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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/27/2023, 11/01/2023, 06/18/2025, and 12/10/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on March 02, 2026.
Claims 133-148 were previously pending. No claims amendment are made in the response filed on 03/02/2026.
Claims 133-148 are currently pending, with claims 136-138 and 140-144 withdrawn.
Claims 133-135, 139 and 145-148 are under examination. This is the first action on the merits.
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on March 02, 2026 is acknowledged:
Species of kit composition: A) kit comprising at least a second set of signal oligonucleotides per signal element segment (claim 135) 1;
Species of analyte: G) ribonucleic acid (claim 145) 2.
Claims 136-138 and 140-144 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 133-135, 139 and 145-148.
Priority
Regarding instant claims 133-135, 139 and 145-148, the earliest priority is 06/18/2021 because the priority document (PCT/EP2021/066668) filed that date is the first to disclose a decoding oligonucleotide comprising both a first segment (c1) and a second segment (c2) (see in Figs 16 and 17 in PCT/EP2021/066668), as required by independent claim 133.
Claim Objections
Claim 134 is objected to because of the following informalities:
In claim134, lines 2-3 and 4, "the S binding element" should read "the binding element (S) " for consistency with the term used in base claim 133.
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, regarding claim 133, it recites the term "essentially complementary," which is defined by the specification as follows:
" “Essentially complementary” means, when referring to two nucleotide sequences, that both sequences can specifically hybridize to each other under stringent conditions, thereby forming a hybrid nucleic acid molecule with a sense and an antisense strand connected to each other via hydrogen bonds (Watson-and-Crick base pairs). “Essentially complementary” includes not only perfect base-pairing along the entire strands, i.e. perfect complementary sequences but also imperfect complementary sequences which, however, still have the capability to hybridize to each other under stringent conditions. Among experts it is well accepted that an “essentially complementary” sequence has at least 88% sequence identity to a fully or perfectly complementary sequence." (page 27, lines 9-16).
Therefore, as expressly defined by the application's disclosure, the term "essentially complementary" encompasses not only perfect base-pairing, but also base-pairing that comprise mismatches, wherein the “essentially complementary” sequence has at least 88% sequence identity to a perfectly complementary sequence.
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.
Claims 133-135, 139 and 145-148 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.
A) Regarding claim 133, it recites in part (C): "at least one set of signal oligonucleotides per signal element segment," which is indefinite because it is unclear what "signal element segment" refers to. This term lacks antecedent basis, as the claim does not previously recite any "signal element segment," nor does it specify what structure or entity is being segmented. Accordingly, it is unclear how the phrase "per signal element segment" limits the recited "at least one set of signal oligonucleotides."
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, this phrase is interpreted as requiring the claimed kit comprises at least one set of signal oligonucleotides.
B) Regarding claim 133, it further recites in part (C): "wherein the number of different sets of signal elements is lower than the number of different types of analytes," which is indefinite because "the number of different sets of signal elements" lacks antecedent basis. The claim does not previously recite, either explicitly or implicitly, "different sets of signal elements," nor does it recite any "number" associated with such sets. In contrast, the claim only recites "at least one set of signal oligonucleotides."
Accordingly, it is unclear what element this limitation refers to and how it limits the scope of the claimed kit.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, this wherein clause is interpreted as not further distinguish the claimed kit from prior art.
C) Regarding claim 133, it recites in part (B): "a translator element (c) comprising a nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide," and further recites "wherein the translator element (c) comprises a first segment (c1) and a second segment (c2)." But it does not identify this nucleotide sequence "allowing a specific hybridization of at least one signal oligonucleotide" as "c1" or otherwise link it to the sequence "C1" later recited in part (C).
Part (C) then recites signal oligonucleotide comprising "a first translator connector element (C1) comprising a nucleotide sequence… which is essentially complementary to at least a first segment (c1) of the nucleotide sequence of a translator element (c)."
These recitations are indefinite because the structural and functional relationship between the "nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide" in translator element (c), and "first segment (c1)" is unclear. Specifically, it is unclear whether "c1" is the same as, a subset of, or distinct in structure from the previously recited nucleotide sequence "allowing a specific hybridization of at least one signal oligonucleotide."
For example, it is unclear whether
(i) the "first segment (c1)" corresponds exactly to the "nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide" in translator element (c);
(ii) the "first segment (c1)" is comprised by the "nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide" in translator element (c);
(iii) the sequences are entirely different and capable of independently hybridize to separate regions of a signal oligonucleotide, or to separate signal oligonucleotides.
Accordingly, the scope of the claim cannot be reasonably ascertained.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, it is interpreted that the "first segment (c1)" is comprised by the "nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide" in translator element (c).
Claims 134-135, 139 and 145-148 are rejected for depending from claim 133 and not remedying the indefiniteness.
D) Regarding claim 134, it recites:
"wherein the T/t melting temperature and the Cl/cl melting temperature are lower than a temperature necessary to dissociate the S binding element from its analyte such that a T/t double stranded segment and a Cl/cl double stranded segment melt under conditions where the S binding element remains bound to its analyte."
This claim language is indefinite because, based on the specification description, it is unclear what structural features of the analyte-specific probes (comprising S and T), the decoding oligonucleotides (comprising t and c1), and the signal oligonucleotides (comprising C1) that directly support the recited relative temperatures (e.g., melting temperatures of T/t and C1/c1 and "temperature necessary to dissociate the S binding element from its analyte") and the stated functional outcome.
The scope of a kit claim is defined by its structural features. “It is trite to state that the patentability of apparatus claims must be shown in the structure claimed and not merely upon a use, function, or result thereof.” In re Gardiner 171 F.2d 313 (C.C.P.A. 1948) (CCPA 12/07/48).
In this instant case, the claim does not clearly recite any structural feature in the probes comprised by the claimed kit, that directly support the described relative difference in temperatures.
Even considering the specification, it remains unclear what structural differences among T/t, C1/c1, and S/analyte account for the recited temperature difference and its intended outcome. Although the specification describes a method involving selective denaturation to dissociate T/t hybrids, it does not disclose probes having structural features designed to achieve distinct melting temperatures. Instead, the specification relies on modifying external conditions, such as increasing temperature or using denaturing reagents (page 53, lines 13-17; page 55, lines 11-14), which do not define the structure of the claimed kit. For example:
"The following steps (steps 11 and 12) are unnecessary for the last detection round.
○ Step 11: Selective denaturation. The hybridization between the unique identifier sequence (T) and the first sequence element (t) of the decoding oligonucleotides is dissolved. The destabilization can be achieved via different mechanisms well known to the trained person like for example: increased temperature, denaturing agents, etc. " (page 53, lines 13-17)
Thus, the specification does not disclose a kit comprising probes with structural features that provide a lower melting temperature for T/t and C1/c1 relative to the temperature necessary to dissociate the binding element (S) from its analyte.
Further, the claim does not directly compare the melting temperatures of T/t and C1/c1 with that of the S/analyte hybridization. Instead, it recites melting "under conditions where the S binding element remains bound to its analyte," which could be achieved by manipulations that go beyond the structure the probes, such as performing a step to stabilize the S/analyte interaction (e.g., via cross-linking or other covalent linking mechanisms), such that the S/analyte interaction is more stable than subsequent reversible hybridizations under denaturing conditions.
Even assuming that "temperature necessary to dissociate the S binding element from its analyte" specifically refers to the melting temperature of a nucleic acid duplex, the claim and specification fail to identify structural features that would result in the claimed temperature differences. Although the claim recites that T/t and C1/c1 are "essentially complementary," a percentage complementarity alone does not determine melting temperature.
It is well-established that melting temperature depends on multiple factors, including the exact sequence composition and base-pairing of both strands, GC content, duplex length, number and position of mismatches, hybridization type (e.g., DNA-DNA, DNA-RNA, RNA-RNA), DNA and salt concentrations, and nucleic acid modifications (See Dumousseau et al. MELTING, a flexible platform to predict the melting temperatures of nucleic acids. BMC Bioinformatics. 2012 May 16;13:101. doi: 10.1186/1471-2105-13-101. PMID: 22591039; PMCID: PMC3733425.)
None of these factors are recited in the claim or specified in the specification.
Accordingly, the scope of the recited wherein clause cannot be reasonably ascertained.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, the recited wherein clause in claim 134 is interpreted as not further distinguish the claimed kit from prior art, as it lacks clear structural features that directly support the recited functional language. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
E) Regarding claim 135, it recites "at least a second set of signal oligonucleotides per signal element segment," which is indefinite because it is unclear what "signal element segment" refers to. This term lacks antecedent basis, as the claim does not previously recite any "signal element segment," nor does it specify what structure or entity is being segmented. Accordingly, it is unclear how the phrase "per signal element segment" limits the recited "at least one set of signal oligonucleotides."
Claim 135 further recites:
"each signal oligonucleotide comprising:
(aa) a second translator connector element (C2) comprising a nucleotide sequence which is not specific to an analyte, and which is essentially complementary to at least a second segment (c2) of the nucleotide sequence of a translator element (c2) comprised in a decoding oligonucleotide such that a second translator element (c2) and a second translator connector element (C2) form, under annealing conditions, a C2/c2 double stranded segment having aC2/c2 melting temperature, and
(bb) a signal element, wherein the signal element for each signal oligonucleotide is a fluorescent label."
This claim languages is indefinite because it is unclear whether "each signal oligonucleotide comprising… " modifies only the signal oligonucleotides in the "second set of signal oligonucleotides," or if it also modifies the signal oligonucleotides in the "at least one set of signal oligonucleotides," recited in claim 133.
F) Regarding claim 139, it recites:
"wherein the number of different sets of decoding oligonucleotides per analyte comprising different translator elements (c) is less than the number of different sets of signal oligonucleotides comprising different connector elements (C). "
This claim language is indefinite for several reasons.
First, the phrase "the number of different sets of decoding oligonucleotides per analyte" is unclear. The base claim 133 does not recite "different sets of decoding oligonucleotides per analyte," but instead recites "at least one set of decoding oligonucleotides per analyte" and "wherein the decoding oligonucleotides of a set for an individual analyte differ from the decoding oligonucleotides of another set for a different analyte in the identifier connect element (t)."
Thus, the claim recites different sets of decoding oligonucleotides across different analytes, not multiple different sets within a single analyte ("per analyte"). Accordingly, it is unclear what is meant by "different sets of decoding oligonucleotides per analyte."
Second, the phrase "the number of different sets of signal oligonucleotides comprising different connector elements (C)" lacks antecedent basis. The claim does not previously recite "different sets of signal oligonucleotides" or define a "number" of such sets.
Accordingly, it is unclear what groupings of oligonucleotides this limitation refers to and how it limits the claim.
Claim Rejections - 35 USC § 112(a)
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.
Claim 134 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims 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.
Regarding claim 134, it recites:
"wherein the T/t melting temperature and the C1/c1 melting temperature are lower than a temperature necessary to dissociate the S binding element from its analyte such that a T/t double stranded segment and a Cl/cl double stranded segment melt under conditions where the S binding element remains bound to its analyte."
However, the applicant's disclosure lacks sufficient detail to demonstrate possession of the invention, as required under 35 U.S.C. 112(a).
Specifically, the application's disclosure does not disclose a kit comprising probes with defined structural features (e.g., defined nucleotide sequence, length, mismatch profile, type of hybridization, or other factors) that would result in the claimed temperature relationships ꟷ lower melting temperature for T/t and C1/c1 relative to the temperature necessary to dissociate the binding element (S) from its analyte. Nor does it demonstrate possession of a kit designed with specific structural characteristics to achieve the recited selective melting behavior.
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.
As discussed in the 35 U.S.C. 112(b) rejection above, while the specification describes a method involving selective denaturation of probes (page 53, lines 13-17), it does not identify any specific structural features of the probes that directly support such selective denaturation. Instead, the specification relies on modifying method conditions, such as changing temperature or adding denaturing reagents, rather than describing probe structures that provide the claimed function. In fact, Table 1 of the specification shows that both the disclosed method, as well as prior art probes in their respective methods, can achieve selective denaturation.
Further, the specification does not provide sufficient detail regarding how to design probes to achieve the claimed melting temperature relationships, nor does it describe methods for measuring and comparing temperatures in a matter that support the claim limitation. Thus, the disclosure does not demonstrate possession of a kit comprising probes with specific structural features that support the recited functional language.
Moreover, as there are numerous variables known in the art that can affect melting temperature and need to be carefully considered and controlled for ꟷ including the nucleotide sequence, chemical modifications, hybridization type, mismatch profile, duplex length, secondary structure, salt concentration, and probe concentration, etc., ꟷ a person of ordinary skill in the art would not have sufficient guidance from the limited disclosure to make and use the claimed kit.
Thus, the applicant's disclosure does not convey to those skilled in the art that the inventor had possession of the claimed invention at the time of filling, failing to meet the written description requirement of 35 U.S.C. 112(a).
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.
Claims 133-135, 139 and 145-148 are rejected under 35 U.S.C. 103 as being unpatentable over
Cai (Cai et al., US20170212983A1- Error correction of multiplex imaging analysis by sequential hybridization; Published on 2017-07-27)
, in view of Xia (Xia et al.; Multiplexed detection of RNA using MERFISH and branched DNA amplification. Sci Rep. 2019 May 22;9(1):7721. doi: 10.1038/s41598-019-43943-8. PMID: 31118500; PMCID: PMC6531529; cited as Non-Patent Literature #38 on IDS filed 07/27/2023), as evidenced by Moffitt (Moffitt et al., High-performance multiplexed fluorescence in situ hybridization in culture and tissue with matrix imprinting and clearing. Proc Natl Acad Sci USA 113, 14456–14461 (2016); cited as Non-Patent Literature#2 in IDS filed 12/10/2025).
A) Cai teaches probes and oligonucleotides for multiplex analyte encoding (entire document, Fig. 21; para. [0100-101] for examples) by sequential hybridization. The general concept of sequential hybridization is explained in Cai, for example, at para. [0101], [0135-0147] and [0306].
Cai discloses a hybridization complex wherein intermediate oligos bind to target analytes, and sequential hybridization barcodes are generated through recruitment of detectable signals from Hybridization Chain Reaction (HCR) polymers, indirectly linked to the intermediate oligos via bridging probes during contacting and imaging steps. This configuration involves three probe types functioning in a sandwiched format, as illustrated in Fig. 21.
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Regarding claim 133, Cai teaches probes and oligonucleotides for multiplex analyte encoding (entire document, Fig. 21; para. [0100-101] for examples), comprising:
(A) at least twenty (20) different sets of analyte-specific probes for encoding of at least 20 different analytes, each set of analyte-specific probes binding to a different analyte (Fig. 21; [0079]”125 genes are profiled, 100 of which are barcoded and 25 are identified by serial smHCR hybridizations.”; [0099] “a plurality of detectably labeled oligonucleotides target at least 100 targets”; [0100-101]),
wherein the analyte is a nucleic acid (Fig. 21; [0121]; [0111]; [0112] lines 1-3) and
each set of analyte-specific probes comprises at least five(5) analyte-specific probes (Fig. 21; [0112]” 10 or more intermediate oligonucleotides are employed for a target”; [0121] lines ) which specifically bind to different sub-structures of the same analyte by hybridization to form double stranded segments (Fig. 21; [113] “each intermediate oligonucleotide hybridizes with a different sequence of a target”),
each analyte-specific probe ([0112] lines 7-16, intermediate oligonucleotide; Fig. 21) comprising
(aa) a binding element (S) that specifically binds to one of the different analytes to be encoded by hybridization to form a double stranded segment ([0112]; Fig. 21, portion of the intermediate oligo binding to the target), and
(bb) an identifier element (T) comprising a specific identifier sequence which identifies the analyte to be encoded ([0112] intermediate oligonucleotide comprise overhang sequence; Fig. 21, portion of the intermediate oligo binding to the bridging strand; [0100-0101]),
wherein the analyte-specific probes of a particular set of analyte-specific probes share a common identifier element (T) ([0113]), and
wherein the analyte-specific probes of a particular set of analyte-specific probes differ from the analyte-specific probes of another set of analyte-specific probes in the nucleotide sequence of the identifier element (T) ([0113]; [0134]; [0181]lines 1-4; [0090]),
wherein the analyte-specific probes in each set of analyte-specific probes bind to the same analyte and comprise the same nucleotide sequence of the identifier element (T) which is specific to said analyte ([0113]); and
(B) at least one set of decoding oligonucleotides per analyte ([0113], detectably labeled oligonucleotide; [0112] lines 7-11, 24-35; Fig. 21),
wherein in each set of decoding oligonucleotides for an individual analyte each decoding oligonucleotide comprises:
(aa) an identifier connector element (t) comprising a nucleotide sequence which is essentially complementary to at least a section of the specific identifier sequence of the identifier element (T) of the corresponding analyte-specific probe set such that an identifier connector element (t) and an identifier element (T) form, under annealing conditions, a T/t double stranded segment having a T/t melting temperature (Fig. 21, portion of bridge probe binding to intermediate oligo, melting temperature is an inherent property of all nucleic acid duplexes [see Wikipedia (Nucleic acid thermodynamics - Wikipedia; Archived March 25, 2020 on WaybackMachine).]), and
(bb) a translator element (c) comprising a nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide (Fig. 21, portion of bridge probe binding to HCR polymers with fluorophores)
wherein the translator element (c) is not specific to an analyte (Fig. 21, the bridge molecules are not specific to analyte; [0112] lines 24-35) ;
wherein the decoding oligonucleotides of a set for an individual analyte differ from the decoding oligonucleotides of another set for a different analyte in the identifier connect element (t) (Fig. 21; [0155] the overhang sequence, which hybridize to bridge probes differentiates target genes); and
(C) at least one set of signal oligonucleotides per signal element segment,
each signal oligonucleotide comprising:
(aa) a first translator connector element (C1) comprising a nucleotide sequence which is not specific to an analyte (Fig. 21, the HCR polymer with fluorophore do not specifically bind to the analyte; [0062]; [0407]), and
which is essentially complementary to at least a first segment (c1) of the nucleotide sequence of a translator element (c) comprised in a decoding oligonucleotide such that a first translator element (c1) and a first translator connector element (C1)form, under annealing conditions, a C1/c1 double stranded segment having a C1/c1 melting temperature (Fig. 21, the portion of HCR polymer that bind to bridge oligo; [0062]; [0407]), and
(bb) a signal element, wherein the signal element for each signal oligonucleotide is a fluorescent label (Fig. 21, the HCR polymer with fluorophore; [0062]; [0407]).
Cai discloses most of the claimed limitations, including a 3-probe hybridization complex comprising a decoding oligonucleotide (bridge molecule) that connects the analyte-binding probe to the HCR probes labeled with fluorophores. While Cai teaches that the decoding oligonucleotide includes a translator element that hybridizes to a signal oligonucleotide (Fig. 21, portion of bridge probe binding to HCR polymers with fluorophores), it does not explicitly disclose that the translator element comprising two segments. Fig. 21 in Cai illustrates the decoding oligonucleotide (bridge molecule) as having a single binding region for a signal oligonucleotide (HCR probe labeled with fluorophores), which initiates the hybridization chain reaction to form a polymer containing multiple copies of signal oligonucleotides with detectable labels.
However, it would have been obvious to modify a decoding oligonucleotide with more than one translator element segment, each capable of binding to a signal oligonucleotide, in view of the teachings in Xia.
Xia teaches multiplexed fluorescence in situ hybridization (MERFISH) probes and reagents using signal amplification via branched DNA probes (entire document). It teaches that intermediate decoding oligonucleotides, which bind to analyte-binding probes, can de designed as branched DNA probes with multiple binding sites for fluorescent reporter probes (see Figure 1 b, primary amplifier).
Xia further highlights the advantages of using branched DNA probes for signal amplification, such as “drastic signal increase in RNA FISH samples without increasing the fluorescent spot size for individual RNAs or increasing the variation in brightness from spot to spot” (Abstract). Large fluorescent spot size and variations in brightness are known challenges associated with HCR probes design (page 2, para 3, lines 1-6).
In light of the above, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the hybridization probe design taught by Cai to include additional reporter probe ("signal oligonucleotides" as referred to in the claim) binding sites in the intermediate bridge molecule ("decoding oligonucleotide" as referred to in the claim), thereby allowing signal amplification in a branched fashion instead of hybridization chain reaction polymers, as taught by Xia. A skilled artisan would have been motivated to make this modification to leverage the benefits of branched DNA probes, as suggested by Xia, which directly address known challenges with HCR probes, such as those disclosed in Cai.
The person of ordinary skill would have had a reasonable expectation of success in combining the teachings because both references operate within the same field of multiplex fluorescent in situ hybridization, utilizing analyte-binding probes and intermediate probes that bind to both analyte-binding probes and reporter probes. The references share overlapping teachings, are in the same technological domain, and their teachings are technically compatible.
B) Regarding claim 134, it is obvious in view of the combined teachings of Cai and Xia because it does not further limit the claimed kit.
As discussed in the 35 U.S.C. 112(b) rejection above, claim 134 does not distinguish the claimed kit from prior art, as it lacks structural features that directly support the recited functional language.
Regarding claim 135, it recites a second set of signal oligonucleotides,
each signal oligonucleotide comprising:
(aa) a second translator connector element (C2) comprising a nucleotide sequence which is not specific to an analyte, and which is essentially complementary to at least a second segment (c2) of the nucleotide sequence of a translator element (c2) comprised in a decoding oligonucleotide such that a second translator element (c2) and a second translator connector element (C2) form, under annealing conditions, a C2/c2 double stranded segment having aC2/c2 melting temperature, and
(bb) a signal element, wherein the signal element for each signal oligonucleotide is a fluorescent label.
Thus, claim 135 requires another signal oligonucleotide binding to a second translator element segment within a decoding oligonucleotide. As discussed above for claim 133, this limitation is obvious in view of the combined teachings of Cai and Xia. Xia teaches a second set of signal oligonucleotides binding to a second segment of an intermediate decoding probe (see Fig. 1d, fluorescent labeled secondary amplifiers binding to at least two segments of the primary amplifier having multiple binding sites).
Regarding claim 139, it recites:
"wherein the number of different sets of decoding oligonucleotides per analyte comprising different translator elements (c) is less than the number of different sets of signal oligonucleotides comprising different connector elements (C)."
This limitation is obvious in view of the combined teachings of Cai and Xia because it does not further limit the claimed kit, because the claimed kit is not recited to comprise “different sets of decoding oligonucleotides per analyte” as discussed in the 35 U.S.C. 112(b) rejection above.
Therefore, this claim language is interpreted as descriptive statement without any associated structural or compositional element in the kit and do not distinguish the claim from the prior art.
Regarding claim 145, Cai teaches an analyte is a ribonucleic acid (Fig. 21).
Regarding claim 146, Xia teaches a pre-mixture of different sets of decoding oligonucleotides (page 10, para 4, lines3-4).
Regarding claim 147, Xia teaches a pre-mixture of different sets of analyte-specific probes (page 10, lines27-28), as evidenced by Moffitt. While Xia does not explicitly teach a pre-mixture of different sets of analyte-specific probes, it teaches a method of using analyte-specific probes as previously described in Moffitt (page 10, lines27-28). As evidenced by Moffitt, which teach a pre-mixture of different sets of analyte-specific probes (supporting information, page 1, left-hand col, para 3), this limitation is taught by Xia.
Regarding claim 148, Xia teaches a pre-mixture of different sets of signal oligonucleotides(page 10, para 4, lines10-12).
Double Patenting- Obvious Type
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 133-134 and 145-148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13-16 of U.S. Patent No.12442037B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '037 patent.
Instant claim 133 recites:
A kit for multiplex analyte encoding, comprising
(A) at least twenty (20) different sets of analyte-specific probes for encoding of at least 20 different analytes, each set of analyte-specific probes binding to a different analyte (‘037 Patent, claim 1),
wherein the analyte is a nucleic acid (‘037 Patent, claim 1) and
each set of analyte-specific probes comprises at least five(5) analyte-specific probes which specifically bind to different sub-structures of the same analyte by hybridization to form double stranded segments (‘037 Patent, claim 1),
each analyte-specific probe comprising
(aa) a binding element (S) that specifically binds to one of the different analytes to be encoded by hybridization to form a double stranded segment(‘037 Patent, claim 1), and
(bb) an identifier element (T) comprising a specific identifier sequence which identifies the analyte to be encoded (‘037 Patent, claim 1),
wherein the analyte-specific probes of a particular set of analyte-specific probes share a common identifier element (T) (‘037 Patent, claim 1), and
wherein the analyte-specific probes of a particular set of analyte-specific probes differ from the analyte-specific probes of another set of analyte-specific probes in the nucleotide sequence of the identifier element (T) (‘037 Patent, claim 1),
wherein the analyte-specific probes in each set of analyte-specific probes bind to the same analyte and comprise the same nucleotide sequence of the identifier element (T) which is specific to said analyte (‘037 Patent, claim 1); and
(B) at least one set of decoding oligonucleotides per analyte (‘037 Patent, claim 1),
wherein in each set of decoding oligonucleotides for an individual analyte each decoding oligonucleotide comprises:
(aa) an identifier connector element (t) comprising a nucleotide sequence which is essentially complementary to at least a section of the specific identifier sequence of the identifier element (T) of the corresponding analyte-specific probe set such that an identifier connector element (t) and an identifier element (T) form, under annealing conditions, a T/t double stranded segment having a T/t melting temperature (‘037 Patent, claim 1), and
(bb) a translator element (c) comprising a nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide (‘037 Patent, claim 1)
wherein the translator element (c) is not specific to an analyte (‘037 Patent, claim 1) and
wherein the translator element (c) comprises a first segment (c1) and a second segment (c2) (‘037 Patent, claim 1, first segment being “at least a section of the nucleotide sequence of a translator element (c)” that is essentially complementary to C, second segment being the rest of the nucleotide sequence of a translator element (c));
wherein the decoding oligonucleotides of a set for an individual analyte differ from the decoding oligonucleotides of another set for a different analyte in the identifier connect element (t) (‘037 Patent, claim 1); and
(C) at least one set of signal oligonucleotides per signal element segment,
wherein the number of different sets of signal elements is lower than the number of different types of analytes (‘037 Patent, claim 1),
each signal oligonucleotide comprising:
(aa) a first translator connector element (C1) comprising a nucleotide sequence which is not specific to an analyte (‘037 Patent, claim 1), and
which is essentially complementary to at least a first segment (c1) of the nucleotide sequence of a translator element (c) comprised in a decoding oligonucleotide such that a first translator element (c1) and a first translator connector element (C1)form, under annealing conditions, a C1/c1 double stranded segment having a C1/c1 melting temperature, and
(bb) a signal element, wherein the signal element for each signal oligonucleotide is a fluorescent label (‘037 Patent, claim 1).
Therefore, instant claims 133-134 are anticipated by claim 1 of the '037 patent. Instant claims 145-148 are anticipated by claims 16 and 13-15 of the '037 patent, respectively.
Claim 133 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 75 of copending Application No. 18/292,537 (reference application, amended claims filed on 07/22/2024), in view of Eng (Eng, et al., Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH+. Nature 568, 235–239 (2019); cited as Non-Patent Literature Document #7 in IDS filed 07/27/2023).
Instant claim 133 recites:
A kit for multiplex analyte encoding, comprising
(A) at least twenty (20) different sets of analyte-specific probes for encoding of at least 20 different analytes, each set of analyte-specific probes binding to a different analyte (‘537 Application, claim 75)
wherein the analyte is a nucleic acid (‘537 Application, claim 75) and
each set of analyte-specific probes comprises at least five(5) analyte-specific probes which specifically bind to different sub-structures of the same analyte by hybridization to form double stranded segments (‘537 Application, claim 75),
each analyte-specific probe comprising
(aa) a binding element (S) that specifically binds to one of the different analytes to be encoded by hybridization to form a double stranded segment (‘537 Application, claim 75), and
(bb) an identifier element (T) comprising a specific identifier sequence which identifies the analyte to be encoded (‘537 Application, claim 75),
wherein the analyte-specific probes of a particular set of analyte-specific probes share a common identifier element (T), and
wherein the analyte-specific probes of a particular set of analyte-specific probes differ from the analyte-specific probes of another set of analyte-specific probes in the nucleotide sequence of the identifier element (T) (‘537 Application, claim 75),
wherein the analyte-specific probes in each set of analyte-specific probes bind to the same analyte and comprise the same nucleotide sequence of the identifier element (T) which is specific to said analyte(‘537 Application, claim 75); and
(B) at least one set of decoding oligonucleotides per analyte (‘537 Application, claim 75),
wherein in each set of decoding oligonucleotides for an individual analyte each decoding oligonucleotide comprises:
(aa) an identifier connector element (t) comprising a nucleotide sequence which is essentially complementary to at least a section of the specific identifier sequence of the identifier element (T) of the corresponding analyte-specific probe set (‘537 Application, claim 75) such that an identifier connector element (t) and an identifier element (T) form, under annealing conditions, a T/t double stranded segment having a T/t melting temperature, and
(bb) a translator element (c) comprising a nucleotide sequence allowing a specific hybridization of at least one signal oligonucleotide (‘537 Application, claim 75)
wherein the translator element (c) is not specific to an analyte (‘537 Application, claim 75, translator element (c) does not specifically hybridize to analyte) and
wherein the translator element (c) comprises a first segment (c1) and a second segment (c2) (‘537 Application, claim 75, first segment being “at least a section of the nucleotide sequence of a translator element (c)” that is essentially complementary to C, second segment being the rest of the nucleotide sequence of a translator element (c));
wherein the decoding oligonucleotides of a set for an individual analyte differ from the decoding oligonucleotides of another set for a different analyte in the identifier connect element (t) (‘537 Application, claim 75); and
(C) at least one set of signal oligonucleotides (‘537 Application, claim 75) per signal element segment,
wherein the number of different sets of signal elements is lower than the number of different types of analytes,
each signal oligonucleotide comprising:
(aa) a first translator connector element (C1) comprising a nucleotide sequence which is not specific to an analyte (‘537 Application, claim 75), and
which is essentially complementary to at least a first segment (c1) of the nucleotide sequence of a translator element (c) comprised in a decoding oligonucleotide such that a first translator element (c1) and a first translator connector element (C1)form, under annealing conditions, a C1/c1 double stranded segment having a C1/c1 melting temperature(‘537 Application, claim 75), and
(bb) a signal element (‘537 Application, claim 75), wherein the signal element for each signal oligonucleotide is a fluorescent label.
The claims of the ‘537 Application largely overlap with the instant claim 133. While the ‘537 Application does not explicitly claim the signal element being a fluorescent label, this feature is obvious as fluorescent label is commonly used as a signal element, in spatial transcriptome profiling methods known in the art. This is supported by Eng (see in page 235, para 2; Fig. 1; cited reference #14, 20, 31 for examples )
The use of a fluorescent label in spatial transcriptome profiling represents a predictable use of prior art elements according to known methods to yield predictable results (see MPEP §2143). Therefore, instant claim 133 is obvious over claim 75 of the ‘537 Application , in view of Eng .
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Prior Art
Below are relevant prior art not used in rejection but pertinent to the claims or disclosure.
The concept of selective denaturation in multiplex imaging is known in the art.
Kishi (Kishi et al., SABER amplifies FISH: enhanced multiplexed imaging of RNA and DNA in cells and tissues. Nat Methods. 2019 Jun;16(6):533-544. doi: 10.1038/s41592-019-0404-0. Epub 2019 May 20. PMID: 31110282; PMCID: PMC6544483.; cited as NPL#14 in IDS cited 07/27/2023) teaches the selective denaturation of decoding probes bound to analyte-binding probes, while maintaining the binding of the analyte-binding probe to the nucleic acid analyte (Figure 5). This is achieved through melting temperature modeling in probe design and the use of a denaturing agent (Page 8, para 1).
Schueder (Schueder et al., Universal Super-Resolution Multiplexing by DNA Exchange. Angew Chem Int Ed Engl. 2017 Mar 27;56(14):4052-4055. doi: 10.1002/anie.201611729. Epub 2017 Mar 3. PMID: 28256790; PMCID: PMC5540260) teaches a sequential multiplexing imaging approach based on the rapid exchange of DNA probes that hybridize to analyte-binding probes (see Figure 1; page 3, para 1)
Conclusion
Claim 134 is objected to; claims 133-135, 139 and 145-148 are rejected. No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Claims 136-138 and 140-143 are withdrawn as being drawn to non-elected species B-E.
2 Claim 144 is withdrawn as being drawn to non-elected species F.
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