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 .
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.
Priority
This application is a U.S. National Stage (371) application of PCT/US2020/036744 filed on 06/09/2020 which claims priority to U.S. Provisional Application No. 62/859,264 filed on 06/10/2019.
Claim Status
Claim 1 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/28/2025.
The Applicant cancelled claims 2-22, 24-26 and 32. The Applicant amended claim 23 and noted that no new matter is added. The Applicant added non-elected species to claim 23 as noted in the election without traverse in the reply filed on 03/28/2025.
The Applicant previously presented claims 27-31 and 33-34. Claims 35-42 are new, and the Applicant noted that no new matter is added.
Thus, claims 23, 27-31 and 33-42 are under examination.
Withdrawn Objections and Rejections
The previous objection to claims 24-25 regarding informalities is withdrawn in light of Applicant’s cancellation of claims.
The previous objection to claims 29-30 regarding informalities is withdrawn in light of Applicant’s amendments of claims.
The previous rejection of claims 24-26 and 31 under 35 U.S.C. 103, regarding obviousness, is withdrawn in light of Applicant’s cancellation of claims.
Maintained Objections
Claim 31 is still objected to because of the following informalities: The claim still has the abbreviation “Sm” that was not described. Appropriate correction is required.
To move the prosecution, the Examiner is interpreting “Sm” as Smith.
New Objections and Rejections
Claim Objections
Claim 23 is objected to because of the following informalities: The claim is listing species of tumor associated antigens (TAA) and extractable nuclear antigens (ENA) with abbreviations that were not described (i.e., Sm and WNT). Appropriate correction is required.
To move the prosecution, the Examiner is interpreting “Sm” as Smith and “WNT” as Wingless/Integrated.
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 (PHOSITA) to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 23, 27-31, 33-34 and 35-42 are rejected under 35 U.S.C. 103 as being unpatentable over Evans et al. (BMC Cancer (2018) 18:119), Nisihara et al. (Clinical and Experimental Immunology, 193: 178–182) and Madrid et al. (BMC Cancer (2015) 15:407).
Regarding claim 23, Evans teaches an antibody detection marker composition as part of a multiplex beads assay (Abstract; page 3 of 9, right column, third paragraph, “Autoantibodies against the 32 TAAs in the plasma samples were measured simultaneously in a single well utilizing a multiplex bead assay. The xMAP Luminex magnetic beads from 32 distinct regions, each coated with a different TAA-rFc fusion, were combined and distributed to the wells of a 96-well round bottom plate).
Evans teaches one or more first antibody detection marker molecules that bind to human autoantibodies against at least one tumor associated antigen (TAA) (Abstract; page 2 of 9, right column, last paragraph, “Patients newly diagnosed with any type of BCa and were 30 years of age or older were invited to participate”; page 3 of 9, right column, “Autoantibodies against the 32 TAAs in the plasma samples”).
Regarding claims 23 and 35, Evans teaches that at least one or more TAA is selected from the group consisting of DKK1 and A1AT (Page 6 of 9, left column, “significant decreases in levels of response between baseline and 12 month time points against 9 of the 11 TAAs (i.e. A1AT, ANGPTL4, CAPC, CST2, DKK1”).
Regarding claim 28, Evans teaches a first antibody detection marker molecules that bind to human autoantibodies against at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more TAAs (Page 6 of 9, left column, “significant decreases in levels of response between baseline and 12 month time points against 9 of the 11 TAAs (i.e. A1AT, ANGPTL4, CAPC, CST2, DKK1”).
Regarding claim 30, Evans teaches that at least one TAA includes DKK1 (Page 6 of 9, left column, “significant decreases in levels of response between baseline and 12-month time points against 9 of the 11 TAAs (i.e. A1AT, ANGPTL4, CAPC, CST2, DKK1”).
Regarding claim 31, Evans teaches using a combination of one or more TAA such as DKK1 and A1AT (Page 2 of 9, right column, third paragraph, “Each of the 32 TAA-rFc fusions was bound to one Luminex bead region.”; page 4 of 9, Table 1, “DKK1”, “A1AT”).
Regarding claim 32 Evans teaches that one or more first antibody detection marker molecules comprise or consist of the TAA, an antigenic fragment thereof, or a native extracellular domain and/or native secreted version of the TAA or antigenic fragment (Page 2 of 9, right column, first paragraph, “Details for construction of plasmids encoding rabbit Fc (rFc)-tagged tumor-associated antigens (TAAs) have been described previously. Briefly, the extracellular domain of transmembrane proteins or the full-length sequence of secreted and intracellular proteins was cloned”).
Regarding claim 33, Evans teaches that the composition consists of between 2-10,000 antibody detection marker molecules in total (Page 3 of 9, right column, “Autoantibodies against the 32 TAAs in the plasma samples were measured simultaneously in a single well utilizing a multiplex bead assay”).
Regarding claim 34, Evans teaches that the composition consists of between 2 and 1000 antibody detection marker molecules in total (Page 3 of 9, right column, “Autoantibodies against the 32 TAAs in the plasma samples were measured simultaneously in a single well utilizing a multiplex bead assay”).
Regarding claims 36 and 38, Evans teaches how to make detectable fusion proteins of tumor associated antigens (TAA) (Page 2 of 9, “Loading of tumor-associated antigen-rabbit Fc fusion proteins to Luminex beads”, “Beads coupled with the anti-rFc antibody were coated with each TAA-rFc fusion protein … at 4 °C in the dark until use”).
Regarding claims 37 and 39-40, Evans teaching immobilizing the antibody detection marker molecules or fusion proteins on a surface (Page 2 of 9, right column, third paragraph, “Each of the 32 TAA-rFc fusions was bound to one Luminex bead region”; page 3 of 9, right column, third paragraph, “The xMAP Luminex magnetic beads from 32 distinct regions, each coated with a different TAA-rFc fusion, were combined and distributed to the wells of a 96-well round bottom plate.”).
Regarding claims 41-42, Evans teaches that each of 32 TAA-rFc fusions was bound to one Luminex bead region (Page 2 of 9, right column, third paragraph, “Each of the 32 TAA-rFc fusions was bound to one Luminex bead region”).
Regarding claim 23, Evans does not teach one or more second antibody detection marker molecules that bind to human autoantibodies against at least one extractable nuclear antigen (ENA) nor combining the set of TAA marker molecules with one or more second antibody detection marker molecules that bind to human autoantibodies against at least one ENA.
Regarding claims 23 and 35, Evans does not teach that one or more ENA is selected from SS-A/Ro (52kDa), SS-B/La and SS-A/Ro (60kDa).
Regarding claim 27, Evan does not teach a second antibody detection marker molecules that binds to human autoantibodies against at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ENAs.
Regarding claim 29, Evans does not teach that at least one ENA includes 1 or all 2 of SS-A/RO 52kDa and SS-B/La.
Regarding claim 31, Evans does not teaches using a combination of one or more ENA such as SS-A/Ro and SS-B/La nor combining a set of TAA with a set of ENA to make a mixed panel of TAA and ENA.
Regarding claim 23, Nisihara teaches one or more second antibody detection marker molecules that bind to human autoantibodies against at least one extractable nuclear antigen (ENA) (Abstract).
Regarding claims 23 and 35, Nisihara teaches that one or more ENA is selected from SS-A/Ro and SS-B/La (Page 179, left column, “Only samples with positive ANA tests were assessed by enzyme-linked immunosorbent assay (ELISA) for antibodies against ENA antigens [single-strand (SS)-A/Ro, SS-B/La”).
Regarding claim 27, Nisihara teaches second antibody detection marker molecules that bind to human autoantibodies against at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ENAs (Page 179, left column, “Only samples with positive ANA tests were assessed by enzyme-linked immunosorbent assay (ELISA) for antibodies against ENA antigens [single-strand (SS)-A/Ro, SS-B/La, Smith (Sm), ribonucleoprotein (RNP), histidyl-sRNA synthetase (Jo-1) and scleroderma 70 (Scl-70)]”).
Regarding claim 29, Nisihara teaches that at least one ENA includes 1 or all 2 of SS-A/RO 52kDa and SS-B/La (Page 179, left column, “Only samples with positive ANA tests were assessed by enzyme-linked immunosorbent assay (ELISA) for antibodies against ENA antigens [single-strand (SS)-A/Ro, SS-B/La, Smith (Sm), ribonucleoprotein (RNP), histidyl-sRNA synthetase (Jo-1) and scleroderma 70 (Scl-70)]”).
Regarding claim 31, Nisihara teaches using a combination of one or more ENA such as SS-A/Ro and SS-B/La (Page 179, left column, sixth paragraph, “Only samples with positive ANA tests were assessed by enzyme-linked immunosorbent assay (ELISA) for antibodies against ENA antigens [single-strand (SS)-A/Ro, SS-B/La”).
Moreover, regarding claim 31, Madrid teaches that their results suggest developing a panel of breast cancer-specific , premalignant-phase autoantibodies (Abstract, Conclusions, “Results further suggest significant promise for the development of panels of breast cancer-specific, premalignant-phase autoantibodies”). Madrid further teaches studying the autoantibody response to tumor associated antigens in the pathogenesis of cancer (Abstract, Conclusions, “studies on the autoantibody response to tumor associated antigens in the pathogenesis of cancer.”). Madrid teaches that autoantibodies in cancer sera could be a useful biomarker for the early diagnosis of breast cancer (Page 5 of 15, right column, last four lines, “”; Page 6 of 15, right column, first paragraph, “These findings suggest that, in the future, the combination of suspicious mammography and autoantibody signatures could potentially
identify a group of women in the early stages of breast carcinogenesis.”).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine Nisihara’s method of extractable nuclear antigens (ENA) profiling in patients who have malignant lesions with Evans’s method of detecting autoantibodies in cancer patients because Nisihara noted the positivity for ENA profile in patients with malignant lesions (Page 178, Summary, “In the ANA-positive patients with malignant lesions, seven had positivity for ENA profile”), and Evans mentioned the usefulness of detecting autoantibodies in cancer patients for treatment purposes (Page 7 of 9, left column, last four lines, “The ultimate goal of detecting autoantibodies in the follow-up setting is to determine if the autoantibody response to a panel of cancer antigens can predict patient response to treatment and detect recurrence of the disease”). A skilled artisan would have been motivated to combine Madrid’s suggestions for studying autoantibody response to tumor associated antigens (TAA) in the pathogenesis of cancer with the combined method of Nisihara and Evans because Madrid teaches studying the autoantibody response to tumor associated antigens in the pathogenesis of cancer and its usefulness in the detection of breast cancer (Abstract, Conclusions; page 5 of 15, right column, last four lines). Thus, a skilled artisan would have been motivated to combine the above methods and inventions to produce a comprehensive panel that can detect breast cancer with high sensitivity and specificity. A PHOSITA would have had a reasonable expectation of success in combining the methods of Evans, Madrid and Nisihara because the methods are directed to detecting markers of malignant diseases. It would have been obvious for a PHOSITA to combine the panels of Evans and Nisihara as suggested by Madrid to produce a panel for monitoring the response of patients to cancer treatment.
Response to Arguments
Applicant's arguments filed 11/04/2025 have been fully considered but they are not persuasive.
The Applicant alleged that while Nisihara discusses extractable nuclear antigen (ENA)binding autoantibodies as cancer diagnostic markers, Nisihara's results teach away from using anti-ENA antibodies as a relevant diagnostic marker. The Applicant further alleged that while Nisihara writes "Only samples with positive ANA tests were assessed by enzyme-linked immunosorbent assay (ELISA) for antibodies against ENA antigens,", this only describes that a follow-up assay was performed without disclosing the results of that assay. The Applicant alleged that the assay's results show only 2/32 or 4/32 ANA-positive samples were found to have autoantibodies against SSA/Ro or SS-B/La (p. 180). The Applicant alleged that these 32 tests were already limited to patients that had already received a positive result in a test for anti-nuclear antigens (ANA) amongst the 72 patients with malignant tumors (Nisihara p. 179). Therefore, the SS-A/Ro or SS-B/La was only effective at correlating with a cancer diagnosis in 2/72 (2.8%) or 4/72 (5.6%) cases, respectively, where the patient had a malignant tumor. The Applicant alleged that an artisan would reasonably conclude from this that anti-ENA autoantibodies are not effective markers for diagnosing the majority of the population, as such a low classification success rate would lead to a high degree of false negatives. Thus, those of skill in the art would not have been motivated by the combination of Evans and Nisihara to make the composition of claim 23 that combines the recited TAAs and ENAs.
This argument is not persuasive because Nisihara teaches that in their sample, seven patients had positivity for the ENA profile, the most common being anti-RNP and anti-La, followed by anti-Sm and anti-Ro in patients who had tumor invasive forms (Page 181, right column, second paragraph). Furthermore, the teachings of Nisihara are to be combined with the method of Evan that explore TAA. While the Applicant argued against the teachings of Nisihara, the findings of Nisihara are consistent with prior art (Pages 180-181, “Our findings agree with those of Mohammed et al. [18] who, studying 35 newly diagnosed breast cancer patients, found that ANA was increased significantly in these patients irrespective of the grade or tumour stage”). Thus, an artisan would have considered all prior art and the combination of TAA and ENA to increase the diagnostic value of autoantibodies.
The Applicant alleged that at the time of invention's filing, the art provided no motivation to make the composition of claim 23 because Madrid performed a series of diagnostic assays on samples taken from breast cancer patients alongside controls, and in one test looked specifically for the presence of anti-ENA autoantibodies using ELISA assays. These ELISA assays were all negative for anti-ENA autoantibodies.
This argument is not persuasive because Madrid’s teachings are not to be taken alone but rather in combination with the two references of Evans and Nisihara. The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, Madrid teaches studying the autoantibody response to tumor associated antigens (TAA) in the pathogenesis of cancer and its usefulness in the detection of breast cancer (Abstract, Conclusions; page 5 of 15, right column, last four lines). The negative results for extractable nuclear antigens (ENA) antibodies in patients with breast cancer does not teach against including ENA antibodies as part of the panel because ANA antibodies have been shown to be involved in other types of cancer (Page 2 of 15, left column, first paragraph, “We have shown that anti-collagen antibodies [12] and antinuclear antibodies [ANA] [5,13] are found in the sera from lung cancer and head and neck cancer patients as frequently as in the systemic Ads”). Furthermore, anti-nuclear antibodies (ANAs) are known to occur in sera of breast cancer patients as taught by Madrid (Page 2 of 15, left column, last paragraph, “Although ANAs have been known to occur in BC sera for several decades [25], a comprehensive study of autoantibodies on a large collection of sera from patients with pathology-proven BC and a real-life control group using classical techniques has not been reported.”). A skilled artisan would have known that usually positive ANA results are followed by ENA lab tests because ENA is a more specific follow-up test. Last, Madrid’s reference is not a primary reference but is cited to show that a panel of TAA and ENA is doable.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OMAR RAMADAN whose telephone number is (571)270-0754. The examiner can normally be reached Monday-Friday 8:30 am - 5:00 pm.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678