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 petition to revive filed 12/11/2025 was granted on 2/23/2026.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/11/2025 has been entered.
The claims dated 12/11/2025 are under consideration.
The 12/11/2025 claims are non-compliant because they do not properly annotate amendments. For example, the “providing” step of claim 1 in the claims from 3/19/2025, no longer appears, but is not indicated as being deleted and the phrase “attached to a plurality of solid supports” is not annotated as being added. In the interest of compact prosecution the claims will be considered. Failure to properly annotate claim amendments in the future will result in the claims not being entered.
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 6/2/2025 listed below have been reconsidered as indicated.
a) The objection of claim 3 is withdrawn in view of the amendments to the claim.
b) The rejections of claims 1-30 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in view of the amendments to the claims.
c) The rejection of claims 12 and 13 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in view of the amendments to the claims.
d) The rejections of claim(s) 1-14 under 35 U.S.C. 103 as being unpatentable over Li 2016 (Tumor Biol. 2016. 37:13111-13119) as evidenced by Li 2015 (Breast Cancer Res Treat. 2015. 149:767-779) in view of Bell (WO 2016/189288 A1) are withdrawn in view of the amendments.
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 or citation of references throughout 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 on a submitted 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 claim passively describes how the AReS library was prepared, but does not require active method steps of 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 claim, 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.
Claim 15 is drawn to a method. The claims passively 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 claim, even if the composition was prepared by a method different than that in the claim. 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.
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 may be 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 the 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.
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 Objections
Claims 1 and 15 are objected to because of the following informalities: the claims include a number of steps required that are recited in the active form and a number of steps that are not required but describe how a particular element. The steps are separated by various commas, colons, semicolons and conjunctions. It is suggested the claims be rewritten to more clearly delineate the active method steps required from those that are not required to be actively preformed. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The following are new rejections addressing the amendments to the claims.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1, the claim sets forth a process by which an AReS is prepared prior to storage. The description includes “preforming an amplification to produce an excess of the original library”, which is describes as resulting in “forming the AReS library”. The claim further includes an additional amended active method step of “performing an amplification reaction to produce an excess of the original library”, which is stated as resulting in “forming the AReS library”.
The instant specification does not describe a method in which a prepared AReS is actively retrieved from a storage and also separately actively formed by the amplification producing an excess of the original library.
The method encompasses new matter. Claims 2-14 depend from claim 1 and are rejected for the same reason.
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.
Claims 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 rejections have been maintained.
Regarding claim 3, it is unclear how the “unique identifier” is designed “such that the output can be correlated with whether or not the human subject has cancer”. The “unique identifier” allows for “identification of the source of the AReS” and does not identify any nucleic acids from a particular human subject. Amending the claim to describe the cfDNA from each human subject in the plurality of human subjects has a “unique identifier” that allows for the identification of which human subject the cfDNA in the AReS was derived from.
Regarding claim 17, it is unclear how the “unique identifier” is designed “such that the output can be correlated with whether or not the human subject has the condition”. The “unique identifier” allows for “identification of the source of the cfDNA” and does not identify any nucleic acids from being derived one particular human subject and not from another human subject in the plurality of human subject. Amending the claim to describe the cfDNA from each human subject in the plurality of human subjects has a “unique identifier” that allows for the identification of which human subject the cfDNA in the immortalized library was derived from.
The following are new rejections necessitated by the amendments to the claims.
Regarding claim 1, the amended claims states “retrieving an archived reference sample (AReS) library from a storage, wherein the AReS library comprises amplified nucleic acid representative of cfDNA from the plurality of human subject attached to a plurality of solid supports”. The claim then describes the process by which the AReS library was prepared. The steps describing the manner in which the AReS library was prepared does not involve “attaching” the nucleic acids of the AReS to a “plurality of solid support”. The process involved a step of “preparing an original library of the cfDNA attached to a plurality of solid supports. Thus, the manner in which the AReS library was prepared to does not produce the AReS library of the claimed “retrieving” step. It is unclear if the “retrieving” step requires an active process of attaching the AReS library produced by the amplification of the original library to a plurality solid supports. Alternatively, it is unclear if the “original library” and the AReS library are the same.
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 1, it is unclear if the amended step of “performing an amplification reaction” is a required step that generates the AReS that is retrieved in the first active method step. It is unclear in the step of preforming an amplification reaction using “the AReS library” is referring to the one that is retrieved in the first recited active method step, or the one that is generated in the amended step of “performing an amplification reaction to produce an excess of the original library”.
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 1, the claim includes an additional amended active method step of “performing an amplification reaction to produce an excess of the original library”, which is stated as resulting in “forming the AReS library”. The claim is incomplete as the “original library” is not referenced in any of the active method steps. The “original library” is only passively described in how process by which the AReS was produced.
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. produced prior to storage in a process that is outside the scope of the claimed method.
Regarding claim 15, the amended claims states “retrieving an immortalized library of amplified nucleic acids from a storage, wherein the immortalized library comprises amplified nucleic acids representative of cfDNA from the plurality of human subjects attached to a plurality of solid support”. The claim then describes the process by which the immortalized library was prepared “prior to storage”. The steps describing the manner in which the immortalized library was prepared does not involve “attaching” the nucleic acids of the immortalized library to a “plurality of solid support”. Thus, the manner in which the immortalized library was prepared to does not produce the immortalized library of the claimed “retrieving” step. It is unclear if the “retrieving” step requires an active process of attaching the immortalized library from the amplified cfDNA to a plurality solid supports.
Claims 16-30 depend from claim 15 and are rejected for the same reason.
Response to traversal of the 112(b) rejections
The Remarks argue the amendments to the claims overcome the rejections (p. 9-12).
The arguments have been fully considered and the claims remain rejected for the reasons provided above.
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 Li 2016 (Tumor Biol. 2016. 37:13111-13119) as evidenced by Li 2015 (Breast Cancer Res Treat. 2015. 149:767-779) in view of Bell (WO 2016/189288 A1) and Kennedy (WO 2018/119452 A2; previously cited).
The following are new rejections necessitated by the amendments to the claims.
Regarding claim 1, Li 2016 teaches retrieving an “archived reference sample (AReS) library” from storage in the form of a collection of barcoded amplicons derived from cfDNA of a plurality of cancer patients and heathy controls (p. 13112, Patients and healthy controls; cfDNA extraction and bisulfite conversion; and MiSeq sequencing). Li 2016 cites Li 2015 for details how cfDNA samples are bisulfite treated, amplified and barcoded (Li 2015, Methods, High-throughput microfluidic PCR for target enrichment and next generation bisulfite sequencing). The collection of barcoded amplicons is “retrieved” in order to pool the amplicons for sequencing (Li 2015, Methods, High-throughput microfluidic PCR for target enrichment and next generation bisulfite sequencing).
Li 2016 cites Li 2015 for amplifying cfDNA after bisulfite treatment and barcoding (Li 2015, Methods, High-throughput microfluidic PCR for target enrichment and next generation bisulfite sequencing) to form an “AReS” library.
A portion of each barcoded amplicon of the collection is provided through pooling to form a mixture that is representative of the cfDNA from the plurality of human subjects and amplified (Li 2016, MiSeq sequencing; and Li 2015, Methods, High-throughput microfluidic PCR for target enrichment and next generation bisulfite sequencing).
The portions of the library are assayed via MiSeq sequencing for methylation status as a diagnostic parameter, such as methylation status of CpG1 of EFGR (Li 2016, MiSeq sequencing). The methylation status of one or more nucleotides correlates with the presence or absence of cancer (Table 2).
The sequencing data for cancer patients is compared with healthy controls as a reference standard to determine sensitivity and specificity in a ROC curve analysis (Li 2016, Statistical analysis; and Table 5).
Li 2016 is silent regarding the remainder or the collection of barcoded amplicons.
However, Bell teaches that is know that indexed libraries may be stored, for example at -20 oC for long term storage (p. 57 and 71).
It would have been prima facie obvious to the ordinary artisan at the time of filing that the collection of barcoded amplicons may be stored for subsequent use and any remaining portion of the collection of barcoded amplicons may be returned to storage for future use in additional studies, assays, etc. This modification of Li 2016 has a reasonable expectation of success because Bell demonstrates the storage of index libraries, which the collection of barcoded amplicons of Li 2016 is, was known in the field.
Regarding claim 2, as noted above the collection of barcoded amplicons include barcodes that are unique identifiers for the different samples.
Regarding claim 3, as noted above the collection of barcoded amplicons include barcodes that are unique identifiers for the different samples.
The claim includes an intended result of the regarding the use of the unique identifier, but does not require any additional active method steps.
Regarding claim 4, a second portion of the library, either a separate PCR reaction for a different target or a different patient sample, is assayed via MiSeq sequencing for methylation status as a diagnostic parameter, such as methylation status of CpG4 of EFGR or CpG5 of GREM1 (Li 2016, MiSeq sequencing). The methylation status of one or more nucleotides correlates with the presence or absence of cancer (Table 2).
The sequencing data for cancer patients regarding the second portion is compared with healthy controls as a reference standard to determine sensitivity and specificity in a ROC curve analysis (Li 2016, Statistical analysis; and Table 5).
Regarding claims 5 and 14, a second portion of the library, either a separate PCR reaction for a different target or a different patient sample, is assayed via MiSeq sequencing for methylation status as a diagnostic parameter, such as methylation status of CpG6 of EFGR or CpG6 of PDGFRB (Li 2016, MiSeq sequencing). The methylation status of one or more nucleotides correlates with the presence or absence of cancer (Table 2).
The sequencing data for cancer patients regarding the second portion is compared with healthy controls as a reference standard to determine sensitivity and specificity in a ROC curve analysis (Li 2016, Statistical analysis; and Table 5).
Regarding claims 6-7, the diagnostic parameters are the same in regards to it being methylation status, or they are the same because they are both, for example CpG6 of PDGFRB, in the context of different patient samples.
Regarding claim 8, the diagnostic parameters are different, for example, CpG5 of GREM1 versus CpG6 of EFGR versus CpG6 of PDGFRB.
Regarding claim 9, because the diagnostic parameter is the same but assayed in different samples, the output is the same, for example the methylation status of CpG5 of GREM1.
Regarding claim 10, because the diagnostic parameters are different, the output is different, for example the methylation status of pG5 of GREM1 versus CpG6 of EFGR versus CpG6 of PDGFRB.
Regarding claim 11, the MiSeq used by Li 2016 produces a fluorescent output that identifies bases/nucleotides.
Regarding claims 12 and 13, the fluorescent signals are indicative of the presence of cancer in cancer patients and the absence of cancer in healthy controls.
Regarding claim 15, Li 2016 teaches retrieving an “immortalized library” from storage in the form of a collection of barcoded amplicons derived from cfDNA of a plurality of cancer patients and heathy controls (p. 13112, Patients and healthy controls; cfDNA extraction and bisulfite conversion; and MiSeq sequencing). Li 2016 cites Li 2015 for details how cfDNA are bisulfite treated, amplified and barcoded (Li 2015, Methods, High-throughput microfluidic PCR for target enrichment and next generation bisulfite sequencing). The collection of barcoded amplicons is “retrieved” in order to pool the amplicons for sequencing (Li 2015, Methods, High-throughput microfluidic PCR for target enrichment and next generation bisulfite sequencing).
A portion of each barcoded amplicon of the collection is provided through pooling to form a mixture that is representative of the cfDNA from the plurality of human subjects (Li 2016, MiSeq sequencing; and Li 2015, Methods, High-throughput microfluidic PCR for target enrichment and next generation bisulfite sequencing).
The portions of the library are assayed via MiSeq sequencing for methylation status as a diagnostic parameter, such as methylation status of CpG1 of EFGR (Li 2016, MiSeq sequencing). The methylation status of one or more nucleotides correlates with the presence or absence of cancer (Table 2).
The sequencing data for cancer patients is compared with healthy controls as a reference standard to determine sensitivity and specificity in a ROC curve analysis (Li 2016, Statistical analysis; and Table 5).
Li 2016 is silent regarding the remainder or the collection of barcoded amplicons.
However, Bell teaches that is know that indexed libraries may be stored, for example at -20 oC for long term storage (p. 57 and 71).
It would have been prima facie obvious to the ordinary artisan at the time of filing that the collection of barcoded amplicons may be stored for subsequent use and any remaining portion of the collection of barcoded amplicons may be returned to storage for future use in additional studies, assays, etc. The modification has a reasonable expectation of success because Bell demonstrates the storage of index libraries, which the collection of barcoded amplicons of Li 2016 is, was known in the field.
Regarding claim 16, as noted above the collection of barcoded amplicons include barcodes that are unique identifiers for the different samples.
Regarding claim 17, as noted above the collection of barcoded amplicons include barcodes that are unique identifiers for the different samples.
The claim includes an intended result of the regarding the use of the unique identifier, but does not require any additional active method steps.
Regarding claim 18, a second portion of the library, either a separate PCR reaction for a different target or a different patient sample, is assayed via MiSeq sequencing for methylation status as a diagnostic parameter, such as methylation status of CpG4 of EFGR or CpG5 of GREM1 (Li 2016, MiSeq sequencing). The methylation status of one or more nucleotides correlates with the presence or absence of cancer (Table 2).
The sequencing data for cancer patients regarding the second portion is compared with healthy controls as a reference standard to determine sensitivity and specificity in a ROC curve analysis (Li 2016, Statistical analysis; and Table 5).
Regarding claims 19 and 28, a second portion of the library, either a separate PCR reaction for a different target or a different patient sample, is assayed via MiSeq sequencing for methylation status as a diagnostic parameter, such as methylation status of CpG6 of EFGR or CpG6 of PDGFRB (Li 2016, MiSeq sequencing). The methylation status of one or more nucleotides correlates with the presence or absence of cancer (Table 2).
The sequencing data for cancer patients regarding the second portion is compared with healthy controls as a reference standard to determine sensitivity and specificity in a ROC curve analysis (Li 2016, Statistical analysis; and Table 5).
Regarding claim 20, the diagnostic parameters are the same in regards to it being methylation status, or they are the same because they are both, for example CpG6 of PDGFRB, in the context of different patient samples.
Regarding claim 21, the diagnostic parameters are different, for example, CpG5 of GREM1 versus CpG6 of EFGR versus CpG6 of PDGFRB.
Regarding claim 22, because the diagnostic parameters are different, the output is different, for example the methylation status of pG5 of GREM1 versus CpG6 of EFGR versus CpG6 of PDGFRB.
Regarding claim 23 because the diagnostic parameter is the same but assayed in different samples, the output is the same, for example the methylation status of CpG5 of GREM1.
Regarding claim 24, because the diagnostic parameters are different, the output is different, for example the methylation status of pG5 of GREM1 versus CpG6 of EFGR versus CpG6 of PDGFRB.
Regarding claim 25, the MiSeq used by Li 2016 produces a fluorescent output that identifies bases/nucleotides.
Regarding claims 26 and 27, the fluorescent signals are indicative of the presence of cancer in cancer patients and the absence of cancer in healthy controls.
Regarding claims 29 and 30, Kennedy teaches the component is biotin as described above. Biotin is a detectable moiety, for example by interacting it with labeled streptavidin.
Li 2016 is silent regarding the amplified nucleic acids of the AReS or immortalized library being attached to a plurality of solid supports.
However, Kennedy teaches forming an “immortalized library” of template nucleic acid that comprise a solid support, such as streptavidin magnetic beads that is attached to a biotin moiety added to the template (Fig. 4) is known in the field.
It would have been prima facie obvious to the ordinary artisan at the time of filing to have modified the amplification process of Li 216 such that is incorporates solid support and component for recovering the template nucleic acid of Kennedy. The modification allows for one to separate copied or amplified nucleic acids from templates as described by Kennedy.
Response to the traversal of the rejections over Li, Bell and Kennedy
The Remarks argue the combination does not teach an AReS or immortalized library attached to a plurality of solid supports (p. 14-15).
The arguments have been fully considered but are not persuasive as Kennedy teaches magnetic streptavidin beads which capture biotinylated template nucleic acids. It would have been prima facie obvious to have generated nucleic acids of Li bound to the streptavidin beads of Kennedy in order to recover original templates.
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 retrieving 92 patient samples that are divided into a training set and a test set comprising 75% and 25%, each respectively, of the patient samples (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 a number of manners in which cfDNA samples of the “library” may be further prepared for sequencing analysis.
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.
Arensdorf teaches for assaying 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 further teaches “assaying” 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 above.
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.
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.
While Arensdorf is silent regarding the remainder of the 92 patient samples, it would have been prima facie obvious to have returned them to storage for later use or for archival purposes
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 that is attached to a solid support (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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-30 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 18/444,227 (reference application) in view of Bell (WO 2016/189288 A1).
The claim sets are not patentably distinct from each other because the difference lines in the accessing and returning of an AReS or immortalized library from storage.
However, Bell teaches that is know that indexed libraries may be stored, for example at -20 oC for long term storage (p. 57 and 71).
It would have been prima facie obvious to the ordinary artisan at the time of filing that the collection of barcoded amplicons may be stored for subsequent use and any remaining portion of the collection of barcoded amplicons may be returned to storage for future use in additional studies, assays, etc. The modification has a reasonable expectation of success because Bell demonstrates the storage of index libraries is done in the field.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to the traversal of the provisional nonstatutory double patenting rejections
The Remarks address a rejection over the 18/131,634 application and not over the 18/444,227 application.
Conclusion
No claims allowed.
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/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682
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