DETAILED ACTION
Prosecution Reopened
In view of the appeal brief filed on 28 July 2025, PROSECUTION IS HEREBY REOPENED. New grounds of rejection are set forth below.
To avoid abandonment of the application, appellant must exercise one of the following two options:
(1) file a reply under 37 CFR 1.111 (if this Office action is non-final) or a reply under 37 CFR 1.113 (if this Office action is final); or,
(2) initiate a new appeal by filing a notice of appeal under 37 CFR 41.31 followed by an appeal brief under 37 CFR 41.37. The previously paid notice of appeal fee and appeal brief fee can be applied to the new appeal. If, however, the appeal fees set forth in 37 CFR 41.20 have been increased since they were previously paid, then appellant must pay the difference between the increased fees and the amount previously paid.
A Supervisory Patent Examiner (SPE) has approved of reopening prosecution by signing below:
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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 .
Claim Interpretation
Attention is directed to MPEP 904.01 [R-08.2012].
The breadth of the claims in the application should always be carefully noted; that is, the examiner should be fully aware of what the claims do not call for, as well as what they do require. During patent examination, the claims are given the broadest reasonable interpretation consistent with the specification. See In re Morris, 127 F.3d 1048, 44 USPQ2d 1023 (Fed. Cir. 1997). See MPEP § 2111 - § 2116.01 for case law pertinent to claim analysis.
It is noted with particularity that narrowing limitations found in the specification cannot be inferred in the claims where the elements not set forth in the claims are linchpin of patentability. In re Philips Industries v. State Stove & Mfg. Co, Inc., 186 USPQ 458 (CA6 1975). While the claims are to be interpreted in light of the specification, it does not follow that limitations from the specification may be read into the claims. On the contrary, claims must be interpreted as broadly as their terms reasonably allow. See Ex parte Oetiker, 23 USPQ2d 1641 (BPAI, 1992). In added support of this position, attention is directed to MPEP 2111 [R-11.2013], where, citing In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550-51 (CCPA 1969), is stated:
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.
Additionally, attention is directed to MPEP 2111.01 [R-01.2024], wherein is stated:
II. IT IS IMPROPER TO IMPORT CLAIM LIMITATIONS FROM THE SPECIFICATION
“Though understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment.” Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875, 69 USPQ2d 1865, 1868 (Fed. Cir. 2004).
Attention is also directed to MPEP 2111.02 II [R-07.2022]. As stated herein:
II. PREAMBLE STATEMENTS RECITING PURPOSE OR INTENDED USE
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The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "'extraneous' limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020) (The court found that the preamble in one patent’s claim is limiting but is not in a related patent); Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation")… (Emphasis added)
Attention is directed to MPEP 2111 [R-10.2019]. As stated therein:
During patent examination, the pending claims must be "given their broadest reasonable interpretation consistent with the specification." The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) expressly recognized that the USPTO employs the "broadest reasonable interpretation" standard:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1). (Emphasis added).
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.
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.
Standard for Obviousness.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Attention is directed to In re Jung, 98 USPQ2d 1174, 1178 (Fed. Cir. 2011) wherein is stated:
There has never been a requirement for an examiner to make an on-the-record claim construction of every term in every rejected claim and to explain every possible difference between the prior art and the claimed invention in order to make out a prima facie rejection. This court declines to create such a burdensome and unnecessary requirement. “[Section 132] does not mandate that in order to establish prima facie anticipation, the PTO must explicitly preempt every possible response to a section 102 rejection. Section 132 merely ensures that an applicant at least be informed of the broad statutory basis for the rejection of his claims, so that he may determine what the issues are on which he can or should produce evidence.” Chester, 906 F.2d at 1578 (internal citation omitted). As discussed above, all that is required of the office to meet its prima facie burden of production is to set forth the statutory basis of the rejection and the reference or references relied upon in a sufficiently articulate and informative manner as to meet the notice requirement of § 132. As the statute itself instructs, the examiner must “notify the applicant,” “stating the reasons for such rejection,” “together with such information and references as may be useful in judging the propriety of continuing prosecution of his application.” 35 U.S.C. § 132.
Attention is directed to the decision in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007):
When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
It is further noted that prior art is not limited to the four corners of the documentary prior art being applied. Prior art includes both the specialized understanding of one of ordinary skill in the art, and the common understanding of the layman. It includes “background knowledge possessed by a person having ordinary skill in the art. . . [A] court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1396.
Suggestion, teaching or motivation does not have to be explicit and “may be found in any number of sources, including common knowledge, the prior art as a whole or the nature of the problem itself’” Pfizer, Inc. v. Apotex, Inc. 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007) citing Dystar Textilfarben GMBH v. C. H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006).
Holding and Rationale
Claim(s) 1-5, 7-8, and 20-29 are rejected under 35 U.S.C. 103 as being unpatentable over Astier et al. (WO 2019/092269 A1, publication date 05/16/2019, PCT/EP20181/081049, filed on 11/13/2018, which claims priority to a US Provisional Patent Application, 62/585,219, filed on 11/13/2017, the effective filing date) in view of Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Astier et al. (US 2020/0282392) teach “devices for effecting epitachophoresis. Epitachophoresis may be used to effect sample analysis, such as by selective separation, detection, extraction, and/or pre-concentration of target analytes such as, for example, DNA, RNA, and/or other biological molecules. Said target analytes may be collected following epitachophoresis and used for desired downstream applications and further analysis.”2 (See Abstract).
Astier et al. (US 2020/0282392), at paragraph [0100], teach:
“Furthermore, metastatic tumor cells can also be detected at the nucleic acid, such as by using a Next Generation Sequencing panel looking to identify cancer-associated mutations, including mutations present in the primary tumor. As described herein, in exemplary embodiments devices and methods disclosed herein may be used to separate, focus/concentrate, and collect such nucleic acids. Moreover, DNA purified from representative sampling from the primary and lymph nodes, as well as DNA from circulating tumor DNA from any distant metastatic cells could be separated, focused /concentrated, and/or collected in exemplary embodiments
Astier et al. (US 2020/0282392) teach:
As used herein, the term ‘epitachophoresis’ generally refers to methods of electrophoretic separation that are performed using a circular or spheroid and/or concentric device and/or circular and/or concentric electrode arrangement, such as by use of the circular/concentric and/or polygonal devices as described herein. Due to a circular/concentric or another polygonal arrangement that is used during epitachophoresis; unlike conventional epitachophoresis devices, the cross section area changes during migration of ions and zones, and the velocity of the zone movement is not constant in time due to the changing cross sectional area. Thus, an epitachophoretic arrangement does not strictly follow conventional isotachophoretic principles, wherein the zones migrate with constant velocities. Notwithstanding these significant differences as shown herein epitachophoresis can be used to efficiently separate and focus charged particles by using an electric field to create boundaries or interfaces between materials that may have different electrophoretic mobilities (e.g., between the charged particles and other materials in a solution). LE and TE, as described for use with ITP, can be used for epitachophoresis as well. A description of the movement of the zones under constant current, constant voltage, and constant power for embodiments wherein circular or spheroid device architectures, e.g., devices comprising one or more circular electrodes, may be used, are presented in the Examples section infra. In exemplary embodiments, epitachophoresis may be effected using constant current, constant voltage, and/or constant power. In exemplary embodiments, epitachophoresis may be effected using varying current, varying voltage, and/or varying power. In exemplary embodiments, epitachophoresis may be effected within the context of devices and/or an arrangement of electrodes whose shape may be described in general as circular or spheroid, such that the basic principles of epitachophoresis may be accomplished as described herein. In some embodiments, epitachophoresis may be effected within the context of devices and/or an arrangement of electrodes whose shape may be described in general as polygons, such that the basic principles of epitachophoresis may be accomplished as described herein. In some embodiments, epitachophoresis may be effected by any non-linear, contiguous arrangement of electrodes, such as electrodes arranged in the shape of a circle and/or electrodes arranged in the shape of a polygon.
See Fig. 1.
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[0009] FIG. 1 provides a schematic representation of an exemplary device for effecting epitachophoresis.
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[0014] FIG. 5 provides a schematic representation of an exemplary device for effecting epitachophoresis wherein the sample is loaded in between loading the leading and terminating electrolytes.
Astier et al., in paragraph [0005], teach:
Moreover, in exemplary embodiments, said device may comprise dimensions that accommodate 1 μl or less, 1 μl or more, 10 μl or more, 100 μl or more, 1 mL or more, 4 mL or more, 5 mL or more, 10 mL or more, or 15 mL or more of sample volume. (Emphasis added)
The above showing is deemed to fairly teach limitations of claims 8 and 20-29.
Astier et al. (US 2020/0282392), at paragraph [0120], teach:
[0120] In some embodiments, the devices and methods described herein may also include the use of at least one detectable label selected from fluorescent molecules or fluorochromes (such as sold by Invitrogen, e.g., see, The Handbook—A Guide to Fluorescent Probes and Labeling Technologies, Invitrogen Detection Technologies, Molecular Probes, Eugene, Oreg., or disclosed in U.S. Pat. No. 5,866,366 to Nazarenko et al.), such as 4-acetamido-4′-isothiocyanatostilbene-2,2′disulfonic acid, acridine and derivatives… (Emphasis added)
The above showing is deemed to fairly suggest limitations of claim 2.
Regarding claim 3, Astier et al. (US 2020/0282392), at paragraph [0033], teach
An epitachophoretic arrangement does not strictly follow conventional isotachophoretic principles, wherein the zones migrate with constant velocities. Notwithstanding these significant differences as shown herein epitachophoresis can be used to efficiently separate and focus charged particles by using an electric field to create boundaries or interfaces between materials that may have different electrophoretic mobilities ( e.g., between the charged particles and other materials in a solution). LE and TE, as described for use with ITP, can be used for epitachophoresis as well.
As used herein, the terms "in vitro diagnostic application (IVD application)", "in vitro diagnostic method (IVD method)" and the like generally refer to any application and/or method and/or device that may evaluate a sample for a diagnostic and/or monitoring purposes, such as identifying a disease in a human subject, optionally a human subject. In exemplary embodiments, said sample may comprise blood and/or plasma from a subject. In exemplary embodiments, said
sample may comprise nucleic acids and/or target nucleic acids from a subject, optionally further wherein said nucleic acids originated from blood and/or plasma
from a subject.
Regarding claim 4, Astier et al. (US 2020/0282392), at paragraph [00275], teach
Recently, methods of diagnosing cancer through the measurement of DNA methylation have been suggested. DNA methylation occurs mainly on the cytosine of CpG islands in the promoter region of a specific gene to interfere with the binding of transcription factors, thus silencing the expression of the gene. Thus, detecting the methylation of CpG islands in the promoter of tumor inhibitory genes greatly assists in cancer research. Recently, an attempt has been actively made to determine promoter methylation, by methods such as methylation-specific PCR (hereinafter referred to as MSP) or automatic DNA sequencing, for the diagnosis and screening of cancer. See WO2009069984A2, which is hereby incorporated by reference in its entirety.
Regarding claim 5, Astier et al. (US 2020/0282392), at paragraph [006], teach
In exemplary embodiments, said method may further comprise: a. providing a device for effecting epitachophoresis; b. providing a sample on said device that comprises one or more target analytes; c. providing a leading electrolyte and a trailing electrolyte on said device; d. performing epitachophoresis using said device; and e. collecting said one or more target analytes. In exemplary embodiments, the device may comprise a circular or spheroid or polygonal geometry. In further exemplary embodiments, during said method of sample analysis an epitachophoresis zone of the device may move from the edge of the polygon or circle towards the center of the polygon or circle. Moreover, in exemplary embodiments, said method may use of 1 μl or less, 1 μl or more, 10 μl or more, 100 μl or more, 1 mL or more, 4 mL or more, 5 mL or more, 10 mL or more, or 15 mL or more of sample volume. In exemplary embodiments, said method may comprise extraction, concentration, and/or collection of a target analyte from a sample, e.g., a biological sample. In further exemplary embodiments, said method may comprise extraction of ctDNA from a sample and/or said method may comprise extraction of cfDNA from a sample, e.g., blood or plasma from a pregnant woman. In further exemplary embodiments, said method may comprise extraction, concentration, and/or collection of a target analyte from a sample, e.g., a biological sample, and said target analyte may be used for one or more downstream in vitro diagnostic applications.
Regarding claim 7, Astier et al. (US 2020/0282392), at paragraph [00131] and [00135], teach
[00131] Fluids can be applied for pretreatment (e.g., protein-crosslinking, exposing nucleic acids, etc.), denaturation, hybridization, washing (e.g., stringency washing), detection (e.g., linking a visual or marker molecule to a probe), amplifying (e.g., amplifying proteins, genes, etc.), counterstaining, or the like. In various embodiments, the substances include, without limitation, stains (e.g., hematoxylin solutions, eosin solutions, or the like), wetting agents, probes, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, etc.), antigen recovering fluids (e.g., aqueous- or non-aqueous-based antigen retrieval solutions, antigen recovering buffers, etc.), solvents (e.g., alcohol, limonene, or the like), or the like. Stains include, without limitation, dyes, hematoxylin stains, eosin stains, conjugates of antibodies or nucleic acids with detectable labels such as haptens, enzymes or fluorescent moieties, or other types of substances for imparting color and/or for enhancing contrast. See WO2015197742 and WO2015150278, each of which is hereby incorporated by reference in its entirety.
[00135] The visible marker may be a fluorescent dye, colloidal metal, hapten, radioactive marker or an enzyme. Regardless of the method of preparation, maximal signal strength with minimal background or non-specific staining can be desirable to give optimal antigen visualization. See WO2013139555 which is hereby incorporated by reference in its entirety.
Astier et al. (US 2020/0282392) does not explicitly teach clean up step using SPRI-beads recited in step e of claim 1.
Maggi et al. (2018) teaches “develop a method for whole genome cell-free DNA (cfDNA) methylation analysis in humans and mice with the ultimate goal to facilitate the identification of tumor derived DNA methylation changes in the blood. Plasma or serum from patients with pancreatic neuroendocrine tumors or lung cancer, and plasma from a murine model of pancreatic adenocarcinoma was used to develop a protocol for cfDNA isolation, library preparation and whole-genome bisulfite sequencing of ultra low quantities of cfDNA, including tumor-specific DNA. The protocol developed produced high quality libraries consistently generating a conversion rate >98% that will be applicable for the analysis of human and mouse plasma or serum to detect tumor-derived changes in DNA methylation” (See Abstract).
Maggi et al. (2018) teaches Isolation of cfDNA from Human and Mouse Plasma/Serum:
To isolate the cfDNA we utilized the Qiagen QIAamp Circulating Nucleic Acid kit (Cat no./ID: 55114) with the modifications described in Section “Results.” For cfDNA purification we compared Solid Phase Reversible Immobilisation beads (SPRI) from Beckman Coulter (Agencourt AMPure cat#A63880) with the DNA Clean & Concentrator kit, Zymo Research (D4003T) (See left column, page 3).
In view of the detailed teachings in the prior art and its applicability to epitachophoresis and methods of isolating and detection of nucleic acids, one of ordinary skill in the art would have been amply motivated and would have had a most reasonable expectation of success. Given such, and in the absence of convincing evidence to the contrary, claims 1-5, 7-8, and 20-29 are rejected under 35 U.S.C. 103 as being unpatentable over 1 Astier et al. (US 2020/0282392 Al, Pub. Date. 09/10/2020, US application number 16/763,782, is 371 US National Stage Application of an International Patent Application, PCT/EP20181/081049, filed on 11/13/2018, which claims priority to a US Provisional Patent Application, 62/585,219, filed on 11/13/2017, the effective filing date) inn view of Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi: 10.3389/fgene.2018.00006. eCollection 2018).
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.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-20 of U.S. Patent No. 11,691,141 in view of Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Claims 12-20 of U.S. Patent No. US 11,691,141:
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Maggi et al. (2018) teaches “develop a method for whole genome cell-free DNA (cfDNA) methylation analysis in humans and mice with the ultimate goal to facilitate the identification of tumor derived DNA methylation changes in the blood. Plasma or serum from patients with pancreatic neuroendocrine tumors or lung cancer, and plasma from a murine model of pancreatic adenocarcinoma was used to develop a protocol for cfDNA isolation, library preparation and whole-genome bisulfite sequencing of ultra low quantities of cfDNA, including tumor-specific DNA. The protocol developed produced high quality libraries consistently generating a conversion rate >98% that will be applicable for the analysis of human and mouse plasma or serum to detect tumor-derived changes in DNA methylation” (See Abstract).
Maggi et al. (2018) teaches Isolation of cfDNA from Human and Mouse Plasma/Serum:
To isolate the cfDNA we utilized the Qiagen QIAamp Circulating Nucleic Acid kit (Cat no./ID: 55114) with the modifications described in Section “Results.” For cfDNA purification we compared Solid Phase Reversible Immobilisation beads (SPRI) from Beckman Coulter (Agencourt AMPure cat#A63880) with the DNA Clean & Concentrator kit, Zymo Research (D4003T) (See left column, page 3).
As evidenced above, claims 12-20 of U.S. Patent No. US 11,691,141 are directed to a method of sample analysis using epitachophoresis (ETP), like claim 1 of the instant application. Heitzer et al., teaches the use of such means in the detection of cancers and how such methods have advanced over the years. Given such knowledge and means for performing such cell-free nucleic acids, one of ordinary skill in the art would have been amply motivated and would have had a most reasonable expectation of success.
In view of the above analysis and in the absence of convincing evidence to the contrary, claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-20 of U.S. Patent No. 11,691,141 in view of Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 8 of U.S. Patent No. 12,311,357 B2 (Astier et al.) in view of Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Claims 1, 7 and 8 of U.S. Patent No. US 12,311,357:
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As evidenced above, claims 1, 7, and 8 of the ‘357 patent are drawn to a method of analyzing nucleic acids. As evidenced above, the method requires the use of electrophoretic means, and results in “focused zones” of the different nucleic acids present in the sample. As evidenced above, the method also requires the use of first and second electrodes. The teachings of Maggi et al. (2018) have been documented above.
In view of the above analysis and in the absence of convincing evidence to the contrary, claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 8 of U.S. Patent No. 12,311,357 B2 (Astier et al.) in view of Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,153,013 in view of Heitzer et al. (2015) (Heitzer et al., Circulating tumor DNA as a liquid biopsy for cancer, Clin Chem., 2015 Jan;61(1):112-23. doi: 10.1373/clinchem. 2014.222679. Epub 2014 Nov 11) and Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Claims 1-11 of U.S. Patent No. US 12,153,013
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Heitzer et al. (2015) teach that “cfDNA was initially identified by Mandel and Me´tais in the blood of healthy individuals. However, their pioneering work did not arouse much interest and it took 30 years until Leon et al. reported increased concentrations of cfDNA in the circulation of cancer patients. It took another 10 years until Stroun et al. demonstrated the presence of neoplastic characteristics in the circulation. These findings were then confirmed by several other groups, and in the following years tumor specific aberrations, including mutations in tumor suppressors and oncogenes, microsatellite instability (MSI) (16 ), and DNA methylation (17 ), were identified and provided concrete evidence that cfDNA is released into the circulation by tumors (Fig. 3). (See left column, page 114).
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Fig. 3. Schematic representation of the liquid biopsy as a tool for cancer monitoring.
Cell-free DNA is released from different tumor locations and healthy/inflamed tissue through multiple mechanisms from cells undergoing apoptosis or necrosis. Tumor-derived DNA (ctDNA) can be extracted from plasma and a variety of tumor-specific genetic changes can be detected. However, the amount of tumor-specific DNA can greatly vary (<1% to >90%) and numerous techniques for the analysis of ctDNA have been proposed. The liquid biopsy may find its clinical application in various clinical settings, including cancer diagnosis, detection of minimal residual disease, prognosis, and therapy monitoring [Taly et al. (65 ), Vogelstein and Kinsler (66 ), Diehl et al. (52 ), Kinde et al. (68 ), Newman et al. (67 ), Forshew et al. (71 ), Chan et al. (11 ), Murtaza et al. (72 ), Heitzer et al. (69 ), Leary et al. (46 ), Chan et al. (10 )]. WGS, whole genome sequencing. (Emphasis added; p. 115)
Heitzer et al. (2015) further teaches “A study that analyzed total plasma DNA concentrations and tumor specific KRAS mutations in CRC patients showed that a higher amount of tumor-specific fragments and that a higher number of CTCs were linked to biphasic size distributions of plasma DNA fragments (Fig. 4) (See section “cfDNA AS A DIAGNOSTIC BIOMARKER” on page 117).
Heitzer et al. (2015), at page 116, teaches the use of fluorescent dyes.
The teachings of Maggi et al. (2018) have been documented above.
As evidenced above, the method of claim 1 in the ‘013 patent requires the use of epitachophoresis in its automated method of detecting and collecting the target analytes.
In view of the above presentation and in the absence of convincing evidence to the contrary, claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,153,013 in view of Heitzer et al. (2015) (Heitzer et al., Circulating tumor DNA as a liquid biopsy for cancer, Clin Chem., 2015 Jan;61(1):112-23. doi: 10.1373/clinchem. 2014.222679. Epub 2014 Nov 11) and Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 4 of copending Application No. 17/907,362 (reference application) in view of Heitzer et al. (2015) (Heitzer et al., Circulating tumor DNA as a liquid biopsy for cancer, Clin Chem., 2015 Jan;61(1):112-23. doi: 10.1373/clinchem. 2014.222679. Epub 2014 Nov 11) and Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Claims 1 and 4 of copending Application No. 17/907,362
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Heitzer et al. (2015) teach that “cfDNA was initially identified by Mandel and Me´tais in the blood of healthy individuals. However, their pioneering work did not arouse much interest and it took 30 years until Leon et al. reported increased concentrations of cfDNA in the circulation of cancer patients. It took another 10 years until Stroun et al. demonstrated the presence of neoplastic characteristics in the circulation. These findings were then confirmed by several other groups, and in the following years tumor specific aberrations, including mutations in tumor suppressors and oncogenes, microsatellite instability (MSI) (16 ), and DNA methylation (17 ), were identified and provided concrete evidence that cfDNA is released into the circulation by tumors (Fig. 3). (See left column, page 114).
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Fig. 3. Schematic representation of the liquid biopsy as a tool for cancer monitoring.
Cell-free DNA is released from different tumor locations and healthy/inflamed tissue through multiple mechanisms from cells undergoing apoptosis or necrosis. Tumor-derived DNA (ctDNA) can be extracted from plasma and a variety of tumor-specific genetic changes can be detected. However, the amount of tumor-specific DNA can greatly vary (<1% to >90%) and numerous techniques for the analysis of ctDNA have been proposed. The liquid biopsy may find its clinical application in various clinical settings, including cancer diagnosis, detection of minimal residual disease, prognosis, and therapy monitoring [Taly et al. (65 ), Vogelstein and Kinsler (66 ), Diehl et al. (52 ), Kinde et al. (68 ), Newman et al. (67 ), Forshew et al. (71 ), Chan et al. (11 ), Murtaza et al. (72 ), Heitzer et al. (69 ), Leary et al. (46 ), Chan et al. (10 )]. WGS, whole genome sequencing. (Emphasis added; p. 115)
Heitzer et al. (2015) further teaches “A study that analyzed total plasma DNA concentrations and tumor specific KRAS mutations in CRC patients showed that a higher amount of tumor-specific fragments and that a higher number of CTCs were linked to biphasic size distributions of plasma DNA fragments (Fig. 4) (See section “cfDNA AS A DIAGNOSTIC BIOMARKER” on page 117).
Heitzer et al. (2015), at page 116, teaches the use of fluorescent dyes.
The teachings of Maggi et al. (2018) have been documented above.
Analysis of DNA samples by substitution a Formalin-Fixed Paraffin-Embedded Tissue ("FFPET") sample recited in claim 1 of copending 17/907,362 with Cell-free circulating tumor DNA from a liquid biopsy for cancer detection taught by Heitzer et al. (2015) is prima facie obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
In view of the above analysis and in the absence of convincing evidence to the contrary, claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 4 of copending Application No. 17/907,362 (reference application) in view of Heitzer et al. (2015) (Heitzer et al., Circulating tumor DNA as a liquid biopsy for cancer, Clin Chem., 2015 Jan;61(1):112-23. doi: 10.1373/clinchem. 2014.222679. Epub 2014 Nov 11) and Maggi et al. (2018) (Maggi et al., Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, Front Genet., 2018 Jan 23:9:6. doi:10.3389/fgene.2018.00006. eCollection 2018).
Conclusion
Objections and/or rejections which appeared in the prior Office action and which have not been repeated hereinabove have been withdrawn.
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/Bradley L. Sisson/Primary Examiner, Art Unit 1682