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
This instant application was filed on 08/23/2023. This application claims benefit of U.S. Provisional Patent Application 63/400,378, filed on 08/23/2022 and claims foreign priority to Korean Application KR10-2023-0082404, filed on 06/27/2023.
Claims 1-8 and 16 of this instant application contain subject matter supported by the provisional application. Thus, claims 1-8 and 16 have an effective filing date of 08/23/2022.
Claims 9-15 introduce subject matter not supported by the original provisional application. Claims 9-15 introduce subject matter supported by the disclosure provided for the Korean foreign application. Claims 9-15 are directed to method for providing information for predicting the prognosis of cervical cancer according to the classified groups, wherein overexpression of ATP5H is group 1; low expression of ATP5H is group 2; low expression of ATP5H, SCP, and NANOG is group 3; and low expression of ATP5H and SCP and overexpression of NANOG is group 4. This method and these limitations are not disclosed in provisional application as filed; however, this method and limitations are disclosed in the Korean foreign application. Thus, claims 9-15 of this instant application have an effective filing date of 06/27/2023.
Claim 17 introduces subject matter not supported by the original provisional application. Claim 17 introduces subject matter supported by the disclosure provided for the Korean foreign application. Claim 17 is directed to a method for providing information for predicting the prognosis of cervical cancer of claim 16, wherein the clinical data is data on FIGO stage, tumor size, lymph node metastasis, oncological grade, and age. The limitation “tumor size” is not is not disclosed in the provisional application but is disclosed in the Korean foreign application . Thus, the effective filing date for claim 17 of this instant application is 06/27/2023.
Claims 18 introduces subject matter not supported by the original provisional application or the filed Korean foreign application. Claim 18 is directed to a kit for predicting the prognosis of cervical cancer comprising the biomarkers of claim 1. This kit is not disclosed in the provisional application or in the Korean foreign application. Thus, the effective filing date for claim 18 of this instant application is 08/23/2023.
Claim Status
Claims 1-18 are pending and examined herein below.
Information Disclosure Statement
Three Information Disclosure Statements (IDS), filed 08/23/2023, 08/02/2024, and 05/10/2025 are acknowledged and have been considered except for three NPL references in IDS filed on 05/10/2025 that were stricken for the reasons detailed herein.
Document NPL cite No. 1, Han et al., while the abstract is provided, the full article is missing/not provided.
Document NPL cite No. 3, Cho et al., the full article is not provided.
Document NPL cite No. 4, Oh et al., while the abstract is provided, the full article is missing/not provided.
Specification
The disclosure is objected to because of the following informalities:
In para 0078, Table 1, which claims to show a classification result of patient groups for deriving biomarkers, is not legible.
In para 0086, Table 2, which claims to show evaluation results of biomarkers for predicting the prognosis of cervical cancer, is not legible.
In para 0092, Table 3, which claims to show results of analyzing clinicopathological characteristics by group, is not legible.
Appropriate corrections are required.
Claim Objections
Claims 1 and 17 are objected to because of the following informalities:
Claim 1 recites abbreviations ATP5H, NANOG, PTEN, SCP (which may represent Synaptonemal Complex Protein 1, Synaptonemal Complex Protein 2, or Synaptonemal Complex Protein 3), and pERK.
Claim 17 recites abbreviation FIGO.
Claims are objected to for abbreviations in the claims. It is suggested that at the first
instance of an abbreviation, that the claims be amended in order to accompany the abbreviation with the full meaning for clarity (e.g., “Synaptonemal Complex Protein 3 (SCP3) at the first instance of the protein”).
Appropriate corrections are required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
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 when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: preparation for measuring expression levels of proteins in claim 3.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof. The specification describes the preparation for measuring the expression levels of the proteins of ATP5H, SCP, and NANOG may include at least one selected from the group consisting of antibodies, oligopeptides, ligands, peptide nucleic acid (PNA) and aptamers that specifically bind to the proteins of ATP5H, SCP, and NANOG [para 0019] and preparation for measuring the expression levels of the genes encoding the proteins of ATP5H, SCP, and NANOG may include at least one selected from the group consisting of primers, probes and antisense nucleotides that specifically bind to the genes encoding the proteins of and ATP5H, SCP, and NANOG [para 0020].
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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.
Claims 9-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The terms "low-expressed" and "overexpressed" in claims 9-12 are relative terms which render the claims indefinite. The terms "low-expressed" and "overexpressed" are not defined by the claims, 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. Low expression and overexpression levels for a protein is determined by comparing expression levels to a baseline value (eg., native expression levels) that is considered normal for the protein. This native level of expression differs for each protein. The specification fails to disclose what are the native expression levels for the proteins disclosed, therefore, a skilled artisan would not be able to determine, with a reasonable degree of certainty, what is low-expression or overexpression levels for each protein disclosed without undue experimentation.
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 9-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for measuring expression levels of ATP5H, SCP, and NANOG, providing information for expression levels, and providing information consisting of clinical data, does not reasonably provide enablement for determining which proteins are low-expressed and/or overexpressed without native expression levels to serve as reference point. Thus, a skilled artisan is further not enabled to define classified groups according to expression levels, , wherein group 1 is overexpressed ATP5H, group 2 is low-expressed ATP5H, group 3 is low-expressed ATP5H, SCP, and NANOG, and group 4 is low-expressed ATP5H, SCP and overexpressed NANOG.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Wand’s Factor Analysis:
Regarding the nature of the invention, the claimed invention is drawn to a machine-learning-based method and kit for predicting the prognosis of cervical cancer by classifying subjects into risk-level groups according to expression levels of protein biomarkers and subject clinical information data.
Regarding the breadth of the claims, the instant claims encompass a specific subset of protein or gene biomarkers to be monitored. The different expression levels in unhealthy patients at different stages of the disease define each of the four risk groups of patients ranging from favorable to poor prognosis.
Regarding the level of ordinary skill, an ordinary artisan in this area would have experience with cell culture, protein expression, purification, and characterization. A skilled artisan in this area would have a strong background knowledge in protein science and machine learning with machine learning skills including, at a minimum, the capability to organize raw medical datasets, proficiency in supervised learning algorithms for classification models, expertise in techniques that handle imbalanced datasets, and fluency in programming languages.
Regarding the state of the prior art, the prior art teaches that early diagnosis and prognosis of cancer is necessary for proper treatment management (Kourou et al., Machine learning applications in cancer prognosis and prediction, 2015, Computational and Structural Biotechnology Journal, 13, pgs. 8-9). Classifying cancer patients into low- and high-risk groups has become a critical step for developing personalized treatment strategies and for accurately predicting prognosis. Due to advancements in techniques and technologies for studying cancer, a large volume of cancer data is available and be used for creating cancer risk-group classifications. An increasing number of researchers are turning to Machine learning, which enables systems to learn to make predictions and decisions without direct programming, as a tool to make processing the voluminous data to creating risk groups with relevant parameters more feasible (Kourou et al., 2015, Computational and Structural Biotechnology Journal, 13, pgs. 8-9). A trend, referred to as “obvious” in the art, is providing an integration of clinical and genomic data to train the model. Importantly, the prior art teaches that a common problem in the field is the lack of external validation or testing regarding the predictive performance of the models, particularly with models using information consisting of gene expression levels (Kourou et al., 2015, Computational and Structural Biotechnology Journal, 13, pg. 9, full paras 3-4).
The prior art further teaches that there are several mechanisms that regulate protein expression levels to ensure appropriate levels and conditions are maintained for optimal cellular function (see G. Prelich, Gene Overexpression: Uses, Mechanisms and Interpretation, 2012, Genetics, 190, pg. 841 Abstract and full para 1). The prior art teaches that the threshold level, or the native level, for protein expression required for optimal function of cells differs for every protein. To determine if a protein is overexpressed or low-expressed, meaning expressed at a level that deviates from native expression levels, the native, or normal, expression levels must be known and considered (see H. Moriya, Quantitative nature of overexpression experiments, 2015, MBoC Perspectives, 26, pg. 3932; full paras 1-3). Protein expression levels below (low-expressed) or above (overexpressed) its critical threshold may result in defective or loss of protein function, which leads to significant disruption in the cell. For instance, the overexpression of certain proteins is the driving force in a number of human cancers and down syndrome (see G. Prelich, Gene Overexpression: Uses, Mechanisms and Interpretation, 2012, Genetics, 190, pg. 841 Abstract and full para 1 and see H. Moriya, Quantitative nature of overexpression experiments, 2015, MBoC Perspectives, 26, pg. 3932, full para 1 and pg. 3933, full para 2).
Additionally, the prior art teaches that prediction of disease prognosis, such as cancer, consists of at least three components, including: (i) cancer susceptibility (risk assessment), (ii) cancer recurrence/local control and (iii) the prediction of cancer survival (Kourou et al., 2015, Computational and Structural Biotechnology Journal, 13, pg. 11, full para 6).
Further, the art teaches that ATP5H, NANOG, and SCP are prognostic protein biomarker for cervical cancer (see Cho et al., 2014, PLOS ONE, 9, 6, e98712, 1-12, provided in IDS filed on 08/02/2024 as NPL cite No. 1; Song et al., 2018, J. Clinic. Inv., 128, 9, 4098-4114, provided in IDS filed on 08/02/2024 as NPL cite No. 3; and Gu et al., 2012, Am. J. Path., 181, 2, 652-661). Specifically, Cho teaches that high expression of SCP3 is associated with tumor stage, tumor grade, and poor prognosis for cervical cancer patients while low expression of SCP3 is associated for higher survival time and more favorable prognosis (see Cho et al., 2014, PLOS ONE, 9, 6, e98712 pg. 9, full para 2 ). Similarly, Gu teaches that the prior art shows that high expression levels of NANOG are associated with late-stage cervical cancer and oral cancer progression (Gu et al., 2012, Am. J. Path., 181, 2, pg. 659,full para 4).The prior art further teaches that loss or lower expression of ATP5H is strongly correlated with unsuccessful therapeutic treatment, disease progression and poor prognosis for cervical cancer patients. High ATP5H, however, was found in patients with early-stage cancer while low ATP5H was found in late-stage cancer patients with poor prognosis (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4107, full para 2 and pg. 4112, Table 1).
The instant disclosure does not provide a working example of using the claimed invention to accurately predict the prognosis of subjects, not part of the training set, using information such as expression levels of the specific subset of biomarkers. No working examples of using non-training data to validate the accuracy of the method for predicting the prognosis of cervical cancer patients according to groups stratified by expression levels of ATP5H, SCP, and NANOG biomarkers.
Regarding the predictability in the art, the specification lacks validation of the method for predicting prognosing cervical cancer according to classified groups based on low-expressed SCP and varying expression levels of ATP5H and NANOG biomarkers along with clinical data. The prior art teaches the need to validate cancer prognosis prediction models with non-training sets, particularly those using gene expression data, to ensure accuracy or high predictive value (Kourou et al., 2015, Computational and Structural Biotechnology Journal, 13, pg. 9, full paras 3-4). Further, the prior art teaches away from classifying group 4 with low-expressed SCP3 as high-risk patients with poor prognosis. Thus, in the art, low-expressed SCP combined with low-expressed ATP5H and overexpressed NANOG as being high-risk cervical cancer patients with poor prognosis is not predictable, especially for a machine learning-based method that lacks validation.
Regarding the amount of direction provided, the instant disclosure fails to provide guidance for determining the “normal” range of expression levels for ATP5H, SCP, and NANOG biomarkers and thereby fails to provide guidance as to how to determine what is low-expressed and high-expressed for each protein biomarker, which differs for each protein. The lack of working examples for making and using the claimed method further limits the guidance provided and does not enable a skilled artisan to reasonably make and use the full scope of the claimed invention.
Regarding the quantity of experimentation needed to make and use the invention based on the content of the disclosure, given the lack of guidance, working examples, and method validation for the model, it would require undue experimentation for a skilled artisan to (1) define what is low-expression and overexpression for each biomarker; (2) determine the accurate expression levels for biomarkers that corresponds to the different stages of cervical cancer, particularly high-risk, poor prognosis; (3) accurately classify the four risk-groups of cervical cancer patients based on expression level data, particularly the group for high-risk patients, with poor prognosis; and (4) validate the prediction model to ensure high predictive value, generalizability, and robustness.
Claim Rejections - 35 USC § 101
Claims 1-8 and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a nature-based product.
Claims 1-2 and 18 recite “biomarkers” comprising “at least one protein of ATP5H, NANOG, PTEN, SCP and pERK or genes encoding the proteins,” and further comprise “ATP5H, SCP and NANOG,” SCP referring to SCP3 (spec, paras 0016, 0079-0081), which are all naturally occurring proteins or genes in the human body that are isolated and monitored in a subject’s biological sample. Thus, these isolated naturally occurring protein biomarkers and genes encoding these proteins are products of nature. Each protein claimed is identical in its entirety to its corresponding naturally occurring counter parts, ATP5H, NANOG, PTEN, SCP, and pERK that are found in the human body. Additionally, the naturally occurring NANOG gene serves as the counterpart for at least one gene encoding one of the proteins isolated and monitored in a subject’s biological sample (Ting-Ting Gu et al., Cytoplasmic NANOG-Positive Stromal Cells Promote Human Cervical Cancer Progression, 2012, Am. J. Path., 181, 2, 652-661). The subset of isolated proteins (ATP5H, NANOG, PTEN, SCP, and pERK or genes encoding at least one of the proteins) that are detected and monitored in a patient’s sample and the naturally occurring counterparts (ATP5H, NANOG, PTEN, SCP, and pERK or the NANOG gene) circulating in the body do not have markedly different characteristics because the isolated proteins and genes encoding the proteins have the same biological structure, function, and chemical and physical properties as their identical naturally occurring counterparts found in the human body.
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 3-17 are rejected under 35 U.S.C. 101 because the claimed
invention is directed to nonstatutory subject matter. The claims 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 6-17 recite “predicting the prognosis of cervical cancer,” which given the broadest reasonable interpretation in light of the specification, involves making a correlation between an increase or decrease of expression levels of naturally occurring products to a result, namely a prediction about disease prognosis, which is drawn to a natural phenomenon (spec, para 0040). “Predicting the prognosis of cervical cancer” further requires a comparison of aforementioned expression levels of natural products to the expression levels of a control group to determine a result, namely if expression levels are increased or decreased, which is an abstract mental process (spec, para 0040 and claims 9-10). “The courts consider a mental process (thinking) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work’ that are open to all.’" 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012) ("‘[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work’" (quoting Benson, 409 U.S. at 67, 175 USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978) (same). Accordingly, the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions.” See MPEP 2106.049(a)(2).
Claims 7 and 13-15 recite “classifying the proteins or the genes” into one of four risk groups, which is an abstract mental process. The specification clarifies that “classifying” may be performed using a conventional software, which amounts to employing a generic computer to perform the abstract mental process (spec, paras 95-97 and Drawings Fig. 6). The courts do not “distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, “[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind.” Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015). See also Intellectual Ventures I LLC v. Symantec Corp., 838 F.3d 1307, 1318, 120 USPQ2d 1353, 1360 (Fed. Cir. 2016) (‘‘[W]ith the exception of generic computer-implemented steps, there is nothing in the claims themselves that foreclose them from being performed by a human, mentally or with pen and paper.’’); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016) (holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by humans without a computer")”. See MPEP 2106.04.(a)(2)
Step 2A, Prong 2
The judicial exception is not integrated into a practical application in claims 1-2 because using biomarkers to predict disease prognosis, which involves: (1) making a correlation between levels of natural biomarkers detected and monitored with disease prognosis and; (2) making a comparison between an experimental group and a control group to define an increase or decrease in expression levels, are drawn to a natural phenomenon and an abstract mental process, respectively. Therefore, this additional element does not add a meaningful limitation to the abstract idea recited in the instant claims.
The judicial exceptions are not integrated into a practical application in claims 1-18 because measuring expression levels of a biomarker and providing information to aid in predicting disease prognosis are insignificant extra-solution activities, namely data-gathering and data output steps. Further, classifying disease risk-level for recurrence into one of four risk groups is an abstract mental process. Therefore, these additional elements do not add a meaningful limitation to the natural phenomenon or the abstract mental process recited in the instant claims.
The judicial exception is not integrated into a practical application in claims 3-5 because using the composition to enable measuring expression levels of a biomarker is an insignificant extra-solution activity, namely a data-gathering step, that does not add a meaningful limitation to the natural phenomenon recited in the instant claims.
The judicial exception is not integrated into a practical application in claims 7 and 13-15 because predicting disease prognosis using information provided by the classification of disease risk-level involves making a correlation between detection of biomarkers and disease prognosis and a comparison between an experimental group and a control group to determine degree of expression level, which are drawn to a natural phenomenon and an abstract mental process, respectively. Further, providing information to aid in predicting disease prognosis is an insignificant extra-solution activity, namely a data-gathering and/or data output step. Therefore, these additional elements do not add a meaningful limitation to the abstract mental process or the law of nature recited in the instant claims.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS
CONTRIBUTE AN "INVENTIVE CONCEPT"
Step 2B:
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because although prediction of disease prognosis would enable treatment that is tailored or customized for different individuals, the instant disclosure fails to specify a new treatment type or step (spec, paras 0045 and 0083). Using the broadest reasonable interpretation in light of the specification, with a predicted prognosis the tailored personal medicine or treatment plan would be routine, conventional, and well-known for treating cervical cancer. The observe-and-treat routine with well-known and conventional treatments does not suffice to impart patentability to the instant claims.
Further, the additional element of measuring expression levels of genes would be performed by matrix laser desorption/ionization time of flight mass spectrometry (MALDI-TOF) analysis, multiple reaction monitoring (MRM) method, or reverse transcription polymerase reaction (RT-PCR), among several other techniques disclosed, which are all well-established, routine, and conventional methods, and thus fails to amount to significantly more than the judicial exception (spec, paras 0035-0039). For instance, Scott et al. published a protocol comprising a modified method of RT-PCR for performing gene expression analysis to identify and validate cancer biomarkers, which a skilled artisan would easily adapt to measure expression levels of cervical cancer biomarkers (see Scott, A., Ambannavar, R., Jeong, J., Liu, ML., Cronin, M.T., 2011, RT-PCR-Based Gene Expression Profiling for Cancer Biomarker Discovery from Fixed, Paraffin-Embedded Tissues. In: Al-Mulla, F. (eds) Formalin-Fixed Paraffin-Embedded Tissues. Methods in Molecular Biology, 724, Humana Press, 239-257). Further, the aims of a protocol for using MALD-IMS and MRM to identify and validate tumor neovasculature biomarkers by Gambhir and Brooks was published by National Cancer Institute (NCI) Early Detection Research Network (EDRN), where MRM was one method used to quantitate biomarker expression levels (see S. Gambhir, J.D. Brooks, 2012, Using MALDI-IMS and MRM to stablish a pipeline for discovery and validation of tumor neovasculature biomarker candidates, Early Detection Research Network (EDRN)National Cancer Institute).
Further, the courts have recognized methods for measuring or detecting naturally occurring proteins for diagnosing or prognosing a disease as being directed to a law of nature, even if the correlation is novel and non-obvious. The courts have ruled that a novel and non-obvious correlation between a naturally occurring biomarker and a diagnosis, or prognosis, does not suffice to impart patentability or amount to significantly more than the judicial exception when the techniques and methods of detection are routine and conventional (see Athena Diagnostics, Inc. v. Mayo Collaborative Services, 915 F.3d 743 (Fed. Cir. 2019). The Federal Circuit affirmed that a method for diagnosing the neurological disorder myasthenia gravis (MG) by detecting naturally produced MuSK autoantibodies was invalid under 35 U.S.C. § 101. Although the correlation between MuSK autoantibodies and MG was newly discovered and free from the prior art, the detection steps were deemed conventional and did not transform the natural law into a patent-eligible application).
Moreover, based on the clarification provided by the instant specification, the additional elements of classifying the disease by risk levels for recurrence according to expression levels of biomarkers would be performed using algorithms and/or software that perform statistical analysis such as cox regression analysis. However, the instant disclosure fails to provide a specific algorithm or non-conventional software that would be used to improve the processor or technology (spec, para 0085 and Drawings Fig. 6). The methods disclosed for classifying cervical cancer into one of four risk levels based on biomarker expression levels is not distinct from well-known, routine, and conventional methods. For instance, Mohammed et al. used a combination of cox regression analysis and random survival forest model, using data from biomarker gene expression levels, to rank colorectal cancer genes based on association with survival, which enabled prediction of disease prognosis (see M. Mohammed et al., Predictors of colorectal cancer survival using cox regression and random survival forests models based on gene expression data, 2021, PLoS One, 16, 12, e0261625, 1-22).
For these reasons, the claims fail to include additional elements that are sufficient to
amount to significantly more than the judicial exception.
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 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Cho et al., (Hanbyoul Cho et al., Synaptonemal Complex Protein 3 Is a Prognostic Marker in Cervical Cancer, 2014, PLOS ONE, 9, 6, e98712, 1-12, provided in IDS filed on 08/02/2024 as NPL cite No. 1).
Cho et al. teach the clinical relevance of synaptonemal complex protein 3 (SCP3) by examining SCP3 expression in tumor specimens from cervical cancer and cervical intraepithelial neoplasia(CIN) patients using immunohistochemistry. Cho et al further teach analyzing the correlation between SCP3 expression and clinic pathologic factors or survival. Cho teaches high expression of SCP3 is associated with tumor stage, tumor grade, and poor prognosis of cervical cancer patients. Cho further teaches that cumulative analysis of experimental results suggest SCP3 plays a significant role in the progression of cervical cancer and could be a novel cervical cancer therapeutic target.
Regarding claim 1, Cho teaches biomarkers for predicting prognosis of cervical cancer comprising at least one protein of ATP5H, NANOG, PTEN, SCP and pERK or genes encoding the proteins (pg. 9, full para 2 and pg. 10, Table 2).
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.
Claim(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over Cho et al., (Hanbyoul Cho et al., 2014, PLOS ONE, 9, 6, e98712, 1-12, provided in IDS filed on 08/02/2024 as NPL cite No. 1), in view of Song et al., (Kwon-Ho Song et al., Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance, 2018, J. Clinic. Inv., 128, 9, 4098-4114, provided in IDS filed on 08/02/2024 as NPL cite No. 3), Jeter et al., (Collene R. Jeter et al., NANOG in cancer stem cells and tumor development: An update and outstanding questions, 2015, Stem Cells, 33, 8, 2381-2390), and Fleischmann et al (Maximilian Fleischmann et al., Molecular Markers to Predict Prognosis and Treatment Response in Uterine Cervical Cancer, 2021, Cancers, 13, 5748, 1-28).
The teachings of Cho et al and how Cho et al anticipates claim 1 are discussed above (see Claim Rejections - 35 USC § 102). Cho teaches all the limitations of claim 1 and wherein the biomarker is SCP, but Cho does not teach wherein the biomarkers are ATP5H and NANOG (Cho et al., PLOS ONE, 9, 6, e98712, 1-12).
However, Song, in the same field of endeavor, teaches that loss or lower expression of ATP5H is strongly correlated with cervical cancer progression and poor prognosis (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4107, full para 2 and pg. 4112, Table 1). Song teaches that loss of mitochondrial ATP5H is strongly linked to unsuccessful therapeutic treatment, progression of cancers including cervical cancer, and poor survival in patients with cancer including cervical cancer. Specifically, Song et al. found that high ATP5H was found in patients with early-stage cancer while low ATP5H was found in late-stage cancer patients with poor prognosis (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4107, full para 2 and pg. 4112, Table 1). Song does not teach wherein the biomarkers are SCP and NANOG.
However, Jeter, in the same field of endeavor, teaches wherein NANOG is a biomarker (Jeter et al., 2015, Stem Cells, 33, 8, pg. 10, full para 2 and pg. 2, full para 2). Jeter teaches the state of the prior regarding the clinical relevance homeobox domain transcription factor NANOG, which regulates embryonic development and cellular reprogramming. Jeter teaches that functional studies suggest that NANOG plays an important role in malignant disease, tumorgenicity, invasiveness, and resistance to treatment (Jeter et al., 2015, Stem Cells, 33, 8, pg. 2, full para 2). Additionally, Jeter teaches that NANOG is a pro-tumorigenic factor and can be considered a biomarker for cancer diagnosis, prognosis and predictor of therapeutic efficacy (Jeter et al., 2015, Stem Cells, 33, 8, pg. 10, full para 2). Cho, Song, and Jeter do not teach combining biomarkers ATP5H, SCP, and NANOG.
However, Fleischman, in the same field of endeavor, teaches combining more than a single biomarker for precise prediction of disease prognosis (Fleischmann et al., 2021, Cancers, 13, pg. 9, full para 4). Fleischmann teaches the need for a panel of biomarkers to predict response to treatment, predict survival, and identify patients at low- and high-risk for cervical cancer. Fleischmann teaches that the prior art shows that tumor size, FIGO stage, pelvic or paraaortic lymph node involvement, non-squamous-cell carcinoma, performance status, and ethnicity/race were correlated with survival (Fleischmann et al., 2021, Cancers, 13, pg. 3, full para 1). Fleischmann further teaches that the prior art shows the complex gene and cellular changes caused by cervical cancer gives rise to different responses from a diversity of protein biomarkers. Hence, a single biomarker is not likely to prognosticate cervical cancer or predict response to treatment. Fleischmann further teaches that combining two or more biomarkers, however, may enable prediction of response to treatment and disease prognosis (Fleischmann et al., 2021, Cancers, 13, pg. 9, full para 4).
Regarding claim 2, the term “SCP” is not specific enough as a single protein biomarker because SCP1, SCP2, and SCP3 are regulated differently in cancer cells and all may not be suitable biomarkers for cervical cancer. Using the broadest reasonable interpretation and in light of the instant specification, the term “SCP” is interpreted as SCP3 in all relevant instant claims examined herein (see spec title of invention; spec paras 0016 and 0079).
Given the teaching of the prior art above, it would have been prima facie obvious, at the time of filing, to combine measuring expression levels of ATP5H, as taught by Song, with SCP expression levels, as taught by Cho, and NANOG expression levels, as taught by Jeter, in a method of detecting multiple biomarkers, as taught by Fleishmann. The prior art teaches that detecting or measuring a single biomarker is less likely to predict prognosis and treatment response. The prior art teaches that combined marker analysis of more than one biomarker is a promising approach for precisely predicting treatment response and survival more (Fleischmann et al., 2021, Cancers, 13, pg. 9, pg. 9, full para 4). Therefore, a skilled artisan would have been motivated to combine the method of measuring expression levels for ATP5H, SCP, and NANOG biomarkers with the method of detecting/monitoring multiple biomarkers simultaneously because it would enable a skilled artisan to more precisely predict cervical cancer prognosis. A person having ordinary skill in the art would have a reasonable expectation of success because the prior art (1) teaches methods for measuring expression levels of ATP5H, SCP, and NANOG; (2) establishes these as cervical cancer biomarkers; and (3) shows that monitoring a panel of biomarkers increases precision of cancer diagnosis. Thus, combining these known methods and teachings in the prior art would yield predicable results.
Claim(s) 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al., (Ting-Ting Gu et al., Cytoplasmic NANOG-Positive Stromal Cells Promote Human Cervical Cancer Progression, 2012, Am. J. Path., 181, 2, 652-661) , in view of Song et al., (Kwon-Ho Song et al., 2018, J. Clinic. Inv., 128, 9, 4098-4114, provided in IDS filed on 08/02/2024 as NPL cite No. 3), Cho et al., (Hanbyoul Cho et al., 2014, PLOS ONE, 9, 6, e98712, provided in IDS filed on 08/02/2024 as NPL cite No. 1), and Fleischmann et al (Maximilian Fleischmann et al., 2021, Cancers, 13, 5748, 1-28).
Gu teaches that the NANOG protein is transcribed from the NANOG gene in cervical cancer (Gu et al., 2012, Am. J. Path., 181, 2, pgs. 652-653; 657, full para 1; pg. 656, full para 2-pg. 657, full para 1). Gu teaches that NANOG is often expressed in the cytoplasm in cervical cancer cells and NANOG distribution across stromal cells is associated with cervical cancer progression (Gu et al., 2012, Am. J. Path., 181, 2,pg. 653, full para 1; pg. 655, full para 2; and pg. 659, full para 3). Gu further teaches that cellular location of NANOG is associated with cell type and tumor stage. Gu teaches that the prior art shows that high expression levels of NANOG are associated with late-stage cervical cancer progression in other cancers such as oral cancer (Gu et al., 2012, Am. J. Path., 181, 2, pg. 659,full para 4).
Regarding claim 3, Gu teaches a composition for predicting prognosis of cervical cancer comprising a preparation for measuring expression levels of proteins of NANOG but Gu does not teach measuring expression levels of proteins of ATP5H and SCP or genes encoding the proteins (Gu et al., 2012, Am. J. Path., 181, 2, pg. 652, full para 2 continue to pg. 653 and pg. 655, full para 2).
However, Song, in the same field of endeavor, teaches a composition for predicting prognosis of cervical cancer comprising a preparation for measuring expression levels of ATP5H (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4111 full para 2; Figs. 1A and 9A). Song does not teach comprising a preparation for measuring expression levels of SCP.
Cho, in the same of endeavor, teaches a composition for predicting prognosis of cervical cancer comprising a preparation for measuring expression levels of SCP (Cho et al., 2014, PLOS ONE, 9, 6, e98712, pg. 8, full para 1). As explained above, using the broadest reasonable interpretation and in light of the instant specification, the term “SCP” is interpreted as SCP3 (see spec title of invention; spec paras 0016 and 0079).
Gu, Song, and Cho do not teach measuring expression levels for the combination of proteins ATP5H, SCP, and NANOG or genes encoding the proteins.
However, Fleischman, in the same field of endeavor teaches detecting and monitoring molecular features, such as expression levels, of more than a single biomarker for precise prediction of disease prognosis (Fleischmann et al., 2021, Cancers, 13, pg. 9, full para 4).
It would have been prima facie obvious, at the time of filing, to combine (1) the composition used for measuring NANOG expression levels, as taught by Gu, with (2) the composition used for measuring expression levels of ATP5H, as taught by Song, with (3) the composition used for measuring SCP expression levels, as taught by Cho, and 4) for the reasons taught by Fleishmann. A skilled artisan would have been motivated to combine compositions for measuring ATP5H, SCP, and NANOG expression levels with the method of monitoring a combination of expression levels for ATP5H, SCP, and NANOG because it would enable a skilled artisan to more precisely predict cervical cancer prognosis and improve treatment and survival in cervical cancer. A person having ordinary skill in the art would have a reasonable expectation of success because, at the time of filing, the prior art (1) taught compositions for measuring expression levels of ATP5H, SCP, and NANOG; (2) established ATP5H, SCP, and NANOG as prognostic cervical cancer biomarkers; and (3) taught that monitoring molecular features, such as expression levels, for more than one prognostic biomarker increases precision of cancer prognosis. Thus, combining these known methods and teachings in the prior art would yield predicable results.
Regarding claims 4-5, Gu teaches the composition for predicting the prognosis of cervical cancer of claim 3, wherein the preparation for measuring the expression levels of the protein of NANOG includes at least one selected from the group consisting of antibodies, oligopeptides, ligands, peptide nucleic acid (PNA) and aptamers that specifically bind to the protein of NANOG and for measuring the expression levels of the genes encoding NANOG consisting of primers, probes and antisense nucleotides that specifically binds to the gene encoding the protein of NANOG. (Gu et al., 2012, Am. J. Path., 181, 2, pg. 653, full paras 3-5 and pg. 656, full para 2- pg. 657. paras 1-2). Gu does not teach wherein the preparation for measuring the expression levels of the protein of ATP5H and SCP that specifically bind to the protein of SCP and NANOG.
However, Song, in the same field of endeavor, teaches the composition for predicting the prognosis of cervical cancer of claim 3, wherein the preparation for measuring the expression levels of the protein of ATP5H includes at least one selected from the group consisting of antibodies, oligopeptides, ligands, peptide nucleic acid (PNA) and aptamers that specifically bind to the protein of ATP5H and for measuring the expression levels of the genes encoding ATP5H includes at least one from the group consisting of primers, probes and antisense nucleotides that specifically bind to the genes encoding the proteins of ATP5H, SCP3, and NANOG (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4111 full paras 1-2 and Figs. 1A, 1F, and 9A). Song does not teach wherein the preparation for measuring the expression levels of the protein of SCP that specifically bind to the protein of SCP.
Cho, in the same of endeavor, teaches the composition for predicting the prognosis of cervical cancer of claim 3, wherein the preparation for measuring the expression levels of the protein SCP includes at least one selected from the group consisting of antibodies, oligopeptides, ligands, peptide nucleic acid (PNA) and aptamers that specifically bind to the protein of SCP and for measuring the expression levels of the genes encoding SCP includes at least one selected from the group consisting of primers, probes and antisense nucleotides that specifically bind to the gene encoding the protein of SCP (Cho et al., PLOS ONE, 9, 6, e98712, pg.7, full para 1 and pg. 8, full para 1-2). As explained above, using the broadest reasonable interpretation and in light of the instant specification, the term “SCP” is interpreted as SCP3 (see spec title of invention; spec paras 0016 and 0079).
Song, Cho, and Gu do not teach a combination of compositions to that specifically bind to the combination of proteins ATP5H, SCP, and NANOG or genes encoding the proteins.
However, Fleischman, in the same field of endeavor teaches detecting and monitoring molecular features for more than a single biomarker for precise prediction of disease prognosis (Fleischmann et al., 2021, Cancers, 13, pg. 9, full para 4).
It would have been prima facie obvious, at the time of filing, to combine (1-3) the compositions taught by Gu, Song, and Cho, and Gu that bind specifically to NANOG, ATP5H, and SCP proteins and genes that encode them to measure expression levels to predict cervical cancer prognosis and further combine with (4) the method for detecting and monitoring molecular features of multiple biomarkers, as taught by Fleischmann. The prior art teaches that robust molecular markers for predicting therapy response and survival for cervical cancer patients are urgently needed. The prior art teaches that measuring two or more biomarkers would enable precise prediction of disease prognosis and meet this urgent market need (Fleischmann et al., 2021, Cancers, 13, 5748, 1-28, pg. 9, full para 4). Therefore, a skilled artisan would have been motivated to combine these methods because it would enable a skilled artisan to more precisely detect and predict cervical cancer prognosis, which would enable improved cervical cancer management and patient survival times. A person having ordinary skill in the art would have a reasonable expectation of success because the method for using preparations selected from the groups listed in claims 4-5 to detect and track the expression levels of these known cervical cancer biomarkers was taught in the prior at the time of filing. A skilled artisan would have a further reasonable expectation of success because using information gathered from detecting and monitoring expression levels of more than one biomarker to increase accuracy of prediction models for cervical cancer prognosis was known in the art at the time of filing. Therefore, combining these known and conventional elements to improve the precision of a method for predicting disease prognosis would yield predictable results.
Claim(s) 6-10 and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ding et al., (Dongyan Ding et al., Machine learning-based prediction of survival prognosis in cervical cancer, 2021, BMC Bioinformatics, 22, 331, 1-17), in view of Song et al., (Kwon-Ho Song et al., 2018, J. Clinic. Inv., 128, 9, 4098-4114, provided in IDS filed on 08/02/2024 as NPL cite No. 3).
Throughout the article, Ding teaches a gene-expression- or molecular features-based machine learning cervical cancer prognosis prediction model. Ding teaches using subjects’ clinical data alone is insufficient for precise prediction of cervical cancer prognosis (Ding et al., 2021, BMC Bioinformatics, 22, 331, pgs. 2-5). Ding teaches that the prior art teaches molecular features, such as gene expression levels, imply substantial information about cancer cells including malignant level, metastasis ability and therapeutic sensitivity. Ding teaches the development of a molecular features-based prediction model keeps the promise for improving the accuracy of cancer survival prediction model. Ding further teaches that as a part of artificial intelligence, machine learning (ML) provides a solution for accuracy improvement of cancer survival prediction models.
The teachings of Song et al. are discussed above (see Claim Rejections - 35 USC § 103 for instant claim 2).
Regarding claim 6, Ding teaches a method for providing information for predicting prognosis of cervical cancer, comprising measuring expression levels of at least one protein (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 5, full para1 and pg. 6, Fig. 2), but Ding does not teach at least one protein selected from the group consisting of ATP5H, SCP and NANOG or genes encoding the proteins in a biological sample isolated from a subject.
However, Song, in the same field of endeavor, teaches measuring expression levels of at least one protein selected from the group consisting of ATP5H in a biological sample isolated from a subject (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4111 full para 2; Figs. 1A and 9A ).
It would have been prima facie obvious, at the time of filing, to combine the method of providing expression level information for predicting cervical cancer prognosis as taught by Ding, with the method of measuring expression levels of ATP5H, as taught by Song. The prior art teaches that cervical cancer is one of the leading causes of female deaths worldwide, with most women in developing countries at higher risk due to lacking access to preventative vaccinations and medical care, especially during early stages of the disease (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 1). Further, the prior art teaches that expression levels of ATP5H are directly correlated to cervical cancer prognosis (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4107, full para 2 and pg. 4112, Table 1). Therefore, a skilled artisan would have been motivated to combine these methods because it would enable a skilled artisan to accurately predict cervical cancer prognosis and improve early cervical cancer care management. A person having ordinary skill in the art would have a reasonable expectation of success because, at the time of filing, (1) Song taught the method of measuring expression levels of ATP5H along with the direct correlation of ATP5H with disease prognosis and (2) Ding taught providing molecular information to develop a model that predicts cervical cancer prognosis successfully. Therefore, combining these two known methods would yield predictable results.
Regarding claim 7, Ding and Song teach the method for providing information for predicting the prognosis of cervical cancer of claim 6, and Ding further comprising: classifying the proteins or the genes into any one of groups 1 to 4 according to the measured expression level (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 1, “Abstract”; pg. 6, full para 1-pg. 9; pg. 6, Fig. 2A; and pg. 7, Fig. 3).
Regarding claim 8, Ding and Song teach all the limitations of claim 6 and Ding further teaches the method for providing information for predicting the prognosis of cervical cancer of claim 7, further comprising: providing results for predicting the prognosis of cervical cancer for the subject according to the classified groups (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 1, “Abstract; pg. 10, full para 1).
Regarding claims 9-10, Ding and Song teach all the limitations of claim 6 and Ding further teaches the method for providing information for predicting the prognosis of cervical cancer of claim 8, wherein in the providing of the results for predicting the prognosis of cervical cancer for the subject according to the classified groups (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 10, full para 1), but Ding does not teach the group 1 is a group with overexpressed ATP5H as compared with a normal control group and group 2 is a group with low-expressed ATP5H as compared with a normal control group.
However, Song, in the same field of endeavor, teaches that ATP5H expression level is a strong predictor of overall survival and disease prognosis, specifically, high expression levels of ATP5H are found in tumors of patients with early-stage (I–IIA) cancer whereas beginning with low down to loss of expression levels of ATP5H are associated with poor prognosis (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4107, full para 1; pg. 4111, Fig. 10).
It would have been prima facie obvious, at the time of filing, to combine the method of using molecular information to predict disease prognosis according to classified groups, as taught by Ding, with the teachings that high ATP5H expression levels are correlated with favorable cervical cancer prognosis, as taught by Song. The specification of this instant application clarifies that group 1 is defined as patients with low-risk level of recurrence and group 2 is defined as patients with an intermediate-risk level of recurrence (spec, para 0033). Using the broadest reasonable interpretation, group 1 is associated with the most favorable prognosis relative to risk-groups 2, 3 and 4 and group 2 is associated with more favorable prognosis than groups 3 and 4. The prior art teaches that there are 260,000 deaths per year caused by cervical cancer and it is one of the leading causes of death for women globally. Early detection is paramount for improving prognosis (Dinge et al., 2021, BMC Bioinformatics, 22, pg. 1). A skilled artisan would have been motivated to combine the method taught by Ding and the teachings of ATP5H overexpression associated with favorable prognosis, taught by Song, because it would enable a skilled artisan to accurately prognosticate early-stage cervical cancer, track success of prevention efforts, and improve prognosis with early cancer management. A person having ordinary skill in the art would have a reasonable expectation of success because (1) the method of classifying patients into groups, beginning with a low-risk group for successful and accurate cervical cancer prognosis based on expression level information of a biomarker and (2) overexpression of ATP5H associated with low-risk and a favorable prognosis for cervical cancer were known in the art at the time of filing. Combining these known methods and teachings in the prior art would yield predictable results.
Regarding claim 13, Ding and Song teach all the limitations of claim 6 and Ding further teaches the method for providing information for predicting the prognosis of cervical cancer of claim 8, further comprising: classifying the group 1 as a low-risk group (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 8, lines 1-5; pg. 9, lines 1-2 and Fig. 5c; pg. 10, full para 2).
Regarding claim 14, Ding and Song teach all the limitations of claim 6 and Ding further teaches the for providing information for predicting the prognosis of cervical cancer of claims 8, further comprising: classifying the groups 2 and 3 as intermediate-risk groups (Ding et al., pg. 8, lines 1-5; pg. 9, lines 1-2 and Fig. 5c; pg. 10, full para 2).
Regarding claim 15, Ding and Song teach all the limitations of claim 6 and Ding further teaches the method for providing information for predicting the prognosis of cervical cancer of claim 8, further comprising: classifying the group 4 as a high-risk group (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 8, lines 1-5; pg. 9, lines 1-2 and Fig. 5c; pg. 10, full para 2).
Regarding claim 16, Ding and Song teach the method for providing information for predicting the prognosis of cervical cancer of claim 6, wherein the providing of the results for predicting the prognosis of cervical cancer for the subject according to the classified groups further includes providing results for predicting the prognosis of cervical cancer for the subject by including the expression levels of at least one protein selected from the group consisting of ATP5H, SCP and NANOG or genes encoding the proteins in the biological sample isolated from the subject (Ding et al., 2021, BMC Bioinformatics, 22, 331, pg. 6, full para 1-pg. 9; pg. 6, Fig. 2A; and pg. 7, Fig. 3), but in the same embodiment, Ding does not teach combining expression levels of at least one protein with clinical data information on the subject as information provided to predict prognosis of cervical cancer according to classified groups.
However, in a different embodiment in the same disclosure, Ding teaches that providing information including only clinical data information is insufficient for developing an accurate prediction model for cervical cancer prognosis (Ding et al., 2021, BMC Bioinformatics, 22, 331, pgs. 3-5).
It would have been prima facie obvious, at the time of filing, to combine the method for providing only molecular features, such as expression levels of ATP5H, to predict cervical cancer prognosis according to classified groups, as taught by Ding and Song, with the method for providing only subject clinical data information to predict cervical cancer prognosis, as taught by Ding in another embodiment in the same reference. A skilled artisan would have been motivated to combine these methods because it would enable a skilled artisan to increase the accuracy of the prediction model for disease prognosis for each subject. A person having ordinary skill in the art would have a reasonable expectation of success because simply combining the two embodiments taught by Ding in the same reference at the time of filing, with the teachings of ATP5H taught in the prior art at the time of filing, to make predicable improvements to the method for predicting cervical cancer prognosis would yield predictable results.
Claim(s) 11 is rejected under 35 U.S.C. 103 as being unpatentable over Ding et al., (Dongyan Ding et al., 2021, BMC Bioinformatics, 22, 331, 1-17) in view of Song et al., (Kwon-Ho Song et al., 2018, J. Clinic. Inv., 128, 9, 4098-4114, provided in IDS filed on 08/02/2024 as NPL cite No. 3), as applies to claims 6 and 8 above, further in view of Cho et al., ((Hanbyoul Cho et al., 2014, PLOS ONE, 9, 6, e98712, 1-12, provided in IDS filed on 08/02/2024 as NPL cite No. 1), and Gu et al., (Ting-Ting Gu et al., 2012, Am. J. Path., 181, 2, 652-661), as evidenced by Fleishmann et al., (Maximilian Fleischmann et al., Molecular Markers to Predict Prognosis and Treatment Response in Uterine Cervical Cancer, 2021, Cancers, 13, 5748, 1-28).
The teachings of Ding, Song, Cho, Gu, and Fleischmann are discussed above.
Regarding claim 11, Ding and Song teach all the limitations of claim 6 and Ding further teaches all the limitations of claim 8. The specification of this instant application defines group 3 as intermediate-risk patients, with worst prognosis than group 1 (spec, paras 0003 and 0033). Song teaches that patients with amounts ranging from low expression to loss of ATP5H expression had increasingly poorer prognosis. However, patients with high expression of ATP5H during early-stage cervical cancer had a favorable prognosis (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4107, full para 1; pg. 4111, Fig. 10; pg. 4112, Table 2, provided in IDS filed on 08/02/2024 as NPL cite No. 3). Therefore, using the broadest reasonable interpretation and in light of the specification, Song teaches the group 3 is a group with low-expressed ATP5H. Ding and Song do not teach wherein group 4 is a group with low-expressed SCP and overexpressed NANOG.
However, Gu, in the same field of endeavor, teaches that expression levels of NANOG in cervical cancer cells are associated with progression and prognosis of cervical cancer (Gu et al., 2012, Am. J. Path., 181, 2, pg. 656). Gu further teaches that overexpression of NANOG is positively associated with late-stage progression of the disease and poor prognosis (Gu et al., 2012, Am. J. Path., 181, 2, pg. 659, para “Discussion”). Using the broadest reasonable interpretation in light of the specification, group 3 is an intermediate risk-level with a more favorable prognosis relative to group 4, therefore, Gu reads on the following limitation in claim 11: wherein group 3 is an intermediate-risk group with low-expressed NANOG. However, Gu does not teach wherein group 3 is a group with low-expressed SCP.
However, Cho, in the same field of endeavor, teaches overexpression of SCP is associated with shorter survival times or poor prognosis relative to lower levels of SCP expression in cervical cancer cells. Using the broadest reasonable interpretation in light of the specification, group 3 is an intermediate risk-level with a more favorable prognosis relative to group 4, therefore, Cho reads on the following limitation in claim 11: wherein group 3 is an intermediate-risk group with low-expressed SCP (see Cho et al., 2014, PLOS ONE, 9, 6, e98712 pg. 9, full para 2).
Ding, Song, Gu, and Cho do not teach combining the molecular information, such as expression levels, of ATP5H, SCP, and NANOG in one classified group to predict cervical cancer prognosis.
However, Fleischman in the same field of endeavor teaches detecting and monitoring molecular features, such as expression levels, of more than a single biomarker for precise prediction of disease prognosis (Fleischmann et al., 2021, Cancers, 13, pg. 9, full para 4).
It would have been prima facie obvious, at the time of filing, to combine (1) the method of providing information, such as expression levels of a prognostic biomarker for predicting cervical cancer prognosis according to classified groups, as taught by Ding and Song, with (2-4) measuring expression levels of prognostic biomarkers ATP5H, SCP, and NANOG, as taught by Song, Gu, and Cho, respectively, with (5) with the method of combining information from more than one prognostic biomarker for accurately predicting cervical cancer prognosis, as taught by Fleischmann. The prior art teaches that detecting or measuring a single biomarker is less likely to accurately predict cervical cancer prognosis and treatment response. The prior art further teaches that combined marker analysis using more than one biomarker is a promising approach for precisely predicting treatment response and survival times for cervical cancer patients (see Fleischmann et al., 2021, Cancers, 13, pg. 9, full para 4). Therefore, at the time of filing, a skilled artisan would have been motivated to combine these methods because it would enable a skilled artisan to more accurately predict cervical cancer prognosis, which would improve treatment management and patient survival time. A person having ordinary skill in the art would have a reasonable expectation of success because (1) methods for providing molecular information such as biomarker expression levels to predict cervical cancer prognosis according to classified groups; (2) teachings that low expression of ATP5H, SCP, and NANOG are associated with more favorable disease prognosis; and (3) teachings that combining molecular information for multiple prognostic biomarkers would increase accuracy of prediction for disease prognosis were all known in the art at the time of filing. Therefore, combining these known elements would yield predictable results.
Claim(s) 17 is rejected under 35 U.S.C. 103 as being unpatentable over Ding et al., (Dongyan Ding et al., 2021, BMC Bioinformatics, 22, 331, 1-17) in view of Song et al., (Song et al., 2018, J. Clinic. Inv., 128, 9, 4098-4114), as applies to claims 6, 8, and 16 above, further in view of Fleischmann et al., (Maximilian Fleischmann et al., 2021, Cancers, 13, 5748, 1-28 ), and McCluggage (W. Glenn McCluggage, Towards developing a meaningful grading system for cervical squamous cell carcinoma, 2018, J Path: Clin Res, 4, 81-84).
The teachings of Ding et al. and how instant claims 6, 8 and 16 are obvious over Ding et al. are discussed above.
The teachings of Song et al. and how instant claims 6 and 16 are obvious over Song et al. are discussed above.
The teachings of Fleischmann et al. are discussed above (see Claim Rejections - 35 USC § 103, claim 2).
Regarding claim 17, Ding and Song teach all the limitations of claim 6 and Ding further teaches the method for providing information for predicting the prognosis of cervical cancer of claim 16, wherein the clinical data is data on FIGO stage, and age, but Ding and Song do not teach wherein the clinical data is data on tumor size, lymph node metastasis, and oncological grade
However, Fleischmann, in the same field of endeavor, teaches clinical data information for predicting cervical cancer prognosis wherein the clinical data is on tumor size and lymph node metastasis (2021, Cancers, 13, pg. 3, full para 1), but Fleishman does not teach wherein the clinical data is data on oncological grade.
However, McCluggage, in the same field of endeavor, teaches using an oncological grading system for cervical cancer to predict disease prognosis and suggests combining oncological tumor grade with molecular features, such as expression levels of cervical cancer biomarker to accurately predict disease prognosis (McCluggage, 2018, J Path: Clin Res, 4, pg. 83, last para and pg. 85).
Throughout the article, McCluggage teaches that current grading systems for cervical squamous cell carcinomas, a type of cervical cancer, cannot be used to predict disease prognosis (McCluggage, 2018, J Path: Clin Res, 4, pg. 82, full para 1). McCluggage teaches meeting this need by developing a meaningful and straight-forward grading system. McCluggage teaches a grading method that has been shown to be prognostic for squamous cell carcinomas located in different anatomical sites, suggesting a promising method that can serve as the basis for a common grading system applicable to various types of squamous cell carcinomas, including cervical cancer (McCluggage, 2018, J Path: Clin Res, 4, pgs. 83-85). McCluggage further teaches and suggests combining information from oncological grading with molecular features, such as biomarker expression levels (McCluggage, 2018, J Path: Clin Res, 4, pg. 85).
It would have been prima facie obvious, at the time of filing, to combine (1) the method for providing molecular features such as expression levels of a prognostic biomarker to predict cervical cancer prognosis, as taught by Ding and Song, with (2) the method for providing subject clinical data information for predicting disease prognosis, as taught by Ding in a different embodiment in the same reference, with (3) the method for providing clinical data information for predicting cervical cancer prognosis, as taught by Fleischmann, with (4) the methods for including oncological grade as clinical data for predicting cervical cancer prognosis and combining with molecular features, as taught and suggested by McCluggage. A skilled artisan would have been motivated to combine these methods because it would enable a skilled artisan to amplify the accuracy and predictive power of a prognostic model for cervical cancer when combining multiple prognostic features including molecular information on a prognostic biomarker and clinical information with prognostic features, which would enable improved and timely treatment management and improved patient survivability. A person having ordinary skill in the art would have a reasonable expectation of success because, at the time of filing, the method for providing expression level information of prognostic biomarkers and subject clinical information with some prognostic features to predict cervical cancer prognosis was taught separately and successfully and their combination thereof was already suggested in the prior. Therefore, combining these known elements would yield predictable results.
Claim(s) 18 is rejected under 35 U.S.C. 103 as being unpatentable over Ding et al., (Dongyan Ding et al., 2021, BMC Bioinformatics, 22, 331, 1-17) , further in view of Deregowski et al., International Publication No. WO 2011/036173 A1, and Cho et al., (Hanbyoul Cho et al., 2014, PLOS ONE, 9, 6, e98712, 1-12, provided in IDS 08/02/2024, NPL cite No. 1).
The teachings of Cho are discussed above (see Claim Rejections - 35 USC § 102, claim 1). Cho teaches all the limitations of claim 1 including at least one biomarker for predicting prognosis of cervical cancer. Cho does not teach a kit for predicting prognosis of cervical cancer.
Throughout the disclosure, Deregowski teaches methods and kits for identifying, diagnosing, prognosing, and monitoring cervical cancer. Deregowski teaches that these methods involve determining the methylation status or the expression level of particular genes and panels comprising these particular genes. Regarding claim 18, Deregowski teaches a kit for predicting prognosis of cervical cancer.
It would have been prima facie obvious, at the time of filing, to combine a kit for predicting prognosis of cervical cancer, as taught by Deregowski, with predicting prognosis of cervical cancer comprising at least one protein biomarker listed in claim 1, as taught by Cho. The prior art teaches that cervical cancer is one of the deadliest cancers in women worldwide, with half a million cases diagnosed and 250,000 deaths annually (see WO2011/036173A1, pg.1, lines 10-12). The prior art further teaches Hr-HPV cervical scrapings for cervical cancer screening helps reduce incidences of the disease, however, it is not ideal because the sensitivity of this screening is about 55%. The prior art teaches those preventive vaccinations for HPV, which is linked to cervical cancer, are not sufficient for eliminating the disease because the HPV vaccines do not cover all cervical cancers (see WO2011/036173A1, pg. 1, lines 20-29 and pg. 2, lines 1-7). The prior teaches the need for specific cervical cancer biomarkers to improve detection and predictive value of screens for cervical cancer (see WO2011/036173A1, pg. 2, lines 8-9 and 12-13). Additionally, the prior art teaches that expression levels of proteins, such as SCP, in cervical cancer cells are associated with disease progression and prognosis and thus can serve as prognostic biomarkers for cervical cancer (see Cho et al., 2014, PLOS ONE, 9, 6, e98712). A skilled artisan would have been motivated to combine the kit taught by Deregowski with the known cervical cancer biomarker associated with predicting disease prognosis, as taught by Cho, because it would enable a skilled artisan to increase the sensitivity of and add specificity to the kit, further enabling more sensitive detection of cervical cancer and more accurate prediction of disease prognosis. A person having ordinary skill in the art would have a reasonable expectation of success because a kit for predicting cervical cancer prognosis and cervical cancer prognostic biomarkers, such as SCP were known in the art at the time of filing. Thus, combining the known prognostic kit with the known prognostic biomarker amounts to combining known elements to yield predictable results.
Conclusion
Claim 12 is free of the prior art. While the prior art of record discloses methods for predicting the prognosis of cervical cancer by detecting the expression level of ATP5H, SCP and NANOG, they do not teach or make obvious that patients may be classified in Group 4, high-risk patients, if ATP5H and SCP are low-expressed and NANOG is overexpressed. The instant specification defines group 4 high-risk patients with the worst prognosis (spec, paras 0003 and 0033). Song teaches that patients’ ATP5H expression levels ranging between low to loss of expression had increasingly poorer prognosis. In contrast, patients with high expression levels of ATP5H during early-stage cervical cancer had the most favorable prognosis (Song et al., 2018, J. Clinic. Inv., 128, 9, pg. 4107, full para 1; pg. 4111, Fig. 10; pg. 4112, Table 2, provided in IDS filed on 08/02/2024 as NPL cite No. 3). Therefore, using the broadest reasonable interpretation and in light of the specification, Song teaches the group 4 is a group with low-expressed ATP5H. Ding and Song do not teach wherein group 4 is a group with low-expressed SCP and overexpressed NANOG.
However, Gu, in the same field of endeavor, teaches that expression levels of NANOG in cervical cancer cells are associated with progression and prognosis of cervical cancer (Gu et al., 2012, Am. J. Path., 181, 2, pg. 656). Gu further teaches that overexpression of NANOG is positively associated with late-stage progression of the disease and poor prognosis (Gu et al., 2012, Am. J. Path., 181, 2, pg. 659, para “Discussion”). Therefore, using the broadest reasonable interpretation and in light of the specification, Gu teaches the group 4 is a group with overexpressed NANOG. Gu does not teach wherein group 4 is a group with low-expressed SCP.
The prior art teaches that positive expression levels or overexpression of SCP3 is associated with cervical cancer progression and predicts poor prognosis, serving as a promising prognostic biomarker for cervical cancer. Thus, the prior art teaches away from the limitation: group 4 is a group with low-expressed SCP [claim 12] (see Cho et al., PLOS ONE, 9, 6, e98712, 1-12, pg. 5, provided in IDS filed on 08/02/2024 as NPL cite No. 1; Chung et al., Synaptonemal complex protein 3 as a novel prognostic marker in early-stage non-small cell lung cancer, Hum Pathol. 2013, 44, 4, 472-479; Oh et al., Interaction between SCP3 and JAB1 confers cancer therapeutic resistance and stem-like properties through EGF expression, 2021, Int. J. Mol. Sci., 22, 16, 8839, 1-10; and Oh et al., Targeting cyclin D-CDK4/6 sensitizes immune-refractory cancer by blocking the SP3-NANOG axis, 2018, Cancer Res, 78, 10, 2638–2653, pg. 15, full para 2).
Note, claim 12 is rejected under 35 U.S.C. 101 above.
All claims (1-18) in this instant application are rejected. No claims are allowed.
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/MELISSA LIZETTE LIRIANO/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/ Supervisory Patent Examiner, Art Unit 1677 March 23, 2026