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 Non-Final Office Action based on application 18/014872 RCE filed 04/20/2026.
Claims 1-5, 7-18 are pending and have been fully considered.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/20/2026 has been entered.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition ofmatter, or any new and useful improvement thereof, may obtain a patent therefor, subject to theconditions and requirements of this title.
Claim 16 is rejected under 35 U.S.C. 101 because it is directed to non-statutory subject matter.
*It is noted that only Claim 16 is currently rejected under 101 since the claimed diagnosis use in prenatal screening for diagnosis brings the natural correlation back into the claims, and due to the clarity/112 issues in Claim 1, it is not clear if the items amended into Claim 1 on 04/20/2026 are actually processing the sample in a way in which practically applies or adds significantly more to the claimed judicial exception. As Claim 1, is now drawn towards a “method of detecting,” due to the elements added to the claim dated 04/20/2026, even though they are unclear, since detection is claimed in addition with the other elements in Claim 1--- it is no longer considered to be directed to a judicial exception.
Through 101, inquiry:
Inquiry: Are the claims directed to a statutory category of invention?
Yes, Claim 16 is drawn towards a statutory category of a method.
Step 2A, Prong 1: Do the claims involve a Judicial Exception?
Yes, Claim 16 involves an a natural correlation/law of nature judicial exception. The correlation is also an abstract idea, the correlation being the amount/concentration of acid molecules in the sample and it’s correlation with leukocyte cells/correlation with diagnosis.
See MPEP 2106.03 & 2106.04.
Step 2A, Prong 2: Has the abstract idea or natural correlation idea been integrated into a particular practical application?
In Claim 16, there is no particular practical application.
Claim 16 depends on Claim 1 and Claim 1 requires:
(1) Encapsulating each non-tumor cell in a volume of 10 pl to 10 nl via a microfluidic device which has a T-junction that generates monodisperse aqueous droplets in an immiscible carrier oil;
(2) Incubating the volume at a temperature of 4 to 37 degrees Celsius for 1 minute;
(3) Detecting a pH or concentration of an acid molecule in the volume- which correlated with the extra-cellular acidification rate of the cell wherein change (increase or decrease) compared to a reference level indicate metabolic activity of the non-tumor cells in the biological fluid, by “using fluorescence-based pH detection comprising SNARF-5f dye as a pH sensitive dye, laser excitation, and photomultiplier tube detection.”
(4) “classifying said leukocyte cell…”;
(5) Obtaining information on a cell type by means of at least one marker configured to allow a discrimination between different leukocyte populations…..”
For (1) as claimed this reads on “encapsulating,” the non-tumor cell in the biological fluid it is naturally present in. There is no derivatization of the sample or anything else claimed which changes it from its natural state. This step as claimed is equivalent to stating that an amount of biological sample is take that have non-tumor cells (such as white blood cells or red blood cells) in it. The fact that this is done in a microfluidic device with a T junction does not change matters as still no derivatization is done, nor is anything which practically applies the claimed “evaluating,” judicial exception. Therefore, this is extra pre-solution activity and does not integrate the judicial exception into a practical application. This is true especially as claimed as there is no real positive step of the sample flowing through a microfluidic device T junction nor of the microfluidic device ejecting the monodisperse droplets in the immiscible carrier oil.
For (2)- this reads on incubating the fluid a room temperature for 1 minute, through broadest reasonable interpretation. Really- nothing is done here after step (1) except letting the sample sit. Therefore, the analysis is the same as for (1), and this does not integrate the judicial exception into a practical application. See MPEP 2106.04 (d) I. & MPEP 2106.05 (g) for insignificant extra-solution activity.
For (3)- it claims detecting a pH or concentration of an acid molecule in the biological sample. Taking pH or concentration measurements here are used for a data pull to accomplish the judicial exception (evaluating—and in addition a judicial exception of comparing to a reference). Data pull to perform judicial exceptions are insignificant extra-solution activity. Therefore, this does not integrate the judicial exception into a practical application. See MPEP 2106.04 (d) I. & MPEP 2106.05 (g) for insignificant extra-solution activity. For amendments dated 04/20/2026, this remains the case as in claiming, “using fluorescence-based pH detection comprising SNARF-5F dye as a pH sensitive dye, laser excitation, and photomultiplier tube detection,” as instantly worded does not make specific any derivatization or change in the sample. As instantly claimed- this reads as extra-solution activity, and therefore there is no claimed practical application.
For (4)- it only states that the leukocyte cells are classified into subpopulations based on the pH or concentration. As broadly claimed is another mental process/abstract idea. Therefore- this does not practically apply.
For (5)- adds that the method obtains information on the leukocyte cell type by means of at least one marker configured to allow a discrimination between different leukocyte populations. However, nothing specific is claimed as to what the marker is or how it is used. Further obtaining information as claimed, again can be a mental process/abstract idea itself. Therefore, this does nothing to practically apply the judicial exceptions.
That the “obtaining information,” comprises, “using, as a marker, a physical quantity …..detected,” or comprises contacting the …sample with one or more probes that act as an antibody marker, suitable to bind with antigens on cells to obtain cell type information,” does not change matters. The examiner notes that this limitation is unclear/confusing as noted in the 112 rejection. Further, the claimed contacting of a biological fluid with one or more probes that act as an antibody marker---as claimed is used as a data pull to accomplish the claimed judicial exception of “evaluating,” and therefore is insignificant extra-solution activity. Things that are insignificant extra-solution activity do not practically apply the judicial exceptions. See MPEP 2106.05 (g).
Further, after the judicial exception is performed, nothing further is done such as a particular and specific treatment. Therefore, there is no practical application of the judicial exceptions.
See USPTO eligibility examples 29.
See MPEP 2106.04 (d)(2) for particular treatment.
Step 2B: Do the claims recite any elements which are significantly more than the natural correlation or abstract idea?
In Claims 1, as is done for determining if there is practical application claimed, steps outlined as (1)-(5) by the examiner above are evaluated to determine if there is anything that adds significantly more to the judicial exceptions.
Nothing is found in the claims that adds significantly more. This is mostly due to the confusing way in which claim limitations were amended into the claims on 04/20/2026.
For steps (1)-(3), “encapsulating,” cells- which as claimed reads on taking a biological sample, incubating at room temperature, and taking pH or concentration measurements and comparing them to a reference all are things that are well understood, routine and conventional (WURC) in the art. Doing this in a microfluidic device with a T junction that generates monodisperse aqueous droplets in a carrier oil does not change the fact that this is WURC, especially since as claimed it is not really clear if the actual sample is processed and passes through the microfluidic device this way or not. The same applies to the newly amended claim limitation that the claimed detecting is done “using fluorescence-based pH detection comprising SNARF-5F dye as a pH sensitive dye, laser excitation, and photomultiplier tube detection, “since as claimed it is not really clear if the actual sample is processed and passes through the microfluidic device this way or not. Things that are well understood, routine and conventional (WURC) do not add significantly more to the claims from the stand point of 101. If these things are made more clearly limiting in Claim 1, it is likely they would overcome the 101 rejection due to being non-routine and conventional and therefore significantly more, even for Claim 16.
For (4), applicant merely added that the cells are leukocytes and that they are classified. This is something that is commonly done in the art. The examiner notes that applicant has not claimed any specifics about how they perform this functional classification. Therefore, especially at the level of generality claimed- this is WURC in the art, and does not add significantly more.
For (5), it is added that information is obtained on the cell type by means of at least one marker configured to allow a discrimination between different leukocyte populations. Markers are WURC in the art. Again, especially at the level of generality claimed- this is WURC in the art, and does not add significantly more.
That the “obtaining information,” comprises, “using, as a marker, a physical quantity detected, or comprises contacting the …sample with one or more probes that act as an antibody marker, suitable to bind with antigens on the non-tumor cells to obtain cell type information,” was amended into the claims. The examiner notes that this limitation is unclear/confusing as noted in the 112 rejection. Further, the claimed contacting of a biological fluid with one or more probes that act as an antibody marker and binding to their antigens---are something that is well understood, routine and conventional in the art. It is not claimed if any specific detection of the marker is performed and how so. Therefore, this does not add significantly more at step 2B.
Further, nothing is claimed in a way which shows any improvement in technology.
See MPEP 2106.05 (a) & MPEP 2106.05 (d).
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 1-5 & 7-18 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—it is noted that some language used seems inconsistent with common U.S. practice. It is possible this is just due to translation issues. In any event, the claims are very confusing as written and applicant should take time to scan the whole claim set and make corrections to ensure clarity.
With respect to the preamble Claim 1, which is the first paragraph of Claim 1, it remains confusing and unclear. As claimed it is: “Method for detecting leukocytes and classifying the leukocytes into subtypes, using leukocyte subpopulations present in a biological fluid sample selected from blood, serum, or plasma, of 10’4 -10’5 non-tumor leukocyte cells/ml of sample, via detection of extra-cellular acidification rate.”
With respect to the above quoted section of the preamble, it is unclear how the non-tumor leukocytes and the sample relate to one another. Is the biological fluid required to have 10’4 or 10’5 non-tumor leukocytes in it? Further- is the amount of non-tumor leukocytes known before any measurement or detection happens? Correction is required to clear this up.
Even further for the Claim 1 preamble/paragraph 1 of Claim 1, it is unclear what “using leukocyte subpopulations,” means in the claim. This is confusing as it seems many different entities are being claimed using the word “leukocyte,” without any differentiating information in the claim of what makes each term different. Correction is required to clear this up.
With respect to Claim 1, paragraphs 2-6, “said leukocyte cell,” is used a lot throughout these paragraphs. However, since both just “leukocytes,” and “non-tumor leukocyte cells.” Again, many different entities are being claimed using the word “leukocyte,” without any differentiating information in the claim of what makes each term different. Correction is required to clear this up.
Further, with respect to Claim 1, paragraph 2- which starts with “encapsulating,” it claims that each single leukocyte cell, which from the preamble is present in the biological sample, is then encapsulated in the biological fluid sample in “10pL to 10nL,” of volume. This is confusing, since can something really be encapsulated into a fluid which it is already present in?
Further with respect to Claim 1, paragraph 2 that starts with “encapsulating,” with respect to the new claim limitation that “the microfluidic device comprises a T-junction that generates monodisperse droplets in an immiscible carrier oil,” it is unclear if the sample is actually processes through this method or if the microfluidic device just “comprises,” these parts. Therefore, the claim is unclear.
With respect to Claim 1, paragraph 3, which starts with “incubating said volume,” “said volume,” is unclear as to whether it is with respect to just the straight up volume of biological fluid, or if instead it means the volume of fluid after some kind of encapsulation occurs. Correction is required to clear this up.
In Claim 1, paragraph 4, which starts with “detecting,” “said incubated volume,” does not have proper antecedent basis, since the term, “incubated volume,” was not mentioned priorly in the claim set and therefore is unclear in the claim. Though it is reasonably clear here that applicant is intended to refer to the volume mentioned in Claim 1, paragraph 3---- as the overall claim is very unclear, this does not help matters and instead hurts them and makes the claims more unclear.
Claim 1, paragraph 4, starting with “detecting, is also unclear since it claims “detecting pH and/pr concentration,” but then later in the paragraph claims, “using fluorescence-based pH detection.” Therefore, it seems pH detection is required and it cannot just be “or a concentration,” as claimed. Therefore, the claim is unclear and requires correction.
Further--- with respect to Claim 1, paragraph 4 it is unclear how “pH and /or concentration,” is detected from the “SNARF-5F due as a PH-sensitive dye, laser excitation, and photomultiplier tube detection,” as no binding or interaction with the sample is claimed, and further though the section is quotations is claimed to, “correlates with an extra-cellular acidification rate of said leukocyte cell,” however it is not clear when or where one gets a measurement, or value which then gives you a pH or concentration value. Correction is required.
With respect to Claim 1, paragraph 6, which starts with “obtaining information on a cell type,” the use of, “by means of at least one marker,” “as a marker, a physical quantity,” “or comprises contacting the biological sample with one or more probes that act as an antibody marker, suitable to bond with an antigen,” is very confusing and unclear. Specifically, it is unclear if all of the claimed markers are the same thing or not. If they are not the same thing, then then need to very clearly be claimed, as it is very confusing the way they are claimed. If the claimed markers are all the same thing, then the use of the term markers needs to be the same throughout the claim. Correction is required.
With respect to Claims 2 -5, 7-18, applicant should check the claims to make sure that the claim language used is the same as and has proper antecedent basis to the amendments made in Claim 1.
With respect to Claim 2, “said biological fluid sample free of non-tumor cells,” fails to have proper antecedent basis as “free of leukocyte cells,” was not mentioned prior to this in Claim 2 or in Claim 1 which claim 2 depends on.
With respect to Claim 4, “particular,” is a relative term, and not defined by the claim and is a term one person could interpret very differently from another person. Therefore, the claim is unclear and requires correction.
Further with respect to Claim 7, “as a marker, as physical quantity,” fails to have proper antecedent basis, as this was mentioned in Claim 1, but no “the,” or “said,” is used in front of this. Therefore, it is unclear if applicant is referring back to that limitation from Claim 1 or not.
With respect to Claim 10, it is unclear what “cytometer-like architectures,” are. Further- different people would interpret this limitation differently and therefore is unclear in the claim.
With respect to Claim 12, it is unclear what “means,” and “characterized” in Claim 12 means. It is unclear if it is a structure or not. Instead, applicant seems to be trying to define what each row or cell is labeled as in a database.
Further, in Claim 12, it is unclear if “said cell,” refers to a cell of a graph, of if instead applicant is referring to one of the types of cells of leukocytes or non tumor cells. This is unclear.
With respect to Claim 13, it is unclear what “means,” in Claim 13 means. It is unclear if it is a structure or not, or instead applicant is trying to refer to an unclaimed formula.
With respect to Claim 14, “the variation,” and “the metabolic profiles identified under the influence of specific drugs,” both fail to have proper antecedent basis and these things were not referred to priorly in the claims and include use of “the.” Further- “specific,” as claimed is a relative term that would mean something different to different people and therefore is unclear.
With respect to Claim 15, “the evaluation of the variation,” fails to have proper antecedent basis, as “evaluation of the variation,” was not claimed prior to this in Claim 15, or Claim 14 which Claim 15 depends on.
Further for Claim 15, it is unclear what “microfluidic technology,” means. Specifically- it is unclear what “technology,” means and what one person would consider technology, another wouldn’t so this is also a relative term. Further for Claim 15, “the droplets,” fail to have proper antecedent basis and require correction.
Claims 2-5 & 7-18 are also rejected by virtue of being dependent on Claim 1.
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 1-5, 7-12, 14, & 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over SCOLES in EP 3084434 in view of TIROSH in EP 2694962.
With respect to Claim 1, SCOLES teaches a method for detecting circulating tumor cells in a body fluid, wherein a cell is encapsulated in a cell volume of about 10pL to 10nL, the volume is incubated at a temperature of from 4°C to 37°C for at least 1 minute, and then a change in pH and/or in concentration of at least one molecule selected from lactic acid, lactate ions and protons (so this can read on the claimed detection of an “acid molecule,” within the incubated volume) within said incubated volume is detected (paragraph 0001, 0008-0009, 0013; claim 1-10).
SCOLES further teaches of detecting and comparing to a reference volume, wherein a decrease in said pH and/or an increase in the concentration of at least one molecule (the acid molecule) with respect to a pH and/or concentration determining for the same volume before said incubation step, indicates the presence of circulating tumor cells in the body fluid (paragraph 0009). This “correlates,” “with said extra-cellular acidification rate,” as claimed.
SCOLES further teaches of the sample containing 4-11 x 10.sup.6 of white blood cell per ml and 10 ^9 red blood cells, and of removing the red blood cells before analysis (so this includes the claimed analysis of 10 ^ 4 or 10 ^ 5 cells/ml of sample) which are non-tumor cells (paragraph 0017). SCOLES further teaches that the single cells (at least one cell) are “encapsulated,” (field of the invention) and even further teaches of the encapsulation being within a microfluidic device (paragraphs 0013-0015).
SCOLES teaches of the microfluidic device which is used for the encapsulation comprising a T-junction (paragraph 0037) and also of using a laser and a photomultiplier tube (PMT) (paragraph 0036) and teaches of processing a droplet through this system wherein the aqueous droplet is in a water in oil emulsion within the microfluidic device (paragraph 0025).
SCOLES further teaches that detection of a decrease in pH and/or increase in the concentration of the acid molecule with respect to the reference indicates the presence of circulating tumor cells in the body fluid (Claim 1). The presence of circulating tumor cells and of the non-tumor in the body fluid can be considered a “change in metabolic activity,” through broadest reasonable interpretation, since cancer cells have metabolic activity.
SCOLES teaches that the detection of a pH or concentration is performed by using a SNARF-5F or 4F dye (paragraph 0037).
SCOLES further teaches of the sample contains 4-11 x 10.sup.6 of white blood cell (leukocytes) per ml and 10 ^9 red blood cells, and of removing the red blood cells before analysis (so this includes the claimed analysis of 10 ^ 4 or 10 ^ 5 cells/ml of sample) (paragraph 0017). These cells are considered the claimed, “non-tumor cells present in a biological fluid,” (also see paragraph 0006).
SCOLES even further teaches of detection of physical properties and also of detecting markers to detect cells (paragraph 0004 & 0006).
SCOLES does not teach of the white blood cells/leukocytes being used for functional classification of leukocyte cells by detection of acidification, nor does it teach of obtaining cell type information by means of at least one marker which allows discrimination between types of leukocytes.
TIROSH is used to remedy this. TIROSH teaches of a method for monitoring and analyzing metabolic activity profiles (abstract). TIROSH further teaches of monitoring acidification profiles of healthy cells and that they are indicative of changes in the metabolic activity of a cell. To do this a fluid sample is encapsulated in a chamber and pH and lactate are measured. The measurements are performed at a constant temperature (37 °C). The influence of various drugs on metabolic profile is analyzed (paragraph 0014, 0134, 0054, 0062, 0097-0098; claims1-14).
TIROSH further teaches of the method being used for differentiation of cells, including differentiation of different types of white blood cells/leukocytes including neutrophils, eosinophils, basophils, lymphocytes, monocytes, macrophages, and dendritic cells (again, non-tumor cells) (paragraphs 0053-0054). TIROSH further teaches of analyzing the metabolic activity and classifying the results (paragraphs 0105-0109). TIROSH teaches that the types of cancers which are detected or diagnosed can be specific to the type of white blood cells found such as leukemia with increased basophils and lymphotic leukemia, or leukemia with eosinophilia (paragraph 0132). TIROSH teaches that the cells have markers which allow their discrimination (paragraph 0042).
TIROSH further teaches of using a pH sensitive impermeable fluorescence probe (paragraph 0043). TIROSH also teaches of using a cell free antigen (that interacts with antibody) as stimulant for the reaction and probe (paragraph 0028).
TIROSH also teaches that they can use antigens or antibodies to help with the detection (paragraph 0091-0092).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the methods of detection of acidification and differentiation of leucocytes f TIROSH and one would have had reasonable expectation of success of combination with the method of SCOLES due to the advantage the taught non invasive measuring offers for early and simple diagnosis if disease is present(TIROSH, paragraph 0033).
With respect to Claim 2, SCOLES teaches of detecting and comparing to a reference volume, wherein a decrease in said pH and/or an increase in the concentration of at least one molecule (the acid molecule) with respect to a pH and/or concentration determining for the same volume before said incubation step, indicates the presence of circulating tumor cells in the body fluid (paragraph 0009). This “correlates,” “with said extra-cellular acidification rate,” as claimed.
SCOLES further teaches of the sample is a blood sample and contains 4-11 x 10.sup.6 of white blood cell per ml and 10 ^9 red blood cells, and of removing the red blood cells before analysis (so this includes the claimed analysis of 10 ^ 4 or 10 ^ 5 cells/ml of sample) (paragraph 0017) and that these, “non-tumor,” cells are what is encapsulated (paragraph 0008-0009, 0013; claim 1-10).
With respect to Claim 3, SCOLES teaches of detecting (classifying) both white blood cells and tumor cells based on the pH detection (Figure 5 A and 5B, paragraphs 0036-0037, and paragraph 0020).
With respect to Claim 4, SCOLES teaches of the above, but does not teach of acidification rate or of comparison to a “normal” cell population for a reference.
TIROSH is used to remedy this.
TIROSH teaches of measuring a metabolic activity (MA) of a cell, the method comprising independently measuring in an extracellular environment of the cell, time-dependent acidification profiles due to secretion (paragraphs 0007-0008). TIROSH further teaches of comparison to a normal unaffected cell sample as a reference (paragraph 0008). It would have been obvious to one of ordinary skill in the art to compare to a normal population for measuring the acidification rate and metabolic activity, due to the advantage since this had advantages of disease detection and diagnosis and treatment purposes (TIROSH, paragraph 0033, 0008-0009).
With respect to Claim 5, SCOLES teaches of isolating the encapsulated volume (paragraph, 0015, 0018).
With respect to Claim 7, SCOLES teaches of detecting an optical quality (fluorescence) (paragraphs 0036-0037, and paragraph 0020).
With respect to Claim 8, SCOLES teaches of the pH being detected using a pH indicator and the detection being a function of the irradiation and emitted signal (paragraphs 0036-0037, and paragraph 0020).
With respect to Claim 9, SCOLES teaches of using laser light to irradiated and detect and that the pH is a function of the irradiation and emitted signal (paragraphs 0036-0037).
With respect to Claim 10, SCOLES teaches of using Olympus IX81 inverted epifluorescence microscope was used for fluorescence measurements. Microscope was equipped with xCite 120Q lamp (Lumen Dynamics Group Inc.), filter set and iXon 897 camera (Andor). Observation of flowing droplets: As shown in Figure 1, an Olympus IX71 inverted microscope was used to analyse flowing droplets one by one. A laser (Cube, Coherent Inc.) beam was expanded (∼ 10x) and focused down at the middle of the detection channel. The fluorescence signal of excited droplets was detected by a PMT detector (H8249, Hamamatsu) (paragraph 0036). All of this can be considered a “flow cytometer like architecture,” through broadest reasonable interpretation.
With respect to Claim 11, SCOLES teaches of detecting lactic acid, lactate ions and protons (so this can read on the claimed detection of an “acid molecule,” within the incubated volume) within said incubated volume is detected (paragraph 0001, 0008-0009, 0013; claim 1-10).
With respect to Claim 12, SCOLES teaches of the above, but does not teach of the claiming modeling and database.
TIROSH is used to remedy this and teaches of building a model for evaluation using data mining and machine learning (AI) in order to evaluate and compare (compare relationships).
It would have been obvious to one of ordinary skill in the art to model utilizing AI and machine learning as is done in TIROSH in the method of SCOLES due to the advantage this offers in being able to classify individuals as having a condition such as cancer or not (paragraphs 0108, 0183-0185, and Figure 12).
With respect to Claim 14, SCOLES teaches of using the method for drug screening purposes (paragraph 0012). SCOLES further teaches of the instant invention being useful for studying tumor cell line metabolism by studying body tumor cells and non-tumor cells (white blood cells) (paragraph 0008, Figure 5 A and 5B, paragraphs 0036-0037, and paragraph 0020).
With respect to Claim 16, SCOLES does not teach of using the method to detect fetal cells or prenatal conditions.
TIROSH is used to remedy this and teaches of using the method to detect autoimmune diseases such as repeated fetal loss (paragraph 0125). This makes using fetal cells obvious. It would have been obvious to one of ordinary skill in the art to detect for other cells and conditions as is done in TIROSH in the method of SCOLES due to the advantage metabolic activity assays will have for many conditions (TIROSH, paragraph 0109).
With respect to Claim 17, SCOLES further teaches of the instant invention being useful for studying tumor cell line metabolism by studying body tumor cells and non tumor cells (white blood cells) (identifying them) (paragraph 0008, Figure 5 A and 5B, paragraphs 0036-0037, and paragraph 0020).
With respect to Claim 18, SCOLES teaches of the above, but does not teach of acidification rate or of comparison to a “normal” cell population for a reference.
TIROSH is used to remedy this.
TIROSH teaches of measuring a metabolic activity (MA) of a cell, the method comprising independently measuring in an extracellular environment of the cell, time-dependent acidification profiles due to secretion (paragraphs 0007-0008). TIROSH further teaches of comparison to a normal unaffected cell sample as a reference (paragraph 0008). It would have been obvious to one of ordinary skill in the art to compare to a normal population for measuring the acidification rate and metabolic activity, due to the advantage since this had advantages of disease detection and diagnosis and treatment purposes (TIROSH, paragraph 0033, 0008-0009).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over SCOLES in EP 3084434 in view of TIROSH in EP 2694962 and in further view of COLLEY in US 20210090694.
With respect to Claim 13, SCOLES teaches of the above, but does not teach of capturing images.
TIROSH is used to remedy this and teaches of using a CCD camera and capturing images of the MA test (paragraph 0096).
SCOLES and TIROSH also do not teach of the association with the database and artificial intelligence.
COLLEY is used to remedy this. COLLEY further teaches of using a database and performing data- mining using artificial intelligence and determining if the data matches or exceeds and threshold (paragraph 0309, 0349, 0291-0292).
It would have been obvious to one of ordinary skill in the art to using the database and AI analysis as is done in COLLEY in the methods of SCOLES and TIROSH due to the advantage information pulled by these techniques can offer as insights that are passed on to physicians via intuitive and simplified interfaces in ways that are easily digested by treating physicians to provide the best in personalized, precision medicine to patients (COLLEY, paragraph 0291).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over SCOLES in EP 3084434 in view of TIROSH in EP 2694962 and in further view of KAPLAN in US 20220299494.
With respect to Claim 15, SCOLES and TIROSH teaches of the claims as shown above.
They do not teach of screening drugs.
KAPLAN is used to remedy this. KAPLAN further teaches of a method of screening drug delivery (abstract). KAPLAN further teaches of performing the method for a plurality of different drugs (paragraph 0008, 0068). KAPLAN also teach of coordinating this with imaging process that takes pictures of encapsulated particles (paragraph 0041), and the use of a flow cytometer (paragraph 0078-0079), and assessing metabolic activity (paragraph 0098). It would have been obvious to screen drugs as done in KAPLAN in the methods of SCOLES and TIROSH due to the advantage it has as being an efficient, high-throughput way to screen and analyze drug delivery systems in vitro (KAPLAN, paragraph 0008).
Response to Arguments
Applicant's arguments filed 04/20/2026 have been fully considered but they are not persuasive.
The examiner notes that after careful consideration of amendments dated 04/20/2026, which were filed after-final initially, then filed in RCE dated 04/20/2026 the claims are very unclear.
It is noted that especially the addition with respect to “the microfluidic device comprises a T-junction that generates monodisperse droplets in an immiscible carrier oil,” and the amendment that “using fluorescence-based pH detection comprising SNARF-5F dye, laser excitation, and photomultiplier tube detection,” could prove helpful in the claims if amended in such a way that it is clear that the sample is processed through these devices as methods. As currently claimed, the processing steps in Claim 1 and the overall claim is very unclear and confusing.
With respect to the 112 rejection, some of the prior rejections have been overcomes as shown above, however the claims remain very unclear as indicated by the 112 rejections which were updated for Claims as significantly amended 04/20/2026, as shown above. Therefore, all claims remain rejected under 112.
With respect to the 101 rejection, it is overcome for all claims pending in this application other than Claim 16. This is because Claim 1 and the claims that depend therefrom are now drawn towards detection/detecting, and not a diagnosis (law of nature/natural correlation judicial exception) or the mental process (abstract idea judicial exception) of evaluating, which it was priorly drawn towards. It is noted due to the preamble now claiming “detecting,” and the addition of “the microfluidic device comprises a T-junction that generates monodisperse droplets in an immiscible carrier oil,” and the amendment that “using fluorescence-based pH detection comprising SNARF-5F dye, laser excitation, and photomultiplier tube detection,” the claims through the preponderance of evidence are meant to be specific towards detecting/measuring, and not a judicial exception. This is despite the many clarity issues which make the claims confusing as shown in the above 112 rejections.
With respect to the 101 rejection, the examiner notes that Claim 16 remains rejected under 101. This is due to the fact that it claims diagnosing, which is a natural correlation/law of nature judicial exception. With respect to this though, if applicant fixes the 112 clarity issues with respect to Claim 1, and most specifically with respect to the limitations including, “the microfluidic device comprises a T-junction that generates monodisperse droplets in an immiscible carrier oil,” and the amendment that “using fluorescence-based pH detection comprising SNARF-5F dye, laser excitation, and photomultiplier tube detection,” while leaving the substance of this subject matter in the claims, it is likely that the 101 rejection for Claim 16 will be overcome as well.
With respect to the 103 rejection, applicant argues that the prior art does not teach of the claimed architecture and that they do not teach of suggest a single cell microfluidic encapsulation for metabolic measurement.
The examiner disagrees. SCOLES teaches that the single cells (“at least one cell”) are “encapsulated,” (field of the invention) and even further teaches of the encapsulation being within a microfluidic device (paragraphs 0013-0015). As far as the “for metabolic measurement,” SCOLES also teaches of this. SCOLES teaches that a decrease in pH and/or increase in the concentration of the acid molecule with respect to the reference indicates the presence of circulating tumor cells in the body fluid (Claim 1). The presence of circulating tumor cells and of the non-tumor in the body fluid can be considered a “change in metabolic activity,” through broadest reasonable interpretation, since cancer cells have metabolic activity.
Applicant emphasizes that the instant claims are directed to “non-tumor cells,” and “classification of leukocytes,” and that SCOLES teaches of tumor cells. The examiner notes that there is confusion with how applicant is claiming the cells as to what type of cells are actually detected. This is noted in the 112 rejection. Therefore, this argument is not found convincing as the claims are currently unclear.
Applicant even further argues that the claimed “assigning individual leukocyte cells to subtypes based on single cell…measurements,” is not taught by the prior art and specifically not by SCOLES. The examiner notes that this argument is not commensurate in scope with the claims as nothing is claimed about “assigning…a subtypes,” and instead what is claimed is obtaining information on cell type of a leukocyte cell,” by “means of at least one marker configured to allow a discrimination between different leukocyte subpopulations, wherein obtaining information on the cell type comprises using, as a marker, a physical quantity of the leukocyte cell that is detected, or comprises contracting the biological fluid sample with one or more probes that act as an antibody marker, suitable to bond with an antigen expressed by the leucocyte cell in order to obtain cell type information, “ and “classifying said leukocyte cell into a leukocyte subpopulation.” As currently claimed, the examiner disagrees with applicant, but if applicant can clear this section up, then it is likely applicant’s argument about the prior art, will also be convincing.
Further the secondary piece of prior art teaches of this. Specifically, TIROSH teaches of the method being used for differentiation of cells, including differentiation of different types of white blood cells/leukocytes including neutrophils, eosinophils, basophils, lymphocytes, monocytes, macrophages, and dendritic cells(which are different leukocyte subpopulations) (again, non-tumor cells) (paragraphs 0053-0054).
With respect to TIROSH, applicant argues that it is directed to bulk metabolic assays, conventional flow cytometry, and tumor related metabolic profiling and that all of these serve different purposes than the claimed invention. The examiner disagrees as the instant claim 1 preamble is actually directed towards evaluating metabolic activity, which is metabolic profiling. Applicant argues that TIROSH does not teach of the claimed encapsulation of single cells, however the SCOLE reference already taught of this so SCOLES does not have to as a 103 rejection was made.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues about the newly amended claim limitations dated 04/20/2026 including the photomultiplier tube, laser, SNARF 5F, T-junction, and monodisperse droplets. Since this limitation was newly amended--- where the prior teaches of this is shown in the rejection above. It is noted that the SCOLES reference was found to teach all of these things.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). With respect to this- the examiner notes that the conclusion of obviousness only took into account knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure. Particularly this is true, since the primary reference is by the same author of the instant invention, though it predates the instant application filing by more than a year.
Applicant further argues with respect to dependent Claims 5, 12, 14, & 15. With respect to this, the examiner does agree that the prior art does not specify isolating individual cells in individual droplets, the examiner notes that this is not exactly what is claimed in Claim 5, but instead it requires that the encapsulated volume comprises a leukocyte cell,” which could also include a plurality of cells through broadest reasonable interpretation and SCOLES does teach of.
For Claim 12—though TIRSOH does not call out the claimed rows and cells it does teach of a database which would inherently have these things. Specifically it teaches of building a model for evaluation using data mining and machine learning (AI) in order to evaluate and compare (compare relationships). It would have been obvious to one of ordinary skill in the art to model utilizing AI and machine learning as is done in TIROSH in the method of SCOLES due to the advantage this offers in being able to classify individuals as having a condition such as cancer or not (paragraphs 0108, 0183-0185, and Figure 12).
For Claim 14, SCOLES teaches of using the method for drug screening purposes (paragraph 0012). SCOLES further teaches of the instant invention being useful for studying tumor cell line metabolism by studying body tumor cells and non-tumor cells (white blood cells) (paragraph 0008, Figure 5 A and 5B, paragraphs 0036-0037, and paragraph 0020), and therefore making it applicable to the instant invention.
For Claim 15, the examiner notes that applicant only argues about SCOLES, meanwhile KAPLAN was used to teach of the subject matter in this claim. KAPLAN teaches of a method of screening drug delivery (abstract). KAPLAN further teaches of performing the method for a plurality of different drugs (paragraph 0008, 0068). KAPLAN also teach of coordinating this with imaging process that takes pictures of encapsulated particles (paragraph 0041), and the use of a flow cytometer (paragraph 0078-0079), and assessing metabolic activity (paragraph 0098). It would have been obvious to screen drugs as done in KAPLAN in the methods of SCOLES and TIROSH due to the advantage it has as being an efficient, high-throughput way to screen and analyze drug delivery systems in vitro (KAPLAN, paragraph 0008).
All claims remain rejected. However, if applicant can significantly clear up the claims, possibly by re-writing to make clearer, applicant might be able to overcome the rejections above.
Conclusion
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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