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 .
Claim Status and Formal Matters
This action is in response papers filed 11/20/2025.
Claim 1 has been amended.
Applicant’s election without traverse of I. plasma; II. protein; III. first dilution is a dilution of 0.5%; TV. hybridization; V. both the first aptamer and the second aptamer; VI. amide linker; VII. a naphthyl moiety; VIII. uridine; IX. amide linker; X. a naphthyl moiety; and XI. uridine. in the reply filed on5/28/2024 is acknowledged.
Claims 1-18, 24-31 are being examined.
Priority
The instant application was filed 12/09/2020 and is a national stage entry of PCT/US2019/038022 with an international filing date: 06/19/2019 and claims priority from provisional application 62688770 , filed 06/22/2018.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. It is noted the examiner has not compared to the IDS to the references cited in specification.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-18, 24-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163 IB New or amended claims section II
With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04 which provides that a "simple statement such as ‘applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation ‘___’ in the application as filed’ may be sufficient where the claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported."); see also MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure."); and MPEP § 2163.04
Claim 1 has been amended, “ wherein, the first dilution sample, the second dilution sample, and the third dilution sample are different serial dilutions of the same test sample.” The response does not indicate where support for the amendment can be found. Review and search revealed a single recitation of serial dilution on page 69 which is a specific example which states, “Subsequent dilutions to make 0.5% and 0.005% diluted samples were made into Assay Buffer using serial dilutions on Fluent robot..” Thus the teachings of the specification are limited to a single species of serial dilutions-0.5% and 0.005% using assay buffer for serial dilutions. However the claim as amended encompasses any serial dilutions, which is broader. Thus the amendment has broadened the scope of the claim to encompass any serial dilutions which has broadened the scope of the claims from those disclosed in the originally filed specification.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-18, 24-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The Board has held, “If a claim is amenable to two or more plausible constructions, applicant is required to amend the claim to more precisely define the metes and bounds of the claimed invention or the claim is indefinite under §112, ¶2.” Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) (expanded panel).
The US Supreme Court in NAUTILUS, INC. v. BIOSIG INSTRUMENTS, INC. (2014) held, “we hold that a patent is invalid for indefiniteness if its claims, read in light of the specification delineating the patent, and the prosecution history, fail to inform, with reasonable certainty, those skilled in the art about the scope of the invention.”
Claim 1 recites, “a) contacting a first dilution sample with a first aptamer, wherein a first aptamer affinity complex is formed by the interaction of the first aptamer with its target molecule if the target molecule is present in the first dilution sample;b) contacting a second dilution sample with a second aptamer, wherein a second aptamer affinity complex is formed by the interaction of the second aptamer with its target molecule if the target molecule is present in the second dilution sample; c) contacting a third dilution sample with a third aptamer, wherein a third aptamer affinity complex is formed by the interaction of the third aptamer with its target molecule if the target molecule is present in the third dilution sample.” Claim 1 later recites, “wherein, the first dilution sample, the second dilution sample, and the third dilution sample are different dilutions of the same test sample, and the first aptamer, the second aptamer, and the third aptamer each bind to a different target molecule.” Further the specification teaches, “[00107] As used herein, "nucleic acid ligand,""aptamer,""SOMAmer,""modified aptamer," and "clone" are used interchangeably to refer to a non-naturally occurring nucleic acid that has a desirable action on a target molecule. A desirable action includes, but is not limited to, binding of the target, catalytically changing the target, reacting with the target in a way that modifies or alters the target or the functional activity of the target, covalently attaching to the target (as in a suicide inhibitor), and facilitating the reaction between the target and another molecule. In one embodiment, the action is specific binding affinity for a target molecule, such target molecule being a three dimensional chemical structure other than a polynucleotide that binds to the aptamer through a mechanism which is independent of Watson/Crick base pairing or triple helix formation, wherein the aptamer is not a nucleic acid having the known physiological function of being bound by the target molecule. Aptamers to a given target include nucleic acids that are identified from a candidate mixture of nucleic acids, where the aptamer is a ligand of the target, by a method comprising: (a) contacting the candidate mixture with the target, wherein nucleic acids having an increased affinity to the target relative to other nucleic acids in the candidate mixture can be partitioned from the remainder of the candidate mixture; (b) partitioning the increased affinity nucleic acids from the remainder of the candidate mixture; and (c) amplifying the increased affinity nucleic acids to yield a ligand-enriched mixture of nucleic acids, whereby aptamers of the target molecule are identified. It is recognized that affinity interactions are a matter of degree; however, in this context, the "specific binding affinity" of an aptamer for its target means that the aptamer binds to its target generally with a much higher degree of affinity than it binds to other, non-target, components in a mixture or sample. An aptamer, "SOMAmer," or "nucleic acid ligand" is a set of copies of one type or species of nucleic acid molecule that has a particular nucleotide sequence. An aptamer can include any suitable number of nucleotides. "Aptamers" refer to more than one such set of molecules. Different aptamers can have either the same or different numbers of nucleotides. Aptamers may be DNA or RNA and may be single stranded, double stranded, or contain double stranded or triple stranded regions. In some embodiments, the aptamers are prepared using a SELEX process as described herein, or known in the art. “ The metes and bounds are unclear as an aptamer as describe in the specification includes probes, clones, etc. and thus is not consistent with an aptamer being a nucleic acid which binds a specific target molecule such a protein, carbohydrate, etc. Thus the recitation of aptamer is vague, unclear and confusing in view of the teachings of the specification.
Response to arguments
The response begins traversing the rejection asserting the specification in 0107 teaches an aptamer is a “non-naturally occurring nucleic acid.” This argument has been thoroughly reviewed as the cited paragraph states, “[00107] As used herein, "nucleic acid ligand," "aptamer," "SOMAmer," "modified aptamer," and "clone" are used interchangeably to refer to a non-naturally occurring nucleic acid that has a desirable action on a target molecule.” Thus while the specification teaches an aptamer refer to, “a non-naturally occurring nucleic acid that has a desirable action on a target molecule” it prefaces that with “nucleic acid ligand," "aptamer," "SOMAmer," "modified aptamer," and "clone." The inclusion of “nucleic acid ligand," and "clone" are much broader than a non-naturally occurring nucleic acid. The response continues by asserting, “the specification disclosing related terms such as "clone" or "nucleic acid ligand," does not render the claim unclear because each refers to a species of non-naturally occurring nucleic acid sequence selected to bind a target molecule. One of ordinary skill in the art would understand that the "aptamer" recited in claim 1 includes such clones or nucleic acid ligands.” This argument has been thoroughly reviewed but is not considered persuasive as paragraph 0107 states, “As used herein, "nucleic acid ligand," "aptamer," "SOMAmer," "modified aptamer," and "clone" are used interchangeably.” Thus the specification teaches they are interchangeable or synonyms and one of skill in the art would not specifically envision a nucleic acid ligand or clone as an aptamer.
The issues with dilutions has been withdrawn in view of the amendments.
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.
Claim(s) 1-18, 24-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gold ((2010) A PLoS ONE 5(12):e15004. doi:10.1371/journal.pone.0015004).
With regards to claim 1, Gold teaches
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.Gold teaches samples examined at 3 dilutions (Preparation of 10%, 1% and 0.03% SOMAmer Solutions, page 14) and use of aptamers to killstatin, LBP, and TIG2 (figure 8. ) Gold teaches “The protein solutions were serially diluted 15.8-fold into SB17T for a total of six points (lowest concentration: 20.3 fM). All of the protein preparation was maintained on ice. Eight replicate protein titrations per set were pipetted into 96-well plates.” (Limits of Quantification (LOQ) Experiment) Gold teaches, “SOMAmers were grouped into three unique mixes. The placing of a SOMAmer within a mix was empirically determined by assaying a dilution series of serum or plasma with each SOMAmer and identifying the sample dilution that gave the largest linear range of signal. The segregation of SOMAmers and mixing with different dilutions of sample (10%, 1% or 0.03%)”( Preparation of 10%, 1% and 0.03% SOMAmer Solutions)
Gold does teach diluting the samples and placing the SOMAmers in 3 different groups , each with 3 different dilutions, which is encompassed by the breadth of the claims. Thus each group would have different sets of beads as demonstrated in figure 3. The second and/or third catch which either can be considered the second solid support as the second catch is all on mmonomeric avidin beads and the third is on primer beads.
Gold teaches,” Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (∼100 fM–1 µM), and 5% median coefficient of variation. “ (abstract)
Gold does not specifically teach serial dilution of test samples or sequentially releasing and capturing the first, second and third aptamer affinity complex on a second support.
However, Gold teaches:
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The courts have haled that rearrangement of steps is obvious in the absence of unexpected results. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims, the sequentially release and transfer of 3 different SOMAers and respective target proteins each in a serial dilutions to a second solid support. The artisan would be motivated to sequentially release and transfer different SOMAers and respective target proteins to a second solid support to provide for greater control and/or examination of release and binding conditions and allowing washing. The artisan would be motivated to use serial dilutions to allow for detection of target analytes that are present in a sample at different concentrations. The artisan would have a reasonable expectation of success as the artisan is performing steps taught by the art in a logic order.
With regards to claim 2, Gold teaches samples of serum or plasma(Preparation of 10%, 1% and 0.03% SOMAmer Solutions, page 14)
With regards to claim 3, Gold teaches aptamers complex are non-covalent (figure 7)
With regards to claim 4, Gold teaches killstatin, LBP, and TIG2 which are proteins.
With regards to claim 5-8, Gold teaches the first dilution is 0.03 (Preparation of 10%, 1% and 0.03% SOMAmer Solutions, page 14)
With regards to claim 9-10, Gold teaches Preparation of 10%, 1% and 0.03% SOMAmer Solutions, page 14)
With regards to claim 11, Gold teaches detection by hybridization (figure 7).
With regards to claim 12-18, 25-31Gold teaches dATP, dGTP, 5-methyl-dCTP (MedCTP) and either dTTP or one of three dUTP analogs: 5- benzylaminocarbonyl-dU (BndU), 5-tryptaminocarbonyl-dU =TrpdU, and 5-isobutylaminocarbonyl-dU (iBudU) (Figure 1).
With regards to claim 24, Gold teaches the first dilution is 10% (Preparation of 10%, 1% and 0.03% SOMAmer Solutions, page 14)
Response to Arguments
The response begins traversing the rejection by, “Applicant respectfully traverses the rejection. Applicant submits that claim 1 recites contacting a first, second, and third dilution of the same test sample with different aptamers (steps a-c); forming separate aptamer affinity complexes (steps a-c); incubating the dilution samples separately (step d);” This argument has been thoroughly reviewed but is not considered persuasive as Gold teaches “The protein solutions were serially diluted 15.8-fold into SB17T for a total of six points (lowest concentration: 20.3 fM). All of the protein preparation was maintained on ice. Eight replicate protein titrations per set were pipetted into 96-well plates.” (Limits of Quantification (LOQ) Experiment) Gold teaches, “SOMAmers were grouped into three unique mixes. The placing of a SOMAmer within a mix was empirically determined by assaying a dilution series of serum or plasma with each SOMAmer and identifying the sample dilution that gave the largest linear range of signal. The segregation of SOMAmers and mixing with different dilutions of sample (10%, 1% or 0.03%)”( Preparation of 10%, 1% and 0.03% SOMAmer Solutions) Gold teaches,” Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (∼100 fM–1 µM), and 5% median coefficient of variation. “ (abstract) Thus contrary to the assertion of the response, Gold does teach diluting the samples and placing the SOMAmers in 3 different groups , each with 3 different dilutions, which is encompassed by the breadth of the claims. Thus each group would have different sets of beads as demonstrated in figure 3. The second and/or third catch which either can be considered the second solid support as the second catch is all on mmonomeric avidin beads and the third is on primer beads.
The response continues by arguing, “The claimed method therefore recites different and additional steps, not merely a rearrangement of known steps as alleged by the Examiner.” This argument has been thoroughly reviewed but is not considered persuasive as Gold teaches, “Gold teaches “The protein solutions were serially diluted 15.8-fold into SB17T for a total of six points (lowest concentration: 20.3 fM). All of the protein preparation was maintained on ice. Eight replicate protein titrations per set were pipetted into 96-well plates.” (Limits of Quantification (LOQ) Experiment) Gold teaches, “SOMAmers were grouped into three unique mixes. The placing of a SOMAmer within a mix was empirically determined by assaying a dilution series of serum or plasma with each SOMAmer and identifying the sample dilution that gave the largest linear range of signal. The segregation of SOMAmers and mixing with different dilutions of sample (10%, 1% or 0.03%)”( Preparation of 10%, 1% and 0.03% SOMAmer Solutions) Gold teaches,” Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (∼100 fM–1 µM), and 5% median coefficient of variation. “ (abstract)
The response continue by providing arguments with respect to Ex parte Rubin, In re Burhans, and In re Gibson and alleges unexpected results. The response alleges, “The specification describes that multiplex assays with a two-catch system are particularly impacted by the ability of the detection method to resolve true signal from signal that arises due to nonspecific protein associations during the assay, which results in an unwanted detectable signal (false positive or assay "noise"). See specification at paragraphs [00346] and [00347].” This argument has been thoroughly reviewed but is not considered persuasive as Gold teaches 3 catch steps. Gold teaches, “The assay uses one SOMAmer per analyte rather than a sandwich of binding reagents and thus depends on equilibrium binding and kinetics for specificity. The difference in dissociation rates between cognate and non-cognate interactions contributes significantly to specificity in the assay (Figure 3). The use of sequential capture of protein-SOMAmer complexes on two sets of streptavidin beads, first through biotin-labeled SOMAmers (Catch-1) and then through biotin-labeled proteins (Catch-2), substantially reduces non-specific interactions. We assessed the specificity of select SOMAmers for the targets they were selected against in an affinity binding assay that mimics our multiplexed proteomics assay. The experimental method is outlined in Figure 5 and detailed in Materials and Methods. This experiment mimics Catch-1 and Catch-2 in the proteomics assay and then uses a third step to capture the bound SOMAmer-protein complex with an oligo that is complementary to a portion of the SOMAmer and acts as an affinity tag. This “Catch-3” step is analogous to the DNA microarray hybridization step in the proteomics assay.
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Thus the rejection is maintained.
Claim(s) 1-18, 24-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schneider (US patent 9,404,919)
Regarding Claim 1, Schneider teaches
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Schneider discloses a method (The present disclosure describes methods, Abstract) comprising: a) contacting a first dilution sample with a first aptamer (the test sample may be prepared as two or more dilutions of the test sample, Col. 18, Lns. 61-62; a test sample is contacted with an aptamer that has a specific affinity for a target molecule. If the test sample contains the target molecule, an aptamer affinity complex will form in the mixture with the test sample, Col. 3, Lns. 20-24), wherein a first aptamer affinity complex is formed by the interaction of the first aptamer with its target molecule if the target molecule is present in the first dilution sample (a test sample is contacted with an aptamer that has a specific affinity for a target molecule. If the test sample contains the target molecule, an aptamer affinity complex will form in the mixture with the test sample, Col. 3, Lns. 20-24); b) contacting a second dilution sample with a second aptamer, wherein a second aptamer affinity complex is formed by the interaction of the second aptamer with its target molecule if the target molecule is present in the second dilution sample (It will be appreciated that a molecule that is a non-target for a first aptamer may be a target for a second aptamer, Col. 29, Lns. 21-23; a set of test samples is prepared as serial dilutions to which a tagged aptamer (or tagged photo aptamer) with a specific affinity for a target molecule is introduced, Col. 19, Lns. 25-27; a test sample is contacted with an aptamer that has a specific affinity for a target molecule. If the test sample contains the target molecule, an aptamer affinity complex will form in the mixture with the test sample, Col. 3, Lns. 20-24); c) incubating the first and second dilution samples separately to allow aptamer affinity complex formation (The individual dilution test samples are separately assayed up to and including aptamer (or covalent) complex formation, Col. 18, Lns. 64-66; here the target molecule is present in the sample, aptamer-target molecule complexes (aptamer affinity complexes) are formed. The mixture may optionally be incubated for a period of time sufficient to achieve equilibrium binding of the aptamer to the target molecule, Col. 14, Lns. 32-37); d) transferring the first dilution sample with the first aptamer affinity complex to a first mixture, wherein the first aptamer affinity complex is captured on a solid support in the first mixture (the test sample may be prepared as two or more dilutions of the test sample, Col. 18, Lns. 61-62; a test sample is contacted with an aptamer that has a specific affinity for a target molecule. If the test sample contains the target molecule, an aptamer affinity complex will form in the mixture with the test sample, Col. 3, Lns. 20-24; The tagged aptamer affinity complex is next captured on a solid Support by exposing the mixture to the Solid Support, Col. 3, Lns. 32-35); e) after step d), transferring the second dilution sample to the first mixture to form a second mixture, wherein the second aptamer affinity complex of the second dilution is captured on a solid support in the second mixture (the test sample may be prepared as two or more dilutions of the test sample, Col. 18, Lns. 61-62; Aptamer affinity complexes contained in the mixture are thereby bound to the solid support through the binding interaction of the target (second) capture tag and the second capture element on the second solid Support. The aptamer affinity complex is then partitioned from the remainder of the mixture, Col. 15, Lns. 43-48); f) detecting for the presence of or determining the level of the first aptamer and second aptamer of the first and second aptamer affinity complexes, or the presence or amount of one or more first and second aptamer affinity complexes (The photoaptamer that is part of the aptamer covalent complex can be detected and/or quantified (while still attached to the solid Support) using any of a variety of suitable methods, Col. 6, Lns. 8-11; the aptamer affinity complex is diluted and the mixtures containing the aptamer affinity complex are incubated for a time such that the ratio of the measured level of aptamer affinity complex to the measured level of the non-specific complex is increased, Col. 32, Lns. 51-56); wherein, the first dilution and the second dilution are different dilutions of the same test sample (the test sample may be prepared as two or more dilutions of the test sample, Col. 18, Lns. 61-62). Schneider teaches,” In any of the embodiments disclosed herein, the test sample may be prepared as two or more dilutions of the test sample, which may increase the dynamic range of target detection by the methods disclosed herein. The individual dilution test samples are separately assayed up to and including aptamer (or covalent) complex formation, after which the dilution test samples may be pooled for the remainder of the assay and detected simultaneously on a single solid support. In one embodiment, each dilution test sample includes a unique aptamer, thereby enabling a single measurement of the corresponding target. In another embodiment, an aptamer can be added to two or more dilutions, each dilution contacting a distinctly tagged aptamer for a particular target, allowing for the detection of a specific aptamer signal for each of the different dilution samples on a single solid support. Chaining together diluted samples in this manner can extend a dynamic range for a single target molecule over many orders of magnitude and add accuracy when overlapping regions of quantification lead to multiple determinations of a single target's concentration.” (column 18, line 61-column 19, line 13).
Schneider teaches, "(the test sample may be prepared as two or more dilutions of the test sample, Col. 18, Lns. 61-62;). Further Schneider teaches, "“In another embodiment, an aptamer can be added to two or more dilutions, each dilution contacting a distinctly tagged aptamer for a particular target, allowing for the detection of a specific aptamer signal." Thus Schneider specifically envision two or more dilutions and each having a distinctly tagged aptamer (different).
Schneider teaches, “In one embodiment, a set of test samples is prepared as serial dilutions.(column 19, lines 25-265).
Schneider teaches, “ For multiplexed detection of a small number of aptamers still bound to the second solid support, fluorescent dyes with different excitation/emission spectra can be employed to detect and quantify two, or three, or five, or up to ten individual aptamers.” (column 40, lines 36-41). Schneider teaches, “Multiplexed Assays. In another embodiment, the assays and methods described above are used to detect and/or quantify two or more targets.” (column 8, lines 54-56)
Schneider teaches, “In another embodiment, an aptamer can be added to two or more dilutions, each dilution contacting a distinctly tagged aptamer for a particular target, allowing for the detection of a specific aptamer signal for each of the different dilution samples on a single solid Support. Chaining together diluted Samples in this manner can extend a dynamic range for a single target molecule over many orders of magnitude and add accuracy when overlapping regions of quantification lead to multiple determinations of a single targets concentration..” (column 19, 1st paragraph). Schneider teaches, “The same aptamer with a different tag can be added to each test sample dilution. As further described herein, following the formation of an aptamer affinity complex (or the optional conversion to an aptamer covalent complex) the individual test samples can be pooled and contacted with a labeling agent either before or after attachment of the aptamer (or covalent) complex to the Solid Support.”(column 19, 3rd paragraph). Schneider teaches, “For multiplexed detection of a small number of aptamers still bound to the second solid support, fluorescent dyes with different excitation/emission spectra can be employed to detect and quantify two, or three, or five, or up to ten individual aptamers.” (column 40, lines 36-40)
Schneider teaches the use of microtiter plates with different sample dilutions with aptamers. Schneider teaches the different aptamers are captured in the microwells. (example 7). Each well of the microtiter plate can be considered a different solid support.
Schneider does not explicitly teach sequentially releasing and recapturing of the first, second and third affinity complexes.
However, Schneider teach, “it is to be understood that any number of permutations of the specified sequence of steps is possible, so long as the objective of the particular assay being described is accomplished. Stated another way, the steps recited in any of the disclosed methods may be performed in any feasible order, and the methods of the invention are not limited to any particular order presented in any of the described embodiments, the examples, or the appended claims.” (column 11, lines 6-14.) Schneider teaches, “As discussed above, the assays described here have been grouped for ease in presentation into 4 assay formats: Single Catch Affinity Assays: Dual Catch Affinity Assays, Single Catch Photocrosslink Assays; and Dual Catch Photocrosslink Assays. However, it should be understood that other groupings, combinations, and ordering of steps are contemplated and all fall within the scope of the disclosure.” (column 11, lines 45-53).
The courts have haled that rearrangement of steps is obvious in the absence of unexpected results. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims, the sequentially release and transfer the 3 different aptamers in different serial dilutions of the sample to a second solid support. The artisan would be motivated to sequentially release and transfer serial dilutions 3 aptamers and ligands to a second solid support to provide for greater control and/or examination of release and binding conditions. The artisan would be motivated to use 3 serial dilutions to enhance the ability of the aptamer to detect the target at concentrations in the sample. The artisan would have a reasonable expectation of success as the artisan is performing steps taught by the art in a logic order.
With regards to claim 2, Schneider teaches, “The term “biological sample” refers to any material, solution, or mixture obtained from an organism. This includes blood (including whole blood, leukocytes, peripheral blood mononuclear cells, plasma, and serum), sputum, breath, urine, semen, saliva, meningeal fluid, amniotic fluid, glandular fluid, lymph fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, cells, a cellular extract, and cerebrospinal fluid. This also includes experimentally separated fractions of all of the preceding. The term “biological sample” also includes materials, solutions, or mixtures containing homogenized solid material, such as from a stool sample, a tissue sample, or a tissue biopsy, for example. The term “biological sample” also includes materials, solutions, or mixtures derived from a tissue culture, cell culture, bacterial culture, or viral culture.” (column 28, 2nd paragraph)
With regards to claim 3, Schneider teaches, “ In another embodiment of the present disclosure a non-covalent complex of an aptamer and a target is provided, wherein the aptamer has a K.sub.d for the target of about 100 nM or less, wherein the rate of dissociation (t.sub.1/2) of the aptamer from the target is greater than or equal to about 30 minutes; is between about 30 minutes and about 240 minutes; is ≧ about 30 minutes, ≧ about 60 minutes, ≧ about 90 minutes, ≧ about 120 minutes, ≧ about 150 minutes, ≧ about 180 minutes, ≧ about 210 minutes, ≧ about 240 minutes; and/or wherein one, several or all pyrimidines in the nucleic acid sequence of the aptamer are modified at the 5-position of the base. The modifications may be selected from the group of compounds shown in FIG. 16. Aptamers may be designed with any combination of the base modified nucleotides desired.” (column 24)
With regards to claim 4, Schneider teaches, “As used herein, “target molecule” and “target” are used interchangeably to refer to any molecule of interest to which an aptamer can bind with high affinity and specificity and that may be present in a test sample. A “molecule of interest” includes any minor variation of a particular molecule, such as, in the case of a protein, for example, minor variations in amino acid sequence, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component that does not substantially alter the identity of the molecule. A “target molecule” or “target” is a set of copies of one type or species of molecule or multimolecular structure that is capable of binding to an aptamer. “Target molecules” or “targets” refer to more than one such set of molecules. Exemplary target molecules include proteins, polypeptides, nucleic acids, carbohydrates, lipids, polysaccharides, glycoproteins, hormones, receptors, antigens, antibodies, affybodies, antibody mimics, viruses, pathogens, toxic substances, substrates, metabolites, transition state analogs, cofactors, inhibitors, drugs, dyes, nutrients, growth factors, cells, tissues, and any fragment or portion of any of the foregoing. An aptamer may be identified for virtually any chemical or biological molecule of any size, and thus virtually any chemical or biological molecule of any size can be a suitable target. A target can also be modified to enhance the likelihood or strength of an interaction between the target and the aptamer. A target can also be modified to include a tag, as defined above. In exemplary embodiments, the target molecule is a protein. See U.S. Pat. No. 6,376,190 entitled “Modified SELEX Processes Without Purified Protein” for methods in which the SELEX target is a peptide.” (column 28).
With regards to claims 5-10, Schneider teaches dilutions encompassed by the claims figures 7-13.
With regards to claim 11, Schneider teaches
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Schneider teaches, “The aptamer affinity complex(or aptamer covalent complex) is detected and/or quantified. A number of different detection methods can be used to detect the aptamer affinity complex, for example, the Invader assay, hybridization assays or DNA chips, mass spectroscopy, or Q-PCR.” (column 11, lines 40-44)
With regards to claim 12, Schneider teaches the first aptamer and/or the second aptamer, independently, comprises at least one 5-position modified pyrimidine (chemical modifications of a nucleotide can include, singly or in any combination,2'-position Sugar modifications, 5-position pyrimidine modifications, Col. 22, Lns. 6-8).
With regards to claim 13-18, 25-31 Schneider teaches, “In one embodiment, the term “C-5 modified pyrimidine' refers to a pyrimidine with a modification at the C-5 position including, but not limited to those moieties illustrated in FIG. 16. Examples of a C-5 modified pyrimidine include those described in U.S. Pat. Nos. 5,719,273 and 5,945,527. Examples of a C-5 modification include substitution of deoxyuridine at the C-5 position with a substituent selected from: benzylcarboxyamide (alternatively benzylaminocarbonyl) (Bn), naphthylmethylcarboxyamide (alternatively naphthyl methylaminocarbonyl) (Nap), tryptaminocarboxyamide (alternatively tryptaminocarbonyl) (Trp), and isobutylcarboxyamide (alternatively isobutylaminocarbonyl) (iBu).” (column 22 lines 22-34).
With regards to claim 20, Schneider teaches the individual dilution test samples are separately assayed up to and including aptamer (or covalent) complex formation, after which the dilution test samples may be pooled for the remainder of the assay and detected simultaneously on a single solid support. In one embodiment, each dilution test sample includes a unique aptamer, thereby enabling a single measurement of the corresponding target. In another embodiment, an aptamer can be added to two or more dilutions, each dilution contacting a distinctly tagged aptamer for a particular target, allowing for the detection of a specific aptamer signal for each of the different dilution samples on a single solid support. Chaining together diluted samples in this manner can extend a dynamic range for a single target molecule over many orders of magnitude and add accuracy when overlapping regions of quantification lead to multiple determinations of a single target's concentration.” (column 18, line 61-column 19, line 13).
Response to Arguments
The response begins providing the representatives interpretation of the rejection and previous arguments. These are noted.
The response traverses the rejection with respect to the art rejection, by asserting Schneider does not have a third aptamer or dilution. This argument has been thoroughly reviewed but is not considered persuasive as Schneider teaches, "(the test sample may be prepared as two or more dilutions of the test sample, Col. 18, Lns. 61-62;). Further Schneider teaches, "“In another embodiment, an aptamer can be added to two or more dilutions, each dilution contacting a distinctly tagged aptamer for a particular target, allowing for the detection of a specific aptamer signal." Schneider teaches, “Multiplexed Assays. In another embodiment, the assays and methods described above are used to detect and/or quantify two or more targets.” (column 8, lines 54-56) Schneider teaches, “For multiplexed detection of a small number of aptamers still bound to the second solid support, fluorescent dyes with different excitation/emission spectra can be employed to detect and quantify two, or three, or five, or up to ten individual aptamers.” (column 40, lines 36-40) Schneider teaches, “Multiplexed Assays. In another embodiment, the assays and methods described above are used to detect and/or quantify two or more targets.” (column 8, lines 54-56)
Thus Schneider specifically envision two or more dilutions and each having a distinctly tagged aptamer (different). The response continues arguing that Schneider does not render the claims obvious based on steps and order of steps. This argument has been thoroughly reviewed but is not considered persuasive as Schneider does teach, “it is to be understood that any number of permutations of the specified sequence of steps is possible, so long as the objective of the particular assay being described is accomplished. Stated another way, the steps recited in any of the disclosed methods may be performed in any feasible order, and the methods of the invention are not limited to any particular order presented in any of the described embodiments, the examples, or the appended claims.” (column 11, lines 6-14.) Schneider teaches, “As discussed above, the assays described here have been grouped for ease in presentation into 4 assay formats: Single Catch Affinity Assays: Dual Catch Affinity Assays, Single Catch Photocrosslink Assays; and Dual Catch Photocrosslink Assays. However, it should be understood that other groupings, combinations, and ordering of steps are contemplated and all fall within the scope of the disclosure.” (column 11, lines 45-53).
The response traverses the rejection alleging Schneider requires the samples are pooled together prior the remainder of the assay. This argument has been thoroughly reviewed but is not considered persuasive as Schneider teaches, “The individual dilution test samples are separately assayed up to and including aptamer (or covalent) complex formation, after which the dilution test samples may be pooled for the remainder of the assay and detected simultaneously on a single solid Support. In one embodiment, each dilution test sample includes a unique aptamer, thereby enabling a single measurement of the corresponding target.” )column 18 bottom- column 19 top) Schneider teaches, “As further described herein, following the formation of an aptamer affinity complex (or the optional conversion to an aptamer covalent complex) the
individual test samples can be pooled and contacted with a labeling agent either before or after attachment of the aptamer (or covalent) complex to the Solid Suppor.” (column 19, lines 29-34) Schneider teaches, “As further described herein, following the formation of aptamer affinity complexes (or the optional conversion to aptamer covalent complexes) the individual test samples can be pooled and contacted with a labeling agent either before or after attachment of the aptamer (or covalent) complexes to the Solid Support). (column 19m lines49-54) The use of can be pooled or may be pooled clearly envisions they do not have to be pooled.
The response further alleges an unexpected result in example 3, however the teachings of example 3 are limited to specific aptamers, labeling, etc., which are of different scope than the instant claims. Thus the allegation is not commensurate in scope
Summary
No claims are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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