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 .
Claims 1-18 are pending and will be examined.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 60703415, 60739882, 60742305, 8532930, 8515679, 8682592, 9424392, 10083273, 9430611, 10179937, 10227652, 11306359, 11111543, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. None of the claimed priority documents provide enabling support for each of the steps and features of the method, as claimed. While many of the priority documents provide support for the steps related to cell-free DNA, adaptor ligation, universal amplification and enrichment, none of the priority documents provide specific, enabling support for targeted or selective enrichment of at least 1000 preselected loci.
The claimed method is therefore provided an earliest effective date of the filing date of the instant application, November 24, 2025.
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 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12486542 in view of Lee et al. (Cancer Lett, 2013, 340, 171-178).
While the claims are not identical the instant claims are not patentably distinct from the claims of the ‘542 Patent. The primary difference between the instantly claimed method and the claims of the ‘542 Patent is the inclusion of treatment of the extracted cell-free DNA with an agent that discriminates between methylated and unmethylated cytosines. Many aspects of the method, as claimed, are captured within dependent claims. Compare, for instance, instant claims 3-4 to claims 5-6 of the ‘542 patent where overlapping ranges of enriched preselected loci are claimed. Compare instant claim 5-6 to claims 7-8 of the ‘542 patent where the same steps of selective enrichment are described.
Finally, while the agent that distinguishes between methylated and unmethylated cytosines is not recited in main claim 1, instant claim 11 is focused on differential methylation, as captured by the claims of the ‘542 patent. Further, the agent which distinguishes between methylated and unmethylated cytosines is bisulfite (see claim 11 of the ‘542 patent), a known agent useful for this type of treatment.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of the instant claims to include treatment with a bisulfite agent to distinguish between methylated and unmethylated cytosines to arrive at the claimed invention with a reasonable expectation for success. Lee teaches “Accumulating evidence has indicated that epigenetic alterations are at least as common as, if not more frequent than, mutational events in the development of cancer [13]. Compared to normal cells, the malignant cells exhibit overall genomic hypomethylation (primarily in repeat elements and pericentromeric regions), but simultaneously show hypermethylation of normally protected CGIs [14,15]. Hypermethylation within promoters serves to turn off critical tumor suppressor genes that could otherwise suppress tumorigenesis [15]. Given their important functions in cancer ini tiation and progression, aberrant methylation patterns may be used as biomarkers for diagnosis and prognosis of cancer [16]” (p 171, col 2). Lee also teaches “Due to the conversion of unmethylated cytosine to thymine after bisulfite treatment and PCR, different cleavage products are generated for methylated and unmethylated DNA” (p 172, col. 1). Lee also teaches “Tens of millions of bisulfite sequencing reads can be generated for each sample using the TBS-seq approaches discussed above. Analyzing the bisulfite sequencing data is quite challenging because the sequence reads do not exactly match the reference genome, and the complexity of sequences is reduced due to bisulfite conversion. The bisulfite treatment and subsequent PCR amplification results in the conversion of unmethylated cytosines to thymine without changing methylated cytosines. Therefore, Ts in bisulfite sequencing reads are ambiguous during the sequence alignment process because they can be either original Ts or unmethylated Cs converted by bisulfite-treatment. Two basic strategies have been developed to map the bisulfite sequences to the reference genome” (p 176, col. 1). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of the instant claims to include treatment with a bisulfite agent to distinguish between methylated and unmethylated cytosines to arrive at the claimed invention with a reasonable expectation for success with a reasonable expectation for success.
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 1-18 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 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.
The claimed method, as currently recited, is not supported by the disclosure of the instant specification or any of the claimed priority documents. While the specification teaches the primary steps of the method as including extraction of cell free DNA from blood, performing selective enrichment, performing universal amplification on adapted DNA to generate amplified adapted DNA and performing massively parallel sequencing, the specification does not specifically or generally teach essential steps of the method, as claimed.
Specifically, neither the instant specification or any of the claimed priority documents teach “selectively enriching for at least 1000 preselected loci from the amplified adapted DNA”. Next, while the specification teaches aspects of methylation analysis related to cancer, and mentions terms like cancer or tumor or epigenetics, none of these documents provide either general or specific description to support the claimed method which includes “using sequence reads of the preselected loci to identify one or more genetic or epigenetic features associated with cancer”.
Further, while the specification teaches multiplex amplification, the specification does not focus on specific support for selective or preferential enrichment of “at least 1,000 preselected loci.. and generating enriched DNA”.
Guidance in the specification
Regarding the subject matter and claim terminology of selective enrichment, while the specification provides discussion of enrichment, the specification does not provide specific support for enrichment of a particular number of loci, let alone 1000 preselected loci. Further, the specification also does not provide any support for the terminology of “preselected loci” as claimed. At most, the specification provides support for selective enrichment steps that do not include enrichment of a particular number of loci. See paragraph 408, 417, 564 and 719. Regarding the term “preselected loci”, at most the specification provides support for selected loci (see paragraph 720) and yet that teaching is specific for non-invasive prenatal diagnosis.
Finally, while the specification and the claimed priority documents provide general support for the application of the method of adaptor ligation and universal amplification to loci associated with diseases, incluing cancer. When the specification mentions epigenetics and methylation differences the specification notes “differential methylation between the maternal and fetal cells at specific alleles” (paragraph 553).
While the specification provides written description for many steps within the method, Applicant has not demonstrated possession of the claimed method.
Citation of Pertinent Prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Cai et al. (Scientific Reports, 2019, 9:18962, p 1-8) and Singh et al. (Diagnostics, 2022, 12:1539).
Conclusion
No claims are allowed. All claims stand rejected.
The claim method, as currently recited, are free of the art because while there are references that teach extraction of cell free DNA, selective enrichment and steps of adaptor ligation and universal amplification, none of the prior art teaches selective enrichment of at least 1000 loci which include cell free DNA, as claimed. Therefore the claims are free of the art but stand rejected for other reasons.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE KANE MUMMERT whose telephone number is (571)272-8503. The examiner can normally be reached M-F 9:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681
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