DETAILED ACTION
Status of the Claims
Claim 1 has been cancelled by Applicant.
Claims 2-31 have been newly added and are examined herein.
The following Office Action is in response to Applicant’s communication dated 08/08/2025. Rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. Specifically, all objections/rejections of claim 1 are withdrawn in light of Applicant cancelling the claim. The following rejection(s) and/or objection(s) are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Terminal Disclaimer(s)
The terminal disclaimers filed on 04/16/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. patents 12,203,142 B2 and 11,530,454 B2, and any patent granted on Application Numbers 17/692,469, 18/111,790, 19/028,651, 18/753,991, and 19/028,575 have been reviewed and are accepted. The terminal disclaimers have been recorded.
Claim Objections
Claim 20 is objected to as being dependent upon a rejected base claim, but would be free from the prior art if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Appropriate correction is required.
New Claim Rejections – 35 U.S.C. 112(b)
Necessitated by Amendments
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 28-31 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 pre-AIA the applicant regards as the invention.
Claims 28-31 each depend from cancelled claim 1, and therefore the metes and bounds of the claim are unascertainable. In the interest of compact prosecution, they will be treated herein as if they instead depend from independent claim 21.
As per MPEP 2173: It is of utmost importance that patents issue with definite claims that clearly and precisely inform persons skilled in the art of the boundaries of protected subject matter. Therefore, claims that do not meet this standard must be rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph as indefinite. Further, as per MPEP 2173.02: If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112, second paragraph, would be appropriate. As currently written, the metes and bounds of the rejected claims are unascertainable for the reasons set forth above, thus the above claim(s) and all dependent claims are rejected under 35 USC 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
New Claim Rejections – 35 U.S.C. 102
Necessitated by Amendments
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 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)(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.
Diehn et al.
Claims 2-19 and 21-31 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Diehn et al. (U.S. PGPub 2024/0392387, of record).
Regarding claim 2, Diehn discloses a method for preparing a sample of a subject having cancer or suspected of having cancer comprising:
(a) selectively enriching 100 to 100,000 target loci from a first cell-free DNA sample obtained from a first biological sample of the subject to obtain a first set of selectively enriched DNA molecules, wherein the 100 to 100,000 target loci span 100 to 100,000 tumor-specific variants previously identified from a tumor biopsy sample of the subject (e.g., selectively enriching target loci from a cfDNA sample based on a personalized selector set as per [0264], [0273-0274], [0508], [0727-0731], Example 2, and/or Fig. 1A); and
(b) determining the sequence of at least some of the first set of selectively enriched DNA molecules and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus (e.g., as per Fig. 2), and identifying one or more tumor-specific variants present in the first cell-free DNA sample from the sequence reads (e.g., as per [0727-0731], Example 2, and/or Fig. 22), wherein the tumor-specific variants comprise one or more duplications, deletions, inversions, translocations, or a combination thereof (e.g., as per [0509]).
Regarding claim 3, Diehn discloses the above, wherein the tumor biopsy sample of the subject includes a tumor tissue from a solid tumor (e.g., as per [0090]).
Regarding claim 4, Diehn discloses the above, wherein the first cell-free DNA sample is obtained from a blood, plasma, serum, or urine sample of the subject (e.g., as per [0732]).
Regarding claim 5, Diehn discloses the above, wherein the first cell-free DNA sample comprises circulating tumor DNA (e.g., as per [0730]).
Regarding claim 6, Diehn discloses the above, wherein step (a) comprises selectively enriching 100 to 1,000 target loci, wherein the 100 to 1,000 target loci span 100 to 1,000 tumor-specific variants previously identified from a tumor biopsy sample of the subject, wherein the selective enrichment of the target loci is performed using target locus-specific primers or probes in one reaction volume, wherein the first set of selectively enriched DNA molecules are tagged with a plurality of different molecular barcodes.
Regarding claim 7, Diehn discloses the above, wherein step (a) comprises selectively enriching 100 to 200 target loci, wherein the 100 to 200 target loci span 100 to 200 tumor-specific variants previously identified from a tumor biopsy sample of the subject, wherein the selective enrichment of the target loci is performed using target locus-specific primers or probes in one reaction volume, wherein the first set of selectively enriched DNA molecules are tagged with a plurality of different molecular barcodes (e.g., as per [0264], [0273-0274], [0508], [0727-0731], Example 2, and/or Fig. 1A, 22).
Regarding claim 8, Diehn discloses the above, wherein step (b) comprises identifying at least one duplication or deletion present in the first cell-free DNA sample from the sequence reads (e.g., as per [0142] and/or [0243]).
Regarding claim 9, Diehn discloses the above, wherein step (b) comprises identifying at least one inversion or translocation present in the first cell-free DNA sample from the sequence reads (e.g., as per [0141] and/or [0638+]).
Regarding claim 10, Diehn discloses the above, wherein step (b) further comprises identifying at least one single nucleotide variant present in the first cell-free DNA sample from the sequence reads (e.g., as per [0141] and /or [0678]).
Regarding claim 11, Diehn discloses the above, wherein step (b) comprises determining the sequence of at least some of the first set of selectively enriched DNA molecules and obtaining sequence reads with a depth of read of 20,000 to 250,000 per target locus (e.g., as per Fig. 2B).
Regarding claim 12, Diehn discloses the above, wherein the subject is a human subject (e.g., as per [0761]).
Regarding claim 13, Diehn discloses the above, wherein the cancer is colorectal cancer, lung cancer, bladder cancer, or breast cancer (e.g., as per [0090]).
Regarding claim 14, Diehn discloses the above, wherein the method further comprises performing barcoding PCR prior to step (b) (e.g., as per [0056] and/or Example 2).
Regarding claim 15, Diehn discloses the above, wherein the method further comprises the steps of:
selectively enriching 100 to 100,000 target loci from a second cell-free DNA sample obtained from a second biological sample of the subject to obtain a second set of selectively enriched DNA molecules, wherein the 100 to 100,000 target loci span at least one of the 100 to 100,000 tumor-specific variants previously identified from a tumor biopsy sample of the subject; and
determining the sequence of at least some of the second set of selectively enriched DNA molecules and obtaining sequence reads with a depth of read of 10,000 to 500,000 per target locus, and identifying one or more tumor-specific variants present in the second cell-free DNA sample from the sequence reads (e.g., as per [0031] and/or [0141]).
Regarding claim 16, Diehn discloses the above, wherein the first biological sample and the second biological sample are taken from the same subject at different points in time (e.g., as per [0031] and/or [0141]).
Regarding claim 17, Diehn discloses the above, wherein the first biological sample and the second biological sample are taken from the same subject from different sources (e.g., as per [0141]).
Regarding claim 18, Diehn discloses the above, wherein the method further comprises detecting recurrence and/or metastases of the cancer from the tumor-specific variants detected in the first cell-free DNA sample or the second cell-free DNA sample (e.g., as per [0748]).
Regarding claim 19, Diehn discloses the above, wherein the method identifies a tumor-specific variant present in the first cell-free DNA sample or the second cell-free DNA sample at a limit of detection of less than or equal to 0.015% (e.g., as per ¶0471 and/or ¶0733).
Regarding claim 21, Diehn discloses a method for preparing a sample of a subject having cancer or suspected of having cancer useful for identifying one or more tumor-specific variants in a biological sample of the subject, the method comprising:
(a) selectively enriching 100 to 100,000 target loci from a first cell-free DNA sample obtained from a biological sample of the subject to obtain a first set of selectively enriched DNA molecules, wherein the 100 to 100,000 target loci span 100 to 100,000 tumor-specific variants previously identified from a tumor biopsy sample of the subject; and
(b) determining the sequence of at least some of the first set of selectively enriched DNA molecules and obtaining sequence reads, and identifying one or more tumor-specific variants present in the first cell-free DNA sample from the sequence reads (e.g., as per [0264], [0273-0274], [0508], [0727-0731], Example 2, and/or Fig. 1A, 22), wherein the method identifies a tumor-specific variant present in the first cell-free DNA sample at a limit of detection of less than or equal to 0.05% (e.g., as per ¶0471 and/or ¶0733), wherein the tumor-specific variants comprise one or more duplications, deletions, inversions, translocations, or a combination thereof (e.g., as per [0141]).
Regarding claim 22, Diehn discloses the above, wherein the method identifies a tumor-specific variant present in the first cell-free DNA sample at a limit of detection of less than or equal to 0.015% (e.g., as per ¶0471 and/or ¶0733).
Regarding claim 23, Diehn discloses the above, wherein the tumor biopsy sample of the subject includes a tumor tissue from a solid tumor, wherein the first cell-free DNA sample is obtained from a blood, plasma, serum, or urine sample of the subject (e.g., as per [0732]).
Regarding claim 24, Diehn discloses the above, wherein step (b) comprises identifying at least one duplication or deletion present in the first cell-free DNA sample from the sequence reads (e.g., as per [0141]).
Regarding claim 25, Diehn discloses the above, wherein step (b) comprises identifying at least one inversion or translocation present in the first cell-free DNA sample from the sequence reads (e.g., as per [0141]).
Regarding claim 26, Diehn discloses the above, wherein step (b) further comprises identifying at least one single nucleotide polymorphism present in the first cell-free DNA sample from the sequence reads (e.g., as per [0141] and/or [0678]).
Regarding claim 27, Diehn discloses the above, wherein step (b) comprises determining the sequence of at least some of the first set of selectively enriched DNA molecules and obtaining sequence reads with a depth of read of 20,000 to 250,000 per target locus (e.g., as per Fig. 2B).
Regarding claim 28, Diehn discloses the above, further comprising identifying the tumor-specific variants from the tumor biopsy sample by whole genome sequencing (e.g., as per [0274]).
Regarding claim 29, Diehn discloses the above, further comprising identifying the tumor-specific variants from the tumor biopsy sample by whole exome sequencing (e.g., as per [0274]).
Regarding claim 30, the claim requires the above, wherein step (b) comprises identifying at least 10 tumor-specific variants from the sequence reads. Diehn discloses in Figure 5 that whole exome sequencing finds over 200 mutations, while whole genome sequencing finds >15,000. In Example 2 (and elsewhere), Diehn discloses to create selector sets based on tumor mutations found when performing whole exome or whole genome sequencing on tumor biopsy-derived cells, then these “would then be applied for capture of the fragments of interest, sequenced and analyzed in the same manner as the 'off-the-shelf' CAPP-Seq workflow, allowing the tracking and quantitation of those mutations originally discovered in the primary tumor within the corresponding cfDNA.” Diehn also reports that sensitivity of detection of selector sequences in the ctDNA sample can be incredibly high, from 60% to greater than 99% (e.g., as per [0624-0637]), such that there is good reason to believe that at least 10 tumor-specific variants could readily be identified, noting that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
Regarding claim 31, Diehn discloses the above, wherein step (b) comprises identifying at least two tumor-specific variants that are phased alleles from the sequence reads (e.g., as per [0430-0437]).
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Response to Arguments
The 08/08/2025 remarks argue: not all elements are taught.
Applicant's arguments have been fully considered but they are not persuasive for at least the following reasons.
Specifically, the remarks assert that “almost all of Diehn’s disclosure is directed to a methodology that is not tumor-specific and does not require designing a personalized panel specific to each cancer patient.” Applicant acknowledges that Diehn does teach the use of “personalized selector sets” as per at least ¶0264 (which states, inter alia, that “[t]he selector set may be a personalized sector set”) and Example 2 (which states, inter alia, that “[i]n certain circumstances, monitoring tumor burden in a patient known to have cancer is likely to be impractical using an 'off-the-shelf' strategy applying knowledge from a cohort of patients with the same tumor type, to selectively capture genomic regions that are recurrently mutated in that tumor type using CAPP-Seq” and that in such cases “tumor(s) from a patient known to have cancer are genotyped by profiling the tumor genome, exome, or targeted region expected to be enriched for somatic aberrations. The genotype of the cancer may be compared to a genotype of the germline of the same patient. The resulting lesions are then catalogued and used to build a custom, personalized selector comprising a set of biotinylated oligonucleotides for selective hybrid affinity capture of corresponding circulating tumor DNA (ctDNA) molecules”). However, Applicant argues that Diehn criticizes and teaches away from use of such a personalized selector set and therefore cannot be relied upon to anticipate or render obvious the present claims.
This is not persuasive, at least because Diehn does not discourage the use of a personalized selector set, but rather instruct how to apply its use in their method. Example 2 states, inter alia, “[t]he personalized selector would then be applied for capture of the fragments of interest, sequenced and analyzed in the same manner as the 'off-the-shelf' CAPP-Seq workflow, allowing the tracking and quantitation of those mutations originally discovered in the primary tumor within the corresponding cfDNA”).
Furthermore, assuming, arguendo, that this were a nonpreferred embodiment (with which the Examiner does not agree), as per MPEP § 2123, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989), which states “[t]hat the [prior art] discloses a multitude of effective combinations does not render any particular formulation less obvious. This is especially true because the claimed composition is used for the identical purpose taught by the prior art.”
Further, Applicant points to an embodiment of Diehn not relied on in the rejection (e.g., ¶0773 and ¶0778) to assert that “so far as Diehn fails to disclose each and every limitation of claim 2, Diehn cannot anticipate or render obvious the claimed invention”. At least because Applicant is relying on an embodiment not used in the rejection, and there is no indication that it would be relevant to the embodiments that are relied on, such arguments are not persuasive.
On page 9, the remarks cite Diehn as reporting that their ‘off-the-shelf’ selector set finds a median of 4 SNVs per patient, which is ~4-fold more mutations per patient compared to whole exome sequencing. However, this fails to recognize that Diehn is discussing mutations per patient for a ~125 kb region, which is only about 0.004% of the human genome. See Diehn at [0773]. When looking at the whole exome, this will be considerably larger. In fact, in Fig. 5B, Diehn reports finding over 200 mutations per patient in whole exome sequencing, which can be used to make a personalized selector set. Then, Diehn in Example 2 states that such a personalized selector set “would then be applied for capture of the fragments of interest, sequenced and analyzed in the same manner as the 'off-the-shelf' CAPP-Seq workflow” (emphasis added). Therefore, it is reasonable that given 200 (or more) mutations discovered in a biopsy sample, that they would all be used to create the personalized selector set, noting that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
Next, the remarks assert that Diehn does not disclose (as per pending claims 11 and 27) that “determining the sequence of at least some of the first set of selectively enriched DNA molecules and obtaining sequence reads with a depth of read of 20,000 to 250,000 per target locus.” As per Fig. 2B (and as the remarks acknowledge), there is at least a single locus that has a read depth of >20,000, which reads on the limitation of “at least some” in the claim.
Finally, the remarks assert that Diehn does not disclose a limit of detection less than or equal to 0.015% as per claims 19 and 22. In response, as noted in the rejection above, Diehn discloses in at least [0471] and/or [0733] detection limits less than or equal to 0.015%.
Conclusion
No claims are allowed.
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 extension fee 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 date of this final action.
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/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684