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 .
Claims 10-26 are cancelled.
Applicant’s election without traverse of Group I, claims 1-9, in the reply filed on 04/22/2026 is acknowledged. In the interest of advancing prosecution, the species election requirement regarding claim 5, as set forth in the Restriction Requirement dated 10/30/2025, is withdrawn.
Claims 1-9 are pending and under examination on the merits.
Priority
This application claims priority to US Provisional Application No. 63/436,978, filed 01/04/2023, and is a CON of PCT/US21/50465, filed 09/15/2021, which claims priority to US Provisional Application No. 63/078,672, filed 09/15/2020.
IDS
The information disclosure statement (IDS) filed 07/07/2023 has been considered.
Drawings
The drawings are objected to because the conditions of Figures 8 and 9 as filed on 03/09/2023 and Figure 14 as filed on 05/12/2023 are indistinguishable. In figure 8, the conditions of KLKB1+ inotrope trope therapy, KLKB1, and inotrope therapy are indistinguishable from one another. In figure 9, the conditions of KLKB1+ inotrope therapy, CVP/PCWP, MELD, and radial score are indistinguishable from one another. In figure 14, the label conditions are too pixelated to be clearly read and the figure does not permit for disguising the conditions from one another. 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.
Claim Interpretation
Regarding recitations of measuring a level of one or more PGD biomarkers (such as KLKB1), no measurement steps are recited and no comparison/reference/control/reference value/baseline is disclosed or recited. Therefore, any means of measuring one or more PGD biomarkers and any comparison/reference/control/reference value/baseline will be interpreted to meet the generic recitation of the claims as drafted, in the interest of advancing compact prosecution.
Recitations of a “subject” are being interpreted such that the subject is the recipient, not the donor. It is important to know whether the subject is the transplant-recipient or the organ-donor in order to know the metes and bounds of the claims as well as how to practice the claims. The specification never provides a clear and closed definition of the subject so as to unambiguously indicate whether the sample taken is from the organ-donor or the transplant-recipient or whether the additional therapy is given to the organ-donor or transplant-recipient. In the interest of advancing clear prosecution of the claims, the Examiner is interpreting the subject to mean the recipient such that samples are taken from the transplant-recipient prior to transplantation and additional therapies are given to the transplant-recipient before or after the transplant. This is consistent with a full reading of the specification. The instant specification supports this interpretation at, for example, lines 9-17 of page 18. Logically, it would only make sense that administration of a therapy to the transplant-recipient, not the organ-donor, would reduce PGD risk post-transplant.
Where ‘assessing’ is recited in claim 2, the effect of a therapy administered prior to sampling and performance of the method of claim 1 is understood to be assessed and the effect of a therapy administered after sampling and performance of the method of claim 1 is understood to be predicted (as there is no affect to assess where the therapy has not yet been given). As no step for “assessing” or the implied predicting is provided in the claim, the step is understood to be accomplished by performing the steps of claim 1, where the assessing/predicting is merely a mental step of analyzing the result/data obtained in the method of claim 1.
Claim 4 is understood to mean that the subject’s medical history regarding having had or not having had pre-transplant inotrope therapy is obtained by any reasonable means, such as by asking the subject or referring to the medical record for said subject.
Claim Objections
Claim 1 is objected to because of the following informalities: “Collecting” in line 3 should not be capitalized as the claim should read as a single sentence (see MPEP §608.01(m)). Appropriate correction is required.
35 U.S.C. 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 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extra solution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to mathematical concepts.
Claim 1 is directed to a method for identifying risk of primary graft dysfunction (PGD) of a subject comprising: Collecting a sample of the subject; measuring a level of a PGD marker from the sample, wherein the PGD marker comprises plasma kallikrein (KLKB 1); providing a PGD risk value that is quantified based on the level of the PGD marker using an adaptive Monte Carlo cross-validation (MCCV) model; and identifying the risk of PGD based on the PGD risk value.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
YES-Claim 1 is directed to a method which is a process.
Step 2A – Prong I: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
YES- Claim 1 includes correlating a measured level of KLKB1 with a PGD risk (a natural phenomenon) and use of a MCCV model (an abstract idea). The claim language reciting the judicial exception is found in exemplary lines 6-7.
Step 2A – Prong II: Does the claim integrate the judicial exception into a practical application?
NO- Here, the instant claim 1 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B- Does the claim recite additional elements that amount to significantly more than the judicial exception?
NO-The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
The generic recitation of measuring a KLKB1 level from a sample amounts to no more than mere data gathering steps and does not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in lines 6-7.
Claims 2-9 incorporate, via dependency, the judicial exceptions recited in claim 1 and are therefore included in this rejection.
Claim 2 recites assessing an effect of a therapy on the heart transplant by estimating the PGD risk value (this appears to recite a further judicial exception by reciting the natural phenomenon of the biomarker (KLKB1) as correlated with a PGD risk value which is further correlated with assessed effect of a therapy administered prior to the method of claim 1 or afterwards. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps are added by claim 2 so as to add significantly more.
Claim 3 recites identifying a clinical variable, which is a medical history of the subject. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. Identifying a medical history (such as by asking the patient or by referring to the electronic medical record of the patient) in the course of treatment/transplant evaluation of a patient amounts to no more than mere data gathering and does not add significantly more.
Claim 4 recites that the medical history comprises a pre-transplant inotrope therapy. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. Identifying a medical history of pre-transplant inotrope therapy (such as by asking the patient or by referring to the electronic medical record of the patient) in the course of treatment/transplant evaluation of a patient amounts to no more than mere data gathering and does not add significantly more.
Claim 5 recites further measuring a level of an additional biomarker from the sample, from a closed group. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. The measurement of a further biomarker, generically recited amounts to no more than mere data gathering.
Claim 6 recites quantifying the PDG risk value based on the level of KLKB1 and the additional biomarker recited in claim 5 (therefore adding a new natural phenomenon of the correlation of the additional biomarker and PGD risk, which is a further judicial exception). There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. The measurement of a further biomarker, generically recited amounts to no more than mere data gathering.
Claim 7 further recites that the MCCV model has a training set for machine learning for continuous evolution (this is an abstract idea and represents a further judicial exception). There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. The recitation is merely a judicial exception which cannot add significantly more.
Claim 8 recites providing an additional therapy to the subject based on the PGD risk value. The recited step of providing an additional therapy is so generic that it fails to integrate the claim or to add significantly more. This amounts to no more than a suggestion to apply the judicial exceptions of claim 1 (see MPEP §2106.05(f)).
Claim 9 narrows that the additional therapy of claim 8 comprises KLKB1 activators, anti-inflammatory agents, or combinations thereof. The recited step of providing an additional therapy comprising KLKB1 activators, anti-inflammatory agents, or combinations thereof is so generic that it fails to integrate the claim or to add significantly more. This amounts to no more than a suggestion to apply the judicial exceptions of claim 1 (see MPEP §2106.05(f)).
Therefore, claims 1-9 are rejected under 35 USC §101 as being directed towards patent ineligible natural phenomena and abstract ideas, failing to integrate or add substantially more so as to transform the metes and bounds of the claims into subject matter eligible for patentability.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-9, it is unclear what value the PGD biomarker(s) is/are being compared to and whether an increased or decreased value/expression level is correlated so as to identify an increased/decreased PGD risk value which is the same as identifying the risk of PGD. Artisans are left to dispute whether an increased or decreased level of the one or more PGD biomarkers correlates with an increased/decreased PGD risk value such that the metes and bounds of the claims are ambiguous. Furthermore, artisans are left to dispute the reference point for comparison of the measured level of the one or more PGD biomarkers (a healthy control value, a value pulled from the literature as indicating a high, low, or average risk, etc.). The claims are so vague that they function more as a suggestion to the artisan to invent the method rather than to convey the metes and bounds of what Applicant invented.
Regarding claim 2, the claim recites the limitation "the heart transplant" in line 2. There is insufficient antecedent basis for this limitation in the claim. This issue makes it unclear what is necessarily included or excluded by the language of claim 2 because no heart transplant is explicitly referred to by the language of claim 1, from which claim 2 is dependent. Thus it is unclear how the limitations of claim 2 are applicable to the claimed method when there is no prior context regarding a heart transplant.
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.
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 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Perrot et al (US 20130029873 A1; as cited in the 07/07/2023 IDS at US Patent Document 6) in view of Shah et al (Plasma Complement Levels Are Associated with Primary Graft Dysfunction and Mortality after Lung Transplantation (to the editor), Am J Respir Crit Care Med. 2014 Jun 15;189(12):1564-7. doi: 10.1164/rccm.201312-2121LE.), Brodksy (Blood (2015) 126 (22): 2459–2465; https://doi.org/10.1182/blood-2015-06-640995), and Pelliccia, D. (K-fold and Montecarlo cross-validation vs Bootstrap: a primer, NIRPY Research, obtained from: h ttps://nirpyresearch.com/kfold-montecarlo-cross-validation-bootstrap-primer/ (2019)).
Regarding claim 1, Perrot et al teach a method for identifying (assessing) the risk of primary graft dysfunction (PGD) in a subject (see for example, the title and paragraphs 002, 004, and 0035 at pages 1-2). The method comprises measuring the level of 1 of more biomarkers (genes, gene expression levels, and/or pattern of gene expression levels) useful for predicting risk of PGD and comparing the measured level from a sample to a reference level/profile (see for example, paragraph 0035 at page 2). Perrot further teaches that the method comprises providing a PGD risk value based on the level of the PGD biomarker (see for example, paragraphs 0002-0005, 0035, 0078, 0111, 0195, and 0205, 0232-0233 at pages 1-2, 6-8, 11, and 20). Perrot et al teach that PGD on arrival in the ICU was defined according to the ISHLT criteria (see for example, paragraphs 0202 and 021+) and ISHLT criteria refers to the definition of primary graft dysfunction established by the International Society for Heart and Lung Transplantation (see for example, paragraph 0044).
Perrot et al do not teach measurement of KLKB1.
However, Shah et al teach that, in animal models, activation of the complement system during lung ischemia and reperfusion can lead to cellular injury and lung allograft failure, and supported that plasma levels of C3a, C4a, and C5a would be associated with both PGD and mortality after lung transplantation (see for example, column 2 of page 1564, column 1 of page 1565, and page 1566).
Shah et al do not teach that c3a, c4a, or c5a are connected to KLKB1.
However, Brodsky teaches that kallikrein that directly cleaves C3 and its activation fragments and that all of the activating pathways converge to form C3 convertases. Cleavage of C3 yields C3a and C3b, the latter of which triggers the formation of the C5 convertase. The C5 convertase cleaves C5 into C5a and C5b (see for example, column 1 of page 2459 and Figure 1 and its caption at page 2460).
The combined references do not teach the use of MCCV.
However, Pelliccia teaches that Cross-Validation (CV) is a standard procedure to quantify the robustness of a regression model. The basic idea of CV is to test the predictive ability of a model on a set of data that has not been used to build that model (see for example, paragraph 1). To quantify the robustness of a regression model with a single dataset — i.e. without an independent test set — requires splitting the available data into two or more subsets, so that model fitting and prediction can be performed on independent subsets. This typical strategy can be implemented in various ways, all aimed at avoiding overfitting. Overfitting refers to the situation in which the regression model is able to predict the training set with high accuracy, but does a terrible job at predicting new, independent, data. In other words, the model is mostly built on features that are specific to training set, with can bear little correlation with new data. A cross-validation strategy avoids or mitigates this occurrence (see for example, page 3). K-Fold and Montecarlo give quite comparable performances. If anything Montecarlo tends to be a bit more repeatable (less variance) due to the fact that we have enough samples to generate statistically different splits. The bias however is generally higher than the corresponding value for K-Fold. This thing is well known in machine learning. In fact it’s got a name: it’s called Bias-Variance tradeoff (see for example, pages 12-13).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to because Perrot et al teach a method of determining a PGD risk value based upon the measured level of a PGD biomarker, where Shah et al in view of Brodksy motivate the artisan to modify the method of Perrot et al to use KLKB1 as the PGD biomarker as higher relative KLKB1 levels increase downstream C5a levels, which are associated with an increased risk/incidence of PGD. The art further motivates modification of the method of Perrot et al to use an MCCV model because MCCV machine learning using a training set is a repeatable means for testing the predictive ability of a model on a set of data that has not been used to build that model as taught by Pelliccia. Where Perrot et al use IHLT criteria for determining PGD, the artisan would have understood the method of Perrot et al for predicting PGD risk to be applicable to PGD in the setting of either lung transplant or heart transplant. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 7, as discussed above, the combined references make obvious the method of claim 1 using MCCV, where Pelliccia teaches that MCCV is a machine learning model that uses a training (train) set with higher variance than the k-fold model regarding the bias-variance tradeoff. There is no definition of a continuously evolving system provided in the instant disclosure. The closest definition of the open and exemplary statement that the processor can include a machine learning program, which can mitigate confounding in biological enrichment analyses and improve predictive accuracy with modest population size and/or the MCCV model can be improved by providing a training set for machine learning, etc. (see for example page 31 of the instant specification. Therefore, the machine learning MCCV model of Pelliccia which is a standard procedure to quantify the robustness of a regression model/ test the predictive ability of a model on a set of data that has not been used to build that model using machine learning and a training set to maximize variance for higher repeatability is understood to meet the definition of a continuously evolving system as presently drafted.
Claim(s) 2-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Perrot et al in view of Shah et al, Brodksy, and Pelliccia, D. as applied to claim(s) 1 and 7 above, in further view of Singh et al (Heart Failure Reviews (2019) 24:805–820 https://doi.org/10.1007/s10741-019-09794-1; citation 20 under NPL on the 07/07/2023 IDS).
Regarding claim 2, from the plain language of the claim as presently drafted, it is clear that the recitation of assessing an effect of a therapy on a heart transplant is accomplished by estimating the PGD risk value of the subject which is part of the method of claim 1. This is not a separate active step as drafted, but represents a mental step made using the data from the method of claim 1 where the subject has wither had a therapy prior to the transplant or will receive therapy after the transplant (in which case, the recitation of assessing is understood to mean predicting the effect of the therapy on the transplant as it is impossible to assess the effect of a therapy which has yet to be administered). As discussed above, the combined references make obvious they limitations of instant claim 1. Note that no step of resample, such as after both the heart-transplant and the subsequent administration of the therapy is recited.
The combined references do not teach or suggest measurement of a PGD risk value for assessing the effect of a therapy given prior to heart transplant.
However, Singh et al teach that, in the setting of PGD after heart transplant, pre-operative recipient ECMO/VAD (mechanical support) usage has also been linked to PGD post-operatively (see for example, page 809, column 1). Additionally, studies have indicated a dose-dependent or duration dependent link between amiodarone (a class III antiarrhythmic used for a variety of arrhythmias including both ventricular, supraventricular and atrial tachyarrhythmias) use and PGD post-transplant (see for example, column 1 of page 810).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to because the prior art reference in combination make obvious the method of claim 1, where the artisan would understand the desirability of assessing the effect of a therapy given before transplant, that effect being the determined PGD risk value for a number of potential reasons (such as comparison of the PGD risk value in a control subject not given the therapy for experimental purposes or to determine the safety/utility of proceeding with a heart transplant in the subject), where Sing et al teach that certain therapies, such as mechanical support and antiarrhythmics administered pre-operatively after linked to post-operative PGD development/risk/status. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 3 and 4, note that the disclosure fails to provide a clear and closed definition of the terms ‘clinical variable’ and ‘medical history’, therefore, simply asking the recipient for their date of birth, name, address, or any other question would meet the limitation as drafted. Singh et al teach that some recipient factors may also predispose a patient to PGD, such as having been on inotropic support (inotrope therapy) and mechanical devices (see for example, the Recipient factors section of column 1 of page 808).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to ask or otherwise find out if the recipient (subject) had pre-transplant inotrope therapy and/or mechanical support in order to better understand that recipient’s unique risk factors for developing PGD post-transplant as taught by Singh et al. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 5-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Perrot et al in view of Shah et al, Brodksy, and Pelliccia, D. as applied to claim(s) 1 and 7 above, in further view of Li et al (RSC Adv.,2019, 9,10264-10271; DOI: 10.1039/c9ra00425d (2019)).
Regarding claim 5, as discussed above, Perrot, Brodksy, Shah et al, and Pelliccia make obvious claim 1.
The combined references do not teach the connection of troponin to PGD.
However, Li et al teach that while, the etiology of PGD is multifactorial but remains incompletely understood, ischemia/reperfusion (I/R) injury has been proposed as common risk factors for PGD. Recently, extracellular histones have been characterized as key mediators of I/R injuries in many organs including the liver, kidney, heart, and brain. Extracellular histones increase remarkably after I/R injury, which are either released passively by stressed or injured cells, or are actively secreted by innate immune cells (e.g. neutrophils, monocytes/macrophages). Extracellular histones not only correlate with disease severity and poor outcomes, which can reflect ongoing cellular damage or the inflammatory states, but also serve as a therapeutic target for I/R injury. Targeting extracellular histones attenuates the I/R injury of many organs (see for example, page 10264). Li et al further teach that it is known that the process of I/R recruits neutrophils and activated macrophages that exaggerate organ inflammation, tissue injury and malfunction. MPO activity is an index of neutrophil, monocyte/macrophage activation, whereas S100A8/A9, which is abundantly stored in neutrophil cytoplasm, is another classical marker for neutrophil activation.21,22 Therefore, Li et al assayed both MPO and S100A8/A9 levels to assess activation of innate immune cells particularly neutrophils, in the sera of patients undergoing liver transplantation using commercially available kits (see for example, column 2 of page 10265). There was also a positive correlation between extracellular histones and MPO (r= 0.5262, p= 0.003) and S100A8/A9 (r= 0.4738, p= 0.015) (see for example, section 3.3 at column 2 of page 10266).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to measure/assay the level of MPO in the recipient as an indirect measure of extracellular histones and of activation of innate immune cells particularly neutrophils because Li et al teach that extracellular histones are positively correlated with MPO (allowing for MPO measurement using commercially available kits to act as an indirect measure of extracellular histones and as a predictor of innate immune activation) where Li et al observed that compared with patients without PGD, patients with PGD had significantly higher levels of extracellular histones after transplantation, thereby suggesting the likelihood that extracellular histones are an important cause for PGD (see the above cited teachings as well as exemplary column 2 of page 10268). Li et al further teach they detected a remarkable immune cell activation and a significant inflammatory response during the course of transplantation. There was a clear correlation between extracellular histones and immune cell activation and systemic inflammation, which was consistent with previous reports that extracellular histones can promote systemic inflammation through activation of immune cells particularly neutrophils (see for example, column 2 of page 10268). Therefore, measurement of MPO allows for convenience of commercial kit use and allows for data gathering regarding extracellular histone levels and innate immune activation, both of which are linked to the development/pathogenesis of PGD after transplant. While Li et al focus on liver transplant, they mention that the driving force being investigated for causing PGD is I/R injury, which has been observed in a number of organs, including the heart (as discussed above). The artisan would have found it obvious to measure/assay for MPO as part of the methods resulting from Perrot et al, Brodksy, Shah et al, and Pelliccia to have a more detailed and accurate method for identifying a risk of PGD. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 6, as discussed above, Perrot et al in view of Brodksy, Shah et al, and Pelliccia make obvious the method of instant claim 1 and Li et al motivates modification of the method resulting from the combination of Perrot et al in view of Brodksy, Shah et al, and Pelliccia to further incorporate measuring the level of MPO as a second biomarker linked with PGD development in order to quantify a PGD risk value as part of identifying risk of PGD in a subject where the organ being transplanted is liver, heart, lung, kidney, or brain, for example. It is noted that no particular quantification step is required so, the quantification of the prior art methods, as combined herein, would make obvious the quantification of PGD risk value based upon 2 PGD biomarkers (KLKB1 and MPO).
Claim(s) 8-9is/are rejected under 35 U.S.C. 103 as being unpatentable over Perrot et al in view of Shah et al, Brodksy, and Pelliccia, D. as applied to claim(s) 1 and 7 above, in further view of Wan et al (Ann Thorac Surg. 1996 Feb;61(2):674-8. doi: 10.1016/0003-4975(95)01059-9. PMID: 8572786).
Regarding claims 8-9, as discussed above, Perrot et al in view of Brodksy, Shah et al, and Pelliccia make obvious the method of instant claim 1.
The combined references do not teach administering an additional therapy to the subject based on the PGD risk value. It is noted that the recited additional therapy is the only therapy as no other therapy is mentioned as being administered in the method of claim 1 from which claim 8 depends.
However, Wan et al teach that in a first group of 10 patients/subjects (group I, 6 undergoing heart transplant (HTx) and 4 undergoing heart-Lung transplant (HLTx), 500 mg of methylprednisolone (understood in the art to be an anti-inflammatory steroid (as suggested by the Background and conclusions sections, for example) was first given as usual (indicating the routine and conventional procedure of administering the drug after HTx) at 1.5 hours after aortic declamping (at the end of cardiopulmonary bypass). In the next 10 patients/subjects (group II, 6 HTx and 4 HLTx), the first doses of methylprednisolone were given 1 hour before operation. In both groups, 125 mg of methylprednisolone were given every 8 hours thereafter during the first postoperative day (see for example, the methods section). Wan et al conclude that, earlier steroid administration in the immunosuppressive protocol for HTx or HLTx may be preferable to reduce the inflammatory response to cardiopulmonary bypass, as reflected by a lower production of tumor necrosis factor α and IL-8, and a greater release of IL-10 (see for example, the conclusions section).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to modify the prior art method to further comprise administering a therapy to the subject based on their PGD risk value because Wan et al teach that administration of methylprednisolone (a steroid anti-inflammatory) is conventional in the art and that administration prior to transplant is beneficial in reducing post-operative inflammation in the setting of heart transplant and/or heart-lung transplant. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
No claim is allowed.
Notice:
The prior art does not reasonably teach a method where a lower/decreased KLKB1expression is predictive or/correlated with an increased risk of developing PGD. In fact, the art teaches that a higher/increased level of KLKB1 would be is predictive or/correlated with an increased risk of developing PGD.
Synapse (Patsnap; What are KLKB1 modulators and how do they work?; pub. 06/25/2024; obtained from: https://synapse.patsnap.com/article/what-are-klkb1-modulators-and-how-do-they-work) teach that plasma kallikrein is responsible for the cleavage of high molecular weight kininogen (HMWK) to produce bradykinin (see for example, paragraph 2). Kienle et al (CA2600168 A1) teach that Kininogens are inhibitors of thiol proteases. HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII. HMW-kininogen inhibits the thrombin- and plasmin-induced aggregation of thrombocytes. the active peptide bradykinin that is released from HMW-kininogen shows a variety of physiological effects: (A) influence in smooth muscle contraction, (B) induction of hypotension, (C) natriuresis and diuresis, (D) decrease in blood glucose level, (E) it is a mediator of inflammation and causes (E1) increase in vascular permeability, (E2) stimulation of nociceptors (E3) release of other mediators of inflammation (e.g. prostaglandins), (F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action) (see for example, page 63 bridging page 64). Harmonizome 3.0 (Gene - KLKB1, obtained from: htps://maayanlab.cloud/Harmonizome/gene/KLKB1; accessed 05/29/2026) teaches that experimental reduction of prekallikrein levels yields an antithrombotic phenotype without impairing normal hemostasis, while its proteolytic activity, suggesting that higher KLKB1 levels increase thrombin. Gob et al (Ann Neurol., 77: 784-803. https://doi.org/10.1002/ana.24380) teach that plasma kallikrein (PK) cleaves high–molecular-weight kininogen to release bradykinin (BK) and is a key constituent of the proinflammatory contact-kinin system. In addition, PK can activate coagulation factor XII, the origin of the intrinsic coagulation cascade (see for example the objective subsection of the abstract) and that reduction of FXII activation probably represents a key mechanism through which PK deficiency prevents thrombus formation in vivo. Other mechanisms might include reduced generation of functional thrombin in the absence of PK (see for example, paragraph 4 of the conclusion).
However, Salvatierra et al (Circulation. 2001 Dec 11;104(24):2975-80. doi: 10.1161/hc4801.100032. PMID: 11739315) teach that anti-thrombin medications reduce prevents ischemia-reperfusion injury in a dog model of lung transplantation (see for example, the conclusion section).
Therefore, the prior art would seem to suggest that only a higher level of KLKB1 would be predictive/correlated with higher PGD risk. Alternatively, there is nothing in the prior art to reasonably suggest a method of measuring KLKB1 as predictive or correlated with PGD risk with a reasonable expectation of success, including the closest prior art, which is Perrot et al (US 20130029873 A1; as cited in the 07/07/2023 IDS at US Patent Document 6).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHLEY GAO whose telephone number is (571) 272-5695. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent
Application Information Retrieval (PAIR) system. Status information for published applications
may be obtained from either Private PAIR or Public PAIR. Status information for unpublished
applications is available through Private PAIR only. For more information about the PAIR
system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR
system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would
like assistance from a USPTO Customer Service Representative or access to the automated
information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights