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 the 17/227042 response filed 11/03/2025.
Claims 1-2, 4-6, 8-10, 12-23, 28-29 & 110-115 have been elected and fully been examined.
Claim 30-31, 35-42, 50-51 are withdrawn from prosecution.
Claims 3, 7, 11, 24-27, 32-34, 43-49 & 52-109 have been cancelled.
Claims 114-115 are newly added.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
For Claim 1-2, 4-6, 8-10, 12-23, 28-29 & 110-115, the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) a judicial exception which is an abstract idea. The 101 analysis is shown below:
Step 2A, Prong One: Identify the law of nature/natural phenomenon/abstract ideas.
Claim 1 recites a method for quantification of one or more distinguishable compounds in a blood or serum sample that is suspected of having or developing a chronic liver disease or hepatic disorder. Though the claim does not use the word “diagnosis,” this is clearly what is being done by the claimed quantification, since this method is only performed on a sample from a subject that is suspected of having the disease. Therefore, though a law of nature/natural correlation judicial exception is not explicitly claimed (biomarker present= disease), it is still implicitly in Claim 1 and those which depend therefrom.
In addition to what is in Claim 1, “quantifying,” as claimed is mental process, which is an abstract idea. Claim 112 also includes abstract idea judicial exception, including “computing,” area which is math and can be a mental process and generating a curve is also math. Further, “dividing,” as claimed in math. All of these things are abstract ideas judicial exceptions.
Claim 112 further recites a method for determining a portal hepatic filtration rate (HFR). Portal hepatic filtration is the natural process of how the liver filters and processes blood and measurement of portal hepatic filtration rate is either the measurement of the portal veins blood flow rate, or the rate of another hepatic filtration process that occurs in the liver. The rate at which the liver or portal vein processes fluid is a natural process.
Claim 112, like Claim 1 is only performed in a sample from a subject to is “suspected of having or developing a chronic liver disease or hepatic disorder.” Though Claim 112 is specific to hepatic filtration rate, it also includes all of the steps required for Claim 1—and as it is shown for claim 1 a law of nature/natural correlation judicial exception is present for Claim 1, so the same applies to Claim 112.
Step 2A Prong Two: Has the natural correlation or abstract idea been integrated into a particular practical application?
For both Claims 1 & Claim 112 the answer is no.
The claimed measuring requires processing blood of serum samples by adding a protein precipitation solution comprising and internal standard to form a precipitate and supernatant, injecting the supernatant into a mass detection system comprising a tandem mass spectrometer, and measuring the cholates by tandem mass spec in multiple reaction monitoring mode.
With respect to this, the examiner notes that especially at the level of generality claimed, no particular processing or measurement method is claimed. In fact, the claimed measurement seems to be just a data pull/data gathering to perform the judicial exception, “quantifying,”. Data gathering to be used in an abstract idea or natural correlation, is insignificant extra-solution activity, and not a particular practical application. See MPEP 2106.05(g).
Further, for both claims 1 & 112 a “distinguishable cholate compound,” is claimed, and it is specified that the subject receives the cholate compound before the instant method is started and then that this compound is what is measured. However, the claims treatment/administration of the distinguishable cholate compound does not occur within the boundaries of the instant claims since Claims 1 & 112 start with “receiving….sample.” Since the treatment is not performed within the boundaries of the claim, measurement of any compound that is found after is just measurement of something which is present in a natural blood sample, which is the judicial exception itself. Therefore, there is no is particular treatment performed as claimed within the boundaries of the claim, nor is there other particular practical application.
Further- for Claim 112, though not currently claimed as done by a computer- the instant steps iii, iv, and v are likely meant to be performed on a computer. However- as claimed even if a computer was added and seemingly the only functions performed are comparison to a model, computing area, and dividing—this would be considered a general-purpose computer, as all of this can be performed by the human mind. Therefore, even if a computer was claimed- the claims generally recite a general-purpose computer to perform the abstract ideas. Performing the abstract idea on a general-purpose computer is not enough to integrate the exception into a practical application (MPEP 2106.05(b)I.
Step 2B: Does the claim recite any elements which are significantly more than the natural correlation or abstract idea?
Here, we look to the elements other than the abstract idea to see if there is significantly more.
For Claims 1 & 112 they require measuring. Claim 112 recites the element of a measuring “according to claim 1.”
Claim 1 requires that the measuring is done by multiple reaction monitoring mode mass spectrometry. Multiple reaction monitoring mode mass spectrometry, and processing a sample to form a supernatant is something which is well-understood, routine and conventional (WURC) and therefore is not enough to make the claims significantly more than the claimed judicial exceptions.
The measuring in Claim 1 also requires processing blood of serum samples by adding a protein precipitation solution comprising and internal standard to form a precipitate and supernatant, injecting the supernatant into a mass detection system comprising a tandem mass spectrometer. Especially at the level of generality claimed, all of this as claimed is WURC and therefore does not add significantly more to the claimed judicial exceptions.
Claim 1 also requires “receiving,” a sample and also processing and sample. These are also WURC in the art and therefore do not make the claims significantly more, especially at the level of generality claimed.
Further- in Claim 112, the additional steps of generating a curve, computing area under curve, and dividing oral clearance are claimed. As shown above, these are part of the judicial exceptions themselves so are not significantly more.
The dependent claims undergo a similar analysis.
Claims 2, 4-6, 8-10, 12-14, 16, 110 & 113-115 make further specifications on how the sample is processed or measured including that: a supernatant is used, a separation system is used that is chromatography or liquid chromatography, that mass resolution or an ion source is used such as ESI or MALDI, that TOF-MS or MS/MS is used, that a resin is used in a column such a normal or reversed phase resin or that aliquots are used. All of these things are WURC in the art, especially at the level of generality claimed and therefore do not add significantly more to the judicial exceptions. They also do nothing to practically apply the judicial exceptions.
Claim 15 specifies something that “had,” in the past happened prior to the method in the claims starting. Therefore, this does nothing to change the matters above as the limitations are not within the boundaries of the claims.
Claims 17-19 specify that an organic solvent is used for protein precipitation which is something like methanol or acetone or that an internal standard is used. This is WURC in the art, especially at the level of generality claimed and therefore does not change matters.
Claim 20 specifies how much of a sample is taken for an aliquot. How big the sample is does not change the fact that the sample is still a naturally occurring blood sample—therefore does not change the matters above.
Claim 21 specifies that the sample is taken from a dried blood spot of capillary blood sample. These are all WURC ways to take a sample and therefore do not change the matters above.
Claim 22 requires that the sample is combined with extraction solution. This is WURC in the art, especially at the level of generality claimed and therefore does not change the matters above.
Claim 23 specifies that the sample is “capable of,” exhibiting high hepatic extraction, however this “capable of,” does not mean anything. Again this seems to be a limitation to clarify what is administered before the instant method begins so that does not change matters above, nor do it’s capabilities, as the method is not drawn towards what the compounds are capable of.
Claims 28 & 111 specify what the isotope labeled compound that is measure is. However, some of the stated compounds for example “sodium salt,” aren’t isotopically labeled always also all of the claimed compounds are measured in a natural blood sample and therefore, these compounds are all part of the judicial exception itself.
Claim 29 specifies what the extraction recovery is. High extraction recovery is WURC in the art, especially at the level of generality claimed and therefore does not change matters.
Therefore, the additional elements do not amount to significantly more.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-6, 8-10, 12-20, 28, 110-111, 113-115 are rejected under U.S.C. 103 as being obvious over EVERSON1 in 8778299 in view of SAKAI in US 20050118666.
With respect to Claims 1, Everson1 discloses a method for quantifying one or more distinguishable compounds in a blood or serum sample from a subject (Col. 3, Lns. 48-56, method comprising: administering orally a first distinguishable isotopically labeled cholic acid to a subject having, or suspected of having or developing, a hepatic disorder; co-administering intravenously a second distinguishable isotopically labeled cholic acid to the subject; collecting blood or serum samples over intervals for a period of less than 3 hours after administration of the agents to the subject; quantifying the first and the second isotopically labeled cholic acids in the samples by HPLC-MS), the method comprising: receiving a blood or serum sample obtained from a subject having or suspected of having or developing a chronic liver disease or hepatic disorder, wherein the sample was collected from the subject less than 3 hours after oral and/or intravenous administration of the one or more distinguishable compounds to the subject (Col. 3, Lns. 48-56, administering orally a first distinguishable isotopically labeled cholic acid to a subject having, or suspected of having or developing, a hepatic disorder; co-administering intravenously a second distinguishable isotopically labeled cholic acid to the subject; collecting blood or serum samples over intervals for a period of less than 3 hours after administration of the agents to the subject); processing the blood or serum sample to form a processed sample (Col. 48, Lns. 10-15, The LCMS system is prepared and tuned; the column is stabilized at 40° C. and conditioned by running the mobile phase for 30 min. EVERSON1 teaches that the samples can be a carbon 13 cholate (Column 2, line 51-65, Column 13, paragraph 5, “baseline measurement of natural abundance is also performed”).
EVERSON1 also teaches of determining the levels of not labeled natural cholate and that this can be done alone or in combination with the other tests above (so can be done simultaneously)(Column 9, last paragraph-column 10, first paragraph).
The samples are loaded to the autosampler. The column flow rate is 0.4 ml/min of isocratic mobile phase buffer: 60% 10 mM Ammonium Acetate Methanol/40% 10 mM Ammonium Acetate Water); injecting the processed sample onto a mass detection system (Col. 48, Lns. 15-18, 5 microliters of each sample is injected by the autosampler. The MS is run in multimode electrospray (MN-ES) ionization with atmospheric pressure chemical ionization (APCI) ionization); measuring the concentration of the one or more distinguishable compounds in the processed sample comprising mass detection (Claim 1, measuring concentration of the labeled cholic acid in each sample; Col. 48, Lns. 15-18, 5 microliters of each sample is injected by the autosampler. The MS is run in multimode electrospray (MM-ES) ionization with atmospheric pressure chemical ionization (APCI) ionization); and quantifying the concentration of the one or more distinguishable compounds in the blood or serum sample (Claim 1, measuring concentration of the labeled cholic acid in each sample; Claim 5, the measuring step comprises quantifying the isotopically labeled cholic acid in the samples by gas chromatography-mass spectrometry (GC MS) or high pressure liquid chromatography-mass spectrometry (HPLC-MS)).
EVERSON 1 teaches that the cholate concentrations for both the natural/endogenous cholate and the distinguishable labeled cholate are calculated using calibration curves based on these compounds (Column 13, lines 33-57).
Everson1 discloses the method as shown above, but fails to explicitly disclose that the mass spec used is tandem mass spec, wherein the processing of the blood or serum sample comprises forming a supernatant, nor does Everson1 teach of multiple reaction mode mass spectrometry.
Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the processing of the blood or serum sample comprises forming a supernatant (Sakai Para. [0010], supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution ... the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture). SAKAI teaches wherein the triple quadrupole mass spectrometer (MS/MS) (which is tandem mass spec) is run in a multiple reaction mode (MRM) (Sakai Para. [0053, 0062],20 pl thereof was used in an LC/MS/MS system; Para. [(0056], Mass analyzer API3000 (Applied Biosystems); Para. [(0062], Peak identification was carried out based on the retention time obtained by MRM). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include the multiple reaction mode as taught by Sakai. The motivation for doing so would have been to perform quantification in a precise and reproducible manner (Sakai Para. [0076]). It would also have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include forming a supernatant as taught by Sakai due to the advantage this offers in preparing the sample for subsequent separation techniques (Sakai Para. {0028)).
With respect to Claim 2, Everson1 discloses the method of claim 1, wherein the processed sample is a supernatant or an eluate (Col. 13, Lns. 25-32), sodium hydroxide is added to the serum samples, samples are subjected to solid phase extraction by passage over SepPak C18 cartridges, samples are eluted from cartridges, the samples are dried, the samples are acidified with an HCI solution and extracted with ether, The ether is dried and samples are taken into the HPLC mobile phase buffer. Samples are added to an autosampler and subjected to HPLC-MS with selective ion monitoring).
With respect to Claim 4, modified Everso1n discloses the method of claim 3, but fails to explicitly disclose further comprising injecting the supernatant onto a separation system comprising a preparative component, and/or an analytical component to form an eluate. Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches further comprising injecting the supernatant onto a separation system comprising a preparative component, and/or an analytical component to form an eluate (Sakai Para. [0010}, The solid phase extraction step is characterized by being a step wherein the supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution is neutralized, and then applied to a reverse phase cartridge packed with silica gel containing an octadecylsilyl group or octylsilyl group, washed with an aqueous solvent, and eluted with an organic solvent. In particular, the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson to include injecting the supernatant onto a separation system as taught by Sakai due to the advantage this would offer in aiding in the separation of the compound and internal standard substance (Sakai Para. [0038)).
With respect to Claim 5, modified Everso1n discloses the method of claim 4, but fails to explicitly disclose a chromatography system for supernatant separation. Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the separation system comprises a chromatography system (Sakai Para. [0010], The solid phase extraction step is characterized by being a step wherein the supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution is neutralized, and then applied to a reverse phase cartridge packed with silica gel containing an octadecylsilyl group or octyisilyl group, washed with an aqueous solvent, and eluted with an organic solvent. In particular,the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture; Para. (0038), For HPLC separation of the CoA and the internal standard substance, a liquid chromatography separation column which is commercially available for ordinary reverse phase chromatography may be used). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include the chromatography system as taught by Sakai due to the advantage this offers in aiding in the separation of the compound and internal standard substance (Sakai Para. (0038)).
With respect to Claim 6, modified Everson1 discloses the method of claim 5, but fails to explicitly disclose wherein the chromatography system for supernatant separation includes a liquid chromatography (LC) (Sakai, Abstract) and teaches wherein the chromatography system includes a liquid chromatography (LC) system, optionally wherein the LC system is selected from the group consisting of an HPLC and a UPLC system (Sakai Para. [0010], The solid phase extraction step is characterized by being a step wherein the supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution is neutralized, and then applied to a reverse phase cartridge packed with silica gel containing an octadecylsilyl group or octylsilyl group, washed with an aqueous solvent, and eluted with an organic solvent. In particular,the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture; Para. [0038], For HPLC separation of the CoA and the internal standard substance, a liquid chromatography separation column which is commercially available for ordinary reverse phase chromatography may be used). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include the chromatography system as taught by Sakai due to the advantage this offers in aiding in the separation of the compound and internal standard substance (Sakai Para. [0038)).
With respect to Claim 8, Everson1 discloses the method of claim 7, wherein the mass spectrometer comprises an ion source system (Col. 48, Lns. 15-18, 5 microliters of each sample is injected by the autosampler. The MS is run in multimode electrospray (MM-ES) ionization with atmospheric pressure chemical ionization (APCI) ionization), but fails to explicitly disclose a mass resolution/detection system.
With respect to Claim 9, Everson1 discloses the method of claim 8, wherein the ion source system is selected from the group consisting of electrospray ionization (ES), matrix-assisted laser desorption/ionization (MALDI), fast atom bombardment (FAB), chemical ionization (Ct), atmospheric pressure chemical ionization (APCl), liquid secondary ionization (LSI), laser diode thermal desorption (LDTD), and surface-enhanced laser desorption/ionization (SELDI) (Col. 48, Lns. 15-18, 5 microliters of each sample is injected by the autosampler. The MS is run in multimode electrospray (MM-ES) ionization with atmospheric pressure chemical ionization (APCI) ionization).
With respect to Claim 10, modified Everson1 discloses the method of claim 9, but fails to explicitly disclose wherein the mass resolution/detection system is selected from the group consisting of triple quadrupole mass spectrometer (MS/MS), single quadrupole mass spectrometer (MS); Fourier-transform mass spectrometer (FT-MS); and time-of-flight mass spectrometer (TOF-MS).
Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the mass resolution/detection system is selected from the group consisting of triple quadrupole mass spectrometer (MS/MS); single quadrupole mass spectrometer (MS); Fourier-transform mass spectrometer (FT-MS); and time-of-flight mass spectrometer (TOF-MS) (Sakai Para. [0053, 0040],20 pl thereof was used in an LC/MS/MS system; Para. [0056], Mass analyzer API3000 (Applied Biosystems)). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include the mass resolution/detection system as taught by Sakai due to the advantage this offers for performing quantification in a precise and reproducible manner (Sakai Para. [(0076)).
With respect to Claim 12, modified Everson1 discloses the method of claim 4, but fails to explicitly disclose wherein the processing comprises: injecting the supernatant to the preparative component; and eluting the preparative component onto the analytical component to form the eluate. Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the processing comprises: injecting the supernatant to the preparative component; and eluting the preparative component onto the analytical component to form the eluate (Sakai Para. [0010], The solid phase extraction step is characterized by being a step wherein the supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution is neutralized, and then applied to a reverse phase cartridge packed with silica gel containing an octadecylsilyi group or octylsilyl group, washed with an aqueous solvent, and eluted with an organic solvent. In particular, the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1 M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include injecting the supernatant and eluting the preparative component as taught by Sakai due to the advantage this offers in aiding in the separation of the compound and internal standard substance (Sakai Para. [0038}).
With respect to Claim 13, modified Everson1 discloses the method of claim 12, but fails to explicitly disclose wherein the preparative component comprises a solid phase resin and the analytical component each comprise a solid phase resin. Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the preparative component comprises a solid phase resin and the analytical component each comprise a solid phase resin (Sakai Para. [0010], The solid phase extraction step is characterized by being a step wherein the supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution is neutralized, and then applied to a reverse phase cartridge packed with silica gel containing an octadecylsilyl group or octylsilyl group, washed with an aqueous solvent, and eluted with an organic solvent. In particular, the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1 M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include the preparative component and analytical component as taught by Sakai due to the advantage this offers in aiding in the separation of the compound and internal standard substance (Sakai Para. [(0038)).
With respect to Claim 14, modified Everso1n discloses the method of claim 13, but fails to explicitly disclose wherein the solid phase resin of the preparative and analytical components are each independently selected from the group consisting of a normal phase resin, reverse phase resin, hydrophobic interaction solid phase resin, hydrophilic interaction solid phase resin, ion-exchange solid phase resin, size-exclusion solid phase resin, and affinity-based solid phase resin(packing). Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the solid phase resin of the preparative and analytical components are each independently selected from the group consisting of a normal phase resin, reverse phase resin, hydrophobic interaction solid phase resin, hydrophilic interaction solid phase resin, ion-exchange solid phase resin, size-exclusion solid phase resin, and affinity-based solid phase resin (Sakai Para. [0010], The solid phase extraction step is characterized by being a step wherein the supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution is neutralized, and then applied to a reverse phase cartridge packed with silica gel containing an octadecylsilyl group or octylsilyl group, washed with an aqueous solvent, and eluted with an organic solvent. In particular, the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include the solid phase resin as taught by Sakai. The motivation for doing so would have been to aid in the separation of the compound and internal standard substance (Sakai Para. [0038)).
With respect to Claim 15, Everson1 discloses the method of claim 1, wherein the subject had received the oral and intravenous one or more distinguishable compounds less than 3 hours prior to collecting the sample from the subject (Col. 3, Lns. 48-56, method comprising: administering orally a first distinguishable isotopically labeled cholic acid to a subject having, or suspected of having or developing, a hepatic disorder; co-administering intravenously a second distinguishable isotopically labeled cholic acid to the subject; collecting blood or serum samples over intervals for a period of less than 3 hours after administration of the agents to the subject).
With respect to Claim 16, modified Everson1 discloses the method of claim 3, but fails to explicitly disclose wherein the processing comprises adding a protein precipitation solution to the sample to form a protein precipitate and the supernatant. Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the processing comprises adding a protein precipitation solution to the sample to form a protein precipitate and the supernatant (Sakai Para. [0009], the step of extracting the Coenzyme A molecule from the biological sample is a step wherein a freeze-shattered biological sample is agitated in a perchloric acid solution and the supernatant is subjected to centrifugal separation). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify method in Everson to include adding a protein precipitation solution as taught by Sakai. The motivation for doing so would have been to prepare the sample for subsequent separation techniques (Sakai Para. [0028)).
With respect to Claims 17-18, Sakai disclose using acetonitrile and acetone for elution/precipitation (paragraph 0010).
With respect to Claim 19, Everson1 discloses the method of claim 1, further comprising adding an internal standard distinguishable compound to the blood or serum sample (Col. 46, Lns. 49-51, to each patient sample and each QC sample and each STD sample tube, add 50 pl of the Unlabeled Cholic Acid Internal Standard?).
With respect to Claim 20, Everson1 discloses collecting 5 ul samples of blood/serum (Example 12). It would have been obvious to adjust the amount of sample used, dependent on the instrument used to test and amount of sample needed.
With respect to Claim 23, Everson1 discloses that cholic acid has hepatic extraction of 85% which falls into the claimed range for “high hepatic extraction,” (Col 1, ln 41-50).
With respect to Claim 28, Everson1 discloses that the distinguishable substance is a cholic or bile acid that is isotopically labeled(13C) (Col. 41, line 33-48).
With respect to Claim 110, EVERSON1 teaches of using HPLC. Specifically, Everson1 discloses the method of claim 1, wherein the processed sample is a supernatant or an eluate (Col. 13, Lns. 25-32), sodium hydroxide is added to the serum samples, samples are subjected to solid phase extraction by passage over SepPak C18 cartridges, samples are eluted from cartridges, the samples are dried, the samples are acidified with an HCI solution and extracted with ether, The ether is dried and samples are taken into the HPLC mobile phase buffer. Samples are added to an autosampler and subjected to HPLC-MS with selective ion monitoring).
With respect to Claim 111, Everson1 discloses detecting a distinguishable compound wherein the distinguishable substance is a cholic or bile acid that is isotopically labeled(13C) (Col. 41, line 33-48). It is noted that the instant claims require “measuring the concentration of the one or more distinguishable compounds,” but it does not require that any of the distinguishable compound is actually found/detected. Therefore- the teaching of detecting a distinguishable compound of cholic or bile acid which is isotopically labeled by 13 C as is shown in EVERSON1- makes it obvious to one of ordinary skill in the art to detect/measure the concentration of all isotopically labeled bile acids. It is also noted that no dosing/labeling is actually required (which is where the isotopic label would come from), within the boundaries of Claim 111, or Claim 1, which Claim 111 depends on.
With respect to Claim 113, EVERSON1 teaches of collecting samples over intervals spanning a period of time of 90 minutes or less after administration of the compounds and teaches of collecting/using 5 samples collected at 5, 20, 45, 60 and 90 minutes post administration (Column 1, line 51-65).
With respect to Claim 114, EVERSON teaches of taking sample aliquotes(Column 45, lines 41-50). SAKAI teaches of adding an internal standard to the substance/supernatant (abstract, paragraph 0027-0028).
With respect to Claim 115, SAKAI teaches of taking a supernatant and adjusting it with another solvent (this reads on diluting it) (paragraph 0027-0028).
Claim 21, 22, & 29 is rejected under U.S.C. 103 as being obvious over EVERSON1 in 8778299 in view of SAKAI in US 20050118666 in view of ORY in US 20170285015.
With respect to Claim 21, Everson1 and Sakai discloses the invention as shown above, but does not disclose the use of capillary or dried blood sample. Ory is used to remedy this.
Ory teach of a method for identifying bile acids in dried blood spots (abstract). It would have been obvious to one of ordinary skill in the art to use dried blood spots as the sample as is done in Ory in the method of Everson1 and SAKAI due to the advantage this type of testing has in ease of use wherein the sample can be located on an easy-to-use screening card (Ory, paragraph 0015).
With respect to Claim 22, Everson1 and Ory discloses the method, as shown in the above rejection. SAKAI teaches wherein the processing of the blood or serum sample comprises forming a supernatant (Sakai abstract, Para. [0010], supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution ... the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include forming a supernatant as taught by Sakai due to the advantage this offers in preparing the sample for subsequent separation techniques (Sakai Para. {0028)).
With respect to Claim 29, EVERSON1 teach that the accuracy and precision of an assay are assessed by running multiple replica samples at the lower limit of quantification (LLOQ), low, medium, and high range of concentrations. Accuracy is the closeness of the average measured value to the actual value. Precision is the reproducibility of the measured value as indicated by the CV. Further, the recovery is assessed by comparing the detector response of the analyte extracted from serum relative to that of pure analyte measured at low, medium, and high concentrations (Col 44, ln 16-40). Though EVERSON1 does not call out extraction recovery of greater than 97%, it is obvious for one of ordinary skill in the art to try to make recovery as high as possible. Further- extraction recovery as claimed- will be a function of which distinguishable compound is used ( a material property of this).
If this is unclear from EVERSON1, ORY is used to remedy. ORY teaches of wanting to improve extraction recovery (paragraph 0330). It would have been obvious to one of ordinary skill in the art to improve extraction recovery due to improve sample preparation (ORY, paragraph 0330).
Claim 112 is rejected under U.S.C. 103 as being obvious over EVERSON1 in 8778299 in view of SAKAI in US 20050118666 and further in view of EVERSON2 in US 20140147875.
With respect to Claim 112, Everson1 discloses a method for quantifying one or more distinguishable compounds in a blood or serum sample from a subject (Col. 3, Lns. 48-56, method comprising: administering orally a first distinguishable isotopically labeled cholic acid to a subject having, or suspected of having or developing, a hepatic disorder; co-administering intravenously a second distinguishable isotopically labeled cholic acid to the subject; collecting blood or serum samples over intervals for a period of less than 3 hours after administration of the agents to the subject; quantifying the first and the second isotopically labeled cholic acids in the samples by HPLC-MS), the method comprising: receiving a blood or serum sample obtained from a subject having or suspected of having or developing a chronic liver disease or hepatic disorder, wherein the sample was collected from the subject less than 3 hours after oral and/or intravenous administration of the one or more distinguishable compounds to the subject (Col. 3, Lns. 48-56, administering orally a first distinguishable isotopically labeled cholic acid to a subject having, or suspected of having or developing, a hepatic disorder; co-administering intravenously a second distinguishable isotopically labeled cholic acid to the subject; collecting blood or serum samples over intervals for a period of less than 3 hours after administration of the agents to the subject); processing the blood or serum sample to form a processed sample (Col. 48, Lns. 10-15, The LCMS system is prepared and tuned; the column is stabilized at 40° C. and conditioned by running the mobile phase for 30 min. The samples are loaded to the autosampler. The column flow rate is 0.4 ml/min of isocratic mobile phase buffer: 60% 10 mM Ammonium Acetate Methanol/40% 10 mM Ammonium Acetate Water); injecting the processed sample onto a mass detection system (Col. 48, Lns. 15-18, 5 microliters of each sample is injected by the autosampler. The MS is run in multimode electrospray (MN-ES) ionization with atmospheric pressure chemical ionization (APCI) ionization); measuring the concentration of the one or more distinguishable compounds in the processed sample comprising mass detection (Claim 1, measuring concentration of the labeled cholic acid in each sample; Col. 48, Lns. 15-18, 5 microliters of each sample is injected by the autosampler. The MS is run in multimode electrospray (MM-ES) ionization with atmospheric pressure chemical ionization (APCI) ionization); and quantifying the concentration of the one or more distinguishable compounds in the blood or serum sample (Claim 1, measuring concentration of the labeled cholic acid in each sample; Claim 5, the measuring step comprises quantifying the isotopically labeled cholic acid in the samples by gas chromatography-mass spectrometry (GC MS) or high pressure liquid chromatography-mass spectrometry (HPLC-MS)).
EVERSON1 further teaches of generating an oral clearance curve (Figure 7 and associated description) and a model clearance curve and algorithm for deriving an oral clearance curve (Column 5, line 1-50, Column 33, lines 1-58) and further of determining AUC (area under curve) for the administered distinguishable compounds ().
Everson1 discloses the method as shown above, but fails to explicitly disclose that the mass spec used is tandem mass spec, wherein the processing of the blood or serum sample comprises forming a supernatant, nor does Everson teach of multiple reaction mode mass spectrometry.
Sakai is also in the field of methods of determining quantities in biological samples (Sakai, Abstract) and teaches wherein the processing of the blood or serum sample comprises forming a supernatant (Sakai Para. [0010], supernatant obtained by extraction of the Coenzyme A with a strongly acidic solution ... the supernatant is applied after conditioning the reverse phase cartridge with acetonitrile and 1M ammonium acetate solution, and elution is performed with an acetonitrile and ammonium acetate mixture). SAKAI teaches wherein the triple quadrupole mass spectrometer (MS/MS) (which is tandem mass spec) is run in a multiple reaction mode (MRM) (Sakai Para. [0053, 0062],20 pl thereof was used in an LC/MS/MS system; Para. [(0056], Mass analyzer API3000 (Applied Biosystems); Para. [(0062], Peak identification was carried out based on the retention time obtained by MRM). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson to include the multiple reaction mode as taught by Sakai. The motivation for doing so would have been to perform quantification in a precise and reproducible manner (Sakai Para. [0076]). It would also have been obvious to one of ordinary skill in the art at the time of the invention to modify the method in Everson1 to include forming a supernatant as taught by Sakai due to the advantage this offers in preparing the sample for subsequent separation techniques (Sakai Para. {0028)).
EVERSON1 and SAKAI do not teach of dividing the distinguishable compound clearance by weight of subject to obtain portal HFR value.
EVERSON2 is used to remedy this and teaches of determining portal HFR value and dividing the oral cholate clearance by the weight of the patient in kg to obtain portal HFR value (paragraph 0034). It would have been obvious to determine portal HFR value as is done in EVERSON2 in the methods of EVERSON 1 & SAKAI due to the advantage portal HFR values have for distinguishing disease severity (EVERSON2, paragraph 0017).
Response to Arguments
Applicant's arguments filed 11/03/2025 have been fully considered but they are not persuasive.
112 rejections:
The prior 112 rejections are overcome by amendments dated 11/03/2025.
101 rejections:
The 101 rejections are maintained and are on the record for all pending claims. The 101 rejection is made for the reasons shown in the above office action, 101 section.
Applicant argues that the method of Claim 1 and 112 has a distinct and practical advantage over EVERSON1 since EVERSON1 does not disclose or suggest “simplified processing method of blood or serum samples,” or “quantifying processed samples analytes by MS/MS with MRM,” which are both active steps and result in practical advantages.
With respect to this, the examiner is confused of why applicant is arguing about the prior art, in the 101 rejection. The 101 rejection, which was not made with EVERSON1 and the 103 rejection, was made with EVERSON1.101 and 103 are separate issues.
However, since applicant argues about the 103 prior art, EVERSON1 with respect to the 101 rejection--- the examiner will respond to it. The examiner disagrees that, “simplified processing method of blood or serum samples,” or “quantifying processed samples analytes by MS/MS with MRM,” which are both active steps are practical application in light of 101 subject matter eligibility (though the examiner understand that these are physical steps). Though they are physical steps, they are very general and do nothing to practically apply the claimed abstract idea judicial exception itself. In claim 1, nothing happens after the “quantifying,” step. In Claim 112, what happens is math--- which is a judicial exception of an abstract idea itself. Further the claimed physical steps of, “simplified processing method of blood or serum samples,” or “quantifying processed samples analytes by MS/MS with MRM,” are all things which especially at the level of generality claimed, are WURC in the art and therefore are not things that make the claims significantly more than the judicial exceptions.
Applicant further argues that the instant invention offers improved extraction recovery, an increase in analyte selectivity, a reduction in sample volume, reduced processing time, higher throughput, and improved limit of quantitation. The examiner notes with respect to this, that this is not claimed in the independent Claim 1 & 112, nor is anything about using lower sample volume or increase sensitivity or lower limit of quantitation. Applicant goes through the EVERSON1 reference in detail, in attempt to try to back up their arguments to this affect. The examiner again, notes that none of this is claimed--- therefore, this is not convincing and these arguments are not commensurate in scope with the claims. Further--- the examiner is still quite confused at why applicant is arguing about the prior art, EVERSON1, especially in such detail, in response to the 101 rejection which did not use EVERSON1.
Further applicant argues that EVERSON1 does not “appear,” to disclose processing comprising adding a protein precipitation solution directly to the blood or serum sample to form a precipitate or supernatant MS/MS, MRM, and that these things are a practical application. The examiner disagrees that these things are a practical application and instead maintains that they are all things which are WURC in the art and therefore are not things that make the claims significantly more than the judicial exceptions. They also do nothing to practically apply the claimed judicial exceptions. Further--- see the claim rejections for how the prior art teaches of this.
Claim interpretation:
The examiner notes that the instant independent claims 1 & 112 do not require within the boundaries of the claims any actual dosing of “distinguishable compound.” Therefore-no labeling occurs within the boundaries of the claims either—the distinguishable compounds can be “a stable isotope labeled distinguishable cholate compound,” according to Claim 1. In the claims, the dosing occurs before the claims start and the claim starts at receiving of the blood or serum sample (which is after any dosing).
103 rejection
With respect to EVERSON1, applicant argues that EVERSON1 does not appear to disclose processing comprising adding a protein precipitation solution to the blood or serum and forming a supernatant, a tandem mass spectrometer or MRM of “administered distinguishable cholate compounds.” The examiner notes that these are the exact reasons why a secondary reference, SAKAI was used as shown in the above rejection.
Applicant then goes into detail with respect to what EVERSON teaches and how it is different from what the instant application does however applicant makes no specific arguments with respect to what exactly is claimed versus what EVERSON1 teaches. For example, applicant argues that “the instant claimed method replace several previous manual sample processing steps with a simplified and at least partially automated online extraction procedure,” and that the “present sample preparation includes smaller sample size.” Applicant also argues that the protein precipitation solution is methanol or acetonitrile with and internal standard and that vortexing, centrifugation is required. Applicant further argues that “instant extraction recovery is greater than 90%, whereas EVERSON1 discloses only about 60-80% analyte extraction recovery.”
With respect to this, the examiner points out that claims are the name of the game for patents. Therefore- making arguments like this are not helpful, since none of the above is recited in the instant claims. Therefore, these arguments are not commensurate in scope with the instant claims. It is surprising that applicant’s representative has not focused their arguments on how specific claim language and the instant prior art different.
Applicant further argues that Claim 1’s use of MS/MS and MRM result in increase sensitivity and specificity. The examiner again notes that nothing with respect to sensitivity or specificity is claimed and therefore these arguments are not commensurate in scope with the claims. Further, with respect to this, if this is actually the case---- it is not claimed--- nor is it seen how, and it is not claimed how endogenous cholates are distinguished from the “distinguishable cholate,” compounds, in any way, shape, or form.
The same applies to all of applicant’s arguments with respect to all of the “distinct advantages,” they argue about on Page labeled as 14 of arguments dated 11/03/2025. None of the “advantages,” argued there are claimed, so all of this is not commensurate in scope with the instant claims.
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections, but instead applicant seems only to go into great detail with respect to each individual reference and then argue how the results of the instant method (which are unclaimed) and the results of the prior art references are different.
With respect to the SAKAI reference, applicant argues that SAKAI is not combinable with EVERSON and that the purported deficiencies of EVERSON1 are not remedied by SAKAI. One of applicant’s reason for thinking this is since EVERSON1 and SAKAI use different samples (tissues versus fluid samples) and employ different analytes. The examiner disagrees that this makes the references un-combinable. In fact SAKAI teaches that all types biological samples can be used (paragraph 0001), though yes they emphasize using tissues. Further, though the examiner agrees a different analyte is measured in SAKAI than in the EVERSON and in the instant invention, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, SAKAI is still in the field of applicants endeavor which is detecting components in blood/biological samples.
Applicant further argues that the prior art references do not teach of “adding a protein precipitation solution to a blood or serum sample.” With respect to this—the examiner points out that as claimed the protein precipitation solution only comprises an “internal standard.” The prior art teaches of this as shown in the above rejection for the newly amended subject matter which was added 11/03/2025.
With respect to Claims 21, 22 & 29, applicant argues again about the different analytes detected in ORY the same as was argued for EVERSON1 and SAKAI. The examiner has already responded to this above, so does not again.
With respect to Claim 29, applicant also argues that the references do not appear to teach greater than 97% extraction recovery. The examiner agrees that the references do not teach this number, though maintains that extraction recovery is a material property of the compound detected, method in which it is detected by. As the prior art has made both the claimed detected compounds and method of detection obvious, the claimed extraction recovery is also obvious. Though- if applicant disagrees, they should consider adding this limitation to the independent claims.
In response to applicant's arguments against the references individually, one cannot show non-obviousness 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 makes the same arguments for the EVERSON2 reference that were made for the other references as shown above. The examiner has already stated that they disagree with applicant’s arguments for the other references and this is maintained for the EVERSON2 reference.
The examiner further notes that if applicant adds detail to overcome the 101 rejections, then it might be easier to overcome the prior art rejections as well.
It is also noted, that is applicant chooses to respond, they should focus their arguments on how what is claimed differs if so, what the prior art references teach--- not what is disclosed in the instant specification.
All claims remain rejected.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
US 9759731
US 8961925
US 10222366
US 10697956
US 12007383
US 8613904
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758