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 .
Notice of New Examiner
The Examiner would like to note for the Applicant that this case has been
transferred to a new examiner for examination. Any further communications on this case may be directed to the contact information included in the conclusion of this
office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 11th, 2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6, 8, 11-15, 17, and 18, in the reply filed on July 8th, 2026 is acknowledged.
Claims 20, 22, 23-25, and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 8th, 2026.
Claim Summary
Claims 7, 9-10, 16, 19, 21, and 26-28 have been canceled. Claims 1-6, 8, 11-15, 17-18, 20, 22-25, and 29 are pending. Claims 20, 22-25, and 29 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-6, 8, 11-15, and 17-18 are under examination and discussed in this Office action.
Specification
The use of terms such as Illumina, which is a trade name or a mark used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 6 and 15 are objected to because of the following informalities:
Claim 6 uses colons to separate the options in the claimed list. The colons should be replaced with semicolons or commas. There is also a comma included in the parenthesis with the (ii). This should be deleted.
Claim 15 recites the limitation “a genetic variation; or (ii) a sequencing error”. There appears to be a list identifier missing before “a genetic variation” like that seen for “(ii) a sequencing error”. It is suggested to add (i) immediately before “a genetic variation” to clarify the list identifiers.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 14 and 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 14 recites the limitation “wherein only the first subsequence and/or the second subsequence with a unique UMID sequence is analyzed”. It is unclear from this recitation which subsequence is intended to have the UMID. It could be they each have a UMID, the first has a UMID, or the second has a UMID. In addition, it is unclear if the presence of the UMID is determining that a subsequence is being analyzed or not, which is complicated by the lack of clarity regarding which subsequence has the UMID. Therefore, the claim is found indefinite. For the purpose of compact prosecution, this claim will be interpreted to mean wherein the first subsequence and/or the second subsequence, which comprises a unique UMID sequence, is analyzed.
Claim 15 recites the limitation “the method of claim 14, wherein analysis comprises comparing the sequence of the first subsequence to the sequence of the second subsequence”. It is unclear from this recitation how this method would be possible if, given the method of claim 14, there is optionality to which subsequence is analyzed. Claim 14 as written recites “wherein only the first subsequence and/or the second subsequence with a unique UMID sequence is analyzed”, which indicates that either the first subsequence or the second subsequence may be analyzed. If this option is exercised, it is unclear how the subsequences may be compared to each other as required by claim 15. Therefore, the claim is found indefinite. For the purpose of compact prosecution, it will be interpreted that both the first subsequence and the second subsequence are analyzed, and therefore can be compared as claimed in claim 15.
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.
Claims 1-6, 8, 11-15, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Glezer (US 20210277461 A1, effectively filed March 6th, 2020), as evidenced by NEB (DNA Ligation [online]. New England Biosciences, [2026] [retrieved on September 23rd, 2026]. Retrieved from: https://www.neb.com/en-us/tools-and-resources/video-library/dna-ligation).
Regarding instant claim 1, Glezer teaches a method to prepare an error-corrected nucleic acid library for sequencing, the method comprising: providing a double stranded nucleic acid molecule, comprising a positive strand and a negative strand, wherein the positive strand and the negative strand are substantially complementary, and wherein the double stranded nucleic acid molecule has a first end and a second end (Page 15, paragraphs [0093]-[0094]); covalently attaching a sequencing adapter to the positive strand at the first end of the double stranded nucleic acid molecule and the negative strand at the first end of the double stranded nucleic acid molecule (Page 16, paragraphs [0099]-[0100]); and covalently attaching a first end of a single hairpin adapter to the positive strand at the second end of the double stranded nucleic acid molecule and covalently attaching a second end of the single hairpin adapter to the negative strand at the second end of the double stranded nucleic acid molecule (Page 16, paragraphs [0099]-[0100]), wherein the single hairpin adapter covalently joins the positive strand and the negative strand into a single covalently linked duplex strand (Page 18, paragraph [0112]). As evidenced by NEB, ligation forms covalent bonds between adjacent DNA fragments (Page 1).
Glezer does not directly teach covalently attaching a first sequencing adapter to the positive strand at the first end of the double stranded nucleic acid molecule and covalently attaching a second sequencing adapter to the negative strand at the first end of the double stranded nucleic acid molecule. However, as cited above, Glezer teaches Y adapters that covalently attach to both the positive and negative strand at one end of the double stranded nucleic acid molecule (Pages 16-17, paragraphs [0101]-[0102]). The two strands of the Y adapter can reasonably serve as each of the first sequencing adapter and the second sequencing adapter. Furthermore, the instant specification makes clear that a Y adapter can serve as an adapter in the method (see instant specification at page 9, lines 1-4 and also Figure 1, wherein a Y adapter is ligated to one end of the Linked Duplex). Therefore, it would be obvious that a Y adapter can serve as both the first sequencing adapter and second sequencing adapter simultaneously.
With respect to self-correction of sequencing errors, in an example of the generally described methodology, Glezer teaches analyzing sequencing results of linked duplexes, which includes distinguishing sequencing errors from true variants (Pages 47-48, paragraphs [0305] and [0307]-[0308]). It would be obvious to one of ordinary skill in the art, given this example, that any embodiment of a method taught by Glezer could include this analysis. This amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
Regarding instant claim 2, Glezer teaches the method of claim 1. Glezer further teaches wherein the single hairpin adapter is a partially double stranded nucleic acid molecule that has a secondary structure comprising a double stranded stem domain and a loop domain, wherein the stem domain comprises each end of the hairpin adapter to covalently attach to the positive end and the negative end of the second end of the double stranded nucleic acid molecule (Page 18, paragraphs [0110]-[0111]).
Regarding instant claim 3, Glezer teaches the method of claim 1. Glezer further teaches wherein the single hairpin adapter comprises a number (N) of nucleotides, wherein each nucleotide is selected independently, and wherein N is an integer selected from 6 to 300 (Page 18, paragraph [0110]).
Regarding instant claim 4, Glezer teaches the method of claim 2, wherein the loop domain comprises a unique molecule identifier (UMID) sequence (Page 18, paragraph [0113]).
Regarding instant claim 5, Glezer teaches the method of claim 4, wherein the loop domain comprises a secondary index sequence adjacent to the UMID sequence (Page 18, paragraph [0113]).
Regarding instant claim 6, Glezer teaches the method of claim 1. In an example of the generally described methodology, Glezer teaches producing the double stranded nucleic acid molecule by (i) shearing a larger double stranded nucleic acid molecule or (ii,) enzymatically fragmenting a larger double stranded nucleic acid molecule (Page 33, paragraph [0211]). Glezer teaches that DNA fragmentation is a typical step in preparation of a nucleic acid library (Page 33, paragraph [0210]). It would be obvious to one of ordinary skill in the art, given this example, that any embodiment of a method taught by Glezer would first include production of the double stranded nucleic acid molecule by fragmentation. This amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
Regarding instant claim 8, Glezer teaches the method of claim 6. Glezer further teaches wherein the double stranded nucleic acid molecule has an overhang end or a blunt end (Page 15, paragraph [0094]).
Regarding instant claim 11, Glezer teaches the method of claim 1. Glezer further teaches the method further comprising adding one or more adenine residues at a 3' end of the positive strand and/or adding one or more adenine residues at a 3' end of the negative strand (Page 15, paragraph [0094]).
Regarding instant claim 12, Glezer teaches the method of claim 1. Glezer further teaches the method further comprising amplifying the single covalently linked duplex strand to provide a plurality of covalently linked duplex strand amplicons (Page 16, paragraph [0100]). In another embodiment, Glezer also teaches further details related to amplifying the single covalently linked duplex strand to produce a plurality of covalently linked duplex strand amplicons (Pages 20-21, paragraphs [0127]-[0128]). It would be obvious to one of ordinary skill in the art, given this embodiment, that embodiments of the method taught by Glezer would include these amplification options. This amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
Regarding instant claim 13, Glezer teaches the method of claim 12. Glezer further teaches the method further comprising sequencing at least one covalently linked duplex strand amplicons to produce at least one sequence read comprising a first subsequence corresponding to at least a portion of the positive strand of the double stranded nucleic acid molecule and a second subsequence corresponding to at least a portion of the negative strand of the double stranded nucleic acid molecule (Page 16, paragraph [0100]; Pages 20-21, paragraph [0128]).
Regarding instant claim 14, Glezer teaches the method of claim 13.
With respect to analyzing the subsequences, in an example of the generally described methodology, Glezer teaches analyzing sequencing results of linked duplexes (e.g. the first subsequence and the second subsequence) (Page 47, paragraphs [0305] and [0307]; see 112(b) interpretation). It would be obvious to one of ordinary skill in the art, given this example, that any embodiment of a method taught by Glezer could include this analysis. This amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
Glezer further teaches wherein the second subsequence is sequenced off of the loop or stem of the hairpin adapter (Page 16, paragraph [0100]; see 112(b) interpretation). Glezer teaches the loop of the hairpin adapter comprises a UMI (Page 18, paragraph [0113]; see 112(b) interpretation). Therefore, it would be obvious to one of ordinary skill in the art, given this teaching, that the second subsequence would include a UMID. This amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
Regarding instant claim 15, Glezer teaches the method of claim 14. In an example of the generally described methodology, Glezer teaches wherein analysis comprises comparing the sequence of the first subsequence to the sequence of the second subsequence and a variation observed in both the first subsequence and the second subsequence is a genetic variation; or (ii) a sequencing error (Pages 47-48, paragraphs [0305] and [0307]-[0308]; see 112(b) interpretation). It would be obvious to one of ordinary skill in the art, given this example, that any embodiment of a method taught by Glezer could include this analysis. This amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
Regarding instant claim 17, Glezer teaches the method of claim 1. Glezer further teaches wherein the double stranded nucleic acid molecule is a double stranded DNA molecule (Page 15, paragraph [0093]).
Regarding instant claim 18, Glezer teaches the method of claim 1. Glezer further teaches the method comprising preparing a plurality of double stranded nucleic acid molecules for sequencing (Page 15, paragraph [0093]). While Glezer does not explicitly state that this is by performing the method a plurality of times for different double stranded nucleic acid molecules using a plurality of hairpin adapters, it would be obvious that this is encompassed by the language of Glezer, which specifically states: “[i]n some embodiments, a method comprises sequencing both strands of a plurality of double stranded nucleic acids” (Page 15, paragraph [0093]) and “[i]n some embodiments, a method herein comprises ligating one or more adapters to a plurality of double stranded nucleic acids” (Page 16, paragraph [0099]). This language encompasses performing the method a plurality of times for different double stranded nucleic acid molecules using a plurality of hairpin adapters, and it is obvious to one of ordinary skill in the art because it amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
In a separate teaching on UMIs, Glezer teaches UMIs are unique in a pool of UMIs that differ from one another in sequence, or are uniquely associated with a particular sample polynucleotide in a pool of sample polynucleotides (Pages 8-9, paragraph [0058]). Glezer teaches that hairpin adapters have UMIs (Page 18, paragraph [0113]). It would be obvious to one of ordinary skill in the art, given these teachings, that there is the option for a plurality of hairpin adapters comprising different UMID sequences as claimed. This amounts to combining prior art elements according to known methods to yield predictable results (see MPEP 2141(III)).
Conclusion
All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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