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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 11, 2026 has been entered.
Status of Claims / Response to Amendment
This office action is in response to an amendment filed on March 11, 2026.
Claims 1-4, 6, 8, 10-12, 15-19, 22-24, 26, 30-31 and 51 were previously pending. Applicant added new claim 71.
Claims 1-4, 6, 8, 10-12, 15-19, 22-24, 26, 30-31, 51 and 71 are currently pending, with claims 8, 10-12, 15-17, 22, 31, 51 and 71 withdrawn.
Claims 1-4, 6, 18-19, 23-24, 26 and 30 are under consideration.
Applicant's arguments filed on March 11, 2026 have been fully considered.
The prior rejections of Claims 1-4, 6, 18-19, 23-24, 26, and 30 under 35 U.S.C. 103 as being unpatentable over Forsyth, in view of Callewaert ), as evidenced by Xiong and Wikipedia has been withdrawn, in light of the Applicant's argument asserting that a skilled artisan would not find the combination of T4 polymerase treatment with blunt-end digestion using DpnI to be an obvious embodiment in Forsyth. Specifically, while Forsyth teaches both T4 polymerase treatment and DpnI digestion, it teaches using T4 polymerase as an optional step for generating blunt ends, a skilled artisan, understanding that DpnI already generates blunt ends, would not apply the optional T4 polymerase treatment step. No prior art teaches or suggests the combination of T4 polymerase treatment with blunt-end restriction digestion within the context of an enrichment method as claimed.
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains new grounds for rejection.
Election by Original Presentation
Newly submitted claim 71 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
This application contains claims directed to the following patentably distinct species:
Species of Library Generation
A) further comprising: e. contacting the adapter-ligated nucleic acids from (d) with a second modification- sensitive restriction enzyme under conditions that allow the second modification- sensitive restriction enzyme to cut a second recognition site, wherein at least a subset of the nucleic acids targeted for depletion comprise a plurality of second recognition sites for a second modification-sensitive restriction enzyme, and wherein the second modification-sensitive restriction enzyme targets recognition sites comprising at least one modified nucleotide and does not target recognition sites that do not comprise at least one modified nucleotide, thereby generating a collection of nucleic acids targeted for depletion that are adapter-ligated on one end and a collection of nucleic acids of interest that are adapter-ligated on both ends (claim 16);
B) further comprising contacting the sample after step (d) with a plurality of nucleic acid-guided nuclease-guide nucleic acid (gNA) complexes, wherein the gNAs are complementary to targeted sites in the nucleic acids targeted for depletion, thereby generating cut nucleic acids targeted for depletion that are adapter-ligated on one end and nucleic acids of interest that are adapter-ligated on both the 5' and 3' ends (claim 17);
C) further comprising amplifying, sequencing or cloning the nucleic acids of interest that are adapter-ligated on their 5' and 3' ends using the adapters (claim 18);
i) further comprising: e. enriching nucleic acids of interest based on the presence of unmodified cytosines in the nucleic acids of interest (claim 71).
The species are independent or distinct because the different species recite separate characteristics of such species, and there is no disclosure of relationship between species (see MPEP § 806.04(b)). In addition, these species are not obvious variants of each other based on the current record. The species necessitate separate searches, leading to serious search and/or examination burden (see MPEP § 808.01(a)) because the species of library generation reflect different method steps with different mechanisms, materials, and outcomes.
Among the listed species above, Applicant has previously elected, without traverse, species C) further comprising amplifying, sequencing or cloning the nucleic acids of interest that are adapter-ligated on their 5' and 3' ends using the adapters for "Species of Library Generation." (see page 7 on in Response to Election / Restriction Filed on January 27, 2025)
Therefore, specie C) in claim 18 is the originally presented and elected invention, and has been previously examined on its merits in past Office Actions; species A) and B) are withdrawn from consideration as being drawn to non-elected species; species i) is presented in newly added claim 71.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 71 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Priority
The priority date of the instant claims 1-4, 6, 18-19, 23-24, 26 and 30 is 04/09/2019, filling date of the US provisional application NO. 62/831,302.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For the purpose of applying prior art, claim 1 recites "a sample comprising nucleic acids of interest and nucleic acids targeted for depletion." The applicant's disclosure does not define the terms "nucleic acids of interest" and "nucleic acids targeted for depletion" with any structural features that can distinguish them with any nucleic acids known in the art. Thus, under BRI, the terms "nucleic acids of interest" and "nucleic acids targeted for depletion" are both interpreted to encompass any nucleic acids.
The different modifiers in the terms are interpreted as used for identification purposes to distinguish between repeated instances of an element or limitation, and do not impose any additional features, such as any structural or composition differences. Thus, the phrase “a sample comprising nucleic acids of interest and nucleic acids targeted for depletion" is interpreted under BRI to mean a sample comprising two groups of nucleic acids.
For the purpose of applying prior art, claim 1 recites "first modification-sensitive restriction enzyme," terms such as "first" and "second" are interpreted as adjectives for identification purposes and do not impose any additional features, such as any specific temporal limitation, any sequential order of steps, or any structural or composition differences.
This interpretation aligns with the claim language, as evidenced by claim 1, which recites DpnI ꟷ a modification--sensitive restriction enzyme. However, DpnI appears to be distinct from the "first modification-sensitive restriction enzyme" and performs step prior to those involve "first modification-sensitive restriction enzyme."
Claim Rejections - 35 USC § 112(b) -- New
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.
Claims 1-4, 6, 18-19, 23-24, 26 and 30 are rejected under 35 U.S.C. 112(b), 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.
Regarding claim 1, it recites:
A method of enriching a sample for nucleic acids of interest comprising:
a. providing a sample comprising nucleic acids of interest and nucleic acids targeted for depletion,
wherein at least a subset of the nucleic acids of interest or a subset of the nucleic acids targeted for depletion comprise a plurality of first recognition sites for a first modification-sensitive restriction enzyme;
b. terminally dephosphorylating a plurality of the nucleic acids in the sample;
c. contacting the sample from (b) with the first modification-sensitive restriction enzyme; and
d. ligating adapters to a 5' and 3' end of a plurality of the nucleic acids of interest;
thereby generating a sample enriched for nucleic acids of interest that are adapter-ligated on their 5' and 3' ends,
wherein the method further comprises, prior to step (c), contacting the sample with DpnI and T4 polymerase thereby replacing methylated A and C nucleotides with unmethylated A and C nucleotides within or adjacent to the at least one Dpnl recognition site.
This claim language is indefinite because it is unclear how the recited steps and their resulting products interrelate to achieve the claimed "enriching a sample for nucleic acids of interest."
Under BRI, unless otherwise specified, method steps are not limited to a particular order1. Here, the claim specifies that step (c) occurs after step (b), and that the "further comprising" step (contacting the sample with DpnI and T4 polymerase) occurs prior to step (c).
However, it is unclear whether:
1. The terminally dephosphorylated products from step (b) are then treated with DpnI and T4 polymerase, resulting in partially terminally phosphorylated products (since the cleaved ends by DpnI would not be terminally dephosphorylated), before proceeding to step (c); or
2. The sample is treated with DpnI and T4 polymerase before terminal phosphorylation, such that all nucleic acids are terminally dephosphorylated when entering step (c).
The claim does not clarify these relationships. The specification also fails to resolve this ambiguity.
Protocol 1 ([00172]) appears to be most relevant to the claimed method. It describes a method in which nucleic acids of interest and nucleic acids targeted for depletion are distinguished based on the presence of nucleotide modification on recognition sites for a modification-sensitive restriction enzyme, enabling selective cleavage and adaptor ligation:
“[0172] Protocol 1: Exemplary methods of the application described herein are depicted in FIG. 1. A sample of nucleic acids comprising nucleic acids of interest (101) and nucleic acids targeted for depletion (102) is terminally dephosphorylated (105) to produce unphosphorylated nucleic acids of interest (106) and nucleic acids targeted for depletion (107). In some embodiments, the nucleic acids are fragmented prior to dephosphorylation. In some embodiments, the nucleic acids in the sample are terminally dephosphorylated with a phosphatase, for example recombinant shrimp alkaline phosphatase (rSAP). In some embodiments, both the nucleic acids of interest and the nucleic acids targeted for depletion comprise one or more recognition sites for a modification-sensitive restriction enzyme (103, 104, respectively). In the nucleic acids of interest, the recognition sites for the modification-sensitive restriction enzyme do not comprise modified nucleotides (103), or alternatively, contain modified nucleotides less frequently than the corresponding recognition sites of the nucleic acids targeted for depletion. In the nucleic acids targeted for depletion, the recognition sites for the modification-sensitive restriction enzyme comprise modified nucleotides within or adjacent to the restriction site (104), or alternatively, comprise modified nucleotides more frequently than the corresponding recognition sites of the nucleic acids of interest. Activity of the modification-sensitive restriction enzyme (109) is blocked by the presence of modified nucleotides within or adjacent to its cognate recognition site (108), thereby targeting the activity of the modification-sensitive restriction enzyme to the nucleic acids of interest (compare 110 and 111). In some embodiments, the modification-sensitive restriction enzyme (109) comprises AatII, AccII, Aor13HI, Aor51HI, BspT104I, BssHII, Cfr10I, ClaI, CpoI, Eco52I, HaeII, HapII, HhaI, MluI, NaeI, NotI, NruI, NsbI, PmaCI, Psp1406I, PvuI, SacII, SalI, SmaI, SnaBI, AluI or Sau3AI. In some embodiments, the modification-sensitive restriction enzyme (109) comprises AluI or Sau3AI. Digesting the sample with the modification-sensitive restriction enzyme (113) produces nucleic acids of interest with terminal phosphates at the 5′ and 3′ ends of the terminal phosphates (114). These terminal phosphates are used to ligate adapters (115, ligation step; 116, adapters) to the ends of the nucleic acids of interest, producing nucleic acids of interest that are adapter ligated on both ends (117). In contrast, the nucleic acids targeted for depletion are not adapter ligated (111)”
However, protocol 1 does not describe or reference a step involving contacting the sample with DpnI and T4 polymerase, prior to using the modification-sensitive restriction enzyme.
In a separate section ([00142]), the specification describes using DpnI to differentiate bacterial DNA from mammalian DNA in a sample, because "DpnI GATC recognition sites comprising both adenine methylation and cytosine modification occur in bacterial DNA, but not in mammalian DNA." Para. [00142] explains that a mixed sample can be treated with DpnI, followed by T4 polymerase "to replace methylated adenines and modified cytosines at the cleaved ends with unmodified adenines and cytosines." But it does not reference protocol 1 or describe how the DpnI and T4 polymerase treatment can be incorporated with steps of terminal dephosphorylation, digestion with another modification-sensitive restriction enzyme and adaptor ligation, into a single enriching method:
“ [00142] In some embodiments, the modification comprises adenine methylation and the methods comprise digestion with DpnI. DpnI cleaves a GATC recognition site when the adenines on both strands of the GATC recognition are methylated. In some embodiments, DpnI GATC recognition sites comprising both adenine methylation and cytosine modification occur in bacterial DNA, but not in mammalian DNA. These recognition sites comprising both methylated adenines and modified cytosines can be selectively cleaved by DpnI in a sample (e.g., of mixed bacterial and mammalian DNA), and then treated with T4 polymerase to replace methylated adenines and modified cytosines at the cleaved ends with unmodified adenines and cytosines. T4 polymerase catalyzes the synthesis of DNA in the 5′ to 3′ direction, in the presence of a template, primer and nucleotides. T4 polymerase will incorporate unmodified nucleotides into the newly synthesized DNA. This produces a sample that now comprises unmodified cytosines in the nucleic acids of interest and modified cytosines in the nucleic acids targeted for depletion. These differences in modified cytosines can be used to enrich for nucleic acids of interest using the methods of the disclosure.” [emphasis added]
Therefore, these separate disclosures in the specification do not resolve whether the step involving DpnI and T4 polymerase should occur before or after terminal dephosphorylation.
Although the disclosures in para. [00142] and [00172] share similar language, describing the general concept of distinguishing nucleic acids based on nucleotide modification levels at specific modification-sensitive restriction enzyme recognition sites, there is no disclosed description supporting a direct interrelation between these separate disclosures. These separate disclosures each rely on distinct restriction enzymes with distinct recognition sites. For example, the enzyme AatII is listed in protocol 1 as a modification-sensitive restriction enzyme ([0172] line 21), which has a restriction recognition site of "5' GACGTC 3', 2" that differs from DpnI's recognition site "5' GATC 3'." As such, it is unclear how DpnI digestion and the replacement of modified nucleotides at its digestion sites can relate to or support an enrichment method involving AatII digestion, particularly when the disclosure provides no information regarding the modification status of bacterial and mammalian DNA (disclosed in [00142] for selective DpnI cleaving) at the AatII recognition sites.
Thus, the description for DpnI and T4 polymerase treatment of a sample ([00142]) is not clearly integrated with the description for the rest of the claimed steps (Protocol 1, [0172]). In particular, it is unclear how the DpnI and T4 polymerase treatment relates to the method using modification-sensitive restriction enzyme treatment in protocol 1, and how these processes are combined into a single, coherent method for enrichment.
Accordingly, the claim fails to clearly define the sequence and interrelation of steps required to achieve the claimed enrichment, rendering the scope of the claim unclear.
Claims 2-4, 6, 18-19, 23-24, 26 and 30 are rejected for depending from claim 1 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 112(a) -- New
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.
Claims 1-4, 6, 18-19, 23-24, 26 and 30 are rejected under 35 U.S.C. 112(a), 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 recites a method of enriching a sample for nucleic acids of interest, comprising multiple steps including terminal dephosphorylation, contacting the terminally dephosphorylated sample with modification-sensitive restriction enzyme, adaptor ligation, and a further step of prior to step (c), contacting the sample with DpnI and T4 polymerase thereby replacing methylated A and C nucleotides with unmethylated A and C nucleotides within or adjacent to the at least one Dpnl recognition site.
However, the applicant's disclosure lacks sufficient detail to demonstrate possession of the invention, as required under 35 U.S.C. 112(a).
First, the disclosure lacks sufficient description to support the claimed method as a single, coherent embodiment. As discussed in detail in the rejection under 35 U.S.C. 112(b) above, the application's disclosure fails to provide a unified and complete description of how the claimed steps interrelate to achieve the claimed enrichment.
Accordingly to MPEP 2163 (written description requirement), the specification must clearly demonstrate that the inventor was in possession of the claimed invention at the time of filling. Explicit phraseology alone by merely mentioning the terms as claimed is not sufficient in meeting this requirement.
While the specification describes the claimed elements in separate disclosures (i.e., in [00142] contacting the sample with DpnI and T4 polymerase; in [0172] terminal dephosphorylation, contacting the terminally dephosphorylated sample with modification-sensitive restriction enzyme, adaptor ligation), they rely on distinct restriction enzymes with distinct recognition sites. There is no disclosed description supporting a direct interrelation between these separate disclosures.
As such, the application's disclosure does not provide sufficient written description support on how the claimed steps and their resulting products interrelate to achieve the claimed enrichment method in a single embodiment. While each element may be individually described in the specification, the deficiency is the lack of adequate description of their combination, see Hyatt v. Dudas, 492 F.3d 1365, 1371, 83 USPQ2d 1373, 1376-1377 (Fed. Cir. 2007).
As stated in MPEP 2163.IA:
“issues of adequate written description may arise even for original claims, for example, when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the inventor had possession of the claimed invention at the time of filing.”
In this instance, a skilled artisan would not have been conveyed that the inventors had possession of the full scope and breath of claimed invention at the time of filling due to the insufficient description.
Second, the disclosure further lacks sufficient description to support the feature "contacting the sample with DpnI and T4 polymerase thereby replacing methylated A and C nucleotides with unmethylated A and C nucleotides within or adjacent to the at least one Dpnl recognition site."
The application's disclosure does not provide sufficient detail to support this feature, the combined use of "DpnI and T4 polymerase" for "replacing methylated A and C nucleotides with unmethylated A and C nucleotides within or adjacent to the at least one Dpnl recognition site" is not well-known in the art. The Examiner cannot find prior art that teaches the use of the combination of DpnI and T4 polymerase in a step to specifically achieve the claimed result. Stated differently, this seems to be a nascent, or previously unknown feature. The duty of disclosure is greater in this situation. See Bos. Sci. Corp. v. Johnson & Johnson, 647 F.3d 1353, 1367 (Fed. Cir. 2011) (“Given the nascent state of using drug-eluting stents to treat restenosis at this time, the lack of such blaze marks in the ′662 patent prevents any conclusion that the patent contains sufficient written description of the claimed triene analogs of rapamycin”); Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 918, 923 (Fed. Cir. 2004) (patent claims directed to COX–2 inhibitors were invalidated for lack of adequate written description because the existence of such inhibitors was merely “hypothesized”; no such inhibitors were yet known and none were described in the patent). To this end, the specification fails to provide any details as to the critical conditions that are required to perform the claimed step to achieve the claimed result.
Specifically, the specification does not provide any detail on how this reaction step with DpnI and T4 polymerase should be carried out, including the conditions, reagents, and protocols required to achieve the claimed result. Although para. [00142] notes that "T4 polymerase catalyzes the synthesis of DNA in the 5′ to 3′ direction, in the presence of a template, primer and nucleotides," this description is insufficient to support the claimed step as it appears unrelated. Particularly, the claimed step involves contacting a nucleic acid sample with DpnI, which results in blunt ends. Blunt ends lack the features necessary for the described T4 polymerase activity, such as template or primer. Also, the claimed step does not recite nucleotides, which are required for T4 polymerase to catalyze DNA synthesis according to the description.
Without sufficient information describing how to carry out the step using DpnI and T4 polymerase in the claimed enrichment method, a skilled artisan, even in view of the disclosure, would not know how to make and use the claimed invention to achieve the claimed result. For instance:
DpnI digestion is typically performed at 37°C, while T4 polymerase incubation is typically performed at 12°C. 3 What incubation temperature should be used when these two enzymes are used together as claimed?
What reaction buffer should be used to support the activity of both enzymes simultaneously?
What dNTP concentration and T4 DNA Polymerase unit should be inputted to achieve the claimed replacement of methylated A and C nucleotides with unmethylated A and C nucleotides within or adjacent to the at least one Dpnl recognition site? This will require the T4 DNA Polymerase to first "chew back" the modified blunt ends, then polymerase with unmodified bases, and keep the unmodified blunt ends as the main substrate in the reaction (i.e., no more chewing back once the modified nucleotides have been replaced).
What reaction time is required to ensure the claimed result is achieved?
The application's disclosure fails to provide any guidance or experimental details addressing these critical parameters. Without such information, a skilled artisan would not be able to perform the claimed method to achieve the claimed result.
Therefore, the application's disclosure does not meet the written description requirement under 35 U.S.C. 112(a), for there is insufficient disclosure that convey to a person skilled in the art that the inventor was in possession of the full breadth of the claim at the time of filling.
Claims 2-4, 6, 18-19, 23-24, 26 and 30 are rejected because they depend from claim 1 and inherit the deficiencies of the base claim.
Prior Art
Below are relevant prior art not used in rejection but pertinent to the claims or disclosure.
Performing modification-sensitive restriction enzyme digestion for selective enrichment is well-known in the art:
See Sharma et al. Tools for DNA adenine methyltransferase identification analysis of nuclear organization during C. elegans development. Genesis. 2016 Apr;54(4):151-9. doi: 10.1002/dvg.22925. PMID: 26845390;
See US20130065776A1 - Selective enrichment of non-methylated nucleic acids;
See WO2019006269A1 - Methods and systems for evaluating dna methylation in cell-free dna; 2019-01-03; see Fig. 2;
See US20050202490A1 - Methods and compositions for generating and amplifying DNA libraries for sensitive detection and analysis of DNA methylation; see Fig. 33C, 42, 43A, 46;
See US20110076726A1 - Differential enzymatic fragmentation by whole genome amplification.
The use of T4 polymerase and DpnI, along with another methylation-sensitive restriction enzyme, in an enrichment method is known in the art.
See Wu et al. , DamID-seq: Genome-wide Mapping of Protein-DNA Interactions by High Throughput Sequencing of Adenine-methylated DNA Fragments. J Vis Exp. 2016 Jan 27;(107):e53620. doi: 10.3791/53620. PMID: 26862720; PMCID: PMC4781701;
See Gutierrez-Triana et al., iDamIDseq and iDEAR: an improved method and computational pipeline to profile chromatin-binding proteins. Development. 2016 Nov 15;143(22):4272-4278. doi: 10.1242/dev.139261. Epub 2016 Oct 5. PMID: 27707796; PMCID: PMC5117216.
See Luo, et al. Characterization of eukaryotic DNA N6-methyladenine by a highly sensitive restriction enzyme-assisted sequencing. Nat Commun 7, 11301 (2016); see Figure 1
However, no prior art specifically teaches or suggests the particular order of steps and combination of elements as claimed ꟷ namely, treating a nucleic acid sample with both T4 polymerase and DpnI (or another blunt-end restriction enzyme) prior to treating the sample with another modification-sensitive restriction enzyme.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN NMN YU whose telephone number is (703)756-4694. The examiner can normally be reached Monday - Friday 8:30 am - 5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at (571) 272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 “As a general rule, unless the steps of a method claim actually recite an order, the steps are not ordinarily construed to require one.” Mformation Techs., Inc. v. Rsch. in Motion Ltd., 764 F.3d 1392, 1398 (Fed. Cir. 2014) (cleaned up). “However, a claim requires an ordering of steps when the claim language, as a matter of logic or grammar, requires that the steps be performed in the order written, or the specification directly or implicitly requires an order of steps.” Id. Although not an ironclad rule, when the current step of a method claim refers to a previous step using the definite article “the,” the claim language indicates that the previous step occurs sequentially before the current step. E.g., Wi-Lan, Inc. v. Apple Inc., 811 F.3d 455, 462 (Fed. Cir. 2016).
2 see “AatII”; www .neb.com/en-us/products/r0117-aatii
3 See "DpnI" ; www .neb.com/en-us/products/r0176-dpni;
See also "Protocol for blunting ends by 3’ overhang removal and 3’ recessed (5’ overhang) end fill-in using T4 DNA Polymerase (M0203)"; www. neb.com/en-us/protocols/protocol-for-blunting-ends-by-3-overhang-removal-and-fill-in-of-3-recessed-5-overhang-ends-using1
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