Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
Summary
This is the Final Office Action based on application 17/910546 RCE filed 01/26/2026. CON 18/669414 is co-pending.
Claims 112, 114-118, 120-124 & 130 have fully considered.
Claims 1-111, 113, 119, & 125-129 are cancelled.
Claims 131-133 are withdrawn.
Double Patenting
The non-statutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A non-statutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 112, 114-118, 120-124 & 130 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19, 22, & 24-28 & 31-34 of copending Application No. 18/669414 in view of PEARSON in A novel pressure-jump apparatus for the microvolume analysis of protein-ligand and protein-protein interactions: its application to nucleotide binding to skeletal-muscle and smooth- muscle mysosin subfragment-1 (as cited on IDS dated 10/11/2022) in view of HASSARD in US 20050054081 and further in view of YANG in US 20220003661, and WEIGL in US 20020090644.
Application and 18/669414 claims, “a method for determining a characteristic property of a molecular interaction, the method comprising: providing a liquid sample comprising a particle capable of being in a state of equilibrium and in a state of non-equilibrium in said liquid sample, the particle comprises a marker in at least one of its state of equilibrium and state of non-equilibrium; e bringing the particle in a state of non-equilibrium by subjecting the sample to a condition jump; detecting said marker as a function of time during at least a portion of a relaxation time for said particle; and e determining said characteristic property of said molecular interaction, wherein said condition jump comprises subjecting the sample to a jump in temperature from at least one first temperature to a second condition at a second temperature and the method further comprises maintaining said second temperature during at least a part of the time of detecting of said marker.” 18/669414 does not claim, “ a jump time of less than 1 minute,” “detecting an optical signal,” or that the “detecting is performed at a reading rate of at least 5 readings per minute….using an optical reader arrangement or an electrochemical reader arrangement.”
However, KINTES, YANG and WEIGL make these things obvious as shown in the rejections below. It would have in particular been obvious to combine the teachings of KINTES with the 18/669414 to arrive at the instant invention and to study reactions using the timing and device components claimed and as is taught by KINTES due to the advantages this offers for studying reaction kinetics (KINTES, abstract). This is a provisional non-statutory double patenting rejection.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition ofmatter, or any new and useful improvement thereof, may obtain a patent therefor, subject to theconditions and requirements of this title.
The claimed invention of Claims 112, 114-118, 120-124 & 130 are directed to non-statutory subject matter.
The invention of instant claims is drawn towards a method for determining a characteristic property of molecular interaction.
Through 101, inquiry:
Inquiry: Is the claims directed to a statutory category of invention?
Yes, the claims are drawn towards a statutory category (a method).
Step 2A, Prong 1: Do the claims involve a Judicial Exception?
Independent claim 112 and 115 and those that depend therefrom involve the judicial exception of an abstract idea.
“Determining a kinetic parameter,” and “determining a folding parameter,” in and in both the preamble and claim body. “Determining,” as claimed, is mental processes, which is an abstract idea judicial exception. Kinetic parameters and folding parameters---are values derived from experimental data that characterize things such as rate of chemical reaction, or how fast other processes move. This is all math & data analysis or calculations from data.
Step 2A, Prong: Has the abstract idea been integrated into a particular practical application? Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
For independent Claim 112, the answer here is no.
Claim 112 includes the additional steps of:
Providing a liquid sample comprising a particle and a binding partner (that are capable of being in equilibrium or non-equilibrium). This can read on many natural things. For example, providing a blood sample that contains protein (particle) and antibodies or antibody bound to optical label (binding partner and marker); or a blood sample that contains red blood cells (particle) and hemoglobin/bound to optical label (binding partner).
Bringing the particle into a state of non-equilibrium and subjecting the sample to a condition jump. This is then further limited to that the condition jump occurs in 1 minute or less. This is then further limited to that the condition jump is a temperature jump that is brough on by a “heating or cooling arrangement,” and that the second temperature is homogenous throughout the sample. It could also be some kind of unspecified device that is not claimed. A “homogenous,” temperature also happens naturally through the laws of thermodynamics. Therefore, this does nothing to practically apply the judicial exception. Also, heating and cooling arrangements are well understood routine and conventional in the art, therefore does not add significantly more to it.
Detecting optical signals of a marker of the particle as a function of time wherein the detecting is performed by an optical reader arrangement or an electrochemical reader arrangement. Detecting is done during at least a portion of the relaxation time and the liquid sample is not diluted. It is also specified that the reading rate is 5 readings per minute.
The detecting further includes performing two or more readings from different fractions of the liquid as a function of time from different fractions of the sample as the sample is flowing in a reading section of a microfluidic unit. The instant “detecting,” is done specifically to use the judicial exception—“determining a kinetic property.” Therefore the generic detection is done as a data pull/is extra-solution activity for the claimed judicial exception. (See data gathering – see MPEP 2106.05(g)).
After that in the claim a computer system is provided to “process the detected signals for and determining the kinetic parameter of said molecular interaction from the particle/marker the optical signals,” however as the computer is not claimed “configured to,” “or programmed to,” and nothing more specific than “kinetic parameter,” is claimed which can be many different things, as claimed- this on using a general computer to perform general math. Math is an abstract idea itself.
Further, both optical measurement and readers and microfluidic units and heating and cool arrangements are routine and conventional detection devices in the art, as shown by the prior art in the rejection below—therefore do not add enough to practically apply or add significantly more to the judicial exception, especially at the level of generality claimed. This holds true when a microfluidic unit is used to detect a flowing sample and the claimed use of them in making multiple measurements from fractions and the claimed computer making kinetic or folding parameter calculations are also well understood routine and conventional (WURC) in the art and therefore does not make the claims significantly more. This is evidenced by the PEARSON reference-- A novel pressure-jump apparatus for the microvolume analysis of protein-ligand and protein-protein interactions: its application to nucleotide binding to skeletal-muscle and smooth- muscle mysosin subfragment-1 (as cited on IDS dated 10/11/2022). . This is evidenced in PEARSON, (Page 644, column 2, last paragraph). (abstract, pages 644-645 and figure 1, Figure 3, 4, 6).
Determining the kinetic property of the molecular interaction based on the optical signal of the marker as a function of time. This determining as claimed is a mental process at simplest and math at most as claimed. Therefore, is an abstract idea, and therefore does not add significantly more to it.
Again, as claimed the “determining,” of this kinetic parameter can be a mental process which is an abstract idea, even when it’s claimed as doing it as a function of time by a generic computer. It is noted that applicant does not claim a specifically or specially programmed computer.
Though not claimed-- since applicant is claiming binding, the kinetic parameters could be things such as the rate of association or disassociation, or determination of equilibrium dissociation constants.
All of these determinations are done by reading off a chart or graph, and performing math. Therefore, this is a generic comparison that can be done by a computer as claimed--- therefore is not a practical application. Therefore, this remains a mental process and does not add significantly more to the judicial exception.
See MPEP 2106.04(a)(2) III. C. A Claim That Requires a Computer May Still Recite a Mental Process. & further 1. “Performing a mental process on a generic computer.”
In amendments dated 01/26/2026, for Claim 112, it was also added to the claims that the method is performed, “while reducing the risk of degrading the sample.” This is a result of the claimed taking multiple readings from different fractions, however this as claimed is just an intended result. As claimed, what is actually done is the taking of multiple samples and measurements, respectively from different fractions of samples--- which is well understood, routine and conventional. Therefore, this does not add significantly more- nor does it add a technological improvement.
Therefore, for all the reasons above, the independent claim 112 does not recite significantly more than the abstract idea, nor does it integrate the abstract idea into a practical application.
Claim 115- was amended 01/26/2026 and carries mostly the same analysis as for Claim 112. Claim 115 adds limitations including:
That the optical or electrochemical signals are detected during a relaxation time.
This does not change the fact that optical signals and signal detection is routine and conventional in the art, and as claimed are being used as a data pull. Therefore this does not add significantly more or practically apply the judicial exception.
That the liquid sample is non-diluted;
If blood is the liquid sample in question here as per the example the examiner gave above, blood is routinely used in the art without dilution. Therefore, this does not add significantly more or practically apply the judicial exception.
That the particle has a structure which differs in structure at the second condition after the condition jump from what it was prior to the condition jump (and that this structure difference is a protein folding change).
All proteins have structures which can denature when exposed to high heat. Therefore this is a natural occurrence and therefore does not practically apply or add significantly more to the judicial exception.
That the temperature controlled maintaining compartment is “configured for maintaining…sample at a second temperature.” With respect to this, the examiner notes that heaters, which maintain temperatures of compartments are WURC, and therefore this does not add significantly more. This is evidenced by the PEARSON reference, (Page 644, column 2, last paragraph). (abstract, pages 644-645 and figure 1, Figure 3, 4, 6).
Analysis of the dependent claims
For the dependent claims we would look to see if they add limitations that change the above analysis (e.g. does the new limitation integrate or amount to significantly more?). Here, none of the dependent claims 114, 116-118, 120-124 & 130 integrate the abstract idea into a practical application or add significantly more.
Claim 114 recites more specification on what is meant by the particle being in equilibrium- and that the sample contains both particle and binding partner. However- at the level of generality claimed—both these pieces seem to be present in the initial sample (for instance, in water) and therefore this does nothing to integrate or add significantly more.
Claim 116 specifies that the conformation (spatial arrangement of constituent atoms) of the protein changes after the condition jump, and further specifies that the marker changes signal based on its conformation change. Again- this is something that routinely and naturally happens to proteins when temperature changes occur. Therefore does not practically apply or add significantly more to the judicial exception.
Claim 117 specifies that the condition jump is performed in a microfluidic unit and that the microfluidic unit is partly in a temperature-controlled compartment. However- this is very general and at the level of generality claimed—it is routine and conventional to provide and us a somewhat temperature controlled microfluidic unit. Therefore- this does not practically apply or add significantly more to the abstract idea.
Claim 118 specifies that the microfluidic unit and that the microfluidic unit comprises an introduction section that has a cross section of 1 mm or less and that it’s a capillary channel. However as claimed, this is extra solution activity— an uses a routine and conventional device (microfluidic capillary device). Size of an introduction does not change this as under 1mm is routine for microfluidic units, and this is also not considered analysis with a particular device. Therefore- this does not practically apply or add significantly more to the abstract idea.
Claim 120 specifies that the temperature control can be done by blowing air--- which can occur naturally in nature—any flow of air can be considered blowing air. Therefore, especially at the level of generality claimed, this routine and conventional in the art and does not practically apply or add significantly more to the judicial exception.
Claim 121 specifies that the temperature jump is at least 2 degrees. Again- temperature jumps are something that naturally occurs—for example as the day turns from morning to afternoon. Therefore, this is routine and conventional and not enough to turn the judicial exception into a practical application or significantly more.
Claim 122 specifies that the second temperature is from about 5 degrees Celsius (41 Fahrenheit) to about 50 degrees Celsius (122 degrees Fahrenheit). Again- temperature jumps are something that naturally occurs—for example as the day turns from morning to afternoon and the temperature at the later half of the day often falls above 50 degrees. Therefore, this is routine and conventional and not enough to turn the judicial exception into a practical application or significantly more.
Claim 123 specifies that the microfluidic unit comprises an introduction section that is a capillary channel and reading out section and that reading out occurs while sample is flowing through microfluidic device and also the condition jump occurs while the liquid sample is in the device. Microfluidic devices having inlets and analysis section of capillary size are routine and common in the art and especially at the level of generality claimed--- these limitations do not integrate the judicial exception into a practical application or add significantly more.
Claim 124 specifies that reading of consecutive samples happens at different times. Again- the claimed reading is an abstract idea so this does not practically apply or add significantly more to the judicial exception.
Claim 130 specifies that the microfluidic unit comprises a channel and that reading out section and that reading out occurs while sample is flowing through the channel. Microfluidic devices having channels are routine and common in the art and especially at the level of generality claimed, including that the sample is fed at a “pressure,” to “ensure elected velocity” and that velocity is adjustable--- these limitations do not integrate the judicial exception into a practical application or add significantly more.
See MPEP 2106.04 & 2106.05. In re Alappat; Also, process claims that are directed to abstract ideas, such as the claims in Bilski v. Kappos & MPEP § 2106.01. Also see Parker v. Flook, and also Alice.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 112, 114-118, 120-124 & 130 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With respect to Claim 112, in the first paragraph of the claim the language “wherein the particle and binding partner are selected such that….are capable of being in a state of equilibrium and in a state of non-equilibrium,” and “ marker is selected to be,” is unclear and confusing.
First of all, any particle and binding partner put together “are capable,” of being in equilibrium (state of balance or concentration) and non-equilibrium (state of imbalance or involving energy flows or changing conditions). Therefore- it is unclear what it means by that they are “selected such that,” they are “capable of being in a state of equilibrium and in a state of non-equilibrium,” means. Are there any particles and binding partners of them that are not “capable of,” being in both equilibrium and non-equilibrium? Further, what if any meaning does “selected such that,” give the “capable of?”
Further for Claim 112, the claimed particle is “selected such that,” and the claimed particle comprises a marker which is further “selected to be,” so it is unclear how/if these selections/ mental process influence each other and what is doing the “selected to be,” does to the “selected such that.” Further- is the claimed selecting done by a computer selecting from a database? Or is it a person selecting from all possible particles and markers known to man? Instead of claiming what the particle (comprising a marker) and binding partner are, applicant is claiming that they can be “selected,” from seemingly any particle and binding partner known to man—so it is unclear what applicant is doing here.
For the particle the instant specification discloses on Page 13, paragraph 3 that
“the particle comprises a biomolecule; a protein, such as an antibody (monoclonal or polyclonal), a nanobody, an antigen, an enzyme and/or a hormone; a nucleotide; a nucleoside; a nucleic acid, such a RNA, DNA, PNA or any fragments thereof and/or any combinations comprising at least one of these,”
and on Page 10, last paragraph, that “The particle may for example comprise a drug or a toxin or a candidate for a drug and the binding partner may for example be a biological compound naturally present in a living being, such as a mammal. In another embodiment, the binding partner may comprise a drug or a toxin or a candidate for a drug and the particle may be a biological compound naturally present in a living being, such as a mammal.
Further, on Page 14 of the instant specification, it is claimed:
“Where the molecular interaction comprises a liquid-liquid phase separation, the condition jump is advantageously a temperature jump comprising a jump in temperature from at least one first temperature to a second temperature and wherein the particle comprises at least two different molecules and an optional additional solvent, which molecules are capable of forming a liquid- liquid phase separation at the condition prior to or after the temperature jump.
For example the at least two different molecules may comprise at least one protein, such as an antibody or an enzyme; at least one polymer, such as polyethylene glycol (PEG) or a PEGylated molecule; at least one lipid, such as phospholipid or cholesterol and/or at least one glycosaccharide, such as dextran. In an embodiment, one or more of the two or more different molecules is/are biomolecules. In an embodiment, at least one of the two or more different molecules is a salt in dissociated stage.”
These paragraphs in the specification are seemingly the extent of what the particles can be selected from, however claimed selecting of a particle and binding partner reads much more broadly than this.
For claim 112, the “selected such that,” for the claimed temperature is unclear and confusing. Further- is the claimed selecting done by a computer selecting from a database? Or is it a person selecting the temperature mentally?
For Claim 115, the “selected such that,” for the claimed temperature is unclear and confusing. Further- is the claimed selecting done by a computer selecting from a database? Or is it a person selecting the temperature mentally?
Further with respect to Claims 112 & 115, the newly recited “while reducing the risk of degrading,” is a relative phrase as is risk reduction. What one would consider a reduced risk, another might not. Therefore, the claims are unclear.
Claims 114, 116-118, 120-124 & 130 are rejected by virtue of their dependency on Claims 112 and 115.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 112, 114-118, 120-122 & 130 are rejected under 35 U.S.C. 103 as being obvious by PEARSON in A novel pressure-jump apparatus for the microvolume analysis of protein-ligand and protein-protein interactions: its application to nucleotide binding to skeletal-muscle and smooth- muscle mysosin subfragment-1 (as cited on IDS dated 10/11/2022) in view of HASSARD in US 20050054081 and further in view of YANG in US 20220003661.
With respect to Claims 112 & 115, PEARSON teaches of a method for determining a characteristic property of a molecular interaction (protein-ligand interactions between rabbit skeletal muscle-derived myosin fragment skS1 and ADP). PEARSON teaches that the method is used for determination of relaxation kinetics and kinetic data (kinetic parameters) and protein folding (folding parameter) (abstract, Page 649, column 2, paragraph 1, line 2 and paragraph 2, line 17), the method comprising:
providing a liquid sample comprising a particle capable of being in a state of equilibrium and in a state of non-equilibrium (ADP), the particle comprises a marker in at least one of its state of equilibrium and state of non-equilibrium (has fluorescent marking- which is optically readable as claimed)(Page 644, column 2, figure 1 & description & Figure 2 and description), in a solvent (the buffer in PEARSON can be considered to be the claimed solvent, Page 644, column 1, paragraph 7).
bringing the particle in a state of non-equilibrium by subjecting the sample to a condition jump comprising a jump in pressure from a first pressure (0.6MPa) to a second pressure (10MPa), reading out said marker as a function of time during at least a portion of a relaxation time for said particle (see figure 4), and
determining said characteristic property of said molecular interaction, wherein said reading out comprises reading out as a function of time comprising performing two or more readings from different fractions of said sample (see figure 4--- each line of graph can be considered to be a different fraction,), in a microfluidic unit (the size of the apparatus is within the micro- ranges and is therefore a microfluidic device; see figure 1) (PEARSON, abstract; page 646, right-hand column, paragraph 3 and figure 4).
PEARSON further teaches an apparatus associated with this method for determining a characteristic property of a molecular interaction, and comprising
a sample compartment for containing at least one liquid mother sample;
a withdrawing arrangement arranged for withdrawing a sample from a at least one mother sample stored in said sample compartment;
a condition jump arrangement arranged for performing a jump in pressure from a first pressure to a second pressure, and
at least one reader arrangement for reading at least one marker as a function of time, wherein the apparatus can perform reading out as a function of time by performing two or more readings from different fractions of said sample, with the sample contained in a microfluidic unit (abstract, pages 644-645 and figure 1, Figure 3, 4, 6).
As claimed, “while reducing the risk of degrading the sample.” This is a result of the claimed taking multiple readings from different fractions---so the instant prior art teaching would result in this intended result, since it teaches of the process step as claimed.
PEARSON teaches of detecting changes in conformation as a result in the changes in condition jump/change (which in this case is a pressure jump/change—which leads to temperature change/jump) and this is due to binding and conformation changes. The changes detected are fluorescent/optical signals/changes by an optical/fluorescent signal reader. (Page 650, column 2, paragraph 3, line 7 & on & Page 644, column 1, paragraph). This results in a change in fluorescence signal due to fluorescent marker (abstract). Figure 1 shows the pressure jump apparatus and the microfluidic inlet.
PEARSON further teaches wherein the apparatus can perform reading out as a function of time by performing two or more readings from different fractions of said sample, with the sample contained in a microfluidic unit (abstract, pages 644-645 and figure 1, Figure 3, 4, 6).
PEARSON further teaches of using a computer to collect and analyze the collected data (Page 644, column 2, last paragraph).
If the condition jump being a temperature jump and specifically the temperature arrangement (creating a temperature) is unclear to one of ordinary skill in the art from PEARSON, HASSARD is used to remedy this.
HASSARD teaches a method for analyzing temperature-dependent molecular configurations such as folding that comprises a multi-channel flow-through chip (12) along which molecules to be analyzed pass. A temperature gradient (which leads to homogenous temperature through the laws of thermodynamics) is maintained along the length of the chip. As molecules pass along the channels they fold or unfold, in response to the changing temperature (abstract). HASSARD further teaches of using protein samples (paragraph 0051, 0016, 0019) and that the sample (protein-liquid since it flows) contained in a buffer (paragraph 0036—so the proteins are contained in the same non-diluted way as instantly disclosed by applicant meaning in a buffer), flows through the chip/channel (abstract). HASSARD teaches that they use heating elements along the chip (heating arrangements) (paragraph 0013).
It would have been obvious to one of ordinary skill in the art to use a temperature jump as the condition jump and a heating arrangement as is done in HASSARD in the method of PEARSON before the effective filing date of the instant invention due to flow through method as is done in HASSARD due the affect temperature has on protein folding and unfolding advantage this would offer for studying protein folding and unfolding which will understanding of protein folding and stability will provide a clearer insight into the causes of disease, and therefore will allow the development of better treatments or preventative measures for disease. (HASSARD, paragraphs 0004-0006).
PEARSON and HASSARD does not specifically call out that the jump takes 1 minute. They also do not call out making 5 readings per minute.
YANG is used to remedy this and further teaches of establishing a temperature gradient across a holder holding a sample- wherein the temperature stabilizes in 1 minute (paragraph 0006) and that the phase separation temperature (condition jump) happens after 1 minute (paragraph 0048). YANG also teaches of making continuous measurements ( so more than 5 readings per minute (paragraph 0048, 0170 Figure 32, 0082). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to subject the sample to a temperature to perform a condition jump in 1 minute or less as is done in YANG in the method of PEARSON and HASSARD due to the advantage this has for giving information for reaction kinetic study (YANG, paragraph 0048) and due to the advantage it has for studying temperature dependent reaction kinetics (paragraph 0082).
With respect to Claim 114, see Claim 1 rejection for PEARSON. PEARSON further teaches of using the apparatus and method of claim 1 to study protein folding (protein folding structure changes happen at changes in temperature) (Page 649, column 2, paragraph 2).
With respect to Claim 116, see Claim 1 rejection for PEARSON. PEARSON further teaches of using the apparatus and method of claim 1 to study protein folding (protein folding structure changes happen at changes in temperature) (Page 649, column 2, paragraph 2). PEARSON teaches of detecting changes in conformation as a result in the changes in condition jump/change (which in this case is a pressure jump/change—which leads to temperature change/jump) and this is due to binding and conformation changes. The changes detected are fluorescent/optical signals/changes by an optical/fluorescent signal reader. (Page 650, column 2, paragraph 3, line 7 & on & Page 644, column 1, paragraph). This results in a change in fluorescence signal due to fluorescent marker (abstract).
With respect to Claim 117, PEARSON teaches wherein the apparatus can perform reading out as a function of time by performing two or more readings from different fractions of said sample, with the sample contained in a microfluidic unit (abstract, pages 644-645 and figure 1, Figure 3, 4, 6).
PEARSON teaches of detecting changes in conformation as a result in the changes in condition jump/change (which in this case is a pressure jump/change—which leads to temperature change/jump) and this is due to binding and conformation changes. The changes detected are fluorescent/optical signals/changes by an optical/fluorescent signal reader. (Page 650, column 2, paragraph 3, line 7 & on & Page 644, column 1, paragraph). This results in a change in fluorescence signal due to fluorescent marker (abstract). Figure 1 shows the pressure jump apparatus and the microfluidic inlet.
With respect to Claim 118, PEARSON teaches of the claim as shown above for Claim 117 and further teaches of the inlet being an introduction section. PEARSON does not teach of the dimensions of the capillary.
YANG is used to remedy this and teaches of loading the sample into a capillary with dimensions of 1 mm by 1 mm (paragraph 0182). It would have been obvious to one of ordinary skill in the art to use the capillaries the size used in YANG in the method of DUHR due to the advantage this has as being a readily available (VitroCom) capillary (paragraph 0182).
With respect to Claim 120, PEARSON and HASSARD teaches of the claimed invention, but does not teach of controlling the temperature by blowing air or by fill level.
YANG is used to remedy this and teaches that as liquid droplets grow/increase temperatures decrease (therefore teaches of the fill level in the device controlling temperature) (paragraph 0156). It would have been obvious to one of ordinary skill in the art to control the temperature by fill level as is done in YANG in the method of PEARSON and HASSARD due to the advantage this has for controlling reaction kinetics (YANG, paragraph 0156).
With respect to Claim 121, PEARSON teaches of the invention as shown above, but does not teach of a temperature jump of 2 degrees Celsius. HASSARD teaches that the temperature across the gradient will depend upon the nature of the protein being analyzed, and may be adjusted according to the type of protein, and/or to the degree of folding or unfolding which is desired. Typically, the temperature range will be in the region of 20 degree. C. to 200.degree. C. The exact range for any particular molecule may be readily determined using techniques available in the art (paragraph 0020). See reason for combination from claim 112.
With respect to Claim 122, PEARSON teaches of the invention as shown above, but does not teach of a temperature jump of 2 degrees Celsius. HASSARD teaches that the temperature across the gradient will depend upon the nature of the protein being analyzed, and may be adjusted according to the type of protein, and/or to the degree of folding or unfolding which is desired. Typically, the temperature range will be in the region of 20 degree. C. to 200.degree. C. The exact range for any particular molecule may be readily determined using techniques available in the art (paragraph 0020). See reason for combination from claim 112.
With respect to Claim 130, PEARSON and HASSARD teach of the invention as shown above. They do not teach of the temperature jump being performed in the channel of the microfluidic device.
YANG is used to remedy this and teaches of the invention as shown above for claim 15 and further teaches of doing the temperature jump experiments in a channel (paragraph 0049, 0171, 0037). It would have been obvious to one of ordinary skill in the art to perform the method in the channel of the microfluidic device as is done in YANG in the primary references and one would have had reasonable expectation of success due to the advantage this offers for single experiment/device simplicity purposes (YANG, paragraph 0049, 0004).
Claims 113 & 123-124 are rejected under 35 U.S.C. 103 as being obvious by PEARSON in A novel pressure-jump apparatus for the microvolume analysis of protein-ligand and protein-protein interactions: its application to nucleotide binding to skeletal-muscle and smooth- muscle mysosin subfragment-1 in view of HASSARD in US 20050054081in view of YANG in US 20220003661 in view of WEIGL in US 20020090644.
With respect to Claims 113 & 124, PEARSON and HASSARD and YANG teach of the claimed invention as shown above. They do not teach of making two or more readings from different fractions of the sample.
WEIGL is used to remedy this and further teaches of methods and apparatuses are provided for determining presence and concentration of analytes by exploiting molecular binding reactions and differential diffusion rates(abstract). WEIGL further teaches of performing the method in batch mode using multiple sample aliquots (fractions)(paragraph 0053), and of using a computer or processor to analyze/determine/read the presence of the analyte particles (paragraph 0052). It would have been obvious to one of ordinary skill in the art to use sample aliquots or fractions as is done in WEIGL in the method of PEARSON, HASSARD, and YANG due to the advantage this offers in comparing a profile of streams or samples (WEIGL, paragraph 0052).
With respect to Claim 123, PEARSON teaches of the claim as shown above for Claim 112 and 117 and further teaches of the inlet being an introduction section. PEARSON does not teach of the dimensions of the capillary.
YANG is used to remedy this and teaches of loading the sample into a capillary with dimensions of 1 mm by 1 mm (paragraph 0182). It would have been obvious to one of ordinary skill in the art to use the capillaries the size used in YANG in the method of DUHR due to the advantage this has as being a readily available (VitroCom) capillary (paragraph 0182).
Since YANG does not teach of making readings for multiple fractions, WEIGL is used to remedy this.
WEIGL teaches of the device having inlets (paragraph 0012-0014). WEIGL further teaches of performing the method in batch mode using multiple sample aliquots (fractions) as they flow through the device (paragraph 0053), and of using a computer or processor to analyze/determine/read the presence of the analyte particles (paragraph 0052) and making the readings as a function of time (paragraph 0039, 0041, 0078, 0087). WEIGL also teach of measuring/detecting (reading) at the junction using detector arrays (paragraph 0092). It would have been obvious to one of ordinary skill in the art to use sample aliquots or fractions and monitor over time as is done in WEIGL in the method of PEARSON, HASSARD, and YANG due to the advantage this offers in comparing a profile of streams or samples (WEIGL, paragraph 0052).
Response to Arguments
The double patenting rejection is maintained. Applicant has made not arguments about it presently, other that reciting that the time for filing a terminal disclaimer has not come yet. Therefore, the rejection is maintained.
112, 2nd rejections were added to the record as shown above, since amendments dated 01/26/2026 created clarity issues in the independent claims 112 & 115.
With respect to the 101 rejection, after consideration and consultation with the examiner’s SPE on 05/11/2026, the 101 rejection is maintained. As the claims were amended 01/26/2026- the substantive reasons for this are shown in the rejection above and the examiner has not responded in full to every single comment by applicant in the response to arguments here.
Nothing in the claims practically applies the abstract idea judicial exception, since nothing further is done after the claimed “kinetic parameter,” in independent Claim 112 or “folding parameter,” in Claim 115 is determined. These parameters are done by unclaimed calculations- though that is absolutely how the determination is done. Math/ mathematical processes are abstract idea judicial exceptions. This remains the case even when claimed that “a computer system to process the detected signals,” is used, as this as generally claimed is just a general purposed computer that is being used to perform a calculation which can be performed in the human mind. Therefore, there is no practical application of the judicial exception.
See MPEP 2106.04(a)(2) III. C. A Claim That Requires a Computer May Still Recite a Mental Process. & further 1. “Performing a mental process on a generic computer.”
Also, the claimed optical detections from a marker which is optically readable, use of a particle and a binding partner, use of a heating or cooling arrangement, and microfluidic units with reading sections are all well understood, routine, and conventional in the art along with the claimed steps of utilizing these things (including making multiple readings from different fractions) are all well understood, routine and conventional (WURC) in the art. Therefore, they do not add significantly more to the claimed abstract ideas. Even further- as claimed and disclosed, there does not seems to be any clear technological improvement, and therefore nothing in the claims which move the claims past the 101 rejection.
It is noted, that the applicant says the examiner argues with respect to the 101 that “nothing is done is done after detection.” The examiner notes that this is not accurate. The examiner noted in the action that nothing is done after the “determining,” of the kinetic or folding parameter. “Determining,” is different that “detection.” The detecting of optical signals as shown above is a data pull and therefore insignificant extra-solution activity, and therefore not significantly more at step 2B. Nothing is done after the last step in the claim--- the “determining,” of the kinetic parameter or folding parameter. As this is the last step in the claim (encompasses the judicial exception, as claimed the determining is math), and nothing is done after this step, there is no practical application in light of U.S. subject matter eligibility law/35 USC 101, at step 2A, 2.
Though the examiner understands that kinetic parameters are “important,” as applicant argues—this does not make the claimed calculation of them patent eligible, especially as instantly claimed, in light of U.S. subject matter eligibility law/35 USC 101.
Lastly for the 101 rejection--- the examiner will note that the specification for the instant invention makes mention that the method provides for improved, rapid, and simpler identification of liquid-liquid phase separation systems (PGPub paragraph 0090-0091). The instant specification also shows that the instant method has a computer system which is programmed to improve reading accuracy in a signal that exceeds a preset threshold (paragraph 0224). None of this is claimed. It is further noted that there are many other methods and steps which are disclosed with respect to how these improvements are take place, but neither the improvement itself, nor all elements leading to any supposed improvement/s are claimed.
If applicant would like to overcome the 101 rejection, it is suggested that they add more specific details to the claims, and they could consider adding elements/details of any disclosed technological improvements, along with the device parts and methods steps which allow for any supposed improvements to occur.
With respect to the 103 rejection, the rejection is maintained and applicant’s arguments are not convincing. The examiner notes that if applicant is able to add sufficient detail to the claims to overcome the 101 rejection, then it will be easier to overcome the 101 rejection as well.
With respect to PEARSON, applicant argues that PEARSON teaches of a pressure jump and not a temperature jump. With respect to this, the examiner notes a secondary reference was used to teach of the temperature jump and a 103 rejection was made, so PEARSON does not need to teach of all things which are claimed.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that PEARSON does not teach of the claimed, reading out as a function of time from multiple fractions. The examiner disagrees, and maintains that the claimed language can be interpreted more broadly than applicant argues. The examiner notes that PEARSON does teach of this (abstract, pages 644-645 and figure 1, Figure 3, 4, 6) which would further be capable of the claimed result, “while reducing the risk of degrading the sample.” This is a result of the claimed taking multiple readings from different fractions---so the instant prior art teaching would result in this intended result, since it teaches of the process step as claimed.
With respect to the HASSARD reference applicant argues that HASSARDS maintaining of a temperature gradient along the length of a chip does not maintain a second temperature as claimed. The examiner disagrees—as the gradient is maintained along the length of the chip, the past of the length of the chip that is at the second temperature will be maintained at the second temperature throughout the maintaining of the temperature gradient.
Applicant argues that the heating strips used in HASSARD would introduce errors and lead to incorrect determinations and that in HASSARD the molecules fold or unfold dynamically as they pass along the channel and therefore no equilibrium stage is determined or “capable of,” being determined. With respect to this, the examiner notes that this is not exactly what is claimed, “Determining an equilibrium stage.” Instead, what is claimed is that the particle and binding partner are capable of being in equilibrium and non equilibrium and further that the particle is brought into a stage of non-equilibirum (where unfolding occurs in the case of protein folding when exposed to high temperatre). The temperature gradient in HASSARD is capable of this, and does in fact perform this step, albeit probably in a less direct from point A directly to point D method, and since a gradient is used in HASSARD the folding to unfolding can include for example points A, B, C, and then D for example. The instant claims does not have any language which prevent this stepwise movement of folding from occurring.
With respect to the YANG reference, applicant argues that YANG does not teach of a temperature jump nor start the reading before the system is stabilized.
With respect to this, the examiner notes that YANG does teach of a temperature jump ( a gradient includes a temperature jump), and further the examiner notes that the claim does not require starting, “the reading before the system is stabilized.”
Specifically, YANG teaches of establishing a temperature gradient across a holder holding a sample- wherein the temperature stabilizes in 1 minute (paragraph 0006) and that the phase separation temperature (condition jump) happens after 1 minute (paragraph 0048). YANG also teaches of making continuous measurements ( so more than 5 readings per minute (paragraph 0048, 0170 Figure 32, 0082).
Applicant further argues that the pieces of prior art are incompatible with each other. In response to applicant's arguments, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Please see the reasons for combination cited in the 103 rejection above.
All claims remain rejected.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
BAASKE in US 20170361326.
BAASKE teaches of methods and systems are in particular suitable for experiments with respect to folding and unfolding of proteins and the examination of the stability of biomolecules like proteins. Here, the structure of the biomolecule to be examined, in particular protein or protein complex, is changed by addition of suitable chemicals, for example chaotrops as urea or guanidine hydrochloride or organic solvents, or by change of the temperature (i.e. for example “melting” by increasing the temperature). The secondary and tertiary structure of biomolecules as proteins and nucleic acids is often also dependent on the presence of ligands or cofactors like ions (for example Mg.sup.2+ or Ca.sup.2±). This may be effected for example by measuring the fluorescence (preferably tryptophan fluorescence in case of proteins) under different concentrations of the ligands and/or cofactors.
The biomolecule, preferably protein, may be denatured chemically or thermally, and structural amendments may be measured by intrinsic fluorescence (preferably tryptophan fluorescence in case of proteins). There, for example changes in the fluorescence intensity or shifting of fluorescence maxima may be detected. The melting point of the biomolecule to be examined, for example protein, may also be determined. The melting point is the state in which one half of the biomolecule to be examined, for example protein, is folded and the other half is unfolded. In case proteins are examined, for example the tryptophan fluorescence at a wavelength of 330 nm and/or 350 nm can be measured. Here, the change of the intensity of the fluorescence, for example dependent on the temperature or on the addition of a denaturant or cofactor/ligand may be determined and/or a periodical process may be recorded. The quotient of the fluorescence intensity at 330 nm to the fluorescence intensity at 350 nm (F330/F350) is a preferred indicator. For example, the melting point may be determined from the maximum of the first derivative of the F330/F350 curve (paragraphs 0038-0039).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached on 571-270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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