DETAILED CORRESPONDENCE
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 29, 2025 has been entered.
This action is in response to the papers filed December 29, 2025. Currently, claims 1-4, 6-12, 21-27 are pending.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
The Improper Markush rejection has been withdrawn in view of the amendment to delete Claim 5.
The 101 rejection has been withdrawn in view of the amendments to the claim that requires an adaptor comprising a barcode that creates a non-natural juxtaposition of nucleotide sequences.
The 102 rejections have been withdrawn in view of the amendments to require at least one of the plurality of converted amplified cfDNA molecules is 100nts in length and has an adaptor comprising a barcode that creates a non-natural juxtaposition of nucleotide sequences.
Election/Restrictions
Applicant's election without traverse of SEQ ID NO: 1280 in the paper filed January 10, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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The provisional application does not disclose bar-code sequences or attaching two oligonucleotides to a flow cell surface. Therefore, claims 21-22, and 25-26 enjoy the benefit of April 14, 2015.
Drawings
The drawings are acceptable.
New Matter
Claims 1-4, 6-12, 21-27 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to a composition comprising a nucleic acid library comprising a plurality of converted and amplified cfDNA molecules. The specification does not describe or discuss a “library of converted and amplified cfDNA molecules…:. Instead the specification uses the term library once in the specification (para 230). The specification:
[0230] The methylation-independent primers of this aspect of the present invention may comprise adaptor sequences which include barcode sequences. The adaptors may further comprise sequences which are necessary for attaching to a flow cell surface (P5 and P7 sites, for subsequent sequencing), a sequence which encodes for a promoter for an RNA polymerase and/or a restriction site. The barcode sequence may be used to identify a particular molecule, sample or library. The barcode sequence may be between 3-400 nucleotides, more preferably between 3-200 and even more preferably between 3-100 nucleotides. Thus, the barcode sequence may be 6 nucleotides, 7 nucleotides, 8, nucleotides, nine nucleotides or ten nucleotides. The barcode is typically 4-15 nucleotides.
This description does not support a “library of converted and amplified cfDNA molecules…:.
Further, the specification does not contemplate a “library of converted and amplified cfDNA molecules…:. comprising adaptors flanking a sequence comprising the at least four methylation sites. The specification does not contemplate these limitations.
The specification does not provide any description for adaptors that comprise a barcode sequence that creates a non-natural juxtaposition of nucleotide sequences. As noted in para 230, the adaptors and the barcodes are not defined as “non-natural juxtaposition”. The specification is silent with respect to “juxtaposition”. The concept of “a non-natural juxtaposition of nucleotide sequences” does not appear to be part of the originally filed invention. The response provides no citation for support in the specification for this concept.
The specification does not teach adaptors in a library. Instead, the sole teaching of adaptors is on methylation-independent primers (para 230). Adaptors on primers is not support for adaptors on library members where the library is converted and amplified cfDNA molecules.
The specification does not teach cfDNA molecules of at least 100 nucleotides in length. The specification does not contemplate sequence lengths of 500, 1000 or 10,000 for example in a library. With respect to Claims 2-3, the specification does not teach library elements that are 50-250 nucleotides or 20-200 nucleotides. The teachings of these ranges is relative to barcode lengths or the lengths of the cfDNA of the fluid sample with methylation sites. This is not a teaching of length of library members.
The specification does not teach a library of non-natural sequences comprising on or more converted thymidines. The specification teaches in methods, DNA is treated with bisulfite to convert cytosine residue to uracil which are then converted to thymidine. However, the specification does not provide any description of a library of converted and amplified cfDNA molecules that are at least 100 nucleotides in length and comprise a non-natural sequence comprising one or more converted thymidines.
When taken together, Claims 1-3 encompass a single converted and amplified cfDNA molecule comprising at least 100 nucleotides in length in addition to other library members that are 50 nucleotides in length. There is no teaching in the specification of a library that has cfDNA molecules of different lengths.
With respect to Claim 21-22, the claims are directed to converted cfDNA molecule in the library is bound to a solid support. The specification teaches that methylation dependent oligonucleotide probes may be affixed to a solid support (para 246). The specification does not teaches the methylation dependent oligonucleotides probes are a library with a thymidine, adaptor, barcode, etc. The instant claims differentiate between the probe and the library of converted and amplified cfDNA molecules. Thus, probes are no library cfDNA molecules.
Therefore, the claims recite elements that constitute new matter. Applicant is required to cancel the new matter in the reply to this Office Action.
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. See 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);and, 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) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
The third sentence of 35 U.S.C. 121 prohibits the use of a patent issuing on an application in which a requirement for restriction has been made, or on an application filed as a result of such a requirement, as a reference against any divisional application in a nonstatutory double patenting rejection, if the divisional application is filed before the issuance of the patent. The 35 U.S.C. 121 prohibition applies only where the Office has made a requirement for restriction. The prohibition does not apply where the divisional application was voluntarily filed by the applicant and not in response to an Office requirement for restriction. The U.S. Court of Appeals for the Federal Circuit has concluded that the protection of 35 U.S.C. 121 does not extend to all types of continuing applications, stating that “the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353, 1362, 86 USPQ2d 1001, 1007-1008 (Fed. Cir. 2008). Here the child application is a continuation, rather than a divisional of the instant application.
Claims 1-4, 6-12, 21-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20, 23-42 of copending Application No. 18/169,821 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
With respect to Claims 1-4, 6-14, the claims of ‘821 are directed to primers and probes of 15-250 bp comprising at least four methylation sites on the amplified DNA. Claim 25 of ‘821 requires a detectable moiety (see instant Claim 12).
The claims of ‘821 require amplifying cell-free DNA with primers that flank a sequence with at least four methylation sites and 15-250bp in length. ‘821 further requires the primers are bar-code sequences or may be attached to a flow cell.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The Applicant requests that this rejection be held in abeyance until allowable subject matter is found in the pending application. This request has been noted and is denied. See 804(I)(b)(1) and 37 C.F.R. 1.111(b), which allows that some objections may be held in abeyance but includes no provision for holding rejections in abeyance. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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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 on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
June 29, 2026
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