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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/16/2025 has been entered.
Claim Status and Formal Matters
This action is in response to papers filed 7/16/2025.
Claims 1 and 6 have been amended.
Claim 83-85 have been added by amendment.
Claims 1, 6, 9-10, 12, 14, 83-85 are being examined.
Applicant’s election without traverse of group 1, claims 1, 6, 9-10, 12, 14, 82 in the reply filed on 4/11/2024 is acknowledged.
Applicant elects "the barcodes encode spatial information". At least claims 1, 6, 9-10, 12, 14, and new claim 82 are readable on the elected species. For the species of "a barcode of the first or second nucleic acid", Applicant elects "the first nucleic acid is selected from a library having a minimum Hamming distance of 4". At least claims 1, 6, 9-10, 12, 14, and new claim 82 are readable on the elected species.
Claims 41, 43, 44, 46, 48, 51, 53, 59, 63, 67, 69, 70, 74, and 80 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/11/2024.
Priority
The instant application was filed 04/29/2021 and is a National Stage entry of PCT/US19/59484 with an International Filing Date: 11/01/2019 and claims priority from provisional application 62754450 , filed 11/01/2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on8/20/2021are being considered by the examiner.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required:
Claim 1 has been amended to recite, “a first nucleic acid comprising a first barcode flanked by a first crosslinking strand and a first complementary strand, and (2)a second nucleic acid comprising a second barcode flanked by a second crosslinking strand and a second complementary strand, wherein the first and second crosslinking strands each comprise a photoreactive element, wherein the first complementary strand of the first nucleic acid hybridizes to the second crosslinking strand of the second nucleic acid, or wherein the first crosslinking strand of the first nucleic acid hybridizes to the second complementary strand of the second nucleic acid.” The response asserts, “claim 1 is amended to refer to "A method of producing a concatemer of barcodes" in the preamble and to remove the phrases related to "writing or storing data", thus obviating the rejection. Such an amendment is supported throughout the application as filed (see e.g., par. [0037], [0044], [0047], FIG. 1D, FIG. 8, FIG. 11).” The cited portion and drawings do not provide antecedent basis for the limitations. Thus the amendment has introduced new matter.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim1, 6, 9-10, 12, 14, 83-85 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite, “a first nucleic acid comprising a first barcode flanked by a first crosslinking strand and a first complementary strand, and (2)a second nucleic acid comprising a second barcode flanked by a second crosslinking strand and a second complementary strand, wherein the first and second crosslinking strands each comprise a photoreactive element, wherein the first complementary strand of the first nucleic acid hybridizes to the second crosslinking strand of the second nucleic acid, or wherein the first crosslinking strand of the first nucleic acid hybridizes to the second complementary strand of the second nucleic acid.”.” The response asserts, “claim 1 is amended to refer to "A method of producing a concatemer of barcodes" in the preamble and to remove the phrases related to "writing or storing data", thus obviating the rejection. Such an amendment is supported throughout the application as filed (see e.g., par. [0037], [0044], [0047], FIG. 1D, FIG. 8, FIG. 11).” The cited portion and drawings do not provide antecedent basis for the limitations. Thus the amendment lacks adequate.
Claim 84 has been added by amendment and recites, “wherein the first nucleic acid comprises from 5' to 3': the first crosslinking strand, the first barcode, and the first complementary strand; and the second nucleic acid comprises from 5' to 3': the second crosslinking strand, the second barcode, and the second complementary strand.” The response asserts the paragraph 0058 as originally filed supports the amendment. Paragraph 0058 does not appear to support the amendment, While the specification in 0057 teaches, “A nucleic acid barcode generally comprises the following domain structure in the 5' to 3' direction: 5'-Crosslinking strand-to-Barcode strand-to-Complementary strand.” However this is of different scope as a barcode strand appears to be of different scope than a barcode.
Claim 85 has been added by amendment and recites, “wherein each barcode strand is at least 5 nucleotides in length, and wherein each crosslinking strand and complementary strand is at least 5 nucleotides in length.” The response asserts support can be found in paragraph 0026, 0052, 0054, 0084 and original claim 17. This argument has been thoroughly reviewed as the cited paragraphs and original clam 17 provide close ended ranges, however the amended claim encompasses 5 to infinite, which is not a range supported by the original specification.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
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, 9-10, 12, 14, 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 indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method of producing a concatemer of barcodes, however the last positive active step is drawn photocrosslinking _1)the first nucleic acid to (2)the second nucleic acid. Therefore it is unclear as to whether the method is drawn to producing a concatemer of barcodes or photocrosslinking _1)the first nucleic acid to (2)the second nucleic acid.
Claim 1 has been amended to recite, “a first nucleic acid comprising a first barcode flanked by a first crosslinking strand and a first complementary strand.” The metes and bounds are unclear as to what is required of the crosslinking strand and first complementary strand. It is unclear if these encompass two separate nucleic acids which can hybridize or something else. Further it is unclear what “a first complementary strand” is complementary to, while the claim later recites, “wherein the first complementary strand of the first nucleic acid hybridizes to the second crosslinking strand “ this merely requires it hybridize by any standard.
Claim 1 has been amended to recite, “a second nucleic acid comprising a second barcode flanked by a second crosslinking strand and a second complementary strand.” The metes and bounds are unclear as to what is required of the second crosslinking strand and second complementary strand. It is unclear if these encompass two separate nucleic acids which can hybridize or something else. Further it is unclear what “a second complementary strand” is complementary to, while the claim later recites, “the second complementary strand of the first nucleic acid hybridizes to the first crosslinking strand “ this merely requires it hybridize by any standard
Claim 1 recites, “the first and second barcodes are each assigned an independent bit value, and wherein the bit value identifies a barcode domain in a barcode library.” The specification teaches, “As used herein, the term "barcode domain" or "DNA data domain" refers to the part of the barcode strand that comprises a nucleic acid sequence that represents special information, an arbitrary value, or code. The barcode domain sequence can be predetermined by a barcode library. The barcode domain can be a sequence comprising DNA, RNA, synthetic nucleobases, or any combination thereof.” Thus the specification defines a barcode domain as being part of a barcode strand which is not a limitation of the claim. Thus the claim is unclear what is required. Further the recitation of independent bit value suggests there are non- independent bit value. The specification does not provide a standard to differentiate the two. Further it is unclear if the first and second nucleic acids are different nucleic acids.
Claim 6 depends from claim 1 and requires, “wherein a barcode of the first or second nucleic acid is selected from a barcode library having a minimum Hamming distance of 4 between each barcode.” The metes and bounds are unclear how the barcode library relates to the first and second nucleic of the independent claims, which require additional elements. Further the specification teaches, “An example barcode library shown has a minimum of Hamming distance 4, meaning that at least 4 substitution errors must be made by a sequencing device before barcode aliasing occurs.” (0068) Thus it is unclear if there are errors in the barcode of the first and second nucleic acid. Further the teachings of the specification suggesting Hamming is dependent on the sequencing device.
Claim 85 has been added by amendment and recites, “each barcode strand is at least 5 nucleotides in length.” The metes and bounds are unclear as claim 1 does not reach “barcode strand.” Thus it is unclear what the recitation is limiting.
Response to Arguments
The response traverses the rejection with respect to the preamble and last active step in view of the amendment of the claim to present thereby clauses. This argument has been thoroughly reviewed but is not considered persuasive as a thereby clause as presented in the claim is not an active step, but an intended outcome. Thus this argument is not persuasive.
With respect to claim 6 the response asserts, “Claim 6 is allegedly unclear regarding the "minimum Hamming distance of 4". Applicant respectfully disagrees. Without conceding the correctness of the rejection and solely to expedite prosecution, claim 6 is amended to state: "the first and second barcode are selected from a barcode library having a minimum Hamming distance of 4 between each barcode." Such an amendment is supported throughout the application as filed (see e.g., par. [0069], FIG. 1A). As known to a person of ordinary skill in the art, a minimum Hamming distance of 4 between two barcodes means that the nucleotide sequences of the first and second barcodes differ in at least 4 corresponding positions. For example, the barcodes b0 and bI in FIG. 1A differ at 5 corresponding positions (which is greater than 4; see e.g., dotted boxes in the FIG. 1A excerpt below showing the 5 differing nucleotide positions); barcodes b0 and b1 are selected as the first and second barcodes in FIG. 1A. A minimum Hamming distance of 4 between two barcodes means "that at least 4 substitution errors must be made by a sequencing device before barcode aliasing occurs".” This argument has been thoroughly reviewed but is not considered persuasive as the response appears to concede this is relative to the sequencer. Further, First, MPEP 716.01(c) makes clear that "The arguments of counsel cannot take the place of evidence in the record. In re Schulze , 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Here, the statements regarding one of skill in the arts understanding are not persuasive.
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.
Claim(s) 1, 14, 83 -85 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee ( Nature Nanotechnology (2009) volume 4, pages 430-436), Bystrykh (PLOS one (2012) volume 7, issue 5 e36852) and Navarro (Bioinformatics, 33(16), 2017, 2591–2593)
As noted in the MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Further, a preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Accordingly, the claim language of "a method of writing or storing data” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims.
The active steps of the claim are providing a first and second oligonucleotide each with a barcode and hybridization domains which comprise photoreactive element and photocrosslinking.
The specification teaches, “In some embodiments, the photoreactive element is a photoreactive Nucleotide” (0075), (00191).
The specification teaches in 0057 a preferred embodiment of a nucleic acid barcode, while 0058 teaches, “[00058] As used herein, the term "barcode domain" or "DNA data domain" refers to the part of the barcode strand that comprises a nucleic acid sequence that represents special information, an arbitrary value, or code. The barcode domain sequence can be predetermined by a barcode library. The barcode domain can be a sequence comprising DNA, RNA, synthetic nucleobases, or any combination thereof.”
Thus while the specification provides preferred embodiments of some of the limitations, the specification does not provide limiting definitions and thus are broad.
Further the claims have been amended to provide what the barcode is intended to represent in the wherein clause of the providing step, this does not provide for an active step or explicitly limit the active step.
This rejection is drawn to the interpretation claim 14 requires spatial information.
Lee teaches
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744
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Lee does not specifically teach barcodes.
However, Lee teaches the nucleic acids have sequences and thus represents the information of the sequence of the nucleic acid.
Therefore it would have been prima facie obvious to one of skill in the art prior to the effective filing date of the claims the art of Lee teachings encompass a first and second oligonucleotide comprising a complementary strand, barcode and crosslinking domain. The artisan would be motivated to recognize the sequence is data as the artisan recognizes the sequences were known as they were synthesize. The artisan would have a reasonable expectation of success as the artisan is merely recognizing the breadth of barcode.
Lee does not specifically teach spatial information, which is bit information
However, Navarro teaches the use of barcodes to provide spatial information (figure 1).
Bystrykh teaches, “Every tag design relies on the simple combinatorial rule that,
with a given number of bases q and defined length of the sequence d, the total number of combinations is q. This predetermines a minimal required length of the tag and generates enough barcoded primers for all samples. The difference in approaches resides in the way of selecting barcodes out of all possible combinations. A literature search revealed a great diversity of selection approaches. The first DNA barcodes were probably designed by random selection, for instance by Bonaldo et al. [3]. Later the problem was dealt with by introducing thorough selection principles out of all possible sequences of a given length [4–6]. In some cases, unfortunately, selection principles were not revealed [7–9]. Commercially available barcoded primers from Illumina (https://icom.illumina.com/download/summary/ ATZRuMiBPkukcRQOJ792Xg) and Epicentre (http://www. epibio.com/pdftechlit/312pl1110.pdf) belong to this group as well. Finally, some proportion of designs (not all of them were aimed at barcodes generation) used not only well defined strategies for the selection of DNA oligonucleotides, but also used elements of coding theory [10–15]. All those designs appeared several decades after the pioneering works of Shannon [16], Hamming [17], Reed and Solomon [18] and Levenshtein [19], who established the basics of the coding principles as well as correction of errors in corresponding code words. Considering such a variety of approaches, using coding principles or not, one can argue that since code-containing and code –free barcodes are equally popular, it proves that coding theory is not strictly required for such barcode designs. This is partially true: an invariant property of the DNA barcodes is not a coding principle, but sequence difference between those barcodes. Measures of such differences are known in coding theory as either Hamming or Levenshtein distance, and it is a built-in component of error-correcting codes. In the case of code-free designs, this distance must be achieved using an alignment algorithm and by counting mismatches. Although minimal distance can be achieved by various restrictive algorithms or by simple hand-picking, one is never sure that the best solution has been found. An analysis by alignment is computationally intense, and it often requires custom scripts especially for analysis of short tags. As I will demonstrate here, the benefit of using coding theory is that one can achieve a better result with less computational effort. As a bonus it will retain the benefit of error detection and correction without use of alignment. Considering constraints of size and the subject area, I will focus on linear codes, based mostly on the design of Hamming [17], while not discussing edit-metric codes. This paper aims to provide relatively easy and ready-made examples, to be used by molecular biologists whenever they need to select their own list of tags suited to their application in order to achieve the best possible result. “(page 1, 2nd column-page 2)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use barcodes with spatial information which has been assigned an independent value which identifies the value or barcode in a barcode library.. The artisan would be motivated to use spatial barcodes to provide information with respect to the location of nucleic acids. The artisan would have a reasonable expectation of success as the artisan is merely using known barcodes in known methods.
Bystrykh teaches, “This coding system is unique in its compactness regarding numbers of possible tags generated with a minimal distance of 3 and higher as well as for its algorithm that corrects substitution errors. Briefly, a Hamming code is a binary code constructed from data bits interrupted by parity bits at every 2n position. Parity bits are used for checksum function over different subsets of the data bits, allowing the identification of substitution errors [17]. Hamming used a rather elaborate checksum scheme: the 1st parity bit checks every odd position of the code word starting from the 1st position, the second parity bit checks consecutive pairs of bits starting with the 2nd position and interval of 2 bits, the 3rd bit will check 4 bits in a row starting from position 4 and interval 4, and so on. The whole reason for this system is to have simple error detection algorithm that operates in a binary code only. The classic version of the Hamming code has a length of 7 bits composed of 4 data and 3 parity bits, denoted as Hamming(7,4) code. In a context of DNA coding we might need a binary code with an even number of bits. For this case Hamming suggested adding extra parity position at the end of the code word to check all bits in the word. From this perspective the Hamming(7,4) code can be extended to Hamming(8,4), consequently Hamming(15,11) will be extended to the Hamming(16,11) code. Details of the code design are provided in the Supplementary File S1) (page 2, 2nd column).
With regards to claims 9-10, Lee teaches the first and second nucleic acid in a predestined polymeric sphere and attached to the slide as they are attached in
With regards to claim 83, the Lee teaches 3 or more concatemerized.
With regards to claim 84, Therefore it would have been prima facie obvious to one of skill in the art prior to the effective filing date of the claims the art of Lee teachings encompass a first and second oligonucleotide comprising a complementary strand, barcode and crosslinking domain. The artisan would be motivated to recognize the sequence is data as the artisan recognizes the sequences were known as they were synthesize. The artisan would have a reasonable expectation of success as the artisan is merely recognizing the breadth of barcode.
With regards to claim 85, Lee does not specifically teach the length of the barcode, crosslinking strand and complementary strand.
However it would have been prima facie obvious to one of skill in the art prior to the effective filing date of the claims to use more than 5 nucleotides for barcode, crosslink and hybridization strands. The artisan would be motivated to provide 5 or more nucleotides in each to allow sufficient length to allow strong and specific hybridization. The artisan would have a reasonable expectation of success as the artisan is merely using art accepted methods of designing nucleic acids for hybridization.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683