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 .
Office Action: Notice
A request for continued examination under 37 CFR 1.114, including the fee set forth in
37 CFR 1.17(e), was filed in this application after final rejection. Since this application is
eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e)
has been timely paid, the finality of the previous Office action has been withdrawn pursuant to
37 CFR 1.114. Applicant's submission filed on 3/2/2026 has been entered.
Claim Status
Applicant amended claims 1, 8, and 14 (3/2/2026). Claims 7 and 16 were previously cancelled (7/16/2025). No new matter was added. Thus, claims 1-6 and 8-15 are under examination (3/2/2026).
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of 35 U.S.C. (pre-AIA ). See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosures of the prior-filed applications, Application Nos. EP 18/205046.8, EP 19177466.0 and PCT/EP2019/080592 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112 (pre-AIA ), first paragraph for one or more claims of this application. The application fails to provide support for the claims under examination, since there is no disclosure therein of the goal of a system comprising three main components; for processing information using a reversible algorithm, providing a library pf distinct oligonucleotide strings, and for assembly via permutation number; the incorporation of system-led goals is first disclosed in the PCT patent application, filed November 7, 2019. Therefore, claims 1-15 are deemed to have an effective filing date of November 7, 2018, the filing date of the earliest European Patent Application No. 18/205046.8. Claim 16 is deemed to have an effective filing date of November 7, 2019, the filing date of the PCT Patent Application No. PCT/EP2019/080592.
Rejections Withdrawn
Claim Rejections – 35 USC § 102
The 102 (a) (1) and 102 (a) (2) rejections of claims 1-6, 8-13 and 15 are withdrawn in view of Applicant’s arguments and significant amendments (3/2/2026). Specifically, newly amended independent claim 1 requires a single, uniquely decodable ordered linear chain of oligonucleotide sequences with exclusive head-to-tail adjacency, which Roquet does not expressly or inherently disclose under the broadest reasonable interpretation.
New Rejections
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 1-6 and 8-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The claims recite and place emphasis on methods for storing digital information in DNA using permutation algorithms, as well as rules of organizing information, via assembling oligonucleotide strings into strands and braids, and converting information into permutation numbers using mathematical formulas. Further, the instant claims are directed to methods of collecting and analyzing information (particularly digital data) and mathematical calculations.
The integration of the judicial exception into the claims does not render them patent eligible because the claims are written at a high level of generality and merely use well-known, routine, and conventional techniques in the field. Specifically, the instant claims recite generic computer-implemented steps for DNA data storage, oligonucleotide assembly, and mathematical calculations that are conventional in the biotechnology and bioinformatics field.
Subject Matter Eligibility Test for Products and Processes
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES.
The claims provide for a method comprising:
processing units of information into permutation numbers by reversible algorithms;
providing a library of n distinct oligonucleotide strings of predetermined length in a fixed order, wherein n is a positive integer, wherein each distinct oligonucleotide string is associated with a distinct index indicating the ordinal position; and
assembling distinct oligonucleotide strings to create strands comprising at least two oligonucleotide strings.
Thus, the claims are directed to statutory categories (i.e., processes).
Step 2A, Prong One — Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES.
Abstract ideas have been identified by the courts by way of example, including fundamental economic practices, certain methods of organizing human activities, an idea ‘of itself,’ and mathematical relationships/formulas. The claims recite a judicial exception. The “mental process” of determining data storage methods for storing information in nucleic acids and assembling oligonucleotide strings through mathematical analysis and making arrangement decisions based on calculated permutation numbers corresponds “an abstraction” (an idea having no particular concrete or tangible form). The mathematical concepts involving permutation algorithms, indexing calculations, braid assembly patterns, and algorithmic equations used to organize oligonucleoside are abstract ideas. Thus, the claimed invention describes a judicial exception, which correspond to abstractions (ideas, having no particular concrete or tangible form) and mathematical relationships.
Step 2A, Prong Two — Does the Claim Recite an Additional Elements that Integrate the Judicial Exception into a Practical Application? NO.
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. However, absent are any additional elements recited in the claim beyond the judicial exceptions which integrate the exception into a practical application of the exception. The “integration into a practical application” requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception.
The claim limitations are considered to be; (a) a mental process of calculating permutation numbers and DNA assembly using mathematical formulars and algorithmic analysis, and (b) data gathering steps for obtaining oligonucleotide information (i.e., abstract ideas).
While the claims recite steps of “providing a library”, “assembling oligonucleotides”, “creating strands with braids”, “performing library construction and sequencing” and “annealing strands”, these steps are recited at a high level of generality and amount to mere data gathering steps, including the sequencing of nucleic acids. There are no additional steps which apply either of the identified judicial exceptions into a practical application. Thus, the claims do not provide for any element/step that integrates the law of nature into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to “significantly more” than the judicial exception(s) itself. The claims as a whole are analyzed to determine whether any additional element/step, or combination of additional elements/steps, in addition to the identified judicial exception(s) is sufficient to ensure that the claim amounts to “significantly more” than the exception(s).
However, the additional elements of the instant application, individually and in combination, do not amount to “significantly more.” Under the Step 2B analysis, the “physical” elements/steps of, “providing a library”, “assembling oligonucleotides”, “creating braids”, “performing PCR amplification”, “annealing strands” and “calculating permutation numbers” are “physical” steps telling a practitioner to simply implement the abstract idea and are considered to be within the purview of one in the art as being routine and conventional in the art when investigating DNA data storage systems.
For example, Yazdi et al. discloses (“A Rewritable, Random-Access DNA-Based Storage System”, Scientific Reports, published 9/18/2015), the first DNA-based storage architecture that enables random access to data blocks and rewriting of information stored at arbitrary locations within the blocks, which overcomes drawbacks of existing read-only methods that require decoding the whole file in order to read one data fragment (Abstract). Further, Yazdi discloses that due to dynamic changes in biotechnological systems, none of the three coding schemes represents a suitable solution from the perspective of current DNA sequencer designs: Huffman codes are fixed-to-variable length compressors that can lead to catastrophic error propagation in the presence of sequencing noise; the same is true of differential codes and further homopolymers do not represent a significant source of errors in Illumina sequencing platforms, while single parity redundancy or RS codes and differential encoding are inadequate for combating error-inducing sequence patterns such as long substrings with high GC content (Introduction: Paragraphs 2-3). Yazdi also discloses that the main feature of the new storage architecture which enables highly sensitive random access and accurate rewriting is addressing; specifically, the rationale behind the proposed approach is that each block in a random-access system must be equipped with an address that will allow for unique selection and amplification via DNA sequence primers (Results: Paragraph 1), establishing these forms of storage techniques for DNA analyses as conventional techniques.
Further, Ouahabi et al. (“Mass spectrometry sequencing of long digital polymers facilitated by programmed inter-byte fragmentation”, Nature Communications, published 10/17/2017) discloses, a method, of analyzing intact multi-byte digital polymers that can be sequenced in a moderate resolution mass spectrometer and that full sequence coverage can be attained without requiring pre-analysis digestion or the help of sequence databases via polymers that are designed to undergo controlled fragmentations in collision-induced dissociation conditions (Abstract). Further Ouahabi discloses that digital polymers can be used to store digital information, since the monomer units that constitute the chains are used as molecular bits and assembled through controlled synthesis into readable digital sequences and that these ordered oligonucleotide sequences enable storage of several kilobytes of data in DNA chains (Introduction: Paragraphs 1-2). These detailed design and synthesis of digital storage blocks (Figure 1) demonstrate that practitioners were well-versed in creating storage techniques and systems for nucleic acids using algorithmic models.
Further, Xie et al. (“A note on using permutation-based false discovery rate estimates
to compare different analysis methods for microarray data”, Bioinformatics, published 9/2005) discloses that DNA microarrays are biotechnologies that allow highly parallel and
simultaneous monitoring of the whole genome and are used to detect genes expressed differentially under different conditions using two steps are used to declare differentially expressed (DE) genes: first, one computes a summary or test statistic (i.e., the sample mean) for each gene and rank the genes in order of their test statistics; second, one chooses a threshold for the test statistics and call genes whose statistics are above the threshold ‘significant’ ones (Introduction: Paragraph 1). Further, Xie discloses that some regularized statistics, such as the SAM-statistic perform well for microarray data, but their null distributions are in general unknown; per mutation methods have become popular to estimate null distributions owing to their flexibility and generality; however, there are some problems when using permutation to estimate null distributions for microarray data (Introduction: Paragraphs 2-3). Also, Xie discloses that the bias depends on the test statistic being used, caution should be used when using estimated false discovery rate as a criterion to evaluate the performance of various test statistics. (Discussion: Paragraphs 1-2), thus establishing a high level of routine and convention for calculating permutation numbers.
Therefore, performing sequencing reactions, determining statistical measures, comparing read coverage to thresholds, and calculating required sample amounts was routine and conventional before the effective filing date of the claimed invention.
Simply appending routine and conventional activities previously known to the industry specified at a high level of generality to the judicial exception and/or generally linking the use of the judicial exception(s) to a particular technological environment or field of use, are not found to be enough to qualify as “significantly more.” Nothing is added by identifying the techniques to be used (i.e., “providing a library”, “assembling oligonucleotides”, “creating braids”, “performing PCR amplification”, “annealing strands” and “calculating permutation numbers”) because those techniques were well-understood, routine, and conventional techniques that a practitioner would have thought of when instructed to process and analyze DNA samples for data storage applications. In context with the other recited claim limitations, the language describes mathematical calculations for determining permutation-based indexing and DNA assembly patterns that merely indicate whether or not the relationship/correlation between digital information data and physical DNA storage capability exists.
This information simply tells a practitioner about the relevant statistical relationships between DNA oligonucleotide patterns and data storage capability, at most adding a suggestion that the data storage practitioner should take those relationships into account. Thus, when viewed both individually and as an ordered combination, the claimed elements/steps in addition to the identified judicial exception are found insufficient to supply an inventive concept because the elements/steps are considered conventional and specified at a high level of generality. The claim limitations do not transform the abstract idea that they recite into patent-eligible subject matter because “the claims simply instruct the practitioner to implement the abstract idea with routine, conventional activity.”
Accordingly, the claims do not qualify as patent-eligible subject matter.
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 1-6 and 8-15 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.
Claim 1 is rejected. Claim 1 recites the limitation "the terminal string" in line 23. There is insufficient antecedent basis for this limitation in the claim.
Claims 2-6 and 8-15 are included in this rejection due to their dependency on claim 1.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6 and 8-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Roquet et al. (US PGPub 2018/0137418; published 5/17/2018), in view of Qi et al. (“DNA-directed self-assembly of shape-controlled hydrogels”, Nature Communications, published 2013) and in further view of Chandran et al. (“An autonomously self-assembling dendritic DNA nanostructure for target DNA detection”, Biotechnology Journal, published 2013).
Regarding claim 1, Roquet teaches methods and systems for encoding digital information in nucleic acid (i.e., deoxyribonucleic acid) molecules without base-by-base synthesis, by encoding bit-value information in the presence or absence of unique nucleic acid sequences within a pool, comprising specifying each bit location in a bit-stream with a unique nucleic sequence and specifying the bit value at that location by the presence or absence of the corresponding unique nucleic acid sequence in the pool (Abstract). Further, Roquet teaches that the previously described method is processed via reversible recombination or algorithms (Paragraph 98, lines 5-10) and implemented by way of software upon execution by the central processing unit (1905; Paragraph 179, lines 5-10). Roquet teaches an identifier library as determined by sequencing (Figure 18A; Paragraph 182, lines 1-5) composed of a certain number of constructed identifiers or distinct oligonucleotides directed to undergo one or more subsequent reactions to add barcodes, common sequences, variable sequences, numbers, or tags to one or more ends of the identifiers and then be directed to a region or partition to generate an identifier library (Paragraph 163, lines 10-20). Specifically, Roquet teaches that an identifier or distinct oligonucleotide from an identifier library may comprise sequences on one or both of its ends that are distinct to that library, thus enabling a single library to be selectively accessed from a pool or group of more than one identifier libraries (Figure 17A; Paragraph 139, lines 10-20). Further, Roquet teaches that the nucleic acid molecule can have various lengths; including single-stranded or double-stranded or having two strings (Paragraph 62-63).
Roquet also teaches a permutation scheme (Figures 11A-11G), for constructing identifiers or distinct oligonucleotides with permuted components (i.e., nucleic acid sequences), composed of hyper-pools, a particular subset of information or data bearing portion (i.e., all nucleic acids relating to a particular barcode) can be accessed and retrieved by using a primer or braid that binds the specific barcode or braid-like series at one edge of the identifier in the forward orientation or ordinal position, along with another primer that binds a common sequence or semantic part on the opposite edge of the identifier in a reverse orientation (Paragraph 138, lines 5-10).
Specifically, Roquet teaches that the previously described library is composed of a parent sequence or head braid that comprises components flanked by nuclease-specific target sites (which can be 4 or less bases in length), and where the parent may be incubated with one or more double-strand-specific nucleases or terminal braid corresponding to the target sites or starter string therefore allowing an individual component to be targeted for deletion with a complementary single stranded DNA (or cleavage template) that binds the component DNA (and flanking nuclease sites) on the parent or head braid, thus forming a stable double stranded sequence on the parent that may be cleaved on both ends by the nucleases (Figure 15B; Paragraph 112, lines 1-5). Further, Roquet teaches that each parent sequence or head braid is embedded with a distinct nucleic acid sequence (Paragraph 114, lines 1-5) and therefore allowing encoding of binary sequence data using nucleic acids (Paragraph 27, lines 1-3).
Regarding claim 2, Roquet teaches that the previously described method of storing information is composed of barcodes that can facilitate information indexing when the amount of digital information to be encoded exceeds the amount that can fit in one pool alone, including information comprising longer strings of bits and/or multiple bytes can be encoded by layering (Figure 3; Paragraph 118, lines 1-5).
Regarding claim 3, Roquet teaches that the previously described permutation method includes templates or staples exist for any possible junction between any two layers or integers or scaffolds such that the order in which components from different layers are incorporated or shortened via size selection into an identifier in the reaction depends on the templates selected for the reaction in order to enable any possible partial permutation of layers (Figure 11C; Paragraph 103, lines 1-10).
Regarding claims 4-6, Roquet teaches that the previously described method of storing information is composed of identifiers or distinct oligonucleotides with permuted and repeated components to form a layer or rope that may be present multiple times in an identifier as a braid via using a staple with adjacent complementary hybridization regions for both the 3′ end and 5′ end of the same component (Figures 11D-G; Paragraph 104, lines 1-10). Additionally, Roquet teaches that the previously described library includes either double stranded portions or single stranded versions that can anneal or glue to the staples or braids for more complex identifiers or oligonucleotides that can later be used or implemented in an algorithmic or Cartesian format (Paragraph 179, lines 5-10).
Specifically, Roquet teaches that the within the previously described library, the braids can be created to represent a partial permutation of layers or templates via concatenated in any order with an integer number of layers, each with an integer number of components, therefore the permutation scheme enables a combinatorial space (Figures 11A-B; Paragraph 102, lines 1-5).
Regarding claim 8, Roquet teaches that the previously described library of distinct oligonucleotides or identifiers is composed of linearly increased or assembled sample set (Paragraph 127, lines 5-10) and is generated from three layers each comprising three distinct components in a fixed order (Figures 6A-6B; Paragraph 91, lines 1-8). Further, Roquet teaches that enzymatic reactions may be used to assemble components from the different layers or sets and assembly can occur in a one pot reaction because components (i.e., nucleic acid sequences) of each layer have specific hybridization or attachment regions for components of adjacent layers including a nucleic acid sequence (i.e., component) X1 from layer X (i.e., head string), a nucleic acid sequence Y1 from layer Y (i.e., terminal string), and a nucleic acid sequence Z1 from layer Z (i.e., center string) may form the assembled nucleic acid molecule (i.e., identifier) X1Y1Z1 or distinct oligonucleotide (Paragraph 93, lines 1-5).
Roquet teaches that the previously described method of storing information is composed of identifiers or distinct oligonucleotides with permuted and repeated components to form a layer or rope that may be present multiple times in an identifier as a braid via using a staple with adjacent complementary hybridization regions for both the 3′ end and 5′ end of the same component (Figures 11D-G; Paragraph 104, lines 1-10). Additionally, Roquet teaches that a component from layer Z or string may be annealed with the generated nucleic acid molecule and may be extended to generate a unique identifier comprising a single component from layers X, Y, and Z in a fixed order via DNA size selection or specified integer using polymerase chain reaction (PCR) with primers or ropes flanking the outer most layers may be implemented to isolate identifier products from other byproducts that may form in the reaction (Paragraph 94, lines 10-20).
Regarding claim 9, Roquet teaches that the previously described method of library assembly includes sticky end ligation or a method of gluing via single-stranded 3′ overhangs or oligonucleotides that are used to assemble distinct identifiers via combining strings through a common or complementary 3′ overhang (Figure 8). Specifically, Roquet teaches that the 3′ overhang in one string can be complementary to the 3′ end in another string and the other 3′ overhang in a separate string can be complementary to the 3′ end in a third string allowing the components to hybridize and ligate via gluing (Paragraph 95, lines 1-10). Further, Roquet teaches that this methodology of single-stranded annealing ensures distinct or complete identifiers or oligonucleotides (Paragraph 95, line 10).
Regarding claims 10-11, Roquet teaches that the previously described method of library assembly includes a separate step of instances where the sample comprises hyper-pools, a particular subset of information (i.e., all nucleic acids relating to a particular barcode) can be accessed and retrieved by using a primer that binds the specific barcode at one edge of the identifier in the forward orientation, along with another primer that binds a common sequence on the opposite edge of the identifier in a reverse orientation (Paragraph 138, lines 5-10). Further, Roquet teaches that the distinct oligonucleotides or identifiers include (1) an identification barcode or coding sequence, (2) a hybridization region for staple-mediated ligation of the 5′ end to a scaffold or primer, and (3) a hybridization region for staple mediated ligation of the 3′ end to a scaffold or primer (Paragraph 109, lines 10-20).
Roquet also teaches that checksum sequences may indicate whether identifiers or distinct oligonucleotides are missing from a sampling of the identifier library or an accessed portion of the identifier library and via PCR or affinity tagged probe hybridization may amplify and/or isolate braids after library assembly (Paragraph 155, lines 10-15).
Regarding claim 12, Roquet teaches that the previously described method of library assembly includes a separate step, prior to decoding the information, the identifiers or distinct oligonucleotides may be enriched from the supplemental nucleic acid sequences via enrichment by a nucleic acid amplification reaction using primers specific to the identifier ends as a pool by sequencing (i.e., sequencing by synthesis) using a specific primer (Paragraph 157, lines 1-5).
Regarding claim 13, Roquet teaches that the previously described method of library assembly includes sticky end ligation or a method of gluing via single-stranded 3′ overhangs or oligonucleotides that are used to assemble distinct identifiers via combining strings through a common or complementary 3′ overhang (Figure 8). Specifically, Roquet teaches that the 3′ overhang in one string can be complementary to the 3′ end in another string and the other 3′ overhang in a separate string can be complementary to the 3′ end in a third string allowing the components to hybridize and ligate via gluing (Paragraph 95, lines 1-10). Further, Roquet teaches that this methodology of single-stranded annealing ensures distinct or complete identifiers or oligonucleotides (Paragraph 95, line 10). Additionally, Roquet teaches that the previously described library includes either double stranded portions or single stranded versions that can anneal or glue to the staples or braids for more complex identifiers or oligonucleotides that can later be used or implemented in an algorithmic or Cartesian format (Paragraph 179, lines 5-10). Additionally, Roquet teaches that steps for retrieving digital data can comprise sequencing a nucleic acid sample or nucleic acid pool comprising sequences of nucleic acid (i.e., identifiers or distinct oligonucleotides) that map to one or more bits, referencing an identifier rank to confirm if the identifier is present in the nucleic acid pool and decoding the location and bit-value information for each sequence into a byte comprising a sequence of digital information (Paragraph 161, lines 1-10).
Regarding claim 15, Roquet teaches that the previously described library for data storage is processed via reversible recombination or algorithms (Paragraph 98, lines 5-10) and implemented by way of software upon execution by the central processing unit (1905; Paragraph 179, lines 5-10).
Roquet does not teach or suggest a single, uniquely decodable, ordered chain of nucleic acid components per data unit defined by exclusive one-to-one head-to-tail adjacency relationships, but instead relies on combinatorial pool-based identifiers lacking a deterministic linear arrangement.
Qi teaches using DNA as programmable, sequence-specific ‘glues’, shape-controlled hydrogel units are self-assembled into prescribed structures, and specifically report that aggregates are produced using hydrogel cubes with edge lengths ranging from 30 μm to 1 mm, demonstrating assembly across scales (Abstract). Further, Qi teaches a simple one-pot agitation reaction, 25 dimers are constructed in parallel from 50 distinct hydrogel cube species, demonstrating highly multiplexed assembly, where using hydrogel cuboids displaying face-specific DNA glues, diverse structures are achieved in aqueous and in interfacial agitation systems (Abstract). Specifically, Qi teaches that for the dimer experiments (Figure 5b), two copies of each component were included; for the linear (Figure 5c), T-junction (Figure 5d) and square (Figure 5e) structures, only one copy of each component was included, where assembly of each system was tested for three times or more, and all together more than 20 experiments were performed for these structures and out of these more than 20 experiments, the intended structure always formed as desired (Interfacial self-assembly of hydrogel to complex structures: Paragraph 2). Qi also teaches that it is important to note that such systems (involving only one copy of each component) are significantly simpler than systems that involve multiple copies of the same components and this experiment formed two copies of the T-junction (Interfacial self-assembly of hydrogel to complex structures: Paragraph 2).
Chandran teaches that responsive and programmable DNA nanostructures have shown great promise as chemical detection systems and specifically describes a DNA detection system employing the triggered self-assembly of a novel DNA dendritic nanostructure where the detection protocol is executed autonomously without external intervention (Abstract). Specifically, Chandran teaches that detection begins when a specific, single-stranded target DNA strand (T) triggers a hybridization chain reaction (HCR) between two, distinct DNA hairpins (α and β) where each hairpin opens and hybridizes up to two copies of the other, and in the absence of T, α and β are stable and remain in their poised, closed-hairpin form, conversely in the presence of T,α hairpins are opened by toe-hold mediated strand-displacement, each of which then opens and hybridizes two β hairpins (Abstract). Further, Chandran teaches that the target sequence for the first version of this system needed to have a repeated subsequence and the detection system was further modified for detection of any arbitrary target sequence (T 2) by introducing a third hairpin, γ (Fig. 2), where the system was also tested for the detection of unique sequence identifiers of HIV (human immunodeficiency virus) and Chlamydia trachomatis pathogens (Figure 1; Introduction: Paragraphs 3-4; Design of the dendritic HCR system).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Roquet in view of Qi and in further view of Chandran. Roquet teaches encoding information in nucleic acid sequences using assembled oligonucleotide components (braids) formed via hybridization, ligation, and amplification (PCR), thereby providing the foundational framework for constructing ordered nucleic acid assemblies representing data. However, Roquet does not explicitly emphasize controlled structural self-assembly or predictable physical organization of such components in higher-order constructs. One of ordinary skill in the art would have been motivated to incorporate the teachings of Qi and Chandran to improve the predictability, structural control, and efficiency or assembling nucleic acid components, particular more reliable and programmable formation of ordered assembles taught by Roquet. Such a modification would have been desirable because controlling hybridization interactions and assembly pathways was well-known to enhance fidelity, reduce errors, and enable scalable construction of nucleic acid structures, which directly aligns with Roquet’s goal of encoding and retrieving information.
Further, one of ordinary skill in the art would have had a reasonable expectation of success in making this combination because all references operate within the same field of nucleic acid hybridization, rely on well-understood Watson-Crick basepairing principles, and use compatible techniques such as PCR amplification, strand displacement, and sequence-directed assembly. The substitution of known hybridization-driven assembly strategies (Qi, Chandran) into Roquet’s system merely applies predictable prior art elements according to their established functions (see MPEP 2143), yielding no more than the expected result of improved control over the arrangement and interaction of nucleic acid components.
Applicant’s Response: The Applicant argues that Roquet does not teach a single, uniquely decodable ordered chain of braids defined by strict structural constraints, including a starter string appearing only once as a head, a terminal string appearing only once as a tail, and exclusive one-to-one head-to-tail adjacency across intermediate braids. The Applicant further contends that Roquet instead relies on combinatorial identifier pools and does not inherently produce a single deterministic linear arrangement. Accordingly, the Applicant asserts that the amended claims introduce structural limitations not taught or suggested by Roquet and therefore overcome the rejection.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully and fully considered and are found to be partially persuasive, as discussed below.
The new 35 USC 103 rejection, as shown above, incorporates the teachings of Roquet in view of Qi and Chandran. While Roquet may not explicitly disclose a single, uniquely decodable ordered chain with strict one-to-one head-to-tail adjacency, Qi and Chandran collectively teach sequence-programmed, highly controlled nucleic acid assembly using specific hybridization interactions (i.e., DNA “glues”, toehold-mediated strand displacement) that inherently enable deterministic and ordered connectivity between components.
It would have been obvious to one of ordinary skill in the art to apply these known controlled hybridization and assembly strategies to the system of Roquet in order to improve predictability and enforce defined connectivity between nucleic acid components, thereby yielding a single ordered chain as claimed. The modification merely involves the predictable use of prior art elements according to their established functions to achieve improved structural control and decoding reliability (see MPEP 2143). Accordingly, the combined teachings render the claimed limitations obvious, and are newly rejected under 35 USC 103.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Roquet et al. (US PGPub 2018/0137418; published 5/17/2018) in view of Qi et al. (“DNA-directed self-assembly of shape-controlled hydrogels”, Nature Communications, published 2013) and in further view of Chandran et al. (“An autonomously self-assembling dendritic DNA nanostructure for target DNA detection”, Biotechnology Journal, published 2013), as applied to claims 1-6, 8-13 and 15 above, in view of Zhao (“GC content variability of eubacteria is governed by the pol III α subunit”, Biochemical and Biophysical Research Communications, published 4/27/2007). The rejection has been modified as a result of Applicant’s amendments (3/2/2026).
As described above, Roquet teaches methods and systems for encoding digital information in nucleic acid (i.e., deoxyribonucleic acid) molecules without base-by-base synthesis, by encoding bit-value information in the presence or absence of unique nucleic acid sequences within a pool, comprising specifying each bit location in a bit-stream with a unique nucleic sequence and specifying the bit value at that location by the presence or absence of the corresponding unique nucleic acid sequence in the pool (Abstract). Further, Roquet teaches that the previously described method is processed via reversible recombination or algorithms (Paragraph 98, lines 5-10) and implemented by way of software upon execution by the central processing unit (1905; Paragraph 179, lines 5-10). Roquet teaches an identifier library as determined by sequencing (Figure 18A; Paragraph 182, lines 1-5) composed of a certain number of constructed identifiers or distinct oligonucleotides directed to undergo one or more subsequent reactions to add barcodes, common sequences, variable sequences, numbers, or tags to one or more ends of the identifiers and then be directed to a region or partition to generate an identifier library (Paragraph 163, lines 10-20). Specifically, Roquet teaches that an identifier or distinct oligonucleotide from an identifier library may comprise sequences on one or both of its ends that are distinct to that library, thus enabling a single library to be selectively accessed from a pool or group of more than one identifier libraries (Figure 17A; Paragraph 139, lines 10-20). Further, Roquet teaches that the nucleic acid molecule can have various lengths; including single-stranded or double-stranded or having two strings (Paragraph 62-63).
Further, Qi teaches using DNA as programmable, sequence-specific ‘glues’, shape-controlled hydrogel units are self-assembled into prescribed structures, and specifically report that aggregates are produced using hydrogel cubes with edge lengths ranging from 30 μm to 1 mm, demonstrating assembly across scales (Abstract). Further, Qi teaches a simple one-pot agitation reaction, 25 dimers are constructed in parallel from 50 distinct hydrogel cube species, demonstrating highly multiplexed assembly, where using hydrogel cuboids displaying face-specific DNA glues, diverse structures are achieved in aqueous and in interfacial agitation systems (Abstract). More so, Chandran teaches that responsive and programmable DNA nanostructures have shown great promise as chemical detection systems and specifically describes a DNA detection system employing the triggered self-assembly of a novel DNA dendritic nanostructure where the detection protocol is executed autonomously without external intervention (Abstract).
Regarding claim 14, Roquet teaches that the previously described library for data storage includes a sequencing platform that may decode nucleic acid encoded data by reading individual bases (i.e., base-by-base sequencing) or by detecting the presence or absence of an entire nucleic acid sequence (Paragraph 154, lines 1-5). Further, Roquet teaches that the supplemental nucleic acid sequences may have an average length that is within one base, within two bases, within three bases, within four bases, within five bases, within six bases, within seven bases, within eight bases, within nine bases, within ten bases, or within more bases of the average length of the identifiers (Paragraph 123, lines 1-5). Further, Roquet teaches that three sample sets (X, Y, and Z) or data-bearing distances (i.e., Hamming, Levenshtein) each containing two nucleic acid sequences may assemble into eight unique nucleic acid molecules or bases (Paragraph 128, lines 1-2). Roquet also teaches that template or annealing strands range from 10 to 30 bases in length (Paragraph 100, lines 1-20).
Roquet, Qi and Chandran do not teach or suggest a specified range of GC content (0.35-0.75) in which the previously mentioned DNA data storage technique encompasses.
Zhao teaches that eubacterial genomes have highly variable GC content (0.17–0.75) and the primary mechanism of such variability remains unknown (Abstract). See § MPEP 2141. Further, Zhao teaches that the most important intrinsic factor is mutational bias that may come from two basic sources: DNA replication or repair errors and horizontal gene transfer (Introduction: Paragraphs 1-2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Roquet, incorporating the hybridization-driven assembly strategies of Qi and Chandran, to include and/or encompass oligonucleotide sequences with GC content between 0.50 and 0.55 as taught by Zhao for optimizing DNA storage applications. One would be motivated to do so because Zhao’s teachings demonstrate that GC content variability is a fundamental factor affecting nucleic acid characteristics, and that eubacterial genomes successfully function with GC content in the range of 0.17-0.75. Furthermore, Roquet’s teachings demonstrate that such optimization technique can be successfully applied in various DNA storage contexts and Zhao’s GC content range comes from the need for optimization and precise control in designing oligonucleotides with predictable characteristics for reliable data storage applications.
Further, one would have a reasonable expectation of success because the combination would provide the advantage of enabling predictable and optimized oligonucleotide sequences for DNA data storage from the library, enhancing the specificity, efficiency and utility of the method for applications such as digital information storage since GC content optimization is a swell-established technique in molecular biology and Zhao, specifically, provides a clear framework for determining suitable GC content ranges for nucleic acid applications.
Applicant’s Response: The Applicant argues that dependent claim 14 rejected under Roquet in view of Zhao, remains allowable because Roquet fails to teach the common limitations as explained above for amended independent claim 1, and Zhao does not remedy these deficiencies. Specifically, Zhao’s teachings regarding GC content variability governed by the pol III subunit does not teach or suggest the claimed features. Therefore, the combination of Roquet and Zhao fails to teach or suggest the limitations of claim 14, rendering it allowable.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully and fully considered but are not found -persuasive, as discussed below.
Although the Applicant argues that Zhao does not remedy the deficiencies of Roquet, the new rejection relies on the combined teachings of Roquet in view of Zhao, further in view of Qi and Chandran. Further, Roquet does teach encoding digital information using distinct oligonucleotide sequences in a library of varying lengths, including single or double stranded molecules (Paragraphs 62-63, 98, 163 and 182), as discussed above. Roquet further teaches that supplemental nucleic acid sequences may be used in data storage platforms that decode information by sequencing bases (Paragraphs 114, 128, 138).
While Roquet does not directly teach a specified GC content range, Zhao teaches that bacterial genomes have highly variable GC content between 0.17 and 0.75, and that GC content optimization is a fundamental factor affecting nucleic acid stability and function (Abstract; Introduction: Paragraphs 1-2). One of ordinary skill in the art would have been motivated to incorporate Zhao’s GC content range into Roquet’s DNA storage system to enhance reliability, predictability, and efficiency of oligonucleotide design. See MPEP 2141 for obviousness analysis and motivation to combine. Therefore, Zhao teaches a clear framework for determining suitable GC ranges, and Roquet teaches that such optimization techniques are applicable to DNA data storage.
Additionally, Qi teaches DNA as programmable, sequence-specific “glues” enabling controlled self-assembly of nucleic acid structures (Abstract), and Chandran teaches hybridization-driven assembly (i.e., strand displacement and hybridization chain reaction) for forming predictable DNA nanostructures. These references collectively demonstrate that sequence design parameters, including hybridization behavior and stability, were well understood and routinely optimized by one of ordinary skill in the art.
Accordingly, it would have been obvious to modify Roquet to include oligonucleotide sequences with GC content in the range of 0.50 and 0.55 as claimed, because Zhao teaches the relevance and necessity of this range for reliable nucleic acid applications. Further, selecting the appropriate range would act to optimize amplification efficiency, stability, and hybridization performance, as further supported by Qi and Chandran’s teachings regarding predictable and programmable nucleic acid assembly. Such optimization represents the routine selection of a result-effective variable (MPEP 2144.05).
Furthermore, one would have had a reasonable expectation of success because the cited references consistently demonstrate that nucleic acid sequence properties, including GC content, directly influence hybridization, amplification, and structural assembly, and that these parameters can be predictably adjusted to achieve desired performance characteristics. See MPEP 2143 regarding reasonable expectation of success. Therefore, the 35 USC 103 rejection of claim 14 over Roquet in view of Zhao, and in further view of Qi and Chandran, is maintained.
Conclusion
No claim is allowed.
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/ELIZABETH ROSE LAFAVE/Examiner, Art Unit 1684
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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