DETAILED ACTION
Applicant’s response filed 02/20/2026 has been fully considered. The following rejections and/or objections are either reiterated or newly applied.
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
Claims 126-131 are newly added by Applicant.
Claims 1-91, 95 and 98-110 are cancelled by Applicant.
Claims 92-94, 96-97 and 111-131 are currently pending and are herein under examination.
Claims 92-94, 96-97 and 111-131 are rejected.
Claims 94, 123 and 126 are objected.
Priority
The instant application claims domestic benefit as a 371 filing of International Application PCT/US19/64543 filed 12/04/2019, which claims domestic benefit to US Provisional Application No. 62/775,703 filed 12/05/2018. The claims to domestic benefit are acknowledged. As such, the effective filing date for claims 92-94, 96-97 and 111-131 is 12/05/2018.
Drawings
The objection to the drawings is withdrawn in view of amendments.
Specification
The objection to the specification for hyperlinks and abstract is withdrawn in view of amendments.
The abstract filed 02/20/2026 is objected to because it contains implied phrases such as “the present disclosure”. See MPEP § 608.01(b).
Withdrawn Rejections
35 USC 112(b)
The rejection of claims 92-97 and 110-125 under 35 USC 112(b) are withdrawn in view of claim amendment.
35 USC 101
The rejection of claims 116-120 and 121 under 35 USC 101 is withdrawn in view of claim amendments.
35 USC 102
The rejection of claims 92-97, 110-111, 115-120 and 122 under 35 U.S.C. 102 as being anticipated by Shine et al. is withdrawn in view of claim amendment.
35 USC 103
The rejection of claim 125 under 35 U.S.C. 103 as being unpatentable over Shine et al is withdrawn in view of claim amendment.
The rejection of claim 113 under 35 U.S.C. 103 as being unpatentable over Shine et al. rejection, in view of O’Connell et al. is withdrawn in view of claim amendment.
The rejection of claims 95-97, 110, 112 and 115 under 35 U.S.C. 103 as being unpatentable over Shine et al. in view of Doust et al. is withdrawn in view of claim amendment.
The rejection of claim 114 under 35 U.S.C. 103 as being unpatentable over Shine et al. in view of O’Connell et al. and in further view of Doust et al. is withdrawn in view of claim amendment.
The rejection of claim 121 under 35 U.S.C. 103 as being unpatentable over Shine et al. in view of Kilic et al. is withdrawn in view of claim amendment.
The rejection of claim 123 under 35 U.S.C. 103 as being unpatentable over Shine et al. in view of Leverett et al. is withdrawn in view of claim amendment.
The rejection of claim 124 under 35 U.S.C. 103 as being unpatentable over Shine et al. in view of Leverette et al. and in further view of Alapan et al. is withdrawn in view of claim amendment.
Claim Objections
The objection to claims 92, 94 and 117-118 are withdrawn in view of claim amendments.
Claims 94, 123 and 126 are objected to because of the following informalities:
Claims 94 and 123 recite “the one or more RBC permeability parameters” which should be “the one or more RBC permeability parameters from each of the plurality of blood samples” to clarify that all parameters are being limited.
Claim 126 recites the initialisms “ACD” and “ETDA” that should be spelled out first.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC 112(a)
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.
Claim 131 is 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.
This rejection is newly recited as necessitated by claim amendment.
Claim 131 recites new matter. Published specification paras. [191-192] discuss diluting a blood sample from a unit of blood every 7-10 days to 0.5 million RBCs/mL to monitor stored blood viability over time. However, the specification does not dilute different blood samples taken from a patient over time to 0.5 million RBCs/mL to determine a material change in a subject’s health state as required by claims 92 and 131.
35 USC 112(b)
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 92-94, 96-97 and 111-131 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.
Claims dependent from a rejected claim are also rejected, unless otherwise noted.
This rejection is either newly recited as necessitated by claim amendment or maintained from the previous Office action mailed 08/22/2025.
Claim 92, line 5, recites “the plurality of blood samples obtained at different time points from a single subject” which lacks antecedent basis. Lines 1-4 do not teach that the blood samples are from different time points or from a single subject.
Claim 92, lines 9-10, recites “the determined one or more parameters” which renders the claim indefinite. It is unclear which determined one or more parameters from which blood sample is being referenced because lines 4-5 determine one or more RBC parameters from each blood sample. Clarify which parameters are being referenced.
Claim 94, lines 4-5, recites “the osmolality at which the Fluid Flux Curve” which lacks antecedent basis. Provide antecedent basis for the phrase.
Claim 94, line 7, recites “the ratio” which lacks antecedent basis. Provide antecedent basis for the phrase.
Claim 94, line 9, recites “the force” which lacks antecedent basis. Provide antecedent basis for the phrase.
Claims 96-97 and 115 recite “the significant change … over time” which lacks antecedent basis because claim 92 was amended to remove “over time”. Correct the antecedent basis for this phrase.
Claim 116, line 8, recites “the response” which lacks antecedent basis. Provide antecedent basis.
Claim 117 recites “the blood sample” which renders the claim indefinite. It is unclear which blood sample is referenced because claim 116 performs recordings on each blood sample. Clarify which blood sample is being referenced.
Claim 118, lines 1-2, recites “the cell-by-cell graph … the ghost cells” which renders the claim indefinite. It is unclear which ghost cells for which cell-by-cell graph is being referenced because claims 116-117 generate for each blood sample a cell-by-cell graph and ghost cells. Clarify which cell-by-cell graph and ghost cells for which blood sample is being referenced.
Claims 119-121 recite “the cell-by-cell graph” which renders the claims indefinite. It is unclear which cell-by-cell graph is being referenced because claim 116 generates for each blood sample a cell-by-cell graph. Clarify which cell-by-cell graph which blood sample is being referenced.
Claims 124, line 3, and 128-129 recite the relative terms “about” and “around”, which render the claims indefinite. The term “about” 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. Because about is a subjective term, the metes and bounds of “about 44 dynes”, “about 10,000:1”, and “around 5000 cells per second” is unclear.
Claim 127, line 6, recites “the sensor” which lacks antecedent basis. Provide antecedent basis.
Claim 130 recites “the volume of saline discharged” which lacks antecedent basis. Provide antecedent basis.
Response to Arguments under 35 USC 112(b)
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
Applicant argues that the rejection of claim 124 for reciting “about 25 dynes to about 44 dynes” should be withdrawn because “about” has been removed. Applicant’s argument is not persuasive because amended claim 124 recites “from 24 dynes to about 44 dynes”. As such, the rejection for “about” is maintained.
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 of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 92-94, 96-97, 111-115 and 122-125 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Any newly recited portions herein are necessitated by claim amendment.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant application, claims 92-94, 96-97, 111-115 and 122-125 recited a method. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claim 92 recites “determining one or more Red Blood Cell (RBC) membrane permeability parameters from each of the plurality of blood samples obtained at different time points from a single subject … ; comparing the determined one or more parameters from a first time point with that from at least one later time point; detecting a significant change of 5% or greater in at least one of the determined one or more parameters; and indicating, in response to the detected significant change, a material change in the subject's health state.”
Claim 93 recites “wherein the different time points are separated from one another by a regular interval comprising every day, every week, every month, every two months, every 6 months, and/or every 12 months.
Claim 94 recites “wherein the one or more RBC membrane permeability parameters are selected from: coefficient of permeability (Cp), PkO, isotonic volume (IsoV), spherical volume (SphV), maximum % change in cell volume (Inc%), peak height of Cell Scan Plot at 10% below maximum (W10), the osmolality at which the Fluid Flux Curve is at maximum % fluid flux (Pxmax),the osmolality at which the Fluid Flux Curve is at minimum % fluid flux (Pxmin),the maximum fluid flux on the Fluid Flux Curve (Pymax),the minimum fluid flux on the Fluid Flux Curve (Pymin),the ratio of Pymax:Pymin in absolute values (Py ratio), sphericity index_(S, scaled sphericity index(sSI), slope of Fluid Flux Curve (slopeFFC), a measure of the force necessary to convert intact cells at their SphV to ghost cells attheir SphV (S dynes), fragmentation grade, Cell Scan shape, Fluid Flux Curve (FFC) shape, and Combined Probability Profile (CPP).
Claim 96 recites “determining one or more clinical variables of the subject if the significant change in at least one of the determined one or more parameters over time is observed.
Claim 111 recites “wherein the different time points are separated from one another by a day, a week, a month, two months, six months, a year, or longer.
Claim 112 recites “wherein the one or more RBC membrane permeability parameters are determined before, during, and/or after an event to identify susceptibility of the subject to a particular disease, disorder, or condition.
Claim 113 recites “wherein the one or more RBC membrane permeability parameters are determined before and after initiation of therapy and/or prophylaxis.
Claim 114 recites “initiation of the therapy; wherein the therapy is considered ineffective if the significant change is not observed over time; and wherein the first time point is defined by the initiation of the therapy.
Claim 115 recites “performing at least one diagnostic assessment of the subject if the significant change in the determined one or more parameters over time is observed, wherein the at least one diagnostic assessment comprises at least one of taking a medical history, performing a physical examination, performing one or more blood tests, performing one or more urine tests, performing one or more genetic tests, performing imaging, and performing a biopsy.
Claim 122 recites “wherein determining the one or more RBC membrane parameters further comprises recording cell membrane permeability on a cell- by-cell basis and producing a cell scan plot.
Claim 123 recites “wherein the one or more RBC membrane permeability parameters comprises S dynes; and wherein a decrease in the S dynes determined at the later time point compared to the S dynes determined at the first time point indicates a material improvement in the subject's health state.
Claim 124 recites “wherein the decrease in the S dynes from above 60 dynes at the first time point to within a range from 25 dynes to about 44 dynes at the later time point indicates a material improvement in the subject's health state.
Claim 125 recites “wherein the material improvement in the subject's health state comprises an extension of the subject's predicted life expectancy and/or indicates a therapy has been efficacious.
Limitations reciting a mental process.
The above recited limitations in claims 92, 96, 115 and 122 are recited at such a high level of generality that they equate to a mental process because they are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind.
The broadest reasonable interpretation (BRI) of determining RBC membrane permeability parameters from blood samples includes using information derived from the blood samples to calculate the parameters, for example, as described in claim 94. A human can calculate a coefficient of permeability and compare two coefficients of permeability acquired from two time points. A human could determine a clinical variable or perform a diagnostic assessment of a patient as it requires making mental observations and evaluations. A human can record data and generate a graph as it requires organizing data.
Limitations reciting a mathematical concept.
The above cited limitations in claims 92, 110 and 123-124 equate to a mathematical concept
because these limitations are similar to the concepts of organizing and manipulating information
through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d
1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts.
Claims 92 compares numerical values to determine a 5% change. Claims 123-124 recite a mathematical calculation because it contains calculation of determining a delta value.
Limitations included in the judicial exception.
The above cited limitations in claims 93, 111-114 and 125 further limit component of the recited judicial exception and thus are also part of the judicial exception.
As such, claims 92-94, 96-97, 111-115 and 122-125 recite an abstract idea (Step 2A, Prong 1: YES).
Additional Elements:
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. The additional elements are then analyzed under Step 2A, Prong 2 then Step 2B. The instant claims recite the following additional elements:
Claim 92 recites “drawing a plurality of blood samples; diluting each blood sample of the plurality of blood samples; … by monitoring RBC cell volume changes under an altered cell environment”
Claim 97 recites “administering suitable therapy to the subject if the significant change in the determined one or more parameters over time is observed.”
These above recited additional elements are analyzed below under both Step 2A, Prong 2 and Step 2B:
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to insignificant extra-solution activity (MPEP § 2106.05(g)).
The additional elements in claim 92 equate to insignificant extra-solution activity of necessary data gathering. They gather data necessary to perform the judicial exception in claim 92 of comparing, detecting, and indicating.
Claim 97 equates to mere instructions to apply an exception and not a particular treatment because a “suitable” therapy is not a specific/particular type of treatment.
As such, claims 92-94, 96-97, 111-115 and 122-125 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The paragraphs below discuss the additional elements recited above in the instant claims.
The limitations in claims 92 and 97, when viewed individually and in combination, equate to WURC limitations as taught by the instant specification, Shine et al. (“Shine”; FOR ref. B12 on IDS filed 9/22/2021; WO 1997/024598 A1), and Zhurova et al. (“Zhurova”; Clinica Chimica Acta 431 (2014): 103-110; newly cited) and Chang et al. (“Chang”; IEEE transactions on biomedical engineering 40, no. 10 (2002): 1054-1059; newly cited).
The specification recites in paras. [177-178] [221] that conventional techniques such as a Coulter Counter can be used to measure changes in cell volume. Chang heparinized and diluted blood samples collected from volunteers (pg. 1054, col. 2, sec. B), and ionic permeability of RBCs was measured as a result of electric field exposure which caused RBCs to swell (abstract). Chang also discloses treating sickle cell patients with electric field frequencies (pg. 1059, col .1). Zhurova determines osmotic permeability of RBCs by rapidly changing RBC volume by rapidly mixing RBS with anisotonic solution in a stopped-flow spectroscopy system (abstract). Two types of RBC samples were collected from adult donors and umbilical cord blood which diluted (sec. 2.1-2.2). Zhurova teaches treatments using RBCs (pg. 104, col. 1, para. 1).
Shine measures cell permeability of red blood cells (pg. 1, lines 13-16) (pg. 2, lines 2 4), and recites “a measurement of cell permeability is determined by obtaining a measure of the volume of fluid which crosses a sample cell membrane in response to an altered environment” (pg. 3, lines 29-37). The changes in cell volume are then used to obtain various measures of permeability such as a coefficient of permeability (pg. 6, lines 1-14). Shine discusses treatment monitoring and human experimentation of new drugs (pg. 8).
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they equate WURC limitation as taught above. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 92-94, 96-97, 111-115 and 122-125 are not patent eligible.
Response to Arguments under 35 USC 101
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
Applicant argues that claim 92 limitations of detecting a significant change and indicating a material change are not mental processes or mathematical concepts (pg. 15, para. 2 – pg. 16 para. 1 of Applicant’s remarks). Applicant’s argument is not persuasive because these limitations include calculating a percentage change between two values and displaying results of from the calculation.
Applicant argues that because the claims recite physical steps such as sampling and diluting that the claims are not abstract (pg. 16, para. 2 of Applicant’s remarks). Applicant’s argument is not persuasive because a claim can recite both a judicial exception and additional elements. MPEP 2106.I recites “It is well-settled that mere recitation of concrete, tangible components is insufficient to confer patent eligibility to an otherwise abstract idea.”
Applicant’s arguments regarding Cellzdirect and Illumina are noted but are not persuasive because Applicant has not specified which specific limitations, alone or in combination, provide a practical application or provide significantly more (pg. 16, para. 3 – pg. 17, para. 1).
Applicant appears to argue that claim 92 limitation of monitoring RBC cell volume changes is not data gathering (pg. 17, last para. – pg. 18, para. 3). Applicant’s argument is not persuasive because this limitation indeed gathers data necessary to perform the judicial exception in claim 92. See MPEP 2106.05(g)(3) regarding data gathering steps necessary for use of the judicial exception.
Applicant appears to argue a practical application in claim 92 (pg. 18, last para. – pg. 19, para. 2). Applicant’s argument is not persuasive because the alleged improvement appears to be a result of the judicial exception itself. MPEP 2106.05(a) recites “the judicial exception alone cannot provide the improvement.”
Applicant’s arguments regarding claim 92 containing a two step dilution process are not persuasive because claim 92 does not recite a two step dilution process (pg. 19, para. 3 – pg. 20, para. 1).
Applicant’s remarks regarding detecting and indicating being evaluated under step 2B are not persuasive because these limitations recite an abstract idea (pg. 20, para. 2-4).
Applicant’s remarks regarding claim 92 requiring osmolality are not persuasive because claim 92 does not recite osmolality (pg. 20, last para.).
Applicant’s remarks regarding claim 92 providing significantly more than the recited judicial exception is not persuasive because Applicant does not specify which additional elements in the claim that provide significantly more. Rather Applicant lists embodiments from the specification (pg. 21, para. 2).
Applicant states that Examiner’s WURC rationale is invalid, but did not explain why (pg. 21, last para. – pg. 22, para. 1).
Applicant’s remarks regarding claims 116 and 127-131 are noted but are moot because claim 116 is not rejected under 35 USC 101 (pg. 22, para. 2).
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 92, 94, 96-97, 113-122 and 127-130 are rejected under 35 USC 103 for being unpatentable over Shine et al. (“Shine”; FOR ref. B12 on IDS filed 9/22/2021; WO 1997/024598 A1) in view of Kim et al. (“Kim”; Scientific reports 4, no. 1 (2014): 6659; newly cited).
This rejection is newly recited in view of claim amendment.
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 92:
drawing a plurality of blood samples;
Shine measures cell permeability in red blood cells (RBC) from whole blood samples (abstract) (pg. 1, line 5-7). These measurements can be performed on different subjects (pg. 16, lines 12-14).
diluting each blood sample of the plurality of blood samples;
Shine dilutes the whole blood samples (pg. 11, line 30 – pg. 12, line 4). Because a blood sample can be taken from different subjects, this procedure is performed on each sample (pg. 16, lines 12-14).
determining one or more Red Blood Cell (RBC) membrane permeability parameters from each of the plurality of blood samples obtained at different time points from a single subject by monitoring RBC cell volume changes under an altered cell environment;
Shine discloses “a measurement of cell permeability is determined by obtaining a measure of the volume of fluid which crosses a sample cell membrane in response to an altered environment” (pg. 3, lines 29-37). The changes in cell volume are used to obtain various measures of permeability such as a coefficient of permeability and comparison of permeability rates over time in a single sample (pg. 6, lines 1-14) (pg. 2, steps (a)-(h)) (pg. 11, lines 24-35).
Shine does not explicitly teach that multiple samples are taken from a single subject over time. However, this limitation would have been prima facie obvious over the teaching of Shine because the method can be used for screening of routine samples for abnormality as an indication of disease (pg. 10, lines 19-20). One of ordinary skill in the art would have recognized that taking blood samples from a patient over time would constitute routing sampling for screening disease.
comparing the determined one or more parameters from a first time point with that from at least one later time point;
As discussed above, Shine suggests taking RBC measurements from samples over time for disease monitoring (pg. 10, lines 19-20). Shine also teaches a database that stores every measured sample for comparison between previously measured samples (pg. 18, lines 5-7). When these teachings are taken together, they suggest that RBC measurements from samples at different timepoints from a single individual can be compared.
detecting a significant change of 5% or greater in at least one of the determined one or more parameters; and indicating, in response to the detected significant change, a material change in the subject's health state.
As discussed above, Shine suggests comparing samples over time for disease monitoring. However, Shine does not detect a change of 5% or greater in a RBC parameter indicating a change in subject’s health state.
Kim measures RBC sphericity index in healthy patients, in patients with iron deficiency anemia (IDA) and hereditary spherocytosis (HS), and in reticulocytes from a patient with high reticulocyte content (pg. 2, col. 1, para. 2). Mean sphericity index of healthy patients is 0.731 ± 0.05. Mean sphericity in IDA, HS, and the reticulocyte patient are 0.582 ± 0.071, 0.8886 ± 0.049, and 0.619 ± 0.076, respectively (pg. 3, col. 1) (Figure 3E). The difference between sphericity index of healthy patients and IDA, HS, and the reticulocyte patient is greater than 5%.
It would have been prima facie obvious to have modified the method of Shine for measuring changes in RBC permeability parameters in distinct samples over time by comparing changes in sphericity index as taught by Kim. For example, a sphericity index of 0.731 (healthy) measured at a first timepoint in a patient compared to sphericity index of 0.582 (IDA) measured at a second timepoint in the same patient would be a 22% change. Motivation for doing so is because Kim states that RBCs are informative for pathophysiology for many diseases (abstract) and showed that RBC sphericity is different in healthy and diseased individuals (Figure 3E). This aligns with Shine who measures RBC parameters to monitor/detect disease.
There would have been a reasonable expectation of success because it requires calculating changes in values. Also, sphericity indexes are calculated by both Shine (pg. 27) and Kim (Figure 3E) of red blood cells.
Claim 94:
Shine measures a coefficient of permeability and sphericity index (pg. 6, lines 5-14) (pg. 27).
Claim 96-97 and 115:
As discussed above in 35 USC 112(b), these claims are being interpreted as optional. As such, they are not required and are thus rejected because they depend on claim 92.
Claim 113:
Shine discloses that their method may be used to monitor treatment efficacy (pg. 9, lines 33-34). Shine also suggests measuring samples over time and comparing samples (pg. 10, lines 19-20) (pg. 18, lines 5-7). However, Shine does not suggest measuring RBC parameters in samples taken before and after initiation of therapy. However, these limitations are obvious over the teachings of Shine. It would have been prima facie obvious to have measured RBC parameters before and after initiation of therapy because Shine teaches that the method is used for monitoring efficacy of treatment (pg. 9, line 34). There would have been a reasonable expectation of success because Shine suggests taking samples over time and comparing previously measured samples (pg. 10, lines 19-20) (pg. 18, lines 5-7).
Claim 114:
Claim 114 is being interpreted as a contingent limitation because it depends on claim 113 that makes optional initiation of therapy. As such, claim 114 is not required and is thus rejected for being dependent on rejected claim 113.
Claim 116:
As discussed above, the teachings of Shine suggest measuring multiple samples from at least two individuals over time (pg. 16, lines 12-14) (pg. 10, lines 19-20) (pg. 18, lines 5-7). Thus, the following teachings of Shine would be performed for each sample. Cells are measured on a cell-by-cell basis (pg. 36, lines 7-8). Figure 4 shows a graph of cell-by-cell. Shine teaches “The sample suspension passes to a sensing zone 25 comprising an electrical field generated adjacent an aperture through which the individual cells of the sample suspension must pass. As individual blood cells of the sample suspension pass through the aperture the response of the electrical field to the electrical resistance of each individual cell is recorded as a voltage pulse. The amplitude of each voltage pulse together with the total number of voltage pulses for a particular interrupt period, typically 0.2 seconds, is also recorded” (pg. 16, lines 22-32). Also, “In this apparatus the cell suspension is caused to flow through an aperture where it distorts an electrical field. The response of the electrical field to the passage of the cells is recorded as a series of voltage pulses, the amplitude of each pulse being proportional to cell size” (pg 3, lines 23-27). Figure 2 shows a gradient generator.
Claim 117:
Shine discloses ghost cells that slowly release their contents into the surrounding medium (pg. 4, lines 29-34). Figure 4 shows the ghost cells.
Claim 118:
Shine shows in Figure 4 the ghost cells, the ghost gap, expanding intact cell population (i.e., intact cells).
Claim 119:
Shine shows in Figure 10a a cell-by-cell graph with the presence of cell fragments with small size located at the bottom right of the graph.
Claim 120:
Shine shows in Figure 14 a cell-by-cell graph of an unhealthy subject.
Claim 122:
Shine shows in Figure 10b a cell scan plot of permeability on a cell-by-cell basis.
Claims 127-129:
As discussed above, the teachings of Shine suggest measuring multiple samples from at least two individuals over time (pg. 16, lines 12-14) (pg. 10, lines 19-20) (pg. 18, lines 5-7). Thus, the following teachings of Shine would be performed for each sample. Shine recites “the diluter pump 7 is controlled to discharge a sample of blood together with a volume of saline into a first well 10 as part of a first dilution step in the sampling process” (first dilution step) (pg. 11, line 36 – pg. 12, line 4). “The whole blood sample has been diluted by a ratio of typically 10000:1” (fixed numerical ratio) (pg. 14, lines 36-37). Then “In a second dilution step, the diluter pump 7 draws a dilute sample of blood from the first well 10 via multi-position distribution valve 11 into PTFE fluid line 12 and discharges this sample together with an additional volume of saline into a second well 13” (second dilution step) (pg. 12, lines 5-11). “The second dilution step is controlled to achieve an initial cell count of around 5000 cells per second” (predetermined cell count) (pg. 14, lines 36-37).
Claim 130:
Shine recites “varying automatically the volume of saline discharged by the diluter pump 7 from the fluid line 12 in the second dilution step” (pg. 18, lines 21-23).
Claims 93 and 111-112 are rejected under 35 USC 103 for being unpatentable over Shine et al. (“Shine”; FOR ref. B12 on IDS filed 9/22/2021; WO 1997/024598 A1) in view of Kim et al. (“Kim”; Scientific reports 4, no. 1 (2014): 6659; newly cited), as applied to claim 92, and in further view of Doust et al. (“Doust”; The Clinical Biochemist Reviews 34, no. 2 (2013): 85; previously cited on PTO892 mailed 08/22/2025). This rejection is newly recited in view of claim amendment.
The limitations of claim 92 are taught above by Shine and Kim.
Claims 93 and 111-112:
Shine suggests taking RBC measurements from samples over time for disease monitoring routine samples (pg. 10, lines 19-20) and making comparisons between samples (pg. 18, lines 5-7). However, Shine does not teach an interval for routine testing of samples or measure a sample before, during, and/or after an event.
Doust discloses monitoring in clinical biochemistry (abstract). Intervals for testing depend on each patient and can be weekly or annually (pg. 91, col. 1, para. 1) (Figures 3-4). It would have been prima facie obvious to have modified Shine by taking blood samples from a patient at a weekly or annual interval as taught by Doust in order to monitor disease across time. There would have been a reasonable expectation of success because it requires taking samples across time.
Doust teaches that monitoring an asymptomatic patient is beneficial especially regarding lipid levels in order to prevent a cardiovascular event (pg. 87, col. 1, para. 2). It would have been prima facie obvious to have modified Shine by measuring before a health event in order to prevent the health event as taught by Doust. This motivation aligns with Shine who detects and monitors disease (pg. 9, lines 31-35). One of ordinary skill in the art would have had a reasonable expectation of success because it requires taking sample measurements.
Claim 123 is rejected under 35 U.S.C. 103 as being unpatentable over Shine et al. (“Shine”; FOR ref. B12 on IDS filed 9/22/2021; WO 1997/024598 A1) in view of Kim et al. (“Kim”; Scientific reports 4, no. 1 (2014): 6659; newly cited), as applied above to claim, in view of Leverett et al. (“Leverett”; Biophysical journal 12, no. 3 (1972): 257-273; previously cited on PTO892 mailed 08/22/2025). This rejection is newly recited in view of claim amendment.
The limitations of claim 92 have been taught by Shine and Kim.
Claim 123:
Shine suggests taking RBC measurements from samples over time for disease monitoring (pg. 10, lines 19-20) and making comparisons between samples (pg. 18, lines 5-7). However, Shine and Kim do not calculate dynes.
Leverett states that shear stress is an important factor in hemolysis (pg. 257, para. 1), wherein there is a threshold shear stress of 1,500 dynes/cm2, above which extensive cell damage is directly due to shear stress (abstract). It would have been prima facie obvious to have identified a decrease in dynes from one timepoint to another as an indication that a RBC is less likely to suffer from hemolysis as taught by Leverett. This aligns with the motivation of Shine for detecting and monitoring disease (pg. 9, lines 31-35). One of ordinary skill in the art would have had a reasonable expectation of success for the combination because Leverett states that dynes can be calculated for red blood cells and can be used to detect disease such as unwanted hemolysis.
Claims 124-125 are rejected under 35 U.S.C. 103 as being unpatentable over Shine et al. (“Shine”; FOR ref. B12 on IDS filed 9/22/2021; WO 1997/024598 A1) in view of Kim et al. (“Kim”; Scientific reports 4, no. 1 (2014): 6659; newly cited) and of Leverett et al. (“Leverett”; Biophysical journal 12, no. 3 (1972): 257-273; previously cited on PTO892 mailed 08/22/2025), as applied to claims 92 and 123, and in further view of Alapan et al. (“Alapan”; Technology 4, no. 02 (2016): 71-79; previously cited on PTO892 mailed 08/22/2025). This rejection is newly recited in view of claim amendment.
The limitations of claim 92 are taught by Shine and Kim, and the limitations for claim 123 have are taught by Shine, Kim, and Leverett.
Shine suggests taking RBC measurements from samples over time for disease monitoring and making comparisons between samples (pg. 10, lines 19-20) (pg. 18, lines 5-7) (pg. 9, lines 30-35). Leverett discloses that shear stress measured in dynes is related to red blood cell hemolysis (abstract). However, Shine, Kim, and Leverett do teach that a decrease in dynes from above 60 to 25-44 dynes across timepoints indicates improvement in a subject’s health state.
Alapan discloses “we observed significantly greater number of adhered nondeformable RBCs compared to deformable RBCs at a shear stress (50 dyne/cm2) well above the physiological range (1–5 dyne/cm2). The fact that non-deformable sickle RBCs remained adhered at high shear stresses indicates their enhanced adhesion characteristics, which can be indicative of their critical role in vaso-occlusion” (pg. 7, para. 3).
It would have been prima facie obvious to have modified Shine and Leverett comparing RBC dynes across time to monitor disease and determine efficacy of treatment by determining a shear stress change of 50 dynes to 4 dynes would indicate efficacy of disease, particularly in sickle cell anemia patients, as taught by Alapan. One of ordinary skill in the art would have had a reasonable expectation of success because Leverett and Alapan teach that shear force can be measured in dynes in RBCs and is indicative of pathophysiology.
Furthermore, although the claimed range of dynes and the prior art range of dynes is not the exact same as claim 124, Alapan’s disclosure of 50 dynes being unhealthy and 1-5 dynes being normal renders prima facie obvious the claimed range (pg. 7, para. 3). It would have been obvious that dynes greater than 60 when lowered to 25-44 dynes would indicate improvement because the latter is closer to the normal range of 1-5 dynes. See MPEP 2144.05.I regarding overlapping, approaching, and similar ranges.
Claim 126 is rejected under 35 USC 103 for being unpatentable over Shine et al. (“Shine”; FOR ref. B12 on IDS filed 9/22/2021; WO 1997/024598 A1) in view of Kim et al. (“Kim”; Scientific reports 4, no. 1 (2014): 6659; newly cited), as applied to claim 92, and in further view of Brittin et al. (“Brittin”; American Journal of Clinical Pathology 52, no. 6 (1969): 690-694: 85; newly cited). This rejection is newly recited in view of claim amendment.
The limitations of claim 92 are taught above by Shine and Kim.
Shine collects whole blood samples (pg. 11, lines 30-31), but does not draw blood into an anticoagulant.
Brittin discloses quality control for automated hematology systems (abstract). Anticoagulants such as EDTA are used routinely when drawing blood (pg. 691, col. 1, para. 2) (pg. 691, col. 2, para. 3). It would have been prima facie obvious to have drawn blood samples in Shine with EDTA as taught by Brittin because it is a conventional technique in automated hematology systems such as coulter counts. Shine uses a coulter counter (pg. 3, lines 18-20). There would have been a reasonable expectation of success to draw blood with into an anticoagulant because Brittin teaches that it is conventional in automated hematology systems (pg. 691, col. 1, para. 1-2).
Claim 131 is rejected under 35 USC 103 for being unpatentable over Shine et al. (“Shine”; FOR ref. B12 on IDS filed 9/22/2021; WO 1997/024598 A1) in view of Kim et al. (“Kim”; Scientific reports 4, no. 1 (2014): 6659; newly cited), as applied to claim 92, and in further view of Dittami et al. (“Dittami”; Journal of visualized experiments: JoVE 64 (2012): 3842; newly cited). This rejection is newly recited in view of claim amendment.
The limitations of claim 92 are taught above by Shine and Kim.
Shine dilutes RBCs (pg. 11, lines 30-37) but does not recite the specific concentration in claim 131.
Dittami compares coulter counter to a new cell counter technique called Moxi Z (abstract). Figure 2A shows a concentration range of 0 – 500,000 cells/ml. It would have been prima facie obvious to have modified Shine who uses conventional particle/cell counters by using the Moxi Z of Dittami. This is because Moxi Z enables precise sizing and counting of particles ranging from 3-25 microns and when compared to a coulter counter achieves results in less time and with easier operation (abstract). There would have been a reasonable expectation of success to Moxi Z because Shine states that their methods used conventional cell/particle counters (pg. 3, lines 14-20).
Because the prior art range of 0 – 500,000 cell/ml overlaps with the claimed range of 0.5 million RBCs/mL, the prior art range renders obvious the claimed concentration. MPEP 2144.05.I recites “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Response to Arguments under 35 USC 103
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
Applicant argues Shine does not measure samples collected from a single individual over time and does not recite a significant change of 5% or greater (pg. 25 para. 1-2 of Applicant’s remarks). Applicant’s argument is not persuasive for the following reasons:
Shine does teach taking blood samples of a single individual over time. RBC permeability parameters are measured in blood samples (pg. 1, lines 5-7) (pg. 11, line 30). Routine samples (e.g. annual laboratory tests) can be screened for abnormality as an indication of disease (pg. 10, lines 19-20). Every tested sample is stored in a database to make comparisons between previously tested samples (pg. 18, lines 5-7). One of ordinary skill in the art would have recognized that screening of routine samples means that routine samples such as yearly blood work are measured. Thus, the teachings of Shine taken together suggests comparing routine samples taken over time.
However, Shine does not teach a significant change of 5% or greater. This limitation is taught by the combination of Shine and Kim in the newly recited rejection necessitated by claim amendment.
Applicant’s remarks regarding combining Shine and O’Connell for claim 13 are noted but are moot in view of the grounds of rejection necessitated by claim amendment (pg. 25, para. 3). It is noted that claim 113 does not require osmolality driven RBC permeability and newly cited reference Kim et al. teaches the 5% change. Shine does teach measuring samples over time, as discussed in the rejection above.
Conclusion
No claims are allowed. Claims 116-121 and 126-131 were analyzed under 35 USC 101 and were patent-eligible. The following additional elements in claims 92 and 116 were found to be not WURC in Step 2B when viewed in combination: drawing and diluting blood samples, monitoring RBCs under an altered cell environment, recording cell membrane permeability on a cell-by-cell basis by causing each blood sample to flow through an aperture comprising an electric field gradient, wherein the response of the electric field is recorded as a series of voltage pulses for each cell. Claims 117-121 depend on claim 116. Similarly, claims 127-131 all recite additional elements that were not found to be WURC when viewed in combination with additional elements of claim 92.
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.
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685