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 .
Election/Restrictions
Applicant’s election with traverse of Group I in the reply filed on June 22, 2026 is acknowledged. Claims 20-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Group 2, there being no allowable generic or linking claim.
Applicant’s arguments traversing the restriction requirement have been fully considered, but are not persuasive. Applicant argues that there would not be a serious burden on the Examiner if the claims were searched together because of the nature and subject matter of the claims. However, this application is a national stage application under 35 USC 371, and unity of invention is determined in accordance with 37 CFR 1.475 and PCT Rule 13. The relevant inquiry is whether the claimed inventions are technically related through one or more of the same or corresponding special technical features, i.e., features defining a contribution that each claimed invention, considered as a whole, makes over the prior art.
As previously set forth, Groups 1 and 2 share features relating to first and second nucleotide mixtures containing labeled and/or unlabeled nucleotides and a photographic polymerization solution. However, these common features do not constitute a special technical feature because they do not provide the requisite contribution over prior art. As identified in the restriction (4/29/2026), the prior art (CN110691854) teaches these common features, including the nucleotide mixtures and photographic polymerization solution. Accordingly, the common subject matter does not provide the special technical feature necessary to link the method of Group 1 and the kit of Group 2 into a single general inventive concept.
The Applicant has not identified a different same or corresponding special technical feature shared by Groups 1 and 2 that constitutes a contribution over the prior art, nor has the Applicant shown error in the prior art basis underlying the lack of unity determination. Applicant’s assertion that examination of all claims would not impose an undue burden therefore does not overcome the lack of unity under 37 CFR 1.475(a) and PCT Rule 13.2
Accordingly, the restriction requirement is made final and maintained. Claims 11-19 (3/5/2024) corresponding to elected Group 1, will be examined on the merits.
Claim Status
Claims 11-19 are under examination (3/5/2024). No claims have been amended. No new matter was added.
Priority
Claims 11-19 receive a priority date of 9/7/2021, the effective filing date of Chinese Provisional Patent 18689293.
Information Disclosure Statement
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.
Information disclosure statements (IDS) were submitted on 3/5/2024, 6/4/2024, 8/14/2025 and 12/31/2025 are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities (see MPEP § 608.01):
The use of the term “Trinton X-100” (p. 5), “AlexaFlour” (p. 7, 12), “Bodipy” (p. 7, 12), “Texas Red” (p. 7. 12), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears 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 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 11-19 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 11 recites the limitation "the product" in step (d), line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 11 recites the limitation "the protective group" in step (e), line 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 12-19 are included in this rejection due to their dependency on claim 11.
Claim 17 is further rejected. Claim 17 contains the trademark/trade name “AlexaFlour”, “Bodipy”, “Texas Red”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the first, second, third and fourth labels and, accordingly, the identification/description is indefinite.
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.
Claim(s) 11-19 are rejected under 35 U.S.C. 103 as being unpatentable over Glezer et al (US PGPub 2021/0198730 A1; published 7/1/2021) and Decker et al. (“Synthesis and Initial Characterization of a Selective, Pseudo-irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer”, ChemMedChem, published 1/2021).
Regarding claims 11-16, Glezer teaches a method of amplifying tagged complements of a plurality of sample polynucleotides, the method including: (a) hybridizing to each of the plurality of sample polynucleotides a plurality of interposing oligonucleotide barcodes, each of the interposing oligonucleotide barcodes including from 5′ to 3′: (i) a first hybridization pad complementary to a first sequence of a sample polynucleotide; (ii) a first stem region comprising a sequence common to the plurality of interposing oligonucleotide barcodes; (iii) a loop region comprising a barcode sequence, wherein the barcode sequence, alone or in combination with a sequence of one or both of (a) the sample polynucleotide, or (b) one or more additional barcode sequences, uniquely distinguishes the sample polynucleotide from other sample polynucleotides in the plurality; (iii) a second stem region comprising a sequence complementary to the first stem region, wherein the second stem region is capable of hybridizing to the first stem region under hybridization conditions; and (iv) a second hybridization pad complementary to a second sequence of the sample polynucleotide; extending the 3′ ends of the second hybridization pads with one or more polymerases to create extension products; and ligating adjacent ends of extension products hybridized to the same sample polynucleotide thereby making integrated strands comprising complements of the plurality of sample polynucleotides tagged with a plurality of interposing oligonucleotide barcodes; and amplifying the integrated strands by an amplification reaction thereby amplifying the tagged complements of the plurality of sample polynucleotides and in embodiments, the method further includes sequencing the amplified products (Paragraph 5, lines 1-10). Further, Glezer teaches that the nucleotides may be labelled or unlabelled and the nucleotides may be modified with reversible terminators useful in methods provided herein and may be 3′-O-blocked reversible or 3′-unblocked reversible terminators, where in nucleotides with 3′-O-blocked reversible terminators, the blocking group may be represented as —OR [reversible terminating (capping) group], wherein 0 is the oxygen atom of the 3′-OH of the pentose and R is the blocking group, while the label is linked to the base, which acts as a reporter and can be cleaved, where the 3′-O-blocked reversible terminators are known in the art, and may be, for instance, a 3′-ONH.sub.2 reversible terminator, a 3′-O-allyl reversible terminator, or a 3′-O-azidomethyl reversible terminator (Paragraph 62, lines 5-10).
Glezer also teaches a blocking moiety on a nucleotide can be reversible, whereby the blocking moiety can be removed or modified to allow the 3′ hydroxyl to form a covalent bond with the 5′ phosphate of another nucleotide and a blocking moiety can be effectively irreversible under particular conditions used in a method set forth herein and in embodiments, the blocking moiety is attached to the 3′ oxygen of the nucleotide and is independently —NH.sub.2, —CN, —CH.sub.3, C.sub.2-C.sub.6 allyl (e.g., —CH.sub.2—CH═CH.sub.2), methoxyalkyl (e.g., —CH.sub.2—O—CH.sub.3), or —CH.sub.2N.sub.3 and further in embodiments, the blocking moiety is attached to the 3′ oxygen of the nucleotide and is independently wherein the 3′ oxygen is explicitly depicted, and a label moiety of a nucleotide can be any moiety that allows the nucleotide to be detected, for example, using a spectroscopic method. Exemplary label moieties are fluorescent labels, mass labels, chemiluminescent labels, electrochemical labels, detectable labels and the like (Paragraph 41, lines 5-15). Glezer also teaches that one or more of the above moieties can be absent from a nucleotide used in the methods and compositions set forth herein and for example, a nucleotide can lack a label moiety or a blocking moiety or both, where examples of nucleotide analogues include, without limitation, 7-deaza-adenine, 7-deaza-guanine, the analogues of deoxynucleotides shown herein, analogues in which a label is attached through a cleavable linker to the 5-position of cytosine or thymine or to the 7-position of deaza-adenine or deaza-guanine, and analogues in which a small chemical moiety is used to cap the —OH group at the 3′-position of deoxyribose (Paragraph 41, lines 5-20).
Additionally, Glezer teaches that the term “cleavable linker” or “cleavable moiety” as used herein refers to a divalent or monovalent, respectively, moiety which is capable of being separated (e.g., detached, split, disconnected, hydrolyzed, a stable bond within the moiety is broken) into distinct entities, where a cleavable linker is cleavable (e.g., specifically cleavable) in response to external stimuli (e.g., enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, or oxidizing reagents) (Paragraph 42, lines 1-5) and following nucleotide addition, signals produced (e.g., via excitation and emission of a detectable label) can be detected to determine the identity of the incorporated nucleotide (based on the labels on the nucleotides), where reagents can then be added to remove the 3′ reversible terminator and to remove labels from each incorporated base and reagents, enzymes and other substances can be removed between steps by washing where cycles may include repeating these steps, and the sequence of each cluster is read over the multiple repetitions. (Paragraph 69, lines 5-10).
Glezer further teaches that in embodiments, the loop region, alone or in combination with a sequence of one or both of (a) the sample polynucleotide, or (b) one or more barcode sequences, uniquely distinguishes the sample polynucleotide from other sample polynucleotides in a plurality of sample polynucleotides and in embodiments of the interposing oligonucleotide barcodes provided herein, the loop region includes about 5 to about 20 nucleotides or about 10 to about 20 nucleotides, where the loop includes a TT-[UMI sequence]-TT sequence, such as TT-[NNNNNNNNNNNN]-TT (SEQ ID NO:11) sequence, wherein N represents random nucleotides and A, T, C, G represent fixed nucleotides) (Paragraph 83, lines 15-20).
Regarding claim 17, Glezer also teaches Examples of sequencing include, but are not limited to, sequencing by synthesis (SBS) processes in which reversibly terminated nucleotides carrying fluorescent dyes are incorporated into a growing strand, complementary to the target strand being sequenced and in embodiments, the nucleotides are labeled with up to four unique fluorescent dyes and in embodiments, the nucleotides are labeled with at least two unique fluorescent dyes and in embodiments, the readout is accomplished by epifluorescence imaging (Paragraph 124, lines 30-40).
Regarding claims 18-19, Glezer teaches a method of amplifying tagged complements of a plurality of sample polynucleotides, the method including: (a) hybridizing to each of the plurality of sample polynucleotides a plurality of interposing oligonucleotide barcodes, each of the interposing oligonucleotide barcodes including from 5′ to 3′: (i) a first hybridization pad complementary to a first sequence of a sample polynucleotide; (ii) a first stem region comprising a sequence common to the plurality of interposing oligonucleotide barcodes; (iii) a loop region comprising a barcode sequence, wherein the barcode sequence, alone or in combination with a sequence of one or both of (a) the sample polynucleotide, or (b) one or more additional barcode sequences, uniquely distinguishes the sample polynucleotide from other sample polynucleotides in the plurality; (iii) a second stem region comprising a sequence complementary to the first stem region, wherein the second stem region is capable of hybridizing to the first stem region under hybridization conditions; and (iv) a second hybridization pad complementary to a second sequence of the sample polynucleotide; extending the 3′ ends of the second hybridization pads with one or more polymerases to create extension products; and ligating adjacent ends of extension products hybridized to the same sample polynucleotide thereby making integrated strands comprising complements of the plurality of sample polynucleotides tagged with a plurality of interposing oligonucleotide barcodes; and amplifying the integrated strands by an amplification reaction thereby amplifying the tagged complements of the plurality of sample polynucleotides. In embodiments, the method further includes sequencing the amplified products (Paragraph 5, lines 1-10).
Further, Glezer teaches that the nucleotides may be labelled or unlabeled and the nucleotides may be modified with reversible terminators useful in methods provided herein and may be 3′-O-blocked reversible or 3′-unblocked reversible terminators, where in nucleotides with 3′-O-blocked reversible terminators, the blocking group may be represented as —OR [reversible terminating (capping) group], wherein 0 is the oxygen atom of the 3′-OH of the pentose and R is the blocking group, while the label is linked to the base, which acts as a reporter and can be cleaved and the 3′-O-blocked reversible terminators are known in the art, and may be, for instance, a 3′-ONH.sub.2 reversible terminator, a 3′-O-allyl reversible terminator, or a 3′-O-azidomethyl reversible terminator (Paragraph 62, lines 5-10). Additionally, Glezer teaches that the term “cleavable linker” or “cleavable moiety” as used herein refers to a divalent or monovalent, respectively, moiety which is capable of being separated (e.g., detached, split, disconnected, hydrolyzed, a stable bond within the moiety is broken) into distinct entities, where a cleavable linker is cleavable (e.g., specifically cleavable) in response to external stimuli (e.g., enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, or oxidizing reagents) (Paragraph 42, lines 1-5).
Also, Glezer teaches that following nucleotide addition, signals produced (e.g., via excitation and emission of a detectable label) can be detected to determine the identity of the incorporated nucleotide (based on the labels on the nucleotides), where reagents can then be added to remove the 3′ reversible terminator and to remove labels from each incorporated base and reagents, enzymes and other substances can be removed between steps by washing and cycles may include repeating these steps, and the sequence of each cluster is read over the multiple repetitions (Paragraph 69, lines 5-10).
Also, Glezer teaches that in embodiments, the loop region, alone or in combination with a sequence of one or both of (a) the sample polynucleotide, or (b) one or more barcode sequences, uniquely distinguishes the sample polynucleotide from other sample polynucleotides in a plurality of sample polynucleotides and in embodiments of the interposing oligonucleotide barcodes provided herein, the loop region includes about 5 to about 20 nucleotides or about 10 to about 20 nucleotides and in embodiments, the loop includes a TT-[UMI sequence]-TT sequence, such as TT-[NNNNNNNNNNNN]-TT (SEQ ID NO:11) sequence, wherein N represents random nucleotides and A, T, C, G represent fixed nucleotides) (Paragraph 83, lines 15-20).
Further, Glezer teaches that polynucleotides useful in the methods of the disclosure may comprise natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or a combination of such sequences and a “nucleoside” is structurally similar to a nucleotide, but is missing the phosphate moieties, where an example of a nucleoside analogue would be one in which the label is linked to the base and there is no phosphate group attached to the sugar molecule (Paragraph 34, lines 15-20).
Glezer does not teach irreversible blocking groups in reference to unlabeled nucleotides.
Decker teaches that the enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer’s disease (AD) and to monitor disease progression in some forms of cancer and in this study, we present the design, facile synthesis in vitro and preliminary ex vivo and in vivo evaluation of amorpholine-based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo-irreversible binding mode (Abstract). Specifically, Decker teaches a novel protecting group strategy for 18F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound (Abstract). Further, Decker teaches that other irreversible ChE inhibitors are organophosphates and a respective PET tracer was designed to target central nervous system AChE in rats, but these compounds are highly toxic nerve agents, however, due to the lack of results concerning irreversibly acting and selective BChE PET tracers as potential in vivo AD diagnostics, we continued our previous studies, in which we had investigated enzyme kinetics and binding, radiolabeling and preliminary ex vivo brain tissue binding of pseudo-irreversible, selective BChE inhibitors with high affinity (p. 1428, Column 2, Paragraphs 1-3).
It would have been obvious to one of ordinary skill in the art at the time of the invention was made to modify the sequencing method of Glezer to include, in the second nucleotide mixture, an unlabeled nucleotide comprising an irreversible blocking group as taught by Decker. Glezer expressly teaches the use of labeled or unlabeled nucleotides having blocking moieties, including reversible and effectively irreversible blocking moieties, for controlling nucleotide extension during nucleotide acid processing and sequencing. Decker further demonstrates that irreversible/pseudo-irreversible blocking or protecting groups were known in the art and could be incorporated into compounds to prevent or inhibit further reaction while retaining the desired properties of the underlying compound.
One of ordinary skill in the art would therefore have been motivated to employ a known irreversible blocking group, such as taught by Decker, on Glezer’s unlabeled nucleotide as an alternative to Glezer’s reversible blocking group to provide a nucleotide capable of permanently terminating further chain extension when termination, rather than subsequent deblocking and extension, is desired. Such a modification would have amounted to the predictable use of a known blocking technique according to its desired function, with a reasonable expectation that an irreversibly blocked nucleotide would prevent subsequent nucleotide incorporation.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ROSE LAFAVE whose telephone number is (703)756-4747. The examiner can normally be reached Compressed Bi-Week: M-F 7:30-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on 571-272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ELIZABETH ROSE LAFAVE/ Examiner, Art Unit 1684
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684
