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
Claims 73-97 are pending and are herein discussed on their merits.
Priority
Claims to the priority of PCT/US/2022/030370 and to the benefit of the provisional application 63/191,455 are acknowledged. The effective filing date of the instant application is considered to be May 21, 2021.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are in claim 87 as:
“oligonucleotide configured to decode bases” and
“oligonucleotide configured to convert decoded bases into a signal”
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof. The corresponding structure is described in the following locations in the specification:
Par. 85
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 87-89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 87 recites a “fifth oligonucleotide” and a “sixth oligonucleotide.” While the specification recites a “third oligonucleotide” and a “fourth oligonucleotide” that accomplish the same function (decoding bases and converting decoded bases into a signal), there is no support in the specification for a fifth or sixth oligonucleotide. If the oligonucleotides of claim 87 are meant to refer to the third and fourth oligonucleotides described in the specification, it is recommended that the applicant amend the language of claim 87 to reflect that relationship.
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 73-97 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.
Claims 73-97 are rejected over the recitation of “said first complementarity region is adjacent to said fifth complementarity region” in claims 73 and 77. The first complementarity region resides on the first oligonucleotide, while the fifth complementarity region resides on the second oligonucleotide. It is unclear from these claims how regions of two different oligonucleotides can be adjacent to one another. For the purposes of examination, the limitation is taken to mean that the two complementarity regions hybridize to adjacent sequences on the target nucleic acid.
Claims 74-76 and 79-83 are rejected over the recitation of the phrase “said tissue” in claims 74, 79, 80, and 82. There is insufficient antecedent basis for this limitation in those claims, as the original claim from which they depend (claim 73) does not recite “a tissue,” but does recite “a cell.” It is therefore unclear whether the claims are drawn to samples comprising a tissue or a cell or both. If these claims are referring to the cell of claim 73, they must be amended to reflect such.
Claims 74-76 are rejected over the recitation of the phrase “said pair of oligonucleotides” in the last line of claim 74. There is insufficient antecedent basis for this limitation, as there are two pairs of oligonucleotides in the claim. It is therefore unclear whether claim 74 refers to the first pair of oligonucleotides, the second pair of oligonucleotides, or a different pair of oligonucleotides.
Claims 77-78 are rejected over the recitation of a step “(b)” in claim 77. As the claim depends on 73, which already requires a step of ligating, it is unclear whether claim 77’s step (b) is a replacement for claim 73’s step (b), or multiple steps of ligating are being required.
Claim 87 is indefinite over the recitation of the phrase “oligonucleotide configured to decode bases”. This phrase in considered indefinite because “oligonucleotide configured to decode bases” is not clearly defined in the specification and there is no art recognized definition for this phrase. It is not clear how an oligonucleotide should be modified so that it has the ability to decoded bases. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 87 is indefinite over the recitation of the phrase “oligonucleotide configured to convert decoded bases into a signal”. This phrase in considered indefinite because “oligonucleotide configured to convert decoded bases into a signal” is not clearly defined in the specification and there is no art recognized definition for this phrase. It is not clear how an oligonucleotide should be modified so that it has the ability to convert decoded bases into a signal. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 73, 77-78, 84, 90-92, and 96 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bava et al. (published March 28, 2019; Patent Publication No. US 2019/0093156).
Bava et al. describes methods of identifying target molecules including nucleic acids (par. 6).
Regarding claim 73, Bava describes a method comprising contacting a cell comprising a target nucleic acid with at least one pair of oligonucleotides, comprising a first oligonucleotide which has a first complementarity region, a second complementarity region, and a third complementarity region; and a second oligonucleotide which has a fourth complementarity region, a fifth complementarity region, and a sixth complementarity region, as well as a first end and a second end (Figure 12). Bava describes that the first complementarity region is complementary to a first portion of said nucleic acid, the second complementarity region is complementary to the fourth complementarity region, the third complementarity region is complementary to said sixth complementarity region, the fifth complementarity region is complementary to a second portion of the target nucleic acid, and that the second oligonucleotide comprises a unique matching sequence which hybridizes to the first oligonucleotide (Figure 12, par. 6). In the reference, complementarity regions 1 and 5 are named CR1 and CR1’ respectively (and they bind adjacent regions on the target nucleic acid, see Figure 12), complementarity regions 2 and 3 are comprised in CR2 (they are immediately adjacent as shown in Figure 12, step 1), and complementarity regions 4 and 6 are comprised in CR2’ as a ‘split’ region (see par. 6). The CR2’ split regions make up the unique matching sequence that hybridizes to the first oligonucleotide (Figure 12, step 1 and par. 6). Bava discloses ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule and amplifying the circular nucleic acid molecule to generate one or more amplicons (Fig. 12). Bava also discloses imaging amplicons to identify the target nucleic acid (par. 244).
Regarding claim 77, Bava discloses the method of claim 73 as discussed above using more than one pair of oligonucleotides (pars. 7, 114).
Regarding claim 78, Bava discloses multiple rounds of imaging (par. 244).
Regarding claim 84, Bava discloses complementarity regions 1 and 5 (the target binding regions) with melting temperatures between 50-72ºC (par. 115).
Regarding claims 90 and 91, Bava discloses complementarity regions 4 and 6 which comprise a first and second portion of a unique matching sequence which hybridizes to the first oligonucleotide (Figure 12, par. 6).
Regarding claims 92 and 96, Bava discloses complementarity regions 1 and 5 (the target binding regions) having lengths between 19-25 nucleotides (pars. 85, 109).
Claims 73, 77-79, 84, and 90-97 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (published July 27, 2018; Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691)
Wang et al describes methods of identifying nucleic acids using SNAIL probes and primers (Fig. 1).
Regarding claim 73, Wang describes a method comprising contacting a cell with a target nucleic acid with a first pair of oligonucleotides where the first oligonucleotide of that pair has a first complementarity region, a second complementarity region, and a third complementarity region; and a second oligonucleotide has a fourth complementarity region, a fifth complementarity region, and a sixth complementarity region, as well as a first end and a second end (Figure 1A). Wang describes that the first complementarity region is complementary to a first portion of said nucleic acid, the second complementarity region is complementary to the fourth complementarity region, the third complementarity region is complementary to said sixth complementarity region, the fifth complementarity region is complementary to a second portion of the target nucleic acid, and that the second oligonucleotide comprises a unique matching sequence which hybridizes to the first oligonucleotide (Figure 1A). In the reference’s case, complementarity regions 1 and 5 are the parts of the first and second oligonucleotides which bind to adjacent regions on the target nucleic acid (see Figure 1A). Complementarity regions 2 and 3 are the immediately adjacent but distinct regions of the first oligonucleotide or ‘primer’ (Figure S1), which bind to the complementarity regions 4 and 6 on either end of the second oligonucleotide, or ‘padlock.’ Complementarity regions 4 and 6 (shown with two double-sided red arrows in Figure S1) make up the unique matching sequence that hybridizes to the first oligonucleotide (Figure S1). Wang discloses ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule and amplifying the circular nucleic acid molecule to generate one or more amplicons (Fig. 1A). Wang also discloses imaging the amplicons to identify the target nucleic acid (Fig. 1C-E).
Regarding claim 77, Wang discloses using more than one pair of oligonucleotides (Figure 1A; pg. 4, col 3, 1st full par.).
Regarding claim 78, Wang discloses multiple rounds of imaging (Figure 1E).
Regarding claim 79, Wang discloses embedding sample in a hydrogel (pg. 1, col 3, 2nd full par.).
Regarding claims 84, 92, and 96, Wang discloses complementarity regions 1 and 5 (the target binding regions) with lengths of 19-25 nucleotides and with melting temperatures between 50-72ºC (Fig. S1(A), legend).
Regarding claims 90 and 91, Wang discloses complementarity regions 4 and 6 which comprise a first and second portion of a unique matching sequence which hybridizes to the first oligonucleotide (Figure S1(A) and legend).
Regarding claims 93-95 and 97, Wang discloses split complementarity regions 2 and 3 between 4-8 nucleotides in length (Figure S1(A) and legend). Although the reference does not explicitly disclose that immediately adjacent complementarity regions 4 and 6 are 4-8 nucleotides long, they bind to complementarity regions 2 and 3, and therefore share the same length.
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.
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 74-76 are rejected under 35 U.S.C. 103 as being unpatentable over Bava et al. (published March 28, 2019; Patent Publication No. US 2019/0093156) as applied to claim 73 above.
Bava discloses the limitations of claim 73 as discussed above.
Regarding claim 74, Bava does not explicitly teach a second pair of oligonucleotides comprising a unique matching sequence which is different than the unique matching sequence of the first pair of oligonucleotides. However, Bava does discuss multiple sets of probes with at least two members each, and a given set of probes binding to the same target molecule in a confirmation-specific manner (par. 196). Given that there are a finite number of solutions (i.e. the same unique matching sequence for each pair or different unique matching sequences between two pairs), and there is no evidence of unexpected results, it would have been obvious to a person with ordinary skill in the art to try including different unique matching sequences in different sets/pairs of oligonucleotides, in order to achieve high specificity of binding in the probe complex (par. 86). This would be desirable for reducing background and improving signal-to-noise ratios (par. 113).
Regarding claims 75 and 76, Bava discloses at least two pairs of oligonucleotides binding to the same nucleic acid (par. 114) or to different nucleic acids (par. 7, 114).
Claims 74-76 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (published July 27, 2018; Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691) as applied to claim 73 above, and in view of Bava et al. (published March 28, 2019; Patent Publication No. US 2019/0093156).
Wang discloses the limitations of claim 73 as discussed above.
Regarding claims 74-76, Wang does not explicitly teach a second pair of oligonucleotides comprising a unique matching sequence which is different than the unique matching sequence of the first pair of oligonucleotides, where the two pairs bind to different targets or to the same target.
Bava teaches methods of identifying target molecules including nucleic acids (par. 6).
Regarding claim 74, Bava does not explicitly teach a second pair of oligonucleotides comprising a unique matching sequence which is different than the unique matching sequence of the first pair of oligonucleotides. However, Bava does discuss multiple sets of probes with at least two members each, and a given set of probes binding to the same target molecule in a confirmation-specific manner (par. 196). Given that there are a finite number of solutions (i.e. the same unique matching sequence for each pair or different unique matching sequences between two pairs), and there is no evidence of unexpected results, it would have been obvious to a person with ordinary skill in the art to try including different unique matching sequences in different sets/pairs of oligonucleotides, in order to achieve high specificity of binding in the probe complex (par. 86). This would be desirable for reducing background and improving signal-to-noise ratios (par. 113).
Regarding claims 75 and 76, Bava discloses at least two pairs of oligonucleotides binding to the same nucleic acid (par. 114) or to different nucleic acids (par. 7, 114).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention, to combine the teachings of Wang and Bava, in order to reduce variability and improve sensitivity (par. 114).
Claims 79-83 are rejected under 35 U.S.C. 103 as being unpatentable over Bava et al. (published March 28, 2019; Patent Publication No. US 2019/0093156), as applied to claim 73 above, and in view of Moffitt et al. (published May 17, 2018; WO 2018089438 A1).
Bava discloses the limitations of claim 73, as discussed above.
Bava does not disclose a sample embedded in a hydrogel, nor does it disclose gel adaptor or mRNA retention oligonucleotides.
Moffitt discloses a method of identifying nucleic acids in situ which employs multiple sets of oligonucleotides for both anchoring and imaging.
Regarding claim 79, Moffitt discloses embedding a biological sample in hydrogel (pg. 5, ln 23-30; pg. 6 ln 12-27).
Regarding claims 80 and 81, Moffitt discloses contacting a sample with a gel adaptor oligonucleotide with a 5' end and a 3' end, wherein either the 3’ or 5' end is modified to link to a hydrogel embedding the sample (pg. 11, ln 2-5). Moffitt does not recite a binding site for the gel adaptor oligonucleotide adjacent to the first complementarity region of the first of a pair of oligonucleotides which bind to a nucleic acid target. However, Moffitt does recite a gel adaptor nucleotide binding to a target through an intermediary binding component (pg. 12, ln 22-26; pg. 39, example 4), as well as gel adaptor nucleotides complementary to a common binding site (pg. 13, ln 18-21). It would have been obvious to a person with ordinary skill in the art to try including a common binding site on the first oligonucleotide instead of the target nucleic acid itself, as there are a finite number of solutions (i.e. a binding site meant to anchor target nucleic acids residing on the target nucleic acid itself or an oligonucleotide in a target-binding complex), and there is no evidence of unexpected results. One would have been motivated to do so, in order to clear a sample of background while retaining desired target nucleic acids for analysis (pg. 15, ln 4-7).
Regarding claims 82 and 83, Moffitt discloses an mRNA retention oligonucleotide with a 5’ or 3’ modification which links to the hydrogel and a unique hybridization sequence (pg. 11, ln 2-5), as well as a polyT tail comprised of interleaved LNA thymine bases (pg. 11, ln 6-16). In one embodiment, the mRNA retention oligonucleotide is used in combination with the gel adaptor oligonucleotide during in situ analysis of RNA (pg. 39-40: Example 4).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention, to combine the teachings of Bava and Moffitt in order to facilitate detection of nucleic acids of interest while removing components of the sample which may contribute to background noise (pg. 5 ln 1-9).
Claims 80-83 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (published July 27, 2018; Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691), as applied to claim 73 and 79 above, and in view of Moffitt et al. (published May 17, 2018; WO 2018089438 A1).
Wang discloses the limitations of claims 73 and 79, as discussed above.
Wang does not disclose gel adaptor or mRNA retention oligonucleotides.
Moffitt discloses a method of identifying nucleic acids in situ which employs multiple sets of oligonucleotides for both anchoring and imaging.
Regarding claims 80 and 81, Moffitt discloses contacting a sample with a gel adaptor oligonucleotide with a 5' end and a 3' end, wherein either the 3’ or 5' end is modified to link to a hydrogel embedding the sample (pg. 11, ln 2-5). Moffitt does not recite a binding site for the gel adaptor oligonucleotide adjacent to the first complementarity region of the first of a pair of oligonucleotides which bind to a nucleic acid target. However, Moffitt does recite a gel adaptor nucleotide binding to a target through an intermediary binding component (pg. 12, ln 22-26; pg. 39, example 4), as well as gel adaptor nucleotides complementary to a common binding site (pg. 13, ln 18-21). It would have been obvious to a person with ordinary skill in the art to try including a common binding site on the first oligonucleotide instead of the target nucleic acid itself, as there are a finite number of solutions (i.e. a binding site meant to anchor target nucleic acids residing on the target nucleic acid itself or an oligonucleotide in a target-binding complex), and there is no evidence of unexpected results. One would have been motivated to do so, in order to clear a sample of background while retaining desired target nucleic acids for analysis (pg. 15, ln 4-7).
Regarding claims 82 and 83, Moffitt discloses an mRNA retention oligonucleotide with a 5’ or 3’ modification which links to the hydrogel and a unique hybridization sequence (pg. 11, ln 2-5), as well as a polyT tail comprised of interleaved LNA thymine bases (pg. 11, ln 6-16). In one embodiment, the mRNA retention oligonucleotide is used in combination with the gel adaptor oligonucleotide during in situ analysis of RNA (pg. 39-40: Example 4).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention, to combine the teachings of Wang and Moffitt in order to facilitate detection of nucleic acids of interest while removing components of the sample which may contribute to background noise (pg. 5 ln 1-9).
Claims 85-89 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (published July 27, 2018; Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691), as applied to claims 73 and 84 above, in view of Carlson et al. (published November 21, 2019; WO 2019222284 A1).
Wang discloses the limitations of claims 73 and 84, as discussed above.
Regarding claim 86, Wang discloses amplicons comprising a barcode (Fig. 1A). In this case, Wang’s ‘gene-unique identifier’ sequence in the amplicon serves as the barcode.
Regarding claims 87-89, Wang discloses a set of sequencing primers added after amplification which comprise an oligonucleotide configured to decode bases and an oligonucleotide configured to convert decoded bases into a fluorescent signal, which are removed after imaging (Fig. 1A, E). Wang discloses that ligation only occurs when both oligonucleotides are complementary to adjacent sequences of an amplicon (Fig 1E and legend).
Wang does not disclose the use of an antioxidant buffer as an antifade reagent.
Carlson teaches methods for identifying nucleic acids, including the use of STARmap for detection and sequencing of RNA in situ.
Regarding claim 85, Carlson discloses the use antioxidant antifade buffers (pg. 120, par. 393).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Wang and Carlson in order to mitigate photodamage while using the STARmap protocol (pg. 120, par. 393).
Claims 85-89 are rejected under 35 U.S.C. 103 as being unpatentable over Bava et al. (published March 28, 2019; Patent Publication No. US 2019/0093156), as applied to claims 73 and 84 above, in view of Carlson et al. (published November 21, 2019; WO 2019222284 A1), and further in view of Wang et al. (published July 27, 2018; Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691).
Bava discloses the limitations of claims 73 and 84, as discussed above.
Regarding claim 86, Bava discloses amplicons comprising a barcode (par. 112, as a ‘SeqTaq’).
Bava does not disclose the use of an antioxidant buffer as an antifade reagent.
Carlson teaches methods for identifying nucleic acids, including the use of STARmap for detection and sequencing of RNA in situ.
Regarding claim 85, Carlson discloses the use antioxidant antifade buffers (pg. 120, par. 393).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Bava and Carlson in order to mitigate photodamage while using the STARmap protocol (pg. 120, par. 393).
The combination of Bava and Carlson does not disclose the use of sequencing primer pairs where one of the pair decodes bases and the other converts decoded bases into a signal, where ligation only occurs when they are complementary to adjacent sequences of an amplicon.
Wang teaches the identification of nucleic acids using SNAIL probe sets in a predecessor method to STARmap 2 called STARmap (Abstract).
Regarding claim 87, Wang discloses a set of sequencing primers added after amplification which comprise an oligonucleotide configured to decode bases and an oligonucleotide configured to convert decoded bases into a fluorescent signal, which are removed after imaging (Fig. 1A, E). Wang discloses that ligation only occurs when both oligonucleotides are complementary to adjacent sequences of an amplicon (Fig 1E and legend).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Bava and Carlson with the teaching of Wang, in order to reduce background fluorescence and/or improve accuracy while using sequencing-by-ligation methods (Wang: pg. 4, 1st col, 1st par.).
Claims 93-95 and 97 are rejected under 35 U.S.C. 103 as being unpatentable over Bava et al. (published March 28, 2019; Patent Publication No. US 2019/0093156), as applied to claim 73 above, and in view of Wang et al. (published July 27, 2018; Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691).
Bava discloses the limitations of claim 73, as discussed above.
Bava does not disclose complementarity regions 2, 3, 4, and 6 having a length of 4-8 nucleotides
Wang teaches the identification of nucleic acids using SNAIL probe sets in a predecessor method to STARmap 2 called STARmap (Abstract).
Regarding claims 93-95 and 97, Wang discloses split complementarity regions 2 and 3 between 4-8 nucleotides in length (Figure S1(A) and legend). Although the reference does not explicitly disclose that immediately adjacent complementarity regions 4 and 6 are 4-8 nucleotides long, they bind to complementarity regions 2 and 3, and therefore share the same length.
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Bava and Wang, in order to reduce primer-padlock hybridization in favor of binding to the target molecule (Wang: Fig. S1, legend).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 73-97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,008,608. Although the claims at hand are not identical, they are not patentably distinct from each other. Both sets of claims are directed toward methods of analyzing nucleic acids (ref claim 1). Both sets of claims require:
Contacting a cell with at least a pair of oligonucleotides (ref claim 1)
wherein a first oligonucleotide has a first complementarity region that hybridizes to the target, and a second oligonucleotide has a fifth complementarity region which hybridizes to the target, and they hybridize to sites on the target which are adjacent (ref claim 1), and wherein
the first oligonucleotide has a complementarity region which hybridizes to a fourth and sixth complementarity region of the second oligonucleotide to form a matching sequence (ref claims 1),
ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule (ref claim 1)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 1)
imaging amplicons to identify the target nucleic acid (ref claim 1, 13)
Although the reference application does not explicitly say that the method is directed to identification of a nucleic acid target, its claims are directed toward sequencing, which is a manner of identification. Although the reference application does not disclose distinct complementarity regions 2 and 3 in the first oligonucleotide which bind to the second oligonucleotide, CR2 on the first oligonucleotide may be viewed as two immediately adjacent binding sites, consistent with that limitation.
Claims 73-97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,982,271, in view of Wang et al. (Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691). Although the claims at hand are not identical, they are not patentably distinct from each other. Both sets of claims are directed toward methods of identifying nucleic acids (ref claim 1). Both sets of claims require:
Contacting a cell with at least a pair of oligonucleotides (ref claim 1)
wherein a first oligonucleotide has a first complementarity region that hybridizes to the target, and a second oligonucleotide has a fifth complementarity region which hybridizes to the target, and they hybridize to sites on the target which are adjacent (ref claim 1), and wherein
the first oligonucleotide has a complementarity region which hybridizes to a fourth and sixth complementarity region of the second oligonucleotide to form a matching sequence (ref claims 1),
ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule (ref claim 1)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 1)
using amplicons to identify the target nucleic acid (ref claim 1, 13)
Although the reference application does not disclose distinct complementarity regions 2 and 3 in the first oligonucleotide which bind to the second oligonucleotide, CR2 on the first oligonucleotide may be viewed as two immediately adjacent binding sites, consistent with that limitation. Although the reference claims do not include a requirement for imaging, they are directed towards sequencing of amplicons generated from SNAIL probe sets, and it would be obvious to sequence such amplicons using methods such as SEDAL which require imaging (Wang: Fig. 1). One would, for example, be motivated to do so in order to reduce error accumulation during sequencing (Wang: pg. 4, col. 1, 2nd par.).
Claims 73-97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 12,359,253. Although the claims at hand are not identical, they are not patentably distinct from each other. Both sets of claims are directed toward methods of identification of nucleic acids (ref claim 1). Both sets of claims require:
Contacting a cell with at least a pair of oligonucleotides wherein a first oligonucleotide has a first complementarity region, a second complementarity region, and a third complementarity region; and a second oligonucleotide has a fourth complementarity region, a fifth complementarity region, and a sixth complementarity region (ref claim 1),
The first complementarity region is complementary to a first portion of said nucleic acid, the second complementarity region is complementary to the fourth complementarity region, the third complementarity region is complementary to the sixth complementarity region, the fifth complementarity region is complementary to a second portion of the target nucleic acid (ref claim 1)
The first complementarity region hybridizes to a site on the target which is adjacent to the site hybridized by the fifth complementarity region (ref claim 28)
ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule (ref claim 21)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 1)
imaging amplicons to identify the target nucleic acid (ref claim 1)
Although the reference application does not explicitly say that the second oligonucleotide has a unique matching sequence which hybridizes to the first oligonucleotide, complementarity regions 4 and 6 are a sequence which binds to the complementarity regions 2 and 3 in the first oligonucleotide and thus can be said to be a unique matching sequence between the pair (ref claim 1).
Claims 73-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 96-121 of Application No. 18/561,262.
Contacting a cell with at least a pair of oligonucleotides wherein a first oligonucleotide has a first complementarity region, a second complementarity region, and a third complementarity region; and a second oligonucleotide has a fourth complementarity region, a fifth complementarity region, and a sixth complementarity region, as well as a first end and a second end (ref claim 110),
The first complementarity region is complementary to a first portion of said nucleic acid, the second complementarity region is complementary to the fourth complementarity region, the third complementarity region is complementary to said sixth complementarity region, the fifth complementarity region is complementary to a second portion of the target nucleic acid (ref claim 110)
The first complementarity region hybridizes to a site on the target which is adjacent to the site hybridized by the fifth complementarity region (ref claim 110)
ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule (ref claim 112)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 110)
imaging amplicons to identify the target nucleic acid (ref claim 110)
Although the reference application does not explicitly say that the second oligonucleotide has a unique matching sequence which hybridizes to the first oligonucleotide, complementarity regions 4 and 6 represent a sequence which hybridizes to the complementarity regions 2 and 3 in the first oligonucleotide and thus can be said to be a unique matching sequence between the pair (ref claim 110). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 73-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 49-75 of Application No. 17/768,996. Although the claims at hand are not identical, they are not patentably distinct from each other. Both sets of claims are directed toward methods of identification of nucleic acids (ref claim 49). Both sets of claims require:
Contacting a cell with at least a pair of oligonucleotides (ref claim 49)
wherein a first oligonucleotide has a first complementarity region that hybridizes to the target, and a second oligonucleotide has a fifth complementarity region which hybridizes to the target (ref claims 50, 51),
The first complementarity region hybridizes to a site on the target which is adjacent to the site hybridized by the fifth complementarity region (ref claim 52)
the first oligonucleotide has a second and third complementarity region which hybridize to a fourth and sixth complementarity region of the second oligonucleotide (ref claims 53-54)
ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule (ref claim 55)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 49)
imaging amplicons to identify the target nucleic acid (ref claim 49)
Although the reference application does not explicitly say that the second oligonucleotide has a unique matching sequence which hybridizes to the first oligonucleotide, complementarity regions 4 and 6 are a sequence which binds to the complementarity regions 2 and 3 in the first oligonucleotide and thus can be said to be a unique matching sequence between the pair (ref claim 50, 53-54). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 73-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Application No. 19/390,190, in view of Wang et al. (Wang et al. Science. 2018 Jul 27;361(6400):eaat5691. doi: 10.1126/science.aat5691). Although the claims at hand are not identical, they are not patentably distinct from each other. Both sets of claims require:
Contacting a cell with at least a pair of oligonucleotides (ref claim 6) wherein a first oligonucleotide has a first complementarity region, a second complementarity region, and a third complementarity region; and a second oligonucleotide has a fourth complementarity region, a fifth complementarity region, and a sixth complementarity region, as well as a first end and a second end (ref claim 15-19),
The first complementarity region is complementary to a first portion of said nucleic acid (ref claim 15), the second complementarity region is complementary to the fourth complementarity region (ref claim 18), the third complementarity region is complementary to said sixth complementarity region (ref claim 19), the fifth complementarity region is complementary to a second portion of the target nucleic acid (ref claim 16)
The first complementarity region hybridizes to a site on the target which is adjacent to the site hybridized by the fifth complementarity region (ref claim 17)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 9, 20)
imaging amplicons to identify the target nucleic acid (ref claim 1, 11)
While the reference application does not explicitly say that the second oligonucleotide has a unique matching sequence which hybridizes to the first oligonucleotide, there is a sequence in the second oligonucleotide which hybridizes to the first oligonucleotide (ref claim 15, 18-19) which can be said to be a unique matching sequence between the pair. While the reference claims do not explicitly disclose ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule, such a step would be an obvious embodiment of the claims and a routine technique for amplification reactions (see Wang: Figure 1A). Although the claims are directed toward a system, the system as claimed would employ the method of the instant application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 73-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Application No. 19/362,262. Although the claims at hand are not identical, they are not patentably distinct from each other. Both sets of claims are directed to methods of identifying nucleic acids (ref claims 1, 7-8, 15-20). Both sets of claims require:
Contacting a cell with at least a pair of oligonucleotides wherein a first oligonucleotide has a first complementarity region, a second complementarity region, and a third complementarity region; and a second oligonucleotide has a fourth complementarity region, a fifth complementarity region, and a sixth complementarity region (ref claim 1),
The first complementarity region is complementary to a first portion of said nucleic acid, the second complementarity region is complementary to the fourth complementarity region, the third complementarity region is complementary to said sixth complementarity region, the fifth complementarity region is complementary to a second portion of the target nucleic acid (ref claim 1)
ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule (ref claim 11)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 1, 12-13)
imaging amplicons to identify the target nucleic acid (ref claim 1, 7-8)
Although the reference does not explicitly recite that first complementarity region hybridizes to a site on the target which is adjacent to the site hybridized by the fifth complementarity region, it does claim that they both hybridize to the nucleic acid as well as each other (ref claim 1), meaning the first and fifth complementarity regions would hybridize to adjacent regions on the target molecule, making the reference’s claims consistent with the instant application’s limitations. While the reference application does not explicitly say that the second oligonucleotide has a unique matching sequence which hybridizes to the first oligonucleotide, there is a sequence in the second oligonucleotide which hybridizes to the first oligonucleotide (ref claim 1), which can be said to be a unique matching sequence between the pair. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 73-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Application No. 19/213,523. Although the claims at hand are not identical, they are not patentably distinct from each other. Both sets of claims are directed toward methods of identification of nucleic acids (ref claim 1). Both sets of claims require:
Contacting a cell with at least a pair of oligonucleotides (ref claim 1)
wherein a first oligonucleotide has a first complementarity region that hybridizes to the target, and a second oligonucleotide has a fifth complementarity region which hybridizes to the target, and the first and fifth regions bind to adjacent regions on the target (ref claim 1)
the first oligonucleotide has a second and third complementarity region which hybridize to a fourth and sixth complementarity region of the second oligonucleotide to form a matching sequence (ref claims 1)
ligating the first and second ends of the second oligonucleotide to one another to generate a circular nucleic acid molecule (ref claim 1)
amplifying the circular nucleic acid molecule to generate one or more amplicons (ref claim 1)
imaging amplicons to identify the target nucleic acid (ref claim 1, 12, 13)
Although the reference application does not disclose distinct complementarity regions 2 and 3 in the first oligonucleotide which bind to the second oligonucleotide, CR2 on the first oligonucleotide (ref claim 1) may be viewed as two immediately adjacent complementarity regions (complementarity sites 2 and 3), making the reference’s claims consistent with the instant application’s limitations. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/C.M.J./Examiner, Art Unit 1682
/AMANDA HANEY/Primary Examiner, Art Unit 1682