DETAILED ACTION
Claims 1, 35, 38-39, 41, 43, 45, 47-48, and 51-53 are pending.
Status of Claims
Claims 1, 35, 38-39, 41, 43, 45, 47-48, and 51-53 are pending. Claims 1, 35, 38-39, and 52 have been amended. Claims 2-34, 36-37, 40, 42, 44, 46, and 49-50 have been cancelled.
Claims 1, 35, 38-39, 41, 43, 45, 47-48, and 51-53 are under examination.
Withdrawn Claim Rejections and/or Objections
The arguments filed on 09/19/2025 have been considered by the examiner.
The rejection of claims 36-38 under 35 USC 112(b) for being indefinite as set forth on p. 3 of the previous office action (mailed on 06/23/2025) has been withdrawn in view of the amended and cancelled claims (filed on 09/19/2025).
The rejection of claim 50 under 35 USC 112(b) for being indefinite as set forth on pp. 3-4 of the previous office action (mailed on 06/23/2025) has been withdrawn in view of the cancelled claim.
The rejection of claim 3 under 35 USC 103 as being unpatentable over Soldo, Gordon, Anteo, Pugia, and Piletska et al., as set forth on pp. 9-11 of the previous office action (mailed on 06/23/2025) has been withdrawn in view of the cancelled claim.
The provisional rejection of claim 3 for nonstatutory double patenting over 17263809 as set forth on p. 33 of the previous office action (mailed on 06/23/2025) has been withdrawn in view of the cancelled claim.
The provisional rejection of claim 3 for nonstatutory double patenting over 17636012 as set forth on p. 34 of the previous office action (mailed on 06/23/2025) has been withdrawn in view of the cancelled claim.
The provisional rejection of claim 3 for nonstatutory double patenting over 17263809 as set forth on pp. 35-36 of the previous office action (mailed on 06/23/2025) has been withdrawn in view of the cancelled claim.
The rejection of claim 50 under 35 USC 103 as being unpatentable over Soldo, Gordon,
Anteo, Pugia, and Halbert et al., as set forth on pp. 16-18 of the previous office action (mailed on 06/23/2025) has been withdrawn in view of the cancelled claim.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Soldo et al., (US
2015/0361178 A1) (IDS filed 02/22/2023), in view Gordon et al., “Association of 1,25-
Dihydroxyvitamin D Levels with Physical Performance and Thigh Muscle Cross- sectional Area
in Chronic Kidney Disease Stage 3 and 4” (2012), in view of Anteo Diagnostics Limited (AU
2016100182 A4) (IDS filed 02/22/2023), and in further view of Pugia et al., (US 2017/0102390
A1) (IDS filed 02/22/2023).
Regarding claim 1, Soldo teaches a method for isolating a biomarker from a biological
sample ([0021] “C18-0H columns to separate out potentially interfering vitamin D metabolites
such as 24, 25 (OH2)2d, 25, 26 (OH)2D and 25 (OH)D in order to isolate 1,25(OH)2D from the
test sample prior to metabolite measurement”) comprising a volume between 50 and 10,000 µl ([0085] “First, 50 µl of human serum sample was incubated with 100 µl of assay buffer and 50 ul
of VDR-LBD-TAG for 30 minutes.”) and further comprising an interference ([0082] “The assay
buffer formulation consisted of TRIS 50 mM pH 7.4, CHAPS 0.02%, EDTA 1 mM, heparin at 8
mg/ml and 1% mouse serum to mitigate heterophilic human anti mouse (HAMA)
interferences.”), the method comprising: a) Combining the sample with a particle comprising a
capture moiety that binds the biomarker to provide a mixture ([0082] “Paramagnetic
microparticles (PMPs) (Dynal, Norway) were coated with the 11B4 monoclonal antibody
following the supplier instructions. The recombinant VDR-LBD”, [0085] “human serum sample
was incubated with…VDR-LBD-TAG for 30 minutes. Next…PMPs coated with 11b4H11H10
monoclonal antibody were added and the reaction mixture”); and b) mixing the mixture to
provide particles complexes to the biomarker ([0085] “Human serum sample was incubated
with…VDR-LBD-TAG for 30 minutes. Next…PMPs coated with 11b4H11H10 monoclonal
antibody were added and the reaction mixture”, [0071] “VDR- LBD/1,25(OH)2D complex, and
the unbound vitamin D ligand binding domain alone as negative control…microtiter plates were
coated…His-tagged recombinant VDR-LBD protein in the unbound form…the monoclonal
antibodies…with gentle mixing”); thereby isolating the biological sample ([0021] “C18-0H
columns to separate out potentially interfering vitamin D metabolites such as 24, 25 (OH2)2d,
25, 26 (OH)2D and 25 (OH)D in order to isolate 1,25(OH)2D from the test sample prior to
metabolite measurement”, [0038] “Vitamin D Receptor protein or the Ligand Binding Domain
thereof used as the receptor protein in the present invention further comprises or is coupled to
an affinity tag, in order to substantially improve purification”, [0087] “the specific recovery of
1,25(OH)2D in human serum…quantitatively recovers the whole amount of 1,25(OH)2D in
human serum independently of serum total 25(OH)D concentrations”).
Soldo is silent towards a method that further comprises subjecting the particle complexes to diagnostic testing, using a lyophilized particle, removing the particle complexes comprising the biomarker from the mixture and adding a cleavage reagent or releasing agent to the mixture, and removing at least 99% of an interference from a biological sample.
However, Soldo teaches a method that detects 1,25(OH)2D in clinical samples from
patients ([0051] “detection of captured VDR-LBD-1,25(OH)2D complex”, [0029] “determination
of 1,25(OH)2D in clinical samples, [0054] “The detection method of the invention is an in vitro
immunoassay performed on a biological fluid sample of a subject or patient”).
Gordon teaches that circulating levels of 1,25(OH)2D decrease early in the course of
chronic kidney disease (pg. 2 “Circulating levels of 1,25-dihydroxyvitamin D (1,25(OH)2D), the
active form of vitamin D, begin to decline early in the course of CKD1 owing to the decline in
proximal tubular production of 1α-hydroxylase, resulting in the development of secondary
hyperparathyroidism (SHPT)”).
Gordon is silent towards using a lyophilized particle.
Anteo teaches using a lyophilized particle that comprises streptavidin that binds to the
interference (pg. 15 “magnetic beads dried/lyophilized in the primary sample tube”, pg. 3 lines
18-20 “In some embodiments, the member of the binding pair is an antibody, antigen, a Fab, an
SdAb, an immunoglobulin, a binding domain, a ligand, biotin, streptavidin.”, fig. 3A, fig. 3B).
Anteo also teaches removing at least 99% of an interference from a biological sample (pg. 2,
summary of the disclosure, “a method to remove or decrease interference in an analyte
comprising…”, “the analyte is a bodily fluid or biological sample”, pg. 14 lines 20- 30, pg. 15
lines 1-2 “The advantage of this approach is the addition, mixing, and removal of the magnetic
particles can easily be automated on existing sample handling platforms, or via an Anteo
developed sample handling instrument. This approach requires magnetic particles with excellent
magnetic susceptibility and size uniformity for 100% removal after addition, and good colloidal
stability (slow settling rate) to maximize binding kinetics and minimize incubation time needed.
Another magnetic particle approach, which is simpler and similar to the secondary sample tube
approach, is to design new Manufacturer specific sample racks, or modify existing racks, with magnets to pull the magnetic beads to the sides of the sample tube as only the targeted
interference will be captured and bound (sequestered) to the sample tube's walls via the
magnetic particles and magnets, while the supernatant in the sample tube will now be depleted
and free of such interference as well as depleted and free of the magnetic particles which could
interfere in the assay if still present in the sample.”. Anteo teaches the sample being free of the
interferences, thus removing at least 99%of an interference from a biological sample). Lastly,
Anteo teaches the interference comprising biotin (pg. 3 lines 20-22 “In these embodiments, the
interfering substance is an antibody, an antigen, an immunoglobulin, RNA, DNA, a virus, lipid,
streptavidin or biotin.”, fig. 3A, fig. 3B).
Pugia teaches c) removing a particle complexes from the mixture ([0121] “After suitable
washing to remove non-particulate material and to reduce the number of non-rare molecules
and non-rare cells…”); and d) adding to the mixture a cleavage reagent or releasing agent to
provide an isolate comprising the biomarker; thereby isolating the biomarker from the biological
sample ([0119] “one or more linking groups may comprise a cleavable moiety that is cleavable
by a cleavage agent.”, [0220] “A rare cell filtration system (Siemens Healthcare Diagnostics Inc.) was used to isolate the cancer cells, perform affinity reactions and to load the carrier particles onto the cells”). Pugia also teaches the cleavage reagent being a disulfide bond reducing reagent ([0119] “cleavable moieties and corresponding cleavage agents, by way of
illustration and not limitation, include disulfide that may be cleaved using a reducing agent”).
It would have been obvious to one of ordinary skill in the art at the time the application
was filed to combine the teachings of Soldo, Gordon, Anteo, and Pugia, as they teach detection
of biomarkers. Given the high level of skill in the art evidenced by Soldo, Gordon, Anteo and
Pugia, one of ordinary skill in the art would have considered combining Soldo’s and Gordons’s
methods of detecting a biomarker such as 1,25(OH) with Anteo’s method of removing or
decreasing interference in an analyte with Pugia’s methods of detecting biomarkers by isolating
the biomarker from the sample. Anteo teaches motivation towards removing or decreasing
interferences as interferences can have major clinical consequences and may lead to
unnecessary clinical investigation as well as inappropriate treatment with potential favorable outcomes for the patient (pg. 2 lines 4-7). Anteo teaches that it is important to
recognize interferences in immunoassays and put procedures in place to identify them
whenever possible as interferences in immunoassays is a serious but underestimated problem
(pg. 2 lines 7-9). Anteo also provides motivation for using methods to decrease or remove
interferences by teaching that mitigating assay-specific interference can improve the accuracy
and quality of results reported to physicians, and ultimately improve the health and wellbeing of
the patients (pg. 12 lines 26-30). Soldo provides motivation for detecting 1,25(OH)2D in a
sample by teaching that 1, 25 (OH)2D is mediated by binding of the bioactive hormone to a
specific intracellular Vitamin D Receptor (VDR) which acts primarily by regulating the expression
of genes whose promoters contain specific DNA sequences known as Vitamin D Response
Elements (VDRES) ([0007]). Soldo provides further motivation by teaching that the
determination of circulating 1,25(OH)2D is becoming of increasing relevance in many clinical
applications, either as a diagnostic marker and/or as a therapy monitoring indicator ([0015]).
Gordon provides further motivation by teaching decreased levels of 1,25(OH)2D are associated
with chronic kidney disease (pg. 2, 7). Pugia provides motivation by teaching that the disclosed
method releases label for detection and offers several advantages ([0123] “cleavable to release
the MS label or MS label precursor into solution for analysis”, [0131] “The use of peptides as MS
labels has several advantages, which include, but are not limited to, the following: 1) relative
ease of conjugation to proteins, antibodies, particles and other biochemical entities. It would
have been obvious to one of ordinary skill in the art at the time the instant application was filed
to use lyophilized particles and optimize the method to subject the particle complexes to
diagnostics testing, since 1,25(OH)2D in clinical samples would indicate a physical state of a
patient. As Gordon teaches, levels of 1,25(OH)2D decrease in the early course of chronic
kidney disease, making 1,25(OH)2D a good biomarker for early disease diagnosis. The artisan
would have reasonable expectation of success based on the cumulative disclosure of these
prior art references at the time the instant application was filed.
Claims 35, 38 and 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over
Soldo, Gordon, Anteo, and Pugia as applied to claim 1 above, and in further view of Piletska et
al., “Size Matters: Influence of the Size of Nanoparticles on Their Interactions with Ligands
Immobilized on the Solid Surface” (2010).
The teachings of Soldo, Gordon, Anteo, and Pugia as applied to claim 1 are discussed in
the 35 USC 103 rejection above.
Regarding claim 35, Anteo teaches a method for determining whether a biomarker is
present in a biological sample (figure. 13, “IFN-gamma chemiluminescence assay”), comprising
a volume between 50 and 10,000 µl ([0085] “First, 50 µl of human serum sample was incubated with 100 µl of assay buffer and 50 ul of VDR-LBD-TAG for 30 minutes.”), the method
comprising: a) combining the sample with a particle comprising a capture moiety that binds an
interference to provide a mixture (pg. 14-15, “Uniform size, 1.0 to 3.0 micron, paramagnetic
microparticles, functionalized with Mix&GoTM and coated with HAAA and/or MASI specific
blocker(s)…This approach is the addition, mixing, and removal of the magnetic particles can
easily be automated…With magnets to pull the magnetic beads to the sides of the sample tube
as only the targeted interference will be captured and bound (sequestered) to the sample tube’s
wall…”, pg. 16 “can be used to prepare functionalized sample tubes…as paramagnetic
particles, for subsequent binding of functionally active blocking reagents for sample pre-
treatment to mitigate/remove/eliminate heterophiles (i.e. human anti-mouse IgG, goat IgG,
rabbit IgG, bovine IgG, etc.) and/or Manufacture specific interferences (i.e. free biotin and anti-
ruthenium antibodies for Roche, free fluorescein and anti-fluorescein antibodies for Siemens,
anti-alkaline phosphatase antibodies for Beckman, etc...) from patient specimens prior to testing
these specimens on a given analyzer.”; b) mixing the mixture to provide a particle complex to
the interference (pg. 19 “Mix&Go bead(s) are added to the sample, mixed, and removed with
magnet…Mix&Go beads pre-treatment- sample is transferred (aspirated ad dispensed) into the
Mix&Go specific secondary tube, and Mix&Go bead(s) are added to the sample, mixed, and
removed with magnet.); c) removing or eliminating the particle complexes to provide an
interference-depleted solution (pg. 14-15 “Uniform size, 1.0 to 3.0 micron, paramagnetic
microparticles, functionalized with Mix&GoTM and coated with HAAA and/or MASI specific
blocker(s)…magnets to pull the magnetic beads to the sides of the sample tube as only the
targeted interference will be captured and bound (sequestered) to the sample tube’s wall via the
magnetic particles and magnets, while the supernatant in the sample tube will now be depleted
and free of the magnetic particles which could interfere in the assay if still present in the
sample”). Anteo teaches the interference comprising biotin (pg. 3 lines 20-22 “In these
embodiments, the interfering substance is an antibody, an antigen, an immunoglobulin, RNA, DNA, a virus, lipid, streptavidin or biotin.”, fig. 3A, fig. 3B). Anteo also teaches removing at least 99% of an interference from a biological sample (pg. 2, summary of the disclosure, “a method to remove or decrease interference in an analyte comprising…”, “the analyte is a bodily fluid or biological sample”, pg. 14 lines 20- 30, pg. 15 lines 1-2 “The advantage of this approach is the addition, mixing, and removal of the magnetic particles can easily be automated on existing sample handling platforms, or via an Anteo developed sample handling instrument. This approach requires magnetic particles with excellent magnetic susceptibility and size uniformity for 100% removal after addition, and good colloidal stability (slow settling rate) to maximize binding kinetics and minimize incubation time needed. Another magnetic particle approach, which is simpler and similar to the secondary sample tube approach, is to design new
Manufacturer specific sample racks, or modify existing racks, with magnets to pull the magnetic
beads to the sides of the sample tube as only the targeted interference will be captured and
bound (sequestered) to the sample tube's walls via the magnetic particles and magnets, while
the supernatant in the sample tube will now be depleted and free of such interference as well as
depleted and free of the magnetic particles which could interfere in the assay if still present in
the sample.”. Anteo teaches the sample being free of the interferences, thus removing at least
99%of an interference from a biological sample).
Anteo is silent towards d) combining the depleted solution with a second particle
comprising a second capture moiety to provide a second mixture, wherein the 2nd capture
moiety binds the biomarker; e) mixing the second mixture to provide a second particle complex
comprising the biomarker; f) removing the second particle complex from the second mixture;
and g) washing the particle complex with a dilutent; and h) adding to the second mixture a cleavage reagent or releasing agent to provide an isolate comprising the biomarker, wherein the cleavage reagent is a disulfide bond reducing reagent; thereby isolating the biomarker from the biological sample. Anteo is also silent towards the streptavidin binding to biotin.
Soldo teaches a method for isolating biomarkers ([0021] “to isolate 1,25(OH)2D from the
test sample prior to metabolite measurement”) comprising a capture moiety with a sample to provide a particle complex comprising the biomarker with a capture moiety ([0082]
“Paramagnetic microparticles (PMPs) (Dynal, Norway) were coated with the 11B4 monoclonal
antibody following the supplier instructions. The recombinant VDR-LBD”, [0085] “human serum
sample was incubated with…VDR-LBD-TAG for 30 minutes. Next…PMPs coated with
11b4H11H10 monoclonal antibody were added and the reaction mixture”, [0040] “and removing
the biomarker from the mixture”, [0087] “we concluded that the 1,25(OH)2D assay of the
invention specifically and quantitatively recovers the whole amount of 1,25(OH)2D in human
serum independently of serum total 25(OH)D concentrations”). Soldo also teaches washing the particle complex with a diluent (see [0071]).
Pugia teaches the use of particles comprising capture moieties attached via cleavable linkers to isolate and detect analytes, and removal of the particles from a mixture (claim 11 “label particle is magnetic and is removed from the membrane by punching out, filtration, extraction, or pick up”, claim 1 “Detecting one or more different populations of target rare molecules”, claim 6 “the affinity reagent comprises more than one carrier particle wherein each of the carrier particles is linked”, claim 8 “the linking group is cleavable”), [0220] “rare cell filtration system…to isolate cancer cells, perform affinity reactions and to load the carrier particles onto the cells”). Pugia also teaches the cleavage reagent being a disulfide bond reducing reagent ([0119] “cleavable moieties and corresponding cleavage agents, by way of illustration and not limitation, include disulfide that may be cleaved using a reducing agent”).
Regarding claim 38, Pugia teaches that the biomarkers can be used in a diagnostics
test ([0045] “The phrase “non-cellular target rare molecules” refers to target rare molecules that
are not bound to a cell and/or that freely circulate in a sample. Such non-cellular target rare
molecules include biomolecules useful in medical diagnosis of diseases, which include, but are
not limited to, biomarkers for detection of cancer, cardiac damage, cardiovascular disease,
neurological disease, hemostasis/hemastasis, fetal maternal assessment, fertility, bone status,
hormone levels, vitamins, allergies, autoimmune diseases, hypertension, kidney disease,
diabetes, liver diseases, infectious diseases and other biomolecules useful in medical diagnosis
of diseases, for example.”).
Regarding claim 52, Anteo teaches the sample comprises serum (pg. 2 lines 26-28 “In
some exemplary embodiments, the analyte is a bodily fluid or biological sample. Examples of
such analytes include blood, serum, plasma, urine, semen, saliva, stool or mucous.”) and said
capture moiety comprises streptavidin (pg. 3 lines 18-20 “In some embodiments, the member of
the binding pair is an antibody, antigen, a Fab, an SdAb, an immunoglobulin, a binding domain,
a ligand, biotin, streptavidin.”, fig. 3A, fig. 3B). Anteo does not explicitly teach the size of the
particle.
Piletska teaches that nanoparticles are known to have a diameter between 50-200 nm
(abstract). Piletska teaches nanoparticles with biotin-streptavidin interactions (pg. 3784 “This
tendency is in agreement with data published on biotin-streptavidin and biotin-avidin interaction in different systems and can be followed in systems other than silica nanoparticles10,12
(see corresponding reference points in Figure 2). It is well-known that free biotin has the highest
affinity toward free streptavidin and avidin (KD = 10-13 and 10-15 M, correspondingly).4,13 The
size of an avidin molecule is reported as 3.6 nm,14 and the size of streptavidin is 5 nm in
diameter.”). Piletska teaches that particles with higher concentrations of immobilized biotin on
the particle surface demonstrated strong binding with streptavidin (pg. 3785). The sizing of
nanoparticles is generally known in the art as evidenced by Piletska. It would have been
obvious to one of ordinary skill in the art to optimize the parameters of the diameter based on
the demands of the diagnostic testing. Absent evidence of unexpected results, optimizing the
nanoparticle with the diameter of 230 nm would be an obvious matter of choice, depending on
the diagnostic test the particle is being used with.
Regarding claim 53, Piletska teaches streptavidin particle concentrations being 5 ng
mL-1, 50 ng mL-1, 0.5 µg*mL-1, 50 µg*mL-1, and 500 µg*mL-1(fig. 1, pg. 3784 “Figure 1.
Sensorgram of time-dependent binding of 50 nm silica nanoparticles functionalized with biotin to
the streptavidin-coated surface of the Biacore sensor chip. Particle concentrations are 5 ng mL-
1, 50 ng mL-1, 0.5 µg*mL-1, 50 µg*mL-1, and 500 µg*mL-1. The corresponding biotin
concentrations for biotinylated particles are 0.005, 0.05, 0.49, 4.85, 48.5, and 485 nM.”). It
would have been obvious to one of ordinary skill in the art to optimize the concentration of
streptavidin per particle depending on the optimal binding conditions. Absent evidence of
unexpected results, optimizing the streptavidin concentration of 1.6 µg per particle would be an
obvious matter of choice, depending on biotin concentrations and optimal binding conditions.
It would have been obvious to one of ordinary skill in the art to combine the teachings of
Soldo, Gordon, Anteo, Pugia, and Piletska. Given the high level of skill in the art evidenced by
Soldo, Gordon, Anteo, Pugia, and Piletska one of ordinary skill in the art would have considered combining Soldo’s and Gordons’s methods of detecting a biomarker such as 1,25(OH) with
Anteo’s method of removing or decreasing interference in an analyte with Pugia’s methods of
detecting biomarkers by isolating the biomarker from the sample, with Piletska’s teachings of
using streptavidin-biotin nanoparticles. Anteo teaches motivation towards removing or
decreasing interferences as interferences can have major clinical consequences and may lead
to unnecessary clinical investigation as well as inappropriate treatment with potential
unfavorable outcomes for the patient (pg. 2 lines 4-7). Soldo provides motivation by teaching
that the determination of circulating 1,25(OH)2D is becoming of increasing relevance in many
clinical applications, either as a diagnostic marker and/or as a therapy monitoring indicator.
Pugia provides motivation by teaching that the disclosed method releases label for detection
and offers several advantages. Piletska provides motivation by teaching that biotin and
streptavidin have strong binding interactions (fig. 2, abstract “It was found that the particles with
higher concentrations of immobilized biotin on particle surfaces demonstrated stronger binding
with streptavidin.”). The artisan would have reasonable expectation of success based on the
cumulative disclosure of these prior art references at the time the instant application was filed.
Claims 39, 41, 48, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over
Liotta et al (WO 2010/102162 A1) (IDS filed 02/22/2023), in view of Shaw et al., (US
2004/0241762 A1) (IDS filed on 02/22/2023), in view of Pugia et al., (US 2017/0102390 A1)
(IDS filed 02/22/2023), and in further view of Anteo Diagnostics Limited (AU 2016100182 A4)
(IDS filed 02/22/2023).
Regarding claim 39, Liotta teaches a method for increasing the mass of a biomarker relative to the mass of an interference in a sample (abstract, “concentrate and detect low
abundance serum proteins…using hydrogel nanoparticles to sequester and concentrate a
protein of interest…The markers identified”) comprising a volume between 50 and 10,000 µl (pg. 5 lines 14-17 “The study population consisted of 29 serum samples from primary and metastatic melanoma (median age of 49.3 years, 37.8-58.3 interquartile range) and 26 serum samples from patients with atypical melanocytic nevi (median age of 54.5 years, 43.6-61. 7 interquartile range) (Table 1).”, pg. 12 lines 20-21 “500 μL of serum were diluted 1:3 with 50 mM Tris HCL pH 7 and incubated with 200 μL of nanoparticles for 15 minutes at room temperature.”), the method comprising: a) adding to the sample a particle comprising a capture moiety that binds the biomarker to provide a mixture (claim 1 “analytes in biological fluids, comprising: hydrogel capture particles used to sequester and concentrate the analytes of interest; protein enrichment and isolation are conducted by particles ranging from 1nm to 100 µl; containing an affinity bait internally within the particles”; claim 8 “comprising forming the analyte binding portion to be at least one type of moiety”; pg. 11 “sera were frozen…without any additives. Smart nanoparticles were incubated with serum samples”); b) mixing the mixture to provide particle complexes comprising either the biomarker or the interference (pg. 8 “mixes with a biological sample, nanoparticles perform…”, claim 12 “binding the analyte to the analyte binding portion”); c) separating the particle complex (pg. 12 “serum were diluted…and incubated with…nanoparticles for 15 minutes at room temperature. After incubation, samples were centrifuged…and supernatant was discarded”); and enriching the amount of a biomarker in the sample (abstract, “concentrate and detect low abundance serum proteins…using hydrogel
nanoparticles to sequester and concentrate a protein of interest…The markers identified”), and
further wherein the biomarker is subjected to diagnostic testing (abstract “The markers identified by the described methods have wide applicability in diagnosis and treatment of a variety of diseases including myocardial infarction, pulmonary embolus, stroke, and organ infarction”).
Liotta is silent towards the biomarkers being specific for a traumatic brain injury (TBI), Alzheimer’s disease (AD), sexually transmitted disease (STD), or a bacterial infection. Liotta is
also silent towards the use of MALDI-MS and the interference being reduced to less than 100
ppm, the interference being a biotin interference, cleaving the biomarker, the biotin interference
being reduced to at least 99%, and the particle being lyophilized.
Anteo teaches using a lyophilized particle that binds to a biotin interference (pg. 15,
“magnetic beads dried/lyophilized in the primary sample tube”, pg. 3 lines 18-20 “In some
embodiments, the member of the binding pair is an antibody, antigen, a Fab, an SdAb, an
immunoglobulin, a binding domain, a ligand, biotin, streptavidin.”, fig. 3A, fig. 3B). Anteo also
teaches removing at least 99% of an interference from a biological sample (pg. 2, summary of
the disclosure, “a method to remove or decrease interference in an analyte comprising…”, “the
analyte is a bodily fluid or biological sample”, pg. 14 lines 20- 30, pg. 15 lines 1-2 “The
advantage of this approach is the addition, mixing, and removal of the magnetic particles can
easily be automated on existing sample handling platforms, or via an Anteo developed sample
handling instrument. This approach requires magnetic particles with excellent magnetic
susceptibility and size uniformity for 100% removal after addition, and good colloidal stability
(slow settling rate) to maximize binding kinetics and minimize incubation time needed. Another
magnetic particle approach, which is simpler and similar to the secondary sample tube
approach, is to design new Manufacturer specific sample racks, or modify existing racks, with
magnets to pull the magnetic beads to the sides of the sample tube as only the targeted
interference will be captured and bound (sequestered) to the sample tube's walls via the
magnetic particles and magnets, while the supernatant in the sample tube will now be depleted
and free of such interference as well as depleted and free of the magnetic particles which could
interfere in the assay if still present in the sample.”. Anteo teaches the sample being free of the
interferences, thus removing at least 99%of an interference from a biological sample). If the sample is free of interferences, then the interference would be reduced to less than 100 parts per million (PPM).
Shaw teaches a particle comprising a capture moiety for detecting biomarkers for
traumatic brain injury (TBI) ([0012] ““a solid or nanoparticle substrate to which has been bound an appropriate capture antibody…”, [0026-0028] “detecting the presence in the sample of
NFDPs generated from intact Nfs…having or at risk for developing traumatic…neuronal injuries,
such as victims of neuronal injury caused by traumatic insult”). Shaw teaches specifically
looking at neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) ([0012] “a
solid or nanoparticle substrate to which has been bound an appropriate capture
antibody…include reagents to detect NFDP containing art or all of the NF-M, NF-L…”, [0032]
“include antibody probes to glial fibrillary acidic protein (GFAP)”). Shaw is silent towards the use
of MALDI-MS and the interference being reduced to less than 100 ppm.
Pugia teaches d) cleaving the biomarker from the pellet to provide an enriched sample ([0124] “In the extraction of the particle aggregate approach, the membrane area is partially or
completely washed with a liquid to remove the particles. Linker arm 1 can be cleavable for the
particles to be removed without damage to the rare cell or target rare molecule. Alternatively,
sonication of the membrane into a liquid can aid the extraction and break the particles from the
rare cell or target rare molecule without a cleavable linker arm 1. The area extracted can be
selected based on the presence of a cell or capture particle. The extracted particles can be
gathered by centrifuging and then treated with liquids for washing and release of the MS label or
MS label precursor. In another alternative, the particle can be gathered and held by a magnetic
force. Linker arm 4 should be cleavable to release the MS label or MS label precursor into
solution for analysis.”, [0119] “one or more linking groups may comprise a cleavable moiety that
is cleavable by a cleavage agent.”, [0220] “A rare cell filtration system (Siemens Healthcare
Diagnostics Inc.) was used to isolate the cancer cells, perform affinity reactions and to load the
carrier particles onto the cells”). Pugia also teaches the presence of a biomarker being
determined by MALDI-MS ([0130] “for example, the nature of the MS technique employed. For
example, when using MALDI for detection”). Pugia also teaches the cleavage reagent being a disulfide bond reducing reagent ([0119] “cleavable moieties and corresponding cleavage agents, by way of illustration and not limitation, include disulfide that may be cleaved using a reducing agent”).
Regarding claim 41, Shaw teaches a biomarker being S-1003, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), neurofilament light chain (NFL), cleaved tau protein (C-tau), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) ([0012] “a solid or nanoparticle substrate to which has been bound an appropriate capture antibody…include reagents to detect NFDP containing art or all of the NF-M, NF-L…”, [0032] “include antibody probes to glial fibrillary acidic protein (GFAP)”).
Regarding claim 48, Pugia teaches the biomarker being cleaved from the complex by a cleavage reagent (claim 6 “the affinity reagent comprises more than one carrier particle wherein each of the carrier particles is linked”, claim 8 “the linking group is cleavable”).
Regarding claim 51, Liotta teaches the sample comprises one of human serum, animal
serum, plasma, EDTA plasma, blood, whole blood, processed blood, urine, saliva, solid stool,
liquid stool, semen, seminal fluid, amniotic fluid or cerebral spinal fluid (pg. 2 lines 20-23 “Thus,
in a first aspect, the invention provides a method to pre-process blood samples allowing for the
quantitative measurement of phosphorylation, cleavage, or total forms of kinases,
phosphatases, and other cell signaling proteins in serum samples that are undetectable by
standard laboratory methods, such as ELISA and mass spectrometry.”).
It would have been obvious to one of ordinary skill in the art at the time the instant
application was filed to consider combining Liotta, Shaw, Pugia, and Anteo as they all teach
biomarker detection. Given the high level of skill in the art as evidenced by Liotta, Shaw, Pugia,
and Anteo, one of ordinary skill in the art would have considered combining Liotta’s methods for
enriching a biomarker sample with Shaw’s methods of measuring various biomarkers known to
be associated with TBI’s with Pugia’s methods of detecting biomarkers with MALDI-MS, with
Anteo’s methods of making a sample free of interferences. Liotta provides motivation by
teaching that that the methods disclosed can detect and concentrate markers (abstract
“provided to concentrate and detect low abundance serum proteins). Shaw provides motivation
by teaching that GFAP antibodies are used as the gold standard for identification of astrocytes
[0023]. Shaw also teaches that NFs are the major structural components of neurons [0023].
Pugia provides motivation by teaching that MALDI-MS is a known and used technique in the art
([0130]). Anteo provides motivation by teaching that removing or decreasing interferences as
interferences can have major clinical consequences and may lead to unnecessary clinical
investigation as well as inappropriate treatment with potential unfavorable outcomes for the
patient (pg. 2 lines 4-7). Anteo teaches that it is important to recognize interferences in
immunoassays and put procedures in place to identify them whenever possible as interferences in immunoassays is a serious but underestimated problem (pg. 2 lines 7-9). Anteo also provides motivation for using methods to decrease or remove interferences by teaching that mitigating assay-specific interference can improve the accuracy and quality of results reported to physicians, and ultimately improve the health and wellbeing of the patients (pg. 12 lines 26-30). The artisan would have had reasonable expectation of success based on the cumulative
disclosures of these prior art references at the time the application was filed.
Claims 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Liotta,
Shaw, Pugia, and Anteo as applied to claims 39, 41, 48, and 51 above and in further view of
Bhatia et al., (US 2014/0363833 A1) (IDS filed on 02/22/2023).
The teachings of Liotta, Shaw, Pugia, and Anteo as they pertain to claims 39, 41, 48,
and 51 are discussed in the 35 USC 103 rejection above. Liotta, Shaw, Pugia, and Anteo are
silent towards using amyloid beta, BACE 1, phosphorylated tau, total tau, or soluble AP
precursor protein (sAPP) as biomarkers.
Regarding claim 43, Bhatia teaches using amyloid beta, BACE 1, phosphorylated tau,
total tau, or soluble AP precursor protein (sAPP) as biomarkers (table 1, pg. 10, Alzheimer’s
disease).
Regarding claim 45, Bhatia teaches a sexually transmitted disease (STD), being HIV
([0087] “detectable marker can be used to test the activity of that particular therapeutic at the
site of action. HIV is an example of the disease in which active proteases can be monitored”).
It would have been obvious to one of ordinary skill in the art at the time the instant
application was filed to consider combining Liotta, Shaw, Pugia, Anteo and Bhatia as they teach
detecting biomarkers. Given the high level of skill in the art as evidenced by Liotta, Shaw, Pugia,
Anteo, and Bhatia one of ordinary skill in the art would have considered combining Liotta’s
methods for enriching a biomarker sample with Shaw’s methods of measuring various
biomarkers known to be associated with TBI’s with Pugia’s methods of detecting biomarkers, MALDI-MS, with Anteo’s methods of making a sample free of interferences, with Bhatia’s
methods of measuring specific biomarkers for indicators of sexually transmitted diseases.
Bhatia provides motivation by teaching that the methods can be used to detect disease
conditions in an ultra-sensitive manner ([0047] “using the methods of the invention it is now
possible to detect enzymatic activity in a livening subject with ultrasensitive detection
platforms”). The artisan would have had reasonable expectation of success based on the
cumulative disclosures of these prior art references at the time the application was filed.
Claims 47 is rejected under 35 U.S.C. 103 as being unpatentable over Liotta, Shaw,
Pugia, and Anteo as applied to claims 39, 41, 48, and 51 above and in further view of Baker at
al., (US 2015/0306238 A1) (IDS filed 02/22/2023).
The teachings of Liotta, Shaw, Pugia, and Anteo as they pertain to claims 39, 41, 48,
and 51 are discussed in the 35 USC 103 rejection above. Liotta, Shaw, Pugia, and Anteo are
silent towards using a biomarker that is a capture moiety for a bacterium.
Regarding claim 47, Baker teaches the biomarker being a capture moiety for bacterium
(abstract “bacteria-targeting nanoparticles and related methods used. In particular, the present
invention relates to dendrimer nanoparticles conjugated with Vancomycin and/or Polymixin
(e.g., Polymixin B, Polymixin E). In certain embodiments, such dendrimer nanoparticles are
used to sequestered and/or identify bacteria”).
It would have been obvious to one of ordinary skill in the art at the time the instant
application was filed to consider combining Liotta, Shaw, Pugia, Anteo and Baker as they all
teach detecting a biomarker. Given the high level of skill in the art as evidenced by Liotta, Shaw,
Pugia, Anteo, and Baker, one of ordinary skill in the art would have considered combining
Liotta’s methods for enriching a biomarker sample with Shaw’s methods of measuring various
biomarkers known to be associated with TBI’s with Pugia’s methods of detecting biomarkers,
MALDI-MS, with Anteo’s methods of making a sample free of interferences, with Baker’s methods of bacteria-targeting nanoparticles. Liotta provides motivation by teaching that the
methods disclosed can detect and concentrate markers (abstract “provided to concentrate and
detect low abundance serum proteins”). Baker provides motivation by teaching that the
disclosed method is highly sensitive for detecting bacteria ([0006] “a novel nanotechnology that
supports the right combination of higher sensitivity, speed and ease of the assay for detection of
bacteria”). The artisan would have had reasonable expectation of success based on the
cumulative disclosures of these prior art references at the time the application was filed.
Claim Rejections - 35 USC § 103-Response to Arguments
The arguments filed on 09/19/2025 have been considered by the examiner but are not persuasive.
On pp.6-7 applicant argues that the limitation of claim 37 “wherein the cleavage reagent is a disulfide bond reducing agent” overcomes the 35 USC 103 rejections because claim 37 is un-rejected. However, claim 37 was rejected based on the limitations of the claim being unknown, not because there is not prior art for that limitation. Claim 37 was previous rejected in the final (filed on 02/11/2025) on page 10. When claim 37 was amended, it was depending on a cancelled claim, therefore, the full claim limitations were not known, that is why claim 37 had a 35 USC 112 (b) rejection.
The applicant does not provide any arguments directed towards references Gordon, Anteo, Pugia, Halbert, Liotta, Shaw, and Bhatia.
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 1 and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2, 51, and 54 of copending Application No.17/263,809. Although the claims are not identical, they are not patentably distinct from each other because the ‘809 application claims a method for isolating biomarkers from a biological sample, the method comprising: a) combining the sample with a plurality of particles, wherein
each particle independently comprises a capture moiety (i.e., a type of species of capture
moiety), to provide a mixture; b) mixing the mixture to provide one or more particle complexes to
the biomarkers; and c) removing or isolating the particle complexes to provide a depleted
solution and an enriched isolate; thereby isolating biomarkers from the biological sample (claim
2).
Application ‘809 teaches the method of claims 1 or 2, wherein prior to the combining step a), the sample is pre-treated to remove or deplete an interference, comprising: (i) combining the sample with a particle comprising a capture moiety lacking specificity for the biomarkers to provide a mixture; (ii) mixing the mixture to provide particle complexes to the
interference; and (iii) removing or eliminating the particle complexes to provide a depleted
solution (claim 54).
Regarding claim 47, ‘809 teaches wherein the biomarker is a capture moiety for a
bacterium (claim 51).
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 50 are provisionally rejected on the ground of nonstatutory double
patenting as being unpatentable over claims 1 and 50 are of copending Application
No.17/263,667. Although the claims are not identical, they are not patentably distinct from each
other because the ‘667 application claims a method for isolating a biomarker from a biological
sample, the method comprising: a) combining the sample with a particle comprising a capture
moiety to provide a mixture; and b) mixing the mixture to provide particle complexes to the
biomarker; thereby isolating the biomarker from the biological sample (claim 1 of the instant application). Regarding claim 50, ‘667 claims the method of claim 3, wherein the interference is fibrinogen and the removing or eliminating is separation, such as a physical separation by centrifugation, wherein the particle complexes are entrapped in a clot.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 3 are provisionally rejected on the ground of nonstatutory double patenting
as being unpatentable over claim 1 of copending Application No. 17/636,012. Although the
claims at issue are not identical, they are not patentably distinct from each other because the
‘012 application claims a method for mitigating an interference from a liquid biological sample,
the method comprising: a) combining the sample with a particle comprising streptavidin to
provide a mixture; b) mixing the mixture to facilitate binding of the interference to the
streptavidin; and c) separating the particle from the sample; thereby removing or reducing the
amount of the interference (claim 1).
This is a provisional nonstatutory double patenting rejection.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being
unpatentable over claim 1 of copending Application No. 17/917,479. Although the claim at issue
is not identical, they are not patentably distinct from each other because the ‘479 application
claims a method for isolating a antigen-specific antibody from a biological sample, the method
comprising: a) combining the sample with a first particle comprising a capture moiety for the
antigen-specific antibody to provide a mixture; b) mixing the mixture to provide particle
complexes to the biomarker; and c) separating the particle from the biological sample thereby
isolating the antibody from the biological sample (claim 1).
This is a provisional nonstatutory double patenting rejection.
Claim 1 is rejected on the ground of nonstatutory double patenting as being
unpatentable over claim 10 of U.S. Patent No. US11,261,257 in view of Soldo et al., (US
2015/0361178 A1).
Although the claim at issue is not identical, they are not patentably distinct from each
other because ‘257 claims the use of a capture moiety for binding. It would have been obvious
to use the capture moiety from the ‘257 application in view of Soldo.
Claims 1-2, 35 and 52-53 are provisionally rejected on the ground of nonstatutory double
patenting as being unpatentable over claim 31 and 54 of copending Application No.
17/263,809, in view of Soldo, Gordon, Anteo Diagnostics Limited, Pugia, Piletska et al. Although
the claims are not identical, they are not patentably distinct from each other for the reasons set
forth below.
Regarding claim 35, ‘809 teaches a) combining the sample with a particle comprising a
capture moiety that binds to said interference to provide a mixture (claim 54 of ‘809); b) mixing
the mixture to provide a particle complex to the interference (claim 54 of ‘809); c) removing or
eliminating the particle complexes to provide an interference- depleted solution (claim 54 of
‘809); d) combining the depleted solution with a second particle comprising a second capture
moiety to provide a second mixture, wherein the 2nd capture moiety binds the biomarker (claim
2 of ‘809); thereby isolating the biomarker from the biological sample (claim 2 of ‘809). None of
these claims teach the interference is biotin, combining the sample with a particle comprising
streptavidin, wherein at least 99% of the interference is removed or eliminated; e) mixing the
second mixture to provide a second particle complex comprising the biomarker; f) removing the
second particle complex from the second mixture; and g) adding to the second mixture a
cleavage reagent or releasing agent to provide an isolate comprising the biomarker.
However, Anteo teaches the interference being biotin (pg. 3) and the capture moiety
comprises streptavidin (pg. 3).
Soldo teaches a method for isolating biomarkers ([0021]) that comprises a capture
moiety with a sample to provide a particle complex comprising the biomarker with a capture
moiety ([0082], [0085], [0040]).
Pugia teaches the use of particles comprising capture moieties attached via cleavable
linkers to isolate and detect analytes, and removal of the particles from a mixture (claim 1, claim 11).
Piletska teaches biotin and streptavidin binding together (pg. 3784).
Therefore, it would have been prima facie obvious to one at the time of the instant
application to modify the methods of ‘809 with the interference and capture moiety of Anteo,
methods of isolating biomarkers of Soldo, the use of cleavable linkers to isolate and detect
analytes, and removal of particles from a mixture taught by Pugia, and Piletska’s teachings of
biotin and streptavidin’s interactions. Anteo teaches motivation towards removing or
decreasing interferences as interferences can have major clinical consequences and may lead
to unnecessary clinical investigation as well as inappropriate treatment with potential
unfavorable outcomes for the patient (pg. 2 lines 4-7). Soldo provides motivation by teaching
that the determination of circulating 1,25(OH)2D is becoming of increasing relevance in many
clinical applications, either as a diagnostic marker and/or as a therapy monitoring indicator.
Pugia provides motivation by teaching that the disclosed method releases label for detection
and offers several advantages. Piletska provides motivation by teaching that biotin and
streptavidin have strong binding interactions (fig. 2, abstract “It was found that the particles with higher concentrations of immobilized biotin on particle surfaces demonstrated stronger binding with streptavidin.”). One of ordinary skill in the art would have been motivated to make the modification with a reasonable expectation of success.
Regarding claim 52, ‘809 teaches the particle is 230 nm in diameter (claim 31). Anteo
teaches the sample comprises serum (pg. 2), and said capture moiety comprises streptavidin
(pg. 3). Piletska teaches that nanoparticles are known to have a diameter between 50-200 nm
(abstract). Piletska teaches nanoparticles with biotin-streptavidin interactions (pg. 3784). The
sizing of nanoparticles is generally known in the art as evidenced by Piletska. It would have
been obvious to one of ordinary skill in the art to optimize the parameters of the diameter based
on the demands of the diagnostic testing. Absent evidence of unexpected results, optimizing the
nanoparticle with the diameter of 230 nm would be an obvious matter of choice, depending on
the diagnostic test the particle is being used with.
Regarding claim 53, Piletska teaches streptavidin particle concentrations being 5 ng
mL-1, 50 ng mL-1, 0.5 µg*mL-1, 50 µg*mL-1, and 500 µg*mL-1(fig. 1, pg. 3784). .”). It would
have been obvious to one of ordinary skill in the art to optimize the concentration of streptavidin
per particle depending on the optimal binding conditions. Absent evidence of unexpected
results, optimizing the streptavidin concentration of 1.6 µg per particle would be an obvious
matter of choice, depending on biotin concentrations and optimal binding conditions.
This is a provisional nonstatutory double patenting rejection.
Claims 39, 41, 48, and 51 are provisionally rejected on the ground of nonstatutory
double patenting as being unpatentable over claims 1,3, 5-9, and 19-20 of copending
Application No. 17/263,667, in view of Liotta, Shaw, and Pugia. Although the claims are not
identical, they are not patentably distinct from each other for the reasons set forth below.
Regarding claim 39, ‘667 teaches a) adding to the sample a particle comprising a
capture moiety that binds the biomarker to provide a mixture, and further adding to the sample a
lyophilized particle comprising streptavidin that binds the biotin interference (claim 1, claim 5,
claim 6, claim 19, claim 20); b) mixing the mixture to provide particle complexes comprising
either the biomarker or the interference (claim 1, claim 3); c) separating the particle complexes
(claim 3); wherein the amount of the biotin interference is reduced by at least 99% (claim 7);
thereby enriching the amount of a biomarker in the sample, and further wherein the biomarker is
subjected to diagnostic testing (claim 9), and wherein the concentration of the interference is
reduced to less than 100 ppm (claim 8). ‘667 is silent towards increasing the mass of a
biomarker relative to the mass of an interference in a sample comprising a volume between 50
and 10,000 µl, the biomarkers being specific for a traumatic brain injury (TBI), Alzheimer’s
disease (AD), sexually transmitted disease (STD), or a bacterial infection, wherein the biomarker is subjected to diagnostic testing comprising MALDI- MS, and cleaving the biomarker
from the pellet.
However, Liotta teaches a method for increasing the mass of a biomarker relative to the
mass of an interference in a sample (abstract), comprising a volume between 50 and 10,000 µl
(pg. 5).
Shaw teaches a particle comprising a capture moiety for detecting biomarkers for
traumatic brain injury (TBI) ([0012], [0026]-[0028]). Shaw teaches specifically looking at
neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) ([0012], [0032]).
Pugia teaches d) cleaving the biomarker from the pellet to provide an enriched sample
([0124]). Pugia also teaches the presence of a biomarker being determined by MALDI-MS ([0130]).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of
the instant application to modify the methods of ‘667 with Liotta’s methods for enriching a
biomarker, Shaw’s methods of measuring various biomarkers known to be associated with
TBI’s, with Pugia’s methods of detecting biomarkers with MALDI-MS. Liotta provides motivation
by teaching that that the methods disclosed can detect and concentrate markers (abstract).
Shaw provides motivation by teaching that GFAP antibodies are used as the gold standard for
identification of astrocytes [0023]. Pugia provides motivation by teaching that MALDI-MS is a
known and used technique in the art ([0130]). One of ordinary skill in the art would have been
motivated to make the modification with a reasonable expectation of success.
Regarding claim 41, Shaw teaches a biomarker being S-1003, glial fibrillary acidic
protein (GFAP), neuron-specific enolase (NSE), neurofilament light chain (NFL), cleaved tau
protein (C-tau), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) ([0012], [0032]).
Regarding claim 48, Pugia teaches the biomarker being cleaved from the complex by a
cleavage reagent (claim 6 and claim 8).
Regarding claim 51, Liotta teaches the sample comprises one of human serum, animal serum, plasma, EDTA plasma, blood, whole blood, processed blood, urine, saliva, solid stool,
liquid stool, semen, seminal fluid, amniotic fluid or cerebral spinal fluid (pg. 2).
This is a provisional nonstatutory double patenting rejection.
Claims 43 and 45 are provisionally rejected on the ground of nonstatutory double
patenting as being unpatentable over claims 1, 3, 5-9, and 19-20 of copending Application No.
17/263,667, in view of Bhatia et al.
Although the claims are not identical, they are not patentably distinct from each other for
the reasons set forth below.
Regarding claim 43, ‘667 teaches the a) adding to the sample a particle comprising a
capture moiety that binds the biomarker to provide a mixture, and further adding to the sample a
lyophilized particle comprising streptavidin that binds the biotin interference (claim 1, claim 5,
claim 6, claim 19, claim 20); b) mixing the mixture to provide particle complexes comprising
either the biomarker or the interference (claim 1, claim 3); c) separating the particle complexes
(claim 3); wherein the amount of the biotin interference is reduced by at least 99% (claim 7);
thereby enriching the amount of a biomarker in the sample, and further wherein the biomarker is
subjected to diagnostic testing (claim 9), and wherein the concentration of the interference is
reduced to less than 100 ppm (claim 8). ‘667 is silent towards wherein the biomarker is amyloid
beta, BACE1, phosphorylated tau, total tau, or soluble A3 precursor protein (sAPP) and wherein
the STD is Chlamydia, Gonorrhea, Syphilis, Trichomonas, HPV, Herpes, Hepatitis B, Hepatitis
C, or HIV.
Bhatia teaches wherein the biomarker is amyloid beta, BACE1, phosphorylated tau, total
tau, or soluble A3 precursor protein (sAPP) (table 1, pg. 10).
Regarding claim 45, Bhatia teaches wherein the STD is Chlamydia, Gonorrhea,
Syphilis, Trichomonas, HPV, Herpes, Hepatitis B, Hepatitis C, or HIV ([0087]).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of
the instant application to modify the methods of ‘667 with Bhatia’s methods of measuring
varying biomarkers known to be associated with TBI’s and sexually transmitted diseases. Bhatia
provides motivation by teaching that the methods can be used to detect disease conditions in an
ultra-sensitive manner ([0047]). One of ordinary skill in the art would have been motivated to
make the modification with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Double Patenting-Response to Arguments
Applicant disagrees with the rejection and requests the rejection be held in abeyance
until there is allowable subject matter in the application (p. 7 of the arguments filed on
09/19/2025). This has been fully considered but is not found to be persuasive.
Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states:
“A complete response to a nonstatutory double patenting (NSDP) rejection is either a
reply by applicant showing that the claims subject to the rejection are patentably distinct from
the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the
pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of
terminal disclaimers). Such a response is required even when the nonstatutory double patenting
rejection is provisional.”
“As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03. Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner. See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis added)”.
Accordingly, the rejection is maintained and is expressly not held in abeyance.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571)272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MCKENZIE A DUNN/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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