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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 112(a) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or earlier-filed nonprovisional application or provisional application for which benefit is claimed). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. 17/121,012 filed on 12/14/2020 and Provisional Patent Application 62/949,117, filed on 12/17/2019, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The limitations in the claims 3, 5, 7-13, 16-20 are not disclosed in the prior-filed applications. Accordingly, claims 3, 5, 7-13, 16-20 are not entitled to the benefit of the filing date of the prior application. The effective filing date of these claims is the filing date of the instant application, 06/16/2022.
Claim status
Claims 1 and 15-16 are amended. Claims 21-24 are new. Claims 1-24 are pending and examining herein.
Objections/Rejections status
The case is reopened in view of Applicant’s arguments filed on 03/13/2026.
The rejections of claims 21-24 under 35 USC 103 is withdrawn in view of Applicant’s arguments filed on 03/13/26.
The rejections of claims 1-20 under 35 USC 103 are maintained.
The rejection of claims 21-24 under 35 USC 112(a) enablement is new.
New grounds of rejections
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.
Claims 21-24 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 using Arresten as a biomarker of ovarian cancer, does not reasonably provide enablement for using Arresten as a biomarker of type II ovarian cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The breadth of the claims – Claims 21-24 are directed to a method for treating type II ovarian cancer in a subject by administering to the subject a treatment comprising at least one of surgical debulking, chemotherapy, and radiation therapy when the subject has an elevated level of Arresten in a sample above a normal value.
The nature of the invention – the invention is directed toward: 1/ measuring and correlating the elevated level of Arresten to type II ovarian cancer or high-grade serous ovarian cancer; 2/ treating type II ovarian cancer by administering to the subject a treatment comprising at least one of surgical debulking, chemotherapy, and radiation therapy.
The state of the prior art – The prior arts teach that most type II ovarian cancer are high-grade serous carcinomas which are mostly associated with the mutation and dysfunction of TP53 (Silwal-Pandit “TP53 Mutations in Breast and Ovarian Cancer, Cold Spring Harb Perspect Med. 2017 Jan 3; 7(1): a026252” Abstract; and Wu “Type I to Type II Ovarian Carcinoma Progression, Am J Pathol. 2013 Apr; 182(4): 1391-1399” Introduction, page 1391). Silwal-Pandit teaches that TP53 mutations are observed in breast and ovarian cancer (see Title). The role of TP53 in tumor initiation and progression is context dependent, and abrogation of the TP53 pathway seems to be essential for the development of basal-like breast cancers and high-grade serous ovarian cancers. (see Abstract). Wu teaches that most type II OvCAs are high-grade serous carcinomas, virtually all of which harbor mutant TP53 alleles (see Introduction, page 1391). The specification also mentions that ovarian carcinoma has two subsets (e.g., classified as type I or low-grade serous carcinoma, and classified as type II or high-grade serous carcinoma) that are molecularly distinct as separate diseases characterized by differing patterns of genomic variation and prognostic implications.
The prior art teaches a method for treating ovarian cancer in a subject by administering to the subject a treatment comprising at least one of surgical debulking, chemotherapy, and radiation therapy by detecting an elevated expression of type IV collagen polypeptide (Morita US20130224854, par.17-18, 43, 47-51, 127, and Fig.3). The prior arts also teach that the upregulation of the COL4A1 gene leads to release of Arresten which is a part of COL4A1 protein (Assadian “p53 inhibits angiogenesis by inducing the production of Arresten, Cancer Res. 2012 Mar 1;72(5):1270-9” Abstract and page 1271 column 1 paragraph 1; and Morita par.13). The prior art teaches that the expression of COL4A1 and the release of Arresten-containing fragments from the extracellular matrix (ECM) are induced by p53 (Assadian Abstract and page 1271 column 1 paragraph 1). However, the presence of mutant p53 significantly correlated with lack of Arresten staining within the tumor, so "loss of p53 activity in human tumors results in reduced levels of Arresten" (see Assadian, page 1276, right col.).
The predictability or lack thereof in the art – The prior art does not appear to provide a direct relationship between the elevated level of Arresten and type II ovarian cancer. The prior art above teaches that most type II ovarian cancer or high grade serous carcinomas are characterized by p53 mutations. The prior art above also teaches the reduced levels of Arresten in a sample of a patient with mutant p53. Therefore, it is unreasonable to presume that the elevated level of Arresten is increased in type II ovarian cancer because the mutation of p53, which is essential for the development of type II ovarian cancer, results in reduced level of Arresten.
Accordingly, it is not predictable that the claimed treatment is enabled on the subject having an elevated level of Arresten, and the subject with p53 mutations, because there is no support from prior art for the treating of patients with elevated levels of Arresten and patients with type II ovarian cancer who are characterized by p53 mutations.
The presence or absence of working examples – there are three experiments measuring Arresten levels in ovarian cancer patients (the first experiment is disclosed in Examples 1-3, the second experiment is disclosed in Example 4, and the third experiment is disclosed in Examples 5-7).
Examples 1-2 are directed to comparing the plasma level of Arresten from 22 ovarian cancer patients with high-grade serous type to 20 healthy control. Example 3 shows the urine level of Arresten generally correlates with matched plasma level. Results from Example 1-2 show that the Arresten level of type II ovarian cancer patients was 1020 ng/ml, and the Arresten level of the control subjects was 446 ng/ml. Both of these levels are considerably higher than the disclosed cut-off values for ovarian cancer which is 80 to 100 pg/ml (Specification at least par.85). While the level of Arresten in type II ovarian cancer patients in Examples 1-2 is shown to be higher than that in the control subjects, the Arresten level of the control group was still higher than the cut-off value. It is noted that women with breast or ovarian cancer were excluded from the control group of Examples 1-2 (see Specification par.157). Thus, the elevated level of Arresten above a normal cut-off value (80-100 pg/ml) was also shown in healthy controls who did not have breast or ovarian cancer.
Example 4 was conducted to validate the results in examples 1-2. Example 4 is directed to comparing the level of Arresten in plasma samples collected from 400 ovarian cancer patients with different histology, and 400 control samples collected from healthy subjects. Tissue samples from 20 randomly-selected patients were tested for p53 and Arresten expression in tumor tissues. However, no data were presented, so results from this study could not be evaluated. Moreover, Example 4 did not distinguish between patients with Type I, Type II or mixtures thereof. Thus, the result (if it was disclosed) would not definitely correlate an elevated level of Arresten with type II ovarian cancer.
Examples 5-7 showed the results from another validation study on 421 unselected ovarian cancer patients with different histology and 407 hospital control patients. However, among 421 unselected ovarian patients, it is unclear if the patients were type II, type I or a mix thereof. Thus, the result did not definitely correlate an elevated level of Arresten with type II ovarian cancer.
Therefore, data or lack thereof in the specification, is not sufficient to demonstrate that a subject who has an elevated level of Arresten has type II ovarian cancer.
Additionally, the claims are also directed to a method for treating type II ovarian cancer in a subject when the subject has an elevated level of Arresten in a sample above a normal value. However, no working example in the specification is disclosed to demonstrate the result of treatment after diagnosing type II ovarian cancer by measuring the level of Arresten.
The quantity of experimentation necessary – It would be undue experimentation for a skilled artisan to make and use the inventions as claimed, since there is no support from prior art that Arresten can be detected or elevated in a subject with mutant p53, e.g., a subject has type II ovarian cancer. The results provided by the instant specification are insufficient and inconsistent because the subject with an elevated level of Arresten above the normal value may not have type II ovarian cancer (e.g., a healthy control) as discussed in examples 1-7.
The amount of experimentations in the disclosure would not be reasonable because it does not demonstrate that a patient with an elevated level of Arresten has type II ovarian cancer and no experiment shows the successful treatment after diagnosing type II ovarian cancer by measuring the level of Arresten.
The relative skill of those in the art – the level of skill in the art of treating cancer is high, as an ordinary person in this art needs specialized knowledge of cancer development along different molecular pathways.
In summary, there is a lack of disclosure in the art as well as in the specification as to a correlation between the elevated level of Arresten and type II ovarian cancer as claimed. Thus, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with claims 21-24.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-2, 4-6, 14-15 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Morita et al. (US20130224854) in view of Assadian et al. (p53 inhibits angiogenesis by inducing the production of Arresten, Cancer Res. 2012 Mar 1;72(5):1270-9. doi: 10.1158/0008-5472.CAN-ll-2348. Epub 2012 Jan 17) and RnDSystems (Human Arresten DuoSet ELISA, 2018, PTO-892 05/13/2025).
As to claim 1, Morita discloses a method of treating ovarian cancer in a subject comprising: administering to the subject a treatment comprising at least one of surgical debulking, chemotherapy, and radiation therapy (see Morita par(s).17, 116-118: teaching that a therapeutic drug is administered to the subject for cancer treatment; see par.127: teaching that the treatment of the present invention can be applied to every solid cancer such as ovary cancer, and the therapeutic drug is effectively used as a preventive agent for metastasis intended for the prevention of metastasis after solid cancer surgery and the prevention of recurrence).
Morita discloses a method of diagnosing a tumor, e.g., ovary cancer by detecting type IV collagen polypeptide (see par(s).17-18: finding that a single-chain type IV collagen polypeptide is highly expressed in human cancer cell lines, cancer tissues of cancer-bearing animals, and human clinical tumor, see par.127: teaching that the method of diagnosing and treating can be applied to every solid cancer such as ovary cancer). Morita teaches that type IV collagen polypeptide (COL4A1) contains a non-collagenous region called Arresten (see par.13). COL4A1 is highly expressed in human cancer cell lines, cancer tissues of cancer-bearing animals, and human clinical tumor (see par(s).18, 47-51). Figure 3 shows that the expression of COL4A1 from cancer tissue is higher than that from normal tissue (see par.43, Fig.3).
While Morita teaches that Arresten is a part of COL4A1 protein and the expression of COL4A1 increases in ovarian cancer in human subject, Morita does not teach if a level of Arresten also increases in ovarian cancer in human subject as recited in the claim.
Assadian teaches that the expression of a1 collagen IV (COL4A1) and the release of Arresten-containing fragments from the extracellular matrix (ECM) are induced by p53. Particularly, p53 directly activates transcription of the COL4A1 gene and stabilizes the expression of full-length COL4A1. The upregulation of the COL4A1 gene leads to release of Arresten. See Abstract and page 1271 column 1 paragraph 1. Assadian suggests that the serum level of Arresten or other collagen-derived antiangiogenic factors may correlate with clinical parameters in patients with cancer (see Discussion, page 1278).
Morita and Assadian do not teach a method of detecting Arresten.
RnDSystems teaches a method that can detect human Arresten in a sample using ELISA method (see Intended use, page 2). The method comprises:
isolating Arresten that is present in a diagnostic sample of the subject by immobilizing the Arresten on a solid surface (see page 2 Intended use: disclosing that Arresten in a sample is measured, see page 3 col(s).2-3: disclosing the step of immobilizing Arresten on a microplate via a capture antibody);
forming a complex of the immobilized Arresten with a primary antibody specific for Arresten, said complex coupled with an enzyme to form an enzyme complex (see page 3 col(s).2-3: disclosing that a biotinylated anti-Arresten detection antibody is used to detect the immobilized Arresten, so the biotinylated anti-Arresten detection antibody is a primary antibody; the complex of Arresten and detection antibody binds to streptavidin-HRP to form an enzyme complex);
incubating the enzyme complex with a substrate for the enzyme (see page 3: disclosing that the enzyme complex is incubated with streptavidin-HRP and a substrate solution TMB);
measuring a detectable signal produced by the enzyme acting on the substrate (see page 3 col.3: teaching that signal from HRP and TMB substrate is detected using a microplate reader);
and calculating a level of Arresten in the diagnostic sample based on the measurement of the detectable signal (see page 2 Calculation of results, see page 3 col.3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating ovarian cancer taught by Morita, using Arresten as a substitute for COL4A1 because: Morita teaches that COL4A1 is a biomarker for diagnosing ovary cancer, wherein the elevated expression of COL4A1 is observed in cancer tissue relative to normal tissue (see Morita par.43, Fig.3); Morita teaches that COL4A1 contains a non-collagenous region called Arresten (see par.13); Assadian teaches that the upregulation of COL4A1 and production of Arresten into extracellular matrix are simultaneously induced by p53 in cancer patients (see Abstract); the upregulation of the COL4A1 gene leads to release of Arresten (see Assadian page 1271 col.1 par.1); and the increased level of Arresten may correlate with clinical parameters in patients with cancer (see Assadian Discussion, page 1278). Since COL4A1 has been used as a biomarker for diagnosing ovary cancer as taught by Morita, one having an ordinary skill in the art would have had a reasonable expectation of success in using Arresten as an ovarian cancer marker because the increased level of Arresten is a consequence of the increased expression of COL4A1 in cancer patient and may correlate with clinical parameters in patients with cancer as taught by Assadian.
A person of ordinary skill in the art would have been motivated to use Arresten for diagnosing ovarian cancer because it would be interesting to determine whether serum level of Arresten or other factors correlate with clinical parameters such as overall survival in patients with cancer (see Assadian page 1278).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Arresten detection taught by RnDSystems for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian because the method of RnDSystems can measure the concentration of natural human Arresten in the sample such as serum and plasma. The concentration of Arresten in the test sample can be compared with the predetermined cut-off value (e.g., obtained from the normal subject), then one having skill in the art can identify if the test subject has ovarian cancer based on the level of Arresten as taught by Morita in view of Assadian above.
As to claim 2, Morita, Assadian, and RnDSystems teach the invention as discussed above. Morita does not teach the limitation in claim 2.
RnDSystems teaches that the enzyme in the enzyme complex is conjugated to at least one of the following: (a) the primary antibody; (b) a secondary antibody that binds to the primary antibody; and (c) a protein that binds to a biotin labelling: (i) the primary antibody or (ii) the secondary antibody (see page 3 col(s).2-3: disclosing that a biotinylated anti-Arresten detection antibody is used to detect the immobilized Arresten, so the biotinylated anti-Arresten detection antibody is a primary antibody; the complex of Arresten and detection antibody binds to streptavidin-HRP to form an enzyme complex; the teaching encompasses that the enzyme HRP is conjugated to (c) a protein streptavidin that binds to a biotin labelling).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Arresten detection taught by RnDSystems for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian due to the reasons already discussed in claim 1 above.
As to claim 4, Morita, Assadian, and RnDSystems teach the invention as discussed above. Morita does not teach the limitation in claim 4.
RnDSystems teaches that Arresten is immobilized on the well surface via a capture antibody specific to Arresten coated on the well (see page 3 col.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Arresten detection taught by RnDSystems for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian due to the reasons already discussed in claim 1 above.
As to claim 5, Morita, Assadian, and RnDSystems teach the invention as discussed above. Morita does not teach the limitation in claim 5.
RnDSystems teaches that the method comprises comparing the detectable signal to a calibration data set generated using a calibrator at multiple concentrations or level to assess amount, concentration, or level of Arresten in the diagnostic sample, wherein the calibrator is recombinant human Arresten.
(See page 3 col.2: RnDSystems teaches that a calibrator is recombinant human Arresten, which is used as a standard curve having seven-point concentrations. See page 2 col.1 Calculation of Results: RnDSystems teaches that the concentration of Arresten in a test sample is defined based on the standard curve).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Arresten detection taught by RnDSystems for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian due to the reasons already discussed in claim 1 above.
As to claim 6, Morita, Assadian, and RnDSystems teach the invention as discussed above. Morita does not teach the limitation in claim 6.
RnDSystems teaches that the detectable signal is measured by colorimetry using the reader at wavelengths 450nm/540nm or 450nm/570nm (see page 3 col.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Arresten detection taught by RnDSystems for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian due to the reasons already discussed in claim 1 above.
As to claim 14, Morita, Assadian, and RnDSystems teach the invention as discussed above. Morita teaches that a patient confirmed to have the expressed single-chain type IV collagen polypeptide can be diagnosed with cancer (e.g., ovary cancer) or tumor (see Morita par.127 and par.134). Moreover, the state of the tumor can be evaluated with the detection results obtained by the detection method, wherein the state of the tumor means the presence or absence of developed tumor or the degree of progression thereof (see Morita par(s).134-136). For example, the tumor may be evaluated as early cancer or advanced cancer with the detection results as an index. It is noted that the early cancer also means asymptomatic of cancer as disclosed in the instant specification paragraph 6.
While Morita teaches that the diagnosing is to screen the subject for ovarian cancer, who is asymptomatic of ovarian cancer, Morita does not use Arresten as a marker.
Assadian teaches that the increased expression of COL4A1 leads to release of Arresten (see page 1271 col.1 par.1). Assadian suggests that the serum level of Arresten or other collagen-derived antiangiogenic factors may correlate with clinical parameters in patients with cancer (see Discussion).
As discussed in claim 1, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating and diagnosing ovarian cancer taught by Morita, using Arresten as a substitute for COL4A1 as taught by Assadian due to the reasons already discussed in claim 1 above.
One having an ordinary skill in the art would have had a reasonable expectation of success in using Arresten as a marker in a method for treating and diagnosing ovarian cancer in a human female subject in claim 1, wherein the subject is asymptomatic of ovarian cancer because: the method of treating and diagnosing ovarian cancer taught by Morita can detect a subject at early cancer state using COL4A1 marker (see discussion above), Assadian teaches the expression of COL4A1 leading to release of Arresten which may correlate with clinical parameters in patients with cancer. Therefore, using Arresten as a substitute for COL4A1 would results in detecting ovarian cancer who is asymptomatic.
As to claim 15, Morita, Assadian, and RnDSystems teach the invention as discussed in claim 1 above, comprising: treating ovarian cancer in a subject by surgical debulking, chemotherapy (see Morita par.127).
See the discussion of Morita, Assadian, and RnDSystems in claim 1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating ovarian cancer taught by Morita, using Arresten as a substitute for COL4A1 as taught by Assadian due to the reasons already discussed in claim 1.
A person of ordinary skill in the art would have been motivated to use Arresten as a marker for ovarian cancer because it would be interesting to determine whether serum level of Arresten or other factors correlate with clinical parameters such as overall survival in patients with cancer (see Assadian page 1278).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Arresten detection taught by RnDSystems for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian due to the reasons already discussed in claim 1.
Accordingly, it would be obvious to diagnose a subject if he has ovarian cancer by a process comprising: (a) obtaining a diagnostic sample comprising a bodily fluid of the subject (see RnDSystems page 2 col.3: teaching that Arresten can be detected in serum or plasma); (b) analyzing the diagnostic sample for Arresten expression (see RnDSystems); and (c) detecting Arresten expression elevated above normal, thereby diagnosing the subject with ovarian cancer (see Morita par(s).18, 43, 47-51, and Assadian Abstract: teaching that the levels of COL4A1 and Arresten are simultaneously increased in cancer patients).
As to claim 18, Morita, Assadian, and RnDSystems teach the invention as discussed above. See the discussion of Morita, Assadian, and RnDSystems in claim 1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating ovarian cancer taught by Morita, using Arresten as a substitute for COL4A1 as taught by Assadian due to the reasons already discussed in claim 1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Arresten detection taught by RnDSystems for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian due to the reasons already discussed in claim 1.
In addition, RnDSystems discloses the kit for measuring Arresten level as discussed in claim 1 above. Briefly, the kit comprises:
a capture antibody that is capable of specifically binding to human Arresten, thereby isolating human Arresten from the biological sample; (b) a solid matrix to which the capture antibody will bind; (c) a detection antibody that is capable of specifically binding to human Arresten and has a label for generating a detectable signal; (d) a recombinant human Arresten standard for calibration; and (e) at least one reagent suitable for generating the detectable signal in cooperation with the label, thereby detecting a level of human Arresten in the biological sample. See RnDSystems page 3
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the Arresten detection kit as taught by RnDSystems for the purpose of assessing risk of ovarian cancer as taught by Morita in view of Assadian due to the reasons already discussed in claim 1 above.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morita, Assadian, and RnDSystems, as applied to claim 1, and further in view of ThermoFisher (Avidin-Biotin Interaction, 2015).
As to claim 3, Morita, Assadian, and RnDSystems teach the invention as discussed in claim 2. Morita fails to teach streptavidin is native or modified.
According to ThermoFisher, streptavidin can be native or recombinant and it is an ideal reagent choice for many detections systems (see ThermoFisher page 5 Streptavidin section). This teaching encompasses that streptavidin may be native.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the native streptavidin in the method of Arresten detection taught by RnDSystems because ThermoFisher teaches that streptavidin is an ideal reagent choice for many detections systems due to a lower degree of nonspecific binding (see ThermoFisher page 5 Streptavidin section).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the modified method of Arresten detection taught by RnDSystems and ThermoFisher for the purpose of treating and diagnosing ovarian cancer as taught by Morita in view of Assadian because the modified method of RnDSystems and ThermoFisher can measure the concentration of natural human Arresten in the sample such as serum and plasma. The concentration of Arresten in the test sample can be compared with the predetermined cut-off value (e.g., obtained from the normal subject), then one having skill in the art can identify if the test subject has ovarian cancer based on the level of Arresten as taught by Morita in view of Assadian above.
Claim(s) 7-13 and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morita, Assadian, and RnDSystems, as applied to claim 1 above, further in view of Šimundić (Measures of diagnostic accuracy: basic definitions, EJIFCC. 2009 Jan 20;19(4):203–211, PTO-892 05/13/2025).
As to claims 7-10 and 16-17, Morita, Assadian, and RnDSystems teach the invention as discussed in claim 1 above.
For the limitation “the bodily fluid is serum or plasma” in claim 16, RnDSystems in page 2 column 3 teaches that sample can be serum or plasma.
Morita, Assadian, and RnDSystems fail to teach the predetermined cut-off value so that the method has a desired sensitivity and specificity, and AUC as recited in claims 7-10 and 16-17.
Šimundić reviews a basic definition of measures of diagnostic accuracy which relates to the ability of a test to discriminate between the target condition and health. This discriminative potential can be quantified by the measures of diagnostic accuracy such as sensitivity and specificity, the area under the ROC curve etc. (see Abstract).
Šimundić discloses that a diagnostic procedure can make only partial distinction between subjects with and without disease because a perfect test does not exist. Values above the cut-off are not always indicative of a disease since subjects without disease can also sometimes have elevated values. Such elevated values of certain parameter of interest are called false positive values (FP). On the other hand, values below the cut-off are mainly found in subjects without disease. However, some subjects with the disease can have them too. Those values are false negative values (FN). Therefore, the cut-off divides the population of examined subjects with and without disease in four subgroups considering parameter values of interest: true positive (TP), false positive (FP), true negative (TN), and false negative (FN). See Sensitivity and specificity section.
Sensitivity is expressed in percentage and defines the proportion of true positive subjects with the disease in a total group of subjects with the disease (TP/TP+FN). Specificity is a measure of a diagnostic test accuracy, complementary to sensitivity. It is defined as a proportion of subjects without the disease with negative test result in total of subjects without disease (TN/TN+FP). It is noted that sensitivity and specificity are measures of a diagnostic test accuracy and are calculated based on the cut-off because the cut-off defines the TP, FP, TN and FN. See Sensitivity and specificity section.
In addition, there is a pair of diagnostic sensitivity and specificity values for every individual cut-off. To construct a ROC graph, these pairs of values are plotted on the graph with the 1-specificity on the x-axis and sensitivity on the y-axis. The shape of a ROC curve and the area under the curve (AUC) helps estimate how high is the discriminative power of a test. The area under the curve can have any value between 0 and 1 and it is a good indicator of the goodness of the test. A perfect diagnostic test has an AUC 1.0. whereas a nondiscriminating test has an area 0.5. See ROC curve section.
Besides, measures of diagnostic accuracy are extremely sensitive to the design of the study which depends on the researchers (see Design of diagnostic accuracy studies section). Also, sensitivity and specificity can vary greatly depending on the spectrum of the disease in the studied group (see Sensitivity and specificity section).
Therefore, the settings of cut-off value, sensitivity and specificity values, as well as AUC value are routine steps of disease diagnosis method for one of ordinary skill in the art to discover an optimum diagnostic accuracy for a disease of interest.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating and diagnosing ovarian cancer as taught by Morita, Assadian, and RnDSystems, defining the measures of diagnostic accuracy for the purpose of treating and diagnosing ovarian cancer because Šimundić teaches that it can improve the quality of reporting of studies of diagnostic accuracy and serve to provide the best possible evidence to the best for the patient care (see Abstract). One having an ordinary skill in the art would have had a reasonable expectation of success in combining Morita, Assadian, RnDSystems and Šimundić because Šimundić is generic to define the ability of a test to discriminate between the target condition and health.
As to claims 11-12, Morita, Assadian, RnDSystems, and Šimundić teach the invention as discussed above. Morita discloses that the state of the tumor can be evaluated or diagnosed with the detection results obtained by the detection method as an index. It is noted that the state of the tumor means the presence or absence of developed tumor or the degree of progression thereof. The presence or absence of developed tumor is confirmed with the predetermined reference value as a threshold, on the basis of the detection results. See paragraphs 134-136. This teaching encompasses the predetermined cut-off value is based on a state of cancer, e.g., a stage of ovarian cancer.
Moreover, Šimundić teaches that the settings of cut-off value, sensitivity and specificity values, as well as AUC value are routine steps of disease diagnosis method as discussed above.
As to claim 13, Morita, Assadian, RnDSystems, and Šimundić teach the invention as discussed in claim 12 above. The method of treating ovarian cancer taught by Morita in view of Assadian, RnDSystems and Šimundić uses Arresten as a substitute for COL4A1 in diagnosing ovary cancer. See the discussion in claims 1 and 12 above.
In addition, Morita teaches that a patient confirmed to have the expressed single-chain type IV collagen polypeptide can be diagnosed with cancer (e.g., ovary cancer) or tumor (see Morita par.127 and par.134). Moreover, the state of the tumor can be evaluated with the detection results obtained by the detection method, wherein the state of the tumor means the presence or absence of developed tumor or the degree of progression thereof (see Morita par(s).134-136). For example, the tumor may be evaluated as early cancer or advanced cancer with the detection results as an index. It is noted that the early cancer also means asymptomatic of cancer as disclosed in the instant specification paragraph 6.
While Morita teaches that the diagnosing is to screen the subject for ovarian cancer, who is asymptomatic of ovarian cancer, Morita does not use Arresten as a marker.
Assadian teaches that the increased expression of COL4A1 leads to release of the C-terminal non-collagenous domain of COL4A1, which contains Arresten (see page 1271 col.1 par.1). Assadian suggests that the serum level of Arresten or other collagen-derived antiangiogenic factors may correlate with clinical parameters in patients with cancer (see Discussion).
One having an ordinary skill in the art would have had a reasonable expectation of success in using Arresten as a marker in a method for treating ovarian cancer in a human female subject in claim 1, wherein the subject is asymptomatic of ovarian cancer because: the method of treating and diagnosing ovarian cancer taught by Morita can detect a subject at early cancer state using the expressed of COL4A1 marker (see discussion above), Assadian teaches the expression of COL4A1 leading to the release of Arresten which may correlate with clinical parameters in patients with cancer. Therefore, using Arresten as a substitute for COL4A1 would results in a predictable outcome.
Claim(s) 19-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morita in view of Assadian, and RnDSystems, as applied to claims 1 and 18, and further in view of Invitrogen (Human MUCIN 16/CA125 Elisa kit, 2018, PTO-892 05/13/2025) and Spriggs et al (US20070269831).
As to claims 19-20, Morita, Assadian, and RnDSystems teach the invention as discussed in claim 18 above. They do not teach that the kit further comprises reagents to detect CA125 as in claim 19. They do not teach a predetermined cut-off value of human Arresten is 80-100 pg/ml, and a predetermined cut-off value for the human CA125 is 35-100 U/ml as in claim 20.
Invitrogen discloses a kit to detect CA125 in a sample comprising:
a capture antibody that is capable of specifically binding to human CA125 (see 4 par.2 and 4: disclosing that a target-specific antibody has been pre-coated in the wells, which the target is CA125);
a detection antibody that is capable of specifically binding to human CA125, and has a label for generating a detectable signal (see page 3 Content section: disclosing a biotinylated detection antibody, see page 4 par.2: disclosing that samples, standards, or controls are then added into these wells and bind to the immobilized (capture) antibody, the sandwich is formed by the addition of the second (detector) antibody, a substrate solution is added and reacted with the enzyme-antibody-target complex to produce measurable signal);
a recombinant human CA125 standard for calibration (see page 3, 4 par.1, page 7: teaching that the kit discloses a standard, which is recombinant human CA125);
at least one second reagent suitable for generating the second detectable signal in cooperation with the second label, thereby detecting expression of human CA125 (see page 3: disclosing reagents for generating a detectable signal including SAV-HRP and chromogen, see page 4 par.2: disclosing that samples, standards, or controls are then added into these wells and they bind to the immobilized (capture) antibody, the sandwich is formed by the addition of the second (detector) antibody, a substrate solution is added that reacted with the enzyme-antibody-target complex to produce measurable signal).
In addition, Spriggs teaches that CA125 is the first tumor marker available for the management of ovarian cancer, wherein approximately 80% of patients with epithelial ovarian cancer has elevations of CA125 (see par.5). It shows that the upper limit of normal for CA125 was defined as 35 U/mL (see par.42). Spriggs further teaches that the combination of CA125 with other tumor markers may increase the sensitivity and specificity of ovarian cancer detection (see par.29).
Spriggs does not explicitly teach the predetermined cut-off value of CA125 in the test, however, Spriggs discloses a method for evaluating the predetermined cut-off of a biomarker. See paragraph 27: the pre-determined threshold is set based on “normal” values detected in individuals without ovarian cancer at a level such that a detected value of a marker greater than the pre-determined threshold is indicative of the presence of early stage ovarian cancer; the selection of a particular threshold value for diagnostic testing purposes reflects a balancing of the desire to exclude false positives, while at the same time identifies substantially all individuals who have ovarian cancer.
These teaching can be applied on determining the cut-off of Arresten or CA125 in the test sample over control sample to indicate ovarian cancer.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine a kit for detecting CA125 taught by Invitrogen with the kit for assessing risk of ovarian cancer taught by Morita in view of Assadian, and RnDSystems because Spriggs suggests that the combined detection of a plurality of tumor markers may increase the sensitivity and specificity of ovarian cancer detection. Since Morita and Assadian teach that Arresten can be a reasonable marker for ovarian cancer and Spriggs teaches that CA125 is a conventional marker for ovarian cancer, the combination of Arresten and CA125 would increase the sensitivity and specificity of ovarian cancer detection as suggested by Spriggs.
Accordingly, a skilled artisan would have determined the cut-off value of the biomarkers, e.g., Arresten and CA125, based on the desire to exclude false positives and to identify substantially all individuals who have ovarian cancer as taught by Spriggs in paragraph 27.
Response to Arguments
Applicant's arguments filed 03/13/2026 have been fully considered.
For rejection under 35USC 103:
For Remarks II on pages 3-5 and III B on pages 6-7, Applicant argues that Examiner has failed to make out a prima facie case of obviousness built upon a combination of the Morita, Assadian, and RnDSystems references. Applicant argues that the prior art teaches away from the claimed invention.
Applicant argues that a skilled person, reading Morita in view of Assadian, would encounter a consistent and reinforcing view: (a) Arresten is an anti-angiogenic factor that the body produces (via functional p53, per Assadian) to suppress tumor growth (per both Morita and Assadian); and (b) its reduced or absent levels in tumors correlate with aggressive, p53-mutant cancer (per Assadian). Nothing in either reference, read alone or in combination, would lead the skilled person to expect or hypothesize that Arresten would be elevated in cancer patients, let alone that such elevation could serve as a diagnostic biomarker for ovarian cancers.
This argument is not persuasive. While type II ovarian cancer is not well correlated with the presence or amount of Arresten as detailed in the enablement rejection above, it is obvious for one having skill in the art to detect Arresten as a marker of detecting other types of ovarian cancer because the followings: Morita teaches that Arresten is a part of COL4A1 protein and the expression of COL4A1 increases in ovarian cancer tissue relative to normal tissue. Morita teaches that COL4A1 is a biomarker for diagnosing ovary cancer. Assadian teaches the upregulation of the COL4A1 gene leads to release of Arresten. Assadian suggests that the serum level of Arresten or other collagen-derived antiangiogenic factors may correlate with clinical parameters in patients with cancer.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use Arresten as a substitute for COL4A1 for diagnosing ovary cancer, as an obvious matter to try, namely choosing from a finite list of suitable, art recognized marker that correlates to the cancer with a reasonable expectation of success because the increased level of Arresten is a consequence of the increased expression of COL4A1 in cancer patient as taught by Assadian. A person of ordinary skill in the art would have been motivated to use Arresten for diagnosing ovarian cancer because it would be interesting to determine whether serum level of Arresten or other factors correlate with clinical parameters such as overall survival in patients with cancer (see Assadian page 1278).
Applicant argues that replacing Morita's peptide with Arresten fundamentally changes Morita's teachings single-chain type IV collagen polypeptide is a distinct molecule and functions differently from Arresten, in fact, they function in opposite ways.
Examiner respectfully disagrees. While these biomolecules function in opposite ways, they can be used as markers for diagnosing cancer because the levels of the markers in cancer patients are distinguishable from those in control subjects. This is also the scope of the claim where diagnosing ovarian cancer in the subject is based on the difference in level of marker Arresten of the patient from the control subject, but not based on the function of the marker.
Therefore, the rejections of claims 1-20 under 35 USC 103 are maintained.
Applicant argues that nothing in either reference, read alone or in combination, would lead the skilled person to expect or hypothesize that Arresten would be elevated in cancer patients, let alone that such elevation could serve as a diagnostic biomarker for type II ovarian cancers. Moreover, Silwal-Pandit and Wu also teach that type II ovarian cancers, most of which are high-grade serous carcinomas, are characterized by acquisition of somatic TP53 mutations. Combining these teachings with Assadian's own finding that p53 mutation correlates with lack of Arresten, a skilled person would conclude that the dominant form of ovarian cancer (type II) defined by near-universal p53 dysfunction should exhibit reduced, not elevated, levels of Arresten. The skilled person would have no reason to use elevated Arresten as a general diagnostic biomarker for ovarian cancer, because the prior art predicts that the most prevalent and aggressive form of the disease (i.e., HGSOC) would lack, not exhibit, elevated levels of Arresten. To arrive at the claimed invention, the skilled person would have to discard the core teaching by Assadian.
The inventor has surprisingly determined that the Arresten polypeptide or a portion thereof can be used as a biomarker for cancer, particularly ovarian cancer. The mean plasma level of Arresten was significantly higher in ovarian cancer patients than in healthy controls, which is opposite to what was expected. The higher concentration of Arresten in the plasma of ovarian cancer patients makes this protein even more favorable as a screening or diagnostic biomarker, despite the contrary hypothesis that linked Arresten with defective p53 function in ovarian cancers. (Applicant argues that the resulting dysfunctional p53 protein or pathway is the hallmark for the type II OC patient group, but TP53 mutations have been rarely seen in type I OC.)
The arguments are persuasive. The rejections of claims 21-24 under 35 USC 103 are withdrawn.
Conclusion
Claims 21-24 are free of the prior art; however they are rejected under 35 U.S.C. 112 (a) as failing to comply with the enablement requirement. The prior art of record does not suggest or make obvious a method of treating ovarian cancer in a human female subject when the subject is diagnosed with ovarian cancer based on the elevated level of Arresten.
The prior arts of record teach away the possibility of detecting an elevated level of Arresten in type II ovarian cancers because:
Silwal-Pandit teaches that TP53 mutations are observed in breast and ovarian cancer (see Title). The role of TP53 in tumor initiation and progression is context dependent, and abrogation of the TP53 pathway seems to be essential for the development of basal-like breast cancers and high-grade serous ovarian cancers. (see Abstract).
Wu teaches that most type II OvCAs are high-grade serous carcinomas, virtually all of which harbor mutant TP53 alleles (see Introduction, page 1391).
Assadian teaches that the presence of mutant p53 significantly correlated with lack of Arresten staining within the tumor, so "loss of p53 activity in human tumors results in reduced levels of Arresten" (see Assadian, page 1276, right col.).
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/CHAU N.B. TRAN/
Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 May 27, 2026
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