a well-understood, routine, conventional activity as evidenced by Bayega et al. (Bayega, A., Fahiminiya, S., Oikonomopoulos, S., Ragoussis, J. (2018). Current and Future Methods for mRNA Analysis: A Drive Toward Single Molecule Sequencing. In: Raghavachari, N., Garcia-Reyero, N. (eds) Gene Expression Analysis. Methods in Molecular Biology, vol 1783. Humana Press, New York, NY; examples of physical fragmentation stated on page 213 in “2.5 cDNA fragmentation”).
The limitations of a computer-implemented method for determining a sequence of monomer building blocks of a heteropolymer, referred to as a heteropolymer sequence, from measurement data of a current measurement method containing information on current signals obtained upon interaction of different fragments formed from the heteropolymer with the channel of a nanopore; a computer program code which is stored on a data carrier and which determines a sequence of monomer building blocks of a heteropolymer, referred to as heteropolymer sequence, from the measurement data of a current measurement method when executed by the central processor of a computer, the measurement data containing information on current signals which are determined upon the interaction of different fragments formed from the heteropolymer with a nanopore, comprising the respective steps implemented by program code; a data processing system for determining a sequence of monomer building blocks of a heteropolymer, referred to as heteropolymer sequence, from the measurement data of a current measurement method containing information on current signals determined upon interaction of different fragments formed from the heteropolymer with a nanopore, comprising a computer with a central processor, and a program code, in particular the program code according to claim 14, wherein the computer is programmed to perform computer-implemented steps all amount to analyzing DNA to provide sequence information or detect allelic variants, which the courts regard as well-understood, routine, conventional activity. (see Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546).
There are no additional elements that comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-11 and 13-15 are not patent eligible.
Claim Rejections - 35 USC § 102
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.
The present rejection(s) reference specific passages from cited prior art. However,
Applicant is advised that the rejections are based on the entirety of each cited prior art. That is,
each cited prior art reference “must be considered in its entirety”. (See MPEP 2141.02(VI))
Therefore, Applicant is advised to review all portions of the cited prior art if traversing a
rejection based on the cited prior art.
Claim(s) 1-2, 5, 7-8, and 12 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Todd et al. (WO 2020131103 A1) as filed in the IDS on 7/12/2023.
Regarding claim 1, Todd teaches:
A method for identifying a sequence of monomer building blocks of a biological or synthetic heteropolymer (explicitly described as exploration and identification of proteins on page 1 lines 28-31), comprising the steps:
a) perform a fragmentation method in which the heteropolymer is broken down into fragments, thereby obtaining a fragment mixture whose fragments are molecules having different sequence segments of the heteropolymer (fragmentation step disclosed on page 2 lines 5-7);
b) perform a current measurement method in which current signals of a current through the channel of a nanopore are detected, wherein each current signal is based on the interaction of a fragment of the fragment mixture with the channel of the nanopore, wherein the current signals are characteristic of the different fragments such that a representative set of characteristic current signals representing the fragment mixture is determinable (electrical potential imparts an electrophoretic force which is generated by applying the electric potential across the nanopore wherein changes in ionic current is detected; also can determine the number of cleavage sites which yields the number of fragments on page 2 lines 7-20); and
c) perform an evaluation method in which a sequence of monomer building blocks of the heteropolymer is determined from the representative set of characteristic current signals (identification of the single protein (i.e. the heteropolymer) using cleaving proteases necessarily identifies the amino acids that build the protein on page 3 lines 11-22; examples seen process on page 13 lines 1-32).
Regarding claim 2, Todd teaches:
The method according to claim 1, wherein the fragments of the fragment mixture are obtained by enzymatic, chemical and/or physical methods and/or are obtained by successive degradation of the heteropolymer (see page 1 lines 5-8 for protease enzyme introduction for fragmentation).
Regarding claim 5, Todd teaches:
A method according to claim 1, for determining the primary structure of a macromolecule formed at least from heteropolymers, in particular a protein (explicit identification of amino acids as recited on page 10 lines 25-29), comprising the steps of:
i) cleavage of the macromolecule, in particular by enzymatic and/or chemical and/or physical cleavage, to obtain heteropolymers, in particular peptides, as cleavage products of the macromolecule (identification of the single protein (i.e. the heteropolymer) using cleaving proteases necessarily identifies the amino acids that build the protein on page 3 lines 11-22; examples seen process on page 13 lines 1-32); optionally: obtaining the heteropolymers by chromatographic or electrophoretic separation of a heteropolymer mixture obtained by the cleavage
ii) use of the method according to claim 1 for determining a sequence of monomer building blocks, in particular amino acids, of at least one, in particular each, of the heteropolymers (see citations above in addition to explicit identification of amino acids as recited on page 10 lines 25-29);
iii) perform a macromolecule recognition method in which the primary structure of the macromolecule is determined from a sequence listing of the at least one heteropolymer (identification of the single protein (i.e. the heteropolymer) using cleaving proteases necessarily identifies the amino acids that build the protein on page 3 lines 11-22; examples seen process on page 13 lines 1-32).
Of note, during patent examination, claims are given their broadest reasonable interpretation consistent with the specification. See MPEP 2111. Therefore, the optional limitation is interpreted to not be necessarily required and the prior art does not need to satisfy the limitation.
Regarding claim 7,
The method according to claim 1, wherein the nanopore is a solid-state nanopore or a hybrid of solid-state and biological components (solid-state nanopore recited on page 9 Lines 22-24).
Regarding claim 8,
The method according to claim 1, wherein the fragmentation of the heteropolymer is carried out by enzymes (protease examples seen on page 13 lines 1-32).
Regarding claim 12,
Use of a nanopore for performing the method for identifying a sequence of monomer building blocks of a biological or synthetic heteropolymer according to claim 1 (nanopores explicitly used in the identification pipeline on page 25-27).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The present rejection(s) reference specific passages from cited prior art. However,
Applicant is advised that the rejections are based on the entirety of each cited prior art. That is,
each cited prior art reference “must be considered in its entirety”. (See MPEP 2141.02(VI))
Therefore, Applicant is advised to review all portions of the cited prior art if traversing a
rejection based on the cited prior art.
Claim(s) 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Todd et al. (WO 2020131103 A1) as filed in the IDS on 7/12/2023 in view of Chait (US 6271037 B1).
Regarding claim 3,
Todd teaches the claimed invention substantially as stated above.
Todd does not teach the method according to claim 2, wherein the successive degradation of the heteropolymer provides that the heteropolymer is chain-like and, starting from one end of its chain, is stepwise shortened by one monomer building block to obtain length fragments, in particular substantially all length fragments n-(n-1), n-(n-2).... to n-(n-n), of a heteropolymer consisting of n monomer building blocks. Chait teaches the Edman degradation is the best available method to determine amino acid sequences of polypeptides and proteins via sequential amino terminal acid removal (i.e. fragmentation) (see explicit recitation of sequential degradation in Col. 1 Lines 55-64). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute Chait’s disclosure of Edman degradation into Todd’s identification pipeline as Edman degradation is taught to be one of the best available methods of degradation in the art as evidenced by Chait (see Col 1. Lines 52-56). This substitution would have been accomplished with reasonable expectation of success as the Edman degradation method is directed to the same problem in the same field of endeavor.
Regarding claim 4, Chait teaches:
The method according to claim 1, wherein the heteropolymer is a peptide and the fragmentation method is or includes Edman degradation (see explicit recitation of sequential degradation in Col. 1 Lines 55-64).
Claim(s) 6 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Todd et al. (WO 2020131103 A1) as filed in the IDS on 7/12/2023 in view of Clarke (Continuous base identification for single-molecule nanopore DNA sequencing. Nature Nanotech 4, 265–270 (2009) as filed in the IDS on 7/12/2023 further in view of the Beckman Institute for Advanced Science and Technology (Beckman Institute for Advanced Science and Technology. (2006, July 19). Bacterial toxin alpha-Hemolysin. Bacterial Toxin Alpha-Hemolysin. https://www.ks.uiuc.edu/Research/hemolysin/).
Regarding claim 6, Todd teaches:
The method according to claim 5, wherein the macromolecule is DNA, RNA, protein, peptide, or any synthetic polymer (single protein identification disclosed throughout; see page 3 lines 11-22). Todd does not teach wherein, in particular, the nanopore is a biological nanopore or a toxin or pore-forming toxin. Clarke teaches the αHL nanopore can be used in base identification for DNA sequencing (explicit disclosure of the staphylococcal α-haemolysin (αHL) protein pore in paragraph 3 on page 265). Therefore, it would have been obvious to one of ordinary skill in the art to substitute Clark’s nanopore into Todd’s identification pipeline as biological nanopores are a known alternative in sequencing pipelines as evidenced by Clark (description of the foundational concept of nanopore sequencing arose from a biological nanopore as disclosed in paragraph 3 on page 265). The Examiner notes that alpha-hemolysin is a type of beta-barrel protein as evidenced by the Beckman Institute for Advanced Science and Technology (see attached document). The substitution would have been accomplished with reasonable expectation of success as both disclosures are directed towards the same problem of sequencing via nanopores in the same field of endeavor.
Regarding claim 11, Clarke teaches:
The method according to claim 1, wherein the nanopore is aerolysin, alpha-hemolysin, VDAC, or other protein of the beta-barrel protein family (explicit disclosure of the staphylococcal α-haemolysin (αHL) protein pore in paragraph 3 on page 265). The Examiner notes that alpha-hemolysin is a type of beta-barrel protein as evidenced by the Beckman Institute for Advanced Science and Technology (see attached document).
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over Todd et al. (WO 2020131103 A1) as filed in the IDS on 7/12/2023 in view of Gyarmati et al. (P. Gyarmati, Y. Song, J. Hällman, M. Käller, Chemical fragmentation for massively parallel sequencing library preparation, Journal of Biotechnology, Volume 168, Issue 1, 2013, Pages 95-100).
Regarding claim 9,
Todd et al. teaches the claimed invention substantially as claimed above.
Todd does not teach the method according to claim 1. wherein the fragmentation of the heteropolymer is carried out chemically and non-enzymatically. Gyarmati teaches a method for
chemical fragmentation (e.g. iron-EDTA) in parallel sequencing pipelines. (see “Abstract” on page 95 for explicit recitation). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute Gyarmati’s fragmentation method into Todd’s identification pipeline in order to provide alternative methods of fragmentation which are essential for most library preparation protocols as evidenced by Gyarmati (see “Abstract” on page 95 for explicit recitation). The substitution could be accomplished with reasonable expectation of success as Todd already includes a fragmentation step in his identification pipeline and using a chemical non-enzymatic fragmentation method is a known alternative for a ubiquitous step in library preparation as discussed above.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Todd et al. (WO 2020131103 A1) as filed in the IDS on 7/12/2023 in view of Bayega et al. (Bayega, A., Fahiminiya, S., Oikonomopoulos, S., Ragoussis, J. (2018). Current and Future Methods for mRNA Analysis: A Drive Toward Single Molecule Sequencing. In: Raghavachari, N., Garcia-Reyero, N. (eds) Gene Expression Analysis. Methods in Molecular Biology, vol 1783. Humana Press, New York, NY).
Regarding claim 10,
Todd et al. teaches the claimed invention substantially as claimed above.
Todd et al does not teach the method according to claim 1, wherein the fragmentation of the heteropolymer is carried out physically, e.g. by exposure to heat, cold, sound waves, electromagnetic radiation, in particular infrared, ultraviolet or X-ray radiation, microwaves or visible light. Bayega discloses physical methods of fragmentation including acoustic shearing, sonication, and nebulization. (examples of physical fragmentation stated on page 213 in “2.5 cDNA fragmentation”). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute Bayega’s fragmentation method into Todd’s identification pipeline in order to provide alternative methods of fragmentation including enzymatic fragmentation which is used in Todd’s pipeline and physical fragmentation as evidenced by Bayega (see “page 213 in “2.5 cDNA fragmentation”). The substitution could be accomplished with reasonable expectation of success as Todd already includes a fragmentation step in his identification pipeline and using a physical fragmentation method is a known alternative for a ubiquitous step in library preparation as discussed above.
Claim(s) 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Todd et al. (WO 2020131103 A1) in view of Ouldali et al. (Electrical recognition of the twenty proteinogenic amino acids using an aerolysin nanopore. Nat Biotechnol 38, 176–181 (2020)) as filed in the on 7/12/2023.
Regarding claim 13, Todd teaches:
A computer-implemented method for determining a sequence of monomer building blocks of a heteropolymer, referred to as a heteropolymer sequence, from measurement data of a current measurement method containing information on current signals obtained upon interaction of different fragments formed from the heteropolymer with the channel of a nanopore (see rejection on claim 1; see also page 5 lines 25-31 for the computer-implemented method), comprising the steps of:
A) determine residual current values from the measurement data, wherein a residual current describes the interaction of one of the different fragments of the heteropolymer with the channel of a nanopore (nanopore is used to measure the number and length of peptide fragments cleaved on page 19 lines 14-16; mechanism described in further detail via electrical circuitry 110 that measures current as a fragment travels through the nanopore on page 20 lines 5-10);
B) statistically determine of a representative set of characteristic residual current values from the residual current values (probability determination step described on page 22 lines 22-23), a characteristic residual current value describing in each case one fragment type, in particular fragment size, of the number n of fragment types of a fragment mixture formed from the heteropolymer (bioinformatics model 113 describes a variety of characteristics via changes in ionic current (see page 22 line 8-10) including: identity of the fragments and concentration of fragments on page 22 lines 1-12; number of fragments detected on page 22 lines 24-25), the representative set uniquely describing the heteropolymer sequence. However, Todd does not teach the following method steps: C) sort the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence; and D) assign the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types. Ouldali et al. teaches a method of electrical recognition of amino acids in nanopores. Particularly, Ouldali teaches the steps of: sorting the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence (ionic currents are sorted in ascending order and the determination of value differences seen in Fig. 2e,2f comparing currents; see also “Simulation of relative residual current” for explanation on page 182) and assigning the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types (see Fig. 3a where fragments of an ionic current recording is assigned to individual peptide species; Fig. 3f illustrates sequence determination from current values; see paragraphs 5-6 on page 178 for explanation on identification method using current recordings). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute Ouldali’s fragmentation method into Todd’s identification pipeline in order to provide known method of sequence identification including ionic currents as evidenced by Ouldali (explicitly stated that a method of amino acid sequence identification includes that of nanopore ionic currents; see page 213 in “Main”). The substitution could be accomplished with reasonable expectation of success as Todd already includes a nanopore-based current detection step in his identification pipeline and merely including an ordering step wherein the current values are to associate with correlation data for identification is a known variation as discussed above.
Regarding claim 14, Todd as modified by Ouldali teaches:
A computer program code which is stored on a data carrier and which determines a sequence of monomer building blocks of a heteropolymer, referred to as heteropolymer sequence, from the measurement data of a current measurement method when executed by the central processor of a computer, the measurement data containing information on current signals which are determined upon the interaction of different fragments formed from the heteropolymer with a nanopore, comprising the respective steps implemented by program code (explicitly stated that a computer-readable medium would have program instructions stored on the device on page 5 lines 25-31):
A) determine residual current values from the measurement data, wherein a residual current describes the interaction of one of the different fragments of the heteropolymer with a nanopore; (Todd: nanopore is used to measure the number and length of peptide fragments cleaved on page 19 lines 14-16; mechanism described in further detail via electrical circuitry 110 that measures current as a fragment travels through the nanopore on page 20 lines 5-10);
B) statistically determine of a representative set of characteristic residual current values from the residual current values (Todd: probability determination step described on page 22 lines 22-23), a characteristic residual current value describing in each case one fragment type, in particular fragment size, of the number n of fragment types of a fragment mixture formed from the heteropolymer, the representative set describing the heteropolymer sequence unambiguously, but in any case sufficiently for a desired structure elucidation or structure prediction (Todd: bioinformatics model 113 describes a variety of characteristics via changes in ionic current (see page 22 line 8-10) including: identity of the fragments and concentration of fragments on page 22 lines 1-12; number of fragments detected on page 22 lines 24-25),;
C) sort the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence (Ouldali: ionic currents are sorted in ascending order and the determination of value differences seen in Fig. 2e,2f comparing currents; see also “Simulation of relative residual current” for explanation on page 182); and
D) assign the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types (Ouldali: see Fig. 3a where fragments of an ionic current recording is assigned to individual peptide species; Fig. 3f illustrates sequence determination from current values; see paragraphs 5-6 on page 178 for explanation on identification method using current recordings).
Regarding claim 15,
A data processing system for determining a sequence of monomer building blocks of a heteropolymer, referred to as heteropolymer sequence, from the measurement data of a current measurement method containing information on current signals determined upon interaction of different fragments formed from the heteropolymer with a nanopore, comprising a computer with a central processor, and a program code, in particular the program code according to claim 14, wherein the computer is programmed to perform the following computer-implemented steps (explicitly stated that a computer-readable medium would have program instructions stored on the device on page 5 lines 25-31; in addition, processing circuitry is described explicitly on page 5 lines 32-35):
A) determine residual current values from the measurement data, wherein a residual current describes the interaction of one of the different fragments of the heteropolymer with a nanopore; (Todd: nanopore is used to measure the number and length of peptide fragments cleaved on page 19 lines 14-16; mechanism described in further detail via electrical circuitry 110 that measures current as a fragment travels through the nanopore on page 20 lines 5-10);
B) statistically determine of a representative set of characteristic residual current values from the residual current values (Todd: probability determination step described on page 22 lines 22-23), a characteristic residual current value describing in each case one fragment type, in particular fragment size, of the number n of fragment types of a fragment mixture formed from the heteropolymer, the representative set describing the heteropolymer sequence unambiguously, but in any case sufficiently for a desired structure elucidation or structure prediction (Todd: bioinformatics model 113 describes a variety of characteristics via changes in ionic current (see page 22 line 8-10) including: identity of the fragments and concentration of fragments on page 22 lines 1-12; number of fragments detected on page 22 lines 24-25),;
C) sort the characteristic residual current values by their magnitude into a residual current value sequence and determining the current value differences of successive current values of the residual current value sequence (Ouldali: ionic currents are sorted in ascending order and the determination of value differences seen in Fig. 2e,2f comparing currents; see also “Simulation of relative residual current” for explanation on page 182); and
D) assign the current value differences to monomer building block types of the heteropolymer based on previously known correlation data containing information about which monomer building block type is represented by which current value amount to make the determination of the sequence of monomer building block types (Ouldali: see Fig. 3a where fragments of an ionic current recording is assigned to individual peptide species; Fig. 3f illustrates sequence determination from current values; see paragraphs 5-6 on page 178 for explanation on identification method using current recordings).
Conclusion
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/P.N./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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