Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s elections without traverse of Group 1, claims 1-3, 5, 7-11, 18-22, and 24-26 and of the species L (a specific combination of 2 (the 2 being F [SIAH or SIAH2] and HER2)), in the reply filed on 10/21/2024 are reacknowledged.
Claims 4, 6-7, 9, 11-18, 23-24, and 26-29 are cancelled.
Claims 31-38 are new.
Claims 1, 3, 5, and 25 are amended.
Claims 1-3, 5, 8, 10, 19-22, 25, and 31-38 are pending.
Claims 1-3, 5, 8, 10, 19-22, 25, 31-38 are under examination on the merits.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/23/2026 has been entered.
Information Disclosure Statement
The IDS submissions dated 02/23/2026 has been considered.
Withdrawn Objections and Rejections
All objections/rejections of claim 9 are withdrawn as moot in light of its cancellation.
The rejections of the claims under 35 USC §103 and for double patenting are withdrawn and replaced with the rejections presented in this Office Action to better account for the new claim scope resulting from the claim amendments dated 02/23/2026.
Maintained-Claim Interpretation
Claim 1 recites “has an elevated level of activity in a k-ras pathway.” In an effort to advance prosecution, this recitation is being interpreted to mean that the subject has ‘an elevated level of at least one of: K-ras, RAF, MAPK, MEK, ETS or SIAH,’ wherein an elevated level can be a level above (by at least 10%) a control or standardized level, for example, a level in a non-DCIS sample (see for example paragraphs 0003, 0092, and 0215-0258 of the specification; this is also consistent with the drafting of instant claim 2, depending from claim 1). These examples are not limiting, but are encompassed by the scope of the claim as presently drafted when viewing the disclosure in its entirety. It is noted that the subject being SIAH2+ is also encompassed by the scope of the claim as drafted such that prior art teaching a subject being SAIH2+ is presently deemed sufficient to meet the limitation that the subject “has an elevated level of activity in a k-ras pathway,” in accordance with Applicant remarks at page 6, paragraph 2 under the heading ‘Claim Rejections under 35 U.S.C. §103’[“…a subject with DCIS that has an elevated level of activity in the k- ras pathway (e.g., as indicated by a SIAH2 positive status)…”].
Where claim 1 links the elements of “(i) surgical removal of DCIS; and (ii)an anti- HER2 antibody and radiation therapy”, the recitation of ‘and’ between the 3 individual therapies leads the Examiner to interpret the claim such that all three individual therapies are ‘the selected therapy’ to be administered as required by the claim drafting.
Newly Necessitated Claim Rejections
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-3, 5, 8, 10, 19-22, 25, 30, 32-33, and 35-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Prelude (WO2016090323A1; as cited on the IDS dated 06/14/2022 IDS) in view of Paik et al (US2013251710A1).
Regarding claims 1-3 and 5, Prelude teaches a method comprising analyzing a ductal carcinoma in situ (DCIS) sample for PR, HER2 and SIAH2 (see for example claim 1 of Prelude). In some embodiments, a method for treating a subject diagnosed with DCIS at risk of having a subsequent ipsilateral invasive breast cancer is provided (see for example paragraphs 0003, 0005-0006, and 0008-0018, claims 45-57, and Table 2). The method comprises providing a subject having DCIS, wherein the subject has a DCIS sample that is at least one or more of: a) PR-, HER2-, and SIAH2-, b) PR+, FOXA1+, or c) PR+, FOXAl-,and Ki67+; and administering to the subject a therapy that is more aggressive than standard of care for DCIS (see for example paragraph 0012) (noting that Prelude teaches prognosing the subject as having an elevated risk of a subsequent ipsilateral breast DCIS event when the subject is SIAH2+ and HER2+, wherein said subject is given a more aggressive therapy than standard of care, such as a secondary conserving surgery (see for example paragraphs 0011 and 0013))[held to teach claims 1-3]. Prelude further teaches that elevated SIAH2 (being SIAH2+ as submitted by Applicant to be encompassed within an elevated level of activity in a k-ras pathway (see page 6 of the 02/23/2026 remarks) (where DCIS risk means that the subject that provided the sample is at a high or elevated risk of subsequent ipsilateral invasive breast cancer and wherein the level is presumed elevated relative to a non-DCIS control (see for example claim 45, paragraph 0256, and paragraphs 0303 and 0307 of Prelude) which is consistent with the interpretation of the instant claims noted in the claim interpretation section of this Office Action, above) (see table 2 and paragraph 0007, for example). Prelude teaches that HER2 status may be investigated by IHC where staining of 0, 1+, or 2+ is considered negative and 3+ is considered positive (see for example, paragraphs 0265-0266). Prelude further teaches that the avoiding radiation for DCIS patients is desirable for health preservation and that the test taught by Prelude is used to measure risk of DCIS invasion to determine if the patient is low risk (undergoing standard of care lumpectomy) or high risk (requiring radiation, aggressive radiation, adjuvant radiation, cytotoxic chemotherapy, and/or mastectomy (see paragraphs 0070-0077 discussing the desire to avoid unnecessary radiation and paragraphs 0078-0080 discussing more aggressive treatment for identified high risk DCIS (noting that the aggressive radiation of Prelude is deemed to make obvious the recited aggressive radiation of instant claim 5 in light of the lack of a definition by Applicant that would exclude such interpretation and, in the interest of advancing prosecution, a treatment more aggressive than standard of care is held to be any of the options listed as treatment in instant claim 5))). Note that lumpectomy or mastectomy would meet the recitation of surgery as recited in instant claim 1. Throughout the reference, Prelude teaches that radiation is standard of care alongside lumpectomy and that aggressive radiation may be indicated for mastectomy patients or subjects with concerning margins post-lumpectomy (see reference generally). Prelude further teaches that for certain lumpectomy-eligible patients found to be very high-risk (of subsequent ipsilateral breast event (such as DCIS recurrence or invasion)) by the test from the initial biopsy can be candidates for mastectomy with or without adjuvant radiation and/or hormone therapy (or even cytotoxic chemotherapy). The upgrades to more aggressive therapy would minimize the likelihood of potentially life-threatening recurrences and give patients peace of mind (see for example paragraphs 0077-0080; see also paragraphs 0013 and 0070-0076; see further, exemplary paragraph 0190).
Prelude does not explicitly teach treatment with an anti-HER2 antibody.
However, Paik et al teach that currently HER2-targeted therapies such as trastuzumab or lapatinib are only used in the treatment patients diagnosed with HER2 positive breast cancer, which comprise only 15% to 20% of all breast cancer patients. HER2 positivity is defined by either overexpression of HER2 protein, which is determined by immunohistochemical staining (3+ staining score by FDA approved Herceptest assay), or by amplification of the HER2 (ERBB2) gene, which is determined by fluorescence in situ hybridization assay (HER2/CEP17 ratio over 2 using FDA approved PathVysion assay) (see for example, paragraph 0005 at column 1 of page 1).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Prelude and Paik et al. The artisan would have been motivated to make and use the invention as claimed because Prelude further teach that the avoiding radiation for DCIS patients is desirable for health preservation and that the test taught by Prelude is used to measure risk of DCIS invasion to determine if the patient is low risk (undergoing standard of care lumpectomy) or high risk (requiring radiation, aggressive radiation, adjuvant radiation, cytotoxic chemotherapy, and/or mastectomy (see paragraphs 0070-0077 discussing the desire to avoid unnecessary radiation and paragraphs 0078-0080 discussing more aggressive treatment for identified high risk DCIS (noting that the aggressive radiation of Prelude is deemed to make obvious the recited aggressive radiation of instant claim 5 in light of the lack of a definition by Applicant that would exclude such interpretation and, in the interest of advancing prosecution, a treatment more aggressive than standard of care is held to be any of the options listed as treatment in instant claim 5))). Where the sample from the subject is analyzed for the recited biomarkers, DCIS invasion (ipsilateral invasion) risk is determined, and treatment is selected based upon said DCIS invasion risk (base on at least a measurement of SIAH and HER2), the subject is implicitly selected for a treatment, where Prelude teaches that the treatment for high risk (of invasion) DCIS is surgery with or without adjuvant radiation and/or hormone therapy, as discussed in the cited teachings above. The artisan would have found it obvious to treat a subject with HER2+ cancer/DCIS with an anti-HER2 antibody because Paik et al teach that, currently, HER2+ cancers are commonly treated with an anti-HER2 antibody. Where the combination of Prelude and Paik et al teach the combination of surgery, adjuvant radiation, and anti-HER2 antibody as treatment for a cancer that is HER2+, the artisan would have found it obvious to administer said treatments to a subject identified as having a HER2+ cancer because the treatments are all taught to be effective for treating a HER2+ cancer. It is prima facie obvious to combine two or more equivalents (surgery, radiation, and anti-HER2 antibody therapy each being known as effective for treating breast cancer/HER2+ DCIS) each known in the art to be effective for the same purpose (see MPEP §2144.06(I)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 8, as discussed above, Prelude in view of Paik et al teach the method of instant claim 3. Prelude further teaches that in some embodiments, a method for prognosing a risk of a subsequent ipsilateral invasive breast cancer event in a subject is provided. The method comprises providing a DCIS sample (held to read on the recitation of “the subject’s DCIS” as recited in instant claim 8) from a subject, analyzing the sample for: a) PR, HER2, and SIAH2, or b) PR and FOXA1; and prognosing the subject as having an elevated risk of a subsequent ipsilateral invasive breast cancer event when at least one of: a) PR-, HER2-, and SIAH2-, b) PR+, FOXA1+, or c) PR+, FOXA1-, and Ki67+, is present in the DCIS sample (see for example paragraph 0010 and claim 3). One of ordinary skill in the art would have found it obvious to practice the method of claim 3 modified to further comprise measuring levels of Ki67 in the sample relative to baseline and administering the more aggressive therapy to a subject who is Ki67+ (elevated Ki67, presumably (in light of the total disclosure) relative to a non-DCIS control)(such as a non-radiotherapy or aggressive radiation therapy) given the teachings of Prelude that such a sample would likely be at risk of invasion/spread (see for example paragraph 0010-0011, claims 25, 31, 33, 34, 74, and table 10 of Prelude) whereupon one of ordinary skill in the art would have found it desirable to practice said method by administering a more aggressive therapy (held to make obvious the recitations of administering an aggressive therapy in light of the ambiguity of the term, as discussed in the rejection under 35 USC 112(b), above).
Regarding claims 10 and 38, Paik et al teach that trastuzumab is an art-known anti-HER2 antibody used in the art to treat HER2+ cancers (see for example, paragraph 0005 at column 1 of page 1).
Regarding claims 19-20, Prelude teaches that the method comprises providing a subject having DCIS, wherein the subject has a DCIS sample that is at least one or more of: a) PR-, HER2-, and SIAH2-, b) PR+, FOXA1+, or c) PR+, FOXAl-,and Ki67+ (meeting the limitations of instant claims 19-20); and administering to the subject a therapy that is more aggressive than standard of care for DCIS (see for example paragraph 0012)
Regarding claim 21, Prelude and Paik et al make obvious claim 5 and further teaches that, in some embodiments, the method further comprises analyzing at least COX2, Ki67, p16, PR and HER2 (see for example paragraph 0179 of Prelude). Therefore, the claim is made obvious by Prelude and Paik et al. The artisan would have been motivated, with a reasonable expectation of success, to practice the method of Prelude and Paik et al for reasons iterated, above.
Regarding claim 22, note that Prelude teaches that in some embodiments, analysis of each marker is carried out in parallel with each other. In some embodiments, analysis of each marker is carried out at overlapping times (see for example paragraph 0180), whereby the claim is made obvious by Prelude. Thereby, the claim is made obvious by Prelude as modified by Paik et al. The artisan would have been motivated, with a reasonable expectation of success, to practice the method of Prelude and Paik et al for reasons iterated, above.
Regarding claim 25, note that Prelude in view of Paik et al teaches and makes obvious the method of instant claim 5, requiring analysis of HER2 and SIAH2 and Prelude further shows examination of only SIAH2 and HER2 status (with SIAH2+ and HER2+ being associated with DCIS; see for example table 11). Therefore, one of ordinary skill in the art looking for an efficient biomarker combination to optimize the method of diagnosing and treating DCIS in need of more aggressive treatment (non-radiotherapy treatment) would have found it obvious to try, as of the filing date and with a reasonable expectation of success) any of the combinations of Table 11, including the combination of SIAH2 and HER2 (with no further biomarkers included to save on costs and time) and would have found it obvious to administer a HER2 antibody (trastuzumab) to a HER2+ DCIS subject for reasons discussed above, meeting and making obvious the limitations of instant claim 25, where a 2 biomarker assay would reduce the complexity and reagents needed, resulting in a simplified assay capable of detecting DCIS at a high risk of an ipsilateral event (invasion/new ipsilateral lesion) as being identified as for an aggressive cancer therapy, said therapy comprising surgery, treatment with an anti-HER2 antibody, and adjuvant radiation as taught to be appropriate for a DCIS that is HER2+ and SIAH2+ by Prelude in view of Paik et al, as discussed above.
Regarding claims 30, 33, and 36, as discussed above, Prelude in view of Paik et al teach and make obvious instant claims 1, 3, and 5. Prelude, as discussed above, teaches a method for prognosing a risk of a subsequent DCIS event in a subject, said method comprising providing a DCIS sample from a subject analyzing the sample for at least SIAH2 and at least one of i) PR and ii) HER2, and prognosing the subject as having an elevated risk of a DCIS event when the sample is SIAH2+ and HER2+ (see for example, claim 45 of Prelude), wherein the DCIS sample is further analyzed for COX-2 or p16 (see for example, claims 60-61 of Prelude).
Regarding claims 32, 35, and 37, as discussed above, Prelude teaches that HER2 status may be investigated by IHC where staining of 0, 1+, or 2+ is considered negative and 3+ is considered positive (see for example, paragraphs 0265-0266).
Claim(s) 31 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Prelude (WO2016090323A1; as cited on the IDS dated 06/14/2022 IDS) in view of Paik et al, as applied to claims 1-3, 5, 8, 10, 19-22, 25, 30, 32-33, and 35-38 above, in further view of Roses et al (Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1386-9. doi: 10.1158/1055-9965.EPI-08-1101. Epub 2009 Apr 21) and Behling et al (Breast Cancer Res Treat 129, 717–724 (2011); https://doi.org/10.1007/s10549-010-1254-8).
Regarding claims 31 and 34, Prelude in view of Paik et al teach and make obvious the method of claims 1 and 3.
The combined references do not explicitly teach that HER2+ and SAIH2 where the elevated risk for ipsilateral breast event comprises ipsilateral invasive breast cancer, despite teaching that they are linked to an increased risk of DCIS ipsilateral breast event.
However, Roses et al teach that immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 was done on DCIS specimens. Invasive foci were found in association with HER2 overexpressing DCIS at a higher frequency than with DCIS that did not overexpress HER2. HER2 overexpression in DCIS lesions predicts the presence of invasive foci in patients with DCIS and suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression (see for example, the abstract).
Prelude, Paik et al, and Roses et al do not teach that SAIH2 expression is linked to ipsilateral invasive breast cancer.
However, Behling et al teach that hyperactivated HER2/Neu/EGFR/RAS signaling is a major growth-promoting pathway known to drive cellular transformation and oncogenesis in breast cancers. HER2 amplification is detected in ~20% of all human breast cancer and is quite prevalent (up to 49%) in ductal carcinoma in situ (DCIS). The E3 ubiquitin ligase SIAH is considered a key downstream “gatekeeper” required for proper HER2/EGFR/RAS signal transduction. There was significantly increased SIAH expression in tumors with more aggressive features including comedo morphology (13.5% in comedo vs. 7% in other histologic types, P = 0.014). SIAH may represent a useful prognostic biomarker that predicts DCIS progression to invasive breast cancer (see for example, the abstract at page 717). SIAH expression was significantly higher in primary DCIS associated with invasive recurrence (median 21 vs. 15.5%; P = 0.036) (see for example, column 2 of page 720). Two homologues, SIAH1 and SIAH 2, exist in humans, and have been shown to play a role in several pathways including RAS signaling (see for example, column 1 of page 718; note that IHC was conducted for SIAH2 (see for example, page 718 bridging 719)). Therefore, the artisan would have understood the teachings of Behling et al to apply to/refer to SIAH2.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to identify subjects at risk of an invasive ipsilateral breast event (ipsilateral invasive breast cancer) because Prelude and Paik et al teach such a method where the subject at risk of an ipsilateral breast event, including invasive ipsilateral breast cancer, should be given more aggressive treatment, where Roses et al and Behling et al teach that elevated HER2 and SIAH are associated with increased invasion risk in DCIS. Where SIAH and HER2 are individually taught to be useful for identifying DCIS with a risk of invasive breast cancer as the ipsilateral breast event, it would have been obvious to combine the two biomarkers for use to identify subjects with an DCIS with a risk of invasive breast cancer as the ipsilateral breast event (see MPEP §2144.06 (I)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, 8, 10, 19-22, 25, 30, 32-33, and 35-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1 and 3 of US Patent No. 11543411B2 (reference A);
claims 1-18 of US Patent No. 12571798B2 (reference B);
claims 1-28 of US Patent No. 12487242B2 (reference C); and
claims 1-13 of US Patent No. 11821900B2 (reference D; as cited on the 04/15/2024 IDS),
in view of Prelude (WO2016090323A1; as cited on the IDS dated 06/14/2022 IDS) in view of Paik et al (US2013251710A1).
The claims are not verbatim, but pertain to assays for identifying subjects with DCIS with a high risk of an ipsilateral breast event measuring overlapping biomarkers.
Claims 1-3, 5, 8, 10, 19-22, 25, 30, 32-33, and 35-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 2-20 of copending Application No. 19/557,036 (‘036);
claims 15-18, and 74-83 of copending Application No. 19/387,345 (‘345); and
claims 30-54 of copending Application No. 18/998,333 (‘333).
in view of Prelude (WO2016090323A1; as cited on the IDS dated 06/14/2022 IDS) in view of Paik et al (US2013251710A1).
The claims are not verbatim, but pertain to assays for identifying subjects with DCIS with a high risk of an ipsilateral breast event measuring overlapping biomarkers.
The rejections over ‘036, ‘345, and ‘333 are provisional rejections.
Reference A claims a method for treating a subject, said method comprising:
providing a DCIS sample from a subject;
analyzing the DCIS sample for at least PR, FOXA1, COX-2, and KI67 expression levels, by measuring presence/absence and/or measuring expression levels of PR, FOXA1, KI67, and COX2, wherein the analyzed DCIS sample is determined to be at least PR+, FOXA1+, COX-2+, and KI67+; and
based on the analysis of the DCIS sample, treating the subject with at least one of:
adjuvant radiation; or
endocrine therapy,
thereby reducing the subject's risk of subsequent ipsilateral invasive breast cancer,
(see claim 1 of reference A). Wherein the method may further comprise analyzing the sample for p16 expression level (see reference A claim 3).
Reference A does not claim the specific combinations of biomarkers and treatments (such as trastuzumab) which are instantly claimed.
Reference B claims a method of treating breast cancer in a subject, comprising: collecting a tissue sample from an initial DCIS lesion from a subject; analyzing a cell signature of the tissue sample, comprising: detecting whether said sample is positive for Ki67 which may further comprise detection of HER2 (ERBB2), p16, COX2, and/or PR (see claims 1, 4-6, 11, and 14-17 of Reference B).
Reference B does not claim the specific combinations of biomarkers (such as SIAH2) and treatments (such as trastuzumab) which are instantly claimed.
Refence C claims a method of treating/determining treatment for DCIS breast cancer in a subject, comprising: collecting a tissue sample and analyzing the sample for PR (first or overlapping with other biomarkers assayed), HER2, SIAH2, p16, FOXA1, COX2, and/or ki67 wherein treatment to be administered is adjuvant radiation therapy or endocrine therapy (reading on the limitations of an aggressive radiation and a non-radiation therapy as aggressive therapies of instant claim 5, respectively) (see claims 1-28 of Reference B).
Reference C does not claim the specific combinations of biomarkers which are instantly claimed wherein the identified subject is administered surgery, radiation therapy, and anti-HER2 antibody therapy.
Reference D claims a method of treating/determining treatment for DCIS breast cancer in a subject, comprising :collecting a tissue sample and analyzing the sample for PR, HER2, SIAH2, p16, FOXA1, COX2, and/or ki67 (see claims 1-13 of Reference D) wherein treatment may be surgical or an aggressive treatment such as trastuzumab.
Reference D does not claim the specific combinations/sequential testing parameters of biomarkers which are instantly claimed, where the subject identified is administered treatments of surgery, radiation, and anti-HER2 antibody therapy.
‘036 claims a method comprising: analyzing a cell signature of a tissue sample from an initial ductal carcinoma in situ (DCIS) lesion of a subject, comprising: contacting the tissue sample with a nucleic acid probe or nucleic acid primer specific for Ki67, detecting staining of tumor cells in the tissue sample by the nucleic acid probe or nucleic acid primer specific for Ki67, and identifying the sample as positive or negative for Ki67;contacting the tissue sample with a nucleic acid probe or nucleic acid primer specific for PR, detecting staining of tumor cells in the tissue sample by the nucleic acid probe or nucleic acid primer specific for PR, and identifying the sample as positive or negative for PR; and contacting the tissue sample with a nucleic acid probe or nucleic acid primer specific for ERBB2 (HER2), detecting staining of tumor cells in the tissue sample by the nucleic acid probe or nucleic acid primer specific for ERBB2, and identifying the sample as positive or negative for ERBB2 (HER2); and placing the subject in a risk category for subsequent ipsilateral breast cancer based on at least the analysis of the cell signature (see for example, claims 1, 4, 7-11, 13, and 14-17 of ‘036).
‘036 does not claim measurement of elevated activity in a k-ras pathway (SIAH2) or that the identified subject is administered surgery, radiation therapy, and anti-HER2 antibody therapy.
‘345 claims a method for prognosing a risk of a subsequent ipsilateral breast event in a subject with DCIS, comprising: providing a DCIS sample from a subject with DCIS; and analyzing the DCIS sample for at least: PR, HER2, and FOXAl expression levels, by measuring presence/absence and/or measuring expression levels of PR, HER2, and FOXA1, wherein the analyzed DCIS sample being at least (1) PR-, HER2-, and FOXA1-, or (2) PR+, HER2-, and FOXA1+, indicates an elevated risk of subsequent ipsilateral invasive breast cancer, where SIAH2 may be further analyzed (see for example claims 75-83).
‘345 does not claim that the selected/identified subject is administered surgery, radiation, and anti-HER antibody therapy.
‘333 claims a method of treating a subject for breast cancer, comprising: determining a tumor aggressivity of the breast cancer, wherein the tumor aggressivity comprises a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject; determining an Immunescore based on a level of one or more genes from Table 4 in the tissue sample; combining the Proliferative Index score and the Immunescore to generate an integrated score; based at least on the integrated score, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission; and administering to the subject the selected cancer therapy (see exemplary claim 30).
‘333 does not claim measurement of HER2 or SIAH2 or treatment of a subject identified using the method with surgery, radiation, and anti-HER2 antibody therapy.
The teachings of Prelude and Paik et al provide the teachings notably absent from the above enumerated references A-D and ‘036, ‘345, and ‘333, as noted in greater detail below.
Regarding claims 1-3 and 5, Prelude teaches a method comprising analyzing a ductal carcinoma in situ (DCIS) sample for PR, HER2 and SIAH2 (see for example claim 1 of Prelude). In some embodiments, a method for treating a subject diagnosed with DCIS at risk of having a subsequent ipsilateral invasive breast cancer is provided (see for example paragraphs 0003, 0005-0006, and 0008-0018, claims 45-57, and Table 2). The method comprises providing a subject having DCIS, wherein the subject has a DCIS sample that is at least one or more of: a) PR-, HER2-, and SIAH2-, b) PR+, FOXA1+, or c) PR+, FOXAl-,and Ki67+; and administering to the subject a therapy that is more aggressive than standard of care for DCIS (see for example paragraph 0012) (noting that Prelude teaches prognosing the subject as having an elevated risk of a subsequent ipsilateral breast DCIS event when the subject is SIAH2+ and HER2+, wherein said subject is given a more aggressive therapy than standard of care, such as a secondary conserving surgery (see for example paragraphs 0011 and 0013))[held to teach claims 1-3]. Prelude further teaches that elevated SIAH2 (being SIAH2+ as submitted by Applicant to be encompassed within an elevated level of activity in a k-ras pathway (see page 6 of the 02/23/2026 remarks) (where DCIS risk means that the subject that provided the sample is at a high or elevated risk of subsequent ipsilateral invasive breast cancer and wherein the level is presumed elevated relative to a non-DCIS control (see for example claim 45, paragraph 0256, and paragraphs 0303 and 0307 of Prelude) which is consistent with the interpretation of the instant claims noted in the claim interpretation section of this Office Action, above) (see table 2 and paragraph 0007, for example). Prelude teaches that HER2 status may be investigated by IHC where staining of 0, 1+, or 2+ is considered negative and 3+ is considered positive (see for example, paragraphs 0265-0266). Prelude further teaches that the avoiding radiation for DCIS patients is desirable for health preservation and that the test taught by Prelude is used to measure risk of DCIS invasion to determine if the patient is low risk (undergoing standard of care lumpectomy) or high risk (requiring radiation, aggressive radiation, adjuvant radiation, cytotoxic chemotherapy, and/or mastectomy (see paragraphs 0070-0077 discussing the desire to avoid unnecessary radiation and paragraphs 0078-0080 discussing more aggressive treatment for identified high risk DCIS (noting that the aggressive radiation of Prelude is deemed to make obvious the recited aggressive radiation of instant claim 5 in light of the lack of a definition by Applicant that would exclude such interpretation and, in the interest of advancing prosecution, a treatment more aggressive than standard of care is held to be any of the options listed as treatment in instant claim 5))). Note that lumpectomy or mastectomy would meet the recitation of surgery as recited in instant claim 1. Throughout the reference, Prelude teaches that radiation is standard of care alongside lumpectomy and that aggressive radiation may be indicated for mastectomy patients or subjects with concerning margins post-lumpectomy (see reference generally). Prelude further teaches that for certain lumpectomy-eligible patients found to be very high-risk (of subsequent ipsilateral breast event (such as DCIS recurrence or invasion)) by the test from the initial biopsy can be candidates for mastectomy with or without adjuvant radiation and/or hormone therapy (or even cytotoxic chemotherapy). The upgrades to more aggressive therapy would minimize the likelihood of potentially life-threatening recurrences and give patients peace of mind (see for example paragraphs 0077-0080; see also paragraphs 0013 and 0070-0076; see further, exemplary paragraph 0190).
Prelude does not explicitly teach treatment with an anti-HER2 antibody.
However, Paik et al teach that currently HER2-targeted therapies such as trastuzumab or lapatinib are only used in the treatment patients diagnosed with HER2 positive breast cancer, which comprise only 15% to 20% of all breast cancer patients. HER2 positivity is defined by either overexpression of HER2 protein, which is determined by immunohistochemical staining (3+ staining score by FDA approved Herceptest assay), or by amplification of the HER2 (ERBB2) gene, which is determined by fluorescence in situ hybridization assay (HER2/CEP17 ratio over 2 using FDA approved PathVysion assay) (see for example, paragraph 0005 at column 1 of page 1).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the enumerated references A-D, ‘036, ‘345, and ‘333 , individually, in view of Prelude and Paik et al. The artisan would have been motivated to make and use the invention as claimed because Prelude further teach that the avoiding radiation for DCIS patients is desirable for health preservation and that the test taught by Prelude is used to measure risk of DCIS invasion to determine if the patient is low risk (undergoing standard of care lumpectomy) or high risk (requiring radiation, aggressive radiation, adjuvant radiation, cytotoxic chemotherapy, and/or mastectomy (see paragraphs 0070-0077 discussing the desire to avoid unnecessary radiation and paragraphs 0078-0080 discussing more aggressive treatment for identified high risk DCIS (noting that the aggressive radiation of Prelude is deemed to make obvious the recited aggressive radiation of instant claim 5 in light of the lack of a definition by Applicant that would exclude such interpretation and, in the interest of advancing prosecution, a treatment more aggressive than standard of care is held to be any of the options listed as treatment in instant claim 5))). Where the sample from the subject is analyzed for the recited biomarkers, DCIS invasion (ipsilateral invasion) risk is determined, and treatment is selected based upon said DCIS invasion risk (base on at least a measurement of SIAH and HER2), the subject is implicitly selected for a treatment, where Prelude teaches that the treatment for high risk (of invasion) DCIS is surgery with or without adjuvant radiation and/or hormone therapy, as discussed in the cited teachings above. The artisan would have found it obvious to treat a subject with HER2+ cancer/DCIS with an anti-HER2 antibody because Paik et al teach that, currently, HER2+ cancers are commonly treated with an anti-HER2 antibody. Where the combination of Prelude and Paik et al teach the combination of surgery, adjuvant radiation, and anti-HER2 antibody as treatment for a cancer that is HER2+, the artisan would have found it obvious to administer said treatments to a subject identified as having a HER2+ cancer because the treatments are all taught to be effective for treating a HER2+ cancer. It is prima facie obvious to combine two or more equivalents (the three instantly recited treatments of surgery, radiation, and anti-HER2 antibody therapy) each known in the art to be effective for the same purpose (see MPEP §2144.06(I)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 8, as discussed above, the enumerated references A-D, ‘036, ‘345, and ‘333, individually, in view of Prelude and Paik et al teach the method of instant claim 3. Prelude further teaches that in some embodiments, a method for prognosing a risk of a subsequent ipsilateral invasive breast cancer event in a subject is provided. The method comprises providing a DCIS sample (held to read on the recitation of “the subject’s DCIS” as recited in instant claim 8) from a subject, analyzing the sample for: a) PR, HER2, and SIAH2, or b) PR and FOXA1; and prognosing the subject as having an elevated risk of a subsequent ipsilateral invasive breast cancer event when at least one of: a) PR-, HER2-, and SIAH2-, b) PR+, FOXA1+, or c) PR+, FOXA1-, and Ki67+, is present in the DCIS sample (see for example paragraph 0010 and claim 3). One of ordinary skill in the art would have found it obvious to practice the method of claim 3 modified to further comprise measuring levels of Ki67 in the sample relative to baseline and administering the more aggressive therapy to a subject who is Ki67+ (elevated Ki67, presumably (in light of the total disclosure) relative to a non-DCIS control) (such as a non-radiotherapy or aggressive radiation therapy) given the teachings of Prelude that such a sample would likely be at risk of invasion/spread (see for example paragraph 0010-0011, claims 25, 31, 33, 34, 74, and table 10 of Prelude) whereupon one of ordinary skill in the art would have found it desirable to practice said method by administering a more aggressive therapy (held to make obvious the recitations of administering an aggressive therapy in light of the ambiguity of the term, as discussed in the rejection under 35 USC 112(b), above).
Regarding claims 10 and 38, Paik et al teach that trastuzumab is an art-known anti-HER2 antibody used in the art to treat HER2+ cancers (see for example, paragraph 0005 at column 1 of page 1).
Regarding claims 19-20, Prelude teaches that the method comprises providing a subject having DCIS, wherein the subject has a DCIS sample that is at least one or more of: a) PR-, HER2-, and SIAH2-, b) PR+, FOXA1+, or c) PR+, FOXAl-,and Ki67+ (meeting the limitations of instant claims 19-20); and administering to the subject a therapy that is more aggressive than standard of care for DCIS (see for example paragraph 0012)
Regarding claim 21, the enumerated references A-D, ‘036, ‘345, and ‘333 , individually, in view of Prelude and Paik et al make obvious claim 5 and further teaches that, in some embodiments, the method further comprises analyzing at least COX2, Ki67, p16, PR and HER2 (see for example paragraph 0179 of Prelude). Therefore, the claim is made obvious by Prelude and Paik et al. The artisan would have been motivated, with a reasonable expectation of success, to practice the method of the combined references for reasons iterated, above.
Regarding claim 22, note that the enumerated references A-D, ‘036, ‘345, and ‘333 , individually, in view of Prelude and Paik et al teach that in some embodiments, analysis of each marker is carried out in parallel with each other. In some embodiments, analysis of each marker is carried out at overlapping times (see for example paragraph 0180), whereby the claim is made obvious by Prelude. Thereby, the claim is made obvious by the enumerated references A-D, ‘036, ‘345, and ‘333 , individually, in view of Prelude as modified by Paik et al. The artisan would have been motivated, with a reasonable expectation of success, to practice the method of Prelude and Paik et al for reasons iterated, above.
Regarding claim 25, note that the enumerated references A-D, ‘036, ‘345, and ‘333 , individually, in view of Prelude and Paik et al teaches and makes obvious the method of instant claim 5, requiring analysis of HER2 and SIAH2 and Prelude further shows examination of only SIAH2 and HER2 status (with SIAH2+ and HER2+ being associated with DCIS; see for example table 11). Therefore, one of ordinary skill in the art looking for an efficient biomarker combination to optimize the method of diagnosing and treating DCIS in need of more aggressive treatment (non-radiotherapy treatment) would have found it obvious to try, as of the filing date and with a reasonable expectation of success) any of the combinations of Table 11, including the combination of SIAH2 and HER2 (with no further biomarkers included to save on costs and time) and would have found it obvious to administer a HER2 antibody (trastuzumab) to a HER2+ DCIS subject for reasons discussed above, meeting and making obvious the limitations of instant claim 25, where a 2 biomarker assay would reduce the complexity and reagents needed, resulting in a simplified assay capable of detecting DCIS at a high risk of an ipsilateral event (invasion/new ipsilateral lesion) as being identified as for an aggressive cancer therapy, said therapy comprising surgery, treatment with an anti-HER2 antibody, and adjuvant radiation as taught to be appropriate for a DCIS that is HER2+ and SIAH2+ by Prelude in view of Paik et al, as discussed above.
Regarding claims 30, 33, and 36, as discussed above, Prelude in view of Paik et al teach and make obvious instant claims 1, 3, and 5. Prelude, as discussed above, teaches a method for prognosing a risk of a subsequent DCIS event in a subject, said method comprising providing a DCIS sample from a subject analyzing the sample for at least SIAH2 and at least one of i) PR and ii) HER2, and prognosing the subject as having an elevated risk of a DCIS event when the sample is SIAH2+ and HER2+ (see for example, claim 45 of Prelude), wherein the DCIS sample is further analyzed for COX-2 or p16 (see for example, claims 60-61 of Prelude).
Regarding claims 32, 35, and 37, as discussed above, Prelude teaches that HER2 status may be investigated by IHC where staining of 0, 1+, or 2+ is considered negative and 3+ is considered positive (see for example, paragraphs 0265-0266).
Claims 1-3, 5, 8, 10, 19-22, 25, 30, 32-33, and 35-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1 and 3 of US Patent No. 11543411B2 (reference A);
claims 1-18 of US Patent No. 12571798B2 (reference B; as cited on the 02/23/2026 IDS);
claims 1-28 of US Patent No. 12487242B2 (reference C); and
claims 1-13 of US Patent No. 11821900B2 (reference D; as cited on the 04/15/2024 IDS),
in view of Prelude in view of Paik et al, as applied to claims 1-3, 5, 8, 10, 19-22, 25, 30, 32-33, and 35-38 above, in further view of Roses et al (Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1386-9. doi: 10.1158/1055-9965.EPI-08-1101. Epub 2009 Apr 21) and Behling et al (Breast Cancer Res Treat 129, 717–724 (2011); https://doi.org/10.1007/s10549-010-1254-8).
The claims are not verbatim, but pertain to assays for identifying subjects with DCIS with a high risk of an ipsilateral breast event measuring overlapping biomarkers.
Claims 31 and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 2-20 of copending Application No. 19/557,036 (‘036);
claims 15-18, and 74-83 of copending Application No. 19/387,345 (‘345); and
claims 30-54 of copending Application No. 18/998,333 (‘333).
in view of Prelude in view of Paik et al, as applied to claims 1-3, 5, 8, 10, 19-22, 25, 30, 32-33, and 35-38 above, in further view of Roses et al (Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1386-9. doi: 10.1158/1055-9965.EPI-08-1101. Epub 2009 Apr 21) and Behling et al (Breast Cancer Res Treat 129, 717–724 (2011); https://doi.org/10.1007/s10549-010-1254-8).
The claims are not verbatim, but pertain to assays for identifying subjects with DCIS with a high risk of an ipsilateral breast event measuring overlapping biomarkers.
The rejections over ‘036, ‘345, and ‘333 are provisional rejections.
Regarding claims 31 and 34, the enumerated references A-D, ‘036, ‘345, and ‘333 , individually, in view of Prelude and Paik et al teach and make obvious the method of claims 1 and 3.
The combined references do not explicitly teach that HER2+ and SAIH2 where the elevated risk for ipsilateral breast event comprises ipsilateral invasive breast cancer, despite teaching that they are linked to an increased risk of DCIS ipsilateral breast event.
However, Roses et al teach that immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 was done on DCIS specimens. Invasive foci were found in association with HER2 overexpressing DCIS at a higher frequency than with DCIS that did not overexpress HER2. HER2 overexpression in DCIS lesions predicts the presence of invasive foci in patients with DCIS and suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression (see for example, the abstract).
The enumerated references A-D, ‘036, ‘345, and ‘333 , individually, in view of Prelude, Paik et al, and Roses et al do not teach that SAIH2 expression is linked to ipsilateral invasive breast cancer.
However, Behling et al teach that hyperactivated HER2/Neu/EGFR/RAS signaling is a major growth-promoting pathway known to drive cellular transformation and oncogenesis in breast cancers. HER2 amplification is detected in ~20% of all human breast cancer and is quite prevalent (up to 49%) in ductal carcinoma in situ (DCIS). The E3 ubiquitin ligase SIAH is considered a key downstream “gatekeeper” required for proper HER2/EGFR/RAS signal transduction. There was significantly increased SIAH expression in tumors with more aggressive features including comedo morphology (13.5% in comedo vs. 7% in other histologic types, P = 0.014). SIAH may represent a useful prognostic biomarker that predicts DCIS progression to invasive breast cancer (see for example, the abstract at page 717). SIAH expression was significantly higher in primary DCIS associated with invasive recurrence (median 21 vs. 15.5%; P = 0.036) (see for example, column 2 of page 720). Two homologues, SIAH1 and SIAH 2, exist in humans, and have been shown to play a role in several pathways including RAS signaling (see for example, column 1 of page 718; note that IHC was conducted for SIAH2 (see for example, page 718 bridging 719)). Therefore, the artisan would have understood the teachings of Behling et al to apply to/refer to SIAH2.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to identify subjects at risk of an invasive ipsilateral breast event (ipsilateral invasive breast cancer) because Prelude and Paik et al teach such a method where the subject at risk of an ipsilateral breast event, including invasive ipsilateral breast cancer, should be given more aggressive treatment, where Roses et al and Behling et al teach that elevated HER2 and SIAH are associated with increased invasion risk in DCIS. Where SIAH and HER2 are individually taught to be useful for identifying DCIS with a risk of invasive breast cancer as the ipsilateral breast event, it would have been obvious to combine the two biomarkers for use to identify subjects with an DCIS with a risk of invasive breast cancer as the ipsilateral breast event (see MPEP §2144.06 (I)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses:
A. Applicant disagrees with the Examiner’s claim interpretation of “an elevated activity in a k-ras pathway,” (see page 5 of the 02/23/2026 remarks).
Response: Applicant cites to the specification, but fails to articulate how the citations pertain to, let alone inform, the interpretation of the ambiguous statement. Applicant merely concludes that the phrase “has a meaning as understood by one of ordinary skill in the art in light of the present Application”. The Examiner has provided sufficient citations not only to the specification, but to the claims as drafted (see for example, the drafting of claims 1 and 2) which support that the Examiner’s interpretation, while not the only embodiment(s) encompassed within the scope of the claims, is encompassed by the present claim language. Therefore, the rejections reading upon elevation of a K-ras pathway evidenced by an elevated level of SIAH2 or being SIAH2+ would be encompassed by the claim as presently drafted and the rejections of record are maintained at this time. .
B. Applicant argues that the rejections of record do not teach the claimed method(s) as amended on 02/23/2026 (motivating treatment with an anti-HER2 antibody and radiation) (see pages 6-7 of the 2/23/2026 remarks).
Response: With respect to the argument that the rejections do not account for the steps of claim 1, the rejections of record as they appear in this Office action account for the active steps of identifying a subject with DCIS that has an elevated level of activity in a k-ras pathway (has an elevated SIAH2 level relative to a non-DCIS control; consistent with the instant disclose as explained in the claim interpretation section, above) measuring the level/presence of HER2 (+/-), SIAH2(+/-), where a subject with DCIS whose sample from the DCIS is SIAH2+ and HER2+ is then identified as having increased risk of a subsequent ipsilateral event and is a candidate for more aggressive therapy such as lumpectomy with chemotherapy/radiation/hormone therapy/mastectomy, whereupon administration of the recommended therapy is performed in the method of treatment. Paik et al teach that HER2+ cancers are known in the art to be treated with anti-HER2 antibodies such as trastuzumab. Such combination is obvious absent some showing to the contrary (see MPEP section 2143(I)(A)). The rejections as amended in light of Applicants remarks and claim amendments dated 02/23/2026 are deemed to teach and make obvious the claims as presently drafted/amended.
The arguments against the rejections of record under 35 USC §103 are unpersuasive and the rejections of record as they appear in this Office Action are maintained.
C. Applicant alleges surprisingly superior results from the instant method over the prior art method and seems to argue that Prelude teaches away from combining surgery and radiation therapy (see pages 7-11 of the 02/23/2026 remarks)
Response: There is no clearly evidenced, convincing showing of surprising results articulated in the 02/23/2026 remarks. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). Further, the scope of Applicant’s argument is not commensurate with the scope of what is claimed. The instant claims identify a subject based upon biomarker data and the select a treatment for said identified subject. The instant claims do not pertain, as presently drafted, to comparing outcomes based on treatment. The fact that Prelude also states that in some instances, the subject may be treated with breast conserving surgery without radiation does not negate the teachings of prelude that combine surgery and radiation as a treatment for more aggressive (HER2+ and SIAH2+) DCIS. Teaching of different embodiments is not a teaching away sufficient to discourage or discredit the artisan from combining surgery and radiation to treat a subject with HER2+ and SIAH2+ DCIS.
D. Applicant argues that the rejections for double patenting of record do not make obvious the instant claims as amended and requests certain rejections be held in abeyance (see pages 11-16 of the 02/23/2026 remarks).
Response: The rejections for double patenting presented in the previous office action have been withdrawn and replaced with the substantially altered rejections of double patenting as presented in this Office Action to account for newly added and amended scope of the claims resulting from the 02/20/2026 claim amendments, rendering the arguments for withdrawal moot. Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states:
“A complete response to a nonstatutory double patenting (NSDP) rejection is either a
reply by applicant showing that the claims subject to the rejection are patentably distinct
from the reference claims or the filing of a terminal disclaimer in accordance with 37
CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP §
1490 for a discussion of terminal disclaimers). Such a response is required even when the
nonstatutory double patenting rejection is provisional.”
“As filing a terminal disclaimer, or filing a showing that the claims subject to the
rejection are patentably distinct from the reference application’s claims, is
necessary for further consideration of the rejection of the claims, such a filing
should not be held in abeyance. Only objections or requirements as to form not
necessary for further consideration of the claims may be held in abeyance until allowable
subject matter is indicated. Replies with an omission should be treated as provided
in MPEP § 714.03.Therefore, an application must not be allowed unless the required
compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory
double patenting rejection(s) is made of record by the examiner.”
See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome
nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis
added). Accordingly, the rejection is maintained and is expressly not held in abeyance.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
DK 2939026T3 remains relevant to the recited subject matter.
Mylonas et al (Expression of Her2/neu, steroid receptors (ER and PR), Ki67 and p53 in invasive mammary ductal carcinoma associated with ductal carcinoma In Situ (DCIS) Versus invasive breast cancer alone. Anticancer Res. 2005 May-Jun;25(3A):1719-23) as cited on the 07/01/2025 IDS) is deemed relevant to the claimed subject matter. SIAH may represent a useful prognostic biomarker that predicts DCIS progression to invasive breast cancer. (see for example, the abstract). This reference remains relevant to the recited subject matter.
Faratian D et al (DOI:10.1111/J.; as cited on the 07/01/2025 IDS) continues to be deemed relevant.
Chan et al (The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression. Breast Cancer Res. 2011 Feb 9;13(1):R19. doi: 10.1186/bcr2828; as cited in the 06/14/2022 IDS) teach the elevated level of SIAH2 in DCIS sample is associated with radiation resistance by teaching that the seven in absentia homolog 2 (SIAH2) protein plays a significant role in the hypoxic response by regulating the abundance of hypoxia-inducible factor-α. Chan et al further teach that immunohistochemical evaluation of SIAH2 protein expression was conducted in normal breast tissues and in tissue microarrays comprising ductal carcinoma in situ (DCIS) and a cohort of invasive breast carcinomas, leading to the finding that there was a significant increase in nuclear SIAH2 expression from normal breast tissues through to DCIS and progression to invasive cancers (see for example the abstract and pg 8, col 1, para 3). Chan et al further teach that high levels of SIAH2 may be partly responsible for the enhanced hypoxic drive that underlies this tumor type, which is chemotherapy- and radiotherapy-resistant. It would have been obvious to one of ordinary skill in the art to administer an aggressive breast cancer therapy that was not radiation to the subject with an increased level of SIAH2 because an increased level of SIAH2 in DCIS is linked to radioresistance. This reference remains relevant to the recited subject matter.
Knauer et al (The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers. Cytokine Growth Factor Rev. 2015 Aug;26(4):405-13. doi: 10.1016/j.cytogfr.2015.04.002. Epub 2015 May 12) teach that an increasing body of evidence suggests that the E3 ubiquitin ligases SIAH1 and SIAH2 are able to dictate the growth, development, and chemo-/radiosensitivity of breast and prostate cancer cells, supporting that SIAH1 and SIAH2 share common functions and that use of either SIAH variant would yield no more than predictable results, the particular SIAH used being no more than a variable for routine optimization (see MPEP §2141.I, 2143(I)(B), 2144.05(II), and 2144.06(II)). This reference remains relevant to the recited subject matter.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHLEY GAO whose telephone number is (571) 272-5695. The examiner can normally be reached on Monday- Friday 8-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights