DETAILED ACTION
Applicant’s response, filed 06/16/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
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 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.
Claim Status
Claims 1-18 are pending.
Claims 5 and 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, as set forth in the Non-Final Office Action dated 10/03/2025.
Claim 18 are newly added.
Claims 1-4, 6-14, and 18 are rejected.
Applicant's claim for the benefit of a prior-filed application, PCT/IB2020/056251, filed 07/02/2020, is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) to App. No. ITALY 102019000012555, filed 07/22/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 01/21/2022 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
Drawings
The Drawings submitted 01/21/2022 are accepted.
Claim Rejections- 35 USC § 112
The outstanding rejections to the claims are withdrawn in view of the amendments submitted herein as the example language has been removed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
For the following rejections, underlined text indicates newly recited portions necessitated by claim amendment.
Claims 1-4, 6-14, and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portions are necessitated by claim amendment.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to method, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) are as follows:
Independent claim 1:
processing the image to obtain a one- dimensional protein profile (Pp) representing a distribution of molecular weights of the proteins
providing at least one discriminant function (f(a1,a2,...an), g(ai,a2, a3,... an)) and two or more bands of molecular weight (A1, A2...An), ,wherein said bands of molecular weight are defined over predetermined intervals and each peak of the protein profile is assigned to one of said intervals based on molecular weight conversion from the processed gel image, said at least one discriminant function (f(a1,a2,...an), g(a,,a2, a3,... an)) and said bands of molecular weight (A1, A2,....An) being predetermined on the basis of a set of reference samples;
calculating an integral area value (VA1, VA2... VAn) from the processed protein profile (Pp) for each of said bands of molecular weight (A1, A2... An);
calculating at least one discriminant value (VDf, VD9) of said at least one discriminant function (f(a1,a2,...an), g(ai,a2, C3,... an)) for at least one pair of said integral area values (VA1, VA2... VAn);
classifying the plasma sample by comparing said at least one discriminant value (VDf, VD9) with at least one predefined threshold value (VS).
in response to the classification of the plasma sample as at risk, identifying the subject as requiring one or more second-level diagnostic examinations selected from abdomen CT, abdomen MRI, echo endoscopy, or ERCP and
generating an indication of said requirement for clinical follow-up
Dependent claims 2-4, 6-11, and 14 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claim 2 further limits the examination of claim 1, claim 3 further limits the discriminant function of claim 1, claim 4 further limits the discriminant function of claim 1, claims 6 and 8 further limit the bands of molecular weight of claim 1, claim 7 further limits predefined threshold of claim 1, claim 9 further limits the gold nanoparticles of claim 1, claims 10 and 11 further limit the temperature of claim 1, and claim 14 further limits the polyacrylamide gradient of claim 1.
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims further recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations.
The claim recites identifying. The human mind is capable of identifying the subject as requiring one or more second-level diagnostic examinations. The claims recite mathematical concepts of processing the image , calculating an integral area value, calculating at least one discriminant value, generating an indication, and classifying the plasma sample.
Therefore, claims1 and those claims dependent therefrom recite an abstract idea [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claim 1:
providing a plasma sample from a blood sample of a subject to be analyzed;
incubating said plasma sample with gold nanoparticles so as to allow the formation of a protein crown on nanoparticles, wherein the incubating is performed at a temperature between 35 and 40°C for a time between 40 and 120 minutes,
separating the proteins that make up said protein crown from said nanoparticles;
subjecting said proteins to electrophoresis on a denaturing polyacrylamide gradient gel
acquiring an image of the gel
Dependent claim 12:
incubated material is subjected to centrifugation and one or more washes with phosphate buffer to eliminate weakly bound proteins.
Dependent claim 13:
is carried out by boiling for about 10 minutes the gold particles as obtained in point b) or b') suspended in polyacrylamide gel charge buffer comprising SDS.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “acquiring” perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Those steps directed to producing gold nanoparticles coated with the protein crown are insignificant extra solution activity because as all they do is gather the data for the mathematical steps and do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and extra solution activities steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Response to Applicant Arguments
1. Applicant respectfully submits the Office characterizes the laboratory portions of the claim as merely gathering data for the mathematical steps and therefore as insignificant extra-solution activity characterization no longer applies to amended claim 1 [p. 11, par. 2].
It is respectively found not persuasive. Limitations the courts have found indicative that an additional element (or combination of elements) may have integrated the exception into a practical application include
•An improvement in the functioning of a computer, or an improvement to other technology or technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a); (a specific interaction with the computer structure itself). There is no improvement to the technology of corona creation, or image processing.
• Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2) (Vanda Pharmaceuticals); (real world application, specific). There is no specific treatment for a disease claimed.
• Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b); (specific interaction with a particular non-generic computer or computer structure). There is no machine or manufacture that is integral to the claim.
• Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); (a real-world change of one thing to another- but not changing data from one form to another).
• Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e). (must be specific, linked to a specific technology).
The wet lab methods do not transform the material only provides it into data form for analysis.
2. Applicant submits the claimed "calculating" and "classifying" steps could be performed manually, for example with pen and paper, and therefore do not integrate the alleged exception into a practical application [p. 9, par. 1]. The steps of calculating and classifying are mathematical concepts and are judicial exceptions as described in the above 101 rejection. The applicants response also cites “the claimed calculations are not free-standing mental observations but are expressly tied to transformation of a laboratory generated image into a quantitatively defined protein profile that is then used in the claimed analytical workflow” [p. 10, par. 1].
3. The amendments also integrate any recited mathematical relationship into a practical application by amending claim 1 to expressly tie the classification output to identification of the subject for one or more second-level diagnostic examinations, the claim now recites a concrete clinical application of the analytical result, rather than a mere abstract categorization [p. 10, par. 2-p. 11, par. 1].
It is respectfully found not persuasive. The claims classify a sample at risk and identifies the subject needing a second diagnostic examination, but does not require a second diagnostic test to be performed.
4. Applicant respectfully submits that amended claim 1, considered as a whole, is directed to a practical application of laboratory and image-processing technology for assisting in the early diagnosis of pancreatic adenocarcinoma and for identifying subjects who should undergo second-level diagnostic examinations [p. 12, par. 3].
It is respectfully found not persuasive. The wet lab techniques were not improved are where well know in the art as described by Lai et al. (Lai, Wenjia, et al. "Interaction of gold and silver nanoparticles with human plasma: Analysis of protein corona reveals specific binding patterns." Colloids and Surfaces B: Biointerfaces 152 (2017): 317-325, newly cited). Lai discloses plasma protein corona formation for proteomics analysis approximately 1 × 1012 particles of each nanomaterial with the same volume were incubated for 1 h at 37◦C [p. 2, col. 1, par. 5]. Lai further discloses following centrifugation, 10 _L of the supernatant was subjected to SDS-PAGE separation on 8–16% polyacrylamide precast gels for electrophoresis[p. 2, col, 2, par. 5]. Therefore the additional elements are mere data gathering wet lab techniques to provide to the judicial exception.
Claim Rejections - 35 USC § 103
The outstanding 103 rejection to the claims is withdrawn in view of the amendments submitted herein as the prior art does not disclose the use of gold nanoparticles, the gel image processing procedure, and the methodology for one-dimensional protein profile processing and input-variable identification.
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.
A. Claims 1, 3-4, and 6-14 are rejected under 35 U.S.C. 103 as being unpatentable over Caputo et al. (Caputo, D., et al. "A protein corona-enabled blood test for early cancer detection." Nanoscale 9.1 (2017): 349-354, cited on IDS dated 01/21/2022)in view of Lai et al. ((Lai, Wenjia, et al. "Interaction of gold and silver nanoparticles with human plasma: Analysis of protein corona reveals specific binding patterns." Colloids and Surfaces B: Biointerfaces 152 (2017): 317-325, newly cited)
The instant rejection is newly stated and is necessitated by claim amendment.
Claim 1 is directed to a method to assist in the early diagnosis of pancreatic adenocarcinoma which allows the identification of subjects in an early state of disease or at risk of pancreatic adenocarcinoma for whom it is necessary or appropriate to carry out second- level examinations by classifying a plasma sample of these subjects according to two or more levels of risk in which the classification of said sample in at least one of said levels of risk indicates the need or opportunity to carry out second-level examinations, comprising the following steps:
Caputo discloses a protein corona-enabled blood test for early cancer detection [title]. Caputo further discloses developing new methods for the early detection of pancreatic cancer is an urgent task for current research. To date, nanotechnology offers unprecedented opportunities for cancer therapeutics and diagnosis abstract]. Caputo also discloses the aim of this study is the development of a new pancreatic cancer diagnostic technology based on the exploitation of the nano-bio interactions between nanoparticles and blood samples [abstract]. Caputo further discloses for the two classes to be discriminate, so that a positive value of L points to class A and a negative value to class B [p. 353, col. 1, par. 2]. Caputo is silent on second-level examinations. However, early detection implies that second-level examinations will follow.
a) providing a plasma sample from a blood sample of a subject to be analyzed;
Caputo also discloses the aim of this study is the development of a new pancreatic cancer diagnostic technology based on the exploitation of the nano-bio interactions between nanoparticles and blood samples [abstract].
b) incubating said plasma sample with gold nanoparticles so as to allow the formation of a protein crown on said nanoparticles, wherein the incubating is performed at a temperature between 35 and 40°C for a time between 40 and 120 minutes,
Caputo discloses the plasma sample is incubated on lipid NPs [p. 352, col. 2, par. 4]. Caputo is silent on the use of gold nanoparticles.
However, Lai discloses interaction of gold and silver nanoparticles with human plasma: Analysis of protein corona reveals specific binding patterns [title]. Lai further discloses plasma protein corona formation for proteomics analysis approximately 1 × 1012 particles of each nanomaterial with the same volume were incubated for 1 h at 37◦C [p. 2, col. 1, par. 5].
c) separating the proteins that make up said protein crown from said nanoparticles;
Caputo is silent on the use of gold nanoparticles.
However, Lai discloses following centrifugation, 10 _L of the supernatant was subjected to SDS-PAGE separation on 8–16% polyacrylamide precast gels for electrophoresis[p. 2, col, 2, par. 5].
d) subjecting said proteins to electrophoresis on a denaturing polyacrylamide gradient gel
Caputo is silent on the use of gold nanoparticles.
However, Lai discloses Corona proteins analysis by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) and western blot [p. 2, col. 2, par. 5].
and acquiring an image of the gel and
Caputo discloses pictures of gels were captured by KODAK Digital DC120 and densitometry analysis of gels was performed using ImageJ software [p. 353, col. 1, par. 1].
processing the image to obtain a one- dimensional protein profile (Pp) representing a distribution of molecular weights of the proteins;
Caputo discloses a densitometry analysis of electrophoretic gels was performed for semi-quantitative comparison [p. 351, col, 1, par. 1]. Caputo further discloses to properly evaluate changes in the HC, the intensity profiles of healthy individuals (Fig. 2, panel A) and those of pancreatic cancer patients (Fig. 2, panel B) were reduced to the following four regions of molecular weight (MW): (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa [p. 351, col, 1, par. 1].
e) providing at least one discriminant function (f(ai,a2, ... c), g(ai,a2,aX3 ... an)) and two or more bands of molecular weight (A1, A2... An),wherein said bands of molecular weight are defined over predetermined intervals and each peak of the protein profile is assigned to one of said intervals based on molecular weight conversion from the processed gel image, said at least one discriminant function (f(ai,a2, ... an), (g(ai,a2,a3, ... an)) and said bands of molecular weight (A1, A2,....An) being predetermined on the basis of a set of reference samples;
Caputo discloses the second dataset was composed of 4 variables, i.e., the integral areas of the average lane intensity profiles calculated for (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa [p. 353, col. 1, par. 2]. Captuo further discloses clustered and classified the patients by means of Linear Discriminant Analysis (LDA), performed on the principal components [p. 353, col. 1, par. 2]. Caputo also discloses LDA is the method of election to determine whether meaningful differences exist between the groups and to identify the discriminating power of each variable [p. 353, col. 1, par. 2]. Caputo further discloses the technique is constructed of a set of linear functions of predictors, known as discriminant functions, such that L = b1x1 + b2x2 + … + bnxn + c, where the bi are discriminant coefficients the xi are the input variables or predictors, and c is a constant [p. 353, col. 1, par. 2]. Caputo also discloses L is a class index that usually takes the values of 1 and −1, respectively, for the two classes to be discriminate, so that a positive value of L points to class A and a negative value to class B [p. 353, col. 1, par. 2].
f) calculating an integral area value (VA1, VA2... VAn) from the processed protein profile (Pp) bands of molecular weight (A1, A2...An); g) calculating at least one discriminant value (VDf, VDg) of said at least one discriminant function (f(ai,a2, ... an), (g(ai,a2,a3, ... an)) for at least one pair of said integral area values (VA1, VA2... VAn);
Caputo discloses to properly evaluate changes in the HC, the intensity profiles of healthy individuals (Fig. 2, panel A) and those of pancreatic cancer patients (Fig. 2, panel B) were reduced to the following four regions of molecular weight (MW): (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa (Fig. S2 in the ESI†) and subsequently, the integral area was calculated for each region [p. 351, col. 1, par. 1].
h) classifying the plasma sample by comparing said at least one discriminant value (VDf, VDg) with at least one predefined threshold value (VS); and
Caputo discloses the second dataset was composed of 4 variables, i.e., the integral areas of the average lane intensity profiles calculated for (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa [p. 353, col. 1, par. 2]. Captuo further discloses clustered and classified the patients by means of Linear Discriminant Analysis (LDA), performed on the principal components [p. 353, col. 1, par. 2]. Caputo also discloses LDA is the method of election to determine whether meaningful differences exist between the groups and to identify the discriminating power of each variable [p. 353, col. 1, par. 2]. Caputo further discloses the technique is constructed of a set of linear functions of predictors, known as discriminant functions, such that L = b1x1 + b2x2 + … + bnxn + c, where the bi are discriminant coefficients the xi are the input variables or predictors, and c is a constant [p. 353, col. 1, par. 2]. Caputo also discloses L is a class index that usually takes the values of 1 and −1, respectively, for the two classes to be discriminate, so that a positive value of L points to class A and a negative value to class B [p. 353, col. 1, par. 2].
i) in response to the classification of the plasma sample as at risk, identifying the subject as requiring one or more second-level diagnostic examinations selected from abdomen CT, abdomen MRI, echoendoscopy, or ERCP and generating an indication of said requirement for clinical follow-up
Caputo and Lai are silent on a second level diagnostic examination. However, it would be obvious to perform a second level diagnostic examination if any blood test screening for cancer was abnormal. Dependent on the cancer in question the corresponding examination would be performed.
Claim 3 is directed to the method according to claim 1, wherein said at least one discriminant function (f{ai, a2, ... an), (g(ai, a2, m, ... an)) is obtained by linear discrimination analysis.
Caputo discloses the second dataset was composed of 4 variables, i.e., the integral areas of the average lane intensity profiles calculated for (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa [p. 353, col. 1, par. 2]. Captuo further discloses clustered and classified the patients by means of Linear Discriminant Analysis (LDA), performed on the principal components [p. 353, col. 1, par. 2]. Caputo also discloses LDA is the method of election to determine whether meaningful differences exist between the groups and to identify the discriminating power of each variable [p. 353, col. 1, par. 2]. Caputo further discloses the technique is constructed of a set of linear functions of predictors, known as discriminant functions, such that L = b1x1 + b2x2 + … + bnxn + c, where the bi are discriminant coefficients the xi are the input variables or predictors, and c is a constant [p. 353, col. 1, par. 2]. Caputo also discloses L is a class index that usually takes the values of 1 and −1, respectively, for the two classes to be discriminate, so that a positive value of L points to class A and a negative value to class B [p. 353, col. 1, par. 2].
Claim 4 is directed to the method according to claim 1, wherein said at least one discriminant function (f{ai, a2, ... an), (g(ai, a2, m, ... an)) comprises a first function (f(ai, a2)) represented by the equation of a straight line of the type: f (m, m) = rl + r2 * m + r3 * m = 0 in which rl, r2 and r3 are the coefficients of the line and ai and a2 are integral area values.
Caputo discloses the second dataset was composed of 4 variables, i.e., the integral areas of the average lane intensity profiles calculated for (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa [p. 353, col. 1, par. 2]. Captuo further discloses clustered and classified the patients by means of Linear Discriminant Analysis (LDA), performed on the principal components [p. 353, col. 1, par. 2]. Caputo also discloses LDA is the method of election to determine whether meaningful differences exist between the groups and to identify the discriminating power of each variable [p. 353, col. 1, par. 2]. Caputo further discloses the technique is constructed of a set of linear functions of predictors, known as discriminant functions, such that L = b1x1 + b2x2 + … + bnxn + c, where the bi are discriminant coefficients the xi are the input variables or predictors, and c is a constant [p. 353, col. 1, par. 2]. Caputo also discloses L is a class index that usually takes the values of 1 and −1, respectively, for the two classes to be discriminate, so that a positive value of L points to class A and a negative value to class B [p. 353, col. 1, par. 2].
Claim 6 is directed to the method according to claim , wherein said two or more bands of molecular weight (A1, A2 ... An) are determined so that each peak - corresponding to a respective electrophoretic band of each protein profile of the set of reference samples belongs to one and only one of said bands.
Caputo discloses (A) Principal components (PC1, PC2) calculated from the four integral areas of the total lane intensity profiles calculated in the following four regions of molecular weight: (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa. Blue and orange circles refer to the pancreatic cancer and healthy patients, respectively. (B) Centroids of the distributions of panel A [p. 351, fig. 3].
Claim 7 is directed to the method according to claim 1, wherein said at least one predefined threshold value (VS) is equal to zero and said plasma sample is classified as at risk if the discriminant value (VDr, VDg) is greater than zero.
Caputo discloses L is a class index that usually takes the values of 1 and −1, respectively, for the two classes to be discriminate, so that a positive value of L points to class A and a negative value to class B [p. 353, col. 1, par. 2].
Claim 8 is directed to the method according to claim 1, wherein said bands of molecular weight can be, for example, two or more among A1: 10-20 kDa; A2: 20-25 kDa; A3: 25-35 kDa; A4: 35-45 kDa.
Caputo discloses (A) Principal components (PC1, PC2) calculated from the four integral areas of the total lane intensity profiles calculated in the following four regions of molecular weight: (i) MW < 25 kDa; (ii) 25 < MW < 50; (iii) 50 < MW < 120; (iv) MW > 120 kDa. Blue and orange circles refer to the pancreatic cancer and healthy patients, respectively. (B) Centroids of the distributions of panel A [p. 351, fig. 3].
Claim 10 is directed to the method according to claim 1, wherein step b) is carried out at a temperature between 35 and 40°C for a period of time between 40 and 120 minutes.
Caputo is silent on the use of gold nanoparticles.
However, Lai discloses interaction of gold and silver nanoparticles with human plasma: Analysis of protein corona reveals specific binding patterns [title]. Lai further discloses plasma protein corona formation for proteomics analysis approximately 1 × 1012 particles of each nanomaterial with the same volume were incubated for 1 h at 37◦C [p. 2, col. 1, par. 5].
Claim 11 is directed to the method according to claim 10, wherein said temperature is 37°C and/or said time is 55 to 56 minutes.
Caputo is silent on the use of gold nanoparticles.
However, Lai discloses interaction of gold and silver nanoparticles with human plasma: Analysis of protein corona reveals specific binding patterns [title]. Lai further discloses plasma protein corona formation for proteomics analysis approximately 1 × 1012 particles of each nanomaterial with the same volume were incubated for 1 h at 37◦C [p. 2, col. 1, par. 5].
Claim 12 is directed to the method according to claim 1, wherein step b) further comprises in which the incubated material is subjected to centrifugation and one or more washes with phosphate buffer to eliminate weakly bound proteins.
Caputo is silent on the use of gold nanoparticles.
However, Lai discloses the incubated samples were then loaded on to a sucrose cushion (0.5 M in PBS) and centrifuged for 20 min at 19,000 × g at 4◦C and pellets containing the nanoparticle-protein complexes were washed six times via suspension in the PBST [p. 2, col. 1, par. 5-col. 2, par. 1].
Claim 13 is directed to the method according to claim 1, wherein said separation at point c) is carried out by boiling for about 10 minutes the gold particles as obtained in point b) or b') suspended in polyacrylamide gel charge buffer comprising SOS.
Caputo is silent on the use of gold nanoparticles.
However, Lai discloses o provide an overview of the corona proteins, nanoparticles with corona were boiled in an equal volume of SDS loading buffer for 5 min and following centrifugation, 10 _L of the supernatant was subjected to SDS-PAGE separation on 8–16% polyacrylamide precast gels [p. 2, col. 2, par. 5].
Claim 14 is directed to the method according to claim 1, wherein said polyacrylamide gradient is a 4-20% gradient.
Caputo is silent on the use of gold nanoparticles.
However, Lai discloses following centrifugation, 10 _L of the supernatant was subjected to SDS-PAGE separation on 8–16% polyacrylamide precast gels [p. 2, col. 2, [par. 5].
In regards to claim(s) 1, 3-4, and 6-14, 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 combine Caputo and Lai as they both are directed to using gold nanoparticles for downstream biological impacts of the corona proteins. The motivation would be to use the SDS PAGE data from the Lai as input to the model of Caputo. As the model is not trained the SDS-PAGE data from both lipid nanoparticles (LNPs) and gold nanoparticles (AuNPs) will work effectively within this linear discriminant function framework as disclosed by Caputo. A finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
B. Claim 2 are rejected under 35 U.S.C. 103 as being unpatentable over Caputo in view of Lai, as applied to claim 1 as above, and in further view of Miura et al. (Miura, Fumihiko, et al. "Diagnosis of pancreatic cancer." Hpb 8.5 (2006): 337-342, newly cited).
Claim 2 is directed to the method according to claim 1, wherein said second-level examinations comprise one or more among: abdomen CT, abdomen MRI, echoendoscopy, ERCP.
Caputo and Lai are silent on a second-level examination.
However, Miura discloses diagnosis of pancreatic cancer [title]. Miura further discloses the ability to diagnose pancreatic carcinoma has been rapidly improving with the recent advances in diagnostic techniques such as contrast-enhanced Doppler ultrasound (US), helical computed tomography (CT), enhanced magnetic resonance imaging (MRI), and endoscopic US (EUS) [abstract]. It is obvious that if an early risk is detected with a blood test that a follow up diagnostic tool would be used.
In regards to claim(s) 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 combine Caputo and Banstola with Miura as they all are directed to the diagnosis of pancreatic cancer. The motivation would have been to include the second level diagnostic tools with Caputo to as recent advances in diagnostic techniques such as contrast-enhanced Doppler US, helical CT, enhanced MRI, and EUS have led to improvements in sensitivity for identifying pancreatic carcinoma as disclosed by Miura [conclusion].
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dawn Bickham whose telephone number (703)756-1817. The examiner can normally be reached on Monday - Friday 8-4.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached on (571)272-2249. 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 https://ppair-my.uspto.gov/pair/PrivatePair. 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.
/D.M.B./Examiner, Art Unit 1685
/Soren Harward/Primary Examiner, TC 1600
Prosecution Insights