DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed March 30, 2026. Currently, claims 1-3, 5-17 are pending.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
The response filed March 30, 2026 includes the response to the request for information.
The 102 rejections over Liu and Almen have been withdrawn in view of the amendments to the claims to require primer and probes.
Priority
This application claims priority to
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Drawings
The drawings are acceptable.
Claim Rejections - 35 USC § 101- Methods
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 1-3, 5-12, 14-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
Claim 1 is directed to “a method to characterize non-small cell lung cancer by detecting a methylation level”.
Claims 5-6 are directed to “calculating a methylation risk score” with different weights for calculating the methylation risk score.
Claim 11 is directed to providing a diagnosis of NSCLC.
Claim 14 is directed to evaluating a therapy of NSCLC including calculating methylation risk score wherein a change of the methylation risk score is indicative of efficacy of the therapy.
Claim 16 is directed to “wherein an increase of the methylation score is indicative of disease progression”.
The claims are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “a method to characterize NSCLC”, “providing a diagnosis”, “evaluating a therapy” and a comparison/increase is indicative of disease progression” and mathematical concepts of calculating a risk score”) and a law of nature/natural phenomenon (i.e. the natural correlation between the methylation of a gene such as KCNS2 and NSCLC characterization, diagnosis and disease progression).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Herein, the claims involve the patent-ineligible concept of an abstract process. The claims require performing the step of “a method to characterize NSCLC”, “providing a diagnosis”, “evaluating a therapy” and a comparison/increase is indicative of disease progression” and mathematical concepts of calculating a risk score”. Neither the specification nor the claims set forth a limiting definition for "characterizing”, “providing a diagnosis” “evaluating a therapy” and the claims do not set forth how charactering, providing and evaluating are accomplished. As broadly recited the steps may be accomplished mentally by thinking about a subject’s methylation state and assessing whether the subject has NSCLC. Thus, the charactering, providing and evaluating steps constitutes an abstract process idea.
Claim 5 is directed to a mathematical concept of calculating a methylation risk score. The risk score may be calculated mentally.
Claim 14 further recites a comparison between the risk score and a control that is deemed an abstract idea (see MPEP 2106.04(a)(2)(III)(A); • claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)).
A correlation that preexists in the human is an unpatentable phenomenon. The association between methylation states such as BHLHE22 methylation state and risk of endometrial cancer is a law of nature/natural phenomenon. The "assessing" step which tells users of the process to predict endometrial cancer in the sample, amounts to no more than an "instruction to apply the natural law". This assessing step is no more than a mental step. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The "assessing" step does not require the process user to do anything in light of the correlation. The "assessing" step fails to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claim recites obtaining a sample and detecting a methylation level, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The detecting methylation levels are mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the methylation of a gene in a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the methylation of a marker through whatever known processes they wish to use.
The step of determining mutation status was well known in the art at the time the invention was made. The prior art teaches that methylation analysis using commercially available biochips and arrays that comprise the claimed genes. The steps are recited at a high level of generality. The claim merely instructs a scientist to use any methylation analysis to determine the methylation level. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements were well known. Specifically, the specification teaches the Infinium Methylation EPIC BeadChips and Human Methylation 450 Methylation arrays were used (see page 44). These are commercially available.
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments
The response traverses the rejection. The response asserts the newly amended claims recite specific applications of the methylation level in a clinical context. This argument has been considered but is not convincing because the newly added limitations are additional judicial exceptions or generic treatment statements that do not provide meaningful limitations or practical applications.
First, the newly added “prognosis” language and “determining treatment modality” in Claim 1 do not overcome the patent ineligibility. The newly added language of prognosis in Claim 1 is analogous to the diagnosis language in Claim 2 of the 101 Guidelines, namely Example 29. Prognosis of NCLC based on methylation level is a correlation and relationship between the presence of methylation and patient’s phenotype. Adding additional judicial exceptions does not overcome the subject matter eligibility rejection.
Claim 1 has also added a determining treatment modality limitation that is not specific. As provided in MPEP 2106.04(d)(2), a treatment must be “particular” or specifically identified so as not to encompass all applications of the judicial exception.
Furthermore, the mere determination of a treatment modality does not require that the treatment actually be used by the patient. This is not a treatment claim. This does not require additional elements that integrate the exception into a practical application of the exception. While the claim recites determining the appropriate treatment for the subject, this is not an integration of the exception into a practical application. The limitation does not indicate how the patient is to be treated, or what the treatment is but instead covers any possible treatment that a doctor decides to administer to the patient. Even more the limitation is recited at such a high level of generality. The determining the appropriate treatment for the subject limitation fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception.
With respect to Claim 11, the claim has been amended to require providing a treatment of the NSCLC based on the methylation level. Again, this is a mere statement of “apply it”.
With respect to Claim 14, the administration of therapy for the evaluation of therapy is not an integration of a judicial exception. As provided in MPEP 2106.04(d)(2), the administration of a treatment performed in order to gather data for the mental analysis step, and is a necessary precursor for all uses of the recited exception is mere extra-solution and data gathering and is not a treatment limitation that imposes meaningful limits on the judicial exception.
Thus, for the reasons above and those already of record, the rejection is maintained.
Claim Rejections - 35 USC § 112-Description
The following is a quotation 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.
Claims 1-3, 5-12, 14-17 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are broadly drawn to methods which detecting a methylation level of at least one gene which possess the functionality of being associated with NSCLC. The claims are also directed to calculating a methylation risk score based on the methylation level of at least one gene or a disease progression.
Relevant to the lack of particular structural limitations in the rejected claims drawn to nucleic acids, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
In the case of the instant claims, the functionality of CpG sites diagnostic of NSCLC is a critical feature of the claimed methods.
The specification teaches determining genome-wide methylation analysis in primary lung cancer tissues (example 1, pages 26-27). The specification teaches four probes offered the optimal distinction between cancer and adjacent noncancer tissues including KCNS2 (page 27). The specification teaches specific primer and probe combinations based on the genomic locations of the identified methylation EPIC probes were designed and tested (page 28). The specification teaches 4 lung cancer lines showed high methylation in at least 2/4. The specification provides a model logistic regression models (page 33-36). The specification teaches a single methylation risk score
-7.635 + 0.114*age - 1.224*gender + 2.946*active smoking status - 0.054*former
smoking status +0.079*HOXA9 + 0.008*SCT+ 0.004*KCNS2 - 0.008*BARHL2.
The specification teaches a risk score greater than 0.13 may identify 90.5% of lung cancer patients (page 37).
However, it is not clear that any one of the genes are individually associated with NSCLC, as the specification teaches 4 lung cancer lines showed high methylation in at least 2/4. (page 28). The specification teaches a single model for risk score and a single cut off, however the specification does not teach how any one particular CpG site in one of the genes is associated with NSCLC. Given the guidance in the specification and what was taught in the art prior to the invention, the skilled artisan would be unable to predictably correlate a single CpG site in a single gene with NSCLC, simply based on their existence.
Thus, considering the breadth of the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Response to Arguments
The response traverses the rejection. The response asserts the claims have been amended to require four primer pair and probes for analysis and detection of methylation level. This argument has been considered but is not convincing because the claims are directed to detecting methylation of at least one using at least one primer pair and at least one probe. This language does not require all four of the probes as argued by the response.
The response argues Example 1 and Figure 2C demonstrate a high methylation level for any one of the four probes. This argument has been reviewed but is not persuasive. The claims are directed to non-small cell lung cancer. Example 1 is directed to primary lung cancer tissues (30 adenocarcinomas and 35 squamous cell carcinomas). Thus, Example 1 does not teach analysis of the recited genes in NSCLC.
Even more, the claims are directed to probes having at least 80% sequence identity to SEQ ID NO: 3, 6, 9, or 12. The specification does not teach which probes are used in Example 1 or Figure 2C. The specification teaches the Infinium Human Methylat450 Methylation data was used. The Declaration provided Applicant notes that the CpG site identifier for the probes of SEQ ID NO: 3, 6, 9 and 12 are not known. The Examiner mapped probes from the Infinium Human Methylation 450 array and was unable to identify SEQ ID NO: 3, 6, 9 or 12 as the probes on the array. Thus, the probes used in Example 1 do not appear to be the probes of the claims. It is unpredictable that the claimed probes are associated with NSCLC since the specification does not appear directed to the claimed probes or NSCLC.
Thus, for the reasons above and those already of record, the rejection is maintained.
Claim Rejections - 35 USC § 112- Second Paragraph
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.
Claim 13 is 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 pre-AIA the applicant regards as the invention.
Claim 13 is indefinite because it is unclear whether the claimed sequence contain labels or not. When looking at the sequence listing, the sequences do not appear to contain a label. SEQ ID NO: 3, for example states the probe is HOXA9 FAM probe but does not indicate the probe includes a FAM label. Table 1, page 24 of the specification, states the probe is a FAM3 probe. Again, it is not clear whether the sequence includes a FAM label. Clarification is required.
Response to Arguments
The response traverses the rejection. The response asserts claim 13 is definite, as the recited “labeled probe’ corresponds to the specific probes listed in Table 1 of the specification. This argument has been considered but is not convincing because limitations from the specification are not read into the claims. Claim 13 is merely directed to a labeled probe. The specification states the probe is a FAM3 probe however it is unclear whether Claim 13 requires a FAM label or is broadly directed to any label. Thus for the reasons above and those already of record, the rejection is maintained.
Claim Rejections - 35 USC § 102
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.
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 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.
Claim 13 is rejected under 35 U.S.C. 102(b) as being anticipated by NEB catalog (1998/1999), pp. 121, 284.
The claims are directed to a kit comprising a primer pair and a probe of at least one gene. The claim contains additional language that set for the intended use of the kit. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.
The NEB catalog offered for sale a random primer mix of 12mer and 24mer nucleotide primers. As the calculation below shows, about 3.2 x 108 molecules of every 12-mer and about 9 molecules of every single 24 mer are present in each tube of the 24 nucleotide mixtures.
a. Molecular weight of 12-mer:
12 x 325 daltons/nucleotide = 3,900 daltons = 3,900 g/mol
b. Total number of possible 12-mers:
412 = 1.6 x 107 molecules
c. How many molecules of 12-mer in a vial sold by NEB:
1 A260 unit = 33 µg = 3.3 x 10-5 g
3.3 x 10-5 g / 3,900 g/mol = 8.4 x 10-9 mol
(8.4 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 5 x 1015 molecules
d. How many molecules of each 12-mer in a single vial:
5 x1015 molecules / 1.6 x 107 molecules = 3.2 x 108 molecules of each 12-mer per vial
e. Molecular weight of 24-mer:
24 x 325 daltons/nucleotide = 7,800 daltons = 7,800 g/mol
f. Total number of possible 24-mers:
424 = 2.8 x 1014 molecules
g. How many molecules of 24-mer in a vial sold by NEB:
1 A260 unit = 33 µg = 3.3 x 10-5 g
3.3 x 10-5 g / 7,800 g/mol = 4.2 x 10-9 mol
(4.2 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 2.5 x 1015 molecules
h. How many molecules of each 24-mer in a single vial:
2.5 x1015 molecules / 2.8 x 1014 molecules = 9 molecules/vial
The claims encompass a large genus of possible nucleic acid primers with no particular base composition or length, as the claim is directed to only 80% sequence identity. The NEB catalog kits will inherently and necessarily contain 12 and 24 nucleotides primers encompassed by the claimed recitation.
For example, SEQ ID NO: 7 is 20 nucleotides in length. The claim is directed to “has” which has been interpreted as open claim language of “comprising”. Thus, the NEB 24mer comprise SEQ ID NO: 7. SEQ ID NO: 8 and 9 are 30 nucleotides. 80% of 30 is 24nucleotides. Thus, NEB teaches 24mers.
Here, the 24mer NEB primer kit inherently comprises primers and probes as required by claims. Thus, the prior art inherently teaches each and every structural limitation of the instant claim.
Response to Arguments
The response traverses the rejection. The response asserts Claim 13 recites specific primer pairs and probes having a defined base composition and length. This argument has been considered but is not convincing because the primers/probes are comprising a sequence having at least 80% identity to SEQ ID NO: 1, for example. SEQ ID NO: 1 is 22bp in length. 80% identity encompasses 4 substitutions, deletions or alterations. Thus, the claims encompass primers 24mers with additional substitutions. This is not a defined base composition or defined length.
Since the random mers comprise each 24 mer oligonucleotide. The mix would inherently comprise gggttttaygaggygttaaataAA, gggttttaygaggygttaaataTT, gggttttaygaggygttaaataCC, gggttttaygaggygttaaataGG, AAgggttttaygaggygttaaata, TTgggttttaygaggygttaaata, CCgggttttaygaggygttaaata, GGgggttttaygaggygttaaata, for example, which is SEQ ID NO: 1 with each of the bases as the additional nucleotides. NEB anticipates the claimed invention.
The response argues the intended use of the kit “for detecting a methylation level of at least one gene”. The primers of NEB, namely gggttttaygaggygttaaataAA, gggttttaygaggygttaaataTT, gggttttaygaggygttaaataCC, gggttttaygaggygttaaataGG, AAgggttttaygaggygttaaata, TTgggttttaygaggygttaaata, CCgggttttaygaggygttaaata, GGgggttttaygaggygttaaata would inherently be able to detect methylation level. The claimed primers are directed to DNA. There is no evidence the DNA of NEB and the DNA of SEQ ID NO: 1 are different. The NEB mix similarly comprises bisulfite treated probes where the T is replaced with a C. NEB mix comprises each of these probes.
Thus for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng (Winston) Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
May 18, 2026
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