DETAILED CORRESPONDENCE
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/20/2025 has been entered.
Claim Status and Formal Matters
This action is in response to papers filed amendment 11/20/2025.
Claims 38, 60, and 62 have been amended.
Claims 69-72 have been added by amendment.
Claims 38, 41, 43-44, 46, 56, 60-62, 69-72 are pending.
Applicant’s election without traverse of miR-15b in the reply filed on 2/12/2019 is acknowledged. It is noted application provided a further election in for linking claim analysis, which will be examined when and if the election of miR-15b becomes allowable.
Claims 41, 44, 46, 56-57, 66, 68 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on species.
Claims 38, 60-62, 69-72 are being examined.
The 102 and 103 rejection based on Ng have been withdrawn in view of the amendment.
Priority
The instant application was filed 06/28/2018 and is a continuation of 15181578, filed 06/14/2016, which is a continuation of 14352462, filed 04/17/2014, which is a national stage entry of PCT/IB2012/003035 having and international filing date: 10/20/2012 and claims priority from provisional application 61550148, filed 10/21/2011.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e), 120, 121, 365(c), or 386(C) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 61/550,148, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Claim 38 has been amended to recite, “treating the human subject with at least one selected from the group consisting of colonoscopy, an anti-neoplastic agent therapy and a cancer therapy.” Colonoscopy was not in the claims as originally filed.
The standard for satisfying the written description requirement is whether the disclosure “allow[s] one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.” Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1190 (Fed. Cir. 2014) (quoting Enzo Biochem, Inc. v. Gen—Probe Inc., 323 F.3d 956, 968 (Fed. Cir. 2002). “[T]he critical inquiry is whether the patentee has provided a description that ‘in a definite way identifies the claimed invention’ in sufficient detail that a person of ordinary skill would understand that the inventor was in possession of it at the time of filing.” Alcon, 745 F.3d 1190-91 (quoting AriadPharm., Inc. v. EliLilly & Co., 598 F.3d 1336, 1352 (Fed. Cir. 2010)). However, “a description that merely renders the invention obvious does not satisfy the requirement.” Ariad, 598 F.3d at 1352.
Applicant is reminded that obviousness is not the standard for the addition new limitations to the disclosure as filed. It is noted that entitlement to a filing date does not extend to subject matter, which is not disclosed, but would be obvious over what is expressly disclosed. Lockwood v. American Airlines Inc., 41 USPQ2d 1961 (Fed. Cir. 1977). ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]his description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
The provisional application recites, “colonoscopy” 3 times. In paragraph 0053, the provisional application teaches colonoscopy has limited sensitivity and is an invasive approach. Paragraph 0057 describes the subjects of the examples and indicates the subjects had a colonoscopy or were excluded due to inadequate bowel preparation for diagnostic colonoscopy.
The provisional application recites “anti-neoplastic agent therapy” twice in paragraph 0016 and 0034. Both of the recitation are with respect to selecting anti-neoplastic agent therapy, but does not teach treating.
Review and searching of the specification did not reveal antecedent basis for “cancer therapy.”
Thus the amendment as provided is not supported by the provisional application and is being given priority to the instant filing date.
Response to Arguments
The response traverse the objection with respect to the argument with respect to arguments of the 112 (a) rejections. This argument is not persuasive for reasons of record.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 38, 60-62, 69-72 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 38 has been amended to recite, “treating the human subject with at least one selected from the group consisting of colonoscopy, an anti-neoplastic agent therapy and a cancer therapy.” Colonoscopy, an anti-neoplastic agent therapy and a cancer therapy were not in the claims as originally filed.
Claim 62 is drawn to wherein the human subject is treated with at least the colonoscopy.
Claim 69 is drawn to wherein the human subject is treated with at least the anti-neoplastic agent therapy.
Claim 70 is drawn to wherein the human subject is treated with at least the cancer therapy.
The standard for satisfying the written description requirement is whether the disclosure “allow[s] one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.” Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1190 (Fed. Cir. 2014) (quoting Enzo Biochem, Inc. v. Gen—Probe Inc., 323 F.3d 956, 968 (Fed. Cir. 2002). “[T]he critical inquiry is whether the patentee has provided a description that ‘in a definite way identifies the claimed invention’ in sufficient detail that a person of ordinary skill would understand that the inventor was in possession of it at the time of filing.” Alcon, 745 F.3d 1190-91 (quoting AriadPharm., Inc. v. EliLilly & Co., 598 F.3d 1336, 1352 (Fed. Cir. 2010)). However, “a description that merely renders the invention obvious does not satisfy the requirement.” Ariad, 598 F.3d at 1352.
Applicant is reminded that obviousness is not the standard for the addition new limitations to the disclosure as filed. It is noted that entitlement to a filing date does not extend to subject matter, which is not disclosed, but would be obvious over what is expressly disclosed. Lockwood v. American Airlines Inc., 41 USPQ2d 1961 (Fed. Cir. 1977). ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]his description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
The application recites, “colonoscopy” 4 times. The specification on page 18 recites colonoscopy and states:
Currently, there is not optimal and universally accepted strategy for CRC screening [10,11] and fecal-based tests are hampered by their limited sensitivity, colonoscopy constitutes an invasive approach[12]. Therefore, new approaches that can complement and improve on current strategies are urgently needed. In that sense, previous studies have found that some miRNAs are increased in plasma from patients with CRC, suggesting a potential role as non-invasive biomarkers(13-16).
Thus the specification teaches away from the use of colonoscopy as it has limited sensitivity and is invasive.
The second time colonoscopy is recited is on page 19 which states:
Of them, 77 were excluded because they met any of the following criteria: clinical diagnosis of familial adenomatous polyposis or Lynch syndrome, presence of more than 10 colorectal adenomas, diagnosis of cancer at other sites at the time of selection, presenting inflammatory bowel disease, undergoing chemotherapy or radiation therapy at the time of blood sampling, incomplete bowel examination, inadequate bowel preparation at diagnostic colonoscopy, or presence of haemolysis in plasma samples. Finally, 196 individuals were included: 123 patients newly diagnosed with sporadic colorectal neoplasia (63 with CRC and 40 with AA) and 73 healthy individuals without personal history of any cancer and with a recent colonoscopy confirming the lack of colorectal neoplastic lesions.
The again the specification is teaching away from the use of colonoscopy.
The fourth time colonoscopy is recited in the specification is on page 35 of the refences in:
M., Reyes-Melian, J.M., Cacho, G., Diaz-Tasende, J., Herreros-de-Tejada, A., Poves, C., Santander, C. and Gonzalez-Navarro, A. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med, 366, 697-706.
None of the recitation in the specification provide basis for colonoscopy as a treatment with detection of miR-15b overexpression in plasma.
The specification recites,”anti-neoplastic agent therapy” twice on page 5 and page 13. In both cases the specification provides the teachings with respect to selecting an anti-neoplastic agent therapy. The specification does not specifically teach treating with an anti-neoplastic agent therapy.
The specification recites, “cancer therapy” 3 times. The first is on page 2 and is with respect to W02011076142. The other two recitations are on pages 9 and 10 with respect to selecting a cancer therapy for a subject diagnosed as having colorectal neoplasia. Thus the specification does not support the amendment as filed.
Thus, the amendment has introduced new matter
Response to Argument
The response traverses the rejection asserting, “applicants respectfully traverse, because support for complementing and improving current strategies for screening and treating colorectal cancer (e.g., fecal-based tests, colonoscopy, etc.) using inventions of the present disclosure clearly exists in the application.”. This argument has been thoroughly reviewed but is not considered persuasive as the does not specifically envision treatment of subject at risk of colorectal neoplasia with colonoscopy, an anti-neoplastic agent therapy and a cancer therapy .
The response continues by asserting, “In determining whether the written description requirement is met, the standard is "whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (emphasis added). Whereas the specification (WO '635) explains at page 18, lines 15-17 that there is no "optimal and universally accepted strategy for CRC screening," and that "fecal-based tests are hampered by their limited sensitivity", and that "colonoscopy constitutes an invasive approach," the specification then immediately states that "new approaches that can complement and improve on current strategies are urgently needed." This is clearly describing a central objective of the inventions disclosed in the present application-namely, to "complement and improve on currently strategies" for detecting and treating colorectal cancer (CRC) and advanced colorectal adenoma (AA). The specification then goes on to describe various embodiments including the use of miRNA-18a overexpression in the plasma sample of a human subject to detect, diagnose and treat colorectal neoplasia, see, e.g., original Claims 32 and 36 of WO '635.” This argument has been thoroughly reviewed but is not considered persuasive as the specification and originally filed claims do not specifically teach treating subject at risk of colorectal cancer with colonoscopy, an anti-neoplastic agent therapy and a cancer therapy.
The response continues by arguing:
As explained by the Federal Circuit at page 1371 of ScriptPro:
[M]ere recognition in the specification that an aspect of a prior art system is "inconvenient" does not constitute "disparagement" sufficient to limit the described invention-especially where the same specification expressly contemplates that some
embodiments of the described invention incorporate the "inconvenient" aspect.
This argument has been thoroughly reviewed but is not considered persuasive as the response has failed to disclose where the specification support the “inconvenient aspect” of performing colonoscopy as part of the method of treating colonoscopy. As detailed above the none of these suggest the use of colonoscopy of part of invention.
None of the recitation in the specification provide the alleged treatment of CRC by colonoscopy, an anti-neoplastic agent therapy and a cancer therapy
In the instant case the application clearly envisions colonoscopy as a screening method at best, but provides no suggestion or evidence for colonoscopy being used as a part of a treatment method.
Claims 38, 60-62, 69-72 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method comprising: measuring expression level of miRNA15b in a plasma sample, a serum sample or a blood sample obtained from the subject; comparing said expression level of miRNA15b to expression level of miRNA15b measured in a plasma sample, a serum sample or a blood sample obtained from a normal subject, identifying the sample as having increased or decreased expression of miRNA15b relative to normal subjects.
The specification and art does not reasonably provide enablement for selecting (identifying or diagnosing) and treating colorectal cancer based in miR15b over expression. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors have been described by the court in re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in the Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
Independent claim 38 is drawn to “A method for treating a human subject at ris treating the human subject with at least one selected from the group consisting of colonoscopy, an anti-neoplastic agent therapy and a cancer therapy, when the human subject has been identified as being at risk for colorectal cancer by a process comprising: (a) obtaining a plasma sample from the human subjecextracting microRNAs comprising miRNA-15b from the plasma sample obtained from the human subjec(c)amplifying the miRNA-15b in the extracted microRNAs by (i) contacting the microRNAs with a primer specific to miRNA-15b, (ii) reverse transcribing the miRNA-15b into cDNA, and (iii) amplifying the cDNA using polymerase chain reaction to produce an amplification product; f(dd)determining the miRNA-15b expression level in the plasma sample obtained from the human subject by determining the level of amplified cDNA in the amplification product; and (e)obtained from the human subject
The claim encompasses treating colorectal cancer prior to or after determination of miR-15b expression.
Claim 43 depends from claim 38 and draws the method to wherein the one or more healthy control human subjects comprises a healthy cohort.
Claim 60 depends from claim 59 and draws the invention to wherein the expression level is measured using microarray expression profiling, PCR, reverse transcriptase PCR, reverse transcriptase real-time PCR, quantitative real-time PCR, end-point PCR, multiplex end-point PCR, cold PCR, ice-cold PCR, , or nucleic acid sequencing.
Claim 61 depends from claim 38 and draws the invention to wherein the human subject has colorectal cancer.
Claim 62 depends from claim 38 and draws the invention to wherein the human subject is treated with at least the colonoscopy.
Claim 69 depends from claim 38 and draws the invention to wherein the human subject is treated with at least the anti-neoplastic agent therapy.
Claim 70 depends from claim 38 and draws the invention to wherein the human subject is treated with at least the cancer therapy.
Claim 71 depends from claim 38 and draws the invention to further comprising determining miRNA-15b expression level in at least one selected from the group consisting of a serum sample, a blood sample, a tissue sample or a fecal sample.
Claim 72 depends from claim 38 and draws the invention to further comprising determining miRNA-15b expression level in a tissue sample, a fecal sample, or a combination thereof.
The amount of direction or guidance and the Presence and absence of working examples.
The specification teaches, “The invention is said to further provide corresponding methods using such nucleic acid expression biomarkers for identifying colorectal cancer as well as for preventing or treating such a condition. “(page 2)
The specification teaches, “A total of 273 subjects from two hospitals (Hospital Clinic of Barcelona, Catalonia, Spain and Hospital of Donostia, Gipuzkoa, Spain) were prospectively included in this study. Of them, 77 were excluded because they met any of the following criteria: clinical diagnosis of familial adenomatous polyposis or Lynch syndrome, presence of more than 10 colorectal adenomas, diagnosis of cancer at other sites at the time of selection, presenting inflammatory bowel disease, undergoing chemotherapy or radiation therapy at the time of blood sampling, incomplete bowel examination, inadequate bowel preparation at diagnostic colonoscopy, or presence of haemolysis in plasma samples. Finally, 196 individuals were included: 123 patients newly diagnosed with sporadic colorectal neoplasia (63 with CRC and 40 with AA) and 73 healthy individuals without personal history of any cancer and with a recent colonoscopy confirming the lack of colorectal neoplastic lesions. Patients with AA were those with adenomas having a size of at least 10 mm or histologically having high grade dysplasia or
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villous component. These individuals were divided into two different and unrelated sets: set 1, 61 subjects from Hospital Clinic of Barcelona, which were employed to perform genome-wide plasma microRNA expression profiling; and set 2,135 subjects from Hospital of Donostia, which were recruited to further validate the results obtained in set 1.”
The specification in 0057 PGPUB teaches RNA was extracted from plasma.
The specification in 0058 teaches the detection of multiple miRNA on a microarray which is normalized.
The specification in teaches, “MiR16 displayed the highest stability and abundance and, therefore, expression levels of miRNAs were normalized to miR16 as internal control in concordance with other publications.”
The specification in table 2 teaches miR-15b has a 3.21 fold increase and a 4.1 fold increase in miR29a.
The specification teaches, “Validation of plasma miRNA expression by real-time qRT-PCR. Microarray based plasma miRNA expression results are technically reproducible. Initially, a real-time qRT-PCR was performed to confirm microarray results in 28 samples randomly selected from set 1 (19 patients with colorectal neoplasms and 9 healthy controls). For these studies, a total of 14 candidate miRNAs were selected. Twelve candidate miRNAs (miR17-5p, miR92a, miR19b, miR18a, miR29a, miR302a, miR23a, miR27a, miR24, miR335, miR424 and miR15b) were chosen for being present in the top 50 deregulated miRNA in CRC and/or AA and to have a log base 2 microarray intensity >8. Two additional miRNAs (miR19a, and miR20a) were also selected for being part of the miR17-92 cluster, one of the best characterized oncogenic miRNA clusters, although they did not satisfy the previous criteria. Overall, qRT-PCR and microarray results were correlated (data not shown) except for miR424 that did not show any amplification by qRT-PCR and, therefore, it was excluded from subsequent analysis.”
The specification teaches, “Six plasma microRNAs were confirmed to be overexpressed in CRC patients from an independent cohort. Secondly, the 13 candidate miRNAs that showed adequate amplification in the previous phase were analyzed (miR92a, miR17-5p, miR18a, miR19a, miR19b, miR20a, miR15b, miR29a, miR302a, miR23a, miR27a, miR24 and miR335) in plasma of an independent set of 42 patients with CRC and 53 healthy controls, to validate our results by real-time qRT-PCR.”
The specification teaches, “Interestingly, miR18a, miR19a, miR19b, miR15b, miR29a and miR335 were confirmed to be significantly up-regulated in patients with CRC (FIG. 3). In addition, miR-24 was also overexpressed in this group of patients but without reaching statistical significance (p=0.08). Remarkably, validated miRNAs in this second set also demonstrated a high accuracy in discriminating CRC from healthy controls with areas under ROC curve (AUC) ranging from 0.8 (95% CI: 0.71-0.89) to 0.7 (95% CI: 0.59-0.80). Next, we sought to see if any combination of these miRNAs could improve the discriminative accuracy in detecting CRC with respect to each of them alone. Among the combinations showing the best discriminative capacity highlighted the signatures miR19a+miR19b, and miR19a+miR19b+miR15b (Table 6; FIG. 4). Finally, we explored the predictive capacity of these signatures in early (TNM I-II) and advanced (TNM III-IV) CRC patients. As exposed in Table 2, both signatures showed a high discriminative accuracy in both early and advanced cases. Similarly, we examined whether these signatures were also able to detect right-sided tumours as accurately as left-sided ones, and it was the case for both (Table 2).”
The specification teaches, “Accordingly, our results obtained in AA patients are not conclusive and further studies would be necessary to establish whether there is any miRNA alone or in combination able to detect these pre-malignant lesions accurately. In fact, in the cohort of patients with AA analyzed by Huang et al. two plasma miRs (miR-29a and miR-92a) showed quite good accuracy in discriminating AA from controls [16]. These two plasma miRNAs were also significantly overexpressed in our first cohort of AA patients but not in the second set. A potential explanation for this discrepancy between both set of patients could be the less advanced features of AA in the second cohorts of patients (Table 1). Altogether, these results indicate that evaluation of the usefulness of plasma microRNAs in patients with AA constitutes an interesting research line and deserves further investigation.” (page 30-31). Thus, the specification suggests the method requires further investigation.
Presence and absence of working examples
The specification provides no teachings in which subjects with colorectal cancer or healthy subjects are treated.
The state of prior art and the predictability or unpredictability of the art:
MPEP2164.03 teaches, " The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.”
Ng (Gut Online First, published on February 9, 2009 as 10.1136/gut.2008.167817) teaches in supplemental table 1A (page 19) normalized expression of plasma miR-15b is higher in healthy controls (1.7377) than CRC patients (0.0450), Non-normalized plasma miR-15b expression is higher of than plasma miR-15B from healthy controls
Ng teaches, “(i) s the sample size is still small, further validations of this marker in large cohorts and in independent studies are necessary; (ii) qPCR by relative quantification approach becomes less accurate if measuring with low levels of miRNAs, in which they may not fall into the linear range of the assay. Based on the Ct values of all samples, we believe that miR-92 is not low abundance in plasma, yet absolute quantification approach with standard curve calibration would be preferable for further validation of our approach; (iii) although miR-92 elevation in plasma are likely to be derived from CRC, it is uncertain whether this elevation is specific for CRC, and whether it can be used to differentiate sporadic from familial types of CRC. Thus, additional studies will be needed to examine familial and sporadic cases; (iv) despite of the significantly elevated levels of plasma miR-92 in stage I of CRC, it is desirable to examine whether its plasma level changes in patients suffering from adenoma with various degree of dysplasia in the future. If plasma miR-92 can be used for the detection of pre-malignant lesions such as adenoma, it would add more value to use this marker for CRC prevention.”
Kirschner (PLOS one (2011) volume 6(9) e2145) teaches levels of haemolysis increased the amount of miR-15b in plasma sample (page 2) 2nd column).
McDonald (Clinical Chemistry (2011) volume 57, pages 833-840) teaches the speed and use of centrifugation alters miR-15b expression in blood.
Zhang (Diabetes Research and Clinical Practice (2013) volume 99, pages 327-334) teaches, " We found that miR-15b was upregulated in the livers of NAFLD SD rats as well as in NAFLD L02 cells. Increased miR-15b levels could cause decreased cell proliferation and glucose consumption as well as induce the storage of intracellular triglyceride in QSG7701 cells. The expression of miR-15b was also significantly elevated in the serum of fatty liver disease patients compared with healthy subjects.”
Liu (BMJ Open (2012) volume 2, pages 1-10) teaches, “miRNA profiling on
resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study,
combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with
low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP. “
Wang (Renal Failure (2012) volume 34, pages 685-690) teaches, “In this study, we detected miR-15b in the plasma of 30 patients with ESRD and 20 healthy controls using real-time quantitative RT-PCR (RT-qPCR). Compared with healthy controls, the circulating levels of miR-15b were significantly reduced in patients with ESRD. However, there is no significant difference in circulating miR-15b levels when comparing prehemodialysis and posthemodialysis in patients with ESRD. In addition, to further estimate the potential roles of aberrantly expressed candidate miR-15b in the pathogenesis of ESRD, we utilized a bioinformatics exploratory analysis and identified gene ontology “biological process” classifications which revealed that dysregulated circulating miR-15b might be involved in phosphate metabolism.”
The art of Cheung et al (Nature Genetics, 2003, volume 33, pages 422-425) teaches that there is natural variation in gene expression among different individuals. The reference teaches an assessment of natural variation of gene expression in lymphoblastoid cells in humans, and analyzes the variation of expression data among individuals and within individuals (replicates) p.422, last paragraph; Fig 1). The data indicates that, for example, expression of ACTG2 in 35 individuals varied by a factor of 17; and that in expression of the 40 genes with the highest variance ratios, the highest and lowest values differed by a factor of 2.4 or greater (Fig 3).
Hsieh (Journal of Biomedical Science (2012) 19:69, pages 1-11) teaches LPS increases miR-15b expression in a dose and time dependent manner.
TIE (Sci China Ser C-Life Sci, 2009, 52(12): 1117-1122) teaches, “To quantitate miR-16, miR-24 (moderate-abundance plasma miRNAs) and miR-15b (low-abundance plasma miRNAs) by qRT-PCR assays from the plasma of three healthy individuals, these three miRNAs were detected in the plasma of each individual at concentrations ranging from 8910 copies/μL plasma to 133970 copies/μL plasma.” (page 1118, 2nd column, top)
Sun (Oncotarget (2016) volume 7, pages 11434-11449) teaches, “ Although there was no significant difference in plasma miR-15b*, miR486-3p, and miR-526b levels between controls and CRC patients, miR-15b* and miR-526 levels were significantly higher in stage IV CRC patients than in controls (Table S5).”(page 11437, 1st column, top paragraph).
D’Urso (Current Genomics, 2015, 16, 304-311) teaches miR-15b is a biomarker in plasma for glioma (title, abstract, discussion).
Tolle (ONCOLOGY REPORTS 42: 1609-1620, 2019) teaches mir-15b is a biomarker for bladder cancer. (title, abstract, discussion).
Walsh (JAMA (2003) volume 289, pages 1288-1296) teaches colorectal mortality rate can be reduced by screening all men and women 50 years or older for colorectal cancer (1294, bottom, 2nd column-top of 3rd).
Bagheri (Reports of Biochemistry & Molecular Biology Vol.10, No.1, Apr 2021, pages 20-29) teaches, “The bioinformatics prediction indicated that miR-15b and miR-195 target the DLEU7 gene. The expression levels of miR-15b and miR-195 were significantly higher in the plasma of patients with BCLL compared to the healthy individuals (91.6, p= 0.001) (169, p= 0.001).”
Tolle (ONCOLOGY REPORTS 42: 1609-1620, 2019) teaches, “. Our results suggested that circulating miR-15b-5p and miR-590-5p have useful diagnostic potential for BC, but are rather unsuitable as monitoring markers for disease. The reasons of this apparent contradictory observation may be due to the aspect of biological variation of circulating miRNAs and serial measurements could be unreliable.”
Song (expert reviews in molecular medicine (2010) volume 12, e33, pages 1-24) teaches, “Ten of 342 human miRNAs (let-7a, miR-15b, miR-16, miR-17-5p, miR-20a, miR-23b, miR-106a, miR-106b, miR196a and miR-320) were downregulated by more than twofold in the vincristine (VCR)- resistant gastric cancer cell line SGC7901/VCR compared with its parental SGC7901 cell line, and miR-302b and miR-492 were upregulated by more than twofold in SGC7901/VCR cells. The downregulated miR-15b and miR-16 were further validated by qRT-PCR. The overexpression of miR-15b or miR-16 sensitised SGC7901/VCR cells treated with VCR, adriamycin (ADR), etoposide (VP-16) and cisplatin (CDDP), at least in part through increased apoptosis by suppressing Bcl-2. This suggests a potential therapeutic use of miR-15 and miR-16 in gastric cancer” (page 10, 2nd column bottom). Song teaches, “Zhang et al. (Ref. 124) used real-time qRT-PCR to detect the expression levels of 95 cancer-related miRNAs in pancreatic cancer specimens and cell lines as well as pancreatitis tissues. Among the 95 miRNAs, eight miRNAs (miR-196a, miR-190, miR-186, miR-221, miR-222, miR-200b, miR-15b and miR-95)” )
Wikberg (Cancer Medicine 2018; 7(5):1697–1_) teaches, “Patients with CRC with detected distant metastases at blood sampling had significantly lower levels of circulating miR-15b and -19a.”
Chen (Med Sci Monit, 2015; 21: 1864-1871) teaches, “Circulating miR-15b-5p, miR-338-5p, and miR-764 may be biomarkers for diagnosis of HCC.”
Hennessey PT (PLoS ONE 7(2): e323072012) teaches, “Serum microRNA Biomarkers for Detection of Non-Small Cell Lung Cancer.” (title). Hennessey teaches, “.A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value(PPV) and negative predictive value(NPV) of 100% in the training set..”
Frampton (Annals of Surgery _ Volume 262, Number 2, August 2015) teaches, “ miR-15b is upregulated in hepatocellular carcinoma and has been shown to be a good circulating biomarker, in combination with miR-130b.5 Furthermore, a serum miR- 15b/miR-27b classifier is able to detect non– small cell lung cancer with good accuracy”
The level of skill in the art:
The level of skill in the art is deemed to be high.
Quantity of experimentation necessary:
In order to practice the invention as claimed, one would first have to establish that a predicative relationship exists between the detecting expression of miR-15b any plasma sample from any human subject relative to any healthy control plasma and treatment for colorectal cancer including colonoscopy, an anti-neoplastic agent therapy and a cancer therapy. Experimentation would be replete with unpredictable trial and error analysis as the prior art teaches that miR-15b is overexpressed in healthy plasma samples relative to CRC patients. Further the art teaches miR-15B is differentially expressed in subjects treated with LPS, having HCC, having ESRD, bladder cancer, glioma, etc. Further the prior art Sun teaches miR-15b is correlated in with stage IV CRC in the validation subjects only. Thus it would be unpredictable to select or treat colorectal cancer based on expression of miR-15b. Further it would be unpredictable to use any healthy plasma sample in the variability of miR-15b expression in plasma sample. Further the art suggests all subject over the age of 50 should be screened for colorectal cancer, or are at risk of having colorectal cancer. Finally it would be unpredictable to treat all subjects suspected of having colorectal cancer following or prior to detection of miR-15b and comparison to miR-15b in control samples.
While the specification states, “The term "biomarker" as used herein in various embodiments refers to a specific biochemical in the body that has a particular molecular feature to make it useful for diagnosing and measuring the progress of disease or the effects of treatment.” miR-15b cannot be considered a biomarker based on this standard as the prior art demonstrates normalized miR-15b expression is higher in plasma from healthy controls than from CRC patients. Thus, the miR-15b is not a predictable biomarker of CRC or treatment therapy colorectal cancer.
It would further be unpredictable to used normalized expression of the biomarkers as Ng teaches the normalized expression of mir-15b is decreased in CRC patients, while the non-normalized is increased.
Therefore, in light of the breadth of the claims, the lack of guidance in the specification, the high level of unpredictability in the associated technology, the nature of the invention, the negative teachings in the art, and the quantity of unpredictable experimentation necessary to practice the claimed invention, it would require undue experimentation to practice the invention as claimed.
Response to Arguments
The response traverses the rejection asserting, “Regarding issue (I), although the preamble of Claim 38 recites the treatment of a human subject suspected of having CRC, the claimed methods do not strictly require a predictive relationship to exist between the overexpression of miRNA-15b and the presence of CRC..” This argument has been thoroughly reviewed but is not considered persuasive as the claims recites, “A method for treating a human subject at ris treating the human subject with at least one selected from the group consisting of colonoscopy, an anti-neoplastic agent therapy and a cancer therapy, when the human subject has been identified as being at risk for colorectal cancer by a process comprising: (a) obtaining a plasma sample from the human subjecextracting microRNAs comprising miRNA-15b from the plasma sample obtained from the human subjec(c)amplifying the miRNA-15b in the extracted microRNAs by (i) contacting the microRNAs with a primer specific to miRNA-15b, (ii) reverse transcribing the miRNA-15b into cDNA, and (iii) amplifying the cDNA using polymerase chain reaction to produce an amplification product; f(dd)determining the miRNA-15b expression level in the plasma sample obtained from the human subject by determining the level of amplified cDNA in the amplification product; and (e)obtained from the human subject 15b as compared to the expression of miRNA-15b in the plasma sample obtained from the one or more healthy control human subjects.” Thus, the claim requires treatment of all subjects suspected of having risk colorectal cancer for colorectal cancer, which would be unpredictable as not all subjects assayed have colorectal cancer. Thus the rejection is not reading limitations from the specification into the claims, but the response is trying to alter the scope of the claim based on the specification to argue the enablement issue.
The response continues by asserting, “Although the overexpression of miRNA-15b could be due to the presence of diseases other than (or in addition to) CRC-and, thus, could lead to false positives and unnecessary treatment in some instances-because the present Inventors discovered a reproducible methodology by which miRNA-15b overexpression in human plasma can be used as a means for identifying/selecting the population of subjects for neoplasia treatment, the lack of overexpression of miRNA-15b in the plasma sample of a human subject can provide a sound basis for avoiding invasive treatments such as colonoscopy. Stated differently, the lack of overexpression of miRNA-15b in the plasma sample of a human subject can identify the human subject as being in a lower-risk group for CRC, such that a decision not to perform a more invasive treatment may be warranted. “ This argument has been thoroughly reviewed but is not considered persuasive as the response is providing arguments to limitations not present in the claims. Further it is noted the claims require treating if miR-15b is increased. These treatments including anti-neoplastic therapy or cancer therapy, which would not be predictable in view the record. Further
decreased normalized expression of miR-15b in the plasma according to Ng is indicative CRC. Further the art of record demonstrates that increased miR-15b in the plasma is correlated with other cancers and diseases. Thus it would be unpredictable to treat a subject for CRC as required by the claim if the increased expression of miR-15B is due to hemolysis in the sample, speed of centrifugation of sample, bladder cancer, HCC, ESRD, LPS exposure, BCLL Further the art of Ng which actually normalizes the expression of miR-15b teaches the opposite of the correlation encompassed by the claims. Finally the claim requires treatment of all patients with CRC therapy, while the specification teaches not all human subjects in which miR-15b was detected in plasma and compared to healthy controls have CRC.
The response continues by asserting the rejection is reading a predictive relationship for the specification. This argument is confusing as the claim states:
Thus the rejection is maintained.
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 38, 60-62, 69-72 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 38 has been amended to recite, “human subject at risk of having colorectal cancer.” The recitation of risk of colorectal cancer suggests there are subjects not at risk of colorectal cancer. While the specification recites risk, the specification also recite “average risk population.” The specification and claims provide no specific standard or guidance on how to differentiate risk of having colorectal cancer from average risk of colorectal cancer, from not at risk of colorectal cancer. Thus the metes and bounds are unclear.
Response to Arguments
This is a new grounds of rejection necessitated by amendment.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 38, 60-62, 69-72 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step or abstract idea without significantly more. The claim(s) recite(s) the abstract idea or mental step of comparing. While the claim provides an administering step, the claim as amended requires treating subjects with colonoscopy, an anti-neoplastic agent therapy and a cancer therapy. Thus judicial exception is not integrated into a practical application because colonoscopy, an anti-neoplastic agent therapy and a cancer therapy is merely applying the judicial exception f increased of expression of miR-15b with colorectal cancer, and encompasses watchful waitining. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim provides general guidance on obtaining plasma sample, extracting miRNA, amplifying miR-15b expression .
Claim analysis
Independent claim 38 is directed towards A method for treating a human subject at ris treating the human subject with at least one selected from the group consisting of colonoscopy, an anti-neoplastic agent therapy and a cancer therapy, when the human subject has been identified as being at risk for colorectal cancer by a process comprising: (a) obtaining a plasma sample from the human subjecextracting microRNAs comprising miRNA-15b from the plasma sample obtained from the human subjec(c)amplifying the miRNA-15b in the extracted microRNAs by (i) contacting the microRNAs with a primer specific to miRNA-15b, (ii) reverse transcribing the miRNA-15b into cDNA, and (iii) amplifying the cDNA using polymerase chain reaction to produce an amplification product; f(d)determining the miRNA-15b expression level in the plasma sample obtained from the human subject by determining the level of amplified cDNA in the amplification product; and (e) comparing the measured expression of miRNA-15b in the plasma sample to expression of miRNA-15b in a plasma sample obtained from one or more healthy control human subjectsobtained from the human subject has an overexpression of miRNA-15b as compared to the expression of miRNA-15b in the plasma sample obtained from the one or more healthy control human subjects...
The determining, and comparing steps are a mental step or abstract idea. The wherein clause requires the comparison to determine overexpression,.
The claim requires obtaining plasma sample, extracting miRNA, amplifying which are considered to be an active step requiring the analysis of a sample.
Dependent claims set forth further limitations to about the reference level, method of detecting expression, and subject
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea and/or mental step of comparing .
With regards to claim 38, the claim recites, (d)determining the miRNA-15b expression level in the plasma sample obtained from the human subject by determining the level of amplified cDNA in the amplification product; and (e) comparing the measured expression of miRNA-15b in the plasma sample to expression of miRNA-15b in a plasma sample obtained from one or more healthy control human subjects.” This is an abstract idea or mental step. (UNIVERSITY OF UTAH RESEARCH v. AMBRY GENETICS CORPORATION).
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as anti-neoplastic agent therapy and a cancer therapy encompass watchful waiting( van de Velde (European Journal of Cancer (2014) 50, 1.e1– 1.e34) and Mitchell (Surg Endosc (2008) 22:1563– 1569)) is a cancer therapy.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, as the claims fail to provide any specific reagents which could be determined to be significantly more.
Ng (Gut Online First, published on February 9, 2009 as 10.1136/gut.2008.167817) teaches obtaining plasma samples and determining miR-15 expression were routine and conventional.
Response to Arguments
The response traverses the rejection in view of the amendment. This argument has been thoroughly reviewed but is not considered persuasive as the claim encompasses watchful waiting and thus is not significantly more.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 38, 60-62, 69-72 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ng (Gut Online First, published on February 9, 2009 as 10.1136/gut.2008.167817) in view of Aslam (British Journal of Surgery (2009) volume 96, pages 702-710), Xi (Biomarker Insight (2006) volume 2, pages 113-121), Mambo (US 2009/0233297), and Cortez (Expert opinion on biological therapy (2009) volume 9, pages 703-711).
This rejection is drawn to the interpretation the claims require analysis of miR-15b prior to treatment.
Thus the broadest reasonable interpretation of claim 1 is obtaining a plasma sample, measuring miR-15B, comparing miR-15b to healthy controls and treating anyone assayed with higher miR-15b expression for colorectal cancer.
Ng teaches, “Plasma and biopsies from 5 CRC patients (3 male, 2 female; age: 65±9.0 years) and plasma from 5 sex- and age-matched healthy subjects (age: 62±6.4 years) were used for miRNA profiling. Profiling was performed using Cancer MicroRNA Array with QuantiMir system (System Biosciences, CA, USA) which is a real-time PCR-based array containing a panel of 95 cancer-related miRNA assays and the U6 transcript as a normalization signal. In brief, 100 ng of total RNA extracted from plasma and tissue samples was polyadenylated by poly(A) polymerase and then reverse transcribed to cDNA. Real-time qPCR was performed using Power SYBR Master Mix (Applied Biosystems, CA, USA) using miRNA-specific primers provided by the manufacturer in ABI PRISM 7500 Real-time PCR system (Applied Biosystems). The cycle threshold (Ct) is defined as the number of cycles required for the fluorescent signal to cross the threshold in qPCR. ΔCt was calculated by subtracting the Ct values of U6 from the Ct values of the miRNA of interest. ΔΔCt was then calculated by subtracting ΔCt of the control from ΔCt of disease. Fold change of gene was calculated by the equation 2-ΔΔCt. Most of the miRNAs chosen for the array have been characterized with regard to potential roles in cancer, cell development, and apoptosis. The details describing the platform and selection of miRNAs can be obtained from http://www.systembio.com..” (pages 4-5). Supplementary table 1A NG teaches miR-15B expression was increased 35.86 CRC relative 28.2 healthy control.
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Ng teaches, “Phase II (Marker selection and validation): Plasma samples were collected from 25 CRC patients before undergoing endoscopy. Plasma from 20 healthy subjects was collected as normal control. Putative miRNA markers identified in phase I were verified on these plasma from 25 CRC patients and 20 controls. Plasma from another 10 CRC patients was collected before and 7 days after surgical resection. For those markers proceeding to phase III validation, they must be significantly elevated in the 25 CRC patients and reduced after tumor resection.” (pages 3-4)
Ng thus teaches detection of increased expression of miR-15b is increased in CRC plasma samples relative to control plasma and examining biomarker or miRNA expression prior to endoscopy (colonoscopy).
Ng does not specifically teach detecting increased miR15b expression in plasma prior to administering colorectal cancer therapy.
However, Xi teaches, “Ten miRNAs (hsa-let-7b, hsa-let-7g, hsa-miR-15b, hsa-miR-181b, hsa-miR-191, hsa-miR-200c, hsamiR- 26a, hsa-miR-27a, hsa-miR-30a-5p and hsa-miR-30c) were evaluated for their potential prognostic value in colorectal cancer patients. Forty eight snap frozen clinical colorectal samples (24 colorectal cancer and 24 paired normal patient samples) with detailed clinical follow-up information were selected. The expression levels of 10 miRNAs were quantified via qRT-PCR analysis. The statistical significance of these markers for disease prognosis was evaluated using a two tailed paired Wilcoxon test. A Kaplan-Meier survival curve was generated followed by performing a Logrank test. Among the ten miRNAs, hsa-miR-15b (p = 0.0278), hsa-miR-181b (p = 0.0002), hsa-miR-191 (p = 0.0264) and hsa-miR-200c (p = 0.0017) were significantly over-expressed in tumors compared to normal colorectal samples.”
Aslam teaches, “Overexpressed miRNAs such as miR- 20, miR-21, miR-17-5p, miR-15b, miR-181b, miR-191 and miR-200c have been implicated in colorectal cancer tissues22–24. These tumour promoter miRNAs function by targeting and inhibiting different tumour suppressor genes25 such as E2F transcription factor 1, tropomyosin 126, phosphatase and tension homologue gene (PTEN)27 and programmed cell death gene 4 (Pdcd4)” (page 704, 2nd column, 2nd cull paragraph).
Aslam teaches, “MiRNAs are present in body fluids, especially blood, and are potentially useful clinical biomarkers. Recent studies have shown that tumour-derived miRNAs are present in human serum in remarkably stable form and are protected from endogenous ribonuclease activity44. These tumour derived miRNAs are present in circulating blood at levels sufficient to be measurable as biomarkers for the detection of tumours44. The levels of plasma and serum miRNAs correlate strongly, suggesting that either plasma or serum can be used for investigation of these blood based biomarkers45. More than 100 circulating miRNAs can be identified in the blood of healthy individuals44 and this profile differs significantly from that of patients with colorectal cancer who have several tumour-specific miRNAs. Chen and colleagues46 demonstrated 69 miRNAs in the serum of patients with colorectal cancer that were not present in the serum of healthy controls. Moreover, they identified a unique expression profile of 14 serum miRNAs for colorectal cancers that were not present in another cancer group (lung cancer). The detection of placental miRNAs in maternal serum at levels that increase with gestational age45 reveals their potential to serve as biomarkers for diverse physiological and pathological conditions47. The overlapping expression and variability of miRNAs with tumour characteristics have rendered single miRNAs unsuitable as sensitive diagnostic biomarkers, but if a blood-based miRNA profile (fingerprints) can be established for age-matched normal individuals, for patients with early lesions (adenomas) and for those with various stages of colorectal cancer, an accurate assessment would be probable.” (page 706, 1st column).
Alsam further teaches, “Blood-based miRNAs offer a prospect of developing a simple blood test which could be used for detection of tumours and differentiation of adenomas from colorectal cancers in patients referred to surgical outpatient clinics. This test might be arranged either before referral by the general practitioner or during the consultation in the clinic. This would lead to the effective processing of 2-week wait referrals. Based on the model of increasing levels of miRNAs with severity of the condition, the levels of miRNAs in the blood might predict the stage of colorectal cancer. This would reduce the need for exhaustive staging investigations, especially for advanced-stage cancers amenable only to palliative therapy. Furthermore, the detection of blood-based unique miRNA profiles can be used for surveillance of individuals with intermediate or high-risk bowel polyps. This would reduce the burden of colonoscopic surveillance after excision of such polyps.” ((page 706, 2nd t column).
Mambo teaches,” The present invention concerns methods and compositions for identifying a miRNA profile for a particular condition, such as colorectal cancer, and using the profile in the diagnosis and/or prognosis of a patient for a condition, such as colorectal cancer and colorectal cancer recurrence or response to therapy.” (abstract) Mambo teaches the use of a plasma sample in 0028. Mambo teaches examination of miR-15b, expression 0187.
Cortez teaches, “Mitchell et al. [55] demonstrated the presence of circulating tumor-derived miRNAs in blood by using a mouse prostate cancer xenograft model system and showed that measurements obtained from plasma were strongly correlated with those obtained from sera, suggesting that both serum and plasma samples would be adequate for measuring specific miRNA levels. Moreover, these investigators found that by measuring serum levels of miR-141 they were able to distinguish patients with prostate cancer from healthy subjects. Interestingly, miR-141 is expressed in a variety of epithelial cancers including breast, lung, colon and prostate [21].” (page 704, 2nd column).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to identify subjects having colorectal cancer and overexpression of miR15b in plasma samples for treatment with cancer therapy or colonoscopy. The artisan would be motivated as the prior art suggests increased expression of plasma miR15b relative to normal subjects have been has been found in subjects with colorectal cancer. The artisan would be further motivated to screen subjects by non-invasive methods for detecting increased markers of colorectal cancer to identify subjects for further screening or treatment without an invasive biopsy as first level screening. The artisan would have a reasonable expectation of success as the artisan is detecting known nucleic acids by known methods. (claim 63)
Ng, Mambo, Aslam, Xi and Cortez do not specifically teach performing a colonoscopy or treating with antineoplastic agent or cancer therapy based on miR-15b overexpression .
However, Aslam teaches, “Blood-based miRNAs offer a prospect of developing a simple blood test which could be used for detection of tumours and differentiation of adenomas from colorectal cancers in patients referred to surgical outpatient clinics. This test might be arranged either before referral by the general practitioner or during the consultation in the clinic. This would lead to the effective processing of 2-week wait referrals. Based on the model of increasing levels of miRNAs with severity of the condition, the levels of miRNAs in the blood might predict the stage of colorectal cancer. This would reduce the need for exhaustive staging investigations, especially for advanced-stage cancers amenable only to palliative therapy. Furthermore, the detection of blood-based unique miRNA profiles can be used for surveillance of individuals with intermediate or high-risk bowel polyps. This would reduce the burden of colonoscopic surveillance after excision of such polyps.” (page 706, 2nd column)
Aslam teaches, “With the addition of RNA extraction and modifications in the qRT–PCR assay protocols, the technique can be adapted for miRNA study. The time taken for a single qRT–PCR run is 4–6 h15 and multiple samples can be processed together54. The results should be available within 24–48 h. MicroRNAs can be introduced into various aspects of the national bowel cancer screening programme. The best option might be a yearly microRNA blood test in primary care, with colonoscopic assessment for those detected positive.” Aslam teaches, “Surgical resection is highly effective for patients with localized disease (stage I and II or Dukes' A and B), but 25–30 per cent of them develop recurrence and die from relapse. Some may benefit from additional treatment, and the challenge is to identify these so-called high-risk B or high-risk stage II tumours. “ Aslam teaches adjuvant chemotherapy, chemoradiotherapy for treatment of colorectal cancer.
Further it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform colonoscopy on subjects with elevated plasma miR15b and treat with chemotherapy, chemoradiotherapy or adjuvant chemotherapy upon confirmation of colorectal cancer . The artisan would be motivated to perform a colonoscopy to validate or confirm colorectal cancer in the subject with overexpressed miR-15b and provide further treatment for cancer. The artisan would have a reasonable expectation of success as the artisan is merely using two known methods to evaluate subjects for risk or presence of colorectal cancer.
With regards to claims 60, Cortez teaches detection of quantitative real time PCR and microarray (704, 2nd column).
With regards to claims 43 and 67, Xi teaches miR-15b was statistically significantly overexpressed relative to normal controls (p=0.0278, figure 1). Thus there is a comparison to a healthy cohort.
With regards to claims 71-72, Aslam teaches, “Overexpressed miRNAs such as miR-20, miR-21, miR-17-5p, miR-15b, miR-181b, miR-191 and miR-200c have been implicated in colorectal cancer tissues.”
Response to Arguments
The response traverses the 103 rejection asserting, “no motivation would have existed to treat a human subject with one of the enumerated therapies based on overexpression of miRNA-15b in a plasma sample of a human subject...” This argument has been thoroughly reviewed but is not considered persuasive as the claims set forth comprising language and use of colonoscopy to confirm was known as the rejection is directed to. Treatment of subjects based increased risk and diagnosis or having colorectal cancer as required by claim 61 is obvious.
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 time wise 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 38, 60-62, 69-72, provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3-4, 6-8, 11-20 of copending Application No. 17/570221. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a method of identifying a subject having overexpression of miR-15b in plasma. (claim 63). Claim 38 further requires treatment based on overexpression of miR-15b, including colonoscopy
Claims of 674 are drawn to methods of detecting and treating colorectal cancer by expression of miR-15b and miR-29a, wherein the treatment encompasses colonoscopy
Thus it would have been prima facie obvious to one of skill in the art at the time the invention was made that the claims of 221 encompass those of the independent claims as both require detection of expression of miR-15b for detection of colorectal cancer and treatment and include colonoscopy.
Dependent claims are obvious over the claims of ‘221.
Response to Arguments
The response request the ODP rejection be held in abeyance until the instant application is allowable. This argument has been thoroughly reviewed but is not considered persuasive as the claims will not be allowable as long as there is an ODP rejection.
The response further asserts the instant application is the earlier filed application. This argument is not persuasive as the instant claims are not allowable.
Summary.
No claims are allowed.
Conclusion
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/Steven Pohnert/Primary Examiner, Art Unit 1683
Prosecution Insights