DETAILED ACTION
Claim Status
Claims 1, 27-37, 42-43, and 46 are pending. Claims 37 and 42-43 have been withdrawn. Claims 1, 27-36, and 46 are under examination.
Claim Objections
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 46 does not further narrow or limit the subject matter claimed in claim 1. Claims 1 and 46 recite the use of a small molecule. The specification teaches that the term “small molecule” relates to a low molecular weight (<900 Daltons) organic compound that may regulate a biological process, with the size on the order of 1 nm (see page 9 lines 30-33 of the original instant specification). Thus, claim 1’s rejection encompasses claim 46.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 27-31, 33, 35, and 46 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Gothelf et al., (WO2014041024A1) (IDS filed on 1116/2021).
Regarding claim 1, Gothelf teaches a method for determining the presence and/or
concentration of a small molecule analyte in a sample, said method comprising: I. providing a
sample to be analyzed for the presence of the analyte (abstract “The present invention relates
to an analyte detection system for detecting analytes different from DNA and RNA. The system
comprises a set of oligonucleotides which may hybridize to each other in specific ways and is
able to generate a signal based on the specific hybridization events. The system relies on
changes in the hybridization equilibrium between the oligonucleotides in the presence of an
analyte or analytes, which results in a change in signal.”, pg. 2 lines 10-14 “Hence, an improved
detection system for detecting molecules different from DNA and RNA would be advantageous,
and in particular a more efficient and/or reliable detection system for detecting small molecules
different from DNA and RNA would be advantageous.”, pg. 5 lines 12-21 “Still another aspect of
the present invention is to provide a method for detection the presence or level of an analyte
different from DNA and RNA in a sample, the method comprising a) providing a sample
comprising or suspected of comprising an analyte of interest; b) providing the analyte detection
system according to the present invention; c) incubating the sample with the analyte detection
system; d) comparing the detected level of analyte to a reference level; and e) determining the
presence or level of analyte in the sample.”); II. providing an analyte binding protein, said
analyte binding protein being an antibody or fragment thereof (pg. 3 lines 2-3 “X represents the
small molecule labelled on A, and Y is its corresponding binding protein.”, fig. 5) comprising: - a binding site for the analyte (fig. 5, pg. 4 lines 11-13 “Another object is to provide a detection
system which may detect small molecules different from DNA and RNA and only requiring one
binding site on the analyte to detect the analyte.”, pg. 22, lines 31-34 disclosing the covalently
linked binding moiety being an antibody; pg. 23 lines 3-7 “In an embodiment the binding moiety
may also have a sandwich structure, in the sense that a covalently linked first moiety functions
as a handle for a second binding moiety which can be bound covalently or non-covalently to the
first moiety. Thus, a second binding moiety may have a dual function I) binding to the first
moiety and II) binding site for the analyte.”); and- a first member of an optical signal pair
covalently coupled to the analyte binding protein through a first oligonucleotide linker (pg. 4 lines
17-32 “Thus, one aspect of the invention relates to an analyte detection system for detecting
analytes different from DNA and RNA, the system comprising at least a first oligonucleotide A, a
second oligonucleotide B, and a third oligonucleotide S, wherein: each of oligonucleotides A and
B comprise a sequence that is complementary or partly complementary to a sequence on
oligonucleotide S, and wherein oligonucleotides A and B compete for hybridization to
oligonucleotide S in a dynamic equilibrium, and optionally wherein at least one of
oligonucleotides A and B comprises a covalently linked binding moiety capable of interacting
with an analyte different from DNA and RNA; and at least one of oligonucleotides A and B, or a
covalently linked binding moiety bound to said oligonucleotide, is capable of interacting with an
analyte different from DNA and RNA, such that interaction of said analyte with the
oligonucleotide or binding moiety results in a shift in the hybridization equilibrium, the shift in
equilibrium providing a detectable signal.”); III. providing an analyte analogue, said analyte
analogue being covalently coupled to a second member of the optical signal pair through a
second oligonucleotide linker (pg. 4 lines 17-32); wherein, when said analyte binding protein
and said analyte analogue are in proximity, an optical signal is generated which is different from
the optical signal generated when the analyte binding protein and the analyte analogue are not
in proximity (pg. 26 lines 30-36, pg. 27 lines 1-5 “The detecting system according to the present invention comprises a signaling system providing a signal or change in signal when an analyte is detected. The signaling system is based on the principle that a signal is generated or
catalyzed when oligonucleotides are hybridized which comprises the different parts of the
signaling system. As illustrated in e.g. example 1, hybridization of the oligonucleotide 1 (A) and
5 (S) generates an increased signal when the two parts of the signaling system are brought into
proximity, whereas hybridization of oligonucleotide 3 and 5 does not result in the generation of a
signal. Thus, in an embodiment the second oligonucleotide (3) comprises the first group (2),
said first group forming a first part of a signaling system and the third oligonucleotide (5)
comprises the second group (6), said second group forming a second part of a signaling
system.”, pg. 28 lines 30-36, pg. 29 lines 1-10); IV. bringing in contact said sample, said analyte
binding protein and said analyte analogue, wherein said sample is brought in contact with the
analyte binding protein before being brought in contact with said analyte analogue (fig. 14, pg. 8
lines 30-31-36, pg. 9 lines 1-5 “Figure 14 illustrates the detection system when vitamin D (VD) is
the binding moiety and vitamin D-binding protein (DBP) is the analyte. Furthermore, it also
shows free vitamin D as the target in an inhibitive and a competitive assay. The schematic
shows the strand displacement of B aided by the binding of DBP onto VD on B. The band shift
assay shows a fluorescence image of a native polyacrylamide gel, where only oligonucleotide A
is visible. An increase in the AS population is seen upon addition of DBP. The first graph shows
the titration of DBP to the sensor. The second and third graphs show the inhibitive and
competitive detection of VD respectively.”), and V. determining the presence or absence of the
analyte in said sample by measuring an optical signal (abstract “The system relies on changes
in the hybridization equilibrium between the oligonucleotides in the presence of an analyte or
analytes, which results in a change in signal.”); and/or VI. determining the concentration of the
analyte in said sample by measuring an optical signal (figure 15, pg. 38 lines 8-19 “Example 2: Detection of a small molecule: Biotin. By applying the inhibition strategy (Figure 5; Strategy 2) in
the system described in example 1, biotin can be detected. In this experiment, biotin as the
target being detected was first mixed with a predetermined amount of STV, then the whole
mixture was added into the standard assay. In the presence of free biotin, all the active binding
sites on STV will be occupied, thus it can't have an effect on the DNA equilibrium. This signal-off
detection method was tested by using 14nM of DNA, 20nM of STV, and a series of
concentrations of biotin. A titration curve is shown in figure 4e. The molar ratio between biotin
and STV is consistent with the tetravalent property of STV.”).
Regarding claim 27, Gothelf teaches that the first oligonucleotide linker is an
oligonucleotide consisting of between 2 and 100 nucleotides (pg. 15 lines 9-14 “The first
oligonucleotide (1) forms part of the detection system. In an embodiment the length of the first
oligonucleotide (1) is in the range 8-100 nucleotides, such as 10-100, such as 15-100, such as
20-100, such as 30-100, such as 40-100, such as 50-100, such as 60-100, such as 70-100,
such as 80-100, such as 90-100, such as 8-90, such as 8-80, such as 8-70, such as 8-60, such
as 8-50, such as 8-40, such as 8-30, such as 8-20, or such as 8-15 nucleotides.”).
Regarding claim 28, Gothelf teaches that the first oligonucleotide-linker and the second
oligonucleotide linker are non-complementary (Example 1’s table on pg. 35, comparing the DNA
strand sequences shows that the sequence of the first oligonucleotide and the second
oligonucleotide are non-complementary).
Regarding claim 29, Gothelf teaches that the first oligonucleotide-linker and the second
oligonucleotide linker are DNA linkers (pg. 3 lines 1-2 “Here, A, B, and S are the three DNA
oligonucleotides, among which both A and B are partially complementary to S.”).
Regarding claim 30, Gothelf teaches that the concentration of the analyte in the sample
is determined (figure 15, pg. 38 lines 8-19 “Example 2: Detection of a small molecule: Biotin. By
applying the inhibition strategy (Figure 5; Strategy 2) in the system described in example 1,
biotin can be detected. In this experiment, biotin as the target being detected was first mixed with a predetermined amount of STV, then the whole mixture was added into the standard
assay. In the presence of free biotin, all the active binding sites on STV will be occupied, thus it
can't have an effect on the DNA equilibrium. This signal-off detection method was tested by
using 14nM of DNA, 20nM of STV, and a series of concentrations of biotin. A titration curve is
shown in figure 4e. The molar ratio between biotin and STV is consistent with the tetravalent
property of STV.”).
Regarding claim 31, Gothelf teaches that in said determination step V.- when said
generated optical signal is different from a reference optical signal, it is indicative of the
presence of said analyte in said sample; or - when said generated optical signal is not different
from a reference optical signal, it is indicative of the absence of the analyte in said sample (pg. 5
lines 13-21 “Still another aspect of the present invention is to provide a method for detection the
presence or level of an analyte different from DNA and RNA in a sample, the method
comprising a) providing a sample comprising or suspected of comprising an analyte of
interest; b) providing the analyte detection system according to the present invention; c)
incubating the sample with the analyte detection system; d) comparing the detected level of
analyte to a reference level; and e) determining the presence or level of analyte in the sample.”).
Regarding claim 33, Gothelf teaches that said sample is a biological sample selected
from the group consisting of blood, blood plasma, blood serum, saliva, urine, CSF, a tissue
sample, a water sample, an environmental sample, a food sample, a beverage, a surface swap,
a medical formulation, a drug formulation, an addictive substance, and an addictive formulation
(pg. 33 lines 8-11 “In yet another embodiment the biological sample has been obtained from a
mammal, such as a human. In a further embodiment the biological sample is a blood sample,
such as a serum or plasma, a urine sample, a feces sample, a biopsy sample, or a saliva
sample.”).
Regarding claim 35, Gothelf teaches that the analyte is an anticoagulant (pg. 23 lines
16-20, line 24 “Small organic molecules are also preferred analytes for the present invention. Ina more specific embodiment the at least one covalently linked binding moiety (4) is selected
from the group consisting vitamin D, folate, enrofloxacin, digoxigenin. Further examples of small
organic molecules and/or covalently linked binding moieties according to the present invention
are:…Drugs: morphine-3-glucuronide (M3G), oral anticoagulant warfarin, insulin.”, pg. 24 lines
9-10 “It is to be understood that the above list of compounds may also be the analytes to be
detected according to the present invention”).
Regarding claim 46, Applicant’s specification teaches that the term “small molecule” relates to a low molecular weight (<900 Daltons) organic compound that may regulate a biological process, with the size on the order of 1 nm (see page 9 lines 30-33 of the original instant specification). Thus, Applicant’s claim 1 (see discussion above) encompasses claim 46.
Moreover Gothelf teaches the small molecule analyte being biotin (see figure 4e, see page 38 lines 9-20). Further, the instant applications specification teaches that biotin is a known small molecule analyte (see page 18 line 18).
Claim Rejections - 35 USC § 102- Response to Arguments
The arguments filed on 06/30/2025 have been considered by the examiner.
On p. 6 applicant argues that Gothelf does not teach an analyte analog that is coupled to an oligonucleotide comprising a second member of an optical pair as recited in claim 1. The instant specification teaches that an analyte analog is an analyte that has been modified to contain a reporter molecule. Gothelf teaches using split DNA peroxidase as a reporter system (see page 53 lines 11-17). Further, Gothelf teaches that a fluorophore-quencher pair can be used as a reporter system (see page 37 lines 25-26). Gothelf teaches that the DNA peroxidase signaling system (analyte analog) is coupled to the oligonucleotide (see page 28 lines 20-25). Further, Gothelf teaches that the oligonucleotide contains an optical pair (see claim 1). The instant specification teaches that optical pair can be Alexa Fluor 488 and Alexa Fluor 555 (see pages 11-13). Gothelf teaches the use of both Alexa Fluor 488 and Alexa Fluor 555 (see page 7 lines 10-15, see examples 1 and 3). Lastly, Gothelf teaches an analyte analog that is coupled to an oligonucleotide comprising a second member of an optical pair (see claims 1 and 8).
On p. 6 applicant argues that the analyte binding protein in Gothelf is not coupled to an oligonucleotide that comprises a member of an optical pair. However, Gothelf teaches the oligonucleotide and binding moiety are covalently linked (coupled) and the oligonucleotide contains an optical pair (see pages 30 lines 29-35 and page 31 lines 1-2).
On pp. 7-8 applicant argues that Gothelf teaches away from the claimed invention by stating that “this assay circumvents antibody labeling or protein modification”. While Gothelf mentions that labeling or modification is not necessary, Gothelf teaches that both of those processes can still occur. In example 1 (see pages 34-35) Gothelf teaches methods of labeling and modification. Further, examples 4-7 and 9-10 all teach labeling and modification methods.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Gothelf as applied
to claims 1, 27-31, 33, and 35 above, and in view of Kong et al., (US20100255488A1) (IDS filed
on 11/16/2021).
The teachings of Gothelf as it pertains to claims 1, 27-31, 33, and 35 are discussed in
the 35 USC 102 rejection above. Gothelf is silent towards the distance between linkers.
Regarding claim 32, Kong teaches the distance between the first member and the
second member, when the analyte analogue is bound to the analyte binding protein, is in the
range 1-100 Angstrom ([0056] “The use of nucleic acid linker structures provides advantages of
ease of synthesis of the labeled linker, using conventional DNA synthesis and dye coupling
techniques, and resultant control of linker length, e.g., approximately 0.3 nm of distance
imparted for each added monomer in the linker portion. Consequently, one can easily adjust the
length of the linker to accommodate various spacing between the chromophores and the
reactant portion, or between the chromophores themselves.”, 0.3 nm is equal to 3 angstrom).
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to consider combining Gothelf and Kong as they teach detection of analytes. Given
the high level of skill in the art as evidenced by Gothelf and Kong, one of ordinary skill in the art
would have considered combining Gothelf’s methods of determining the presence and/or
concentration of small molecule analytes with Kong’s teachings of the linker distance. Kong
teaches that it is known in the art at the time of the instant application to distance the linkers in a
range from 1-100 Angstrom. Kong provides motivation by teaching that the length can easily be
adjusted to accommodate various spacings ([0056)]. The artisan would have had reasonable
expectation of success based on the cumulative disclosures of these prior art references at the
time the instant application was filed.
Claims 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Gothelf
as applied to claims 1, 27-31, 33, and 35 above, and in view of Schmitz et al., “Determination of
dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography – tandem
mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel
direct oral anticoagulants” (2014).
The teachings of Gothelf as it pertains to claims 1, 27-31, 33, and 35 are discussed in
the 35 USC 102 rejection above. Gothelf is silent towards the anticoagulant being apixaban.
Regarding claims 34 and 36, Schmitz teaches detecting and measuring apixaban
(abstract “To develop and validate a reference ultra-performance liquid chromatography –
tandem mass spectrometry (UPLCMS/ MS) method and to evaluate the analytical performance
of several coagulation assays for quantification of dabigatran, rivaroxaban, and apixaban.”, pg.
1636 “For apixaban, the Liquid anti-Xa assay was superior to the PiCT-Xa assay.”).
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to consider combining Gothelf and Schmitz as they teach measuring and detecting
small molecules such as anticoagulants. Given the high level of skill in the art as evidenced by
Gothelf and Schmitz, one of ordinary skill in the art would have considered combining Gothelf’s
methods of determining the presence and/or concentration of small molecule analytes with
Schmitz’s method of detecting and measuring apixaban. Schmitz provides motivation by
teaching that assays can be used to detect apixaban in plasma (pg.1641). The artisan would
have had reasonable expectation of success based on the cumulative disclosures of these prior
art references at the time the instant application was filed.
Claim Rejections - 35 USC § 103-Response to Arguments
The arguments filed on 06/30/2025 have been considered by the examiner.
On p. 8 applicant argues that one skilled in the art would not have had reasonable expectation of success when using Gothelf and Kong and/or Schmitz.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MCKENZIE A DUNN whose telephone number is (571)270-0490. The examiner can normally be reached Monday-Tuesday 730 am -530pm, Wednesday-Friday 730 am-430 pm.
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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/Ann Montgomery/Primary Examiner, Art Unit 1678