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 .
Response to Amendment
The amendment filed December 1st, 2025 is acknowledged. Regarding the Office Action mailed August 29th, 2025:
The objections to the specification are withdrawn in view of the amendments.
The rejections set forth under 35 U.S.C. 112(b) are withdrawn in view of the amendments.
The rejection set forth under 35 U.S.C. 112(a) is withdrawn in view of the amendments.
Maintained or modified rejections are set forth below. New grounds of rejection are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1-2, 5-7, 9 and 12 have been amended. Claims 3, 10, 13, 18, 20, 22-25, and 28 have been canceled. Claims 29-35 have been added. Claims 1-2, 4-9, 11-12,14-17, 19, 21, 26-27, and 29-35 are pending. Claims 14-17, 19, 21, and 26-27 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-2, 4-9, 11-12, and 29-35 are under examination and discussed in this Office action.
Claim Rejections - 35 USC § 112(d) – New – Necessitated by Amendment
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
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.
Claims 7 and 34 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form.
Claim 7 is rejected as being of improper dependent form for failing to include all the limitations of the claim upon which it depends. Claim 1, from which claim 7 depends, recites having a genomic location defined in Tables 1-4. However, the Tables recited in claim 7 both do not contain all the genomic locations in Tables 1-4, and also introduce new genomic locations not included in Tables 1-4. Therefore, claim 7 fails to include all the limitations of claim 1.
Claim 34 is rejected as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends. Claim 9, from which claim 34 depends, recites a number of subtypes of prostate cancer. However, claim 34 then appears to broaden these options by more generally referring to castration resistant prostate cancer and/or metastatic prostate cancer, neither of which are options in claim 9. Therefore, claim 34 fails to further limit claim 9.
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 § 101 – Modified – Necessitated by Amendment
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 1-2, 4-9, 11-12, and 29-35 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and abstract ideas without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claims recite the natural correlation between the methylome sequence of cfDNA and prostate cancer, as well as the mathematical concept of calculating a methylation score and the mental process of analyzing a methylation score. The correlation is a natural phenomenon because it describes a consequence of natural process in the human body. The mathematical concept of calculating of a methylation score is an abstract idea. Analyzing the methylation score to determine the presence of cfDNA derived from prostate cancer is an abstract idea because it could reasonably be considered a mental process.
The Examiner would like to note for the Applicant that while claim 1 does include a treatment step, it is not specific to just those subjects that have prostate cancer and instead includes all subjects that are tested, regardless of if they have prostate cancer or not. Therefore, the treatment does not represent a practical application of the judicial exceptions.
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe a natural phenomenon (the natural correlation between the methylome sequence of cfDNA and detecting aspects of prostate cancer), a mathematical concept (calculating a methylation score), and a mental process (analyzing the methylation score to determine the presence of cfDNA derived from prostate cancer).
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite a method of treating prostate cancer in a human subject comprising: obtaining a biological sample comprising cfDNA from the subject; characterizing the methylome sequence of a plurality of cfDNA molecules in the sample; determining the average methylation ratio at 10 or more genomic regions; each of the genomic regions covered by at least one sequence read of at least one cfDNA molecule; calculating a methylation score using the average methylation ratio for each of the genomic regions; analyzing the methylation score to determine the presence of cfDNA derived from prostate cancer; initiating treatment selected from a therapeutic agent, surgery, or radiotherapy; each of the genomic regions is covered by at least 10 sequence reads; calculating a methylation score using the average methylation ratio for each genomic region via one of three options; analyzing the methylation score comprises comparing the methylation score to one or more reference methylation scores; determining the average methylation ratio at 25 or more genomic regions; the genomic regions have a 100bp genomic location defined in any one of Table 5, Table 6 or Table 7; at least 25% of the genomic regions are prostate tissue specific genomic regions; options for the type of prostate cancer; options for the sample; repeating the method on a second sample obtained from the subject after the subject has undergone a treatment for prostate cancer, wherein the second sample comprises cfDNA, and comparing the level of prostate cancer fraction in the two samples; specific options for a therapeutic agent; specific options for surgery; specific options for radiotherapy; specific options for a reference methylation score; and a specific prostate cancer fraction of the cfDNA, the claims do not improve upon DNA sequencing or methylation detection techniques, techniques to determine acceptable sequencing reads, techniques to determine a median or a mean, comparison techniques between a reference and a data point of interest, etc. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite a method of treating prostate cancer in a human subject comprising: obtaining a biological sample comprising cfDNA from the subject; characterizing the methylome sequence of a plurality of cfDNA molecules in the sample; determining the average methylation ratio at 10 or more genomic regions; each of the genomic regions covered by at least one sequence read of at least one cfDNA molecule; calculating a methylation score using the average methylation ratio for each of the genomic regions; analyzing the methylation score to determine the presence of cfDNA derived from prostate cancer; initiating treatment selected from a therapeutic agent, surgery, or radiotherapy; each of the genomic regions is covered by at least 10 sequence reads; calculating a methylation score using the average methylation ratio for each genomic region via one of three options; analyzing the methylation score comprises comparing the methylation score to one or more reference methylation scores; determining the average methylation ratio at 25 or more genomic regions; the genomic regions have a 100bp genomic location defined in any one of Table 5, Table 6 or Table 7; at least 25% of the genomic regions are prostate tissue specific genomic regions; options for the type of prostate cancer; options for the sample; repeating the method on a second sample obtained from the subject after the subject has undergone a treatment for prostate cancer, wherein the second sample comprises cfDNA, and comparing the level of prostate cancer fraction in the two samples; specific options for a therapeutic agent; specific options for surgery; specific options for radiotherapy; specific options for a reference methylation score; and a specific prostate cancer fraction of the cfDNA, no such machine are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like an Illumina sequencer, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, sequencing cfDNA does not transform that cfDNA into something else during the sequencing process. Even if that sequencing process involves bisulfite conversion, this does not transform cfDNA into something else.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between the methylome sequence of cfDNA and detecting aspects of prostate cancer, calculating a methylation score, and analyzing the methylation score to determine the level of prostate cancer in the instant case have to do with a method of treating prostate cancer in a human subject comprising: obtaining a biological sample comprising cfDNA from the subject; characterizing the methylome sequence of a plurality of cfDNA molecules in the sample; determining the average methylation ratio at 10 or more genomic regions; each of the genomic regions covered by at least one sequence read of at least one cfDNA molecule; calculating a methylation score using the average methylation ratio for each of the genomic regions; analyzing the methylation score to determine the presence of cfDNA derived from prostate cancer; initiating treatment selected from a therapeutic agent, surgery, or radiotherapy; each of the genomic regions is covered by at least 10 sequence reads; calculating a methylation score using the average methylation ratio for each genomic region via one of three options; analyzing the methylation score comprises comparing the methylation score to one or more reference methylation scores; determining the average methylation ratio at 25 or more genomic regions; the genomic regions have a 100bp genomic location defined in any one of Table 5, Table 6 or Table 7; at least 25% of the genomic regions are prostate tissue specific genomic regions; options for the type of prostate cancer; options for the sample; repeating the method on a second sample obtained from the subject after the subject has undergone a treatment for prostate cancer, wherein the second sample comprises cfDNA, and comparing the level of prostate cancer fraction in the two samples; specific options for a therapeutic agent; specific options for surgery; specific options for radiotherapy; specific options for a reference methylation score; and a specific prostate cancer fraction of the cfDNA. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” However, as will be discussed below, these limitations do not arrive at an inventive concept. In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exceptions are the natural correlation between the methylome sequence of cfDNA and detecting aspects of prostate cancer, calculating a methylation score, and analyzing the methylation score to determine the level of prostate cancer. The additional elements recited in the claims (i.e. a method of treating prostate cancer in a human subject comprising: obtaining a biological sample comprising cfDNA from the subject; characterizing the methylome sequence of a plurality of cfDNA molecules in the sample; determining the average methylation ratio at 10 or more genomic regions; each of the genomic regions covered by at least one sequence read of at least one cfDNA molecule; calculating a methylation score using the average methylation ratio for each of the genomic regions; analyzing the methylation score to determine the presence of cfDNA derived from prostate cancer; initiating treatment selected from a therapeutic agent, surgery, or radiotherapy; each of the genomic regions is covered by at least 10 sequence reads; calculating a methylation score using the average methylation ratio for each genomic region via one of three options; analyzing the methylation score comprises comparing the methylation score to one or more reference methylation scores; determining the average methylation ratio at 25 or more genomic regions; the genomic regions have a 100bp genomic location defined in any one of Table 5, Table 6 or Table 7; at least 25% of the genomic regions are prostate tissue specific genomic regions; options for the type of prostate cancer; options for the sample; repeating the method on a second sample obtained from the subject after the subject has undergone a treatment for prostate cancer, wherein the second sample comprises cfDNA, and comparing the level of prostate cancer fraction in the two samples; specific options for a therapeutic agent; specific options for surgery; specific options for radiotherapy; specific options for a reference methylation score; and a specific prostate cancer fraction of the cfDNA) does amount to mere instructions to apply the correlation, since these limitations serve as mere conventional steps taken for the purpose of gathering data about the cfDNA molecules in a subject, which any practical use of the judicial exceptions would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to gathering samples, sequencing those samples to determine cfDNA sequences and methylation, and further using the methylation to examine aspects of prostate cancer.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method being used in a variety of activities related to prostate cancer is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was known in the prior art to evaluate methylation levels as they relate to aspects of prostate cancer.
Sadikovic (WO2019195941A1; cited on the IDS filed July 15th, 2022) teaches a method of treating prostate cancer in a human subject in need thereof (Page 15, paragraph 6), the method comprising: obtaining a biological sample from the subject, which may be a blood sample and comprise circulating tumor cells (Page 14, paragraph 4; Page 15, paragraph 5); determining the average methylation ratio at 10 or more CpG loci (Page 15, paragraph 2; Page 9, paragraph 3: methylation level equivalent to methylation ratio; Figures 7 and 10, where the line represents average methylation ratio at a CpG locus), with the additional teaching that all loci within 100 nucleotides may also be measured. Sadikovic teaches calculating a methylation score using the average methylation ratio for each of the genomic regions (Page 9, paragraph 3; Page 14, paragraph 4) . Sadikovic teaches analyzing the methylation score to determine the presence of prostate cancer in a sample (Page 9, paragraph 3; Page 14, paragraph 4). The method of Sadikovic is based on using a microarray (Page 13, paragraph 3: discussing using probes to detect CpG loci). Sadikovic also teaches treating the subject for prostate cancer using any conventional or otherwise known treatment following detection via CpG loci (Page 8, paragraph 1; Page 15, paragraph 6).
Zhou (WO2017212428A1; cited on the IDS filed April 21st, 2022) teaches on blood samples containing cfDNA molecules (Page 3, paragraph [0014]). Zhou teaches on characterizing the methylome sequence of a plurality of cfDNA molecules in a sample (Page 3, paragraph [0009]). Zhou also teaches that genomic regions are covered by at least one sequence read of at least one cfDNA molecule in the sample (Page 3, paragraph [0009]). By sequencing the cfDNA molecules, Zhou also inherently teaches that the methylation status at all sequenced nucleotides in every read is known. Zhou also teaches that these methods are used for determining the presence of cfDNA derived from a cancer in a sample (Pages 7-8, paragraph [0030]), where the cancer can be prostate cancer (Page 10, paragraph [0035]).
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), as well as the prior art of Sadikovic and Zhou, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exceptions into a practical application of those exceptions in such a way as to provide meaningful limits on the use of the judicial exceptions. Therefore, claims 1-2, 4-9, and 11-13 are rejected here under 35 U.S.C. 101.
Response to Arguments
Applicant's arguments filed December 1st, 2025 have been fully considered but they are not persuasive.
The Applicant first summarizes the Examiner’s rejection from the previous Office Action (Page 71 of the Remarks filed December 1st, 2025). The Applicant then states that as amended, claim 1 is directed to a method of treating prostate cancer, with a series of process steps leading to initiating prostate cancer treatment (Pages 71-72 of the Remarks filed December 1st, 2025). The Applicant argues that the treatment of a human subject with prostate cancer is a practical application and the claim is directed towards patent-eligible material (Page 72 of the Remarks filed December 1st, 2025).
In response to these arguments, the Examiner would like to direct the Applicant to what has been newly noted at the beginning of rejection, and restated here: while claim 1 does include a treatment step, it is not specific to just those subjects that have prostate cancer and instead includes all subjects that are tested, regardless of if they have prostate cancer or not. Therefore, the treatment does not represent a practical application of the judicial exceptions.
Given this issue, the arguments are not considered persuasive and the rejection under 35 U.S.C. 101 is modified as necessitated by amendment and maintained.
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.
Modified – Necessitated by Amendment
Claims 1, 4-6, 8, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Sadikovic (WO2019195941A1; cited on the IDS filed July 15th, 2022), in view of Zhou (WO2017212428A1; cited on the IDS filed April 21st, 2022), Schultz (‘Leveling’ the playing field for analyses of single-base resolution DNA methylomes, Trends in Genetics, December 2012, 28, 583-585; previously cited), and Chen (Prostate Cancer: Current Treatment and Prevention Strategies, Iranian Red Crescent Medical Journal, April 2013, 15, 279-284).
Regarding instant claim 1, Sadikovic teaches a method of treating prostate cancer in a human subject in need thereof (Page 15, paragraph 6), the method comprising: obtaining a biological sample from the subject, which may be a blood sample and comprise circulating tumor cells (Page 14, paragraph 4; Page 15, paragraph 5); determining the average methylation ratio at 10 or more CpG loci (Page 15, paragraph 2; Page 9, paragraph 3: methylation level equivalent to methylation ratio; Figures 7 and 10, where the line represents average methylation ratio at a CpG locus), with the additional teaching that all loci within 100 nucleotides may also be measured. Sadikovic teaches this with reference to a select group of typical loci, but it would be obvious to one of ordinary skill in the art that any of the loci taught by Sadikovic could include measuring all CpG loci within about 100 nucleotides of the specific loci as this would be simple substitution of one known element for another. Given this reasoning, Sadikovic teaches determining the average methylation ratio at 10 or more genomic regions. Sadikovic therefore also teaches that each genomic region can consist of a 2 to 99bp region within a genomic location defined in Table 1 comprising at least one CpG locus (reference Table 1 containing loci within genomic regions in instant Table 1). Sadikovic teaches calculating a methylation score using the average methylation ratio for each of the genomic regions (Page 9, paragraph 3; Page 14, paragraph 4) . Sadikovic teaches analyzing the methylation score to determine the presence of prostate cancer in a sample (Page 9, paragraph 3; Page 14, paragraph 4). The method of Sadikovic is based on using a microarray (Page 13, paragraph 3: discussing using probes to detect CpG loci). Sadikovic also teaches treating the subject for prostate cancer using any conventional or otherwise known treatment following detection via CpG loci (Page 8, paragraph 1; Page 15, paragraph 6).
While Sadikovic teaches on the sample being a blood sample, Sadikovic does not explicitly teach that the sample comprises circulating free DNA (cfDNA). Sadikovic does not teach characterizing the methylome sequence of a plurality of cfDNA molecules in the sample, wherein the methylome sequence of a cfDNA molecule is the DNA sequence and the methylation profile of the molecule. Sadikovic also does not teach that the already taught genomic regions are covered by at least one sequence read of at least one cfDNA molecule in the sample. Sadikovic does not teach determining an average methylation ratio with regards to sequencing data. Sadikovic also does not teach analyzing the methylation score to determine presence of cfDNA derived from prostate cancer in the sample. Finally, while Sadikovic teaches on treating a subject for prostate cancer, Sadikovic does not teach the modalities of treating prostate cancer consisting of a therapeutic agent, surgery, or radiotherapy.
Zhou, in a reasonably pertinent field, teaches on blood samples containing cfDNA molecules (Page 3, paragraph [0014]). Zhou teaches on characterizing the methylome sequence of a plurality of cfDNA molecules in a sample (Page 3, paragraph [0009]). Zhou also teaches that genomic regions are covered by at least one sequence read of at least one cfDNA molecule in the sample (Page 3, paragraph [0009]). By sequencing the cfDNA molecules, Zhou also inherently teaches that the methylation status at all sequenced nucleotides in every read is known. Zhou also teaches that these methods are used for determining the presence of cfDNA derived from a cancer in a sample (Pages 7-8, paragraph [0030]), where the cancer can be prostate cancer (Page 10, paragraph [0035]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Sadikovic with the sequencing of cfDNA of Zhou. Since Zhou teaches that sequencing of cfDNA can be used to determine methylation levels in prostate cancer, which is reasonably pertinent to the method of Sadikovic, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because sequencing can be used to identify the composition of tissue types in plasma cfDNA and predict cancer diagnosis and prognosis (Zhou, Page 20, paragraph [0087]).
Zhou also does not teach determining an average methylation ratio with regards to sequencing data.
Schultz, in a reasonably pertinent field, teaches on determining an average methylation ratio in a genomic region after whole genome bisulfite sequencing with single base resolution (Page 583, column 2, last paragraph to Page 584, column 1, first paragraph; Figure 1D: mean methylation level).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Sadikovic and Zhou with the average methylation ratio based on sequencing data of Schultz. Since Schultz teaches on detecting methylation level of genomic regions in sequencing data, which is reasonably pertinent to the method of Sadikovic and Zhou, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because this is a known technique for calculating methylation level based on sequencing data with predictable results (See MPEP 2141(III)).
None of the above references teach the modalities of treating prostate cancer consisting of a therapeutic agent, surgery, or radiotherapy.
Chen, in a reasonably pertinent field, teaches on the options of a therapeutic agent, surgery, or radiotherapy for the treatment of prostate cancer (whole document).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Sadikovic, in view of Zhou and Schultz, with the treatment modalities of Chen. Since Chen teaches on treatments for prostate cancer, which is reasonably pertinent to Sadikovic’s, in view of Zhou and Schultz, method of treating prostate cancer, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because the treatments are helpful to control and prevent prostate cancer (Chen, Page 280, column 1, paragraph 1).
Regarding instant claim 4, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Sadikovic further teaches wherein calculating a methylation score using the average methylation ratio for each genomic region comprises: comparing the average methylation ratio at each genomic region to a reference methylation ratio for each genomic region to determine a methylation ratio score for each genomic region (Page 9, paragraph 3; Page 14, paragraph 4).
Regarding instant claim 5, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Sadikovic further teaches wherein analyzing the methylation score to determine the level of prostate cancer fraction in the cfDNA sample comprises comparing the methylation score to one or more reference methylation scores, wherein a reference methylation score is a methylation score calculated for the same genomic regions in a tissue sample from a healthy subject (Page 8, paragraph 3 and 5; Page 9, paragraph 3; Page 10, paragraphs 3-4: the control profile may be a tissue from a subject known to not have cancer; Page 14, paragraph 4).
Regarding instant claim 6, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Sadikovic further teaches the method comprising determining the average methylation ratio at 25 or more genomic regions (Page 15, paragraph 2; also see claim 1 for analysis regarding the obviousness of looking at regions of about 100 nucleotides near a loci, therefore teaching genomic regions).
Regarding instant claim 8, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Sadikovic teaches that the CpG loci of interest are inherently related to prostate tissue because the samples for the method contain molecules that would have originated from prostate tissue (Page 15, paragraph 5: blood samples contain circulating tumor cells). Therefore, at least 25% of the genomic regions are prostate tissue specific genomic regions.
Regarding instant claim 11, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Zhou further teaches wherein the sample comprising cfDNA is a blood sample (Page 3, paragraph [0012]).
Regarding instant claim 12, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1.
As currently presented, none of these references teach repeating the method on a second sample obtained from the subject after the subject has undergone a prostate cancer treatment, wherein the second sample comprises cfDNA, and comparing the level of cfDNA derived from prostate cancer in the two samples.
Zhou, in a reasonably pertinent field and previously combined with Sadikovic, Schultz, and Chen for claim 1, teaches repeating a method before a treatment and at multiple time points after a treatment, and comparing the level of tumor burden between samples (Page 70, paragraph [00257]). As previously cited, Zhou teaches on samples containing cfDNA (Page 3, paragraph [0009]). As previously cited, Zhou teaches methods that are used for detection of cfDNA methylation patterns in cancer, where the cancer can be prostate cancer (Page 10, paragraph [0035]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Sadikovic, Zhou, Schultz, and Chen with repeating the method after treatment of Zhou. Since Zhou teaches on methods that can be used to determine methylation levels in prostate cancer, which is reasonably pertinent to what has already been taught by Sadikovic, Zhou, Schultz, and Chen, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because repeating methods before and after treatment is useful for monitoring cancer progression and treatment (Zhou, Page 70, paragraph [00257]).
Response to Arguments
Applicant's arguments filed December 1st, 2025 have been fully considered but they are not persuasive.
The Applicant first provides a summary of the rejections from the Examiner’s previous Office Action (Pages 72-73 of the Remarks filed December 1st, 2025). The Applicant then argues that no claim is obvious over the cited references, separately or in combination, because they would not lead a person skilled in the relevant arts to arrive at the claimed invention (Page 73 of the Remarks filed December 1st, 2025).
The Applicant then summarizes the claimed method, stating that it enables accurate determination of the presence of cfDNA derived from prostate cancer in a sample and methylation ratios of 10 or more genomic regions from Tables 1-4 correlate stringing with cfDNA derived from prostate cancer (Page 74 of the Remarks filed December 1st, 2025). The Applicant then summarizes the selection process for the genomic regions in Tables 1-4, stating that the target selection of genomic regions enables determination of whether a sample from a subject contains cfDNA from prostate cancer (Page 75 of the Remarks filed December 1st, 2025). The Applicant further states that determining whether a sample comprises cfDNA derived from prostate cancer then allows identification of a subject that would benefit from prostate cancer treatment (Page 75 of the Remarks filed December 1st, 2025).
The Applicant argues that Sadikovic, Zhou, and Schultz fail to teach or suggest the claimed invention, starting with analysis of Sadikovic (Pages 75-76 of the Remarks filed December 1st, 2025). The Applicant first summarizes embodiments of Sadikovic wherein a method for diagnosing prostate cancer uses FFPE tissue samples from prostate tumors and normal tumors to identify relevant CpG sites, leading to 6167 CpG loci that are differentially methylated (Page 76 of the Remarks filed December 1st, 2025). The Applicant then notes that Sadikovic uses a classification model able to detect prostate cancer from methylation states, with a final model using the four CpGs in Table 7 (Page 76 of the Remarks filed December 1st, 2025). The Applicant then argues that Sadikovic does not teach differential methylation of CpG loci in cfDNA can be used to determine if a sample comprises cfDNA derived from prostate cancer (Page 77 of the Remarks filed December 1st, 2025). The Applicant states that Sadikovic does not identify cfDNA as a sample type, but instead circulating tumor cells, and the worked examples only focus on FFPE samples (Page 77 of the Remarks filed December 1st, 2025). The Applicant further notes the Sadikovic identified differentially methylated CpG loci using FFPE samples, and that the classification model used prostates tumor samples (Page 77 of the Remarks filed December 1st, 2025). The Applicant then argues that Sadikovic’s method cannot be directly applied to cfDNA, and that cfDNA and tissue samples are fundamentally different (Page 77 of the Remarks filed December 1st, 2025). The Applicant argues that tissue biopsy provides intact cells with structural and cellular context, while cfDNA is highly fragmented, present in low abundance, and mixed with DNA from normal cells, and therefore lacking cellular context (Page 77 of the Remarks filed December 1st, 2025). The Applicant finally argues that none of the four CpG loci from Table 7 of Sadikovic appear in Tables 1-4 of claim 1, further arguing that Sadikovic provides no teaching that would lead one of ordinary skill in the art to the looking at methylation ratios of the specific set of genomic regions recited in Tables 1-4 for use in determining the presence of cfDNA derived from prostate cancer (Page 78 of the Remarks filed December 1st, 2025).
With regards to Zhou, the Applicant states that the method taught is for detecting tumor derived cfDNA in a sample based on methylation sequences of cfDNA (Page 78 of the Remarks filed December 1st, 2025). The Applicant argues that while Zhou mentions the method can be used for any disease, the worked examples are solely concerned with detection of cfDNA derived from liver cancer (Page 78 of the Remarks filed December 1st, 2025). The Applicant further argues that cancers are highly complex and underlying mechanisms differ greatly between cancers (Page 78 of the Remarks field December 1st, 2025). The Applicant further states that Zhou does not disclose the genomic regions of Tables 1-4, or any other method for detecting cfDNA derived from prostate cancer (Page 78 of the Remarks filed December 1st, 2025). With regards to the combination of Sadikovic and Zhou, the Applicant argues that one of ordinary skill in the art would have no expectation of successfully determining the presence of cfDNA derived from prostate cancer (Page78 of the Remarks filed December 1st, 2025). The Applicant argues that the CpG loci of Sadikovic were identified in prostate tumor biopsy samples and the method is based on four CpG loci that do not correspond to the claimed method (Page 78 of the Remarks filed December 1st, 2025). The Applicant also argues that given the complexity of cancer and the different context of identifying CpG loci, there is no expectation that the CpG loci of Sadikovic and the method of Zhou would be applicable to the instantly claimed method (Pages 78-79 of the Remarks filed December 1st, 2025).
With regards to Schultz, the Applicant argues that it only provides general technical background relating to DNA methylation sequencing and determining methylation level of CpG sites based on WGBS (Page 79 of the Remarks filed December 1st, 2025). The Applicant argues it is not directed to detecting cfDNA derived from diseased tissue based on methylation levels of specific CpGs, nor specifically detecting cfDNA derived from prostate cancer (Page 79 of the Remarks filed December 1st, 2025).
In response to these arguments, the Examiner would first like to generally note for the Applicant that the courts have stated “[A] prior art reference must be considered in its entirety, i.e., as a whole” W.L. Gore & Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983) (see MPEP 2141.02 VI). With reference to the arguments about specific teachings and the worked examples of Sadikovic and Zhou, these worked examples do not represent the entirety of the reference as taught. Both patent documents state that the worked examples are solely for purposes of illustration and are not intended to limit the scope of what is taught. Therefore, the entirety of the references are applicable as previously cited. This is directly applicable to the arguments against Sadikovic regarding FFPE samples and the classification model. While the worked examples may have been performed with tissue samples and a small number of CpG sites, Sadikovic teaches embodiments wherein blood samples comprising circulating tumor cells can be used, as well as at least one loci from Table 1 in Sadikovic, which contains loci within the ranges of genomic regions in instant Table 1. This is also directly applicable to the arguments against Zhou regarding detection of cfDNA derived from liver cancer. While the worked examples may have been performed specifically for methylation in cfDNA from liver cancer, Zhou teaches embodiments wherein it can be determined that methylation in cfDNA derives from a multitude of different cancers, including prostate cancer.
Regarding the arguments directed to tissue biopsy and cfDNA sample being fundamentally different, the Examiner would like to note for the Applicant that, as evidenced by art such as Warton (Methylated circulating tumor DNA in blood: power in cancer prognosis and response, Endocrine-Related Cancer, March 2016, 23, R157-R171), circulating tumor DNA found in the cell free DNA originates from tumor tissue (R159, column 1, paragraph 2). Methylation patterns found in the tumor tissue are then reflected in tumor DNA shed into the bloodstream as cell free DNA (R159, column 1, paragraph 2). Therefore, even though Sadikovic’s work is centered around identifying the taught CpG loci using FFPE tissue, it would still reflect methylation patterns later found in cell free DNA samples.
Regarding the combination of Sadikovic and Zhou, the Examiner would like to again reiterate that a prior art reference must be considered in its entirety. Sadikovic teaches on more than just the working example using tumor tissue and four CpG loci, and the function of the general method of Zhou is not specifically reliant on use for looking at methylation in cfDNA as it relates to lung cancer. In both references, more general teachings are offered that are relevant to the instantly claimed invention. Furthermore, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, this has been provided in the above rejection, wherein Zhou teaches that sequencing can be used to identify the composition of tissue types in plasma cfDNA and predict cancer diagnosis and prognosis (Zhou, Page 20, paragraph [0087]).
With regard to the arguments against Schultz, these appear to be more directed towards it not making up for the deficiencies of Sadikovic and Zhou. Since Sadikovic and Zhou are still found to be satisfactory teachings, as argued above, Schultz is also still satisfactory in combination with Sadikovic and Zhou.
Finally, in an overall response to Applicant's arguments against the references individually and what they do not teach, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). For instance, Sadikovic is not relied upon to teach that the presence of a cancer can be detected with cfDNA; rather this is taught by Zhou as discussed in the rejections above. Zhou is not relied upon for the genomic regions; rather, these are taught by Sadikovic when considering the reference as a whole and as discussed in the rejections above. Schultz is not relied upon to detect cfDNA derived from diseased tissue based on methylation; rather, this is taught by Zhou as discussed in the rejections above.
Overall, the arguments are not considered persuasive, and therefore the rejections previously set forth under 35 U.S.C. 103 are modified as necessitated by amendment and maintained.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Sadikovic (WO2019195941A1; cited on the IDS filed July 15th, 2022), in view of Zhou (WO2017212428A1; cited on the IDS filed April 21st, 2022), Schultz (‘Leveling’ the playing field for analyses of single-base resolution DNA methylomes, Trends in Genetics, December 2012, 28, 583-585), and Chen (Prostate Cancer: Current Treatment and Prevention Strategies, Iranian Red Crescent Medical Journal, April 2013, 15, 279-284), as applied to claim 1 above, and further in view of Illumina (Sequencing Coverage Calculation Methods for Human Whole-Genome Sequencing [online]. Illumina, [2016] [retrieved on August 22nd, 2025]. Retrieved from: https://www.illumina.com/content/dam/illumina-marketing/documents/products/technotes/hiseq-x-30x-coverage-technical-note-770-2014-042.pdf).
Regarding instant claim 2, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1.
None of these references teach wherein each of the genomic regions is covered by at least 10 sequence reads.
Illumina, in a reasonably pertinent field, teaches on sequencing with 30x read depth, with an average of 30 reads spanning any given position in the genome (Page 1, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Sadikovic, Zhou, and Schultz with read depth from Illumina. Since Illumina teaches on whole genome sequencing for humans, which is reasonably pertinent to the method of Sadikovic, Zhou, and Schultz, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because higher levels of sequencing coverage are required to identify low-frequency variants (Illumina, Page 1, column 1, paragraph 2).
Response to Arguments
Applicant's arguments filed December 1st, 2025 have been fully considered but they are not persuasive.
With regards to claim 2, the Applicant first provides a summary of the Examiner’s rejection in the previous Office Action (Pages 79-80 of the Remarks filed December 1st, 2025). The Applicant argues that, given claim 1 is non-obvious over the combination of Sadikovic, Zhou, and Schultz, and Illumina does not satisfy the deficiencies of these references, the combination of all four fails to render claim 2 obvious. The Examiner would like to note for the Applicant that the arguments related to claim 2 rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. Therefore, the claims remained rejected based on the prior art citations presented in the rejections.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Sadikovic (WO2019195941A1; cited on the IDS filed July 15th, 2022), in view of Zhou (WO2017212428A1; cited on the IDS filed April 21st, 2022), Schultz (‘Leveling’ the playing field for analyses of single-base resolution DNA methylomes, Trends in Genetics, December 2012, 28, 583-585), and Chen (Prostate Cancer: Current Treatment and Prevention Strategies, Iranian Red Crescent Medical Journal, April 2013, 15, 279-284), as applied to claim 1 above, and further in view of Hendricks (Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients, The Prostate, November 2017, 78, 336-342), as evidenced by Leslie (Small-Cell Prostate Cancer Variety Surprisingly Common [online]. Cancer Discovery, [2018] [retrieved on January 26th, 2026]. Retrieved from: https://aacrjournals.org/cancerdiscovery/article/8/9/OF4/10144/Small-Cell-Prostate-Cancer-Variety-Surprisingly).
Regarding instant claim 9, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1.
None of these references teach wherein the prostate cancer is acinar adenocarcinoma prostate cancer, ductal adenocarcinoma prostate cancer, transitional cell cancer of the prostate, squamous cell cancer of the prostate, or small cell prostate cancer.
Hendricks, in the same field of endeavor, teaches that methylation determined in cfDNA from blood samples has prognostic value for castration-resistant prostate cancer (Abstract). As evidenced by Leslie, castration resistant prostate cancer includes small cell prostate cancer (Abstract).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Sadikovic, in view of Zhou, Schultz, and Chen, with the prostate cancer of Hendricks. Since both Sadikovic, in view of Zhou, Schultz, and Chen, and Hendricks are in the same field of endeavor (e.g. methylation as it relates to prostate cancer), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because methylated cfDNA shoes promise for developing a test to guide treatment for castration-resistant prostate cancer patients (Hendricks, Abstract).
New – Necessitated by Amendment
Claims 29-33, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Sadikovic (WO2019195941A1; cited on the IDS filed July 15th, 2022), in view of Zhou (WO2017212428A1; cited on the IDS filed April 21st, 2022), Schultz (‘Leveling’ the playing field for analyses of single-base resolution DNA methylomes, Trends in Genetics, December 2012, 28, 583-585; previously cited), and Chen (Prostate Cancer: Current Treatment and Prevention Strategies, Iranian Red Crescent Medical Journal, April 2013, 15, 279-284).
Regarding instant claim 29, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Chen further teaches wherein the prostate cancer treatment comprises a chemotherapy agent (Page 282, column 1, paragraph 2).
Regarding instant claim 30, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 29. Chen further teaches wherein the chemotherapy agent is docetaxel (Page 282, column 1, paragraph 2).
Regarding instant claim 31, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Chen further teaches wherein the prostate cancer treatment comprises performing a radical prostatectomy (Page 280, column 1, paragraph 2).
Regarding instant claim 32, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Chen further teaches wherein the prostate cancer treatment comprises administering of external beam localized radiotherapy of the prostate (Page 280, column 2, paragraph 3 to Page 281, column 1, paragraph 1).
Regarding instant claim 33, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Sadikovic further teaches wherein analyzing the methylation score to determine the level of prostate cancer fraction in the cfDNA sample comprises comparing the methylation score to one or more reference methylation scores, wherein a reference methylation score is a methylation score calculated for the same genomic regions in a tissue sample from a healthy subject (Page 8, paragraph 3 and 5; Page 9, paragraph 3; Page 10, paragraphs 3-4: the control profile may be a tissue from a subject known to not have cancer; Page 14, paragraph 4).
Regarding instant claim 35, Sadikovic, in view of Zhou, Schultz, and Chen, teaches the method of claim 1. Zhou has already been shown to teach on blood samples containing cfDNA molecules (Page 3, paragraph [0014]), and on characterizing the methylome sequence of a plurality of cfDNA molecules in a sample (Page 3, paragraph [0009]). Zhou also teaches that these methods are used for determining the presence of cfDNA derived from a cancer in a sample (Pages 7-8, paragraph [0030]), where the cancer can be prostate cancer (Page 10, paragraph [0035]). Zhou further teaches wherein analyzing the methylation score to determine the presence of cfDNA derived from cancer in the sample comprises determining that the cancer fraction of the cfDNA in the sample is at least 0.01% (Page 8, paragraph [0031]: circulating tumor DNA (cfDNA) burden coefficient Θ). Given the earlier teachings of Zhou, it would be obvious that this more general cancer fraction determination can be applied more specifically to prostate cancer.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Sadikovic (WO2019195941A1; cited on the IDS filed July 15th, 2022), in view of Zhou (WO2017212428A1; cited on the IDS filed April 21st, 2022), Schultz (‘Leveling’ the playing field for analyses of single-base resolution DNA methylomes, Trends in Genetics, December 2012, 28, 583-585), and Chen (Prostate Cancer: Current Treatment and Prevention Strategies, Iranian Red Crescent Medical Journal, April 2013, 15, 279-284), as applied to claim 1 above, and further in view of Hendricks (Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients, The Prostate, November 2017, 78, 336-342), as evidenced by Leslie (Small-Cell Prostate Cancer Variety Surprisingly Common [online]. Cancer Discovery, [2018] [retrieved on January 26th, 2026]. Retrieved from: https://aacrjournals.org/cancerdiscovery/article/8/9/OF4/10144/Small-Cell-Prostate-Cancer-Variety-Surprisingly).
Regarding instant claim 34, Sadikovic, in view of Zhou, Schultz, Chen, and Hendricks (as evidenced by Leslie), teaches the method of claim 9. Sadikovic further teaches wherein the prostate cancer is metastatic prostate cancer (Page 15, paragraph 1).
Conclusion
All claims are rejected.
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.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683