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 .
Election/Restrictions
Applicant’s election without traverse of the invention of claims 1-2, 9-12, and 14-19, drawn to a method of increasing the accuracy of screening and verifying the accuracy of a diagnosis of cancer or an autoimmune condition, in the reply filed on 12/26/2025 is acknowledged.
Applicant’s election without traverse of the species EPCAM and EDG3 as the single specific grouping of species for examination in the reply filed on 12/26/2025 is acknowledged.
A complete and thorough search for the elected species did not uncover any prior art. The search was extended to all non-elected species in Table 1.
Upon reconsideration, the restriction between Groups I and II is withdrawn. Claim 20 is rejoined and examined herein.
Claim Status
Claims 1-20 are pending. Claims 3-8, 13, and 20 are withdrawn due the species election but are rejoined and examined herein. Claims 1-20 are examined herein below.
Priority
The instant application was filed on 05/31/2023. This application claims benefit of a U.S. Provisional Patent Application 63/347,560 filed on 05/31/2022. The effective filing date of this instant application is 05/31/2022.
Information Disclosure Statement
One Information Disclosure Statement (IDS), filed 02/21/2025, is acknowledged and considered.
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.
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s).
If the subject matter can be listed in the specification, that list can be copied and pasted into a claim.
Claims 1 and 18 are rejected under 35 U.S.C. 112(b) for improper incorporation by reference of “Table 1”. Regarding claims 1 and 18, applicant is instructed to copy the table contents into at least one of these claims.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
The term “AMVY2A” in claim 2 is used by the claim to mean “the name of a specific autoantigen,” while “this is not a known autoantigen in the art.” The term is indefinite because the specification does not clearly redefine the term. A skilled artisan, with a reasonable degree of certainty, would not be able to determine how to implement this limitation to make and use the claimed invention.
Further, regarding claims 2 and 19, a coordinating conjunction, such as “and” or “or,” is missing, therefore it is unclear if the first phrase and set of limitations should be taken together or as an alternative to the second phrase and second set of limitations. Specifically, it is unclear whether the method comprises “at least one autoantigen is selected from the group [X]; and the at least one autoantigen is selected from the group consisting of [Y]” versus “at least one autoantigen is selected from the group [X]; or the at least one autoantigen is selected from the group consisting of [Y].”
Claims 3-17 and 19 are rejected as being dependent on rejected claims 1-2 and 18.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
“Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. See also In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. See MPEP § 2164.06 for discussion of quantity of experimentation, including determining reasonableness of experimentation. See also United States v. Telectronics, Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988) (“The test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation.”)”. See MPEP § 2164.01.
Wand’s factors Analysis:
Regarding the nature of the invention, the claimed invention is drawn to a method of increasing the accuracy of a screening and of verifying the accuracy of a diagnosis for a cancer or autoimmune condition of a subject suspected of having cancer or an autoimmune condition by identifying at least one or more false positive indicators.
Regarding breadth of the claims, the instant claims broadly encompass a large group of unspecified cancers and autoimmune conditions (spec, paras 0004, 0030). The claimed invention is directed to a method comprising detecting one or more specific autoantibodies, present in healthy and diseased individuals, to then identify false positive results for a broad group of unspecified cancers and autoimmune conditions
Regarding the level of ordinary skill, a person having ordinary skill in this area would have experience in performing immunoassays and possess a strong background knowledge in protein and antibody structure and general function in healthy and diseased tissues and cells. A skilled artisan in this area would have experience in biological sample collection, storage, and handling. Further, a person of ordinary skill in the art would have experience determining the presence of and quantifying specific antibodies in a properly handled biological sample using complex immunoassay techniques. Determining which autoantibodies present in both healthy and unhealthy patients are false indicators and not true biomarkers, especially for those classified as such in the prior art, in order to identify false positives and increase the accuracy of screenings and diagnostic results.
Regarding the state of the prior art, autoantibodies are produced by activated autoreactive B cells, a component of the mammalian adaptive immune system. The response of the immune system towards self-antigens normally involves both T and B cells. When the host immune system attacks its own antigens (self-antigens) it mistakes for foreign invaders, it may trigger the production of autoantibodies. Molecular mimicry, where foreign infectious antigens share structural similarities to self-antigens, is one mechanism that may trigger production of autoantibodies that mistakenly attack self-antigens. Thus, detection of autoantibodies in biological samples normally proceeds with a diagnosis for an autoimmune condition. Accessibility and ease of autoantibody detection in serum, relative to immune cell reactions, makes autoantibodies ideal biomarkers to detect for defining, classifying, and diagnosing certain diseases. Not all autoantibodies, however, are associated with disease and these are considered to be clinically insignificant (see Haller-Kikkatalo et al., Demographic associations for autoantibodies in disease-free individuals of a European population, 2017, Scientific Reports, 7, 44846, 1-12 and Cusick et al., Molecular Mimicry as a Mechanism of Autoimmune Disease, 2012, 42, 102-111).
The prior art further teaches that IgG autoantibodies identified as disease biomarkers may be detected in seemingly healthy individuals and these seemingly silent bystanders may actually represent preclinical disease in symptom-free individuals that may be diagnosed with the condition up to decades after initial detection (see Haller-Kikkatalo et al., 2017, Scientific Reports, 7, 44846, 1-12 and Lyons et al., Effective Use of Autoantibody Tests in the Diagnosis of Systemic Autoimmune Disease, 2005, Ann. N.Y. Acad. Sci., 1050, 217–228). Thus, these autoantibodies are not classified as false indicators at the time of detection in seemingly heathy, asymptomatic individuals.
Further, the prior art teaches that detection of a single autoantibody, classified as a disease marker and found in all cohorts, does not suffice to diagnose an autoimmune condition. Thus, the prior teaches that distinguishing between healthy, seemingly healthy, and unhealthy subjects involves quantification and determination of threshold levels of autoantibodies present, especially for those strongly associated with disease and found in all cohorts. Specifically, detecting certain autoantibodies, found in all cohorts, above a certain threshold may have diagnostic value for specific diseases especially since titers of certain autoantibodies are significantly increased in unhealthy patients (see Elkon et al., 2008, 4(9): pg. 7, full para 12, IDS dated 2/21/2025, Ref #9). Further, detection of autoantibodies at certain titer levels in seemingly healthy individuals has been shown to be an early indicator of disease when these subjects ae diagnosed years later (Elkon et al., Nature and functions of autoantibodies, 2008, 4, 9, 491-498). Thus, comparison of titer levels to a reference threshold value enables distinction between truly healthy and seemingly heathy, asymptomatic individuals. Importantly, in these cases specific autoantibodies, with strong association to a disease, are not classified as false indicators at the time they are detected at certain titer levels.
Additionally, studies find that autoantigens, which may trigger production of autoantibodies and are classified as disease biomarkers, when detected in truly healthy and diseased individuals, the concentrations, levels of expression, or ratios thereof, differ between the two groups. For example, EpCAM, an autoantigen expressed in normal and malignant epithelial tissues, has been shown to be overexpressed in colon, intestine, breast, lung, and prostate tumors relative to healthy tissue and is used as a diagnostic biomarker for certain cancers. Interestingly, EpCAM expression was found to be less expressed in squamous cell carcinomas relative to adenocarcinomas and absent in other tumors such as sarcomas, lymphomas, melanomas, and neurogenic tumors (see Keller et al., Biology and clinical relevance of EpCAM, 2019, Cell Stress, 3, 6, 165-180). Additionally, EDG3, an autoantigen also referred to as S1P3 in the prior art, is widely expressed in several healthy tissue types but also found to have enhanced expression in glioblastoma cells (see Fan et al., Recent advances of function of sphingosine 1-phosphate (S1P) receptor S1P3, 2021, J. Cell. Phys. 236, 1564-1578). Further, Wang et al. looked at 38 gene signatures in healthy and colon adenocarcinoma (COAD) patients. They found gene expression and regulation differences between the two cohorts. Specifically, autoantigen TRIM29 was upregulated in tumor samples relative to healthy samples while STMN4 was downregulated in tumor samples relative to healthy samples (Wang et al., Identification of gene signatures for COAD using feature selection and Bayesian network approaches, 24 May 2022, Scientific Reports, 12, 8761, pg. 7, Table 2). After statistical treatment of the data, Wang et al used the differences in expression levels of biomarkers, including TRIM29 and STMN4, to distinguish between healthy and tumor samples and determine disease prognosis (Wang et al., 24 May 2022, Scientific Reports, 12, 8761, 1-13). Notably, EpCAM, EDG3, TRIM29 and STMN4 are part of the elected and non-elected species disclosed in the claimed invention (instant claims 2, 10, 12, 16-17, and 19).
The prior art teaches that the gold standard for detecting autoantibody biomarkers is immunofluorescent staining of cells or tissues, which minimizes false positive results relative to conventional immunoassay detection methods (see Ida Herdlevær et al., 2021, Neurol Neuroimmunol Neuroinflamm, 8, e963, pg. 4, para under “Results”; and Ismail, When laboratory tests can mislead even they appear plausible, 2017, Royal College of Physicians, 17, 4, pg. 329, “Abstract,” full para 2 and pg. 329, para “Immunoassays”).
The prior art does not provide evidence that solely detecting the presence of autoantibodies found in both healthy and diseased individuals, especially those classified as disease biomarkers, are used to distinguish between truly healthy, seemingly healthy and asymptomatic, and diseased individuals without quantitative information.
The instant disclosure does not provide working examples of a method for solely
using the detection of one or more autoantibodies, especially those classified as disease biomarkers, found in healthy and diseased individuals, to identify a false positive screen or diagnosis for a cancer or autoimmune condition. The only information provided in the specification focuses on comparing a compilation of studies to determine the identity and number of autoantibodies detected in both healthy and diseased cohorts. Other examples provided analyze results from healthy and diseased cohorts to determine correlations, or lack thereof, of co-occurring autoantibodies in healthy and diseased cohorts, similarities in frequency rates for autoantibody detection in both cohorts, gender biases in autoantibody detection, localization and tissue expression of autoantibodies, and sequence and structural properties of autoantibodies.
Regarding the predictability in the art, autoantibodies associated with disease development and progression are classified as biomarkers and are targeted for detection to define, classify, diagnose, and prognosticate specific diseases. The prior art shows some of these biomarkers are present in seemingly healthy, truly healthy, and/or diagnosed individuals. Therefore, solely detecting the presence of these biomarkers is not enough to distinguish between seemingly healthy, truly healthy, and/or diseased individuals. The prior art shows that quantitative information for biomarkers detected enables a skilled artisan to distinguish between seemingly healthy, truly healthy, and/or diagnosed individuals. Further, this quantitative information enables a skilled artisan to more accurately define, classify, diagnose, and/or prognosticate specific diseases when detecting and quantifying specific subsets of biomarkers. It is, therefore, unpredictable whether solely detecting a specific subset of autoantibodies, especially those classified as disease biomarkers found in both healthy and diseased individuals, without quantification, will enable the identification of false positive screenings and diagnoses. Further, it is unpredictable whether detecting one specific subset of biomarkers will enable a skilled artisan to identify false positive screenings and diagnoses for all unspecified cancers or autoimmune conditions disclosed.
Regarding quantity of experimentation necessary to make or use the claimed invention based on the disclosed content, the prior art and specification teach that autoantibodies are found in both healthy and diseased individuals at different titer levels. Therefore, a threshold concentration, count, autoantigen expression level, or ratio thereof if detecting two or more autoantibodies or autoantigens, needs to be determined to precisely define what is considered a healthy individual in order to increase the accuracy of screens and/or diagnoses for a medical condition. Further, the specification teaches that some combinations of autoantibodies have co-occurrences that are statistically significantly higher than random chance ( spec, para 0047 and Drawings, pg. 21, Fig. 8A ), supporting that autoantibodies can be present in specific combinations. Neither the instant disclosure nor the prior art provides guidance for determining a subset or combination of autoantibodies that would indicate a false positive screen or diagnosis for a specific cancer or autoimmune condition. Therefore, detecting a specific combination of autoantibodies that would indicate a false positive for each type of or subset of cancer or autoimmune condition needs to be determined. If a specific combination of autoantibodies can specifically and consistently indicate a false positive for one specific or a subset of conditions, then a skilled artisan would need to determine if detection alone suffices to identify a false positive without quantitative information. Since, as discussed above, it is not routine to detect false indicators to identify false positive screens and/or diagnoses for a cancer or autoimmune condition, knowing only the identity of a specific subset of autoantibodies as false indicators for a large, unspecified group of cancers and autoimmune conditions would require a significant amount of experimentation to determine which autoantibodies would be false indicators for which cancer or autoimmune condition. Further, a significant amount of experimentation would be required to determine if quantitative parameters are needed for detected autoantibodies that may serve as disease biomarkers and are present in all cohorts to distinguish between healthy, seemingly healthy, and diseased cohorts. If so, a skilled artisan would need to further determine threshold values that would enable a skilled artisan to make these clinical distinctions. Thus, the specification does not provide sufficient teachings to enable identifying a false positive screening or verifying the accuracy of a diagnosis of a cancer or autoimmune condition based solely on detection of autoantibodies that may be classified as disease biomarkers and are found in both healthy and unhealthy cohorts.
Regarding the amount of direction or guidance provided, the specification teaches a specific subset of autoantibodies, some which the prior art classifies as disease biomarkers and are present in both healthy and diseased individuals. The specification does not provide guidance for how to distinguish between healthy and diseased individuals, which may require quantitative information, statistical analysis, and/or detection of specific combinations of biomarkers. As discussed above, it is not routine in the art to rely solely on detection of false indicators to increase the accuracy of a screen or diagnosis for cancer or an autoimmune condition. Therefore, the prior art lacks guidance in this area. As discussed above, the prior art teaches that autoantibodies with a strong association to one or a set of diseases may be classified as diagnostic/prognostic markers for a specific disease or a specific set of diseases. The instant disclosure teaches that the disclosed autoantibodies, classified as false indicators, may have co-occurrences in healthy samples at frequencies greater than chance alone, revealing that specific combinations of autoantibodies can be detected together in a same sample (Drawings, Fig. 8A, pg. 21 and spec, para 0047). Further, due to the lack of working examples for using the detection of false indicators to accurately identify a false positive screen and verify the accuracy of a diagnosis for a cancer or an autoimmune condition, the specification does not provide guidance for determining which specific cancers or autoimmune conditions would a specific subset of autoantibodies indicate a false positive for. Therefore, the claims and specification do not enable accurately identifying a false positive screen or verifying the accuracy of a diagnosis for a specific cancer or autoimmune condition.
For these reasons, the experimentation required to enable a skilled artisan to make and use the claimed invention is undue.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 9-18 rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to an abstract idea without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101
(see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the
claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e.,
mathematical concepts, certain methods of organizing human activity such as a fundamental
economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application
(see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception
into a practical application, do we then look to whether the claim contains an “‘inventive
concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible
application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In
so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood,
routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to
the industry, specified at a high level of generality, to the judicial exception. See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL
EXCEPTION
Step 2A, Prong 1
Claims 1, 9-18 recite “detecting the presence of” at least one or more autoantibodies. Autoantibodies disclosed in the instant claims are produced by the natural immune system and are present in healthy individuals (spec, paras 0005-0006 and 0028; pg. 10, Table 1), therefore, given the broadest reasonable interpretation and in light of the specification in this instant application, the instant claims recite detecting the presence of naturally produced autoantibodies, which is directed to detecting or measuring a natural phenomenon. Further, the claim language in claims 1, 9-18 draws a correlation between the presence/detection of one or more autoantibodies (false indicators) with the result to a screen or diagnosis, namely a false positive for a cancer or autoimmune condition (spec, paras 0033-0034). Similarly, given the broadest reasonable interpretation, the absence of specific autoantibodies (false indicators), in a given biological sample, would indicate a true positive screen or diagnosis for a cancer or autoimmune condition. Therefore, when one or more autoantibodies are detected/present to indicate absence of disease, or conversely in the absence of one or more naturally occurring false indicators to indicate a true positive screen or diagnosis, a skilled artisan is commanded to observe a natural correlation, or a natural relationship, so these claims are directed to a law of nature.
The court has recognized that the correlation between detecting a naturally produced autoantibody with presence of a disease state is directed to a law of nature. For example, in Athena Diagnostics, Inc. v. Mayo Collaborative Services, LLC, a 2019 U.S. Federal Circuit case, later denied review by the Supreme Court, the court held that claims for diagnosing a neurological disorder by detecting naturally-produced antibodies to a specific naturally occurring protein (MuSK) to be ineligible for patent protection. The court ruled that the correlation between anti-MuSK autoantibodies and a disease state, although novel and non-obvious, was directed to a law of nature.
Step 2A, Prong 2
This judicial exception is not integrated into a practical application because the
additional element of providing a biological sample (instant claims 1 and 18) amounts to an insignificant extra-solution activity, namely a data-gathering or preparation step that does not add a meaningful limitation to the law of nature recited in the instant claims.
Further, reciting a panel of additional autoantigens (instant claims 2-8 and 19) is merely a data-gathering step to obtain information, which is an insignificant extra-solution step that does not add a meaningful limitation to the law of nature recited in the instant claims.
Additionally, “identifying” one or more false indicators in a biological sample to increase the accuracy of a cancer or autoimmune condition screen or verify a diagnosis (instant claims 1, 9-12, 14-18 ) is an insignificant extra-solution step, namely a data-gathering or a data output step that does not add a meaningful limitation to the law of nature recited in the instant claims.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS
Instant claims 1, 9-12, and 14-18 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the Applicant explicitly discloses that data-gathering and detection steps would be carried out using methods that are well-established, routine, and conventional in the art (spec, para 0036). The well-established, routine, and conventional detection methods disclosed in the instant specification include Enzyme Linked Immunosorbent Assay (ELISA), Protein microarrays, Western Blot, or bead-based immunoassays (spec, para 0036). Further, the art teaches away from conventional immunoassay methods for detecting autoantibodies, such as anti-CDR2L disclosed in the claimed invention, for diagnosis or prognosis because of the high false positive results using these methods (see Ida Herdlevær et al., 2021, Neurol Neuroimmunol Neuroinflamm, 8, e963, pg. 4, para under “Results”). Thus, the data-gathering and detection steps in the claimed invention comprise neither an improvement to an instrument or process nor a new and non-conventional method/process.
For these reasons, the instant claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception and thus fail to impart patent eligibility to the law of nature recited in the instant claims 1, 9-12, and 14-18.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
Claim 20 is rejected under 35 U.S.C 102(a)(1) and 102(a)2 as being anticipated by Chang Ming Li, International Publication No. WO2005095262.
Throughout the disclosure, Li teaches a microchip device and methods for detecting target molecules and molecular interactions. Li teaches an embodiment wherein the microchip device comprises a plurality of test channels and each test channel is one test site. Li further teaches introducing a fluid sample into the device wherein a molecule or molecular interaction is detected at a test site within the plurality of test sites (paras 0011-0012). Li teaches that fluid samples containing same or different types of target molecules may be transported into different test channels for simultaneous detection of multi-analytes when the different test channels have different probe molecules immobilized therein (para 0050). Li further teaches a sandwich-ELISA embodiment wherein the target protein may be captured by the probe protein (para 0047). Li teaches a target molecule, or a signal generating molecule for indirect detection of the target molecule whereby various techniques, including conventional detection techniques for detecting molecules and molecular interactions can be used (para 0041). The captured molecules or proteins including target molecules, such as antibodies or antigens, can be detected, for example, after introducing a fluid containing substrate molecules that can be converted by enzymatic reactions to colored products for optical detection (para 0048).
Regarding claim 20, Li teaches A kit for detecting one or more target markers of disease in a subject, the kit comprising: at least one antigen or antibody targeting one or more markers; at least one labeled secondary antibody or antigen for detecting the binding of the at least one antigen or antibody with the one target marker and at least one labeled secondary antibody or antigen detecting binding of at least one autoantibody (Li, paras 0041, 0042, 0043, 0047, 0048, and 0050).
Conclusion
Claims 1-19 are free of the prior art.
The prior art of record discloses methods for increasing the accuracy of screening tests, or increasing their predictive value, depends heavily on technical parameters of the test, such as sensitivity and specify, and focusing on a population with prevalence for the disease (see L. D. Maxim, et al., Screening tests: a review with examples, 2014, Inhal Toxicol. 26(13): 811–828). The prior art highlights that detecting a rational combination of biomarkers for a particular disease improves the efficiency and accuracy of screens and diagnostic tests (see Zhou et al., Tumor biomarkers for diagnosis, prognosis, and targeted therapy, Signal Transduction and Targeted Therapy, 9, 132, pg. 63, full para 5). Thus, the prior art teaches away from detecting less than two biomarkers to increase accuracy of a cancer or autoimmune condition screening or to verify a diagnosis of the same. Further, the prior art teaches away from relying on the detection of at least one false indicator to improve the accuracy of a cancer or autoimmune condition screening or to verify a diagnosis of the same.
Additionally, the prior art teaches that there are gene expression and regulation differences of autoantigens identified as disease biomarkers in both healthy and unhealthy cohorts. The prior art further teaches a specific study that found autoantigen TRIM29 was upregulated in tumor samples relative to healthy samples while STMN4 was downregulated in tumor samples relative to healthy samples. Comparing these molecular differences enabled the distinction between healthy and unhealthy subjects (Wang et al., Identification of gene signatures for COAD using feature selection and Bayesian network approaches, 24 May 2022, Scientific Reports, 12, 8761, pg. 7, Table 2). Further, the prior art teaches that EDG3, an autoantigen also referred to as S1P3 in the prior art, is widely expressed in several healthy tissues but has enhanced expression in glioblastoma cells (see Fan et al., Recent advances of function of sphingosine 1-phosphate (S1P) receptor S1P3, 2021, J. Cell. Phys. 236, 1564-1578). Additionally, EpCAM, an autoantigen expressed in normal and malignant epithelial tissues, has been shown to be overexpressed in colon, intestine, breast, lung, and prostate tumors relative to healthy tissue and is thus used as diagnostic biomarker for certain cancers. (see Keller et al., Biology and clinical relevance of EpCAM, 2019, Cell Stress, 3, 6, 165-180). Thus, the prior art teaches that autoantigens found in healthy, seemingly healthy, and unhealthy cohorts may be true disease biomarkers. Since these autoantigens are regulated and expressed differently in unhealthy tissue, when detected, quantitative analysis enables distinction between healthy, seemingly healthy, and healthy individuals.
The prior art further teaches that distinguishing between healthy, seemingly healthy, and unhealthy subjects may involve quantification and determination of threshold levels of autoantibodies present, especially for those strongly associated with disease and found in all cohorts (see Elkon et al., 2008, 4, 9, pg. 7, full para 12). Further, detection of autoantibodies at certain titer levels in seemingly healthy individuals has been shown to be an early indicator of disease when these subjects are diagnosed years later (Elkon et al., Nature and functions of autoantibodies, 2008, 4, 9, 491-498). Thus, these autoantibodies are not classified as false indicators at the time of detection in seemingly heathy, asymptomatic individuals.
Additional antigens and autoantibodies that may be found in healthy, seemingly healthy, and unhealthy individuals and have a strong disease association for a specific cancer, autoimmune condition, or a set thereof are listed in the table below.
The prior art teaches away from classifying a specific subset of autoantibodies found in both healthy and unhealthy individuals, some which are designated as diagnostic/prognostic markers, as false indicators of a large group of cancers and autoimmune conditions. The prior art further teaches away from a method for increasing accuracy of screenings and verifying accuracy of diagnoses for cancer or an autoimmune condition solely by detection of this subset of autoantibodies, especially if they have prognostic/diagnostic value and are found in all cohorts.
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Thus, the prior art teaches away from the methods of increasing the accuracy and verifying the accuracy of a screening and diagnosis of a cancer or autoimmune condition wherein detecting at least one and up to ten autoantigen from the group consisting of EPCAM, EDG3, STMN4, ODF2, RBPJ, AMY2A, ZNF688, CSF3, S1PR3, CDR2L, RASSF1, SPAG8, TRAP1, SART1, GATA2, PML, SOX2, PELI1, TAX1BP1, JUN, PAK1, GTSEl, MAK, RNF138, PMIFBP1, CCDC34, CAPN3, MYLK2, TRIM29, ODF4, RAD51AP1, PSKH1, LENGI, LYSMD1, FAM76A, and CCDC130, or detecting the presence of one or more autoantibodies against at least one autoantigen listed in Table 1 in the biological sample, wherein detecting the presence of one, or up to ten, or more would indicate a false positive for a cancer or an autoimmune condition.
All claims (1-20) in this instant application are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA L LIRIANO whose telephone number is (571)272-0085. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at (571)272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MELISSA LIZETTE LIRIANO/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 March 30, 2026
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