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 .
The amended claims dated 6/27/2025 are under consideration.
The amendments and arguments presented in the papers filed 6/27/2025 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 12/27/2024 listed below have been reconsidered as indicated.
a) The objection to the specification is withdrawn in view of the amendments to paragraph under the heading “Related application”.
b) The rejections of claims 3 and 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in view of the amendments to the claims.
c) The rejections of: claim(s) 3 under 35 U.S.C. 103 as being unpatentable over Houseman (BMC Bioinformatics. 2012. 13(86):16 pages) in view of Reinius (PLoS ONE. 2012. 7(7):e41361); and claim(s) 4 under 35 U.S.C. 103 as being unpatentable over Houseman (BMC Bioinformatics. 2012. 13(86):16 pages) in view of Reinius (PLoS ONE. 2012. 7(7):e41361) as applied to claim 3 and in further view of Beach (WO 2013/022872 A1), are withdrawn in view of the amendments to the claims.
The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Election/Restrictions
Applicant elected with traverse of Group I, claims 3 and 4, in the reply filed on 10/17/2024.
Claims 5-12, the claims of Group II, have been cancelled.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on a submitted IDS, they have not been considered.
Claim Interpretation
Claim 3 recites “for determining methylation status of at least one CpG dinucleotide in the DNA of the sample”. The phrase is interpreted as being in the context of analyzing extent of hybridization of patient sample DNA to each of a plurality of oligonucleotide probes “for determining methylation status of at least one CpG dinucleotide in the DNA of the sample”.
Claim 3 recites “a DNA methylation reference library, to determine proportion of each leukocyte type in the sample”. The phrase “to determine proportion of each leukocyte type in the sample” is interpreted as limiting the type of “reference library”.
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 3 and 4 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more.
The following are new rejections necessitated by amendments to the claims.
The claim(s) recite(s) the following steps:
“determining a methylation status of a plurality of CpG dinucleotides in a patient sample DNA that has been bisulfite converted” (claim 3);
“(ii) analyzing extent of hybridization of the patient sample DNA to each of the oligonucleotide probes” (claim 3);
“comparing the methylation status of the plurality of CpG dinucleotides analyzed in the patient sample to a methylation status of a DNA methylation reference library” (claim 3);
“to determine: (i) a proportion in the sample of one or more leukocyte types selected from CD4+ T-cells, CD8+ T-cells, B cells, natural killer (NK) cells, monocytes, granulocytes, and granulocytic myeloid-derived suppressor cells (gMDSCs)” (claim 3);
“to determine:…(ii) a neutrophil to lymphocyte ratio (mdNLR) of the sample” (claim 3);
“displaying the methylation status of the plurality of CpG dinucleotides in the sample in a graphical representation, thereby generating an image of a methylation profile of each of the one or more leukocyte types in the patient sample” (claim 3);
“prognosing and/or diagnosing the disease state in the patient associated with mdNLR or the methylation profile, wherein the disease state is a glioma” (claim 3);
“determining if a multivariate proportional hazards ratio from the methylation profile in specific leukocyte types is above a pre-determined statistical threshold and associating the multivariate proportional hazards ratio with being equal to or greater than 1.0 as an indicium of a prognosis of an increased risk of death in the patient from the disease or as a diagnosis of the disease;” (claim 4);
“determining if the mdNLR is above a pre-determined statistical threshold, and associating the mdNLR with being equal to or greater than 1.0, at least about 2.0 or at least about or greater than 4.0 as an indicium of a prognosis of an increased risk of death in the patient from the disease or as a diagnosis of the disease” (claim 4); and
“determining if a multivariate proportional hazard value for the gMDSC proportion is above a pre-determined statistical threshold and associating the multivariate proportional hazard value with being equal to or greater than 1.0, greater than 2.0, or at least about or greater than 2.5 as an indicium of a prognosis of an increased risk of death in the patient from the disease or as a diagnosis of the disease” (claim 4).
The step of “determining a methylation status” broadly encompasses the processing and consideration of raw data derived from subparts (i) and (ii). The claim broadly encompasses using 4 oligonucleotide probes (i.e., “a plurality”) for the analysis of two CpG dinucleotides (i.e., a “plurality”). This limited amount of data may be considered by the human mind. The step therefore encompasses an abstract idea.
The step of “analyzing the extent of hybridization” broadly encompasses the processing and consideration of raw data derived from subpart (i). The claim broadly encompasses using 4 oligonucleotide probes (i.e., “a plurality”) for the analysis of two CpG dinucleotides (i.e., a “plurality”). This limited amount of data may be considered by the human mind. The step therefore encompasses an abstract idea.
The step of “comparing the methylation status” broadly encompasses comparing data between the probes and a reference. This limited amount of data may be considered by the human mind. The step therefore encompasses an abstract idea.
The process used “to determine…a proportion in the sample of one or more leukocytes” broadly encompasses the analysis of a limited amount of data that may be considered by the human mind. The step therefore encompasses an abstract idea.
The process used “to determine…a neutrophil to lymphocyte ratio” broadly encompasses the analysis of a limited amount of data that may be considered by the human mind. The step therefore encompasses an abstract idea.
The step of “displaying the methylation status” broadly encompasses conveying information for a limited amount of data. This conveying may be done by the human mind and/or coordinates human behavior. The step therefore encompasses an abstract idea.
The step of “prognosing and/or diagnosing” broadly encompasses making a determination based on a limited amount of data. This limited amount of data may be considered by the human mind. The step therefore encompasses an abstract data.
The three “determining” steps of claim 4 broadly encompasses doing calculations, making comparisons and reaching determinations. This broadly encompasses mathematical concepts and analyses that may be carried out in the human mind. The steps therefore encompass abstract ideas.
The judicial exceptions are not integrated into a practical application because the claims do not involve: improvements to the functioning of a computer or to any other technology or technical field; applying or using the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition; applying the judicial exception with, or by use of, a particular machine; or effecting a transformation or reduction of a particular article to a different state or thing. The claimed limitations add insignificant extra-solution activity to the judicial exceptions. While claim 3 recites “administering to the subject a therapeutic compound to treat glioma”, the treatment is a not a particular treatment and is recited at a high level of generality and broadly encompasses any and all treatments. The step amounts to directions “to apply” the judicial exception by directing the performer to do what a doctor would normally do. The claimed “administering” step is not required by all embodiments of the claims. For example, the “administering” step is “responsive to a diagnosis of glioma”. There is no requirement that in the context of prognosing the glioma that the “administering” step is performed.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims encompass the use of commercially available arrays that are well-known and used in a conventional manner as described in p. 10, 13, 15 and 26 of the instant specification.
Response to the traversal of the 101 rejections
The Remarks summarize the rejection under section 101 (p. 6-7).
The Examiner’s position is detailed above in this Office action.
The Remarks argue Applicant has amended claim 3 to include a preamble reciting "[a] method of treating a glioma in a subject" and step (5) which recites "administering to the subject a therapeutic compound to treat glioma". The Remarks argue amended claim 3 is integrated into a practical application, specifically effecting a particular treatment for a disease. See p. 7.
The arguments have been fully considered and are not persuasive. The treatment is a not a particular treatment and is recited at a high level of generality and broadly encompasses any and all treatments. The step amounts to directions “to apply” the judicial exception by directing the performer to do what a doctor would normally do. The claimed step of “administering” is analogous to a step of "administering a suitable medication to a patient”, which is not particular, and is instead merely instructions to "apply" the exception in a generic way. See MPEP 2106.04(d)(2). Thus, the claimed administration step does not integrate the mental analysis step into a practical application.
Secondly, the step of “administering” is not required in all embodiments of the method. The step is limited to embodiments in which glioma is diagnosed.
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 3 and 4 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.
Regarding claim 3, the claim has been amended to recite “administering to the subject a therapeutic compound to treat glioma”. The instant specification does not recite the phrase “therapeutic compound” or “administering”, and thus does not provide verbatim support for these terms.
The instant specification states the following about “treatments”, “treating” and “therapies”.
On p. 14:
The standard therapies for high-grade glioma, which include surgery, temozolomide (TMZ) chemotherapy, and radiation, have led to relatively modest improvements in survival. See, Stupp R et al. N Engl J Med. 352:987-96 (2005). Previously, three key molecular features of glioma were demonstrated, telomerase (TERT) promoter mutation, IDH mutation, and 1p/19q codeletion, as sufficient to create an integrated molecular classification that defines five principal groups of glioma with characteristic distributions of age at diagnosis, clinical behavior, acquired genetic alterations, and associated germline variants. See, Eckel-Passow JE et al. N Engl J Med. 372:2499-508 (2015). Among these groups, IDH mutant only and TERT mutant only tumors are the most common and comprise about 75% of adult glioma patients. See, Eckel-Passow JE et al. N Engl J Med. 372:2499-508 (2015).
Here the specification is only providing background information about glioma and treatment.
On p. 14:
Furthermore, immune interventions represent a potentially powerful new therapeutic approach in glioma. See, Binder DC et al. Oncoimmunology. 11;5(2) (2015) 1082027 (2016) and Lin Y et al. Expert Opin Biol Ther 10:1265-1275(2016).
Here the specification is describing other approaches used to treat glioma.
On p. 26:
Clinical information was collected on patient treatments including temozolomide (TMZ) chemotherapy, radiation therapy, extent of surgery, and steroid use at the time of blood sampling.
Here the specification describes patients having glioma and already undergoing treatment.
On p. 29:
Patients were selected as /DH mutated only, as TERT promoter mutated only, or as grade II/I1I and IV patients with similar age and treatment status.
Here the specification is describing glioma patients already undergoing treatment.
On p. 31:
Cox model including chemotherapy and steroid use indicates that mdNLR is associated with survival time, independent of therapy; HR 1.84, 95% CI, 1.00-3.38, P =0.049 (Fig 4C).
Here the specification is describing analyzing the survival time of patients already receiving treatment.
On p. 32:
All covariates modeled met proportionality assumptions
mdNLR methylation-derived NLR (neutrophil to lymphocyte ratio)
HR = hazard ratio; Cl = confidence interval; Chemo = last given chemotherapy within 90 days before blood draw; Dex = taking dexamethasone at the time of the blood draw.
Here the specification describes survival models in patients that were being treated with chemotherapy for glioma.
On p. 37:
Currently, there is intense interest in multiscale assessment of immune function in cancer patients receiving traditional treatments and new immunotherapies, See Blank CU et al. Science 352:658-60 (2016).
Here again, the specification is describing assessing glioma patients already receiving treatment.
The instant specification on p. 1, describes the technical field of the application as “Methods, compositions and devices are provided for measuring amounts of types of leukocytes and associated epigenetic methylation status in biological samples” and is silent regarding methods of treating glioma patients.
The instant specification on p. 2-3, describes the invention as follows:
The invention in general provides methods of selecting a CpG site nucleotide
sequence to use as a probe, or a family of probes having plurality of such sequences, that are useful to determine percent composition of various leukocyte subtypes in a biological sample, for example, blood, lymph, serum, plasma, or in a tissue exudate or extract, by analyzing extent of methylation at that site. The invention further provides uses of these sequences to determine by extent of methylation, the proportions of leukocyte subtypes, for example, a neutrophil to lymphocyte ratio (NLR), that can be associated with one or more pathological conditions such as a cancer or inflammation. The probes derived from the sequences are used in devices for such analyses.
and
An aspect of the invention herein provides a method of using an array to determine proportions in a biological sample of a subject of leukocyte subtypes to prognose and/or diagnose a disease state in the subject…
The instant specification does not adequately describe identifying a patient as having glioma based on a methylation analysis and subsequently treating the patient based on this analysis.
Claim 4 depends from claim 3 and is rejected for the same reason.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Houseman (BMC Bioinformatics. 2012. 13(86):16 pages) in view of Mur (J Neurooncol. 2015. 122:441-450) and Gustafson (Neuro-Oncology. 2010. 12(7):631-644).
The following are new rejections necessitated by the amendments to the claims.
Regarding claim 3, Houseman teaches determining the methylation status of CpG sites using the Infinium HumanMethylation27 Beadchip Microarray (p. 4, Validation data), which involves analyzing the extent of hybridization of patient sample DNA using oligonucleotide probes.
Houseman teaches determining the proportion of leukocyte types by comparing the analyzed CpG to a reference library S0 representing normal patients (p. 7, Head and neck cancer; and p. 10, Discussion).
Houseman teaches displaying the methylation status of the plurality of hybridized genes in the sample as depicted in Figure 2.
House suggests using the above approach for prognosis of response to therapy (p. 14, right column), rendering the fourth recited step obvious.
The step of “administering” is not required in embodiments in which a “prognosis” is performed.
While Houseman teaches the above methods, Houseman does not specifically teach probes with nucleotide sequences selected from SEQ ID NOs: 1-100 or the analysis of glioma
However, Mur teaches the use of the Infinium 450K microarray platform, to analyze methylation in the context of glioma samples (Abstract).
It is noted that the instant specification discloses the use of the 450K array as having probes with nucleotide sequences selected from SEQ ID NOs: 1-100 (p. 26, Example 2).
Gustafson demonstrates that it is known that the proportion of immune cells, such as T cells and monocytes, changes in the context of glioma. See entire document, in particular Fig. 1, 2 and 3.
It would have been prima facie obvious to the ordinary artisan at the time of filing to have modified the method of Houseman but incorporating the more comprehensive array of Mur for the analysis of methylation within DNA samples and within purified populations of leukocytes. One would have been motivated to use the 450K array, which includes probes having SEQ ID NOs: 1-100, because it includes more CpG sites, allowing for a more comprehensive analysis of the sample and improving the method of Houseman by identifying more accurate CpG biomarkers for the different populations of leukocytes and to use the modified method to track the relative populations of immune cells which is informative in the context of glioma as demonstrated by Gustafson.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Houseman (BMC Bioinformatics. 2012. 13(86):16 pages; previously cited) in view of Mur (J Neurooncol. 2015. 122:441-450) and Gustafson (Neuro-Oncology. 2010. 12(7):631-644)as applied to claim 3 above and in further view of Beach (WO 2013/022872 A1; previously cited).
Regarding claim 4, the combination of Houseman and Koestler renders obvious the method of claim 3.
The combination does not teach the elements of claim 4.
However, Beach demonstrates that calculating hazard ratios using methylation data in a multivariate analysis was known.
Thus, the analysis described in claim 4 is rendered obvious.
Conclusion
No claims allowed.
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 JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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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 at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH G. DAUNER/Primary Examiner, Art Unit 1682