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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/22/2025 has been entered.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claim 17 has been canceled. Claims 1-6, 9-16, 22, and 25 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Claim Objections
Claims 1-2, 4, 9, 12, and 15 were objected to due to minor informalities. In light of Applicant’s amendments to the claims submitted 10/22/2025, these objections have been withdrawn. However, see new grounds of objection below.
35 USC 112(a) Rejections
Claims 1-6, 9-17, 22, and 25 were rejected for failing to comply with the enablement requirement. In light of Applicant’s amendments to the claims submitted 10/22/2025, these rejections have been withdrawn for all currently pending claims. Claim 17 has been canceled, and so this rejection has been rendered moot. See “Response to Applicant’s Declaration” below.
35 USC 112(b) Rejections
Claim 12 was rejected for an indefiniteness issue. In light of Applicant’s amendments to the claims submitted 10/22/2025, this rejection has been withdrawn. However, see new grounds of rejection.
35 USC 103 Rejections
Claims 1-6, 9-17, 22, and 25 were rejected under 35 U.S.C. 103 as being unpatentable over Tulake et al. (Oncology Letters, 2018), in view of del Pino et al. (Pathology, 2015), in view of Schmitt et al. (Molecular and Cellular Probes, 2011), and in view of Cleveland Clinic (Cervical Intraepithelial Neoplasia (CIN): Management and Treatment, 2018) and various combinations of references. In light of Applicant’s amendments to the claims submitted 10/22/2025, these rejections have been withdrawn for all currently pending claims. Claim 17 has been canceled, and so this rejection has been rendered moot. See however “Response to Applicant’s Arguments” and new grounds of rejection below.
Response to Applicant’s Declaration
The Declaration of Dr. Andreas Kaufmann submitted 10/22/2025 has been entered. Dr. Kaufmann is the inventor of the present Applicant, and provides additional data for the claimed biomarkers in light of the enablement rejection presented in the Final Rejection mailed 7/28/2025. This enablement rejection stated that the use of Sox2, Nanog, POU5FI, and p53 were not enabled in the instant specification.
This declaration specifically provides additional data regarding the biomarkers Sox2, Nanog, POU5Fl, and p53. Figure 1 does not directly detail Sox2, Nanog, POU5FI, and/or p53, nor do Figures 2-3 (shown on pages 3-5 of the Declaration). Dr. Kaufman provides this data as evidence that different biomarkers in risk score formulas can be exchanged (point 10). Figure 4 shows data regarding the performance of Sox2, Nanog, and POU5F1 in cervical cancer patients, showing that they perform similarly to ALDH1A1. Figure 5 shows similar data for p53, showing it performs similarly to BIRC5 in cervical cancer patients.
The declaration also provides Dr. Kaufmann’s opinion regarding the obviousness rejections presented in the Final Rejection mailed 7/28/2025. Specifically, Dr. Kaufmann argues that the combination of claimed biomarkers is not taught in the prior art (point 17), and so there would be no teaching in the prior art or reasonable expectation of success that would lead the ordinary artisan to arrive at the claimed invention (point 18).
In considering the biomarkers Sox2, Nanog, POU5FI, and p53 in view of the newly amended claims, these biomarkers are only used in claim 1 to determine the presence of cervical cancer. P53 can be used instead of BIRC5, and Sox2, Nanog, and POU5F1 can be used instead of ALDH1A1. This is supported by the data provided by Dr. Kaufmann. P53 appears again in claim 12, but is not actually required to be used to determine a grade of dysplasia or the presence of cervical carcinoma.
In considering the claims as Dr. Kaufmann’s Declaration as a whole, the evidence provided in view of the amended claims is persuasive to overcome the enablement rejection.
Regarding the 35 USC 103 Rejections, Dr. Kaufmann provides their opinion as to whether the ordinary artisan would be capable of combining the teachings of the cited references to arrive at the claimed invention. The merits of the obviousness rejections in view of Applicant’s arguments are discussed below in the “Response to Applicant’s Arguments” section.
Response to Applicant’s Arguments
Regarding the 35 USC 112(a) Rejections, Applicant reiterates the arguments of Dr. Kaufmann (Remarks, pages 8-9). As noted above, these rejections have been withdrawn for all currently pending claims.
Regarding the 35 USC 103 Rejections, Applicant first takes note of the Examiner’s interpretation of “strongest HPV genotype” (Remarks, pages 10-11). The Examiner’s interpretation in the Final Rejection was intended to indicate that prior art will still be considered as relevant to the claim if it teaches using multiple HPV genotypes (i.e. the “strongest” HPV genotype and additional genotypes). This is because in the claim, the strongest HPV genotype must be “employed in deducing the severity or grade of the dysplasia,” but this does not prohibit the additional use of other HPV genotypes that may not be the strongest. This interpretation also states that even if the prior art does not specifically state that one HPV genotype of the “strongest” in those evaluated, that if there are multiple genotypes present with different expression levels, and the genotypes with the highest expression level is used, then said prior art will naturally teach utilizing the “strongest” HPV genotype. The interpretation takes into account the limitation of (a)(i) of claim 1. This interpretation is also supported by the dependent claims, where multiple HPV genotypes are evaluated (see claims 9-10 and 12).
Applicant has amended (b) of claim 1 to require use of a multivariate algorithm and to recite specific biomarkers for different stages of disease. Applicant argues that the cited references do not teach utilizing the claimed biomarkers to distinguish between CIN2+, CIN3+, and cervical carcinoma and disease stage-specific treatment. Applicant states that the ability of their claimed invention to distinguish between disease stages provides advantages that would not have been obvious over the prior art (Remarks, pages 13-14). Applicant goes on to state that none of the cited prior art references group the claimed biomarkers into the claimed functional categories (e.g. viral, proliferation, cancer stem cell, tumor), and there would be no reasonable expectation of success in combining the cited references to arrive at the claimed invention. Applicant cites the Examiner’s disclosure in the previous enablement rejection regarding the unpredictability of using Sox2, Nanog, POU5F1, and p53 to determine a grade of cervical dysplasia or the presence of cervical cancer as evidence of this, stating this contradicts the reasonable expectation of success put forth in the obviousness rejections of the Final Rejection (Remarks, page 15).
Applicant states that the cited references do not teach utilizing the “strongest HPV genotype,” and also argues that Bankaitis-Davis, used in the Final Rejection to teach mathematical algorithms to score disease stages, does not utilize biomarkers in the same manner as the instant claims, and does not teach distinguishing between CIN2+, CIN3+, and cervical carcinoma, and thus does not meet the specificity of instant claim 1 (Remarks, page 17). These alleged deficiencies are not remedied by the additional secondary references (Remarks, pages 18-19).
In the instant claims, while Applicant does provide categories of names for their different biomarkers (e.g. cellular proliferation marker, cancer stem cell marker, tumor marker, etc.), these terms have no particular definition in the specification, and provide no additional structure or function to the biomarkers themselves. For example, on page 20, para. 6, cellular proliferation markers are described as “a molecular marker associated with cells undergoing proliferation.” This is a property inherent in the biomarker, and so such a property does not need to be explicitly stated by the prior art. Similar wording is used on pages 20-21, joining para. for the stem cell markers (“a molecular marker associated with a cancer stem cell”) and on page 21, para. 3 for tumor markers (“a molecular marker associated with tumors”). On page 5, para. 2, it is stated that, “The cellular proliferation markers, cancer stem cell markers and tumor markers are known to a skilled person and may be selected and employed without undue effort.” Furthermore, the claims are written as a method comprising the listed steps, and the cellular mRNA used comprises the listed markers. Thus, prior art utilizing the claimed markers in addition to other, unclaimed markers, does not discount the teachings of the prior art in relation to the claimed markers. Prior art will therefore be considered to read upon the teachings of the claim if it generally teaches the claimed biomarkers in relation to the claimed disease states, even if said prior art does not classify the biomarkers as is done in the instant claims – e.g. with the “cellular proliferation” or “tumor marker” labels.
Additionally, instant claim 1 as a whole is directed to determining the presence of dysplasia or cervical carcinoma in a subject, and if the subject has dysplasia, also deducing the severity or grade of said dysplasia. In a), markers for expression are used. In b), a disease determination is made, where particular markers are used for dysplasia versus cervical cancer. Only one set of markers need be used, as evidenced by the “or” between the markers for CIN3+ and those for cervical carcinoma. The determination is made based on inputting the expression markers into a multivariate algorithm that “provides a score value for determining the severity or grade of the dysplasia or the presence of cervical carcinoma,” (emphasis added). In considering the claim as a whole, if the subject has cervical carcinoma, for example, then only the final markers in the wherein clause of claim 1 need be used (i.e. strongest HPV genotype, at least one of TERT, BIRC5, or p53, at least one of ALDH1A1, Sox2, Nanog, and POU5F1, and at least one of MCM2, STMN1, Topo2a, and Ki-67), and the multivariate algorithm need provide a score to determine if the subject has cervical carcinoma. In other words, the claim is not drawn to measuring all of the markers presented in the wherein clause, and is directed to deducing the presence of dysplasia (and if present, the grade of said dysplasia, where the grade may be CIN2+ or CIN3+) or the presence of cervical carcinoma, where the multivariate algorithm need only deduce one or the other. It is noted that at least one biomarker from each category in (a)(ii) also need be measured, even if this biomarker is not used in the deduction of dysplasia or cervical cancer.
Applicant has amended claim 1 to be much more specific with regard to the required biomarkers to indicate a particular disease. A summary of the relevant teachings of the previously cited references in relation to these required biomarkers is provided below:
Tulake teaches that mRNA expression of ALDH1A1 significantly increases in cervical cancer compared to non-cancerous and dysplasia tissues, and generally increased with worsening disease, reading on the cervical carcinoma limitation of instant claim 1. The reference also performs HPV genotyping and found the most common HPV genotype in non-cancerous, CIN II-II, and cervical carcinoma tissues, reading on the strongest HPV genotype limitations of instant claim 1.
del Pino teaches measuring expression levels of BIRC5, p16, TOP2A, and MKI-67 between low and high grade lesions. In Table 2, BIRC5, p16, TOP2A, and MKI-67 were all found to significantly differ between control, low, and/or high grade lesion groups, reading on the CIN2+, CIN3+, and cervical carcinoma limitations of instant claim 1.
Schmitt evaluates HPV genotypes and p16 in cervical cancer and low and high grade lesions. Figure 2 shows how the HPV genotypes and p16 changed with disease progression, reading on the claimed viral mRNA, strongest HPV genotype, and CIN2+, CIN3+, and cervical carcinoma limitations of instant claim 1.
Howitt teaches evaluating STMN1 in CIN1-3 and cervical cancer samples, and found an increasing expression trend as disease progressed, reading on the CIN2+, CIN3+, and cervical carcinoma limitations of instant claim 1.
Ishimi teaches evaluation of MCM2 mRNA in cervical cancer cells, and found that the mRNA was more highly expressed in cervical cancer cells compared to wild-type cells (Figure 4A and page 1096, column 2, para. 1), reading on the cervical carcinoma limitation of instant claim 1.
Liu teaches measurements of TERT expression with increasing dysplasia and cervical carcinoma (see Figure 2), and also teaches that TERC expression correlates with TERT expression, where TERC also increases in expression as disease progresses (Figure 1 and page 6, column 2, para. 2), reading on the cervical carcinoma limitation of instant claim 1.
In addition to the biomarker teachings of the references, the Final Rejection also cited Cheng, which taught matching expression level with CIN status/cervical cancer and then using this to identify the status of unknown samples with the same marker expression (paras. 196-200 and Figure 7). The Final Rejection then provides rationale to use these measuring/categorizing methods on the already established biomarkers in the combination of references.
In many of the references above, differences in expression levels between disease states are observed. MPEP 2141.03 I states, “"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.” The Examiner’s position is that the ordinary artisan would be capable of combining the provided references, which teach the levels of various biomarkers for different levels of dysplasia/cervical cancer, to evaluate multiple biomarkers simultaneously, and would be capable of using ordinary skill, knowledge, and creativity to recognize the utility of such a combination to be able to accurately diagnose patients, which would naturally impact treatment plans and outcomes. This advantage is made clearer by the Cleveland Clinic reference, which specifically notes differences in prognosis and treatment plans between low and high grade dysplasia (see page 2, paras. 1-2). Though this may be a purported unobvious advantage of Applicant’s instant invention, proper and non-invasive diagnosis of disease is a generally clear advantage to both clinicians and patients, and such an advantage is achieved by this combination of references.
In addressing the rejections presented in the Final Rejection, Applicant does not particularly point out issues with the motivations/rationale for the combinations of references. Applicant does point out an alleged contradiction in stating that there would be a reasonable expectation of success in combining the references when there was unpredictability in the art described in the enablement rejection (Remarks, page 15, para. 3). The enablement rejection was related to the previous version of claim 1, which was much more general with regard to the use of the claimed markers in determining a level of dysplasia or cervical carcinoma in a subject. The markers described in the previous enablement rejection were considered unpredictable in the art specifically because there was either no evidence in the art that they had been successfully used to distinguish between dysplasia stages/lesions and/or cervical cancer (see p53 and Nanog in the enablement rejection in the Final Rejection), provided weak evidence for diagnostic use in determining dysplasia grade/cervical cancer (see Sox2 in para. 36), or were not clearly linked to different CIN levels (see POU5F1 in the enablement rejection in the Final Rejection, though this biomarker had the most provided evidence, as noted in the rejection). The lack of strong evidence in combination with the other factors considered in enablement (see In re Wands 8 USPQ2d 1400 (CA FC 1988)) led to the final determination of undue experimentation related to those biomarkers specifically. Due to this determination, these biomarkers were not evaluated in the claims in relation to 35 USC 103. No such enablement issue was noted for the other biomarkers, as they were adequately supported for use in the claimed method by both the instant specification and the prior art. Thus, these biomarkers were evaluated under 35 USC 103. Unpredictability in the art as evaluated under 35 USC 112(a) is not directly related to a reasonable expectation of success under 35 USC 103, particularly because the latter is based on specific combinations of references or teachings with particular rationale (see MPEP 2143, for example). Thus, the findings of obviousness made in the Final Rejection are considered proper.
Regarding the use of the “strongest HPV genotype” and more specifically discussing the Tulake and Schmitt references used above, both references analyze multiple HPV genotypes in clinical samples to test for expression levels (see Tulake Table III for example and Schmitt Figures 1 and 2). Though Tulake and Schmitt do not specifically declare that certain HPV genotypes are the “strongest,” these tables and figures make the general trends and expression levels clear for each biomarker. For a particular disease state (e.g. low grade lesions, high grade lesions, CIN II-III, or cervical carcinoma), it is clear to see which expression levels are the highest. In the combination of references utilizing Tulake and Schmitt in the Final Rejection, the general biomarkers of Tulake and Schmitt are used, and these biomarkers are then used as points of comparison for future analyses (see paras. 47-48 of the Final Rejection). Thus, the strongest HPV genotype found by Tulake and/or Schmitt would be utilized in these future analyses, along with potentially other HPV genotypes. This would still read on the interpretation of the “strongest HPV genotype” as described above.
Regarding the amendments to instant claim 1 to include a multivariate algorithm, as noted by Applicant, this limitation was presented in previous claim 17 and was rejected by a combination of references further in view of Bankaitis-Davis. In this reference, risk scores are made utilizing expression levels of input genes. The reference also notes dysplasia and the need for non-invasive testing and screening (page 2, para. 1). The reference also notes specific values and profiles that can be placed into mathematical algorithms for the generation of the risk scores (e.g. page 54, para. 4). In combining this reference with Tulake, in view of del Pino, in view of Schmitt, and in view of Cleveland Clinic, the use for cervical cancer is specifically noted, and rationale is provided (“By providing risk information and evaluating disease state mathematically, accuracy of conclusions drawn by practitioners would be increased, which would aid in determining the best course of treatment for a patient. Additionally, if a patient is shown to be at a particular risk for cervical cancer, further precautions or more aggressive treatment options can be taken”) as well as a reasonable expectation of success, (“There would be a reasonable expectation of success in employing these methods in Tulake, in view of del Pino, in view of Schmitt, and in view of Cleveland Clinic as this would only add to the analysis steps of the method, and not the laboratory protocols, and Bankaitis-Davis shows that developing risk assessments/algorithms would be possible for the ordinary artisan”). Applicant argues that this reference does not discuss CIN2+ or CIN3+, to which the Examiner agrees, but this is also briefly addressed by the combination of references (“These reference values are based on known disease states of a population, and so the measured expression levels for a subject can be compared to said reference values to determine risk, but also to examine general disease stage, as the biomarkers of Tulake, in view of del Pino, in view of Schmitt, in view of Cleveland Clinic are also associated with low- and high-grade lesions.”). This rationale is further expanded upon in the new grounds of rejection below. The fact that Bankaitis-Davis alone is also not specifically drawn to the claimed biomarkers is not pertinent to the overall rejection, as Bankaitis-Davis is not being used alone, and Applicant has not provided an argument regarding alleged deficiencies in the specific motivation to combine or reasonable expectation of success provided in this paragraph above. Thus, the algorithm taught by Bankaitis-Davis is still considered relevant to the instant claims 1, and is utilized in the rejections below.
Thus, Applicant’s arguments are not overall persuasive, and the references cited in the Final Rejection are still considered relevant to the currently amended claims. Those portions of the references and rejections considered relevant are reiterated below. Additionally, due to Applicant’s claim amendments, new grounds of rejection are required and are presented below.
Claim Objections
Claim 1 is objected to because of the following informalities: the format of the quantities in the newly added wherein clause should be as follows:
-the quantities of the strongest HPV genotype, P16, and at least one of STMN1, MCM2, Topo2a and/or Ki-67
-the quantities of the strongest HPV genotype, P16, and at least one of MCM2, STMN1, Topo2a and/or Ki-67
-the quantities of the strongest HPV genotype, at least one or TERT, BIRC5 and/or p53, at least one of ALDH1A1, Sox2, Nanog and/or POU5F1, and at least one of MCM2, STMN1, Topo2aand/or Ki-67
This ensures similar formatting among all three phrases and more accurately reflects the ability to choose one or more biomarkers from each group. Appropriate correction is required.
Claim 3 is objected to because of the following informality: lines 1-2 should read “the severity or grade of dysplasia or the presence of cervical carcinoma,” as this more closely aligns with the limitation thresholds described later in the claim and in claim 4, which depends on claim 3. Appropriate correction is required.
Claim 6 is objected to because of the following informality: in lines 2-3, “a HPV genotype” should read “an HPV genotype.” Appropriate correction is required.
Claim 12 is objected to because of the following informalities: in (a)(i), “and HPV16 EI”E4” should read “and/or HPV16 EI”E4.” Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-6, 9-16, 22, and 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected because in step (a)(i), it is stated that the strongest HPV genotype is only used in deducing the severity or grade of the dysplasia of a subject, and not that this is used for deducing the presence of cervical carcinoma. Later in the claim however, the strongest HPV genotype is employed in determining the presence of cervical carcinoma. It will thus be interpreted that the strongest HPV genotype is used for deducing the severity or grade of the dysplasia or the presence of cervical carcinoma, and Applicant should amend (a)(i) to make this clear.
Claims 2-6, 9-16, 22, and 25 are rejected based on their dependence on rejected claim 1.
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.
Claims 1, 3-6, 9, 14-16, 22, and 25 are 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).
Tulake teaches analysis of stem cell biomarkers in association with levels of cervical neoplasia or cervical carcinoma (Abstract). Specifically, ALDH1A1, Oct4 (also known as POU5F1), Nanog, and Sox2 mRNA were examined (Abstract). Tissue samples were used, and mRNA was analyzed via RT-PCR using the primers described in Table 1, and an internal control of β-actin was also included (page 5527, column 1, para. 2; instant claim 14). HPV infection genotype was also detected, including analysis of the 8 high-risk genotypes (16, 18, 45, 31, 33, 52, 58, and 67; pages 5526-5527 joining para.; instant claim 15). There was a significant trend of increasing ALDH1A1 and Oct4 expression level with disease progression, where there was a significant difference in expression between non-cancerous and CIN II-III tissues, as well as between cervical cancer tissues and both CIN II-III and non-cancerous tissues (Figure 1 and page 5528, “Transcription of stem cell markers in cervical carcinoma and its precursor lesions”). Nanog and Sox2 showed significantly increased expression in cancer samples compared to non-cancer samples (Figure 1). HPV genotyping revealed that most patients with neoplasia or cervical cancer had HPV 16 (Table III). Tulake teaches that monitoring of this biomarker may aid in monitoring treatment of disease (page 5532, column 1, para. 3).
However, Tulake does not expressly teach the evaluation of mRNA associated with HPV genotype, nor does the reference teach the cellular proliferation and tumor biomarkers recited in instant claim 1, a multivariate algorithm as noted in step (b) of instant claim 1, or actually treating the patients under examination.
Regarding claim 1, Howitt teaches examining STMN1, p16, and Ki67 in benign, low-grade, high-grade, and cancerous cervical lesions (Abstract). It was found that there was a marked increase in STMN1 expression in CIN2+ lesions, with benign and CIN1 expression being much lower, and with all cervical cancer cases showing STMN expression (Table 2). Howitt notes that, “…STMN may have greater specificity for high-grade lesions (HSIL),” (page 93, column 1, para. 1) and that, “In summary, increased STMN expression is present in both high-grade cervical precursor lesions and frankly invasive carcinomas. STMN overexpression appears independent of proliferation, maturation, and HPV cytopathic effect and has potential to be useful diagnostically in identifying HSIL,” (page 95, column 2, para. 3). p16 and Ki67 showed increased expression in diseased tissues generally, with particularly high expression in CIN2+ through cancerous tissues (Table 2).
Regarding claim 1, Liu teaches the evaluation of telomerase-related TERC and TERT in the context of CIN disease stages and cervical cancer (Abstract). TERT was found to be more highly expressed in disease cells compared to normal cells (page 4, “hTERT protein expression”), and TERC expression steadily increased with disease progression (Figure 1). Liu also notes that TERC expression correlates with TERT expression, and that TERT has been evaluated as a cervical disease biomarker in the literature (page 6, column 2, para. 2).
Regarding claims 1, 5, and 6, Schmitt teaches measuring the expression of particular HPV 16 genes in cervical lesions of different grades (Abstract). The reference teaches that this HPV type regulates E6 and E7 oncoproteins (page 260, column 1, para. 1). In analyzing HPV 16, they focused on mRNA for splice sequences, including E6*I and E1^E4, as well as a housekeeping gene (page 261, column 2, para. 3). E6*I was found to be upregulated in cervical cancer compared to control and dysplasia groups, while E1^E4 was downregulated in cancer compared to other groups (Figure 2). The reference also measured p16 and found a steadily increasing expression with disease progression, with a significant upregulation in cervical cancer samples (Figure 2).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to add examining the biomarkers described by Howitt, Liu, and Schmitt to the qRT-PCR mRNA analysis methods of Tulake. While Tulake focuses on stem cell biomarkers, in expanding the method to provide diagnostics, it would be beneficial to use additional types of biomarkers. Taken together, these references would teach analyzing ALDH1A1, POU5F1, STMN1, TERT, p16, and HPV genotype and the HPV biomarkers of Tulake and Schmitt, specifically in the context of detecting a degree of dysplasia or the presence of cervical cancer, as these biomarkers all show distinct patterns with increased disease progression. Tulake teaches specifically examining HPV-genotype with cancer biomarkers for diagnostic purposes, as this will “greatly benefit women in areas with a high prevalence,” (page 5532, columns 1-2 joining para.). Howitt details that an issue with many cervical lesion biomarkers is a lack of specificity for high-grade lesions (page 89, column 2, para. 1), which the reference teaches does not apply to STMN1, highlighting its utility. Liu notes that TERT clearly increases with worsening disease, and the biomarkers of Schmitt are related to viral genes themselves, which would be particularly worthwhile to examine, as HPV provides the onset of disease. Schmitt also notes that the use of a single biomarker for diagnostic purposes is limited (page 264, column 2, para. 3), and so the ordinary artisan would be motivated to use different types of biomarkers to obtain an accurate profile for patients, as diagnostic conclusions can affect patient outcomes, treatments, and resources used. There would be a reasonable expectation of success as these are all known biomarkers, and their expression has been successfully measured, as evidenced by Tulake, Howitt, Liu, and Schmitt.
It is noted that though these references do not explicitly teach utilizing these biomarker expression data to deduce dysplasia grade or the presence of cancer, as they mainly correlate the expression and disease patterns with already diagnosed samples, the ordinary artisan would recognize that the expression values established by these references could be used as points of comparison for future analysis in order to diagnose a dysplasia grade or the presence of cancer. This is generally the purpose of discovering useful biomarkers, and it would allow for patients to be examined with non-invasive sampling methods, such as cervical swabs or blood tests, rather than using invasive biopsy techniques.
However, none of these references teach the use of a multivariate algorithm as claimed, nor specific treatments for dysplasia or cervical cancer. Additionally, though the references also all discuss the claimed biomarkers in terms of lesions/dysplasia and cervical cancer, not every reference clearly delineates between CIN2+, CIN3+ and cervical cancer in a manner that would lend itself to clear diagnostics.
Regarding claims 1 and 3-4, Cheng teaches methods and assays for the use of biomarkers for detecting early stage cervical lesions and cancer (Abstract). In an example, a standard curve was first made to measure absorbance output for different expression levels of E6 proteins of interest. Then, absorbance output was obtained for samples with known CIN/cancer status. This could then be used to identify the status of unknown samples using the E6 protein expression levels (Figure 7 and paras. 196-200).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings provided by Cheng to create similar thresholds by which to compare biomarker expression levels in the method of Tulake, in view of Howitt, in view of Liu, and in view of Schmitt. Tulake in particular makes distinctions between at least CIN2, CIN3, and cancerous samples in their expression methods (see the caption of Figure 1). By using the methods of Cheng (i.e. making standard curves for the biomarkers of interest, measuring expression level output for samples of known disease stages, and comparing these to determine disease stage for samples at an unknown stage), the biomarkers of Tulake, in view of Howitt, in view of Liu, and in view of Schmitt could be used to parse out CIN2+/3+/cervical cancer disease stages, rather than just cancer and low versus high-grade lesions. This additional level of detail could aid in monitoring disease progression over time and with particular treatment – for instance, if a patient is first determined to be at a level CIN2, if at a future timepoint they are now at a level CIN3, then more aggressive treatment options would likely need to be considered. There would be a reasonable expectation of success because this would involve methodologies already taught by Tulake and Schmitt (e.g. measuring mRNA expression levels in sample) and standard curve calculations that are taught by Cheng to be successful.
However, none of these references teach the use of a multivariate algorithm as claimed, nor specific treatments for dysplasia or cervical cancer.
Regarding claims 1 and 16, Bankaitis-Davis teaches methods for a determining expression profile data associated with cervical cancer or conditions related to cervical cancer (Abstract). RNAs are primarily utilized (page 3, para. 2). The profile contains the expression levels of desired RNAs for a subject (page 4, para. 2). An expression profile can be used with mathematical and statistical methods in order to determine the subject’s risk of cervical cancer (pages 13-14, joining para. and pages 21-22, joining para.). Risk evaluations can include comparisons to reference values and profiles (page 23, paras. 2-3). Reference values and profiles can then be compared to values in a subject of interest to determine risk (page 24, para. 6). Pages 50-51 detail a particular mathematical algorithm that can provide a risk for cervical cancer, where the inputs involve the expression levels of the measured biomarkers. Bankaitis-Davis states that, “the application of such techniques to panels of multiple cancer associated gene(s) is provided, as is the use of such combination to create single numerical "risk indices" or "risk scores" encompassing information from multiple cancer associated gene(s) inputs,” (page 54, para. 4) which can involve the use of mathematical algorithms (page 55, para. 1). Figure 4 shows a risk probability index of developing cervical cancer based on the expression levels of two genes (Figure 4 and page 9, para. 6 and page 70, para. 2). The reference also teaches the treatment of cervical cancer via removal of the cancer cells, specifically with LEEP (Loop Electrosurgical Excision Procedure), cryotherapy, and laser therapy (instant claim 25).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the analysis methods of Bankaitis-Davis in the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, and in view of Cheng. Specifically, the expression levels of the biomarkers in Tulake, in view of Howitt, in view of Liu, in view of Schmitt, and in view of Cheng could be incorporated into a mathematical algorithm to determine the risk of cervical cancer, where said risk is in part determined based on the use of reference values. Additionally, utilizing the teachings of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, and in view of Cheng, a similar algorithm can be developed to create a score and determine the risk of CIN2+ and CIN3+ dysplasia in addition to cervical cancer. This is because Tulake, in view of Howitt, in view of Liu, in view of Schmitt, and in view of Cheng taken together teach expression values to determine if a particular patient has passed an expression threshold for diagnosis of CIN2+, CIN3+, and/or cervical cancer. Thus, the same basic data would be available for each of these conditions. The reference values discussed by Bankaitis-Davis are based on known disease states of a population, which are obtained in Tulake, in view of Howitt, in view of Liu, in view of Schmitt, and in view of Cheng, and so the measured expression levels for a particular subject can be compared to said reference values to determine risk. By providing risk information and evaluating disease state mathematically, accuracy of conclusions drawn by practitioners would be increased, which would aid in determining the best course of treatment for a patient. Additionally, if a patient is shown to be at a particular risk for cervical cancer, further precautions or more aggressive treatment options can be taken, whereas if there is more risk for CIN2+ and less of a cervical cancer risk, less aggressive or invasive treatment options may be available, which may be of interest to patients. This is also a natural extension of the teachings of Cheng specifically, as this reference provides disease thresholds for CIN2+, CIN3+, and cervical cancer for diagnostic purposes, and so adding risk assessment as shown in Bankaitis-Davis may also aid in determining if a particular treatment is effective at reducing the risk of worsening disease. There would be a reasonable expectation of success in employing these methods in Tulake, in view of Howitt, in view of Liu, in view of Schmitt, and in view of Cheng as this would only add to the analysis steps of the method, and not the laboratory protocols, and Bankaitis-Davis shows that developing risk assessments/algorithms would be possible for the ordinary artisan.
Additionally regarding claims 1 and 25, Cleveland Clinic teaches that high grade cervical dysplasia can be treated via loop electrosurgical excision, a biopsy, or a hysterectomy (“Management and Treatment”).
Prior to the effective filing date of the claimed invention, it would have also been prima facie obvious for one of ordinary skill in the art to treat the patients who have dysplasia or cervical cancer in the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, and in view of Bankaitis-Davis with the methods described by Bankaitis-Davis and Cleveland Clinic order to improve patient prognoses and outcomes. By specifically removing dysplasia and cancer cells in appropriate patients, it may also prevent the need for treatments with more deleterious side effects, such as chemotherapy. As Bankaitis-Davis and Cleveland Clinic teaches that these are known cervical cancer and dysplasia treatments, there would be a reasonable expectation of success.
Thus, claims 1, 3-6, 14-16, and 25 are prima facie obvious over Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic.
Regarding claim 9, Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic teach the use of multiple HPV genotypes, p16, and STMN1, as described above. Tulake teaches the use of HPV16, and Schmitt specifically teaches that E6*I, E1^E4, and p16 show distinct patterns with disease progression (see Figures 1 and 2). In the rejection of claim 1 above, the use of the biomarkers of Tulake, Howitt, Liu, and Schmitt is rendered prima facie obvious for detecting CIN2+, CIN3+, and cervical cancer, and so these references read on the specific limitations of instant claim 9.
Regarding claim 22, it is noted that the phrase “statistically established” has no specific definition in the instant specification. It is therefore interpreted, within the context of the claim, that any method in which threshold values are obtained using statistics in any step of said method would satisfy this limitation. In Tulake, Liu, and Schmitt, statistically significant differences were found between the biomarkers of interest and different disease stages (see Tulake Figure 1, Liu Figure 1, and Schmitt Figure 2). Thus, as statistics were used to evaluate the levels of these biomarkers, and the levels of these biomarkers are used to evaluate threshold levels, as described in the rejection of claims 3-4 above, this combination of references is also considered to meet the limitations of claim 22. Additionally, any patient that has high-grade dysplasia or cervical carcinoma will need treatment, and so if a patient is determined to have these conditions, they will be treated as taught in Cleveland Clinic and Bankaitis-Davis above (Cleveland Clinic also notes that low-grade CIN, or CIN1, typically does not need treatment, see para. 2).
Thus, claim 22 is prima facie obvious over Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic.
Claim 10 is 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).
Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic teach the methods of claims 1, 3-6, 9, 14-16, 22, and 25, as described above. Schmitt also teaches that E6*I, E1^E4, and p16 show distinct patterns with disease progression (see Figures 1 and 2).
However, none of these references teach the measurement of MCM2 in relation to dysplasia or cervical cancer.
Ishimi teaches the measurement of MCM proteins 2-7 in relation to cervical cancer (Abstract). Specifically, the reference teaches the measurement of MCM2 mRNA in cervical carcinoma cells (Abstract). RT-PCR was used (page 1094, column 1, para. 1). It was found that MCM2 mRNA was much more highly expressed in cancer cells compared to normal cells (Figure 4), and specifically, 4-8 times more abundant (page 1096, column 2, para. 1).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to add MCM2 as a biomarker in the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic. Ishimi teaches that MCM2 mRNA expression is increased with cervical cancer, in much the same way as in E6*I and p16. By using three biomarkers that exhibit similar patterns, the accuracy of said patterns and the conclusions drawn from them can be more confident. By then combining these three biomarkers with E1^E4 measurements, which show a different trend, it can be ensured that the samples and methods are free from contamination, and are not simply showing a positive trend in every examined biomarker due to error. Many of these biomarkers in particular have been shown to distinguish between low grade lesions, high grade lesions, and cervical cancer, and so could be employed to distinguish CIN3+ lesions from lower grade lesions, as there would be distinct expression differences between these disease states. As these biomarkers are successfully measured by Schmitt and Ishimi, there would be a reasonable expectation of success.
Thus, claim 10 is prima facie obvious over Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi.
Claims 2 and 11 are 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).
Regarding claim 11, Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic teach the methods of claims 1, 3-6, 9, 14-16, 22, and 25, as described above. Additionally, as noted above in the rejection of claim 10, the use of the teachings of Ishimi in Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi renders obvious utilizing MCM2 as a biomarker for diagnosing dysplasia or cervical cancer, and the rejection of claim 10 describes the advantages in including this biomarker. However, none of these references teach the use of BIRC5 in conjunction with dysplasia or cervical cancer diagnostics.
del Pino teaches analysis of the mRNA of particular biomarkers associated with HPV-lesions and cervical cancer (Abstract). The biomarkers examined included BIRC5, p16, TOP2A, and MKI-67 (Abstract). Reverse transcription and PCR were performed for the biomarkers, and reference genes (GUSB and PKG1) were also examined for normalization (page 314-315, “RNA Isolation, Reverse Transcriptase Polymerase Chain Reaction and Quantitative PCR” and Table 1). Expression levels were found to differ significantly for BIRC5, p16, TOP2A, and MKI-67 between the control and different treatment groups (Table 2). del Pino teaches that their biomarkers may be particularly useful in detecting high-grade cervical lesions (and thus can aid in diagnostics before cervical cancer develops; page 319, column 1, para. 2). BIRC5 in particular is stated to be associated with adverse prognosis (page 318, column 2, para. 1), and demonstrates lower expression levels in high grade lesions compared to normal tissues (pages 315-316, joining para.).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of del Pino to add at least BIRC5 as a biomarker in the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi. del Pino shows that BIRC5 expression is lower in higher grade lesions, which is the opposite trend from many of the biomarkers already examined in the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi. By including a marker that shows a different trend, it can be ensured that the samples and methods are free from contamination, and are not simply showing a positive trend in nearly every examined biomarker due to error. Many of the biomarkers in del Pino in particular are shown to distinguish between normal tissue, low grade lesions, and high grade lesions, and so the ordinary artisan would be capable of measuring and employing these markers to aid in distinguishing cervical cancer from dysplasia lesions (particularly in view of the other markers being used in the combination of references), as there would be distinct expression differences between these disease states. As these biomarkers are successfully measured by Tulake, Howitt, Liu, Schmitt, Ishimi, and del Pino, there would be a reasonable expectation of success.
Thus, claim 11 is prima facie obvious over Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi and del Pino.
Regarding claim 2, as noted above, del Pino teaches the use of housekeeping genes GUSB and PKG1 for normalization (page 314, column 2, para. 3) and displays normalized mRNA expression values in Table 2. These genes were chosen because of their high stability in normal samples and those with lesions (page 314, column 2, para. 3). It would be prima facie obvious to not only use housekeeping genes in the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi and del Pino (which are already taught in Tulake page 5527, column 1, para. 2 and Schmitt page 261, column 2, para. 3), but to use housekeeping gene expression values to normalize the expression values for the biomarkers of interest. This would allow for comparisons of expression levels between the biomarkers, as well as correlation of the biomarker expression levels between different disease states. This could aid in the accuracy of diagnostic conclusions, and could provide additional metrics by which to make diagnoses. There would be a reasonable expectation of success as this would not add any additional expression measurements to the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi and del Pino – it would simply require an additional analysis step that has already been shown to be successful in del Pino.
Therefore, claim 2 is prima facie obvious over Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi and del Pino.
Claim 12 is 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).
Instant claim 12 requires the same basic method as claim 1, with the direct inclusion of a housekeeping gene, and the marker groups for specific disease stages previously described in claims 9-11. As the Ishimi and del Pino references already render obvious the use of MCM2 and BIRC5 (respectively) in the method of Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic, those same rationale would apply in claim 12. Tulake, del Pino, and Schmitt also all teach the use of housekeeping genes, as described above in the rejections of claims 1 and 2 (Tulake page 5527, column 1, para. 2, del Pino page 314-315, “RNA Isolation, Reverse Transcriptase Polymerase Chain Reaction and Quantitative PCR” and Table 1, and Schmitt page 261, column 2, para. 3).
Thus, claim 12 is prima facie obvious over Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic, and further in view of Ishimi and del Pino.
Claim 13 is 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).
Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic teach the methods of claims 1, 3-6, 9, 14-16, 22, and 25, as described above. Tulake also teaches that for their RNA extraction and RT-PCR protocols, PCR was performed using the iQ5 PCR system (page 5527, column 1, para. 2).
Bio-Rad teaches that this system can hold up to 96 samples at one time, can be used for multiplexing, and is capable of thermal gradient control – allowing for a range of temperatures to be used simultaneously (page 4, “iQ5 System” and page 5, “Optimize Reactions in a Single Experiment”). One-step RT-PCR kits can be used with the device, the reagents used do not have to be optimized for particular targets, and the output for multiple targets can be viewed at once (page 7).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the iQ5 machine described by Bio-Rad and used by Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic. This would allow viral and cellular mRNA in a sample to be analyzed simultaneously, either in a single multiplex reaction, or in the same well-plate with differing PCR conditions. Bio-Rad teaches that their RT-PCR can be a single step method, which would be appealing to the ordinary artisan for purposes of efficiently using resources and time, and this device would allow easy comparisons between the expression levels of multiple targets at the same time. The viral and cellular mRNA used in Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, and in view of Cleveland Clinic come from human samples (see Tulake, page 5527, column 1, para. 2), and so could be analyzed together in a multiplex fashion if desired after extraction. The teachings of Bio-Rad regarding the iQ5 system and the successful use of this device in Tulake would provide a reasonable expectation of success.
Thus, the method of claim 13 is prima facie obvious over Tulake, in view of Howitt, in view of Liu, in view of Schmitt, in view of Cheng, in view of Bankaitis-Davis, in view of Cleveland Clinic and further in view of Bio-Rad.
Conclusion
No claims are currently allowable.
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/F.F.G./Examiner, Art Unit 1681
/GARY BENZION/Supervisory Patent Examiner, Art Unit 1681