DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ arguments, filed November 17, 2025 have been fully considered and they are persuasive in-part. The following rejections are either reiterated or newly applied as necessitated by amendment. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Status of the Claims
Claims 75, 83, 86, 88-90, 99, and 101-112 are under examination.
Claims 77-82, 84, 85, 87, 92-98 and 100 are withdrawn.
Claim Rejections - 35 USC § 112
2. 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.
Claim 112 is 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 term “higher” or “lower” in claim 112 is a relative term which renders the claim indefinite. The term “higher” or “lower” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
This rejection is necessitated by amendment.
Claim Rejections - 35 USC § 101
3. 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 75, 83, 86, 88-90, 99, and 101-112 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claims 75, 83, 86, 88-90, 99, and 101-112 are directed to method of determining the expression profile of a subject. As described in Alice Corp. Pty. Ltd. V. CLS Bank Int’l, 573 U.S._, 134 S. Cr. 2347, 110 U.S.P.Q.2d 1976 (2014), a two-step analysis is required in considering the patent eligibility of the claimed subject matter. The first step requires determining if the claimed subject matter is directed to a judicial exception. The instant claims require the steps of aligning a plurality of sequence reads to a reference genome and computer processing the aligned sequences reads to determine an expression profile. However, these steps are drawn to a mental step or a mathematical algorithm. Dependent claims 83, 86, 99, and 109 recite additional characteristics of the mathematical algorithm. Dependent claims 88 and 89 recite the source of the data. Mental steps are a judicial exception. The courts have found mathematical algorithms to be drawn to the judicial exception of an abstract idea (In re Grams, 888 F.2d 835, 12 U.S.P.Q.2d 1824 (Fed. Cir. 1989)). Thus, the instant claims are drawn to a judicial exception.
This judicial exception is not integrated into a practical application. The instant claims do not recite an element that reflects an improvement in the functioning of a computer or other technology, an element that applies the judicial exception to effect a particular treatment, an element that implements the judicial exception with a particular machine, or an element that effects a transformation of a particular article to a different state or thing. The instant claims recite the additional steps of obtaining a nucleic acid sample, purifying the nucleic acid sample, enriching nucleic acid samples, using a probe set, sequencing enriched nucleic acid samples, and a computer processor. The instant claims do not recite any structural limitations of the computer processor. Thus, the instant claims do not recite a particular machine. Obtaining a nucleic acid sample, purifying the nucleic acid sample, enriching nucleic acid samples, using a probe set, sequencing the enriched nucleic acid samples, amplifying the enriched nucleic acid sample, separating one or more type of nucleic acid molecules, and removing higher or lower molecular weight nucleic acid sequences are data gathering steps. Data gathering steps are extra solution activity which are not sufficient to integrate the judicial exception into a practical application (MPEP §2106.05(g)). The instant claims do not integrate the judicial exception into a practical application.
The second part of the analysis requires determining if the claims include additional elements that are sufficient to amount to significantly more than the judicial exception. The instant claims recite the additional elements of obtaining a nucleic acid sample, purifying the nucleic acid sample (isolating cfDNA), enriching nucleic acid samples, using a probe set, sequencing enriched nucleic acid samples, amplifying the enriched nucleic acid sample, separating one or more type of nucleic acid molecules, and removing higher or lower molecular weight nucleic acid sequences and a computer processor. The steps of obtaining a nucleic acid sample, purifying the nucleic acid sample (isolating cfDNA), enriching nucleic acid samples, using a probe set, sequencing enriched nucleic acid samples, amplifying the enriched nucleic acid sample, separating one or more type of nucleic acid molecules, and removing higher or lower molecular weight nucleic acid sequences are well-known, routine, and conventional data gathering steps (Aarthy et al., “Role of Circulating Cell-Free DNA in Cancers” Molecular Diag. Therp. (2015) Volume 19, number 6, pages 339-350, especially pages 341, 342 and 344; Mamanova, et al. “Target-Enrichment Strategies for Next-Generation Sequencing” Nature Methods (2010) volume 7, number 2, pages 111-118, especially pages 114 and 15). The use of a computer processor is well-understood, routine, and conventional for implementing a mathematical algorithm (Specification, pages 31-37). Reciting such well-understood, routine, and conventional elements do not transform a judicial exception into patent eligible subject matter. In addition, the recitation of the specific types of data or source of data, as in instant claims 88 and 89, to be used in the judicial exception does not transform the abstract idea into a non-abstract idea. (See buySAFE, Inc. v Google, Inc. 765 F.3d 1350, 112 U.S.P.Q.2d 1093 (Fed.Cir.2014)). Furthermore, the elements taken as a combination are also well-understood, routine, and conventional, since the elements are merely specifying gathering data for the judicial exception and processing the judicial exception on a computer. Thus, the instant claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Response to Arguments
4. Applicants have responded to this rejection by amending the claims and stating that it was not well-understood, routine, or conventional for one of skill in the art to perform "(b) purifying said nucleic acid sample to obtain a purified nucleic acid sample; [and] (c) enriching said purified nucleic acid sample, wherein said enriching comprises contacting said purified nucleic acid sample with a probe set comprising hybridization probes having sequence complementarity to said plurality of TSS, wherein said plurality of TSS comprises at least two genomic regions selected from the group listed in TABLE 2, wherein each genomic region of said at least two genomic regions comprises a chromosomal start region coordinate and a chromosomal stop region coordinate, wherein said probe set has an enrichment efficiency for said plurality of TSS that is greater than an enrichment efficiency for other regions of a genome of the subject". However, purifying (isolating) a nucleic acid sample and enriching that sample with a probe set is well-understood conventional and routine. (Aarthy et al., “Role of Circulating Cell-Free DNA in Cancers” Molecular Diag. Therp. (2015) Volume 19, number 6, pages 339-350, especially pages 344; Mamanova, et al. “Target-Enrichment Strategies for Next-Generation Sequencing” Nature Methods (2010) volume 7, number 2, pages 111-118, especially pages 114 and 15). In addition, Mamanova et al. teaches it is well-understood in the art to perform targeted amplification by contacting probes hybridizing probes to a sequence and sequencing the amplified nucleic acids (pages 114 and 115). This method of enriching and sequencing may be applied to any type of nucleic acid. Thus, it would have been well-understood, conventional and routine to apply the method of enriching with hybridization probes and sequencing the enriched nucleic acids to the sequence of TABLE 2. Furthermore, the purpose of targeted amplification is to amplify only the targeted nucleic acid. The hybridizing probes would be specific to the targeted nucleic acid (such as a sequence of Table 2) and would necessarily have a greater enrichment efficiency for the targeted nucleic acid than for other regions of the genome of the subject. Thus, the instant claims do not recite an element that is significantly more than the judicial exception.
This rejection is maintained and modified as necessitated by amendment.
Double Patenting
5. 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 75, 83, 86, 88-90, 99, and 101-112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 10, 14, 17, 21, and 26 of copending Application No. 18/163,106 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 75, 90 and 86 recite similar limitations as in claims 1 and 5 of the reference application. The instant claims differ in that claims 1, 5 and 25-27 of the reference application includes the additional step of processing the TSS availability profile to detect cancer. Thus, the instant claims encompasses the subject matter of the reference application and are not patentably distinct.
Instant claims 83 and 99 recite similar limitations as claims 14 of the reference application. The claims differ in that claim 14 of the reference application include additional mathematical algorithms. us, the instant claims encompasses the subject matter of the reference application and are not patentably distinct.
Instant claim 86 recites where the quantifying sequence reads determine the transcriptional availability of the regulatory elements which is recited in claim 1 of the reference application. Thus, the claims are not patentably distinct.
Instant claims 88 and 89 recite where the subject is with or without cancer, which is recited in claim 1 of the reference application. Thus, the claims are not patentably distinct.
Instant claims 101-112 recite similar limitations as in claims 10, 17, 21, 26, and 28 of the reference application. Thus, the claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
6. Applicants state that the amendments are sufficient to distinguish the instant claims form the claims of the reference application. However, the amended limitations of instant claims 75 and 90 are found in claims 5 and 25-27 of the reference application. The instant claims are not patentably distinct from the claims of the reference application.
This rejection is maintained and modified as necessitated by amendment.
Withdrawn Rejections
7. Applicant’s arguments and amendments, filed November 17, 2025, with respect to the rejection made under 35 U.S.C. §112 regarding TABLE 2 have been fully considered and are persuasive. Applicants have submitted TABLE 2, and there is no practical method of including TABLE 2 in the instant claims. These rejections have been withdrawn.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JERRY LIN whose telephone number is (571)272-2561. The examiner can normally be reached T-F 7am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached at (571) 272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JERRY LIN/Primary Examiner, Art Unit 1685