DETAILED ACTION
Applicant’s response filed 12/4/2025 has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. 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 .
Status of the Claims
Claims 1-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 are pending and under consideration in this action. Claims 14-15, 20, 24-25, and 28 were canceled in the amendment filed 12/04/2025. Claims 4-8, 32, and 39-72 were previously canceled.
Priority
The instant application is a 371 of PCT/EP2020/070344, filed 7/17/2020, which claims priority to European Patent Office Application PCT/EP2019/069342, filed 7/18/2019, as reflected in the filing receipt mailed on 11/16/2022. Acknowledgment is made of applicant' s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The claims to the benefit of priority are acknowledged and the effective filing date of claims 1-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 is 7/18/2019.
Claim Objections
The objection to claims 1, 21, 26, and 28 are withdrawn in view of Applicant’s amendments to the claims filed 12/4/2025 (Applicant’s Remarks, Pg. 8).
Claim Rejections - 35 USC § 112(b)
Withdrawn Rejections
The rejection of claims 1-3, 9-31, 33-38, and 73 under 25 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments to the claims filed 12/4/2025 (Applicant’s Remarks, Pg. 8).
Newly Recited Rejections
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 9-13, 22-23, and 26-27 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.
This rejection is newly recited and necessitated by claim amendment.
Claim 9 recites the limitation “wherein the integrity of the RNA contained in the sample composition is calculated using the integrity of a control RNA” in lines 1-2 of the claim. There is insufficient antecedent basis for this limitation in the claim, as there is no prior mention of “the integrity of RNA” in the list of calculated parameters in claim 1, to which this claim depends. This rejection can be overcome by amendment of claim 9 to recite “wherein an integrity of the RNA contained in the sample composition is calculated using the integrity of a control RNA”. Claims 10-13 are also rejected due to their dependency from claim 9.
Claim 22 recites the limitation “wherein the size of RNA containing particles is determined by calculating from the LS signal obtained from step (b) the radius of gyration (Rg) values and/or the hydrodynamic radius (Rh) values” in lines 1-3 of the claim. There is insufficient antecedent basis for this limitation in the claim, as there is no prior mention of “the size of the RNA containing particles” in claim 21, to which this claim depends. This rejection can be overcome by amendment of claim 22 to recite “wherein a size of RNA containing particles is determined by calculating from the LS signal obtained from step (b) the radius of gyration (Rg) values and/or the hydrodynamic radius (Rh) values”. Claims 23 and 27 are also rejected due to their dependency from claim 22.
Claim 26 recites the limitation “the method of claim 25, wherein the quantitative size distribution includes quantitative quality parameters D10, D50, and/or D90 values” in lines 1-2 of the claim. There is insufficient antecedent basis for this limitation in the claim, since claim 25 has been canceled. For the purpose of compact prosecution, this claim will be interpreted to be dependent on claim 1, which contains the phrase “quantitative size distribution”; however, correction is respectfully requested.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 16-19, 21-23, and 27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
This rejection is newly recited and necessitated by claim amendment.
Claim 16, which depends from claim 1, recites the limitation “wherein the amount of total RNA is determined by (i) treating at least a part of the sample composition with a release agent; (ii) performing steps (a) to (c) with at least the part obtained from step (i); and (iii) determining the amount of RNA by using an RNA extinction coefficient or an RNA calibration curve”. Claim 1 recites the limitations “the amount of total RNA is determined by (i) treating a part of the sample composition with a release agent; (ii) performing steps (a) to (c) with the part obtained from step (i); and (iii) determining the amount of total RNA” and “wherein an amount of total RNA and the amount of free RNA are determined by using (i) an RNA extinction coefficient or (ii) an RNA calibration curve”. The limitations recited in claim 16 are also recited in claim 1. Therefore, claim 16 fails to further limit the subject matter of claim 1. Claims 17-18 are also rejected due to their dependency on claim 16.
Claim 19, which depends from claim 1, recites the limitation “wherein the amount of free RNA is determined by performing steps (a) to (c) without addition of a release agent; and determining the amount of RNA using an RNA extinction coefficient or an RNA calibration curve”. Claim 1 recites the limitations “wherein the amount of free RNA is determined by performing steps (a) to (c) without the addition of a release agent and determining the amount of free RNA” and “wherein an amount of total RNA and the amount of free RNA are determined by using (i) an RNA extinction coefficient or (ii) an RNA calibration curve”. The limitations recited in claim 19 are also recited in claim 1. Therefore, claim 19 fails to further limit the subject matter of claim 1.
Claim 21, which depends from claim 1, recites the limitation “wherein step (b) further comprises measuring the LS signal of at least one of the one or more sample fractions obtained from step (a)”. Claim 1 recites the limitation “measuring at least an ultraviolet (UV) signal and a light scattering (LS) signal, of at least one of the one or more sample fractions obtained from step (a)”. The measurement of the LS signal recited in claim 21 is already recited in step (b) of claim 1. Therefore, claim 21 fails to further limit the subject matter of claim 1. Claims 22-23 and 27 are also rejected due to their dependency from claim 21.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
Maintained Rejections
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 1-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite both (1) mathematical concepts (mathematical relationships, formulas or equations, or mathematical calculations) and (2) mental processes, i.e., concepts performed in the human mind (including observations, evaluations, judgements or opinions) (see MPEP § 2106.04(a)).
Any newly recited portion is necessitated by claim amendment.
Step 1:
In the instant application, claims 1-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 are directed towards a method, which falls into one of the categories of statutory subject matter (Step 1: YES).
Step 2A, Prong One:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong One). The following instant claims recite limitations that equate to one or more categories of judicial exceptions:
Claim 1 recites a mental process (i.e., an evaluation of the sample composition) in “wherein the sample composition comprises RNA and particles to which RNA is bound”; a mathematical calculation in “calculating from the UV signal, and optionally from the LS signal, the one or more parameters, wherein the at least two parameters are selected from the group consisting of: an amount of free RNA, an amount of RNA bound to particles, a size distribution of RNA containing particles, and a quantitative size distribution of RNA containing particles”; a mathematical concept in “wherein an amount of total RNA and the amount of free RNA are determined by using (i) an RNA extinction coefficient or (ii) an RNA calibration curve”; a mathematical concept in “wherein the amount of RNA bound to particles is determined by subtracting the amount of free RNA from the amount of total RNA”; mathematical calculations (i.e., e.g. by extinction coefficient or calibration curve; see Specification Pg. 16, Line 21 – Pg. 17, Line 2) in “determining the amount of free RNA” and “determining the amount of total RNA”; and a mathematical concept in “wherein the size distribution of RNA containing particles is determined by plotting the UV signal obtained from step (b) against radius of gyration (Rg) or hydrodynamic radius (Rh) values calculated from the LS signal obtained from step (b), and the quantitative size distribution of RNA containing particles is calculated from the plot showing the UV signal as function of the Rg or Rh values by transforming the UV signal into a cumulative weight fraction and plotting the cumulative weight fraction against the determined Rg or Rh values”.
Claim 2 recites a mental process (i.e., an observation of the type of field-flow fractionation) in “wherein the field-flow fractionation is flow field-flow fractionation”.
Claim 3 recites a mental process (i.e., a judgement of what parameters/protocol to use for step (a)) in “wherein step (a) is performed using: (1) a membrane having a molecular weight (MW) cut-off suitable to prevent RNA from permeating the membrane; (2) a polyethersulfon (PES) or regenerated cellulose membrane; (3) a cross flow rate of up to 8 mL/min; (4) a cross flow rate profile: 1.0 to 2.0 mL/min for 10 min, an exponential gradient from 1.0 to 2.0 mL/min to 0.01 to 0.07 mL/min within 30 min; 0.01 to 0.07 mL/min for 30 min; and 0 mL/min for 10 min; (5) an inject flow in a range of 0.05 to 0.35 mL/min; or (6) a detector flow in a range of 0.30 to 0.70 mL/min”.
Claim 9 recites a mathematical calculation in “wherein the integrity of the RNA contained in the sample composition is calculated using the integrity of a control RNA”.
Claim 10 recites a mathematical calculation in “calculating from the UV signal obtained in step (b') the area from the maximum height of one UV peak to the end of the UV peak, thereby obtaining A50%(control)”; a mathematical concept in “calculating from the UV signal obtained in step (b') the total area of the one peak used in step (c'1), thereby obtaining A100%(control)”, and a mathematical calculation in “determining the ratio between A50%(control) and A100%(control), thereby obtaining the integrity of the control RNA (I(control))”.
Claim 11 recites a mathematical calculation in “calculating from the sample UV signal obtained from step (b) the area from the maximum height of the sample UV peak corresponding to the control UV peak used in step (c'1) to the end of the sample UV peak, thereby obtaining A50%(sample)”, a mathematical calculation in “calculating from the sample UV signal obtained from step (b) the total area of the sample UV peak used in step (c1), thereby obtaining A100%(sample)”, a mathematical calculation in “determining the ratio between A50%(sample) and A100%(sample), thereby obtaining I(sample)”, and a mathematical concept in “determining the ratio between I(sample) and I(control), thereby obtaining the integrity of the RNA contained in the sample composition”.
Claim 12 recites a mental process (i.e., an evaluation of the height of a peak) in “determining from the UV signal obtained in step (b") the height of one UV peak (H(control)), thereby obtaining the integrity of the control RNA”.
Claim 13 recites a mental process (i.e., an evaluation of the peak heights) in “determining from the UV signal obtained in step (b) the height of the sample UV peak corresponding to the control UV peak used in step (c") (H(sample))” and a mathematical calculation in “determining the ratio between H(sample) and H(control), thereby obtaining the integrity of the RNA contained in the sample composition”.
Claim 16 recites a mathematical concept in “determining the amount of RNA by using an RNA extinction coefficient or an RNA calibration curve”.
Claim 18 recites a mental process (i.e., an observation of the type of release agent) in “wherein the release agent is (i) a surfactant; (ii) an alcohol; or (iii) a combination of (i) and (ii)”.
Claim 19 recites a mathematical concept in “determining the amount of RNA by using an RNA extinction coefficient or an RNA calibration curve”.
Claim 22 recites a mathematical calculation in “wherein the size of RNA containing particles is determined by calculating from the LS signal obtained from step (b) the radius of gyration (Rg) values and/or the hydrodynamic radius (Rh) values”.
Claim 23 recites a mathematical calculation in “wherein Rg and/or Rh values are smoothed”.
Claim 26 recites a mental process (i.e., an evaluation of the distribution) in “wherein the quantitative size distribution includes quantitative quality parameters D10, D50, and/or D90 values”.
Claim 27 recites a mathematical calculation in “step (c) comprises calculating the Rh values from the DLS signal”.
Claim 30 recites a mental process (i.e., an observation of the size of the particles) in “wherein the size distribution of RNA containing particles and/or the quantitative size distribution of RNA containing particles is/are within the range of 10 to 2000 nm”.
Claim 31 recites a mental process (i.e., an observation of the length of the RNA) in “wherein the RNA has a length of 10 to 15,000 nucleotides” and a mental process (i.e., an evaluation of how the RNA was transcribed) in “wherein the RNA is in vitro transcribed RNA”.
Claim 35 recites a mental process (i.e., an observation of the solvent mixture components) in “wherein the solvent mixture is a mixture of water and an organic solvent”.
Claim 37 recites a mental process (i.e., an evaluation in comparing variables) in “comparing the one or more parameters of the first composition obtained in step (C) with the corresponding one or more parameters of the second composition obtained in step (D)”.
Claim 38 recites a mental process (i.e., a judgement of the reaction conditions to include) in “wherein the one or more reaction conditions comprise any of the following: salt concentration/ionic strength; temperature; pH or buffer concentration; light/radiation; oxygen; shear force; pressure; freezing/thawing cycle; drying/reconstitution cycle; addition of excipient(s); type and/or source of particle forming compounds; charge ratio; physical state; and ratio of RNA to particle forming compounds”.
These recitations are similar to the concepts of collecting information, and displaying certain results of the collection and analysis is Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)), and 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)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships.
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification, and are determined to be directed to mental processes that in the simplest embodiments are not too complex to practically perform in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind. The instant claims must therefore be examined further to determine whether they integrate the abstract idea into a practical application (Step 2A, Prong One: YES).
Step 2A, Prong Two:
In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP § 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP § 2106.04(d)(I)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP § 2106.04(d)(III)). The following claims recite limitations that equate to additional elements:
Claim 1 recites “subjecting at least a part of the sample composition to field-flow fractionation, thereby fractioning components contained in the sample composition by their size so as to produce one or more sample fractions”, “measuring at least an ultraviolet (UV) signal, and the light scattering (LS) signal, of at least one of the one or more sample fractions obtained from step (a)”, and “wherein the amount of free RNA is determined by performing steps (a) to (c) without the addition of a release agent” and “the amount of total RNA is determined by (i) treating a part of the sample composition with a release agent; (ii) performing steps (a) to (c) with the part obtained from step (i)”. It is noted that step (c) is defined as a mathematical calculation in Step 2A, Prong One above.
Claim 10 further recites “subjecting at least a part of a control composition containing control RNA to field-flow fractionation, thereby fractioning the components contained in the control composition by their size so as to produce one or more control fractions” and “measuring at least the UV signal of least one of the one or more control fractions obtained from step (a')”.
Claim 12 further recites “subjecting at least a part of a control composition containing control RNA to field-flow fractionation, thereby fractioning the components contained in the control composition by their size so as to produce one or more control fractions” and “measuring at least the UV signal of least one of the one or more control fractions obtained from step (a")”.
Claim 16 further recites “treating at least a part of the sample composition with a release agent” and “performing steps (a) to (c) with at least the part obtained from step (i)”. It is noted that step (ii) of claim 16 includes steps (a) and (b), which are additional elements in claim 1 above, while step (c) in claim 1, is defined as a mathematical calculation in Step 2A, Prong One above.
Claim 17 further recites “the field-flow-fractionation is performed using a liquid phase containing the release agent”.
Claim 19 further recites “wherein the amount of free RNA is determined by performing steps (a) to (c) without the addition of a release agent”. Similar to claim 16, it is noted that steps (a) and (b) are additional elements, and step (c) is a mathematical calculation as described for claim 1.
Claim 21 further recites “measuring the LS signal of least one of the one or more sample fractions obtained from step (a)”.
Claim 27 further recites “measuring the dynamic light scattering (DLS) signal of least one of the one or more sample fractions obtained from step (a)”.
Claim 29 further recites “wherein the amount of RNA is determined by measuring the UV signal at 260 nm and using the RNA extinction coefficient at 260 nm or by measuring the UV signal at 280 nm and using the RNA extinction coefficient at 280 nm”.
Claim 33 further recites “wherein measuring the UV signal, optionally the LS signal, is performed on-line and/or step (c) is performed on-line”.
Claim 34 further recites “wherein before subjecting at least a part of the sample composition to field-flow fractionation, the at least part of the sample composition is diluted with a solvent or solvent mixture, said solvent or solvent mixture being able to prevent formation of aggregates of the particles”.
Claim 36 further recites “wherein measuring the UV signal is performed by using circular dichroism (CD) spectroscopy”.
Claim 37 further recites “providing a first composition comprising RNA and optionally particles”, “providing a second composition comprising RNA and optionally particles, wherein the provision of the second composition differs from the provision of the first composition only in the one or more reaction conditions”, “subjecting a part of the first composition to a method of claim 1, thereby determining one or more parameters of the first composition”, and “subjecting a corresponding part of the second composition to the method used in step (C), thereby determining one or more parameters of the second composition”. It is noted that step (c) of claim 37 includes steps (a) and (b), which are additional elements in claim 1 above, while step (c) in claim 1, is defined as a mathematical calculation in Step 2A, Prong One above.
Claim 73 further recites “wherein the field-flow fractionation is asymmetric flow field-flow fractionation (AF4) or hollow fiber flow field-flow fractionation (HF5)”.
Regarding the above cited limitations in claims 1, 10, 12, 16-17, 19, 21, 27, 29, 33-34, 37, and 73 of (i) subjecting at least a part of the sample/control composition to field-flow fractionation, thereby fractioning the components contained in the sample composition by their size so as to produce one or more sample/control fractions (claims 1, 10, 12, 16, and 19); (ii) measuring at least the UV signal, and the light scattering (LS) signal, of least one of the one or more sample/control fractions (claims 1, 10, 12, 16, and 19); (iii) performing steps (a) and (b) without the addition of a release agent (claim 1 and 19); (iv) treating at least a part of the sample composition with a release agent (claims 1 and 16); (v) the field-flow-fractionation is performed using a liquid phase containing the release agent (claim 17); (vi) measuring the LS signal of least one of the one or more sample fractions (claim 21); (vii) measuring the dynamic light scattering (DLS) signal of least one of the one or more sample fractions (claim 27); (viii) wherein the amount of RNA is determined by measuring the UV signal at 260 nm and using the RNA extinction coefficient at 260 nm or by measuring the UV signal at 280 nm and using the RNA extinction coefficient at 280 nm (claim 29); (ix) wherein measuring the UV signal, optionally the LS signal, is performed on-line and/or step (c) is performed on-line (claim 33); (x) wherein before subjecting at least a part of the sample composition to field-flow fractionation, the at least part of the sample composition is diluted with a solvent or solvent mixture (claim 34); (xi) wherein measuring the UV signal is performed by using circular dichroism (CD) spectroscopy (claim 36); (xii) providing a first/second composition comprising RNA and particles to which RNA is bound (claim 37); and (xiii) wherein the field-flow fractionation is asymmetric flow field-flow fractionation (AF4) or hollow fiber flow field-flow fractionation (HF5) (claim 73). These limitations equate to insignificant, extra-solution activity of mere data gathering because these limitations gather data before or after the recited judicial exceptions of calculating one or more parameters from the UV signal, and the LS signal (see MPEP § 2106.04(d)). As such, claims 1-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 are directed to an abstract idea (Step 2A, Prong Two: 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). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The instant claims recite same additional elements described in Step 2A, Prong Two above.
Regarding the above cited limitations in claims 1, 10, 12, 16, 19, 20-21, 27, 29, 33, and 36-37 of (ii) measuring at least the UV signal, and the light scattering (LS) signal, of least one of the one or more sample/control fractions; (vi) measuring the LS signal of least one of the one or more sample fractions; (vii) measuring the dynamic light scattering (DLS) signal of least one of the one or more sample fractions; (viii) wherein the amount of RNA is determined by measuring the UV signal at 260 nm and using the RNA extinction coefficient at 260 nm or by measuring the UV signal at 280 nm and using the RNA extinction coefficient at 280 nm; (ix) wherein measuring the UV signal, optionally the LS signal, is performed on-line and/or step (c) is performed on-line; (xi) wherein measuring the UV signal is performed by using circular dichroism (CD) spectroscopy; and (xii) providing a first/second composition comprising RNA and optionally particles. These limitations are considered to be insignificant extra-solution activity of mere data gathering. These steps are incidental to the primary process of calculating one or more parameters from the UV signal, and the LS signal, wherein the measured signals are merely inputs for the parameter calculation (see MPEP § 2106.05(g)).
Regarding the above cited limitations in claims 1, 10, 12, 16-17, 19-20, 24, 34, and 73 of (i) subjecting at least a part of the sample/control composition to field-flow fractionation, thereby fractioning the components contained in the sample composition by their size so as to produce one or more sample/control fractions; (iii) without the addition of a release agent; (iv) treating at least a part of the sample composition with a release agent; (v) the field-flow-fractionation is performed using a liquid phase containing the release agent; (x) wherein before subjecting at least a part of the sample composition to field-flow fractionation, the at least part of the sample composition is diluted with a solvent or solvent mixture; and (xiii) wherein the field-flow fractionation is asymmetric flow field-flow fractionation (AF4) or hollow fiber flow field-flow fractionation (HF5). These limitations when viewed individually and in combination, are WURC limitations as taught by Wagner et al. (Asymmetric Flow Field-Flow Fractionation in the Field of Nanomedicine. Analytical Chemistry. 86(11): 5201-5210 (2014); previously cited). Wagner et al. discloses the use of asymmetric flow field-flow fractionation (AF4) as a gentle separation and characterization method for biomacromolecules (limitation (xiii)) (Abstract). Wagner et al. further discloses the easy collection of fractions, and the full characterization according to size (limitation (i)) (Pg. 5202, Col. 2, Para. 3 and Pg. 5205, Col. 1, Para. 3). Wagner et al. further discloses the dilution of the sample prior to fractionation during the optimization process (limitation (x)) (Pg. 5204, Col. 1, Para. 2). Wagner et al. further discloses that a surfactant can be added if the interactions with the membrane cannot be avoided (limitations (iii), (iv), and (v)) (Pg. 5203, Col. 2, Para. 1).
These additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the instant claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 1-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 are not patent eligible.
Response to Arguments under 35 U.S.C. 101
Applicant’s arguments filed 12/4/2025 have been fully considered but they are not persuasive.
1. Applicant argues that the claimed methods are in the technological field of nucleic acid analysis and provide an improvement in determining parameters of a sample composition containing RNA. The claimed method requires that an amount of total RNA is determined by treating a part of the sample composition with a release agent, and performing steps (a) and (b) with the part treated with the release agent. It is not well-understood, routine, or conventional to perform the recited steps (a) and (b) upon a sample composition that comprises RNA and particles to which RNA is bound. (Applicant’s Remarks, Pg. 9). Applicant’s arguments are not persuasive for the following reasons:
Claim 1 is directed to a method for determining at least two parameters of a sample that comprises RNA and particles to which RNA is bound. Step (a) of subjecting at least a part of the sample to field-flow fractionation… and step (b) of measuring the UV and LS signals of the samples from (a), are merely collecting data to be used in the calculation of at least two parameters in step (c). Accordingly, steps (a) and (b) were identified as insignificant, extra-solution activity of mere data gathering in Step 2A, Prong Two above. These data gathering steps are similar to the example of pre-solution activity in MPEP § 2106.05(g) of “a step of gathering data for use in a claimed process, e.g., a step of obtaining information about credit card transactions, which is recited as part of a claimed process of analyzing and manipulating the gathered information by a series of steps in order to detect whether the transactions were fraudulent”. In the instant case, the gathered data (i.e., the measured UV and LS signals from the samples subjected to field-flow fractionation with a release agent) is used in the subsequent analysis and calculation of the two or more parameters.
Further analysis of steps (a) and (b) under Step 2B above shows that step (a) is a WURC limitation as taught by Wagner et al., and step (b) is mere data gathering, as the gathered data is incidental to the primary process of calculating one or more parameters, wherein the measured signals are merely inputs for the parameter calculation. Regarding step (a), Wagner et al. discloses the application and progress of field-flow fractionation in biomacromolecules such as RNA and RNA bound particles as disclosed above (see Step 2B above, and Wagner et al., Abstract and Pg. 5205, Col. 2, Para. 1). Wagner et al. also discloses that a surfactant can be added if the interactions with the membrane cannot be avoided (see Step 2B above, and Wagner et al, Pg. 5203, Col. 2, Para. 1). Therefore, step (a) and the use of release agents are WURC limitations as taught by Wagner et al. Regarding step (b), the measurement of the UV and LS signals are incidental to the primary process of calculating at least two or more parameters, as claim 1 is directed towards a method for determining at least two parameters from a sample of RNA and RNA-bound particles. Therefore, when viewed in combination, steps (a) and (b) are data gathering steps that do not meaningfully limit the claim. This argument is thus not persuasive.
2. Applicant argues that steps (a) and (b) are not merely insignificant extra-solution activity because they limit the use of the alleged judicial exceptions to the practical application of analyzing a sample composition containing RNA and determining its parameters, and move them from abstract principles to a specific application. Classen Immunotherapies Inc. v. Biogen IDEC, 659 F.3d 1057, 1066-68 (Fed. Cir. 2011) (Applicant’s Remarks, Pg. 9). Applicant’s arguments are not persuasive for the following reasons:
MPEP § 2106.05(e) recites:
Classen Immunotherapies Inc. v. Biogen IDEC provides another example of claims that recited meaningful limitations. 659 F.3d 1057, 100 USPQ2d 1492 (Fed. Cir. 2011) (decision on remand from the Supreme Court, which had vacated the lower court’s prior holding of ineligibility in view of Bilski v. Kappos, 561 U.S. 593, 95 USPQ2d 1001 (2010)). In Classen, the claims recited methods that gathered and analyzed the effects of particular immunization schedules on the later development of chronic immune-mediated disorders in mammals in order to identify a lower risk immunization schedule, and then immunized mammalian subjects in accordance with the identified lower risk schedule (thereby lowering the risk that the immunized subject would later develop chronic immune-mediated diseases). 659 F.3d at 1060-61; 100 USPQ2d at 1495-96. Although the analysis step was an abstract mental process that collected and compared known information, the immunization step was meaningful because it integrated the results of the analysis into a specific and tangible method that resulted in the method "moving from abstract scientific principle to specific application." 659 F.3d at 1066-68; 100 USPQ2d at 1500-01. In contrast, in OIP Technologies, Inc. v. Amazon.com, Inc., the court determined that the additional steps to "test prices and collect data based on the customer reactions" did not meaningfully limit the abstract idea of offer-based price optimization, because the steps were well-understood, routine, conventional data-gathering activities. 788 F.3d 1359, 1363-64, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015).
In Classen Immunotherapies Inc. v. Biogen IDEC, the gathered data was analyzed in order to identify a lower risk immunization schedule. Subsequently, mammalian subjects were immunized in accordance with the identified lower risk schedule, thereby lowering the risk that the immunized subject would later develop chronic immune-mediated diseases. The immunization step was meaningful because it integrated the results of the analysis into a specific and tangible method that resulted in the method "moving from abstract scientific principle to specific application." In the instant case, steps (a) and (b) are gathering data for subsequent calculation at least two parameters in step (c). However, the calculated parameters are not used or integrated into a tangible method, they are simply calculated as a result of the collected data. As such, steps (a) and (b) are merely insignificant extra-solution activity that does not integrate the abstract ideas into a specific practical application. This argument is thus not persuasive.
3. Applicant argues that the claimed method is an improved analytical technique, similar to other cases which have been found patent-eligible. See, e.g., Thales Visionix Inc. v. United States, 850 F.3d 1343, 1349 (Fed. Cir. 2017) ("Far from claiming the equations themselves, the claims seek to protect only the application of physics to the unconventional configuration of sensors as disclosed. As such, these claims are not directed to an abstract idea and thus the claims survive Alice step one."). (Applicant’s Remarks, Pg. 9-10). Applicant’s arguments are not persuasive for the following reasons:
MPEP § 2106.05(f) recites:
… in Thales Visionix, the particular configuration of inertial sensors and the particular method of using the raw data from the sensors was more than simply applying a law of nature. Thales Visionix, Inc. v. United States, 850 F.3d 1343, 1348-49, 121 USPQ2d 1898, 1902 (Fed. Cir. 2017). The court found that the claims provided a system and method that "eliminate[d] many ‘complications’ inherent in previous solutions for determining position and orientation of an object on a moving platform." In other words, the claim recited a technological solution to a technological problem.
In Thales Visionix, the raw data from the sensors was used in a particular method with particular configuration of sensors, therefore reciting a technological solution to a technological problem. This is different from the instant case, where the data collected in steps (a) and (b) are used in the calculation step (c), but then step (c) is not subsequently used or integrated into a practical application (see also arguments directly above). Therefore, as recited, the claims are not an improved analytical technique, and this argument is thus not persuasive.
Claim Rejections - 35 USC § 102
The rejection of claims 1-3, 14-15, 19, 28, 30-31, and 73 under 35 U.S.C. 102 as being anticipated by Zhong et al. is withdrawn in view of Applicant’s amendments to the claims filed 12/4/2025 and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 10). Specifically, Zhong et al. does not disclose the calculation of RNA parameters using both the UV and LS signals, the use of release agents for total RNA calculation, or the calculation of size distribution / quantitative size distribution of RNA containing particles.
Claim Rejections - 35 USC § 103
The rejection of claims 9-13 under 35 U.S.C. 103 as being unpatentable over Zhong et al in view of Imbeaud et al. is withdrawn in view of Applicant’s amendments to the claims filed 12/4/2025 and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 10-12). Specifically, Imbeaud et al. also does not disclose the calculation of RNA parameters using both the UV and LS signals, the use of release agents for total RNA calculation, or the calculation of size distribution / quantitative size distribution of RNA containing particles.
The rejection of claims 16-18, 20, 29, 33-35, and 37-38 under 35 U.S.C. 103 as being unpatentable over Zhong et al in view of Wagner et al. is withdrawn in view of Applicant’s amendments to the claims filed 12/4/2025 and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 10-12). Although Wagner et al. discloses the use of release agents to optimize the AF4 conditions, Wagner et al. does not disclose the use of release agents for the calculation of total RNA. Wagner et al. also does not disclose the calculation of RNA parameters using both the UV and LS signal or the calculation of size distribution / quantitative size distribution of RNA containing particles.
The rejection of claims 21-27 under 35 U.S.C. 103 as being unpatentable over Zhong et al in view of Ma et al. is withdrawn in view of Applicant’s amendments to the claims filed 12/4/2025 and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 10-12). Although Ma et al. discloses the calculation of RNA parameters using both the UV and LS signals as well as the calculation of size distribution / quantitative size distribution, Ma et al. uses a DNA system instead of an RNA system. Ma et al. also does not disclose the use of release agents for the calculation of total RNA.
The rejection of claim 36 under 35 U.S.C. 103 as being unpatentable over Zhong et al in view of Leszczyszyn et al. is withdrawn in view of Applicant’s amendments to the claims filed 12/4/2025 and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 10-12). Specifically, Leszczyszyn et al. also does not disclose the calculation of RNA parameters using both the UV and LS signals, the use of release agents for total RNA calculation, or the calculation of size distribution / quantitative size distribution of RNA containing particles.
Conclusion
No claims allowed.
Claims 1-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 appear to be free from the prior art because the prior art does not fairly suggest or teach the calculation of RNA parameters using both the UV and LS signals, the use of release agents for total RNA calculation, or the calculation of size distribution / quantitative size distribution of RNA containing particles. The closest prior art is Zhong et al. (U.S. Patent Application Publication, U.S. 2017/0284975 A1; previously cited) and Ma et al. (Complete physicochemical characterization of DNA/chitosan complexes by multiple detection using asymmetrical flow field -flow fractionation. Anal Chem. 82(23): 9636-43 (2010); previously cited). Zhong et al. discloses a fractionation method for determining the distribution of circulating RNAs in a sample using AF4 and UV absorption to quantify RNA parameters. However, Zhong et al. does not teach the calculation of RNA parameters using both the UV and LS signals, the use of release agents for total RNA calculation, or the calculation of size distribution / quantitative size distribution of RNA containing particles, as disclosed in instant claim 1. Additionally, Ma et al. discloses a method to characterize size distribution and composition of DNA complexes using AF4 coupled with UV-Vis, MALS, and DLS measurements. However, Ma et al. does not teach the application of the method for RNA or the use of release agents for total RNA calculation, as disclosed in instant claim 1. Claims 2-3, 9-13, 16-19, 21-23, 26-27, 29-31, 33-38, and 73 are free from the prior art due to their dependency on claim 1.
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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/D.P.S./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687