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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/5/2025 has been entered.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 13-15, 19, and 20 remain withdrawn. Claims 1-8, 10-12, and 16-18 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Nucleotide and/or Amino Acid Sequence Disclosure Objections
The specification was objected to because it contained sequence identifiers that were not present in the previous version of the Sequence Listing. Applicant has attempted to submit a new Sequence Listing to amend this issue. However, the new computer readable format file of the Sequence Listing has been marked as defective, as Applicant has submitted an XML file rather than an ASCII file. Additionally, the Sequence Listing XML file appears to contain SEQ ID NOs: 83-86 based on the number of sequences that are in the file, but the XML file itself cannot currently be viewed. See additional details in the “Nucleotide and/or Amino Acid Sequence Disclosures” section below.
Claim Objections
Claims 1, 6, and 17 were objected to for various informalities. In light of Applicant’s amendments to the claims submitted 12/5/2025, the objection for claim 6 has been withdrawn. The objections for claims 1 and 17 have been maintained-in-part, as they have not been fully addressed by Applicant’s claim amendments. It is noted that Applicant has not provided any arguments against these objections in their Remarks.
35 USC 112(b) Rejections
Claim 8 was rejected due to various indefiniteness issues. In light of Applicant’s amendments to the claims submitted 12/5/2025, this rejection has been withdrawn. See also new grounds of rejection below.
35 USC 103 Rejections
Claims 1, 3-8, 10-12, 16-18 were rejected as unpatentable over Gines et al. (WO 2017/141068 A1) in view of Chen et al. (Chem. Commun., 2018). Claim 2 was rejected as unpatentable over Gines et al. (WO 2017/141068 A1), in view of Chen et al. (Chem. Commun., 2018), and further in view of Rondelez et al. (WO 2017/140815 A1). Applicant’s arguments and amendments have been thoroughly reviewed and considered. These rejections have been maintained. See “Response to Applicant’s Arguments” below.
Response to Applicant’s Arguments
Regarding the previously presented 35 USC 103 Rejections, Applicant argues that no prima facie obviousness case has been established for the instant claims in view of Gines and Chen (the primary and secondary references cited), particularly because the references do not allegedly teach every limitation of the instant claims (Remarks, page 13). Applicant states that as Gines is related to detection methods based on qPCR/PCR variants while Chen is focused on LAMP detection methods, and because of the differences between these two methods (e.g. thermal cycling or lack thereof and primer design), the references could not reasonably be combined (Remarks, pages 15-16). Additionally, Applicant alleges that any combination of Gines and Chen represents impermissible hindsight reconstruction, as no reason is provided to combine the references (Remarks, pages 17-18).
In the Final Rejection, the teachings of Gines primarily used involve incubation of the microsphere particles and enzyme mixture at a constant temperature, allowing amplification to occur (para. 26 of Gines). Thus, this reference teaches isothermal amplification methods. In fact, though Applicant states that the methods of Gines are based on qPCR or PCR variants, this is a mischaracterization of the reference as a whole. Gines does discuss PCR methods (e.g. paras. 32 and 85), but the main amplification teachings in the reference concern isothermal methods (see Figures 4-5, 7-9, 11, 13, 15, 17, 19, and 21).
In relating Gines to the instant claims, the Examiner states, “though Gines mentions droplet methods, the reference seems to mainly contemplate these in the context of PCR and continuous flow/microfluidics methods (para. 75), which are not recited in the method of their invention.” Thus, Gines teaches isothermal amplification methods, but not in conjunction with droplet methods. Chen is then used because this reference does teach the use of droplets with isothermal amplification methods (see page 291, column 2, para. 2 and Figure 1 of the reference for example). In combining these references in para. 30 of the Final Rejection, the Examiner states, “it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Chen to add droplet methodology to the overall method of Gines to arrive at the method of claim 1. Specifically, this would involve using the water-in-oil droplet methodology of Chen with the particles of Gines as the incubation step before performing subsequent isothermal amplification and detection…” Motivation for the combination is provided (“By utilizing droplets, beads can be further separated from one another – Chen teaches that most droplets created in their method contained only single beads (page 293, column 1, para. 2), so this would be particularly useful for Gines, which teaches the use of multiple targets in a single solution, as distinct targets would be further separated from one another. Chen teaches sample concentrations for use in their method (e.g. page 292, column 2, paras. 2-3, page 293, column 1, para. 1, and page 294, column 1, para. 1), and teaches that the empty beads present are due to sample concentrations, and so the ordinary artisan would be capable of providing samples at low enough concentrations (such as those taught by Chen) that a Poissonian distribution of target-particle hybridization would be possible for each desired target. Utilizing this type of distribution would also allow for copy number calculations, as shown in Chen, and so this could provide a check on absolute quantification values derived from fluorescence calculations (page 293, column 1, para. 1). Chen also details several benefits regarding the utility of this method as described in the above paragraph that would motivate the ordinary artisan.”), as well as a reasonable expectation of success (“There would be a reasonable expectation of success with this combination as the only change to the general method steps of Gines would be the addition of the water-in-oil emulsions to create the droplets and a subsequent washing step – these are techniques that would well-known to the ordinary artisan, as evidenced by Chen and Gines (see Gines paras. 26, 46, 56, and 71 for examples of washing the recited particles),”). Thus, Chen teaches droplet methods for use with isothermal amplification, and the Examiner combined these teachings with the teachings of Gines that also use isothermal amplification, and not PCR, as erroneously stated by Applicant. In this combination, the obviousness rationale described in MPEP 2143 I (G) was used – namely, motivation from Chen and in knowledge generally available to one of ordinary skill in the art was used to combine the references, and a finding of a reasonable expectation of success was made.
Regarding Applicant’s arguments concerning hindsight reconstruction, MPEP 2145 X (A) states, “"[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). "A factfinder should be aware, of course, of the distortion caused by hindsight bias and must be cautious of arguments reliant upon ex post reasoning. . . . Rigid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). With regard to this guidance, the combination of Gines in view of Chen does not rely on any teachings in the instant specification, nor does it rely on knowledge that would only be available to the ordinary artisan after the filing date of the instant invention. Applicant appears to argue that this is not the case, but does not state what teaching or rationale used in the rejection would allegedly be hindsight reasoning (Remarks, pages 17-18).
In the newly amended claims, it is specifically stated that the amplification signal in the amplification reaction is produced by an amplification oligonucleotide, narrowing the more broad claim interpretation of the amplification signal presented in the Final Rejection. It is noted that these amendments do pose a 35 USC 112(b) issue (see the rejections below), but are being interpreted as though “an amplification oligonucleotide” refers to the third oligonucleotide originally stated in step (a) of the claim. Gines does teach an amplification oligonucleotide, as noted in the Final Rejection (para. 25), where the amplification oligonucleotide is used to amplify a particular target and produce a detectable signal when used in conjunction with the reporter oligonucleotide (see paras. 16, 18, 26, 32, and 49 and Figures 10 and 14 of Gines for example, and see “Claim Interpretation” below). The final step of claim 1 has also been amended to more clearly recite absolute quantification of each target biomolecule in the sample. This is still addressed by the combination of Gines in view of Chen. In para. 25 of the Final Rejection, Gines is noted to teach barcode and reporter detection. In para. 28, it is stated, “though [Gines] teaches detecting target biomolecules (e.g. Figures 8, 10, and 12), it is unclear if absolute quantification of target particles occurs,” then in para. 29, absolute quantification of targets is shown by Chen, and in para. 30, and these methods are combined with those of Gines in para. 31.
Overall, Applicant does not specifically state what supposed limitations of the instant claims are not met by Gines in view of Chen. The Examiner argues that the references do teach each limitation, as is clearly laid out in the Final Rejection and reiterated below.
Thus, Applicant’s arguments are overall not persuasive, and the 35 USC 103 Rejections presented in the Final Rejection have been maintained.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 12/7/2025.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
Claim Objections
Claim 1 is objected to because of the following informalities: in step (c), line 3 reads “multiplicity of targets” but should read “multiplicity of target biomolecules” so as to keep constant the terminology as used earlier in the claim. Similarly, “target” rather than “target biomolecule” also appears in line 5 of step (c) and line 4 of step (f), and these informalities should also be amended. Additionally, in the final line of the claim, “initial sample” should read “sample” so as to keep constant the terminology as used earlier in the claim. Appropriate correction is required.
Claim 17 is objected to because of the following informality: the wherein clause of the claim should read “wherein the water-in-oil droplets have a volume of…” 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 1-8, 10-12, and 16-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being -indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected because in steps (f) and (g), the use of “an amplification oligonucleotide” is recited. It is unclear if this amplification oligonucleotide is intended to be the same in both steps (f) and (g), and if this is the same amplification oligonucleotide as already recited in step (a). The claim will be interpreted as though steps (f) and (g) use the same amplification oligonucleotide as recited in step (a). Additionally, in step (g), “the barcode signal” is recited, but “a barcode signal” is not recited earlier in the claim. Therefore, this phrase lacks antecedent basis. This phrase will be interpreted to be a signal generated by the barcodes recited in step (b).
Claims 2-8, 10-12, and 16-18 are rejected based on their dependence on rejected claim 1.
Claim Interpretation
In the newly amended claims, an amplification signal is generated by an amplification oligonucleotide, and this signal is then detected and/or measured. The term “signal” in this context is taken to encompass the production of a particular sequence, and is not necessarily detectable on its own (see pages 11-12 of the instant specification, which note that amplification oligonucleotides produce a signal sequence that the reporter oligonucleotide may then translate to a detectable signal). Claim 1 also does not specifically recite that direct detection/measurement of the amplification signal must occur. Thus, the instant claims do not require the amplification signal to be detected/measured directly, and so detection/measurement may occur indirectly by measuring the signal of a reporter oligonucleotide.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-8, 10-12, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Gines et al. (WO 2017/141068 A1) in view of Chen et al. (Chem. Commun., 2018).
Gines teaches methods of molecular computing involving microspheres with particular DNA modules attached (Abstract). Mesoporous particles are functionalized in solution with a mixture of DNA modules and a fluorescent barcode element that allows for multiplexing (paras. 24 and 26-27 and Figure 1; instant claims 3 and 18). These DNA modules can be conversion, reporting, amplification, and leak-absorbing oligonucleotides (para. 26 and (f) of para. 27). The particles are then exposed to one or more biomolecular targets (such as DNA or RNA; instant claims 10 and 11), an enzyme mixture is added, and the resulting composition is incubated at a constant temperature, allowing amplification to occur (para. 26). Detection of the amplification of specific targets in the sample can then be done by detecting the fluorescent barcodes and signals from the reporter oligonucleotide (which generates a fluorescent signal based on amplification products, see para. 18). Different barcodes may be used in the same solution (para. 39), particularly to detect several different targets (paras. 26 and 60). Gines teaches that the particles in the solution can perform identical yet independent functions (para. 89), and can thus act independently. The enzyme mixture can contain one or more of polymerase, nickase, and exonuclease (claim 17; instant claim 5). dNTPs and buffers are also included in the solution (Figure 1 and para. 26, and see mixtures in Figures 5, 7, and 11, for example). The particles specifically contemplated by Gines are porous microspheres and have a mean diameter of 34 μm (para. 40; instant claims 8 and 16).
The constant temperature contemplated by Gines is 45°C (para. 48 and Figures 5, 7, and 11 for example; instant claim 7).
Gines teaches that their invention can be applied to miRNA targets for diagnostic purposes to detect diseases such as cancer (paras. 79-81; instant claim 12).
However, though Gines mentions droplet methods, the reference seems to mainly contemplate these in the context of PCR and continuous flow/microfluidics methods (para. 75), which are not recited in the method of their invention. Additionally, Gines does not discuss target hybridization following a Poissonian distribution, and though the reference teaches detecting target biomolecules (e.g. Figures 8, 10, and 12), it is unclear if absolute quantification of target particles occurs. Gines does discuss measuring concentrations of targets (paras. 26 and 81), and teaches the use of multiple target concentrations (para. 72), including small concentrations (para. 86).
Chen teaches a BEAMing LAMP reaction. The basic methodology is shown in Scheme 1. Molecules are captured on beads in solution. The beads are then mixed with LAMP reagents and water-in-oil droplet emulsions are formed (instant claim 6). LAMP then occurs, the beads are washed, and then flow cytometry is used to detect targets (page 291, final para through page 292, para. 1; instant claim 4). Chen also teaches taking microscopy images of the beads by simply shaking them in solution (Figure 2 and page 293, columns 1-2 joining para.), where the detectable beads can be easily identified. The droplets had diameters of 5–13 µm, equating to a volume of 0.523-9.202 pL (page 293, column 1, para. 2; instant claim 17). Chen teaches that this method is highly sensitive, accurate, can be useful for diagnostics, and improves detection rates of targets (page 294, columns 1-2 joining para.). These methods allow for absolute quantification of target sequences (Abstract, page 293, column 1, para. 1, page 294, column 1, paras. 1-2, and Figures 1 and 3). The reference mentions that when little target DNA is present, most incubated beads will contain zero or one hybridized target (page 292, column 1, para. 1), and that the pattern for droplet analysis in detecting beads that do and do not have targets follows a Poisson distribution (page 293, column 1, para. 1).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Chen to add droplet methodology to the overall method of Gines to arrive at the method of instant claim 1. Specifically, this would involve using the water-in-oil droplet methodology of Chen with the particles of Gines before performing subsequent isothermal amplification and detection. Gines teaches that droplets in flow systems are not useful for the suspensions and solutions of their invention as it is difficult to fabricate and program the microparticles and requires the use of multiple distinct probes for multiplexing (para. 75). However, Gines already solves this second problem via the use of multiple barcodes. Chen teaches a mechanism by which droplets can be created in solution (i.e. not in a flow) for isolation of particles during amplification, solving the first problem presented by Gines, and shows that fluorescent reporters can be successfully detected later with the use of flow methods in order to absolutely quantify target sequences. By utilizing droplets, beads can be further separated from one another – Chen teaches that most droplets created in their method contained only single beads (page 293, column 1, para. 2), so this would be particularly useful for Gines, which teaches the use of multiple targets in a single solution, as distinct targets would be further separated from one another. Chen teaches sample concentrations for use in their method (e.g. page 292, column 2, paras. 2-3, page 293, column 1, para. 1, and page 294, column 1, para. 1), and teaches that the empty beads present are due to sample concentrations, and so the ordinary artisan would be capable of providing samples at low enough concentrations (such as those taught by Chen) that a Poissonian distribution of target-particle hybridization would be possible for each desired target. Utilizing this type of distribution would also allow for copy number calculations, as shown in Chen, and so this could provide a check on the absolute quantification values derived from droplet fluorescence calculations (page 293, column 1, para. 1). Chen also details several benefits regarding the utility of this method as described in the above paragraph that would motivate the ordinary artisan. There would be a reasonable expectation of success with this combination as the only change to the pre-analysis method steps of Gines would be the addition of the water-in-oil emulsions to create the droplets and a subsequent washing step – these are techniques that would well-known to the ordinary artisan, as evidenced by Chen and Gines (see Gines paras. 26, 46, 56, and 71 for examples of washing the recited particles; instant claim 1).
Thus, claims 1, 3-12, and 16-18 are prima facie obvious over Gines in view of Chen.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Gines et al. (WO 2017/141068 A1), in view of Chen et al. (Chem. Commun., 2018), and further in view of Rondelez et al. (WO 2017/140815 A1).
Gines in view of Chen renders obvious the methods of claims 1, 3-12, and 16-18, as described above. Gines also teaches that DNA modules can be added after the initial functionalization of the particles. Para. 66 details particles being created with the amplification and leak-absorbing oligonucleotides, and then the conversion oligonucleotide being added later (Figure 19). However, this addition is not done with the addition of the amplification mixture. It is noted that the amplification and leak-absorbing oligonucleotides are considered a bistable system when paired together (para. 64), and that the purpose of the leak-absorbing oligonucleotide is to avoid unspecific amplification when amplification is initiated (para. 16).
Rondelez teaches methods of isothermal amplification while eliminating background noise (Abstract). This is done by preparing a mixture including buffer and enzymes, and adding amplification, leak-absorption, and conversion oligonucleotides (para. 8). A reporting probe can also be added (para. 19). This reference teaches that reaction mixtures with nucleic acid templates and enzymes can be prone to leaking reactions (para. 34), and that the use of these oligonucleotides may absorb such leaks (para. 35). The leak-absorption and amplification oligonucleotides are also complementary to one another, and their hybridization can decrease background amplification (para. 35). These oligonucleotides can be included in the final mixtures used for amplification (e.g. paras. 61, 66, 67, 79, and 82).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Gines in view of Chen and Rondelez to arrive at the invention of instant claim 2. Though Gines teaches four functional oligonucleotides, these do not all need to be present on every particle at the outset of the method, as shown in Example 5. Gines also details the importance of the leak-absorbing oligonucleotide in preventing unspecific amplification, providing reason to pair this oligonucleotide with the amplification oligonucleotide specifically. Rondelez teaches that oligonucleotides with identical functions to those of Gines can be added with amplification mixtures during isothermal amplification to prevent background noise. In Rondelez, the leak-absorbing and amplification oligonucleotides are also clearly functionally linked. Thus, it would be prima facie obvious to the ordinary artisan that the leak-absorbing and amplification oligonucleotides could be added with the amplification mixture in Gines in view of Chen while still allowing for the reduction of nonspecific amplification. By not including these oligonucleotides on the particles of Gines in view of Chen, more conversion and reporter oligonucleotides can be included on the particles, which would allow for the capture and detection of additional target sequences (Gines paras. 17-18), allowing for more accurate results. Additionally, by adding the amplification and leak-absorbing oligonucleotides in the amplification mixture (i.e. later in the method of Gines in view of Chen), this may prevent any premature hybridization of the two oligonucleotides before amplification can occur. There would be a reasonable expectation of success with this combination because Rondelez shows that these oligonucleotides can be added with an amplification mixture and still result in effective target amplification with background noise reduction. Also, the basic principles of the method of Gines in view of Chen would not be changing, as all four oligonucleotides would still be present together in solution with amplification reagents and target sequences in order to perform amplification (and later detection) reactions.
Thus, the method of claim 2 is prima facie obvious over Gines, in view of Chen, and further in view of Rondelez.
Conclusion
No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681