Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 23-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 of claims 1-22 was made without traverse in the reply filed on 13 January 2026.
Specification
The use of the following terms, which are trade names or marks used in commerce, have been noted in this application:
Zoladex, Prostap, Vantas, Decapeptyl, Firmagon, Drogenil, Casodex (page 21)
WiMax and Bluetooth (page 27, 28)
Sarstedt Micro, QIAamp Circulating Nucleic Acid Kit, Qubit dsDNA HS assay, TapeStation HS D5000, microTUBE-50 AFA Fiber Screw-Cap, NEBNext Enzymatic Methyl-seq kit, Stop Reagent, NEBNext Q5U Master Mix, NovaSeq 6000 sequencer, Trim Galore, and deepTools (35-37)
The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™ or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b) and (d):
(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.
(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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second and fourth paragraph:
(2nd) 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.
(4th) Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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 14 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 14, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 21 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 15, from which claim 21 depends, recites the steps for calculating the TFAScore. Claim 21 merely states that it is “indicative of genome-wide activity of transcription factors…”, which constitutes an intended result or characterization of the score, rather than an additional limitation adding structure to how the score is calculated or used. Therefore, as the recited characterization of the score does not modify, narrow, or further define the method steps of the parent claim, claim 21 does not further restrict the claim from which it depends.
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.
Claim Rejections - 35 USC § 103
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.
Claims 1-22 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (US 20220380853 A1), as evidenced by Vaisvila (Vaisvila R, et al. Genome research. 2021 Jul 1; 31(7):1280-9), in view of Zhao (Zhao SG, et al. Nature genetics. 2020 Aug; 52(8):778-89).
Wu teaches a method for detecting, screening, monitoring, staging, classifying, selecting treatment for, ascertaining whether treatment is working in, and/or prognostication of prostate cancer [Wu; abstract] through the isolation and analysis of cfDNA from a blood, plasma, or urine sample [Wu; 0084, 0094, 0175] from a human subject diagnosed with metastatic castration-resistant prostate cancer (mCRPC) [Wu; 0016, 0624].
Wu teaches the use of methylation aware sequencing methods, in which enzymatic methylation sequencing is offered as an example [Wu, 0177]. This sequencing method, exemplified by the NEBNext® Enzymatic Methyl-seq Kit according to Wu, includes steps of enzymatically treating a DNA molecule to convert methylated cytosine sites into a form protected from deamination and converting unprotected cytosine residues to uracil via deamination [Wu, 0180]. The NEBNext® Kit was first described in an article by Vaisvila, which details the conversion of 5-methyl cytosine and 5-hydroxymethyl cytosine to a protected form via the use of TET2 and T4-BGT (analogous to the first agent of the instant application) followed by deamination via APOBEC3A (analogous to the second agent of the instant application) [Vaisvila; abstract].
Sequencing reads are aligned to a reference genome, allowing for the assignment of genetic location [Wu; 0186]. According to Wu, the reference genome can originate from either a healthy subject or a subject having a cancer or specific cancer subtype [Wu; 0099].
For each genetic location, a methylation ratio can be calculated for the questioned sample and the reference sample (individually) by determining the proportion of all sequence reads which show methylation for that location [Wu; 0095]. The methylation ratios of the questioned and reference samples can then be compared to determine the “methylation score” for each genomic location [Wu; 0124]. Similarly, a methylation score can be calculated for the profile as a whole by taking the average of the calculated methylation ratios for each genetic location (which can be considered equivalent to the TFAScore of the instant application) [Wu; 0017].
Therefore, by determining the methylation score at 10 or more genomic regions of the isolated cfDNA, Wu is able to determine the methylation profile (aka methylome) of the subject [Wu; 0017]. This methylome can correspond to the full or partial genome of the subject [Wu; 0080], and can be used to determine the prostate cancer subtype of the subject [Wu; 0017]. Once this has been determined, the subject can then be treated via the administration of an effective amount of a therapeutic agent, such as a hormonal, targeted, biologic, immunotherapy, chemotherapy, or radionuclide agent [Wu; 0478, 0494].
The methylation score of Wu can also be used as a more specific method of determining the prostate cancer fraction in a sample, through the comparison of methylation in cancer vs. non-cancer samples [Wu; 0155].
Wu does not teach localizing the examination of differential methylation to transcription factor binding sites, nor that neuroendocrine prostate cancers (NEPCs) are the subtype of cancer being assessed by their methodology. NEPCs are defined by the instant specification [p16] as those having lost androgen receptors and gained stem-like and neuroendocrine features.
Zhao applied whole-genome, whole-methylome, whole-transcriptome sequencing in the analysis of metastatic castration-resistant prostate cancer, the lethal form of prostate cancer, to gain a better understanding of the regulatory role of methylation (Zhao; p778). Through this analysis, Zhao found that many recurrent hypomethylated regions (HMR sites) overlapped with regulatory regions of the genome, such as transcription factor binding sites (TFBSs) (Zhao; p779). By performing unsupervised hierarchical clustering of the recurrent HMR sites, Zhao was able to identify distinct methylation patterns for different prostate cancer subtypes, including those previously identified as being characterized by decreased androgen receptor signaling and elevated expression of neuroendocrine markers (Zhao; p779).
Therefore, one of ordinary skill in the art prior to the effective filing date of the claimed invention seeking to improve Wu’s method, in which characterization of prostate cancer subtype is used to inform treatment decisions, would have been motivated to incorporate the TFBS targeting of Zhao as Zhao teaches that differential methylation of TFBSs plays an important regulatory role in cancer progression and provides an informative way to distinguish between different prostate cancer subtypes.
Applying a known technique to a known device (method or product) ready for improvement to yield predictable results is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681