DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claims dated 12/11/2025 are under consideration.
The amendments and arguments presented in the papers filed 12/11/2025 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 6/17/2025 listed below have been reconsidered as indicated.
a) The rejections of claims 12, 13, 26 and 27 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in view of the amendments to the claims.
b) The rejections of claim(s) 1-14 under 35 U.S.C. 103 as being unpatentable over Arensdorf (WO 2020/061380 A1) are withdrawn in view of the amendments claim 1.
The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action.
New and modified grounds of rejection necessitated by amendment are detailed below.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited by applicant on an IDS, they have not been considered.
Drawings
High resolution copies of the drawings may be accessed via PAIR/Patent Center Retrieval using the Supplemental Content tab.
Claim Interpretation
Claim 1 is drawn to a method. The active method steps required for the method are:
1) providing an archived reference sample (AReS) library attached to a plurality of solid support;
2) amplifying the AReS library in any manner;
3) assaying the amplified AReS library in a manner that generates any type of sequencer data; and
4) comparing the sequencer data to any reference standard.
The claim then repeats the above steps using the “same AReS library”.
The “providing” step describes how the AReS library was prepared, but does not require active method steps for preparing the AReS library. The description of how it is prepared merely imposes structural limitations on the AReS library. The structure implied by the steps are nucleic acids representative of cfDNA in which unmodified cytosines have been deaminated. The providing of any composition of nucleic acids that has these structural features satisfies the claimed “providing” steps, even if the composition was prepared by a method different than that in the claims. The claims do not require performing the steps but rather describe features of the “AReS library” or “immortalized library” imposed by how they are made. It is noted that the process steps of making the “AReS library” are not performed in any particular order, nor does it specify that the entirety of the library is treated uniformly.
The overall structure of the “AReS library” or “immortalized library” is not defined in the claim. The “libraries” broadly encompass a single tube comprising DNA derived from a plurality of cfDNA from human subjects, e.g., a library of pooled samples. In this embodiment an aliquot of the tube is used to generate the various “assayable libraries” or “clone libraries” for sequencing. Alternatively, the libraries broadly encompass a collection of DNA derived from a plurality of cfDNA from human subjects. For example, each DNA derived from a human subject is in a separate container, e.g., a separate well or separate tube and the library is a collection of wells or tubes. In this embodiment DNA from a subset of individuals are sequenced or an aliquot from a subset or all of the individual containers are used for sequencing.
Claim 15 is drawn to a method. The active method steps required for the method are:
1) providing an immortalized library attached to a plurality of solid supports;
2) amplifying the immortalized library in any manner;
3) assaying the amplified immortalized library in any manner that produces sequencer data; and
4) comparing the sequencer data to any reference standard.
The claim then repeats the above steps using the same “immortalized library”.
The “providing” step describes how the immortalized library was prepared, but not require active method steps for preparing the immortalized library. The description of how it is prepared merely imposes structural limitations on the immortalized library. The structure implied by the steps are nucleic acids representative of cfDNA in which unmodified cytosines have been deaminated and a component or means for recovering the template nucleic acid if present. The providing of any composition of nucleic acids that has these structural features satisfies the claimed “providing” steps, even if the composition was prepared by a method different than that in the claims. The claims do not require performing the steps but rather describe features of the “immortalized library” imposed by how they are made. It is noted that the process steps of making the “immortalized library” are not performed in any particular order, nor does it specify that the entirety of the library is treated uniformly. Thus, the final structure of the “immortalized library” is broad as a number of methods may have been used for its preparation.
Claims 3 and 17 describes a property or use of the “unique identifier”, in that it allows for the identification of “the sample”. The “unique identifier” is broadly interpreted as encompassing “barcodes”, “unique molecular identifiers” or “UMIs”, “unique identifiers” or “UIDs”, etc. that are well-known in the art. The claim is broadly interpreted as not requiring an active method step of “correlating the output with whether or not the human subject as cancer”.
Claim Rejections - 35 USC § 112
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.
Claim 1-30 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.
The following are new rejections.
Regarding claim 1, the amended claims states “providing an archived reference sample (AReS) library attached to a plurality of solid support”. The claim then describes in the manner in which the AReS library was prepared. The steps describing the manner in which the AReS library was prepared does not involve “attaching” nucleic acids to a “plurality of solid support”. Thus, the manner in which the AReS library was prepared to does not produce the claimed AReS library that is provided. Therefore, it is unclear if the “providing” step requires an active process of attaching the AReS library to solid supports.
Claims 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 depend from claim 1 and are rejected for the same reason.
Regarding claim 3, it is unclear how the unique identifier allows for the output to be correlated with a “human subject” as the unique identifier is associated with the “original library” of a plurality of human subjects as opposed to any particular human subject. In order to be able to correlated output with a “human subject” each “human subject” would need to have a unique identifier. Thus, the claim is incomplete and there is gap between elements that allow for output to be correlated with “a human subject”.
Regarding claim 15, the amended claims states “providing an immortalized library attached to a plurality of solid support”. The claim then describes in the manner in which the immortalized library was prepared. The steps describing the manner in which the immortalized library was prepared does not involve “attaching” nucleic acids to a “plurality of solid support”. Thus, the manner in which the immortalized library was prepared to does produce the claimed immortalized library that is provided. Therefore, it is unclear if the “providing” step requires an active process of attaching the immortalized library to solid supports.
Claims 16-30 depend from claim 15 and are rejected for the same reason.
Regarding claim 17, it is unclear how the unique identifier allows for the output to be correlated with a “human subject” as the unique identifier is associated with the “clone library” of a plurality of human subjects as opposed to any particular human subject. In order to be able to correlated output with a “human subject” each “human subject” would need to have a unique identifier. Thus, the claim is incomplete and there is gap between elements that allow for output to be correlated with “a human subject”.
Response to the traversal of the 112(b) rejections
The Remarks address the issues raised in the prior Office action (p. 8-10).
The arguments have been fully considered but are not persuasive because they do not address the above rejections necessitated by the amendments to the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arensdorf (WO 2020/061380 A1; previously cited) in view of Kennedy (WO 2018/119452 A2; previously cited).
The following are new rejections.
As noted above, the libraries of the claims broadly encompass a collection of DNA derived from a plurality of cfDNA from human subjects. For example, each DNA derived from a human subject is in a separate container, e.g., a separate well or separate tube. In this embodiment, DNA from a subset of individuals are sequenced or an aliquot from a subset or all of the individual containers are used for sequencing. It is this interpretation/embodiment that the teachings of Arensdorf and Kennedy are relevant to.
Regarding claims 1, 15, 29 and 30, Arensdorf teaches conducting two human clinical studies using a plurality of human subjects to evaluate the use of 5-hydroxymethylcytosine (5hmC) status in cfDNA as a diagnostic parameter in the context of pancreatic cancer as condition (Abstract; see entire document).
Arensdorf teaches providing 92 patient samples that are divided into a training set and a test set comprising 75% and 25%, respectively (para. 235). The patients were 41 PDAC patients and 51 non-cancer subjects (para. 223). The samples are plasma samples (para. 226), and cell-free DNA was prepared from them and ultimately sequenced (para. 226). Together the 92 patient samples that are obtained represent a pool of cfDNA samples that constitute a “library”, such as an “original” library, as encompassed by the broad scope of the term.
Arensdorf teaches for “a first human clinical study” using the training set from which sequencer data was obtained (para. 226). Arensdorf demonstrated between cases and controls a sensitivity or specificity of the diagnostic parameter of 0.96 based on elastic net and lasso analysis. See para. 236. See also, para. 237; and Figs. 3, 4, 5, 6 and 7, depicting the comparison of non-cancer patients and PDAC patients. These samples that were sequenced where amplified from a “library”, e.g., an AReS library or an immortalized library as described below.
Arensdorf teaches “for a second human clinical study” using the internal sample test set, essentially repeating the process done on the training set, but using the internal sample test set instead to obtain sequencer data. These samples are part of the “same library” described above. Arensdorf demonstrated between PDAC cases and non-cancer controls a sensitivity or specificity of the diagnostic parameter of 0.84 based on elastic net analysis and 0.88 based on lasso analysis. See para. 236. See also, para. 237; and Figs. 3, 4, 5, 6 and 7, depicting the comparison of non-cancer patients and PDAC patients. These samples that were sequenced where amplified from a “library”, e.g., an AReS library or an immortalized library as described below.
Arensdorf teaches a number of manners in which cfDNA samples of the “library” may be further prepared for sequencing analysis.
For example, the training set and internal sample test set are from the same “library” of cfDNAs samples. The providing or obtaining of the “library” of cfDNA samples “prepares an original library” of a plurality of cfDNA samples.
Arensdorf teaches a dual-biotin technique in which an affinity tag is added to a 5hmC containing cfDNA, which is then attached to streptavidin beads as a solid support (para. 186), this constitutes a part of an “archived reference sample (AReS) library”. Arensdorf further teaches labeling residual 5mC and making additional bead bound cfDNA. This constitutes a second part of an “archived reference sample (AReS) library”.
Arensdorf teaches a method of processing cfDNA which is an alternative to a dual biotin technique, which Arensdorf identifies as “Pic-Borane Methodology” (para. 186-187). The “Pic-Borane Methodology” includes:
a) obtaining cfDNA from samples of a subjects (para. 186-187) and thus, preparing an original library;
b) attaching biotin and beads as solid supports to cfDNA (para. 186-187);
c) subjecting the cfDNA to a cytosine deamination step using an organic borane (par. 187-188); and
d) amplifying the prepared cfDNA to form a library.
By performing the dual-biotin or “Pic-Borane Methodology” on each of the 92 patient samples, a library of treated and amplified cfDNA for each patient is generated, which is encompassed by the full scope of the claimed “assayable library” or “clone library of amplified nucleic acid” from each human subject.
By sequencing the training set samples, Arensdorf provided an “assayable library” or a “clone library”, assayed the provided library via sequencing and identified the hydroxymethylation state of nucleotides in the cfDNA that may correlate with the presence or absence of PDAC. Arensdorf then compared the sequencing data between PDAC samples and non-cancer samples as a “reference standard” to determine sensitivity or specific using an AUC analysis.
By sequencing the internal test set samples, Arensdorf provided another “assayable library” or another “clone library”, assayed the portion via sequencing and identified the hydroxymethylation state of nucleotides in the cfDNA that may correlate with the presence or absence of PDAC. Arensdorf then compared the sequencing data between PDAC samples and non-cancer samples as a “reference standard” to determine sensitivity or specific using an AUC analysis.
As whole, Arensdorf teaches methods in which cfDNA is obtained and an original library of samples, the samples are enriched for methylation status which involves adding a solid support to the library of samples, performing cytosine deamination of the samples, amplification and sequencing.
Regarding claims 15, 29 and 30, Kennedy teaches forming an “immortalized library” of template nucleic acid that comprise a component, i.e., biotin, for recovering the template nucleic acid (Fig. 4).
Kennedy teaches the component is biotin as described above. Biotin is a detectable moiety, for example by interacting it with labeled streptavidin.
It would have been prima facie obvious to the ordinary artisan at the time of filing to have modified the amplification process of Arensdorf for creating various libraries and versions of libraries such that it incorporates component for recovering the template nucleic acid. The modification allows for one to separate copied or amplified nucleic acids from templates as described by Kennedy.
Regarding claims 2 and 16, Arensdorf teaches amplified nucleic acids include barcodes as “a unique identifier”, that are used to identify a various of elements, including the origin of a sample, different fragments and different strands (para. 138-145).
Regarding claims 3 and 17, Arensdorf teaches barcodes that identify a sample as noted above. Arensdorf further teaches that samples may be pooled and sequenced (para. 169, 183).
The ordinary artisan would recognize that adding a sample barcode to each sample would allow one to map sequences back to the original sample and be identified as being present in PDAC patients or non-cancer subjects. Then upon further analysis the sequences can be identified as being correlated with the presence or absence of PDAC in a subject.
Regarding claims 4, 5, 18, 19 and 28, Arensdorf assay portions of the clone library in the form of 287 genes with increased 5hmC and a portion of the clone library in the form of 343 gens with decreased 5hmC (para. 237). These individual genes are broadly encompassed by “second” and “additional” portions of the clone library of Arensdorf and genes present “second” and “additional” diagnostic parameters as encompassed by claims 4 and 5.
Regarding claims 6, 7, 20 and 22, Arensdorf teaches the diagnostic parameters are the same, i.e., genes with increased 5hmC (para. 237).
Regarding claim 8, 21, Arensdorf teaches the diagnostic parameters are the different, i.e., genes with increased 5hmC versus genes with decreased 5hmC (para. 237).
Regarding claims 9, 11, 23 and 25, Arensdorf teaches sequencing that produces fluorescence as an output (para. 135).
Regarding claim 10, 24, Arensdorf teaches sequencing that produces fluorescence of different wavelengths as different outputs (para. 135).
Regarding claim 12 and 26, as noted above, Arensdorf teaches the outputs of the sequencing assay are indicative of the presence of the condition in PDAC patients as they correlate with 5hmC levels.
Regarding claim 13 and 27, as noted above, Arensdorf teaches the outputs of the sequencing assay are indicative of the absence of the condition in non-cancer subjects as they correlate with 5hmC levels.
Response to the traversal of the 103 rejections
The Remarks summarize the rejections (p. 12-13).
The Examiner’s position is detailed in the above rejections.
The Remarks argue Claim 15, as amended, recites, at least, "...(a) providing an immortalized library... (b) amplifying the immortalized library of template nucleic acid to form at least one clone library... (c) assaying the at least one clone library with an assay for the diagnostic parameter to generate an output ... and for a second human clinical..., repeating steps (a)-(e) using the same immortalized library." and Arensdorf does not teach or disclose "b) amplifying the immortalized library of template nucleic acid to form at least one clone library... (c) assaying the at least one clone library with an assay for the diagnostic parameter to generate an output ... and for a second human clinical..., repeating steps (a)-(e) using the same immortalized library." (p. 13). The Remarks further argue Kennedy does not cure the deficiencies of Arensdorf as Kennedy fails to teach "b) amplifying the immortalized library of template nucleic acid to form at least one clone library... (c) assaying the at least one clone library with an assay for the diagnostic parameter to generate an output ... and for a second human clinical..., repeating steps (a)-(e) using the same immortalized library," as recited in claim 15, as amended (p. 13).
The arguments have been fully considered but are not persuasive. As described above, Arensdorf teaches a library of samples that once processed are attached to beads for separation. Arensdorf teaches amplifying the bead bound cfDNA for example for barcoding (para. 186) or using PCR carried out directly from beads (para. 226). Kennedy similarly teaches using beads to enrich for/recover cfDNA after amplification.
In short, it is the Examiner’s position that the combination of Arensdorf and Kennedy teaches cfDNA that is attached to beads via biotin-streptavidin interactions as a library encompassed by an AReS library and/or an immortalized library.. These bound cfDNA are used as templates in amplification reactions, barcoded and sequenced as encompassed by the “assayable library” or “one clone library” of the claims.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682