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 .
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 26-27 have been added. Claims 1-6, 9-16, 22, and 25-27 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Claim Objections
Claims 1, 3, 6, and 12 were objected to due to minor informalities. In light of Applicant’s amendments to the claims submitted 7/6/2026, these objections have been withdrawn, but see new grounds of objection below.
35 USC 112(b) Rejections
Claims 1-6, 9-16, 22, and 25 were rejected for indefiniteness issues associated with claim 1. In light of Applicant’s Amendments to the claims submitted 7/6/2026, these rejections have been withdrawn.
35 USC 103 Rejections
Claims 1, 3-6, 9, 14-16, 22, and 25 were rejected under 35 U.S.C. 103 as being unpatentable over Tulake et al. (Oncology Letters, 2018), in view of Howitt et al. (Am J Surg Pathol, 2013), in view of Liu et al. (Diagnostic Pathology, 2012), in view of Schmitt et al. (Molecular and Cellular Probes, 2011), in view of Cheng et al. (WO 2011/084598 A1), in view of Bankaitis-Davis et al. (WO 2008/143639 A2), and in view of Cleveland Clinic (Cervical Intraepithelial Neoplasia (CIN): Management and Treatment, 2018).
Claim 10 was rejected under 35 U.S.C. 103 as being unpatentable over Tulake et al. (Oncology Letters, 2018), in view of Howitt et al. (Am J Surg Pathol, 2013), in view of Liu et al. (Diagnostic Pathology, 2012), in view of Schmitt et al. (Molecular and Cellular Probes, 2011), in view of Cheng et al. (WO 2011/084598 A1), in view of Bankaitis-Davis et al. (WO 2008/143639 A2), in view of Cleveland Clinic (Cervical Intraepithelial Neoplasia (CIN): Management and Treatment, 2018), and further in view of Ishimi et al. (Eur. J. Biochem., 2003).
Claims 2 and 11 were rejected under 35 U.S.C. 103 as being unpatentable over Tulake et al. (Oncology Letters, 2018), in view of Howitt et al. (Am J Surg Pathol, 2013), in view of Liu et al. (Diagnostic Pathology, 2012), in view of Schmitt et al. (Molecular and Cellular Probes, 2011), in view of Cheng et al. (WO 2011/084598 A1), in view of Bankaitis-Davis et al. (WO 2008/143639 A2), in view of Cleveland Clinic (Cervical Intraepithelial Neoplasia (CIN): Management and Treatment, 2018), and further in view of Ishimi et al. (Eur. J. Biochem., 2003) and del Pino et al. (Pathology, 2015).
Claim 12 was rejected under 35 U.S.C. 103 as being unpatentable over Tulake et al. (Oncology Letters, 2018), in view of Howitt et al. (Am J Surg Pathol, 2013), in view of Liu et al. (Diagnostic Pathology, 2012), in view of Schmitt et al. (Molecular and Cellular Probes, 2011), in view of Cheng et al. (WO 2011/084598 A1), in view of Bankaitis-Davis et al. (WO 2008/143639 A2), in view of Cleveland Clinic (Cervical Intraepithelial Neoplasia (CIN): Management and Treatment, 2018), and further in view of Ishimi et al. (Eur. J. Biochem., 2003) and del Pino et al. (Pathology, 2015).
Claim 13 was rejected under 35 U.S.C. 103 as being unpatentable over Tulake et al. (Oncology Letters, 2018), in view of Howitt et al. (Am J Surg Pathol, 2013), in view of Liu et al. (Diagnostic Pathology, 2012), in view of Schmitt et al. (Molecular and Cellular Probes, 2011), in view of Cheng et al. (WO 2011/084598 A1), in view of Bankaitis-Davis et al. (WO 2008/143639 A2), in view of Cleveland Clinic (Cervical Intraepithelial Neoplasia (CIN): Management and Treatment, 2018), and further in view of Bio-Rad (“MyiQ and iQ5 Real-Time PCR Detection Systems”, 2013).
In light of Applicant’s amendments to the claims submitted 7/6/2026, along with Applicant’s provided declaration and remarks, these rejections have been withdrawn. See the full response to Applicant’s reply below.
Response to Applicant’s Declaration and Arguments
The declaration from the inventor, Dr. Andreas Kaufmann, submitted on 7/6/2026, has been entered.
Point 4 of the declaration points out data from the instant specification showing that the use of p16, STMB, and MCM2 with strongest HPV genotype improves diagnostic accuracy and sensitivity compared to the use of p16 alone. Point 5 discusses the importance of accurately diagnosing CIN2+ and CIN3+, as treatment is different for the two, and histological methods of differentiating between the conditions are not as consistent and as accurate as the claimed methods. Point 6 notes that the references cited in the prior art rejections previously of record that discriminate between CIN2+ and CIN3+ utilize protein levels, which are distinct from the claimed mRNA levels and do not necessarily correlate with such mRNA levels, and those which focus on mRNAs generally do not discriminate between CIN2+ and CIN3+. Point 7 discusses the benefits of the algorithm and measurement method used.
Regarding the 35 USC 103 Rejections, Applicant reiterates Dr. Kaufmann’s points concerning differentiating between CIN2+ and CIN3+ and how current methods for doing so are inconsistent, and summarizes how each of Tulake, Schmitt, Ishimi, and del Pino fail to distinguish between CIN2+ and CIN3+. Applicant notes that the remaining references used to read on the claimed biomarkers, Howitt and Liu, do distinguish between CIN2+ and CIN3+, but both use immunohistochemistry to measure protein expression (Remarks, pages 12-13).
On page 14, Applicant argues that Howitt teaches away from the claimed invention because the reference notes high levels of p16 in both CIN2 and CIN3 patients, thus making it allegedly ineffective for discrimination between CIN2+ and CIN3+ as claimed. Liu also allegedly does not provide evidence to support using TERT as a marker for cervical lesions generally, let alone with regard to mRNA levels specifically.
The points made by Applicant and Dr. Kaufmann concerning the references of record not specifically teaching evaluating mRNA levels of the cited biomarkers in relation to each of CIN2+, CIN3+, and cervical carcinoma are persuasive, particularly in view of Applicant’s amendments to the claims and the arguments concerning inconsistencies associated with immunohistochemistry diagnostics and differences between protein and mRNA expression. This is the basis for the withdrawal of the rejections presented in the Non-Final rejection mailed 3/24/2026, and thus any additional arguments presented against these references are rendered moot.
Claim Objections
Claim 1 is objected to because of the following informalities: in the final bullet point under “wherein the algorithm is configured to utilize,” “at least one of MCM2 and STMN1” should read “at least one of MCM2 and/or STMN1” to match the format of similar phrases used earlier in the claim. Appropriate correction is required.
Claims 2-6, 9-16, 22, and 25-27 are objected to due to their dependence on objected to claim 1.
Claim 9 is objected to because of the following informality: the space between “E1” and “^E4” should be removed. Appropriate correction is required.
Claim 10 objected to because of the following informality: based on the instant specification and elsewhere in the claims, it is believed that “E1”E4” should read “E1^E4”. If this is correct, appropriate correction is required.
Claim 12 is objected to because of the following informalities: based on the instant specification and elsewhere in the claims, it is believed that each instance of “E1”E4” should read “E1^E4”. If this is correct, appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Clam 12 depends on claim 1, and claim 1 requires the determination of three cellular proliferation markers: P16, MCM2, and STMN1. In claim 12, the claim is written as a more specific method comprising the same general steps (a) and (b) as claim 1. However, this claim states that the expression level of “at least one cellular proliferation marker” need be determined, where said markers are P16, MCM2, and STMN1. Thus, the claim encompasses measuring any one, two, or three of these markers, and so does not include all the limitations of the claim upon which it depends, as claim 1 requires the determination of the expression levels of all three markers.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Free of the Prior Art
After further search and consideration of the claims, no known prior art could be found that specifically analyzes all of the required biomarkers in the manner described by the instant claims. Particularly, for STMN1, prior art could not generally be found that analyzed mRNA in relation to cervical cancer or HPV-induced dysplasia. As pointed out by Applicant, Howitt teaches examination of STMN1 via immunohistochemistry, and this methodology appears to be what is primarily used throughout the prior art. See Novak et al. (Gynecologic Oncology, 2015), which teaches immunohistochemical staining of STMN1 and examines protein expression (Figures 1-2 and page 107, see section 3.5). Xi et al. (J Cancer Res Clin Oncol, 2009) teaches an examination of both protein and mRNA for stathmin (another name for STMN1), but this is only in cervical carcinoma and not in any stages of dysplasia – see Figures 1-3. For MCM2, Wang et al. (Oncotarget, 2017) examined this gene in CIN2+ and CIN3+ (see Tables 4-5), but this was based on immunocytochemistry staining (see methods on page 83897). Table 2 also notes that several samples examined had squamous cervical cancer, but this table only notes that MCM2 had positive staining in these cases, with no associated expression level. Svanholm et al. (US 2010/0240049 A1) teaches methods of detecting cervical dysplasia using mRNAs (Abstract). MCM2 is specifically pointed out as a potential biomarker (para. 11). Table 16 shows the mRNA targets of this gene, and clinical samples were used based on CIN1, CIN2, and cervical cancer diagnoses (Table 15). Fold changes compared to normal cell lines are shown in Tables 23-24, but para. 321 notes that CIN3 was excluded from these analyses.
Thus, the prior art does not make clear that all the required biomarkers in instant claim 1 can be used in the manner described in instant claim 1 to discriminate between CIN2+, CIN3+, and cervical cancer samples using mRNA expression levels.
Conclusion
Claims 1-6, 9-16, 22, and 25-27 are objected to. Claim 12 is rejected.
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.
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/F.F.G./Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
