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 applicants correspondence mailed 12/12/2025. The amendment to the claims mailed 12/12/2025 has been entered.
Election/Restrictions
Applicant’s election of group I, claims 1-2, 18-20, 22, and 51-59 and species SEQ ID NO 1 and DNA methylation profiling in the reply filed on 12/12/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 2 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/12/2025.
Claims 1, 18-20, 22, and 51-59 are under examination with respect to SEQ ID NO 1.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). There are two sequences on page 239 that do not have sequence identifiers.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 18-20, 52-54 and 58-59 are objected to because the claim contains more than one period (see 609.01(m)). Periods may not be used elsewhere in the claims except for abbreviations. For example, a. b. i. ii. Iii. Iv. contains a period and the end of the claim contains a period. This objection may be overcome by amending i. to read i) (see MPEP 608.01(m)).
Improper Markush Rejection
Claim 1 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of SEQ ID NO 1-29,000 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The recited alternative species in the groups set forth here do not share a single structural similarity, as each different CpG that could be detected is itself located in a separate region of the genome and has its own structure, as evidenced by the distinct SEQ ID NO:s. The CpGs recited in the instant claims, do not share a single structural similarity since each consists of a different nucleotide sequences with different methylation patterns. The only structural similarity present is that all detected positions are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with cancer. Accordingly, while the different markers are asserted to have the property of being correlated with cancer, they do not share a single structural similarity.
MPEP 2117 (II)(A) provides the following guidance as to what constitutes a physical, chemical, or art recognized class:
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”
The recited genes do not belong to a recognized chemical class because there is no expectation from the knowledge in the art that the CpGs will behave in the same manner and can be substituted for one another with the same intended result achieved. In other words, there is no expectation from the knowledge in the art that each of the recited CpGs and SEQ ID NOs would function in the same way in the claimed method; it is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention. Further there is no evidence of record to establish that it is clear from their very nature that each of the recited genes possess the common property of being associated with cancer.
MPEP 2117 (II) further states the following:
Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the compounds do not appear to be members of a recognized physical or chemical class or members of an art-recognized class, the members are considered to share a "single structural similarity" and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The recited alternative species do not share a substantial common structure just because they all have a sugar phosphate backbone. The sugar phosphate backbone of a nucleic acid chain is not considered to be a substantial common structural feature to the group of genes being claimed because it is shared by ALL nucleic acids. Further, the fact that the genes all have a sugar phosphate backbone does not support a conclusion that they have a common single structural similarity because the structure of comprising a sugar phosphate backbone alone is not essential to the asserted common use of being associated with cancer.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 22, 51-55 rejected under 35 U.S.C. 101 because the claimed invention is directed to law of nature and abstract idea without significantly more.
The claims recite an abstract idea and a law of nature.
Claim 22 is directed to “a method …the individual determined to have cancer by the step of performing the method of claim 1”.
Claim 51 recites further comprising a step of stratifying the individual according to their cancer risk or of having cancer. Claims 52-54 further recite individual is stratified as having cancer, high risk of cancer, no cancer, low risk of cancer or moderate risk of cancer.
Claims 22 and 51-55 are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “wherein the individual is stratified as having…cancer..cancer risk” “determined to have cancer”) and a law of nature/natural phenomenon (i.e. the natural correlation between the methylation and cancer or cancer risk).
This judicial exception is not integrated into a practical application because there are no additional steps that recite a practical application. Claim 51 does not recite any additional steps other than the exception itself. Claim 52 recites a test for BRCA1 or BRCA2 or a repeat method of assaying methylation. Claims 53-55 include one or more treatments and includes only repeating the method of assaying methylation. 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 assaying for methylation status, 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.
Claim 22 is directed to treating or preventing cancer by administering one or more treatments to the individual. While the claim recites administering one or more treatments to 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. The claim does not require the treatment is related to cancer, but could instead be a treatment for sleep deprivation or diabetes. Even more the limitation is recited at such a high level of generality, making the limitation’s inclusion in the claim at best nominal. The administering one or more treatments to 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.
The claim(s) do not include additional elements that are sufficient to amount to significantly more than the judicial exception because 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 assaying for mutation status is 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 status without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The assaying step essentially tells users to determine the methylation through whatever known processes they wish to use.
The step of assaying methylation 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 specification teaches commercially available biochips were used for assaying methylation (see pg. 199). The specification teaches SEQ ID NO 1-29,000 are probes on commercially available array (See pg. 27). 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 status. 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 any method available to people skilled in the art for genome wide bisulfite sequences such as Illumina 450K and Epic microarrays may be used (see pg. 199).
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.
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 22, 51-55, and 57 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 22 recites the limitation "the individual determined to have cancer" in line 2-3 of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 22 does not recite or require determining an individual that has cancer. Claim 22 recites the individual determined to have cancer by the step of performing the method of claim 1. Claim 1 does not identify or determine a subject having cancer. Claim 1 only encompasses assaying methylation status from a sample from an individual. Claim 1 does not recite or require identifying a subject with cancer nor does claim 1 indicate the subject has cancer. It is unclear who is being treating in claim 22.
Regarding claims 19, 52-53, 54 and 59 the recitation of "preferably" and “more preferably” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 51 recites “a step of stratifying the individual according to their cancer risk or of having cancer”. Claim 51 depends from claim 22 and neither claim 22 or 51 requires an individual with a cancer risk or having cancer. It is unclear how a step of stratifying the individual occurs when none of the individuals are identified as having cancer or cancer risk. Claim 54 is also indefinite for these reasons. Claim 54 recite a method according to claim 51, wherein the individual is stratified as having cancer or as having a high risk of cancer development however neither claim 51 or 54 identify or stratify an individual with cancer or high risk cancer.
Claim 53 is an incomplete claim. Claim 53 recites anyone of claims 1 to 20 and claims 3-17 have been canceled. Therefore because claim 53 depends from canceled claims, it is incomplete and the metes and bounds are indefinite.
Claim 57 is an incomplete claim. Claim 57 recites wherein one or more treatments are administered to the individual according to claim 10. Claim 10 is a canceled claim. Therefore because claim 57 depends from canceled claim, it is incomplete and the metes and bounds are indefinite.
Claim Rejections - 35 USC § 112 (a) - Enablement
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 22, 51-55 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Scope of the Claims/Nature of the Invention
The claims are drawn to a method of treating or preventing a cancer in an individual by administering one or more treatments to the individual determined to have cancer by assaying methylation status of one CpG identified at nucleotide position 61-62 of SEQ ID NO 1. Dependent claims encompass a step of stratifying an individual according to their cancer risk or of having cancer. Additional claims limit the treatment according to stratification including intensified screening including BRCA1 and BRCA2 germline mutation, CA125 test, cell free tumor DNA methylation, MRI scan, administration of selective estrogen receptor modulators, bilateral mastectomy or salpingo-oophorectomy.
The nature of the invention requires a reliable correlation between the methylation status of CpG site at position 61-62 in SEQ ID NOs: 1 and the presence of any cancer, including breast cancer, lung cancer, colon cancer, pancreatic cancer, uterine (endometrial) cancer, cervical cancer, ovarian cancer and prostate cancer and the correlation with treating or preventing any cancer.
Teachings in the Specification and Examples
The specification asserts a DNA methylation profile to detect the presence or absence of cancer, particularly breast and ovarian cancer. The specification asserts assays involving cancer index values from DNA methylation profiles from samples comprising epithelial cells from an individual. The specification discloses teaching a cancer index for patients without cancer and patients known to possess breast cancer (see pg. 4, lines 18-24). The specification does not teach a cancer index in any other cancer.
The specification discloses the sample may be derived from cervix, vagina, buccal area, blood or urine with a preferred cervical liquid based cytology sample (see pg. 3, lines 15-22).
The specification discloses that the cancer index value is typically increased in individuals with BRCA1 or BRCA2 germline mutations and may be used for individuals cancer status, risk of cancer development and monitor the efficacy of cancer treatment being administered, including therapeutic treatments and preventative treatments (see pg. 5, lines 10-16). While the specification provides cancer index scores, the claim require assaying methylation at position 61-62 of SEQ ID NO 1, the specification does not provide a reliable assay to determine cancer index score of only SEQ ID NO 1 and correlation with a representative number of cancers.
The specification asserts determining a panel of one or more CpGs that comprises nucleotide position 61 to 62 of SEQ ID NO 1-29,000 and an AUC for the assay of at least .84 (see pg. 10, lines 16-20). The specification teaches the algorithm to determined breast cancer index value (see pg. 11). However the specification provides no analysis of only one CpG at position 61 to 62 of SEQ ID NO 1, as elected. The specification does not a representative number of cancers determined by assaying position 61 to 62 of SEQ ID NO 1. Even with regard to assay methylation for the entire panel of SEQ ID NO1-29,000, the specification does not teach a correlation to a representative number of cancers, stratifying any risk in a representative number of cancer nor provide a predictable correlation with breast or cervical cancer.
The specification teaches figure 8-9 demonstrate the performance of the cancer index to ovarian cancer risk and figure 9 demonstrates correlation of cancer index with different samples. is a training of cancer index classifiers and predictive performance of the breast cancer index. The specification provides data for AUC of .85 or less and teaches AUC is dependent on the number of CpGs included in the index score. The analysis for determining cancer and thus treatment encompasses not only assaying methylation but includes stratification and occurs with respect to a training classifier of methylation data, which is not claimed.
The specification provides no methylation data for SEQ ID NO 1. The only data provided by the specification with respect to DNA methylation is a statement on pg. 246, lines 10-12, the DNA methylation data was deposited in the European Genome-phenome archive under accession number EGASXXXXXXXXXXX. Since this data is not available, there is no guidance for what methylation level is measured with respect to the claimed CpG sites of the CpG panel of SEQ ID NO 1-29,000. There is no guidance with respect to assaying CpG sites of methylation and correlation with respect to determining cancer in breast cancer let alone a representative number of cancers and samples.
The specification teaches a study design that includes women diagnosed with breast or ovarian cancer or non-malignant benign gynecological condition (controls) (pg. 235-239). The samples collected were cervical cells and breast tissue samples. DNA methylation analysis was performed using commercially available DNA methylation array, Illumina EPIC beadchip. The specification describes how the data was processed but does not provide the data (see pg. 241-246) or what methylation levels are for the claimed CpG site.
The specification teaches the diagnostic methylation signature, WID-BC-index, cancer index was derived from ridge and lasso regression to classify individuals as case or controls. The specification teaches that each CpG site was divided into epithelia, immune or shared (see pg. 248). The specification provides tables with cancer index scores, ranges, risk, AUC, and clinical action (See table 5, 7, and 8). The specification does not disclose if these index score are determined by a panel of 100, 500, 1000, or 29,000 CpG or some other unstated panel of CpG sites. The specification does not teach a single index score or methylation of the elected CpG of SEQ ID NO 1. The specification does not teach determining cancer or stratifying risk of cancer by assaying CpG at position 61 to 62 of SEQ ID NO 1.
The specification provides no therapy or prevention for breast cancer or any other cancer. While known therapies for treating breast cancer are available, there are no known preventions for breast cancer or any other cancer.
State of the Art and the Unpredictability of the Art
While methods of measuring the methylation status of CpG sites in a DNA methylation are known in the art, correlating the methylation status of CpG sites with the presence of cancer, stratifying risk and treating or preventing cancer based on the methylation status are highly unpredictable. The unpredictability will be discussed below.
The claims are drawn to a method of treating or preventing cancer by administering one or more treatments to the individual determined to have cancer by assaying the individual methylation status of position 61 to 62 of SEQ I DNO 1. The claims require identifying an individual as having cancer by assaying position 61 to 62 of SEQ ID NO 1. The claims further require an individual has no cancer, low or high risk and performing one or more treatments. The specification provides no analysis of the methylation status of position 61 to 62 of SEQ ID NO 1. The specification provides no analysis of preventing cancer or stratifying individuals into no risk, low or high risk by analysis of position 61 to 62 of SEQ ID NO 1. While the specification provides analysis of an index score this index score is not with respect to the elected position and is not predictive of determining any cancer, including breast cancer. It is highly unpredictable if one looked at only one CpG sites of SEQ ID NO 1 if they would be able to detect the large genus of cancer encompassed by the claims.
The specification provides no therapy or prevention for breast cancer or any other cancer. While known therapies for treating breast cancer are available, there are no known preventions for breast cancer or any other cancer. The American Cancer Society (www.asc.org, printed 3/19/2026, pp 1-7) states there is no sure way to prevent cancer but you can reduce your risk (pg. 1). Additionally Barrett (Communications Medicine, 2025, 5:97, pp 1-10) teaches that surgical intervention such as double mastectomy is still the only effective cancer-risk reduction strategy for women at the highest risk (see pg. 2, 1st column).
The prior art and post filing art teach to the unpredictability of correlating methylation with cancer and using AUC as a predictive measure. Here the specification only teaches cancer index with respect to AUC values, which is unpredictable. The specification does not provide any analysis of assaying only one elected CpG with cancer.
Sugden (Patterns 1, 2020, vol 10014, pp 1-12) teaches DNA methylation analysis using Illumina BeadChips (same array as presented in specification). Sugden teaches data points from BeadChips do not yield the equivalent value when quantified twice from the same DNA sample (see column 1, pg. 2). Sugden teaches determining reliability using methylation values and reliability of CpG probes is low and highly variable (see pg. 2 cont’d to pg. 3). Sugden teaches given a significant proportion of probes are unreliable the ability to detect associations between DNA methylation levels and genetic influences will be compromised (See pg. 4, 2nd column).
Van Leeuwen (Statistics in Medicine, 2025, 44:e70011) teaches the instability of AUROC for clinical prediction models. Van Leeuwen teaches there is great irreducible uncertainty in predicting the AUC in a new setting. Van Leeuwen teaches that differences in heterogeneity of the sample and model misclassification (see pg. 7). Van Leeuwen demonstrates the unpredictability of using AUC for predicting or determining cancer in a subject alone.
Additionally it is highly unpredictable if the results obtained using cervical samples could be extrapolated to ANY biological sample type comprising DNA (serum, plasma, synovial fluid, urine, cerebral spinal fluid, etc.). The specification only presents data on the analysis of cervical and blood samples. In the absence of evidence to the contrary, it is highly unpredictable if the CpG site at position 61 to 62 of SEQ ID NO 1 will differentially methylated in other types of DNA samples obtained from cancer subjects in comparison to healthy subjects. While the specification provides data for cervical and blood samples using an undefined panel of methylation sites with an index score, it is unpredictable to determine if the cervical samples are correlated to breast cancer, cervical cancer or other gynecological cancers.
Applicants own work, Barrett (Nature Communication, 2022, 13:449, pp1-14) identifying woman with ovarian cancer and woman with high risk of developing both breast and ovarian cancer using a cancer index score from cervical samples (see pg. 10, 1st column). Barrett further teach that the cancer index is not a marker for disease but rather a surrogate marker associated with development or presence of breast cancer with poor prognostic features. Barrett further assert that further studies will be required to confirm whether the index can be used as a biomarker of breast cancer risk and disease effects cannot entirely be ruled out. Side by side comparison assessing various predictors of risk using the sample population will be required in the future (See pg. 10, 2nd column). Therefore, it would be unpredictable to determine cancer or risk of cancer by assaying only CpG at position 61-62 of SEQ ID NO 1. Even if the association of the methylation is correlative to identifying cancer, it would be unpredictable using cervical sample, if the cancer risk would be for breast or ovarian cancer, both of which would have different treatment methods.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to determine the presence of cancer by assaying the methylation status of CpG site position 61-62 of SEQ ID NO 1.
In order to practice the claimed invention one of skill in the art would first have to identify differentially methylated position 61-62 of SEQ ID NO 1 between subjects with any cancer types, as recited in the claims and healthy subjects. Even within breast and ovarian cancer, one of skill in the art would have to be able to determine risk of one or the other cancer, experimentation would require testing in a large genus of different cancers having different etiologies. Then additional experimentation would need to be conducted to determine if position 61-62 position of SEQ ID NO 1 is differentiated the cancer patients from the non-cancer patients or if combinations of two, three, four, etc. CpG sites are needed. Finally experimentation should include the analysis of different types of biological samples. The specification has merely provided an invitation for further experimentation.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue.
Conclusion:
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the guidance presented in the specification and the working examples, the skill of those in the art and the unpredictability of the art, and the quantity of experimentation necessary, it is the conclusion that an undue amount of experimentation would be required to make and use the invention.
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.
Claims 1, 18-20, 56, 58 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zheng (Epigenomics, 2018, 10(7): 925-940, cited on IDS).
Zheng teaches a method of assaying methylation of a sample by 450k and EPIC methylation beadarray chips (see materials and methods). Zheng teaches analysis of 450k data in normal and cancer samples (see last para, pg. 927). Zheng teaches saliva samples and methylation analysis using Illumina EPIC data (see DNAm datasets used) (claim 18-20). The methylation analysis using Illumina EPIC data comprises assaying a sample for methylation at position 61-62 of SEQ ID NO 1 as this probe and location is on the EPIC beadarray. Zheng teaches the analysis includes isolating DNA, bisulfite treatment, sequencing and analysis using Methylation EPIC bead chip (claim 18-19). Zheng teaches assaying the sample for epithelia cells (see fig 1) (claim 20). Zheng teaches assaying the sample and performing the method at different time points (see generation of saliva DNAm dataset) (claim 56-57).
Claims 1, 18-20, and 59 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pisanic (Clin Cancer Res 2018, 24(24): 6536-6547)
Pisanic teaches obtaining tissue and gynecologic mucosae of endocervix (See free frozen gynecologic tissue sample) (cervical tissue) (claim 59). Pisanic teaches epithelia cells from normal mucosa were enriched. Pisanic teaches analysis of MethylationEPIC beadchip analysis. Pisanic teaches bisulfite treatment of DNA followed by MethylationEPIC array (methylation array, methylation profile) (claims 17-20).
Claims 1, 18-20, 22, 51-54, 56, 59 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Berlin (US20090005268 A1)
Berlin teaches a method of obtaining a biological sample and detecting methylation of one or more markers. Berlin teaches markers comprise SEQ ID NO 1127, which is instant SEQ ID NO 1 (see para 43 and 51). Berlin teaches converting genomic DNA to bisulfited DNA by PCR amplification (see para 51 and 121) (claim 18-19). Berlin teaches diagnosis of breast cancer (see para 55). Berlin teaches methylation comprises CpG methylation. Berlin teaches selecting treatment regimen for breast cancer (see para 59). Berlin teaches subject suspected of having cancer, having one or more risk factors. Berlin teaches detecting the presence or absence of chemotherapy resistant cancer by detecting a DNA methylation patter characteristic of a tumor that is resistant to SERMs (see para 73). Berlin teaches monitoring disease progression in a subject (See para 76). Berlin teaches monitoring or follow up which includes methylation of markers (See para 138, 148) (a first and second time) (claim 56). Berlin teaches analysis of breast tumor tissue (see para 218) (claim 59). Berlin teaches determining risk of developing metastatic disease by DNA methylation pattern of subject’s genomic DNA, which includes SEQ ID NO 1 (see para 75). Risk of developing metastatic disease encompasses moderate and high risk of cancer development and Berlin teaches administering SERM (claim 51, 53-54). Berlin further teaches determining chance of disease free survival and teaches monitoring disease (not having cancer or low risk and repeating method) (see para 75) (claim 51-52).
The claims are enabled to the extent of the specification and in order to provide compact prosecution, Berlin has been provided as it teaches the positive active steps of the claims.
Conclusion
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699