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 filed 9/1/2022 are under consideration.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-17, in the reply filed on 9/9/2025 is acknowledged.
Claims 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/9/2025.
Applicant’s election without traverse of a double stranded DNA molecule comprising a sequence which is comprised in SEQ ID NO: 65, a first probe comprising a sequence of SEQ ID NO: 128 and a second probe comprising a sequence of SEQ ID NO: 129, in the reply filed on 9/9/2025 is acknowledged.
Claims 11 and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/9/2025.
Priority
The present application is a continuation of 16/630,593 (issued as US 11,466,323), which is a 371 national stage entry of PCT/IL2018/050772 (filed 7/13/2018), which claims benefit of 62/531,983 (filed 7/13/2017).
The elected species is not supported by 62/531,983 because it does not disclose SEQ ID NOs: 128 and 129.
Information Disclosure Statement
The listing of references in the specification or the 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 on a submitted IDS, they have not been considered.
Drawings
The drawings are objected to because a copy of colored drawings were submitted on 9/1/2022. A petition for colored drawings was filed on 9/1/2022, which was dismissed on 3/14/2023. It is unclear if applicant still intends the application to include colored drawings.
If applicant does not intend the application to include colored drawings, it is suggested a grayscale or black and white copy of the drawings be filed.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
If applicant still intends the application to include colored drawings, the following information is provided:
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because of the following informalities: the specification references “red” and “green” in the context of Fig. 11. No colored drawings have been accepted in this application; thus, the reference to color in Fig. 11 is improper.
Appropriate correction is required.
The use of terms that are trade names or marks used in commerce, such as TaqMan™, Qubit™ and various fluorescent dyes, has been noted in this application. Applicant is reminded the terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 2 is objected to because of the following informalities: in line 5, the claim recites “stie” rather than “site”. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: the claim includes periods following the step identifiers (i.e. "a.", "b.", etc.). MPEP 608.019(m) states:
Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).
Appropriate correction is required.
Claim 17 is objected to because of the following informalities: the claim includes periods following the alternative option identifiers (i.e. "a.", "b.", etc.). MPEP 608.019(m) states:
Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).
Appropriate correction is required.
Claim 17 is objected to because of the following informalities: the claim recites “said specimen is blood”, which should be identified as (g) and “said method further comprises quantitating…” should be identified as (h). Appropriate correction is required.
Claim Interpretation
The term “methylation stie” is broadly interpreted in view of the instant specification (p. 13, lines 17-18) as encompassing any CpG site, regardless of whether it is methylated or unmethylated.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4-6, 8-10, 12-13, and 15-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more.
The claim(s) recite(s) “determining the methylation status of said at least two methylation sites of said single-stranded DNA molecule in at least one of said specimen fractions”. The step broadly encompasses the analysis of data from two specimen fractions to determine the methylation status of two methylation sites. This limited amount of data may easily be considered by the human mind and thus encompasses an abstract idea.
The judicial exceptions are not integrated into a practical application because the claims do not involve:
improvements to the functioning of a computer or to any other technology or technical field;
applying or using the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition;
applying the judicial exception with, or by use of, a particular machine; or
effecting a transformation or reduction of a particular article to a different state or thing.
The claimed limitations add insignificant extra-solution activity to the judicial exceptions. The additional limitations relate to data gathering steps to provide data to be analyzed in step (c).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims encompass the use of ddPCR, which the instant specification identifies as being known in the field (p. 2-3).
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 2-3, 6 and 15-16 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.
Regarding 2, the claim recited “said amplified DNA” multiple times. The recitations lack proper antecedent basis as no “amplified DNA” is previously set forth or described in the claim.
Claim 3 depends from claim 2 and is rejected for the same reason.
Regarding claim 6, the claim recites “said first probe” and “said second probe” multiple times. The recitations lack proper antecedent basis as no “first probe” or “second probe” is previously set forth or described in the claim.
Regarding claim 6, the claim recites “said contacting”. The recitation lacks proper antecedent as it limits the “contacting” of step of claim 2 and not that of claim 1, from which claim 6 indirectly depends.
Regarding claim 6, the claim recites “said quenching moiety”. The recitation lacks proper antecedent basis as no “quenching moiety” is previously set forth or described.
Regarding 6, the claim recites “said amplified DNA” multiple times. The recitations lack proper antecedent basis as no “amplified DNA” is previously set forth or described in the claim. Furthermore, the references to “the forward strand” and “the reverse strand” lack proper antecedent basis.
Claims 15 and 16 depend from claim 6 and are rejected for the same reasons detailed above.
Regarding claim 16, the claim recites “said detectable moiety”. The recitation lacks proper antecedent basis as no “detectable moiety” is previously set forth or described.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 4-6, 8-10, 12-13 and 16-17 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Akirav (WO 2016/094804 A1).
Regarding claim 1, Akirav teaches contacting double-stranded DNA with bisulfite as part of a methylation specific PCR reaction (para. 39) and as a consequence generates single-stranded DNA molecules in which demethylated cytosines are converted to uracils. The double-stranded DNA includes multiple methylation sites, i.e. CpG sites (Fig. 1).
Akirav teaches fractionating the specimen into a plurality of specimen fractions for a digital droplet PCR reaction (para. 276-288). Digital droplet PCR is a well-known assay in which more than 50% of the fractions contain no more than a single template per droplet.
Akirav teaches determining the methylation status of at least two methylation sites of the DNA molecule in the specimen fractions (paras. 276 and 288; and Fig. 43 and 44). See also Fig. 1. The methylation status of the methylation sites in the digital droplet PCR template is reflective of the methylation status in the original double-stranded DNA.
Regarding claims 4 and 17, Akirav teaches the use of serum as a specimen (para. 68), which contains cell-free double-stranded DNA fragments, including those not longer than 150 bp.
Regarding claim 5, Akirav teaches using two labels, e.g., VIC and FAM (Fig. 43) or HEX, FAM, ZEN and IABkFQ (para. 279-284).
Regarding claims 6 and 16, Akirav teaches a first probe in the form of a total human insulin probe labeled with quenched HEX and a second probe in the form of a demethylated human insulin probe labeled with a quenched FAM (par. 279-284). The signals from HEX and FAM are detected when released from the probe during the ddPCR reaction. In Fig. 43, Akirav teaches the amount of signal detected from each unquenched label.
Regarding claims 8 and 9, Akirav teaches the double-stranded DNA molecule encodes insulin (para. 276), which is differentially methylated in cells and/or tissues, including beta cells.
Regarding claims 9 and 10, Akirav teaches the use of DNA from serum as noted above. Serum includes DNA fragments derived from a variety of tissues, including from cardiac tissue.
Regarding claim 12, Akirav teaches the use of DNA from serum as noted above. Serum includes DNA fragments derived from a variety of tissues, including from liver tissue and fragments having SEQ ID NO: 65, as demonstrated by the instant specification.
Claim 13 describes the first and second probes. The probes comprise “a sequence as set forth in” SEQ ID NO: 128 or 129. The language broadly encompasses any fragment of SEQ ID NO: 128 and 129. The claim language is contrasted with language that would specify the probes “comprise one of the sequences of SEQ ID NO: 128 and 129”.
Regarding claim 13, Akirav teaches a total human insulin probe that comprises a TAT sequence which is a fragment within SEQ ID NO: 128.
Akirav teaches a demethylated human insulin probe that comprises a ACCT sequence which is a fragment within SEQ ID NO: 129.
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 1-10, 12-13 and 15-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,466,323 B1.
Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims are of sufficient breadth so as to encompass the methods of the ‘323 patent.
Conclusion
No claims allowed.
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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