DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I and the species of TMEM240, MROH6, and BEND5 in the reply filed on 9/22/2025 is acknowledged. The traversal is on the ground(s) that there is a specific technical feature and no undue burden (p. 8). This is not found persuasive because there is no requirement for undue burden under 37 CFR 1.475(a). Furhtermore as provided in the requirement for restriction mailed 7/24/2025 on page 5 the technical feature of MROH6 methylation is not considered a special technical feature in view of Naumov 2013 teaches of DNA methylation of colorectal cancer using the Human Methylation 540 bead chip which provides probes for MROH6 (see p 5).
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-5, 8-9,11,14-25 are pending. Claims 6-7,10,12-13 have been cancelled.
Claims 17-24 are withdrawn as being drawn to a nonelected invention.
An action on the merits for claims 1-5,8-9,11,14-16 and 25 is set forth below.
Drawings
The drawings are objected to because Figure 2A, 2B, 2C, 2D are provided upside down. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 3, 14, 11, 15, 16 are objected to because of the following informalities: It is noted that these claims are not dependent on a preceding claim, but rather, claim 25. It is noted that should the claims be found in condition for allowance, these claims would need to be renumbered to clarify the dependency. Appropriate correction is required.
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.
Claims 1-5,8-9,11,14-16 and 25 are 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.
The claims are drawn to a method for detecting a predisposition to colorectal cancer or predicting likelihood, treatment response, prognosis or recurrence of colorectal cancer in any biological sample from any species based upon “methylation status”. The claims are further drawn to any methylation status including hypermethylation, hypomethylation, presence or absence of or any other methylation status.
The claims are drawn to a very large genus of examining methylation levels, amounts, detection of any samples from any type of individual to detecting a predisposition to colorectal cancer or predicting likelihood, any treatment response, prognosis or recurrence of colorectal cancer. Based upon the description in the specification although the skilled artisan could readily use a methylation status analysis, the artisan would first need to determine if it functionally detects predisposition, likelihood, treatment response, prognosis, or recurrence of colorectal cancer in the samples from any of the different species as such the specification has not provided written support for the structures with the recited functionality.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. The instant specification has not provided the critical structures in any species in any sample to functionally detecting a predisposition to colorectal cancer or predicting likelihood, any treatment response, prognosis or recurrence of colorectal cancer. Further, the specification has not provided the critical guidance for functionally determine any treatment response based upon detection of methylation.
The specification describes measuring methylation status of MROH6 in human ccFDNA extracts (p. 23-24). The specification measures methylation in colorectal cancer tissue of MROH6 (p. 25). However, the specification does not provide any critical guidance to functionally associated methylation level or amount of MROH6 to likelihood, predisposition to, treatment, prognosis or recurrence of colorectal cancer. Rather, the specification provides detection of MROH6 methylation in a sample from human colorectal tissue or plasma.
Further, the art does not provide guidance to sufficiently describe relevant identifying characteristics or functional attributes that would distinguish different members of the claimed genus. In the instant case it is not clear that the functionality of likelihood, predisposition to, treatment, prognosis or recurrence of colorectal cancer can be extrapolated to non-human individuals or in any sample type based upon any status of methylation in a particular sample from a specific species. This finding is supported by Feng (PNAS 2010 Vol 107 No 19 pages 8689-8694). Specifically, Feng teaches that although DNA methylation likely has a conserved role in gene silencing, the levels and patterns of DNA methylation appear to vary drastically among different organisms (abstract).
Herein the claims are drawn to any type of sample in any subject and functionally detecting a predisposition to colorectal cancer or predicting likelihood, any treatment response, prognosis or recurrence of colorectal cancer however, there is no written support that methylation detection or levels would between the different types of samples and species and treatment types would be functionally the same.
In analysis of the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note regarding genus/species situations that "Satisfactory disclosure of a ``representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed." (See: 'Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.) In the instant case, the specification fails to teach the necessary common attributes or features of the transcripts consistently detected across array platforms in view of the species disclosed. As such, one of skill in the art would not recognize that applicant was in possession of the genus of markers, encompassed by the broadly claimed invention.
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.
Claims 1-5,8-9,11,14-16 and 25 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 detection of methylation of MROH6 or a fragment thereof, does not reasonably provide enablement for correlation of detection of methylation statues to any colorectal cancer, predisposition, incidence, treatment response, prognosis or recurrence. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in 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 Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence 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 breadth of the claims
Claims 1-5,8-9,11,14-16 and 25 are drawn to detecting methylation status in a human subject wherein the status is indicative of predisposition to colorectal cancer or predicting likelihood, any treatment response, prognosis or recurrence of colorectal cancer. Therefore the claims are drawn detection of methylation of MROH6 and correlation of many phenotypes of colorectal cancer in any sample from any species.
Nature of the Invention
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Guidance in the Specification
The specification states that using illumine methylation 450K that MROH6 appears to have a higher value as compared to normal in colorectal cancer tissue (p. 25).
The specification asserts that cfDNA extracted from primer provides predisposition to colorectal cancer or predicting likelihood, treatment response, prognosis or recurrence of colorectal cancer (p. 27-28). However, the example does not provide that there is predictability for any of the correlations recited in any human patients in any samples. The claims therefore are drawn to correlations however, the specification has not provided any guidance that detection of methylation would provide for predisposition to colorectal cancer or predicting likelihood, treatment response, prognosis or recurrence of colorectal cancer. Further with regard to treatment response, the claims are drawn to correlations of any methylation status with any treatment, including any drug, however, the specification has not provided that methylation status of MROH6 is correlative to any drug interactions. Therefore the specification only provides guidance to detect methylation, but has not provided any guidance to predictably determine predisposition to colorectal cancer or predicting likelihood, treatment response, prognosis or recurrence of colorectal cancer based upon that methylation detection.
The unpredictability of the art and the state of the prior art
Michels, Karin (The promises and challenges of epigenetic epidemiology. Experimental Gerontology 2010 Vol 45 pages 297-301) recognizes that there are several challenges associated with using epigenetic biomarkers. For example Michels (Experimental Gerontology 2010 Vol 45 pages 297-301) teaches that the sample size has important implications for the results of an epigenetic study. Michels teaches that a sufficiently large sample size is a fundamental requirement of a high quality study in epigenetics. Additionally Michels teaches that DNA methylation is tissue specific and may be cell type specific and a certain DNA methylation pattern found in one specific tissue does not permit inferences about its variation across different tissues and possibly not even across different cell types in the same tissue. This is relevant to the instant claims because the claims do not require specific methylation states or cell types. Further Michels teaches that a study of the influence of a specific DNA methylation pattern on a disease outcome could be confounded by a variety of variables that affect methylation and are also risk factors for the disease. Age is a likely confounder of a study in epigenetics since the DNA methylation profile changes with age and age increases the risk for most diseases.
Level of Skill in the Art
The level of skill in the art is deemed to be high.
Quantity of Experimentation and Conclusion
The quantity of experimentation in this area would be extremely large since there is significant number of parameters that would have to be studied. The claims are drawn to a multitude of associations to the detection of MROH6 methylation status. The specification provides detection of methylation of MROH6 however does not provide guidance for correlation to any of these associations. The art indicates that associations are population and disease specific.
To practice the invention as broadly as it is claimed, the skilled artisan would have to determine the association of any methylation status within MROH6 and all the recited correlations. The specification has not provided clear guidance for such association. As these associations are known to be disease specific, the skilled artisan would need to perform undue experimentation to identify which methylation locus within genes is associated with each correlations. Such random, trial by error experimentation is considered to be undue and highly unpredictable.
Thus the applicants have not provided sufficient guidance to enable a skilled artisan to make the claimed invention in a manner reasonably correlated with the claimed method.
Therefore the method as claimed would require a large amount of inventive effort, with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the succeeding steps. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the negative teachings in the art, and the lack of guidance provided in the specification balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Claim Rejections - 35 USC § 112
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 1-5,8-9,11,14-16 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.
Claims 1-5,8-9,11,14-16 and 25 are indefinite over the term “hypermethylation” in claims 1 and 25.The term “hypermethylation” in claim 1 is a relative term which renders the claim indefinite. The term “hypermethylation” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As there is no comparison it is not clear which methylation statuses would be considered hypermethylated. Claims 2-5,8-9,11,14-16 and 25 depend from claim 1 and therefore are indefinite.
Claims 1-5,8-9,11,14-16 and 25 are indefinite over the terms “poor treatment response” and “poor prognosis” in claim 1 and 25. The terms “poor treatment response” and “poor prognosis” in claim 1 are relative terms which renders the claim indefinite. The terms “poor treatment response” and “poor prognosis” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As there is no comparison it is not clear which treatment or prognosis statuses would be considered poor. Claims 2-5,8-9,11,14-16 and 25 depend from claim 1 and therefore are indefinite.
Claim 3 is indefinite over a step of defining a score. The claim depends upon claims 25 and 1, however, claim 1 and 25 does not have a step of determining hypermethylation or hypomethylation. As such it is not clear how to define the score without steps of determination hypermethylation or hypomethylation.
Claim 4 is indefinite the presence of hypermethylation or hypomethylation. The claim depends upon claim 1, however, claim 1 does not have a step of determining hypermethylation or hypomethylation. As such it is not clear how perform the statement in claim 4 without steps of determination hypermethylation or hypomethylation.
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 1-5,8-9,11,14-16 and 25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation ( correlation of predisposition, predicting likelihood, treatment response, prognosis, or recurrence of colorectal cancer) without significantly more. This judicial exception is not integrated into a practical application because no additional steps rely upon or integrate the judicial exceptions of the claims. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no steps that are significantly more or integrate the judicial exceptions.
Claim analysis
The instant claims are directed a method of detecting methylation status for detecting predisposition, predicting likelihood, treatment response, prognosis, or recurrence of colorectal cancer
The correlation is considered a law of nature.
The providing a sample and determining methylation status are a positive active step and thus is a physically active step.
Dependent claims set forth further limitations to about the methods used in detecting, hypermethylation levels, statistical analysis and the origin of the sample.
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, law of nature or natural phenomena.
The correlation of predisposition, predicting likelihood, treatment response, prognosis, or recurrence of colorectal cancer and methylation status is considered a law of nature.
The providing a biological sample and determining step is a positive active step and thus is a physically active step.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no the claim requires no additional steps that integrate the juridical exceptions, rather the active steps are considered general and routine as the steps encompass general methods of determining methylation status and steps of statistical analysis.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No
The specification teaches that methylation status is performed with well-known and conventional methods of methylation assays including the commercial Illumina Methylation 450K array (p 25 and naturally occurring samples (e.g. colorectal tumors). Hayashi et al. (US Patent Application 2016/0273051 September 22, 2016) teaches providing a biological sample and determining the methylation status of MROH6 as it is a biomarker on the Illumina 450K biochip (para 44 and 124). As such the only step in the claims are determining a naturally occurring genes methylation status using conventional assays.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-5, 11, 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hayashi et al. (US Patent Application 2016/0273051 September 22, 2016)
With regard to claim 1, Hayashi et al. teaches providing a biological sample and determining the methylation status of MROH6 as it is a biomarker on the Illumina 450K biochip (para 44 and 124). With regard to the wherein clause, the positive active steps do not require a determination of hypermethylation. As such the claims as broadly written encompass any method which “determining a methylation status”. As such Hayashi et al. teaches the required steps of the claim.
With regard to claim 2, Hayashi et al. teaches a sample that comprises cells, tissues, blood, serum, plasma, or urine (para 49).
With regard to claim 3, the claims require a step of determination hyper or hypomethylation which Hayashi et al. teaches (para 51, 74). Hayashi et al. teaches using scores for determine the presence of methylation (para 124). It is noted that claim 3 is unclear as it is not clear how to perfume the claimed steps based upon the dependency of claim 1. As such it is not clear which steps of claim 3 are positively activity recited.
With regard to claim 4, Hayashi et al. teaches a determining hypermethylation or hypomethylation as compared to a control (para 56, 63).
With regard to claim 5, Hayashi et al. teaches a method of using methylation specific PCR (para 55).
With regard to claims 25 and 11, Hayashi et al. teaches detection of the markers on Illumina 450K biochip (para 44 and 124) and as such teaches TMEM240 as the instant specification teaches that this gene marker is on the biochip (see specification page 24).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi et al. (US Patent Application 2016/0273051 September 22, 2016) in view of Weksberg et al. (US Patent 20170226570 August 10, 2017), Diffenbach (PCR methods and Applications (1993) volume 3, pages S30-S37) and Roux et al (PCR Methods and Applications (1995) volume 4, pages s185-s194) and Hogan (US patent 6773882 Aug 10, 2004).
Hayashi et al. teaches providing a biological sample and determining the methylation status of MROH6 as it is a biomarker on the Illumina 450K biochip (para 44 and 124). With regard to the wherein clause, the positive active steps do not require a determination of hypermethylation. As such the claims as broadly written encompass any method which “determining a methylation status”. As such Hayashi et al. teaches the required steps of the claim.
Hayashi et al does not teach use of primers and probes of MROH6.
With regard to claims 8-9, Weksberg et al. teaches in Table 1, MHO6 and teaches to detect methylation of PCR using primers and probes of a known gene (MRHO6) (para 61-67 and 192). Although Weksberg et al. does not teach the recited sequences, these sequences recite regions of the known MROH6.
The art teaches design optimization to amplify a known region with primers. With regard to Claims 13-15, Diffenbach teaches parameters and principles of promoter design include primer length, terminal nucleotide, GC content, melting temperature, PCR product length and placement of target sequence (s30-s34). Diffenbach teaches PCR software was known (s35).
Roux teaches optimization of PCR by the presence of enhancing agents, Mg2+, annealing temperature, primer design, cycle number, hot start PCR (s185-s194).
Hogan teaches methods for generating Candida species-specific probes which hybridize to rRNA sequences. Hogan (col. 9, beginning at line 9) teaches that:this allows two very different rRNA sequences to be aligned non-target sequences, and by positioning the probe to span rRNA sequences to be "aligned" based on conserved primary sequence and conserved elements of the secondary structure. Once the sequences have been aligned, it becomes possible to identify conserved and variable regions of the rRNA sequence. Variable regions of rRNAs were identified by comparative analysis using published rRNA sequences and sequences that were determined during the development of the present invention. Commercially available software can be used or adapted for the purposes disclosed herein. Since the sequence evolution at each variable regions (for example, spanning a minimum of 10 nucleotides) of rRNA is, for the most part, divergent and not convergent, we can confidently design probes based on a few rRNA sequences which differ between the target organism and its phylogenetically closest relatives….The following guidelines can be used for designing probes having desirable characteristics in accordance with the present invention…First, the stability of the probe:target nucleic acid hybrid should be chosen to be compatible with the assay conditions. This may be accomplished by avoiding long A and T rich sequences, by terminating the hybrids with G:C base pairs and by designing the probe in such a way that the Tm will be appropriate for standard conditions to be employed in the assay. The nucleotide sequence of the probe should be chosen so that the length and %G and %C result in a Tm about 2-10oC higher than the temperature at which the final assay will be performed. The base composition of the probe is significant because G:C base pairs exhibit greater thermal stability when compared with A:T base pairs. Thus, hybrids involving complementary nucleic acids having a high G:C content will be stable at higher temperatures when compared with hybrids having a lower G:C content... Second, the position at which the probe binds its target polynucleotide should be chosen to minimize the stability of hybrids formed between probe:non-target polynucleotides... Third, regions of the rRNA which are known to form strong structures inhibitory to hybridization are less preferred as targets.
Therefore it would be prima facie obvious at the time of the effective filing date to modify the method of detecting methylation of MRHO6 to design primers and probes to detect methylation of MRHO6 for PCR analysis. Designing oligonucleotides (probes and primers) to hybridize to specific targets, which are equivalents to those taught in the art, is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as primers, see Diffenbach and Roux. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primer. As discussed above, the ordinary artisan would be motivated to have designed and tested new primers to obtain additional oligonucleotides that function to detect MRHO6 and identify oligonucleotides (including the primers and probes) with improved properties for such detection. Thus, for the reasons provided above, the ordinary artisan would have designed additional oligonucleotides using the teachings in the art at the time the invention was made. The claimed primer sequences are obvious over the cited prior art, absent secondary considerations.
Claim(s) 14-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi et al. (US Patent Application 2016/0273051 September 22, 2016) in view of Zhang et al. (WO 2015116837 August 6, 2015), Diffenbach (PCR methods and Applications (1993) volume 3, pages S30-S37) and Roux et al (PCR Methods and Applications (1995) volume 4, pages s185-s194) and Hogan (US patent 6773882 Aug 10, 2004).
Hayashi et al. teaches providing a biological sample and determining the methylation status of MROH6 as it is a biomarker on the Illumina 450K biochip (para 44 and 124). With regard to the wherein clause, the positive active steps do not require a determination of hypermethylation. As such the claims as broadly written encompass any method which “determining a methylation status”. As such Hayashi et al. teaches the required steps of the claim. Hayashi et al. teaches detection of the markers on Illumina 450K biochip (para 44 and 124) and as such teaches TMEM240 as the instant specification teaches that this gene markers is on the biochip (see specification page 24).
Hayashi et al does not teach use of primers and probes of TMEM240.
With regard to claims 14-15, Zhang et al. teaches in Table 1, TMEM240 and teaches to detect methylation of PCR using primers and probes of a known gene (MRHO6) (para 8-12). Although Zhang et al. does not teach the recited sequences, these sequences recite regions of the known TMEM240.
With regard to claim 16, Zhang et al. teaches determination using a weighted score (para 62-65).
The art teaches design optimization to amplify a known region with primers. With regard to Claims 13-15, Diffenbach teaches parameters and principles of promoter design include primer length, terminal nucleotide, GC content, melting temperature, PCR product length and placement of target sequence (s30-s34). Diffenbach teaches PCR software was known (s35).
Roux teaches optimization of PCR by the presence of enhancing agents, Mg2+, annealing temperature, primer design, cycle number, hot start PCR (s185-s194).
Hogan teaches methods for generating Candida species-specific probes which hybridize to rRNA sequences. Hogan (col. 9, beginning at line 9) teaches that:this allows two very different rRNA sequences to be aligned non-target sequences, and by positioning the probe to span rRNA sequences to be "aligned" based on conserved primary sequence and conserved elements of the secondary structure. Once the sequences have been aligned, it becomes possible to identify conserved and variable regions of the rRNA sequence. Variable regions of rRNAs were identified by comparative analysis using published rRNA sequences and sequences that were determined during the development of the present invention. Commercially available software can be used or adapted for the purposes disclosed herein. Since the sequence evolution at each variable regions (for example, spanning a minimum of 10 nucleotides) of rRNA is, for the most part, divergent and not convergent, we can confidently design probes based on a few rRNA sequences which differ between the target organism and its phylogenetically closest relatives….The following guidelines can be used for designing probes having desirable characteristics in accordance with the present invention…First, the stability of the probe:target nucleic acid hybrid should be chosen to be compatible with the assay conditions. This may be accomplished by avoiding long A and T rich sequences, by terminating the hybrids with G:C base pairs and by designing the probe in such a way that the Tm will be appropriate for standard conditions to be employed in the assay. The nucleotide sequence of the probe should be chosen so that the length and %G and %C result in a Tm about 2-10oC higher than the temperature at which the final assay will be performed. The base composition of the probe is significant because G:C base pairs exhibit greater thermal stability when compared with A:T base pairs. Thus, hybrids involving complementary nucleic acids having a high G:C content will be stable at higher temperatures when compared with hybrids having a lower G:C content... Second, the position at which the probe binds its target polynucleotide should be chosen to minimize the stability of hybrids formed between probe:non-target polynucleotides... Third, regions of the rRNA which are known to form strong structures inhibitory to hybridization are less preferred as targets.
Therefore it would be prima facie obvious at the time of the effective filing date to modify the method of detecting methylation of TREM240 to design primers and probes to detect methylation of TREM240 for PCR analysis. Designing oligonucleotides (probes and primers) to hybridize to specific targets, which are equivalents to those taught in the art, is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as primers, see Diffenbach and Roux. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primer. As discussed above, the ordinary artisan would be motivated to have designed and tested new primers to obtain additional oligonucleotides that function to detect TREM240 and identify oligonucleotides (including the primers and probes) with improved properties for such detection. Thus, for the reasons provided above, the ordinary artisan would have designed additional oligonucleotides using the teachings in the art at the time the invention was made. The claimed primer sequences are obvious over the cited prior art, absent secondary considerations.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/ Primary Examiner, Art Unit 1682