DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-20 are pending
Claims 1-20 are rejected.
Claims 1-3, 11, and 14-20 are objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application, PCT EP2021/079615 filed 26 Oct. 2021, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority to EP20306278.1 filed 16 Oct. 2020 under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Accordingly, the effective filing date of the claimed invention is 26 Oct. 2020.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted 24 April 2023 and 12 Aug. 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
The information disclosure statement filed 19 Jan. 2026 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered.
Examiner request a translation of the referred to reference that has not been considered if it is within the possession, custody or control of, or is readily available to any individual designated in 37 CFR 1.56(c). See MPEP 609.01.
Drawings
The drawings were received on 24 April 2023.
The drawings filed 24 April 2023 are objected to because:
FIG. 2-7 fail to comply with 37 CFR 1.84(u)(1), which states partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. The figures should be relabeled FIG. 2A, FIG. 2B, FIG. 3A, etc.
FIG. 1-7 fail to comply with 37 CFR. 1.84(u)(2), which states numbers and letters identifying the views must be simple and clear and must not be used in association with brackets, circles, or inverted commas. The underlines underneath view numbers should be removed.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at pg. 3, line 12, pg. 39, line 28, pg. 40, lines 30-31, and pg. 41, line 15. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because of the following informalities:
Pg. 16, line 2 recites “deshydrogenase inhibitor”, which should recite “dehydrogenase inhibitor”.
Appropriate correction is required.
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because:
The abstract refers to the purported merits of the applications of the invention and compares the invention with the prior art in lines 1-5 and 7-9.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 1-3, 11, and 14-20 are objected to because of the following informalities:
Claim 1 recites “…applying…to obtain area-under-the-concentration-over-time value at…”, which is a grammatical error and should recite “to obtain an area-under-the-concentration-over-time value…”.
Claims 2-3 recite “the intelligence artificial technique”, which is a typographical error and should recite “the artificial intelligence technique”.
Claim 11 recites “deshydrogenase inhibitor”, which should read “dehydrogenase inbhitor”.
Claims 14-15 recite “Computer program product…” and “Computer-readable medium…”, which is grammatically incorrect and should recite “A computer program product…” and “A computer-readable medium…”.
Claims 15-18 recite “The method…according to any one of claim 1”, which should be amended to recite “The method…according to claim 1…”.
Claim 19 recites “deshydrogenase inhibitor”, which should read “dehydrogenase inbhitor”.
Claim 19 recites “for several couples of first given time and second given time”, which is a missing an article “a” before first given time and second given time”. The claim should recite “for several couples of a first given time and a second given time”.
Claim 19 recites “applying an extreme…to obtain area-under-the-concentration-over-time”, which is missing an article “an” before “area-under…”. The claim should recite “to obtain an area-under…”.
Claim 20 recites “…other parameters are obtained, among which: the dose…”, which is nonsensical and should recite “…other parameters are obtained, comprising .
Appropriate correction is required.
Applicant is advised that should claim 14 be found allowable, claim 15 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Interpretation
Claim 8 recites “wherein the treatment includes a transplantation of an organ to the subject…”. Claim 1, from which claim 8 depends, recites “A method for assessing…of a subject after administration of a dose of the immunosuppressant, the subject being treated by a treatment…”. However, claim 1 does not recite a step of administering the treatment. Therefore, the wherein clause of claim 8 is interpreted to be a product by process limitation defining the process in which the patient was treated or intends to be treated. See MPEP 2113 I. However, claim 8 does not require a step of performing an organ transplantation on the subject.
Claim 20 recites “wherein the treatment includes a transplantation of an organ to the subject…”. Claim 19, from which claim 20 depends, recites “administrating the drug to the subject in a treatment of the subject…”. Therefore, similar to claim 8, claim 20 is interpreted to further limit the administration of the drug to be performed in a subject as part of a treatment including a transplantation of an organ, thus defining the process in which the subject was treated or intends to be treated. However, claim 20 does not require a step of performing an organ transplantation on the subject.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-20 rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 1, and claims dependent therefrom, recites “…the subject being treated by a treatment comprising administrations of the drug”. There is insufficient antecedent basis for “the drug” in the claim because claim 1 previously does not recite a “drug” and instead recites “an immunosuppressant”. As a result, it is not clear if “the drug” is intended to be the immunosuppressant or another drug not required to be an immunosuppressant. Claims 4-5 also recite “the drug” and therefore are indefinite for the same reasons discussed above for claim 1. For purpose of examination, the drug is interpreted to refer to the immunosuppressant.
Claim 3 is indefinite for recitation of “preferably an extreme gradient boosting technique”. The phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For purpose of examination, claim 3 is interpreted to mean the artificial intelligence technique comprises a gradient boosting technique, but is not required to comprise an extreme gradient boosting technique.
Claim 5 is indefinite for recitation of “the values of difference in concentration…”. There is insufficient antecedent basis for “the values of difference…” in the claim, because claims 1 and 5 do not previously recite any values of difference. It is further unclear if the parameters are intended to comprise multiple values of difference between a first time and a second time (and there are multiple values for each pair of times), or if the parameters comprise the difference between a first and second time, for each of multiple couples of a first and second time (i.e. multiple differences across the pairs of time points). For purpose of examination, the claim is interpreted to mean the parameters include the difference in concentration between a first given time and a second given time, for each of several couples of a first given time and a second given time.
Claim 7 is indefinite for recitation of “the dose administered”. Claim 1, from which claim 7 depends, recites (1) “administration of a dose of the immunosuppressant” in line 3 and (2) “the subject being treated by a treatment comprising administrations of the drug…” in line 4. As discussed in the 112(b) rejection of claim 1 above, “the drug” is interpreted to refer to the immunosuppressant. It is note clear if “the dose administered” in claim 7 is referring to (1) the administered dose of the immunosuppressant in line 3 or (2) a dose of one of the administrations of the drug in line 4. If Applicant intends for claim 7 to refer to one of the administrations of the drug in line 4, it is further unclear which administration is being referenced. Clarification is requested via claim amendment. For purpose of examination, claim 7 is interpreted to refer to the dose in line 3.
Claim 8 is indefinite for recitation of “the delay between a request…and the transplantation”. There is insufficient antecedent basis for this limitation in the claim because claims 1 and 8 do not previously require there was a delay between the request and the transplantation. For purpose of examination, claim 8 is interpreted to mean “comprising a delay between…”.
Claim 13 is indefinite for recitation of “A method for monitoring patients to provide a quantitative measure for the therapeutic efficacy of a therapy by carrying out the steps of a method for assessing on said patients…”. Claim 13 does not recite a transitional phrase such as “comprising” or “consisting”. As a result, it is not clear if the steps of claim 13 for the method for assessing on said patients is closed or open to unrecited elements. For purpose of examination, claim 13 is interpreted to mean “A method for monitoring patients to provide a quantitative measure for the therapeutic efficacy of a therapy [[by]] comprising carrying out the steps of a method for assessing on said patients…”.
Claim 19, and claims dependent therefrom, are indefinite for recitation of “administering the drug to the subject…” in line 7 and “the drug” at lines 10 and 14. There is insufficient antecedent basis for “the drug” in the claim because claim 19 previously does not recite a “drug” and instead recites “an inhibitor”. As a result, it is not clear if “the drug” is intended to be the inhibitor or another drug not required to be an inhibitor.. For purpose of examination, the drug is interpreted to refer to the inhibitor.
Claim 19, and claims dependent therefrom, are indefinite for recitation of “the values of difference in concentration…” for the same reasons discussed above for claim 5. For purpose of examination, the claim is interpreted to mean the parameters include the difference in concentration between a first given time and a second given time, for each of several couples of a first given time and a second given time.
Claim 20 is indefinite for recitation of “the dose administered”. Claim 19, from which claim 20 depends, recites “administering the drug to the subject..” in line 7, and also “the values of difference in concentration…after administration of the drug for several couples of [a] first given time and [a] second given time” (i.e. multiple administrations of the drug”. As a result, it is not clear if “the dose administered” is referring to a dose of a single administration (and if so, it is not clear which administration) or if “the dose administered” is intending to include each administered dose. Clarification is requested. For purpose of examination, claim 20 is interpreted to refer to a dose of the inhibitor administered to the subject.
Claim 20 is indefinite for recitation of “the delay between a request…and the transplantation”. There is insufficient antecedent basis for this limitation in the claim because claim 19 does not previously require there was a delay between a request and a transplantation. For purpose of examination, claim 20 is interpreted to mean “comprising a delay between…”.
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 14-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because:
Claims 14-15 recite “Computer program product comprising computer program instructions” and “Computer-readable medium comprising computer program instructions…”, respectively. The subject matter of claims 14-15 is a computer program on computer readable media. A review of the specification does not show a definition of computer readable media that excludes an embodiment that is information in a signal. As such, an embodiment of the claims read on non-statutory subject matter (In re Nuijten 84 USPQ2d 1495 (2007)). The applicants may overcome the rejection by 1) amendment of the claims to be limited to physical forms of computer readable storage media described in the specification or 2) by amending the claimed subject matter to be limited to “non-transitory computer readable medium”, see the notice regarding Computer Readable Media (1351 OG 212 (23 February 2010)).
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1 and 19 being representative) is directed a method. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES] It is noted that while claims 14-15 do not fall into one of the four statutory categories, claims 14-15 are being examined under Step 2A and Step 2B in the interest of compact prosecution.
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 1 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
providing parameters, the provided parameters comprising: parameters relative to the treatment; and
applying a predicting function to the provided parameters to obtain area-under-the-concentration-over-time value at a specific time of the immunosuppressant, the predicting function being obtained by an artificial intelligence technique.
Claim 19 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
obtaining: several values of concentration of the inhibitor at different times after administration of the drug corresponding to a first parameter, and the values of difference in concentration of the inhibitor at a first given time and a second given time after administration of the drug for several couples of first given time and second given time, corresponding to a second parameter; and
applying an extreme gradient boosting technique to at least the first and second parameters to obtain area-under-the-concentration-over-time value at a specific time of the inhibitor.
The identified claim limitations falls into one of the groups of abstract ideas of mental processes for the following reasons. In this case, providing or obtaining parameters relating to treatment, including concentration values and concentration differences, can be practically performed in the mind by reading a patient record to extract information relating to concentration values, and writing the concentrations and differences via pen and paper. Furthermore, the step of applying a predicting function to provided parameters encompasses inputting parameters into a trained linear regression model (i.e. performing weighted addition), which can be practically performed in the mind aided with pen and paper.
The step of applying a predicting function, including an extreme gradient boosting technique as in claim 19, to parameters to obtain an area-under-the-concentration-over-time value recites the mathematical concept of a mathematical calculation. MPEP 2106.04(a)(2) I. C. states a mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. Here, the claims use mathematical methods (gradient boosting) to calculate an area under the curve of a concentration-time plot.
Dependent claims 2-18 and 20 further recite an abstract idea and/or are part of the abstract idea of claims 1 and . Dependent claim 2 further limits the process in which the prediction function of claim 1 was previously obtained, and thus is part of the abstract idea of applying the predicting function of claim 1. Dependent claim 3 further limits the mathematical concept of applying the prediction function to apply a gradient boosting technique. Dependent claims 4-9 and 20 further limit the parameters of claims 1 and 19, and thus are part of the abstract idea of providing parameters and applying the prediction function to the parameters. Dependent claims 10-12 and 16-18 further limit step of applying the prediction function to obtain an area-under-the-concentration-over-time value for the recited immunosuppressants, and thus are part of the abstract idea of claim 1. Dependent claim 13 recites the same abstract idea as discussed above for claim 1, and further requires performing this abstract idea on multiple patients. Claims 14-15 recite the same abstract idea as discussed above for claim 1. Therefore, claims 1-20 recite an abstract idea. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Claims 1-13, 16-18, and 20 do not recite any elements in addition to the abstract idea, and therefore are part of the abstract idea.
The additional elements of claims 14-15 include:
a computer program product comprising computer program instructions (claim 14); and
computer-readable medium comprising computer program instructions (claim 15).
The additional element of claim 19 includes:
administration of a dose of the inhibitor, the inhibitor being a calcineurin inhibitor, a m-TOR inhibitor or an inosine monophosphate dehydrogenase inhibitor
The additional elements of a computer-readable medium in claims 14-15 only serve to add general purpose computer components after the fact to the abstract idea of claim 1. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
The additional element of claim 19 of administering a dose only serves to collect information for use by the abstract idea in determining the area-under-the-concentration-over-time-curve and therefore amounts to insignificant extra-solution activity that does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Therefore, the additionally recited elements merely invoke computers as a tool and/or amount to insignificant extra-solution activity and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1-20 are directed to an abstract idea. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Claims 1-13, 16-18, and 20 do not recite any elements in addition to the abstract idea, and therefore are part of the abstract idea. The additional elements of claims 14-15 and 19 are outlined above under Step 2A, Prong 2.
The additional elements of a computer-readable medium in claims 14-15 only serve to add general purpose computer components after the fact to the abstract idea of claim 1. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
The additional element of administering a calcineurin inhibitor, a m-TOR inhibitor or an inosine monophosphate dehydrogenase inhibitor is well-understood, routine, and conventional. This position is supported by Zaza et al. (Effects of Antirejection Drugs on Innate Immune Cells After Kidney Transplantation, 2019, Frontiers in Immunology, 10:2978, pg. 1-10). Zaza reviews effects of currently used immunosuppressive agents on innate immune responses in kidney transplantation (Abstract), and discloses that the main immunosuppressive agents employed in the maintenance phase of kidney transplantation include calcineurin inhibitors and mycophenolate mofetil (i.e. a dehydrogenase inhibitor as evidenced by Applicant’s specification at pg. 16, lines 1-2, and mTOR inhibitors (pg. 2, col. 1, para. 2).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea (and/or natural correlation) without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 4-5, 9-10, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (2020) in view of Niel (2018).
Cited references:
Lu, US 20230119698 A1, effectively filed 23 March 2020 based on priority to U.S. Provisional App. No. 62/993,639; and
Niel et al., Artificial intelligence improves estimation of tacrolimus area under the concentration over time curve in renal transplant recipients, 2018, Transplant International, 31: pg. 940-941; cited in IDS filed 24 April 2023.
Regarding claim 1, Lu discloses a method of predicting a pharmacokinetic parameter of an agent administered to a subject (Abstract), comprising the following steps:
Lu discloses providing time-series concentration data of the agent (i.e. parameters relative to the treatment) obtained from a subject ([0009]; [0068]; FIG. 2).
Lu discloses using a machine learning model (i.e. a predicting function obtained by an artificial intelligence technique) to predict pharmacokinetic parameters comprising AUC, which refers to an area of a curve that describes variation of a drug concentration in subject blood plasma as a function of time post administration (i.e. area-under-the-concentration-over-time value at a specific time) ([0034]-[0035]; [0042]).
Further regarding claim 1, Lu does not disclose the following limitations:
Lu does not disclose the agent is an immunosuppressant.
However, Niel discloses a method for using artificial intelligence to improve estimations of area under the concentration over time curve of a calcineurin inhibitor, tacrolimus, (i.e. an immunosuppressant) in renal transplant recipients (title; pg. 940, col. 1, para. 1). Niel discloses that tacrolimus has a narrow therapeutic window, which makes regular drug monitoring necessary, and that AUC calculations are costly, as they may require up to 8 sequential blood samples (pg. 940, col. 1, para. 1). Niel discloses that the use of artificial intelligence is a cheap and easy way to obtain AUC values (pg. 940, col. 2, para. 4).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Lu to have predicted the AUC for a calcineurin inhibitor (immunosuppressant), as shown by Niel above. One of ordinary skill in the art would have been motivated to combine the methods of Lu and Niel to facilitate regular drug monitoring of tacrolimus, which as a narrow therapeutic window, at a reduced cost, as shown by Niel (pg. 940, col. 1, para. 1; pg. 940, col. 2, para. 4). This modification would have had a reasonable expectation of success given Lu discloses the agent may be a drug or biologic ([0019]), and thus the method of Lu is applicable to the immunosuppressant of Niel.
Regarding the dependent claims:
Regarding claim 2, Lu discloses the artificial intelligence technique comprises machine learning or deep learning such as neural networks ([0035]), and therefore, Lu discloses alternative embodiments in which a machine learning model that is not a neural network is used.
Regarding claim 4, Lu discloses the parameters relative to the treatment comprise time-series concentration data (i.e. several values of concentration of the drug at different times after administration) (([0009]; [0068]; FIG. 2).
Regarding claim 5, Lu does not explicitly disclose the parameters comprises the values of difference in concentration between two time points for several pairs of time points.
However, as discussed above, Lu does disclose obtaining time-series concentration data of the agent obtained from a subject ([0009]; [0068]; FIG. 2), and then inputting the time-series concentration into the machine learning model to predict the AUC ([0034]-[0035]; [0042]). Lu demonstrates this time-series concentration values represent differences in concentration between each pair of two adjacent time points (FIG. 2-FIG. 3), thus demonstrating the equivalence of time-series concentration data and values of difference at a first and second time. Therefore, the time-series concentration values are considered values of difference at a first time and a second time.
Therefore, obtaining values of difference in addition to several values of concentration at different times (e.g. time-series data) is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to inputting time-series values representing the values of difference, shown by Lu. Therefore, the use of time-series concentration data, shown by Lu, would perform equally as well in predicting an AUC and such a modification fails to patentably distinguish over Lu.
Regarding claim 9, Lu further discloses the machine learning model takes only the time-series concentration data as input ([0080]; FIG. 5)
Regarding claim 10, Lu in view of Niel make obvious the agent is a calcineurin inhibitor, as applied to claim 1 above.
Regarding claim 13, Lu in view of Niel make obvious the method of claim 1 as applied above. Lu further discloses the method may be applied to a cohort of subjects ([0062]; [0068]).
Regarding claims 14-15, Lu discloses the method may be implemented into a computer-readable medium storing instructions for performing the method ([0129]).
Regarding claim 16, Lu in view of Niel make obvious the agent is a tacrolimus, as applied to claim 1 above.
Therefore, the invention is prima facie obvious.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Niel as applied to claim 1 above, and further in view of Wang (2019).
Cited reference: Wang et al., In Silico Prediction of Human Intravenous Pharmacokinetic Parameters with Improved Accuracy, 2019, J. Chem. Inf. Model, 59(9), pg. 3968-3980.
Regarding claim 3, Lu in view of Niel disclose the method of claim 1 as applied above.
Further regarding claim 3, Lu in view of Niel do not disclose the artificial intelligence technique comprises a gradient boosting technique.
However, similar to Lu, Wang discloses a method for the in-silico prediction of intravenous pharmacokinetic parameters (Abstract), which comprises training and applying XGBoost, an “extreme gradient boosting” approach to predict various pharmacokinetic parameters based on numerical input data (pg. 3970, col. 1, para. 2; Figure 2). Wang discloses XGBoost is a powerful machine learning technique whose learning procedure consecutively fits new models to provide a more accurate estimate of a response variable, and which adds regular items to its cost function to control model complexity (pg. 3970, col. 1, para. 2), and further discloses this model outperformed previously published models (pg. 3969, col. 1, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the machine learning model of Lu in view of Niel, as applied to claim 1 above, to have used an XGBoost machine learning as shown by Wang above. One of ordinary skill in the art would have been motivated to combine Lu in view of Niel with Wang in order to provide an accurate estimate of the response variable of a PK parameter, while controlling model complexity, as shown by Wang (pg. 3970, col. 1, para. 2; pg. 3969, col. 1, para. 2). This modification would have had a reasonable expectation of success given both Lu and Wang use machine learning techniques to predict PK parameters.
Therefore, the invention is prima facie obvious.
Claim 6-8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Niel as applied to claim 1 above, and further in view of Ren (2009).
Cited reference: Ren et al., Prediction of mycophenolic acid exposure in renal transplantation recipients by artificial neural network, 2009, Acta Pharmaceutica Sinica, 44(12), pg. 1397-1401; cited in IDS filed 24 April 2023.
Regarding claims 6-8 and 11, Lu in view of Niel disclose the method of claim 1 as applied above.
Regarding claims 6-7, Lu in view of Niel as applied to claim 1 above do not disclose the parameters comprise parameters relative to the subject, and the parameters relative to the treatment comprise the dose administered.
Regarding claim 8¸ Lu in view of Niel as applied to claim 1 above do not disclose the treatment includes a transplantation of an organ to the subject, and the parameters relative to the treatment comprise the delay between a request of assessment of the area-under-the-concentration-over-time curve of an immunosuppressant and the transplantation.
Regarding claim 11, Lu in view of Niel as applied to claim 1 above do not disclose the immunosuppressant is a inosine monophosphate dehydrogenase inhibition.
However, regarding claims 6-8 and 11, Ren discloses a method for using machine learning to predict mycophenolic acid (MPA) AUC values in renal transplantation recipients the treatment includes a transplantation to the subject) receiving mycophenolate moefetil (i.e. an inosine monophosphate dehydrogenase inhibitor) (Abstract), which comprises obtaining parameters of post transplantation days (i.e. the delay), the daily dose of the drug (i.e. the dose administered), and patient weight (i.e. parameter relative to the subject) (Tables 1-2; Figure 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lu to have obtained parameters of the dose administered of an inosine monophosphate dehydrogenase inhibitor, the delay, and patient weight, as shown by Ren above. One of ordinary skill in the art would have been motivated to combine the methods of Lu and Ren in order to provide additional input parameters to the machine learning model to facilitate the AUC prediction of an inosine monophosphate dehydrogenase inhibitor, as shown by Ren (Figure 2; Table 3). This modification would have had a reasonable expectation of success given both Lu in view of Wang and Ren use machine learning methods to predict AUC of a drug.
Therefore, the invention is prima facie obvious.
Claim 12 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lu in view of Niel as applied to claim 1 above, and further in view of Wong (2017).
Cited reference: Wong et al., Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation, 2017, Expert Opinion on Emerging Drugs, 22(2), pg. 123-136.
Regarding claims 12 and 17-18, Lu in view of Niel disclose the method of claim 1 as applied above.
Regarding claims 12 and 17-18, Lu in view of Niel, as applied to claim 1 above, do not disclose the immunosuppressant is a m-TOR inhibitor, ciclosporin, or sirolimus, respectively.
However, Wong reviews emerging drugs for preventing rejection in liver and kidney transplantation (Abstract), and discloses existing treatments comprise mTOR inhibitors, which include sirolimus (pg. 126, col. 1, para. 2) and cyclosporine (pg. 125, col. 1, para. 2-4).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the agent of Lu to have been an mTOR inhibitor of sirolimus or cyclosporin, as shown by Wong above. One of ordinary skill in the art would have been motivated to substitute the agent of Lu to have been an mTOR inhibitor of sirolimus or cyclosporin as shown by Wong, given an mTOR inhibitor of sirolimus and cyclosporin are known in the art as an immunosuppressant for transplant recipients, as shown by Wong (Abstract; pg. 124, col. 1., section 3. “Existing treatment”), and Lu discloses the agent may be a drug or biologic ([0019]), such that the drugs of Wong could have been predictably used in the method of Lu to obtain an AUC prediction for an mTOR inhibitor of sirolimus or cyclosporin, thus predictably resulting in the reduced cost of determining AUC values as shown by Niel (pg. 940, col. 1, para. 1; pg. 940, col. 2, para. 4).
Therefore, the invention is prima facie obvious.
Claims 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (2020) in view of Ren (2009) and Wang (2019).
Cited references:
Lu, US 20230119698 A1, effectively filed 23 March 2020 based on priority to U.S. Provisional App. No. 62/993,639;
Ren et al., Prediction of mycophenolic acid exposure in renal transplantation recipients by artificial neural network, 2009, Acta Pharmaceutica Sinica, 44(12), pg. 1397-1401; cited in IDS filed 24 April 2023; and
Wang et al., In Silico Prediction of Human Intravenous Pharmacokinetic Parameters with Improved Accuracy, 2019, J. Chem. Inf. Model, 59(9), pg. 3968-3980.
Regarding claim 19, Lu discloses a method of predicting a pharmacokinetic parameter of an agent administered to a subject (Abstract), comprising the following steps:
Lu disclose administering an agent to the subject ([0005]; [0024])
Lu discloses obtaining time-series concentration data (i.e. several values of concentration at different times) of the agent obtained from a subject ([0009]; [0068]; FIG. 2).
Lu discloses using a machine learning model (i.e. a predicting function obtained by an artificial intelligence technique) to predict pharmacokinetic parameters comprising AUC, which refers to an area of a curve that describes variation of a drug concentration in subject blood plasma as a function of time post administration (i.e. area-under-the-concentration-over-time value at a specific time) ([0034]-[0035]; [0042]).
Further regarding claim 19, Lu does not disclose the following limitations:
Regarding claim 19, Lu does not disclose the agent is an inhibitor being an inosine monophosphate dehydrogenase inhibitor.
However, Ren discloses a method for using machine learning to predict mycophenolic acid (MPA) AUC values in renal transplantation recipients receiving mycophenolate moefetil (i.e. an inosine monophosphate dehydrogenase inhibitor) (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the agent of Lu to have been an inosine monophosphate dehydrogenase inhibitor, as shown by Ren above. One of ordinary skill in the art would have been motivated to substitute the agent of Lu to have been an inosine monophosphate dehydrogenase inhibitor, as shown by Ren, given an inosine monophosphate dehydrogenase inhibitor is known in the art as an immunosuppressant for transplant recipients, as shown by Ren (Abstract), and Lu discloses the agent may be a drug or biologic ([0019]), such that the drug of Ren could have been predictably used in the method of Lu to obtain an AUC prediction for an inosine monophosphate dehydrogenase inhibitor.
Regarding claim 19, Lu does not explicitly disclose obtaining second parameters of the values of difference in concentration in addition to the first parameter, and applying the machine learning to both the first and second parameters.
However, Lu does disclose obtaining time-series concentration data of the agent obtained from a subject ([0009]; [0068]; FIG. 2), and then inputting the time-series concentration into the machine learning model to predict the AUC ([0034]-[0035]; [0042]). Lu demonstrates this time-series concentration values represent differences in concentration between each pair of two adjacent time points (FIG. 2-FIG. 3), thus demonstrating the equivalence of time-series concentration data and values of difference at a first and second time.
Therefore, obtaining values of difference, in addition to several values of concentration at different times (e.g. time-series data), is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to inputting only time-series values representing the values of difference, shown by Lu. Therefore, the use of time-series concentration data, shown by Lu, would perform equally as well in predicting an AUC and such a modification fails to patentably distinguish over Lu.
Furthermore, the courts have found the mere duplication of parts has no patentable significance unless a new and unexpected result is produced. See MPEP 2144.04 B. Therefore simply duplicating the information of the time-series concentration data of Lu to in the form of differences is not sufficient to overcome the prior art.
Regarding claim 19, Lu in view of Ren do not disclose the machine learning model is an extreme gradient boosting technique.
However, similar to Lu, Wang discloses a method for the in-silico prediction of intravenous pharmacokinetic parameters (Abstract), which comprises training and applying XGBoost, an “extreme gradient boosting” approach to predict various pharmacokinetic parameters based on numerical input data (pg. 3970, col. 1, para. 2; Figure 2). Wang discloses XGBoost is a powerful machine learning technique whose learning procedure consecutively fits new models to provide a more accurate estimate of a response variable, and which adds regular items to its cost function to control model complexity (pg. 3970, col. 1, para. 2), and further discloses this model outperformed previously published models (pg. 3969, col. 1, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the machine learning model of Lu to have used an XGBoost machine learning as shown by Wang above. One of ordinary skill in the art would have been motivated to combine Lu with Wang in order to provide an accurate estimate of the response variable of a PK parameter, while controlling model complexity, as shown by Wang (pg. 3970, col. 1, para. 2; pg. 3969, col. 1, para. 2). This modification would have had a reasonable expectation of success given both Lu and Wang use machine learning techniques to predict PK parameters.
Regarding claim 20, Lu further discloses obtaining parameters including the age of the subject ([0073]).
Further regarding claim 20, Lu does not disclose the treatment includes a transplantation of an organ to the subject and during the step of obtaining, other parameters are obtained comprising the dose administered and a delay between a request of assessment of the area-under-the-concentration-over-time curve, the transplantation.
However, Ren discloses a method for using machine learning to predict mycophenolic acid (MPA) AUC values in renal transplantation recipients receiving mycophenolate moefetil (i.e. the treatment includes a transplantation to the subject) (Abstract), which comprises obtaining parameters of post transplantation days (i.e. the delay), the daily dose of the drug, and patient age (Tables 1-2; Figure 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lu to have further obtained parameters of a dose and the delay, as shown by Ren above. One of ordinary skill in the art would have been motivated to combine the methods of Lu and Ren in order to provide additional input parameters to the machine learning model to facilitate the AUC prediction, as shown by Ren (Figure 2; Table 3). This modification would have had a reasonable expectation of success given both Lu in view of Wang and Ren use machine learning methods to predict AUC of a drug.
Therefore, the invention is prima facie obvious.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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