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 .
Detailed Action
Summary
This is the Final Office Action based on application 17/635632 response filed 10/04/2025.
Claims 1-8 & 16-26 have been elected, examined and fully considered.
Claims 9-15 are withdrawn.
Claim 26 is newly added.
Claim Rejections - 35 USC § 112
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 1-8 & 16-26 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.
With respect to Claim 1, in step c) “precise,” is a relative term which renders the claim indefinite. The term “precise” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Further every person reading the claim could have a slightly different idea of what they consider precise and what they think is not considered precise. For example, since “precise,” has a similar meaning to exact- “precise temperatures,” could mean temperatures of only full degrees like 25, 26, 27, 28. It could also mean precise in the sense that the temperature does not fluctuate. Further- it’s unclear how/if the claimed, “controlling the temperatures,” “to a plurality of precise temperatures,” “within said at least one microfluidic channel,” is done or if it really can be done. How are multiple (plurality of) temperatures “precise,” in any way if they are all in the same channel where if different temperatures are used, can be mixed. Therefore—it is unclear what is meant by this relative term, “precise.” Correction is required.
Further with respect to Claim 1, step e), “analyzing a gray intensity of said aggregated and precipitated protein,” is claimed. This is a bit confusing, since isn’t a gray intensity of the pattern of the aggregated and precipitated protein analyzed? Saying a grey intensity of said protein is confusing. Further—to have a “gray intensity,” it would seem that imaging has to be performed, but nothing about this is claimed. Therefore, the claim is confusing.
With respect to Claim 3, it claims “where said aggregating increases the concentration of said precipitated protein to create an aggregate protein.” It is unclear what this means. In short it reads--- the aggregating….creates and aggregated protein.” It is unclear how “aggregating increases the concentration of precipitated protein.” This is unclear and confusing. Does applicant mean instead, “ aggregating the precipitated protein/s to concentrate it/them to create an aggregated protein.”
With respect to Claim 5, it is unclear what the “intensity,” or “gray intensity,” is of. For an intensity to be measured--- it would seem that an image has to be taken, but nothing to this affect is claimed. Is the gray intensity of an image, or of an acoustic wave? Further for Claim 5, it is unclear what “measures 50% changes,” means. Does this mean that only 50 % of the changes if present are measured? Or does this mean applicant is expecting a 50% change in some value. Also, what is it changing from and what causes the change? This is unclear in the claim.
Further with respect to Claim 5, it is unclear with respect to the “said precipitated protein,” if applicant is referring back to the “precipitated protein,” in claim 1 or if instead to the “said aggregated and precipitated protein,” as the aggregated and precipitated protein is the only thing which is analyzed for gray intensity in Claim 1.
With respect to Claim 6, it is unclear how a gray intensity “determines,” a “protein melting temperature.” Does applicant mean that the intensity corresponds to the melting temperature through some formula or calculation?
With respect to Claim 16, in step b) “precise,” is a relative term which renders the claim indefinite. The term “precise” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Further every person reading the claim could have a slightly different idea of what they consider precise and what they think is not considered precise. For example, since “precise,” has a similar meaning to exact- “precise temperatures,” could mean temperatures of only full degrees like 25, 26, 27, 28. It could also mean precise in the sense that the temperature does not fluctuate. Further- it’s unclear how/if the claimed, “controlling the temperatures,” “to a plurality of precise temperatures,” “within said at least one microfluidic channel,” is done or if it really can be done. How are multiple (plurality of) temperatures “precise,” in any way if they are all in the same channel where if different temperatures are used, can be mixed. Therefore—it is unclear what is meant by this relative term, “precise.” Correction is required.
Further with respect to Claim 16, step c), what measuring a gray intensity of said aggregated and precipitated protein, means. This is a bit confusing, since isn’t a gray intensity of the pattern on an image and not of the aggregated and precipitated protein analyzed? Saying a grey intensity of said protein is confusing. Further—to have a “gray intensity,” it would seem that imaging has to be performed, but nothing about this is claimed. Therefore, the claim is confusing.
Further for Claim 16, in step c) it is unclear what “measuring a 50% gray intensity change of said first and second precipitated and aggregated protein to,” means. Does this mean that only 50 % of the changes if present are measured? Or does this mean applicant is expecting a 50% change in some value. Also, what is it changing from and what causes the change?
Further for Claim 16, in step d) “conventional,” is a relative term that is not defined by the claim and therefore is unclear and requires correction and it is not clear how one would know what the claimed increase is in comparison to “conventional,” thermal shift assays.
Further with respect to Claim 16, in step c), “to determine,” make it unclear if any actual determining is done in the claimed method or not.
Further with respect to Claim 16, in step d) it is unclear what a “three to thirty-five-fold increased sensitivity,” is of. It seems that this is with respect to the calculation of a different between and first and second melting times. Can one really have “increased sensitivity,” for determinations of melting times?
With respect to Claim 22, “local,” is a relative term which renders the claim indefinite. The term “local” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Further every person reading the claim could have a slightly different idea of what they consider local and what they think is not considered local.
With respect to Claim 22, it is unclear if when applicant claims “said precipitated protein,” if they instead mean “said precipitated and aggregated protein.”
With respect to Claim 23, “aggregating,” and “precipitating,” is no longer claimed in Claim 16 from which Claim 23 depends. Therefore, it is unclear what “said aggregating,” and “said precipitating,” refer to.
Claims 2-8 & 17-26 are rejected by virtue of being dependent on the independent claims which are found to be unclear.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, & 7-8 are rejected under 35 U.S.C. 103 as being obvious over WILSON in US 20130330247 in view of HUFF in US 20180104694 and further in view of SHERMAN in US 20200179929.
With respect to Claim 1, WILSON teaches of a method, comprising:
a) providing:
i) an acousto-thermal device comprising a surface acoustic wave source and at least one microfluidic channel or chamber (abstract, “A fluidics apparatus for manipulation of at least one fluid sample is disclosed. A manipulation surface locates the fluid sample. A surface acoustic wave (SAW) generation material layer is provided,” paragraph 0105, “The fluid sample pinning zone can also be formed by physical structures, for example the pinning zone may be formed as a well in the manipulation surface”), and further that micro particles may be focused in a microfluidic channel (paragraph 0078) and
ii) a sample comprising at least one protein (abstract, “A fluidics apparatus for manipulation of at least one fluid sample is disclosed. A manipulation surface locates the fluid sample,” paragraph 0109, “The fluid sample may consist of or comprise a biological sample such as blood, saliva or urine. For example, the fluid sample may be whole blood,” paragraph 0025, “Notably, for a biological sample containing cells the molecule of interest may be an intracellular molecule,” paragraph 0130, “The term intracellular molecule, or intracellular molecule of interest includes macromolecules (protein, DNA, lipid, polysaccharide)”;
b) introducing said sample into said at least one microfluidic channel or chamber (abstract, “A fluidics apparatus for manipulation of at least one fluid sample is disclosed. A manipulation surface locates the fluid sample. A surface acoustic wave (SAW) generation material layer is provided,” paragraph 0105, “The fluid sample pinning zone can also be formed by physical structures, for example the pinning zone may be formed as a well in the manipulation surface.”);
c) controlling the temperature of the said sample with said surface acoustic wave source to a plurality of precise temperatures within said at least one microfluidic channel or chamber (paragraph 0302).
WILSON further teaches of aggregating the particles which are subjected to the SAW, and the aggregation occurs in concentric rings (in a pattern) (paragraph 0154, & Figure 53).
WILSON further teaches of the surface having a piezoelectric material to form a SAW layer (paragraph 0053-0060) and of parallel transducers (paragraph 0007, 0009, 0021, 0114, 0116, 0208).
WILSON further teaches of separating out particles in the fluid phase to concentrate a specified in the droplet that the particles are essentially centrifuged (though not true centrifugation) (paragraph 0079).
WILSON does not teach in the specific term “precipitating,” the proteins and aggregating specifically precipitated proteins with SAW.
HUFF is used to remedy this. HUFF teaches of an integrated devices that include a sample preparation component integrated with a detection component are disclosed. The sample preparation component may be a digital microfluidics module or a surface acoustic wave module which modules are used for combing a sample droplet with a reagent droplet and for performing additional sample preparation step leading to a droplet that contains beads/particles/labels that indicate presence or absence of an analyte of interest in the sample (abstract). The device of HUFF further uses SAW (as is also done in WILSON) for analyte detection (paragraph 0028, 0037, 0048). HUFF further teaches that the fluid can be concentrated by precipitation (paragraph 0187, 0217). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use precipitation as is done in HUFF in the method of WILSON due to the known advantages this offers for concentration of protein and other additional functionality (HUFF, paragraph 0187).
WILSON and HUFF do not teach of measuring gray or gray intensity for aggregates.
SHERMAN is used to remedy this. SHERMAN teaches of a flow channel device configured to perform an image analysis of the flow chamber (abstract). SHERMAN further teaches the samples which are imaged containing at least one POD which can be a protein, and the assay system is used to generate information from which chemical or biological information may be derived from the optical images of the PODS (paragraph 0011). SHERMAN even further teaches of from the POD parameters determining aggregates of the particles such as the proteins and of analyzing the grayscale images in the PODs (paragraph 0231).
It would have been obvious to one of ordinary scale in the art before the effective filing date of the instant invention to use grayscale image analysis of protein aggregates as is done in SHERMAN in the methods of WILSON And HUFF due to the advantage this offers in being able to calculate protein concentration through scores of the images rather than using fluorescence (SHERMAN, paragraphs 0232, 0231).
With respect to Claim 2, WILSON further teaches of aggregating the particles which are subjected to the SAW, and the aggregation occurs in concentric rings (concentric rings can be considered, parallel lines through broadest reasonable interpretation since all circles are a continuous line and concentric means that the circles are around each other so the lines are parallel to each other) (paragraph 0154, & Figure 53).
With respect to Claim 3, WILSON teaches of the claim as shown above for Claim 1. WILSON does not teach of precipitation. HUFF is used to remedy this and teaches of concentration by precipitation. It would have been obvious to precipitate as is done in HUFF in the method of WILSON due to the advantage this offers for concentration and therefore detection of the sample (paragraph 0187).
With respect to Claim 4, WILSON further teaches of aggregating the particles which are subjected to the SAW, and the aggregation occurs in concentric rings (in a pattern) (paragraph 0154, & Figure 53). WILSON further teaches of separating out particles in the fluid phase to concentrate a specified in the droplet that the particles are essentially centrifuged (though not true centrifugation) (paragraph 0079).
WILSON teaches that the aggregating occurs while SAW occurs (paragraph 0154). WILSON also teach particles are concentrated and separated by SAW (which does the aggregating) (so they occur at the same time.
WILSON does not teach in the specific term “precipitating”. Please see above for claim 1 how HUFF remedies this and teaches of precipitating.
With respect to Claim 7, WILSON teaches that the sample may consist of or comprise a biological sample such as blood, saliva or urine. For example, the fluid sample may be whole blood,” paragraph 0025, “Notably, for a biological sample containing cells the molecule of interest may be an intracellular molecule,” paragraph 0130, “The term intracellular molecule, or intracellular molecule of interest includes macromolecules (protein, DNA, lipid, polysaccharide).”
With respect to Claim 8, WILSON teaches of using SAW to perform lysis (paragraph 0099).
Claims 16-26 & 5-6 are rejected under 35 U.S.C. 103 as being obvious over WILSON in US 20130330247 in view of HUFF in US 20180104694 and further in view of SHERMAN in US 20200179929(using provisional filing date) and further in view of HUYNH in Current Protocols in Protein Science: Analysis of protein stability and ligand interactions by thermal shift assay.
With respect to Claims 16 & 6 WILSON teaches of a method, comprising:
a) providing:
i) an acousto-thermal device comprising a surface acoustic wave source and at least one microfluidic channel or chamber (abstract, “A fluidics apparatus for manipulation of at least one fluid sample is disclosed. A manipulation surface locates the fluid sample. A surface acoustic wave (SAW) generation material layer is provided,” paragraph 0105, “The fluid sample pinning zone can also be formed by physical structures, for example the pinning zone may be formed as a well in the manipulation surface,” “in the form of the arrangement of the SAW scattering elements, the SAW actuator usually an interdigitated transducer, IDT, and the fluidics either as channels (so there is more than 1 channel) (paragraph 0253), and further that micro particles may be focused in a microfluidic channel (paragraph 0078) and
ii) a sample comprising at least one protein (abstract, “A fluidics apparatus for manipulation of at least one fluid sample is disclosed. A manipulation surface locates the fluid sample,” paragraph 0109, “The fluid sample may consist of or comprise a biological sample such as blood, saliva or urine. For example, the fluid sample may be whole blood,” paragraph 0025, “Notably, for a biological sample containing cells the molecule of interest may be an intracellular molecule,” paragraph 0130, “The term intracellular molecule, or intracellular molecule of interest includes macromolecules (protein, DNA, lipid, polysaccharide)”;
b) introducing said sample into said at least one microfluidic channel or chamber (abstract, “A fluidics apparatus for manipulation of at least one fluid sample is disclosed. A manipulation surface locates the fluid sample. A surface acoustic wave (SAW) generation material layer is provided,” paragraph 0105, “The fluid sample pinning zone can also be formed by physical structures, for example the pinning zone may be formed as a well in the manipulation surface.”);
c) controlling the temperature of the said sample with said surface acoustic wave source to a plurality of precise temperatures within said at least one microfluidic channel or chamber (paragraph 0302).
WILSON further teaches of aggregating the particles which are subjected to the SAW, and the aggregation occurs in concentric rings (in a pattern) (paragraph 0154, & Figure 53).
WILSON further teaches of the surface having a piezoelectric material to form a SAW layer (paragraph 0053-0060) and of parallel transducers (paragraph 0007, 0009, 0021, 0114, 0116, 0208).
WILSON further teaches of separating out particles in the fluid phase to concentrate a specified in the droplet that the particles are essentially centrifuged (though not true centrifugation) (paragraph 0079).
WILSON does not teach in the specific term “precipitating,” the proteins and aggregating specifically precipitated proteins with SAW. Though WILSON teaches of the device used having multiple channels, it does not teach of the channels having separate different proteins (first and second protein, though it does teach of two samples as each channel can be said to have a different sample) and repeating the analysis.
HUFF is used to remedy this. HUFF teaches of an integrated devices that include a sample preparation component integrated with a detection component are disclosed. The sample preparation component may be a digital microfluidics module or a surface acoustic wave module which modules are used for combing a sample droplet with a reagent droplet and for performing additional sample preparation step leading to a droplet that contains beads/particles/labels that indicate presence or absence of an analyte of interest in the sample (abstract). The device of HUFF further uses SAW (as is also done in WILSON) for analyte detection (paragraph 0028, 0037, 0048). HUFF further teaches that the fluid can be concentrated by precipitation (paragraph 0187, 0217).
HUFF further teaches of the method being capable of simultaneous analysis of a plurality of different analyte samples (first and second samples holding first and second analytes which can be first and second proteins)(paragraph 0165-0166, 0207, 0179-0182) and that there are an array of wells (multiple microfluidic chambers) for this purposes (paragraph 0396 & 0399, 0402-0403).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use precipitation as is done in HUFF in the method of WILSON due to the known advantages this covers for concentration of protein and other additional functionality (HUFF, paragraph 0187). It also would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to perform the simultaneous analysis as is done in HUFF in the method of WILSON due to the advantage this offers in increasing throughput and in analysis of multiple samples at a time (paragraph 0165-0166). From combining the references--- it would be obvious a second pattern would be present if using two samples/proteins from the teaching of the formulation of a pattern in WILSON.
WILSON and HUFF do not teach of measuring gray intensity or of measuring 50% gray intensity, determining a first or second melting temperature of calculating the difference between a first and second melting temperatures for the different (first and second) proteins.
WILSON and HUFF do not teach of measuring gray or gray intensity for aggregates.
SHERMAN is used to remedy this. SHERMAN teaches of a flow channel device configured to perform an image analysis of the flow chamber (abstract). SHERMAN further teaches the samples which are imaged containing at least one POD which can be a protein, and the assay system is used to generate information from which chemical or biological information may be derived from the optical images of the PODS (paragraph 0011). SHERMAN even further teaches of from the POD parameters determining aggregates of the particles such as the proteins and of analyzing the grayscale images in the PODs (paragraph 0231) and of detecting changes in the measurements for the PODs such as dynamic changes or the parameters which include grayscale intensity measurements(paragraph 0167). It is obvious to one of ordinary skill that this is capable of measuring 50% of the changes of proteins gray intensity as claimed. Since this limitation is unclear as shown in the above 112 rejection, this reads on the instant claims.
It would have been obvious to one of ordinary scale in the art before the effective filing date of the instant invention to use grayscale image analysis of protein aggregates as is done in SHERMAN in the methods of WILSON And HUFF due to the advantage this offers in being able to calculate protein concentration through scores of the images rather than using fluorescence (SHERMAN, paragraphs 0232, 0231).
WILSON, HUFF and SHERMAN do not teach of calculating a first and second melting times/ temperatures for first and second proteins.
HUYNH is used to remedy this teaches of a method of using a thermal device comprising at least one microfluidic channel or chamber (pg 2 para 2 .. The basic scheme of a thermal shift assay (Figure 1) involves incubation of natively folded proteins with SYPRO Orange dye in a 96-well PCR plate. Through a systematic increase in temperature and concomitant monitoring of SYPRO Orange fluorescence emission, it is possible to monitor thermal denaturation of the protein in many conditions simultaneously.) ii) a sample comprising at least one protein; b) introducing said sample into said at least one microfluidic channel or chamber c) controlling the temperature of the said sample to a plurality of precise temperatures within said at least one microfluidic channel or chamber under conditions that create a denatured protein; (pg 2 para 2. The basic scheme of a thermal shift assay (Figure 1) involves incubation of natively folded proteins with SYPRO Orange dye in a 96-well PCR plate. Through a systematic increase in temperature and concomitant monitoring of SYPRO Orange fluorescence emission, it is possible to monitor thermal denaturation of the protein in many conditions simultaneously..).
Specifically, HUYNH teaches of determining the melting points( which can be considered the time at which it melts or melting time as claimed) of multiple proteins (first and second) (Page 2, paragraph 3, line 3) and of forming a MELT curve (Page 4, 1., bullet point 2), and then calculating the different between the temperatures/melting times- which can be done by site on a melting point curve/curves (Page 3, Set up 96-well plate, 1. Paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to determine and derive the differences in melting temperatures/times for different proteins as is done in HUYNH in the methods of WILSON, HUFF, and SHERMAN as it offers advantages in making determinations of protein stability and the thermal shift techniques provides a rapid and inexpensive way to improve recombinant proteins for in vitro study (Page 11, paragraph 2). Further—the prior art does not teach of the instantly specifically claimed 3-to-45 fold increased sensitivity, however this is a material property of the method, and therefore as the method is made obvious, so is its result.
With respect to Claim 17, WILSON, HUFF, and SHERMAN teach of the invention as shown above, but do not teach of protein bound to a ligand. HUYNH is used to remedy this and teaches of studying and discovering protein-ligand interactions. It would have been obvious in the art before the effective filing date of the instant invention to detection protein ligand interactions as they capitalized on increases in protein stability upon binding to a ligand (HUYNH, abstract).
With respect to Claim 18, WILSON, HUFF, and SHERMAN teach of the invention as shown above, but do not teach of protein bound to a ligand. HUYNH is used to remedy this and teaches of studying and discovering protein-ligand interactions. HUYNH also teaches of using small molecule ligands (Page 2, paragraph 2, line 7). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect protein ligand interactions as they capitalized on increases in protein stability upon binding to a ligand (HUYNH, abstract).
With respect to Claim 19, HUFF teaches of measuring mutations (which are mutated in comparison to normal sequences, which are known and wild type(paragraph 0182).
With respect to Claim 20, WILSON teaches of diagnosing diseases (paragraph 0298). Through BRI all diseases can be considered genetic diseases.
With respect to Claim 21, WILSON further teaches of aggregating the particles which are subjected to the SAW, and the aggregation occurs in concentric rings (concentric rings can be considered, parallel lines through broadest reasonable interpretation since all circles are a continuous line and concentric means that the circles are around each other so the lines are parallel to each other) (paragraph 0154, & Figure 53).
With respect to Claim 22, WILSON teaches of the claim as shown above for Claim 1. WILSON does not teach of precipitation. HUFF is used to remedy this and teaches of concentration by precipitation. It would have been obvious in the art before the effective filing date of the instant invention to precipitate as is done in HUFF in the method of WILSON due to the advantage this offers for concentration and therefore detection of the sample (paragraph 0187).
With respect to Claim 23, WILSON further teaches of aggregating the particles which are subjected to the SAW, and the aggregation occurs in concentric rings (in a pattern) (paragraph 0154, & Figure 53). WILSON further teaches of separating out particles in the fluid phase to concentrate a specified in the droplet that the particles are essentially centrifuged (though not true centrifugation) (paragraph 0079).
WILSON teaches that the aggregating occurs while SAW occurs (paragraph 0154). WILSON also teach particles are concentrated and separated by SAW (which does the aggregating) (so they occur at the same time.
WILSON does not teach in the specific term “precipitating”. Please see above for claim 1 how HUFF remedies this and teaches of precipitating.
With respect to Claim 24, WILSON teaches that the sample may consist of or comprise a biological sample such as blood, saliva or urine. For example, the fluid sample may be whole blood,” paragraph 0025, “Notably, for a biological sample containing cells the molecule of interest may be an intracellular molecule,” paragraph 0130, “The term intracellular molecule, or intracellular molecule of interest includes macromolecules (protein, DNA, lipid, polysaccharide).”
With respect to Claim 25, WILSON teaches of using SAW to perform lysis (paragraph 0099).
With respect to Claim 26, HUYNH teaches of determining the melting points( which can be considered the time at which it melts or melting time as claimed) of multiple proteins (first and second) (Page 2, paragraph 3, line 3) and of forming a MELT curve (Page 4, 1., bullet point 2), and then calculating the different between the temperatures/melting times- which can be done by site on a melting point curve/curves (Page 3, Set up 96-well plate, 1. Paragraph 2).
With respect to Claim 5, WILSON teaches of measuring acoustic field intensity (paragraph 0201, 0208, 0213, 0182). HUFF teaches of the claims as shown above. They do not teach of using a gray intensity. SHERMAN is used to remedy this. WILSON and HUFF do not teach of measuring gray or gray intensity for aggregates.
SHERMAN is used to remedy this. SHERMAN teaches of a flow channel device configured to perform an image analysis of the flow chamber (abstract). SHERMAN further teaches the samples which are imaged containing at least one POD which can be a protein, and the assay system is used to generate information from which chemical or biological information may be derived from the optical images of the PODS (paragraph 0011). SHERMAN even further teaches of from the POD parameters determining aggregates of the particles such as the proteins and of analyzing the grayscale images in the PODs (paragraph 0231). Even more specifically, SHERMAN teaches of determining the intensity of the images (paragraph 0106), and specifically of the greyscale images (paragraph 0167). SHERMAN further teaches of detecting changes in the measurements for the PODs such as dynamic changes or the parameters which include grayscale intensity measurements(paragraph 0167). It is obvious to one of ordinary skill that this is capable of measuring 50% of the changes of proteins gray intensity as claimed. Since this limitation is unclear as shown in the above 112 rejection, this reads on the instant claims.
It would have been obvious to one of ordinary scale in the art before the effective filing date of the instant invention to use grayscale image analysis of protein aggregates as is done in SHERMAN in the methods of WILSON And HUFF due to the advantage this offers in being able to calculate protein concentration through scores of the images rather than using fluorescence (SHERMAN, paragraphs 0232, 0231).
Response to Arguments
Applicant's arguments filed 10/04/2025 have been fully considered but they are not persuasive.
With respect to the 112 rejections, they are maintained. Further- due to amendments made 10/04/2025, more 112 rejections are made as shown in the office action above. The examiner notes that it will be easier to overcome the prior art if applicant can overcome the 112 rejections.
With respect to the pages labeled 7-8 of applicant’s arguments applicant recites case law and argues that the examiner has failed to create a prima facie case with the claimed references, but fails to make any concrete arguments with respect to the instant claims. Therefore, the examiner is not convinced by anything on pages 7-8. The examiner maintains, that again--- if applicant can clear up the claims to overcome the 112 b issues, then they are likely to be able to overcome the instant prior art rejection as well. However, as instantly claimed, the claims are unclear, so the prior art reads on the claims.
Starting on Page labeled as 9 of arguments dated 10/04/2025, applicant argues that Claim 1 is not obvious in view of Wilson and Huff. Applicant did however amend Claim 1 and focuses their arguments on this. The examiner notes that the newly used SHERMAN reference was added to teach of the subject matter that is newly recited in Claim 1.
Starting on Page labeled as 10 of arguments dated 10/04/2025, applicant argues that Claim 6 is not obvious in view of Wilson, Huff, Ramos, and Huyhn. The examiner notes again that applicant did in fact amend Claim 16 in their response, and also again emphasizes that if applicant can clear up the claims in light of the 112b rejection, that they will have an easier time overcoming the prior art.
With respect to the RAMOS reference, applicant argues that it focuses on aggregation of bacteria and not proteins. Due to the amendments made, the SHERMAN reference is now used to teach of intensity changes detection as claimed. The SHERMAN reference does not focus on bacteria. Further the SHERMAN references teaches of measuring proteins and aggregates there of and even further of detecting changes in the measurements for the PODs (which can include detection of protein aggregates as shown in the rejection above) and such as dynamic changes or the parameters which include grayscale intensity measurements (paragraph 0167).
Therefore, applicant’s arguments with respect to the RAMOS reference and pages labeled 10-12 of the instant remarks 10/04/2025 are not commensurate in scope with the instant rejection for the claims which were significantly amended 10/04/2025.
Applicant argues about the HYUN reference on pages labeled 12-15 of arguments dated 10/04/2025.
Applicant argues that since HYUNH requires using PCR cycling device, it is incompatible with a surface acoustic wave device. Thought the examiner appreciates that these two types of devices are different, HYUNH was used to teach of mathematical comparisons/comparisons with respect to determined numbers/images. This kind of substance and data analysis capabilities can be utilized the same way, irrespective of different apparatus used. However, the examiner notes, that there were 112 rejections made with respect to this subject matter as shown above. Again, if applicant can clear this up, then they will have an easier time overcoming the prior art.
Applicant argues with respect to the 112 rejections. Many are maintained and further explained in greater detail for the claims which were significantly amended 10/04/2025, as shown in the rejections above. Since this is the case—a response is not found here.
The examiner notes that four references were used for Claim 16, and three for Claim 1. If applicant can clear up the claims--- it might make moving forward easier.
The examiner further notes that withdrawn claims 9-15 remain in the instant application. This differ significantly from the examined method claims. Therefore, they would not be rejoined if the application approaches allowance.
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 REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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