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 .
Response to Amendment
Applicant’s amendment and remark filed on 07/13/26 has been entered. Claim 10 is cancelled. Claims 17-20 are added. Claim 20 is withdrawn by original presentation. Claims 1-9 and 11-19 are pending and examined herein. Applicant’s amendment and remark have overcome each and every rejection under 112(b) set forth in Office Action mailed on 03/16/26.
Status of Rejections
The rejection of claim 1-9 and 11 under 112(b) is withdrawn in view of Applicant’s amendment.
The rejection of claim 10 is obviated by Applicant’s cancellation.
The rejection of claims 1-9 and 11-16 under 101 is maintained.
The rejection of claims 1-9 and 11-16 under 103 is maintained.
Election/Restrictions
Newly submitted claim 20 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 1-9 and 11-19, drawn to a method of testing for disease, classified in G01R 33/465.
II. Claim 20, drawn to a computer system predicting susceptibility to AMS using classification model, classified in G01N 2800/50.
The inventions are independent or distinct, each from the other because:
Inventions I and II are related as process and apparatus for its practice. The inventions are distinct if it can be shown that either: (1) the process as claimed can be practiced by another and materially different apparatus or by hand, or (2) the apparatus as claimed can be used to practice another and materially different process. (MPEP § 806.05(e)). In this case, the process as claimed can be practiced by hand and does not require the apparatus of Group II.
Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply:
Group I would require at least a search and consideration in CPC G01R 33/465, along with a unique text search.
Group II would require at least a search and consideration in CPC G01N 2800/50, along with a unique text search.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of an invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 20 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-9 and 11-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to law of nature and abstract idea without significantly more.
Regarding claims 1, 18, and 19, the claim(s) recite(s) a “method of predicting AMS”; the method comprises the step of analyzing for a quantity of at least one biomarker/metabolite compound (creatine, taurine, N-methylhistidine, hypoxanthine…3-methylhistidine) in an urine sample and comparing the quantity to a threshold.
This limitation, as drafted, is a process that, under its broadest reasonable interpretation, covers a law of nature in the form of a natural correlation. The claim recites detecting illness by measuring the amount of concentration of the biomarker compound in a biological sample. The amounts of biomarkers in the sample naturally correlated with diagnostic of altitude sickness. If a claim limitation, under its broadest reasonable interpretation, covers a natural correlation, then it falls within the law of nature grouping of natural phenomena. Accordingly, the claim recites a law of nature (Step 2A, Prong 1).
This judicial exception is not integrated into a practical application. In particular, the claim recites “analyzing the urine sample for a quantity of at least one metabolite” and comparing the quantity to a threshold to detect/diagnose AMS, which constitutes a natural correlation under broadest reasonable interpretation. There is no integration of the measurement step much less a practical one since after the measurement, a generic and broadly recited diagnostic step is introduced. However, the diagnostic step does not impose any meaningful limit since the limitation is directed toward determining whether or not the subject is “susceptible” (In other word, likely) to experience AMS, and there is no particular threshold value (or how the threshold value is being determined). As such, the measuring of the biomarkers is mere natural correlation that is not significantly more than law of nature. See MPEP 2106.05(g). Accordingly, this additional element does not integrate the natural correlation into a practical application because it does not impose any meaningful limits on practicing the abstract idea. The claim is directed to a judicial exception (Step 2A, Prong 2).
In addition, the claim also recites based on the comparison, determining whether the subject is susceptible to experience AMS at high altitudes. This limitation, as drafted, is a process that, under its broadest reasonable interpretation, covers an abstract idea in the form of a mental process. The claim recites comparing the amount of concentration of a biomarker in a biological sample in a subject to a generically recited “threshold value”. Making decision whether or not the difference of the comparison, under broadest reasonable interpretation, is a mental process that can be performed in the human mind. Nothing in the claim precludes the user from manually comparing the data of a subject to an arbitrary preset threshold and deciding what would be constitute as “suggesting” the subject is “likely” to experience AMS. If a claim limitation, under its broadest reasonable interpretation, covers a mental process, then it falls within the mental process grouping. Accordingly, the claim recites an abstract idea (Step 2A, Prong 1).
This judicial exception is not integrated into a practical application. In particular, the claim recites suggesting that the subject is likely to experience AMS if the quantity of the biomarker exceeds or falls below the threshold, which constitutes a mental process under broadest reasonable interpretation.
Furthermore, the claim recites the additional element of “implementing an AMS mitigation plan for the subject determined to be susceptible to AMS”. Although this limitation indicates that a treatment is to be administered/implemented, it does not provide any information as to how the patient/suspected patient is to be treated, or what the treatment is, but instead covers any possible treatment that a doctor decides to administer to the patient. Like the claims in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 78 (2012), claim 1 here tells the relevant audience (doctors) about the mathematical concepts and at most adds a suggestion that the doctors take those laws into account when treating their patients. The AMS mitigation steps thus fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, the AMS mitigation plan implementation does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception
The claim does not include additional elements that are sufficient to amount to significant more than the judicial exception. With respect to integration of the abstract idea into a practical application, the limitation of obtaining the sample and analyzing the samples for metabolites are conventional ways of data gathering. Routine and conventional data gathering cannot provide an inventive concept, and the limitation of implementing mitigation plan does not require any particular application of the recited calculation and is at best the equivalent of merely adding the words “apply it“ to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept. The claim is not patent eligible.
Claims 2-4 do not cure the deficiency of claim 1. The claims merely recite indicating susceptibility when the quantity of certain metabolites either exceeds or falls below the threshold value. As discussed above, the indication of susceptibility is, at best, an abstract idea that has not been practically integrated.
Claims 5-8 do not cure the deficiency of claim 1. Claim 5 and 8 merely recite how the sample is being analyzed by a broad and generically recited method such as “metabolomic analysis, targeted quantitation, or semi-quantitative method” or “lab method or a point-of-care method”. Furthermore, claims 6 and 7 further narrow the scope of claim 5 to analytical method such as NMR, LC/MS, HPLC/MS, GC/MS, ELISA, or LFA, with claim 7 focuses specifically on ELISA. However, analyzing urine samples for metabolites using these methods are generally well-known and conventional.
Claims 9 and 10 do not cure the deficiency of claim 1. The claim merely recites where the sample is being collected
Claim 11 does not cure the deficiency of claim 1. The claim recites urine sample being normalized and standardized using creatine, which is a well-known and conventional standardization step when analyzing urine sample.
For similar reason, claim 12 and 17 recite(s) a “method of evaluating acclimatization after exposure to high altitude and associated AMS”; the method comprises the step of analyzing for a quantity of at least one biomarker/metabolite compound (creatine, taurine, N-methylhistidine, hypoxanthine…3-methylhistidine) in an urine sample and comparing the quantity to a threshold.
This limitation, as drafted, is a process that, under its broadest reasonable interpretation, covers a law of nature in the form of a natural correlation. The claim recites detecting illness by measuring the amount of concentration of the biomarker compound in a biological sample. The amounts of biomarkers in the sample naturally correlated with diagnostic of altitude sickness. If a claim limitation, under its broadest reasonable interpretation, covers a natural correlation, then it falls within the law of nature grouping of natural phenomena. Accordingly, the claim recites a law of nature (Step 2A, Prong 1).
This judicial exception is not integrated into a practical application. In particular, the claim recites “analyzing the urine sample for a quantity of at least one metabolite” and comparing the quantity to a threshold to detect/diagnose AMS, which constitutes a natural correlation under broadest reasonable interpretation. There is no integration of the measurement step much less a practical one since after the measurement, a generic and broadly recited diagnostic step is introduced. However, the diagnostic step does not impose any meaningful limit since the limitation is directed toward determining whether or not the subject has acclimatized to the new altitude, and there is no particular threshold value (or how the threshold value is being determined). As such, the measuring of the biomarkers is mere natural correlation that is not significantly more than law of nature. See MPEP 2106.05(g). Accordingly, this additional element does not integrate the natural correlation into a practical application because it does not impose any meaningful limits on practicing the abstract idea. The claim is directed to a judicial exception (Step 2A, Prong 2).
In addition, the claim also recites based on the comparison, determining whether the subject has acclimatized at high altitudes. This limitation, as drafted, is a process that, under its broadest reasonable interpretation, covers an abstract idea in the form of a mental process. The claim recites comparing the amount of concentration of a biomarker in a biological sample in a subject at one altitude to a generically recited “threshold value” or a quantity of biomarkers collected from sample at a lower altitude. Making decision whether or not the difference of the comparison, under broadest reasonable interpretation, is a mental process that can be performed in the human mind. Nothing in the claim precludes the user from manually comparing the data of a subject to an arbitrary preset threshold and deciding what would be constitute as “suggesting” the subject has acclimatized. If a claim limitation, under its broadest reasonable interpretation, covers a mental process, then it falls within the mental process grouping. Accordingly, the claim recites an abstract idea (Step 2A, Prong 1).
This judicial exception is not integrated into a practical application. In particular, the claim recites suggesting that the subject has acclimatized if the quantity of the biomarker exceeds or falls below the threshold or another quantity at a lower altitude, which constitutes a mental process under broadest reasonable interpretation.
Furthermore, the claim recites the additional element of “implementing an AMS mitigation plan for the subject determined to be susceptible to AMS”. Although this limitation indicates that a treatment is to be administered/implemented, it does not provide any information as to how the patient/suspected patient is to be treated, or what the treatment is, but instead covers any possible treatment that a doctor decides to administer to the patient. Like the claims in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 78 (2012), claim 1 here tells the relevant audience (doctors) about the mathematical concepts and at most adds a suggestion that the doctors take those laws into account when treating their patients. The AMS mitigation steps thus fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, the AMS mitigation plan implementation does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception
The claim does not include additional elements that are sufficient to amount to significant more than the judicial exception. With respect to integration of the abstract idea into a practical application, the limitation of obtaining the sample and analyzing the samples for metabolites are conventional ways of data gathering. Routine and conventional data gathering cannot provide an inventive concept, and the limitation of implementing mitigation plan does not require any particular application of the recited calculation and is at best the equivalent of merely adding the words “apply it“ to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept. The claim is not patent eligible.
Claims 13-15 do not cure the deficiency of claim 12. Claim 13 merely recites how the sample is being analyzed by a broad and generically recited method such as “metabolomic analysis, targeted quantitation, or semi-quantitative method”. Furthermore, claims 14 and 15 further narrow the scope of claim 5 to analytical method such as NMR, LC/MS, HPLC/MS, GC/MS, ELISA, or LFA, with claim 15 focuses specifically on ELISA. However, analyzing urine samples for metabolites using these methods are generally well-known and conventional.
Claim 16 does not cure the deficiency of claim 12. The claim recites urine sample being normalized and standardized using creatine, which is a well-known and conventional standardization step when analyzing urine sample.
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 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.
Claim(s) 1, 2, 5-9, and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liao (Metabolite Modulation in Human Plasma in the Early Phase of Acclimatization to Hypobaric Hypoxia, 2016) in view of Wijemanne (Development and Validation of a Simple High Performance Liquid Chromatography/UV Method for Simultaneous Determination of Urinary Uric Acid, Hypoxanthine, and Creatinine in Human Urine, 2018) and Julian (Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study, 2011).
Regarding claims 1 and 2, Liao discloses a method of predicting AMS, the method comprising:
collecting plasma sample from a subject at 1400 m/4600 ft (Fasting venous blood (with EDTA as an anticoagulant) was obtained from all subjects both on plain (1400 m) and on the fourth day after arriving at high altitude (5300 m); Experimental Procedures, para. 3);
analyzing the sample for a quantity of at least one metabolite selected from the group consisting hypoxanthine (ESI+, Table 3);
comparing the quantity to a respective threshold value (Ratio of High Altitude vs Plain, Table 3; plain as the threshold);
implementing an AMS mitigation plan (We speculate that supplements of the above-mentioned amino acids (valine, alanine and proline) may be helpful for improving energy metabolism and promoting acclimatization to high altitude. Para. 7; Protecting gastrointestinal mucosal function may be of clinical importance in reducing the incidence of high-altitude diseases and improving treatment regimens. Para. 9, The Interpretation of the Perturbed Metabolic Pathways after Exposure to High Altitude).
Liao does not disclose urine samples are being collected and analyzed and a step of determining whether the subject is susceptible to experience AMS at high altitudes.
Regarding the limitation of collecting urine and analyzing urinary hypoxanthine, Wijemanne discloses laboratory technique of analyzing for urinary hypoxanthine using chromatographic techniques (Abstract), thus confirming the presence of hypoxanthine in urine.
Regarding the limitation of indicating susceptibility based on a threshold, Julian hypothesized and confirmed that individuals who remained healthy with hypobaric hypoxia exposure would have lower levels of proinflammatory, angiogenic, or chemotactic mediators and higher levels of anti-permeability or anti-inflammatory biomarkers compared with individuals who developed AMS (right col., para. 3, page 393) since the presence of “adequate” amount of anti-permeability or anti-inflammatory biomarkers may be an indication of a person’s susceptibility to hypoxic exposure (In summary, our findings support the possibility that resistance to AMS may involve the ability to mount an adequate “defensive” anti-inflammatory or anti-permeability response during hypoxic exposure. We consider it likely that such effects may have prevented downstream pathophysiological events leading to AMS. Right col., page 398, para. 1).
As hypoxanthine is an anti-inflammatory marker known for its potent anti-inflammatory effects, it would have been obvious to one of ordinary skill in the art before the effective filing date to have developed an alternative embodiment of analyzing hypoxanthine in the method of Liao with urine as disclosed by method of Wijemanne instead of blood sample with a reasonable expectation of success as both methods involves chromatographic analysis for hypoxanthine. Furthermore, one would have been motivated to make such substitution as it may be potentially less labor intensive in collecting urine sample compare to blood sample as urine sample simply requires excretion; collecting blood sample, on the other hand, requires withdrawing samples by needle and storing the sample with anticoagulant (Liao, Experimental Procedures, para. 3).
Furthermore, it would have been obvious to one of ordinary skill in the art to further testing fluid sample of both the AMS resistant and susceptible individuals to develop a threshold based on testing from resistant individuals with the expectation that a susceptible person would have a hypoxanthine level below the level of resistant individuals based on the disclosure of Julian (our findings support the possibility that resistance to AMS may involve the ability to mount an adequate “defensive” anti-inflammatory or anti-permeability response during hypoxic exposure. Right col., page 398, para. 1) as lack of adequate anti-inflammatory markers presence is indicative of one’s readiness for high altitude sickness.
Regarding claim 5, Modified Liao discloses the claimed invention as discussed above in claim 1. Liao discloses analyzing the sample includes a metabolomic analysis (This is the first metabolomic study to determine plasma biochemical alterations of healthy individuals after four days at high altitude (5300 m) by using combined LC-MS and GC-MS. Conclusions).
Regarding claim 6, Modified Liao discloses the claimed invention as discussed above in claim 5. Liao discloses the metabolomic analysis is selected from LC-MS or GC-MS (This is the first metabolomic study to determine plasma biochemical alterations of healthy individuals after four days at high altitude (5300 m) by using combined LC-MS and GC-MS. Conclusions).
Regarding claim 7, Modified Liao discloses the claimed invention as discussed above in claim 6. Liao discloses, in addition to GC/MS and LC-MS, an additional quantitation by capture element in ELISA is performed wherein the ELISA method includes evaluation of a peptide (To validate the metabolic changes, the levels of key enzymes in these metabolic pathways were determined by ELISA. The Levels of Key Enzymes Involved in the Pathways of Altered Metabolites).
Regarding claim 8, Modified Liao discloses the claimed invention as discussed above in claim 1. Liao discloses analyzing the urine samples includes a lab method (GC/MS or LC/MS).
Regarding claim 9, Modified Liao discloses the claimed invention as discussed above in claim 1. Liao does not disclose the urine is collected at sea level. However, Liao discloses sample is collected at two altitudes, 1400m and 5300m. Therefore, it would have been obvious design choice to one of ordinary skill in the art to have chosen a different altitude than the one disclosed by Liao such as at sea level to derive the claimed invention, so long a second higher altitude is chosen for testing for AMS susceptibility.
Regarding claim 11, Modified Liao discloses the claimed invention as discussed above in claim 1. Wijemanne, after incorporation with Liao, discloses normalization of the collected urine sample using creatine to standardize against urine sample volume (The method can be employed for the analysis of purine metabolism defects using human urine samples with normalization with creatinine. 20. Conclusion).
Claim(s) 1, 3, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liao in view of Magiera (Determination of carnitine and acylcarnitines in human urine by means of microextraction in packed sorbent and hydrophilic interaction chromatography–ultra-high-performance liquid chromatography–tandem mass spectrometry, 2015) and Horscroft (Metabolic basis to Sherpa altitude adaptation, 2017).
Regarding claims 1, 3, and 18 Liao discloses a method of predicting AMS, the method comprising:
collecting plasma sample from a subject (Fasting venous blood (with EDTA as an anticoagulant) was obtained from all subjects; Experimental Procedures, para. 3);
analyzing the sample for a quantity of at least one metabolite selected from the group consisting acetylcarnitine (ESI+, Table 3);
comparing the quantity to a respective threshold value (Ratio of High Altitude vs Plain, Table 3; plain as the threshold).
implementing an AMS mitigation plan (We speculate that supplements of the above-mentioned amino acids (valine, alanine and proline) may be helpful for improving energy metabolism and promoting acclimatization to high altitude. Para. 7; Protecting gastrointestinal mucosal function may be of clinical importance in reducing the incidence of high-altitude diseases and improving treatment regimens. Para. 9, The Interpretation of the Perturbed Metabolic Pathways after Exposure to High Altitude).
Liao does not disclose urine samples are being collected and analyzed and a step of determining whether the subject is susceptible to experience AMS at high altitudes when the quantity of the acetylcarnitine is above the respective threshold value.
Regarding the limitation of collecting urine and analyzing urinary acetylcarnitine, Magiera presents a laboratory method for analyzing urinary acetylcarnitine in the sample using chromatographic techniques (Abstract), thus confirming the presence of acetylcarnitine in urine.
Regarding the limitation of indicating susceptibility based on a threshold, Horscroft discloses a study of Sherpa’s carnitine concentration compared to that of lowlander. Horscroft found that Sherpas, due to genetic difference and metabolic adaptations, allows their tissues to use oxygen more efficiently (Abstract) after analyzing carnitines present in the sample (Half of the organic fraction and half of the aqueous fraction were combined with 200 μL of acetonitrile containing an internal standard mix of eight deuterated carnitines [1.63 μM (d9) free carnitine, 0.3 μM (d3) acetyl carnitine…; Mass Spectrometry, para. 4]. Horscroft findings concludes lowlanders generally have higher carnitine present in their samples than Sherpas at baseline (35 m above sea level) (Fig. 2C-F).
it would have been obvious to one of ordinary skill in the art before the effective filing date to have developed an alternative embodiment of analyzing acetylcarnitine in the method of Liao with urine as disclosed by Magiera instead of blood sample with a reasonable expectation of success as both methods involves chromatographic analysis for acetylcarnitine. Furthermore, one would have been motivated to make such substitution as it may be potentially less labor intensive in collecting urine sample compare to blood sample as urine sample simply requires excretion; collecting blood sample, on the other hand, requires withdrawing samples by needle and storing the sample with anticoagulant (Liao, Experimental Procedures, para. 3).
Furthermore, it would have been obvious to one of ordinary skill in the art to further testing fluid sample of both the AMS resistant and susceptible individuals to develop a threshold based on testing from resistant individuals with the expectation that a susceptible person would have a acetylcarnitine level above the level of resistant individuals based on the disclosure of Horscroft as lower level carnitine is indicative of oxygen utilization efficiency (Horscroft, Abstract).
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liao in view of Wijemanne and Julian as discussed above in claim 1, and further in view of Magiera and Horscroft.
Regarding claim 4, Modified Liao discloses the claimed invention as discussed above in claim 1. Liao discloses the method is capable of analyzing the sample for a quantity of acetylcarnitine in addition of hypoxanthine (ESI+, Table 3).
Neither Liao nor Wijemanne discloses urine samples are being collected for analyzing acetylcarnitine and a step of determining whether the subject is susceptible to experience AMS at high altitudes when the quantity of the acetylcarnitine is above the respective threshold value.
Regarding the limitation of collecting urine and analyzing urinary acetylcarnitine, Magiera presents a laboratory method for analyzing urinary acetylcarnitine in the sample using chromatographic techniques (Abstract), thus confirming the presence of acetylcarnitine in urine.
Regarding the limitation of indicating susceptibility based on a threshold, Horscroft discloses a study of Sherpa’s carnitine concentration compared to that of lowlander. Horscroft found that Sherpas, due to genetic difference and metabolic adaptations, allows their tissues to use oxygen more efficiently (Abstract) after analyzing carnitines present in the sample (Half of the organic fraction and half of the aqueous fraction were combined with 200 μL of acetonitrile containing an internal standard mix of eight deuterated carnitines [1.63 μM (d9) free carnitine, 0.3 μM (d3) acetyl carnitine…; Mass Spectrometry, para. 4]. Horscroft findings concludes lowlanders generally have higher carnitine present in their samples than Sherpas at baseline (35 m above sea level) (Fig. 2C-F).
It would have been obvious to one of ordinary skill in the art before the effective filing date to have developed an alternative embodiment of analyzing acetylcarnitine in the method of Modified Liao with urine as disclosed by Magiera instead of blood sample with a reasonable expectation of success as both methods involves chromatographic analysis for acetylcarnitine. Furthermore, one would have been motivated to make such substitution as it may be potentially less labor intensive in collecting urine sample compare to blood sample as urine sample simply requires excretion; collecting blood sample, on the other hand, requires withdrawing samples by needle and storing the sample with anticoagulant (Liao, Experimental Procedures, para. 3).
Furthermore, it would have been obvious to one of ordinary skill in the art to further testing fluid sample of both the AMS resistant and susceptible individuals to develop a threshold based on testing from resistant individuals with the expectation that a susceptible person would have a acetylcarnitine level above the level of resistant individuals based on the disclosure of Horscroft as lower level carnitine is indicative of oxygen utilization efficiency (Horscroft, Abstract).
Claim(s) 12-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liao in view of Wijemanne.
Regarding claim 12, Liao discloses a method of predicting AMS, the method comprising:
Collecting a first plasma sample from a subject (Fasting venous blood (with EDTA as an anticoagulant) was obtained from all subjects; Experimental Procedures, para. 3) at a first altitude not more than 1500 m above sea level (1400 m);
Exposing and collecting a second plasma sample from a subject at a second altitude greater than 1500 m above sea level (5300 m);
analyzing the first and second sample for first and second quantity of at least one metabolite selected from the group consisting hypoxanthine and acetylcarnitine (ESI+, Table 3);
comparing the second quantity (High Altitude) to the first quantity (Plain) (Ratio of High Altitude vs Plain, Table 3);
based on the comparison, determining whether the subject has acclimatized to the second altitude (We have identified 50 significantly changed metabolites and predicted the major metabolites network by pattern recognition and pathway analysis….Identified differential metabolites and related pathways provide new insights for further understanding the pathophysiological mechanism of early acclimatization to hypobaric hypoxia and treatment of AMS-S individuals. Blocking or modifying these points of convergence are attractive approaches to promoting acclimatization to hypobaric hypoxia and the treatment of AMS-S individuals. Conclusions); and
implementing an AMS mitigation plan (We speculate that supplements of the above-mentioned amino acids (valine, alanine and proline) may be helpful for improving energy metabolism and promoting acclimatization to high altitude. Para. 7; Protecting gastrointestinal mucosal function may be of clinical importance in reducing the incidence of high-altitude diseases and improving treatment regimens. Para. 9, The Interpretation of the Perturbed Metabolic Pathways after Exposure to High Altitude).
Liao does not disclose urine samples are being collected and analyzed.
Regarding the limitation of collecting urine and analyzing urinary hypoxanthine, Wijemanne discloses laboratory technique of analyzing for urinary hypoxanthine using chromatographic techniques (Abstract), thus confirming the presence of hypoxanthine in urine. It would have been obvious to one of ordinary skill in the art before the effective filing date to have developed an alternative embodiment of analyzing hypoxanthine in the method of Liao with urine as disclosed by method of Wijemanne instead of blood sample with a reasonable expectation of success as both methods involves chromatographic analysis for hypoxanthine. Furthermore, one would have been motivated to make such substitution as it may be potentially less labor intensive in collecting urine sample compare to blood sample as urine sample simply requires excretion; collecting blood sample, on the other hand, requires withdrawing samples by needle and storing the sample with anticoagulant (Liao, Experimental Procedures, para. 3).
Regarding claim 13, Modified Liao discloses the claimed invention as discussed above in claim 12. Liao discloses analyzing the sample includes a metabolomic analysis (This is the first metabolomic study to determine plasma biochemical alterations of healthy individuals after four days at high altitude (5300 m) by using combined LC-MS and GC-MS. Conclusions).
Regarding claim 14, Modified Liao discloses the claimed invention as discussed above in claim 13. Liao discloses the metabolomic analysis is selected from LC-MS or GC-MS (This is the first metabolomic study to determine plasma biochemical alterations of healthy individuals after four days at high altitude (5300 m) by using combined LC-MS and GC-MS. Conclusions).
Regarding claim 15, Modified Liao discloses the claimed invention as discussed above in claim 14. Liao discloses, in addition to GC/MS and LC-MS, an additional quantitation by capture element in ELISA is performed wherein the ELISA method includes evaluation of a peptide (To validate the metabolic changes, the levels of key enzymes in these metabolic pathways were determined by ELISA. The Levels of Key Enzymes Involved in the Pathways of Altered Metabolites).
Regarding claim 16, Modified Liao discloses the claimed invention as discussed above in claim 13. Wijemanne, after incorporation with Liao, discloses normalization of the collected urine sample using creatine to standardize against urine sample volume (The method can be employed for the analysis of purine metabolism defects using human urine samples with normalization with creatinine. 20. Conclusion).
Claim(s) 12 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liao in view of Magiera.
Regarding claims 12 and 17, Liao discloses a method of predicting AMS, the method comprising:
Collecting a first plasma sample from a subject (Fasting venous blood (with EDTA as an anticoagulant) was obtained from all subjects; Experimental Procedures, para. 3) at a first altitude not more than 1500 m above sea level (1400 m);
Exposing and collecting a second plasma sample from a subject at a second altitude greater than 1500 m above sea level (5300 m);
analyzing the first and second sample for first and second quantity of at least one metabolite selected from the group consisting of hypoxanthine and acetylcarnitine (ESI+, Table 3);
comparing the second quantity (High Altitude) to the first quantity (Plain) (Ratio of High Altitude vs Plain, Table 3);
based on the comparison, determining whether the subject has acclimatized to the second altitude (We have identified 50 significantly changed metabolites and predicted the major metabolites network by pattern recognition and pathway analysis….Identified differential metabolites and related pathways provide new insights for further understanding the pathophysiological mechanism of early acclimatization to hypobaric hypoxia and treatment of AMS-S individuals. Blocking or modifying these points of convergence are attractive approaches to promoting acclimatization to hypobaric hypoxia and the treatment of AMS-S individuals. Conclusions); and
implementing an AMS mitigation plan (We speculate that supplements of the above-mentioned amino acids (valine, alanine and proline) may be helpful for improving energy metabolism and promoting acclimatization to high altitude. Para. 7; Protecting gastrointestinal mucosal function may be of clinical importance in reducing the incidence of high-altitude diseases and improving treatment regimens. Para. 9, The Interpretation of the Perturbed Metabolic Pathways after Exposure to High Altitude).
Liao does not disclose urine samples are being collected and analyzed.
Regarding the limitation of collecting urine and analyzing urinary acetylcarnitine, Magiera presents a laboratory method for analyzing urinary acetylcarnitine in the sample using chromatographic techniques (Abstract), thus confirming the presence of acetylcarnitine in urine.
It would have been obvious to one of ordinary skill in the art before the effective filing date to have developed an alternative embodiment of analyzing acetylcarnitine in the method of Liao with urine as disclosed by Magiera instead of blood sample with a reasonable expectation of success as both methods involve chromatographic analysis for acetylcarnitine. Furthermore, one would have been motivated to make such substitution as it may be potentially less labor intensive in collecting urine samples compare to blood sample as urine sample simply requires excretion; collecting blood sample, on the other hand, requires withdrawing samples by needle and storing the sample with anticoagulant (Liao, Experimental Procedures, para. 3).
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liao in view of Magiera as applied to claim 12 above, and further in view of Koundal (“Omics” of High Altitude Biology: A Urinary Metabolomics Biomarker Study of Rats under Hypobaric Hypoxia, 2015).
Regarding claim 19, Modified Liao discloses the claimed invention as discussed above in claim 12. Neither Liao nor Magiera explicitly discloses analyzing urinary creatine and taurine for hypoxia metabolites.
In an analogous art, Koundal discloses a method of studying creatine and taurine (Metabolomics urinalysis showed alterations in TCA cycle metabolites…and others (N-acetyl glutamate, creatine, taurine) in response to hypobaric hypoxia. Abstract) in urine sample of rats after exposing rats to high altitude (Rats were exposed to simulated altitude of 6700 m above the sea level. The urine samples were collected from pre- and post-exposure (1, 3, 7, and 14 days) of hypobaric hypoxia. Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date to have incorporated step of urinary analysis of taurine and creatine of Koundal to the method of analyzing urinary acetylcarnitine of Modified Liao. Koundal discloses change of level of creatine and taurine in response to hypobaric hypoxia and can serve as a potential biomarker (Taurine, a potential biomarker of hepatic function, was elevated after 3 days of hypobaric hypoxia, which indicates altered liver functioning. Liver histopathology confirmed the damage to tissue architecture due to hypobaric hypoxia. Abstract; Elevated creatine levels were found in D1 and D3 HH exposed groups…Further, altered creatine, cholines, and NAG metabolism may be linked to liver dysfunction, which was evident in the present study. Discussion, para. 6-7).
Response to Arguments
Applicant's arguments filed on 07/13/26 have been fully considered but they are not persuasive.
In response to applicant's argument that one of ordinary skill in the art would not have incorporated urinary analysis steps of Wijemanne and Magiera to Liao to derive a method of testing the same metabolites in urine for susceptibility to altitude sickness (Pages 7-11), 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).
In this case, the claimed method is concerned with observing a change in concentration of metabolites to make assessment of one’s susceptibility to AMS. Liao has identified trends of several metabolites that experience changes in concentration in response to being exposed to elevation. However, these metabolites are being tested in blood instead of urine. Although the urinary analysis steps in Wijemanne and Magiera are directed to diagnosis of different diseases (autism and CVD), it is generally known that many metabolites can serve as biomarkers for multiple diseases. As Liao’s method is potentially invasive, one of ordinary skill in the art would have been motivated to use a less invasive technique such as sampling the metabolites in urine instead (Liao, Experimental Procedures, para. 3) as being done in Wijemanne and Magiera.
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.
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/M.H./Examiner, Art Unit 1758
/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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