Office Action 1: Non-Final Rejection (2024-07-22)
Rejection types: 112 - Written Description/Enablement

CLAIMS:
AMENDMENTS TO THE CLAIMSThe current listing of claims replaces all previous versions of the claims.

1\. (Cancelled)
2\. (currently amended) A method, comprising:
measuring a methylation level for four genes in a biological sample of a human individual through treating genomic DNA in the biological sample with a reagent that modifies DNA in a methylation-specific manner;
amplifying the treated genomic DNA using a specific set of primers for each of the selected genes; and
determining the methylation level of the four genes by a method selected from the group consisting of polymerase chain reaction, nucleic acid sequencing, mass spectrometry, methylation-specific nuclease, mass-based separation, and target capture;
wherein the four genes are FAM59B, OSR2, SPHK2, and ODC1.
3\. (previously presented) The method of claim 2, wherein the DNA is treated with a reagent that modifies DNA in a methylation-specific manner.
4\. (previously presented) The method of claim 3, wherein the reagent comprises one or more of a methylation-sensitive restriction enzyme, a methylation-dependent restriction enzyme, and a bisulfite reagent.
5\. (previously presented) The method of claim 4, wherein the DNA is treated with a bisulfite reagent to produce bisulfite-treated DNA.

6\. (previously presented) The method of claim 2, wherein the measuring comprises multiplex amplification.
7\. (previously presented) The method of claim 2, wherein measuring the amount of at least one methylated marker gene comprises using one or more methods selected from the group consisting of methylation-specific PCR, quantitative methylation-specific PCR, methylation-specific DNA restriction enzyme analysis, quantitative bisulfite pyrosequencing, flap endonuclease assay, PCR-flap assay, and bisulfite genomic sequencing PCR.
8\. (previously presented) The method of The method of
wherein amplifying the treated genomic DNA using a specific set of primers for FAM59B is a set of primers that specifically binds at least a portion of a genetic region comprising chromosome 2 coordinates 26407713-26407972 or chromosome 2 coordinates 26407703-26407976,
wherein amplifying the treated genomic DNA using a specific set of primers for OSR2 is a set of primers that specifically binds at least a portion of a genetic region comprising chromosome 8 coordinates 99952233-99952366, chromosome 8 coordinates 99952801-99952919, or chromosome 8 coordinates 99960580-99960630,
wherein amplifying the treated genomic DNA using a specific set of primers for SPHK2 is a set of primers that specifically binds at least a portion of a genetic region comprising chromosome 19 coordinates 49127580-49127683, chromosome 19 coordinates 49127571-49127685,
wherein amplifying the treated genomic DNA using a specific set of primers for ODC 1 is a set of primers that specifically binds at least a portion of a genetic region comprising chromosome 2 coordinates 10589075-10589243 or chromosome 2 coordinates 10589075-10589225.

9\. (previously presented) The method of claim 2, wherein the specific set of primers for each of the four genes is selected from the group consisting of:
for FAM59B a set of primers consisting of SEQ ID NOS: 299 and 300 or SEQ ID NOS: 427 and 428,
for ODC1 a set of primers consisting of SEQ ID NOS: 181 and 182, SEQ ID NOS:
183 and 184, SEQ ID NOS: 185 and 186, SEQ ID NOS: 341 and 342, or SEQ ID NOS: 443 and 444,for OSR2 a set of primers consisting of SEQ ID NOS: 187 and 188, SEQ ID NOS:
343 and 344, or SEQ ID NOS: 445 and 446, andfor SPHK2 a set of primers consisting of SEQ ID NOS: 225 and 226, SEQ ID NOS:
355 and 356, SEQ ID NOS: 337 and 338, or SEQ ID NOS: 433 and 434.

10\. (previously presented) The method of claim 2, wherein the sample comprises tissue.

11\. (previously presented) The method of claim 10, wherein the tissue is breast tissue.

12\. (previously presented) The method of claim 2, wherein the sample is blood, serum, or plasma.

OFFICE ACTION:
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 June 6, 2022.  Currently, claims 2-12 are pending.
Priority
This application claims priority to
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Requirement for Information under 37 CFR 1.105
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
Significantly, an applicant's duty of disclosure of material and information is not satisfied by presenting a patent examiner with a mountain of largely irrelevant [material] from which he is presumed to have been able, with his expertise and with adequate time, to have found the critical [material]. It ignores the real world conditions under which examiners work. Rohm & Haas Co. v. Crystal Chemical Co., 722 F.2d 1556, 1573 [ 220 USPQ 289 ] (Fed. Cir. 1983), cert, denied, 469 U.S. 851 (1984). (Emphasis in original).
Patent applicant has duty not just to disclose pertinent prior art references but to make the disclosure in such way as not to bury it within other disclosures of less relevant prior art; See Golden Valley Microwave Foods Inc. v. Weaver Popcorn Co. Inc., 24 USPQ2d 1801 (N.D.I. 1992); Molins PLC v. Textron Inc., 26 USPQ2d 1889, at 1899 (D.Del. 1992); Penn Yan Boats, Inc. v. Sea Lark Boats, Inc. et al., 175 USPQ 260, at 272 (S.D. FI. 1972).
In total, the IDS filed prior to the writing of this first action on the merits contains 310+ references on 28 pages of IDS. The extraordinary number of references places a serious burden on the office. The examiner finds that not each one of the greater than 310 references listed on the IDS are relevant to the instantly claimed invention which requires only measuring the methylation level of CpG sites in FAM59B, OSR2, SPHK2, ODC1.
For example, NPL reference 57 of the IDS, “Detection of occult upper gastrointestinal tract bleeding:performance differences in fecal occult blood tests”,
NPL reference 89 of the IDS, Revision of consensus sequence of human Alu repeats: a review (1987)”,
NPL reference 100 of the IDS, “Stool DNA screening for colorectal cancer: opportunities to improve value with the next generation tests (2011)”.
Therefore, the burden is shifted to the applicants and they are specifically required to point out the references cited which are most relevant to instant claims. While art has been applied in this first action on the merits, the IDS filed March 18, 2021 and December 1, 2023 has an enormous number of references, and so this requirement for information is set forth.
The following information is required:
Which references disclose methods of detecting methylation of FAM59B, OSR2, SPHK2 and/or ODC1?
Which references teach that methylation of FAM59B, OSR2, SPHK2 and/or ODC1 is found in breast cancer or breast disorders?
The fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to this requirement. This waiver extends only to those documents within the scope of this requirement under 37 CFR 1.105 that are included in the applicant’s first complete communication responding to this requirement. Any supplemental replies subsequent to the first communication responding to this requirement and any information disclosures beyond the scope of this requirement under 37 CFR 1.105 are subject to the fee and certification requirements of 37 CFR 1.97.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
New Matter
Claims 2-12 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
In the claims, reference to “OSR2” is included. However, the specification does not describe or discuss “OSR2”.  Instead, the specification describes
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(pg. 28).
This description does not support OSR2.  The concept of “OSR2” does not appear to be part of the originally filed invention.  Therefore, “OSR2” constitutes new matter.
Applicant is required to cancel the new matter in the reply to this Office Action.
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.
Claims 2-12 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 pre-AIA  the applicant regards as the invention.
A)  The term OSR2 in claim 1 is indefinite.  It is unclear what the OSR2 gene encompasses.  The specification teaches three different positions for different OSR2 genes.  It is unclear the metes and bounds of OSR2.
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B) Claim 8 is indefinite over the recitation of particular coordinates to using primers specific for particular coordinates.  The coordinates are specifically recited in Table 2, page 64-74 and Table 5, pages 85-87 of the specification.  The specification then states Table 3 provides primers for the DMRs.
The DMR start-end positions are entirely without context.  Neither the claims nor the specification provides any context for the positions such that it would be clear which positions are required for primer binding.  Turning to the art, the art teaches different regions for the FAM59B gene, for example. The claims are directed to 26407713-26407972 which is not coextensive within the genomic coordinates (GRCh38) provided in the art for FAM59B.  GeneCards provides the latest assembly and prior assemblies.
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It is entirely unclear whether the primers specifically bind to a genetic region outside the gene, which numbering system is used to determine where the primers may bind.  The region within each of the three assemblies is very different.
The ordinary artisan would be unclear where the set of primers was required to bind and the structure of the primers was required to have to meet the limitations of the newly amended claims.  Clarification is required.
Additionally, the claim language is unclear.  It is unclear whether the set of primers binds within the claimed coordinate or whether the set of primers may bind to a larger genetic region that comprises the coordinates.  It is unclear whether both primers, i.e. the set of primers, must specifically bind within the 250bp region of FAM59B provided or whether the primers may bind to the gene which comprises the 250 bp region.
Claim Rejections - 35 USC § 112-
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA  35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.  Claim 3 requires the DNA is treated with a reagent that modifies DNA in a methylation-specific manner.  Claim 2 already requires this treatment.  Claim 3 does not limit the scope. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
No claims allowable.


NEXT OFFICE 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 .
Response to Request for Information
The response filed December 19, 2024 provides the following response to the request for information.
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The examiner has reviewed the references deemed relevant by Applicant.
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance:
The claims are directed to specifically amplifying DNA treat to modify the DNA in a methylation -specific manner using primers specific for four or more genes, namely SPHK2, ODC1, FAM59B and an OSR2, as recited in the claims to determine the methylation level using PCR, sequencing, mass spectrometry, methylation-specific nuclease, mass-based separation and/or target capture.
The claims require using primers that are specifically directed to each of the recited four genes and thus do not read on simple array-based method using a commercially available array without first specific amplifying for the four genes.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion