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 .
Priority
Acknowledgment is made for domestic priority under 35 U.S.C.119 (e) based on the provisional applications 63/322,007 filed on 03/21/2022.
Information Disclosure Statement
The IDS dated 09/12/2023 and 11/09/2023 have been considered and placed in the application file.
Claim Objections
Claim 1 is objected to because of the following informalities: step (e) reads “where preE or active statis is assigned” the Examiner interprets that this is a spelling error and for examination purposes will interpret the limitation as “where preE or active status is assigned”. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: step (e) reads “ezetimibe, and/or fish oil or” the Examiner interprets that this is a spelling error and there are no additional limitations to be added to the claim and for examination purposes will interpret the limitations ending at “fish oil”. Appropriate correction is required.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the
plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification.
Under MPEP 2143.03, "All words in a claim must be considered in judging the patentability of that claim against the prior art." In re Wilson, 424 F.2d 1382, 1385, 165 USPQ 494, 496 (CCPA 1970). As a general matter, the grammar and ordinary meaning of terms as understood by one having ordinary skill in the art used in a claim will dictate whether, and to what extent, the language limits the claim scope. Language that suggests or makes a feature or step optional but does not require that feature or step does not limit the scope of a claim under the broadest reasonable claim interpretation. In addition, when a claim requires selection of an element from a list of alternatives, the prior art teaches the element if one of the alternatives is taught by the prior art. See, e.g., Fresenius USA, Inc. v. Baxter Int’l, Inc., 582 F.3d 1288, 1298, 92 USPQ2d 1163, 1171 (Fed. Cir. 2009).
Claim 1 recite “and/or ” then listing “method for diagnosing, predicting and/or preventing acute allograft vasculopathy”. Since “and/or” is disjunctive, any one of the elements found in the prior art is sufficient to reject the claim. While citations have been provided for completeness and rapid prosecution, only one element is required. Because, on balance, it appears the disjunctive interpretation enjoys the most specification support and for that reason the disjunctive interpretation (one of A, B OR C) is being adopted for the purposes of this Office Action. Applicant’s comments and/or amendments relating to this issue are invited to clarify the claim language and the prosecution history.
Claim 2 recite “and/or ” then listing “at least one stain specific for endothelial cells and/or connective tissues of the vascular cells and tissues.” Since “and/or” is disjunctive, any one of the elements found in the prior art is sufficient to reject the claim. While citations have been provided for completeness and rapid prosecution, only one element is required. Because, on balance, it appears the disjunctive interpretation enjoys the most specification support and for that reason the disjunctive interpretation (one of A, B OR C) is being adopted for the purposes of this Office Action. Applicant’s comments and/or amendments relating to this issue are invited to clarify the claim language and the prosecution history.
Claim 3 recite “or ” then listing “selected from CD31, CD34, CD68, or combinations thereof.” Since “or” is disjunctive, any one of the elements found in the prior art is sufficient to reject the claim. While citations have been provided for completeness and rapid prosecution, only one element is required. Because, on balance, it appears the disjunctive interpretation enjoys the most specification support and for that reason the disjunctive interpretation (one of A, B OR C) is being adopted for the purposes of this Office Action. Applicant’s comments and/or amendments relating to this issue are invited to clarify the claim language and the prosecution history.
Claim 8 recite “and/or” then listing “increased overall stromal content area in a connective tissue stained slide; increased interstitial collagen content; increased non-collagen interstitial stromal content; increased thickness of staining of individual vascular structures; increased cellularity within stained vascular structures; increased cellularity in the perivascular area immediately surrounding stained vascular structures; and/or decreased overall tissue-density of vascular structures.”. Since “and/or” is disjunctive, any one of the elements found in the prior art is sufficient to reject the claim. While citations have been provided for completeness and rapid prosecution, only one element is required. Because, on balance, it appears the disjunctive interpretation enjoys the most specification support and for that reason the disjunctive interpretation (one of A, B OR C) is being adopted for the purposes of this Office Action. Applicant’s comments and/or amendments relating to this issue are invited to clarify the claim language and the prosecution history.
Claim 12 recite “and/or” then listing “increased overall stromal content area in a Movats pentachrome stained slide; increased interstitial collagen content; increased non-collagen interstitial stromal content; increased CD31 staining of vascular structures; increased cellularity within CD31 vascular structures; increased cellularity in the perivascular area immediately surrounding CD31 vascular structures; and/or area of decreased overall vascular density.”. Since “and/or” is disjunctive, any one of the elements found in the prior art is sufficient to reject the claim. While citations have been provided for completeness and rapid prosecution, only one element is required. Because, on balance, it appears the disjunctive interpretation enjoys the most specification support and for that reason the disjunctive interpretation (one of A, B OR C) is being adopted for the purposes of this Office Action. Applicant’s comments and/or amendments relating to this issue are invited to clarify the claim language and the prosecution history.
Claim 13 recite “and/or ” then listing “(i) actively treated recipient diabetes at one-year post-transplant, (ii) recipient body mass index at one-year post transplant, (iii) recipient low-density lipoprotein at one year post-transplant, (iv) a history of high-grade cellular rejection or treated rejection in first year, (v) the percentage of biopsies in the first year with Quilty lesion, (vi) donor proteinuria, and/or (vi) donor coronary angiography score.” Since “and/or” is disjunctive, any one of the elements found in the prior art is sufficient to reject the claim. While citations have been provided for completeness and rapid prosecution, only one element is required. Because, on balance, it appears the disjunctive interpretation enjoys the most specification support and for that reason the disjunctive interpretation (one of A, B OR C) is being adopted for the purposes of this Office Action. Applicant’s comments and/or amendments relating to this issue are invited to clarify the claim language and the prosecution history.
Claim 16 recite “and/or ” then listing “one or more immunosuppressants, one or more of a statin, mycophenolate mofetil, everolimus, sirolimus, aspirin, vitamins, a PCSK-9 inhibitor, a P2y12 inhibitor, ezetimibe, and/or fish oil or. “Since “and/or” is disjunctive, any one of the elements found in the prior art is sufficient to reject the claim. While citations have been provided for completeness and rapid prosecution, only one element is required. Because, on balance, it appears the disjunctive interpretation enjoys the most specification support and for that reason the disjunctive interpretation (one of A, B OR C) is being adopted for the purposes of this Office Action. Applicant’s comments and/or amendments relating to this issue are invited to clarify the claim language and the prosecution history.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5-7 and 11-12 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 pre-AIA the applicant regards as the invention. The Examiner strongly suggested that appropriate corrections be made to clarify the claim scope.
With respect to Claim 5, the claim recites the following, each of which renders the claim indefinite:
The term “about” in claim 5 is an approximation which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
With respect to Claim 6, Claim 6 depend either directly or indirectly from the rejection of Claim 5, therefore they are also rejected. Appropriate correction is required.
With respect to Claim 7, the claim recites the following, each of which renders the claim indefinite:
“ (c) ” on line 2 (unclear antecedent basis as there is no step (c) in claim 1).
With respect to Claim 11, the claim recites the following, each of which renders the claim indefinite:
The term “about” in claim 11 is an approximation which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
With respect to Claim 12, the claim recites the following, each of which renders the claim indefinite:
“ the computer-implemented analysis of the digital EMB” on line 2 (unclear antecedent basis as there computer-implemented analysis in claim 1).
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. When reviewing independent claims 1, 18, 19, and 20 and based upon consideration of all of the relevant factors with respect to the claim as a whole, claims 1-20 are held to claim an abstract idea without reciting elements that amount to significantly more than the abstract idea and is/are therefore rejected as ineligible subject matter under 35 U.S.C. 101. The Examiner will analyze Claim 1 and similar rationale applies to independent Claim/s 18, 19, and 20. The rationale, under MPEP § 2106, for this finding is explained below:
The claimed invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception, as defined below. The following two step analysis is used to evaluate these criteria.
Step 1: Is the claim directed to one of the four patent-eligible subject matter categories: process, machine, manufacture, or composition of matter?
When examining the claim under 35 U.S.C. 101, the Examiner interprets that the claims is related to a process since the claim is directed to method.
Step 2a, Prong 1: Does the claim wholly embrace a judicially recognized exception, which includes laws of nature, physical phenomena, and abstract ideas, or is it a particular practical application of a judicial exception?
The Examiner interprets that the judicial exception applies since Claim 1 limitation of (a) analyzing clinical risk factors of a cardiac, kidney or liver transplant patient in a model which distinguishes between clinical biomarkers of allograft vasculopathy patients and non-allograft vasculopathy patients, and (b) analyzing digital biopsy images from the transplant patient to morphologically differentiate patients which are prE allograft vasculopathy or which have active allograft vasculopathy from patients without acute allograft vasculopathy; (d) assigning prE-, active or non- allograft vasculopathy status to a patient based on the outcome of (a) and (b); and (e) where preE or active statis is assigned, treating the patient is directed to an abstract idea. The claim is related to mental process, observation by analyzing of images and risk factors for different characteristics visible to the human eye. If the claim recites a judicial exception (i.e., an abstract idea enumerated in MPEP § 2106.04(a), a law of nature, or a natural phenomenon), the claim requires further analysis in Prong Two.
Step 2a, Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application?
The Examiner interprets that Claim 1 limitation does not provide additional elements or combination of additional elements to a practical application since the claims are not adding insignificant extra-solution activity to the judicial exception. Since the claim is generally linking analysis of images and risk factors to treating a patient. Specifically, the analysis method does not integrate a judicial exception into practical application. See Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B. The Examiner interprets that Claim 1 limitation does not provide additional elements or combination of additional elements to a practical application since the claims do not provide clear improvement to a technology or to computer functionality. Since the claim is generally linking analyzing images and data to come to a conclusion for diagnosis and treatment. For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B. If there are no additional elements in the claim, then it cannot be eligible. In such a case, after making the appropriate rejection, it is a best practice for the examiner to recommend an amendment, if possible, that would resolve eligibility of the claim.
Step 2b: If a judicial exception into a practical application is not recited in the claim, the Examiner must interpret if the claim recites additional elements that amount to significantly more than the judicial exception.
The Examiner interprets that the Claims do not amount to significantly more since the Claims state analyzing images and data to make a conclusion on patient treatment, which could easily be performed by a physician. See, simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well-understood, routine and conventional activities previously known to the industry, as discussed in Alice Corp., 573 U.S. at 225, 110 USPQ2d at 1984.
Furthermore, the generic computer components of the processor, recited as performing generic computer functions that are well-understood, routine and conventional activities amount to no more than implementing the abstract idea with a computerized system.
Claims 2-17 depending on the independent claim/s include all the limitation of the independent claim. The Examiner finds that Claim 2 involves data gathering in the form of the biopsy images being stained for vascular cells and tissues. This is seen as data gathering and is insignificant extra solution activity. The claim describes the type of image that is used in the analyzation step. See MPEP 2106.05(g). The Examiner finds that Claim 3 involves data gathering in the form of the biopsy images being stained for vascular cells and tissues with a specific type of stain. This is seen as data gathering and is insignificant extra solution activity. The claim describes the type of image of what type of staining is used in the analyzation step. See MPEP 2106.05(g). The Examiner finds that Claim 4 involves data gathering in the form of the biopsy images being stained for vascular cells and tissues with a specific type of stain. This is seen as data gathering and is insignificant extra solution activity. The claim describes the type of image of what type of staining is used in the analyzation step. See MPEP 2106.05(g). The Examiner finds that Claim 5 involves data gathering in the form of the biopsy images being taken at a specific time after the transplant. This is seen as data gathering and is insignificant extra solution activity. The claim describes character tics of the image used for the analysis. See MPEP 2106.05(g). The Examiner finds that Claim 6 involves performing a diagnosis based on the analysis of the image. This is seen as an abstract idea related to a mental process and well-understood, routine, conventional activity. The claim describes routine image processing techniques commonly used in data augmentation without specifying a novel application or technical improvement that cannot be performed by a doctor, meaning it fails to integrate the abstract idea into a practical application. See MPEP 2106.05(d). The Examiner finds that Claim 7 involves mere data gathering and storage. The claim describes the type of biomarkers that are used within the analysis of the image. The examiner interprets this as data gathering and is insignificant extra solution activity. See MPEP 2106.05(g). The Examiner finds that Claim 8 involves performing a diagnosis based on the analysis of the biomarkers in the image. This is seen as an abstract idea related to a mental process and well-understood, routine, conventional activity. The claim describes routine image processing techniques commonly used in data augmentation without specifying a novel application or technical improvement that cannot be performed by a doctor, meaning it fails to integrate the abstract idea into a practical application. See MPEP 2106.05(d). The Examiner finds that Claim 9 involves data gathering in the form of characteristics of the analysis factors used when analyzing the image. This is seen as data gathering and is insignificant extra solution activity. The claim describes factors that are used in the analysis of determining the CAV of the patient. See MPEP 2106.05(g). The Examiner finds that Claim 10 involves data gathering in the form of characteristics of the analysis factors used when analyzing the image and risk factors. This is seen as data gathering and is insignificant extra solution activity. The claim describes factors that are used in the analysis of determining the CAV of the patient. See MPEP 2106.05(g). The Examiner finds that Claim 11 involves data gathering in the form of characteristics of one of the analysis factors. This is seen as data gathering and is insignificant extra solution activity. The claim describes factors that are used in the analysis of the pre capillary arterioles and their size in determining the CAV of the patient. See MPEP 2106.05(g). The Examiner finds that Claim 12 uses a computer as a tool to perform a process that could be performed in the human mind. This is seen as an abstract idea related to a mental process and well-understood, routine, conventional activity. The claim describes routine image processing techniques commonly used diagnosis of CAV without specifying a novel application or technical improvement that cannot be performed by a doctor, meaning it fails to integrate the abstract idea into a practical application. See MPEP 2106.05(d). The computer is used merely as a tool to implement image analysis technique. See MPEP 2106.05(a). The Examiner finds that Claim 13 involves data gathering in the form of characteristics of one of the risk factors. This is seen as data gathering and is insignificant extra solution activity. The claim describes factors that are used in the analysis clinical risk factors when determining the CAV of the patient. See MPEP 2106.05(g). The Examiner finds that Claim 14 involves data gathering in the form of characteristics of one of the risk factors. This is seen as data gathering and is insignificant extra solution activity. The claim describes factors that are used in the analysis clinical patient factors when determining the CAV of the patient. See MPEP 2106.05(g). The Examiner finds that Claim 15 involves data gathering in the form of gathering additional images from the patient from a biopsy. This is seen as data gathering and is insignificant extra solution activity. The claim describes factors are mentioned in earlier claims that do not amount to significantly more. See MPEP 2106.05(g). The Examiner finds that Claim 16 involves selecting a treatment for a patient. This is seen as an abstract idea related to a mental process and well-understood, routine, conventional activity. The claim describes routine treatment analysis without specifying a novel application or technical improvement that cannot be performed by a doctor, meaning it fails to integrate the abstract idea into a practical application. See MPEP 2106.05(d). The Examiner finds that Claim 17 involves data gathering in the form of gathering additional information regarding the patient. This is seen as data gathering and is insignificant extra solution activity. The claim describes the patient as being a kidney transplant patient. See MPEP 2106.05(g).
Thus, Claims 2-17 recite the same abstract idea and therefore are not drawn to the eligible subject matter as they are directed to the abstract idea without significantly more.
For the analogous independent claims 18, 19, and 20 to the independent claim 1 the analogous limitations can be analyzed in the same way as above for the claim 1, hence rejected under 101. Moreover, the claim of 19, and 20 further recites a different statutory category of “storage medium” and “system” which is a limitation that the examiner interprets that the claims is related to a machine since the claim is directed to a computer or processor performing the method of determining the patients likelihood of having or developing CAV and is consistent with the abstract ideas such as analyzing images and data to come to a diagnosis, which all can be performed by a human mind, this limitation just further implement the abstract ideas to be performed by generic computer or software/hardware components of additional elements of the different types of analyzation methods. Therefore, the Examiner interprets that the claims are rejected under 35 U.S.C. 101.
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.
Claims 1, 5, 6, and 17-20 are rejected under 35 U.S.C. 103 as unpatentable over Quake et al. (US Patent 10,982,275 hereafter referred to as Quake) in view of Peyster et al. (Peyster EG, Madabhushi A, Margulies KB. Advanced Morphologic Analysis for Diagnosing Allograft Rejection: The Case of Cardiac Transplant Rejection. Transplantation. 2018 Aug;102(8):1230-1239. doi: 10.1097/TP.0000000000002189. PMID: 29570167; PMCID: PMC6059998. Hereafter referred to as Peyster).
Regarding Claim 1, Quake teaches a method for diagnosing, predicting and/or preventing (Quake Col 25, Lines 47-53, and Col 12 Lines 52-60 disclose a program that provides a method for evaluating the outcome of a transplant receipt) acute allograft vasculopathy in an organ transplant patient (Quake Col 12 Lines 60-65 and Colo 22 Lines 32-40 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival and diagnosis Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs), the method comprising executing on a processor (Quake Col 25, Lines 17-35, discloses the method being performed by a computer utilizing a processor) the steps of:
(a) analyzing clinical risk factors (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's) of a cardiac, kidney or liver transplant patient (Quake Col 12 Lines 60-65 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs) which distinguishes between clinical biomarkers (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's)
which are prE allograft vasculopathy (Quake Col 6 Lines 15-18 disclose early identification of issues with cardiac transplants) or which have active allograft vasculopathy (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient with long term graft survival) from patients without acute allograft vasculopathy (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival);
(d) assigning prE-, active (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient with long term graft survival) or non- allograft vasculopathy status (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival) to a patient based on the outcome of (a) (Quake Col 1 Lines 50-55 disclose predicting the outcome based on the biomarkers);
(e) where preE or active statis is assigned (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient with long term graft survival), treating the patient (Quake Col 13 Lines 15-22 and Col 23 Lines 61-65 and Col 24 Lines 1-7 disclose treatment of the patient).
Quake does not explicitly disclose in a model of allograft vasculopathy patients and non-allograft vasculopathy patients, and
(b) analyzing digital biopsy images from the transplant patient to morphologically differentiate patients and (b).
Peyster is in the same field of transplant biopsy medical image analysis. Further, Peyster teaches in a model (Peyster Fig 1 and Pg 4 Col ¶04 discloses a prediction model), of allograft vasculopathy patients and non-allograft vasculopathy patients (Peyster Fig 4 and Pg 7 Col 2 ¶01 discloses the model in use for diagnosis of allograft rejection),
(b) analyzing digital biopsy images from the transplant patient (Peyster Fig 1 and Pg 4 Col 2 ¶04 discloses a prediction model that analyzes biopsy images) to morphologically differentiate patients (Peyster Pg 6 Col 2 ¶02 and Pg 7 Col 1 ¶01 discloses a predictive model based on morphologic features) and (b) (Peyster Pg 6 Col 2 ¶02 and Pg 7 Col 1 ¶01 discloses a predictive model for diagnosis of allograft rejection based on morphologic features).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Quake by incorporating the predictive model based on morphological features in a biopsy image as taught by Peyster, to make an invention that can automatically determine the patients status based on both clinical factors and image biopsy factors; thus one of ordinary skilled in the art would be motivated to combine the references since there is a need to improve the overall diagnosis accuracy (Peyster, Abstract).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claim 5, Quake in view of Peyster teaches the method according to claim 1, wherein the patient is a cardiac transplant patient (Quake Col 2 Lines 45-55 disclose transplants of cardiac tissue Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs) and the digital biopsy images (Peyster Pg 6 Col 2 ¶02 disclose digital image analysis) are from an endomyocardial biopsy (EMB) (Peyster Fig 1 and Pg 4 Col 2 ¶04 discloses a prediction model that analyzes biopsy images, Pg 2 Col1 ¶02 discloses EMB samples) obtained at about 1 year post-transplant (Quake Col 6 Lines 10-18 disclose endomyocardial biopsies being performed at intervals during the first year).See Claim 1 for rationale (its parent claim).
Regarding Claim 6, Quake in view of Peyster teaches the method according to claim 5, wherein the patient is assigned prE or active cardiac allograft vasculopathy status (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient with long term graft survival). See Claim 1 for rationale (its parent claim).
Regarding Claim 17, Quake in view of Peyster teaches the method according to claim 1, wherein the patient is a kidney transplant patient (Quake Col 4 Line 50 and Col 5 Line 31 disclose use in kidney transplant cases). See Claim 1 for rationale (its parent claim).
Regarding Claim 18, Quake teaches a computer-implemented method (Quake Col 25, Lines 17-35, discloses the method being performed by a computer utilizing a processor) for detection of a pre-CAV or active CAV patient , comprising executing on a processor (Quake Col 25, Lines 17-35, discloses the method being performed by a computer utilizing a processor) the steps of:
(a) analyzing clinical risk factors (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's) of a cardiac transplant patient (Quake Col 12 Lines 60-65 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs) which distinguishes between clinical biomarkers (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's) of (i) prE-CAV or active CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient will have long term graft survival) and (ii) non-prE-CAV or non-CAV patients (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival), and
from the cardiac transplant patient (Quake Col 12 Lines 60-65 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs), (i) prE-CAV or active CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient will have long term graft survival) and (ii) non-prE-CAV or non-CAV patients (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival); and
(c) assigning (Quake Col 20 Lines 45-47 disclose diagnosing the patient) (i) prE-CAV or active CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient will have long term graft survival) and (ii) non-prE-CAV or non-CAV patients, status to a patient (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival).
Quake does not explicitly disclose in a model, (b) analyzing digital endomyocardial biopsy (EMB) images from the cardiac transplant patient, to morphologically differentiate.
Peyster is in the same field of transplant biopsy medical image analysis. Further, Peyster teaches in a model (Peyster Fig 1 and Pg 4 Col ¶04 discloses a prediction model),
(b) analyzing digital endomyocardial biopsy (EMB) images (Peyster Fig 1 and Pg 4 Col 2 ¶04 discloses a prediction model that analyzes biopsy images, Pg 2 Col1 ¶02 discloses EMB samples) to morphologically differentiate (Peyster Pg 6 Col 2 ¶02 and Pg 7 Col 1 ¶01 discloses a predictive model based on morphologic features).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Quake by incorporating the predictive model based on morphological features in a biopsy image as taught by Peyster, to make an invention that can automatically determine the patients status based on both clinical factors and image biopsy factors; thus one of ordinary skilled in the art would be motivated to combine the references since there is a need to improve the overall diagnosis accuracy (Peyster, Abstract).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claim 19, Quake teaches a non-transitory computer-readable storage medium comprising stored instructions which (Quake Col 3 Lines 8-18 disclose a computer readable medium that includes instructions), when executed by one or more computer processors (Quake Col 25 Lines 39-41, discloses execution by a processor) cause the one or more computer processors to perform (Quake Col 25, Lines 17-35, discloses the method being performed by a computer utilizing a processor) steps of:
(a) analyzing clinical risk factors (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's) of a cardiac transplant patient (Quake Col 12 Lines 60-65 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs) which distinguishes between clinical biomarkers (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's) of (i) prE-CAV or active CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient will have long term graft survival) and (ii) non-prE-CAV or non-CAV patients (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival), and
from the cardiac transplant patient (Quake Col 12 Lines 60-65 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs) (i) prE-CAV or active CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient will have long term graft survival) and (ii) non-prE-CAV or non-CAV patients (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival); and
(c) assigning (Quake Col 20 Lines 45-47 disclose diagnosing the patient) PrE-CAV (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient with long term graft survival) or non-PrE-CAV status to a patient (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival).
Quake does not explicitly disclose in a model, (b) analyzing digital endomyocardial biopsy (EMB) images from the cardiac transplant patient, to morphologically differentiate.
Peyster is in the same field of transplant biopsy medical image analysis. Further, Peyster teaches in a model (Peyster Fig 1 and Pg 4 Col ¶04 discloses a prediction model),
(b) analyzing digital endomyocardial biopsy (EMB) images (Peyster Fig 1 and Pg 4 Col 2 ¶04 discloses a prediction model that analyzes biopsy images, Pg 2 Col1 ¶02 discloses EMB samples) to morphologically differentiate (Peyster Pg 6 Col 2 ¶02 and Pg 7 Col 1 ¶01 discloses a predictive model based on morphologic features).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Quake by incorporating the predictive model based on morphological features in a biopsy image as taught by Peyster, to make an invention that can automatically determine the patients status based on both clinical factors and image biopsy factors; thus one of ordinary skilled in the art would be motivated to combine the references since there is a need to improve the overall diagnosis accuracy (Peyster, Abstract).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claim 20, Quake teaches a system (Quake Col 25, Lines 17-35, discloses the method being performed by a computer utilizing a processor) for detection of a pre-CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient with long term graft survival), comprising at least one processor configured to perform steps (Quake Col 25, Lines 17-35, discloses the method being performed by a computer utilizing a processor) of:
(a) analyzing clinical risk factors (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's) of a cardiac transplant patient (Quake Col 12 Lines 60-65 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs) which distinguishes between clinical biomarkers (Quake Col 4 Lines 39-56 discloses the risk factors associated with CAV and Col 18 Lines 44-47 disclose analyzing SNP's) of (i) prE-CAV or active CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient will have long term graft survival) and (ii) non-prE-CAV or non-CAV patients (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival), and
from the cardiac transplant patient (Quake Col 12 Lines 60-65 disclose the method being used to evaluate a subject who has received a transplant an predict translate survival Col 20 Lines 40-44 disclose the transplant status may comprise vascular organs) (i) prE-CAV or active CAV patient (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient will have long term graft survival) and (ii) non-prE-CAV or non-CAV patients (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival); said at least one processor (Quake Col 25, Lines 17-35, discloses the method being performed by a computer utilizing a processor) being configured to PrE-CAV (Quake Col 13 Lines 1-5 and Col 20 Lines 33-40 and disclose diagnosing the patient or predicting if the patient with long term graft survival) or non-PrE-CAV status (Quake Col 1 Lines 60-67 disclose the transplant status including transplant survival) to a patient (Quake Col 20 Lines 45-47 disclose diagnosing the patient) .
Quake does not explicitly disclose in a model, (b) analyzing digital endomyocardial biopsy (EMB) images from the cardiac transplant patient, to morphologically differentiate.
Peyster is in the same field of transplant biopsy medical image analysis. Further, Peyster teaches in a model (Peyster Fig 1 and Pg 4 Col ¶04 discloses a prediction model),
(b) analyzing digital endomyocardial biopsy (EMB) images (Peyster Fig 1 and Pg 4 Col 2 ¶04 discloses a prediction model that analyzes biopsy images, Pg 2 Col1 ¶02 discloses EMB samples) to morphologically differentiate (Peyster Pg 6 Col 2 ¶02 and Pg 7 Col 1 ¶01 discloses a predictive model based on morphologic features).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Quake by incorporating the predictive model based on morphological features in a biopsy image as taught by Peyster, to make an invention that can automatically determine the patients status based on both clinical factors and image biopsy factors; thus one of ordinary skilled in the art would be motivated to combine the references since there is a need to improve the overall diagnosis accuracy (Peyster, Abstract).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Claims 2, 3, and 7 are rejected under 35 U.S.C. 103 as unpatentable over Quake in view of Peyster in further view of Hurskainen et al (Hurskainen, Maria, Olli Ainasoja, and Karl B. Lemström. "Failing heart transplants and rejection—a cellular perspective." Journal of Cardiovascular Development and Disease 8.12 (2021): 180. hereafter referred to as Hurskainen).
Regarding Claim 2, Quake in view of Peyster teaches the method according to claim 1, wherein the digital biopsy images (Peyster Fig 1 and Pg 4 Col 2 ¶04 discloses a prediction model that analyzes biopsy images).
Quake in view of Peyster does not explicitly disclose comprise at least one stain specific for endothelial cells and/or connective tissues of the vascular cells and tissues.
Hurskainen is in the same field of transplant biopsy medical image analysis. Further, Hurskainen teaches comprise at least one stain specific for endothelial cells and/or connective tissues of the vascular cells and tissues (Hurskainen Pg 8 ¶06 discloses staining for microvascular histological lesions including capillary injury, positive staining for CD68 and C4d in endomyocardial biopsies).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Quake in view of Peyster by incorporating the staining procedures and multiple morphological biomarkers as taught by Hurskainen, to make an invention that factors in the cellular mechanisms behind the failure of heart transplants to further understand the cause of the failure; thus one of ordinary skilled in the art would be motivated to combine the references since there is a need to improve cellular and molecular understanding of failing heart allografts. (Hurskainen, Abstract).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claim 3, Quake in view of Peyster in further view of Hurskainen teaches the method according to claim 2, wherein the stain is selected from CD31, CD34, CD68, or combinations thereof (Hurskainen Pg 8 ¶06 discloses positive staining for CD68). See Claim 2 for rational (its parent claim).
Regarding Claim 7, Quake in view of Peyster teaches at the method according to claim 1, wherein the analysis of morphologic biomarkers in (b) (Peyster Pg 6 Col 2 ¶02 and Pg 7 Col 1 ¶01 discloses a predictive model based on morphologic features) and (c) comprises analysis of (i) interstitial composition and proliferation (Peyster Pg 2 Table 1 discloses Interstitial and/or perivascular infiltration as a grading criteria for analysis), (ii) myocyte density (Peyster Pg 2 Table 1 discloses myocyte damage as a grading criteria for analysis).
Quake in view of Peyster does not explicitly disclose (iii) total microvascular density, (iv) the proportions of vessels of different sizes, and (v) the cellular abundance both within microvessels, and in the immediate perivascular space around these vessels.
Hurskainen is in the same field of transplant biopsy medical image analysis. Further, Hurskainen teaches (iii) total microvascular density (Hurskainen Pg 2 ¶05 discloses how close together the microvascular cell are), (iv) the proportions of vessels of different sizes (Hurskainen Pg 10 ¶02 discloses how the different sizes of the vessels contribute to the detection of CAV), and (v) the cellular abundance both within microvessels (Hurskainen Pg 9 ¶05 discloses the presence of microvessels and the infiltration of the macrophages as an indicator) and in the immediate perivascular space around these vessels (Hurskainen Pg 5 ¶02 and Pg 10 ¶02 disclose disruption of the space around the vessels).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Quake in view of Peyster by incorporating the staining procedures and multiple morphological biomarkers as taught by Hurskainen, to make an invention that factors in the cellular mechanisms behind the failure of heart transplants to further understand the cause of the failure; thus one of ordinary skilled in the art would be motivated to combine the references since there is a need to improve cellular and molecular understanding of failing heart allografts. (Hurskainen, Abstract).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Claims 4, 8, 12, 15 are rejected under 35 U.S.C. 103 as unpatentable over Quake in view of Peyster in view of Hurskainen in further view of Mitchell et al (Mitchell RN, Jonas RA, Schoen FJ. Pathology of explanted cryopreserved allograft heart valves: comparison with aortic valves from orthotopic heart transplants. J Thorac Cardiovasc Surg. 1998 Jan;115(1):118-27. doi: 10.1016/s0022-5223(98)70450-7. PMID: 9451054. Hereafter referred to as Mitchell).
Regarding Claim 4, Quake in view of Peyster in view of Hurskainen teaches the method according to claim 2, wherein the stain is a connective tissue stain (Hurskainen Pg 8 ¶06 discloses positive staining for CD68).
Quake in view of Peyster in view of Hurskainen does not explicitly disclose selected from Mason’s trichrome or Movats pentachrome stain.
Mitchell is in the same field of transplant biopsy medical image analysis. Further, Mitchell teaches selected from Mason’s trichrome (Mitchell Pg 2 Col 2 ¶01 discloses using Mason trichrome) or Movats pentachrome stain (Mitchell Pg 2 Col 2 ¶01 discloses using Movats pentachrome for staining).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Quake in view of Peyster in view of Hurskainen by incorporating Mason trichrome, Movats pentahrome, and CD31 into the staining of the biopsies as taught by Mitchell, to make an invention that can correctly identify the morphological differences in transplant biopsies of patients; thus one of ordinary skilled in the art would be motivated to combine the references since there is a need to determine the role of the cell morphology and mechanisms that lead to the dysfunction of the allografts. (Mitchell, Objective).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claim 8, Quake in view of Peyster in view of Hurskain