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 .
IDS
The IDSs are acknowledged. The signed PTO 1449s have been mailed with this action.
Ref 038 on IDS of 3/26/25 cites Zheng as 2013 and 2015. The citation year is 2013. The year 2015 is lined through on the IDS.
Election/Restriction
Applicant’s species elections with traverse in the reply filed 7/18/2025 are acknowledged. The complete traversal is based upon the grounds that “there is no serious burden upon the Office to examine all the species together”. This is not found persuasive since there is a clear search burden presented by the search required for a suite of species recited relative to a single species. For example, lung cancer is a different form of cancer than bladder cancer, and a search for one species is not coextensive with a search for the other, or for a group of cancer types. Searching more than one species results in an output breadth that is larger than searching a singular species, and thus review of results for a search of multiple species is more complex and time consuming, than searching for, and reviewing the search results, for a single species. The requirement is still deemed proper and is therefore made FINAL.
Drawings
The drawings are objected to because the drawings that must be turned to be read rotate in different directions from one another and should all rotate to the right:
In the current case, the view of some of the Figures, including FIG15,17,18,19A,B, CD and more of the 150 pages of FIGURES. is sufficiently wide that it is necessary to rotate the sheet. However, the orientation of the Figure on the sheet incorrectly necessitates the rotation of the sheet such that the top of the sheet becomes the left hand side. Replacement sheets should be provided that reverses the orientation of the Figure such that the top of the sheet becomes the right hand side after rotation.
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.
Specification
The disclosure is objected to because of the following informalities:
The use of the term TaqMan, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears 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.
Appropriate correction is required.
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 applications, Application No. 61/982,245 (filed 4/21/2014); Application No. 61/987,407 (filed 5/01/2014); Application No. 61/994,791 (filed 5/16/2014; Application No. 62/066,514 (filed October 21, 2014) fail 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.
Claims 1, 11 and 21, drawn to whole exome sequencing from a tumor biopsy, do not have support in the disclosures of these applications. Claims 2-10 and 12-20 that depend from these claims are therefore also not supported.
As well, claims 7, 17, and 18, drawn to clonal and subclonal SNV mutations and clonal heterogeneity of the tumor, also do not have support in the disclosures of these applications. Consequently, the priority date of these claims is April 10, 2015, filing date of the provisional application No. 62/146,188.
Claim Rejections - 35 USC § 112(b)
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 1-21 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.
Claim 1 is indefinite in the recitation of “(a) performing whole exome sequencing to identify a plurality of tumor-specific mutations from a tumor biopsy cancer sample of a subject” since it is not clear how “to identify” occurs since sequencing a biopsy will not identify what bases are mutations, but rather, for example a comparison to healthy sample or matched non-tumor tissue, could be made. Step (b) designing primers encompassing mutations could not be conducted until step (a) identification occurs. Claims 2-10 depend from claim 1 and are indefinite for the same reason. Claim 21 has the same issue as claim 1, in step (a) performing whole exome sequencing on a tumor biopsy sample to identify a plurality of mutations…where again “to identify” suggests a comparison need be made that is not disclosed, to be able to know these are tumor-specific SNV mutations.
Claim 11 is indefinite in the recitation in step a, “mutation previously identified in a tumor biopsy sample”, for which to determine metes and bounds of the claim it would be necessary to know if the phraseology is intended to reference “previously” to this claimed method, or during and as part of, this claimed method. Claims 12-20 depend from claim 11 and are indefinite for the same reason.
Claim 11 is indefinite in the recitation in step c) “determining the presence or absence of one or more tumor-specific mutations based on the sequencing results” however, sequencing results alone do not allow for the determination of the presence or absence of mutations. This would require, for example, comparative methods to make this determination. Claims 12-20 depend from claim 11 and are indefinite for the same reason.
Claim 12 is indefinite in the recitation of “at a subsequent time point” because it is not entirely clear from what the “subsequent time point” is subsequent. This could be referencing, for example: subsequent to the first biological sample, or to the previously identified tumor biopsy, or could mean something different.
Claim Rejections 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3, is a method of claim 1, wherein the method further comprises isolating cell-free DNA from the biological sample of the subject. Whereas Claim 1 disclosed…”from cell- free DNA isolated from a biological sample of the subject”. Further clarification is needed to understand why Claim 3 is further limiting.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1-6, 8-17, 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Diehn (US2016/0032396 A1, filed 3/12/14, priority 3/15/2013) in view of Zheng et al (hereafter Zheng, 2013, International Jour of Oncology, 43: 764) further in view of Mertes et al (hereafter, Mertes, 2011, Brief in Functional Genomics, 10(6): 374-386) further in view of Nguyen-Dumont et al. (hereafter, Nguyen-Dumont, Biotechniques, 2013, V: 55: 69-74; IDS citation) and further in view of Wang et al. (hereafter Wang, 1998, Science, 280: 1077-1082).
Claim 1 recites; a method of detecting tumor-specific mutations comprising: (a) performing whole exome sequencing (WES) to identify a plurality of tumor-specific mutations from subject’s cancer biopsy, (b) design primers to amplify 10+ target loci encompassing tumor-specific mutations from a), (c) performing a multiplex amplification reaction to amplify the at least 10 target loci encompassing the tumor-specific mutations using the PCR primers designed in (b), from cell- free DNA isolated from a biological sample of the subject wherein the biological sample is a blood, serum, plasma (elected), or urine sample, wherein the target loci are amplified together in the same reaction volume; and (d) performing high-throughput sequencing to determine the sequences of the amplified target loci, thereby detecting the tumor-specific mutations in the biological sample.
Claim 3 recites, [t]he method of claim 1, wherein the method further comprises isolating cell-free DNA from the biological sample of the subject.
Claim 11, recites, [a] method for determining the presence or absence of one or more tumor-specific mutations, comprising: (a) performing a multiplex amplification reaction to amplify at least 10 target loci from cell-free DNA isolated from a first biological sample of a subject, wherein the first biological sample is a blood, serum, plasma, or urine sample, wherein the target loci are amplified together in the same reaction volume, wherein the target loci each spans a tumor-specific mutation previously identified in a tumor biopsy sample of the subject by whole exome sequencing of the tumor biopsy sample; (b) determining the sequences of the amplified target loci by high-throughput sequencing; and (c) determining the presence or absence of one or more tumor-specific mutations based on the sequencing results, thereby monitoring the progression of cancer.
Claim 21,recites, [a] method for detecting tumor-specific mutations, comprising: (a) performing whole exome sequencing on a tumor biopsy sample of a subject to identify a plurality of tumor-specific SNV mutations; (b) designing PCR primers for amplifying at least 50 target loci encompassing the tumor- specific SNV mutations identified in (a); (c) isolating cell-free DNA from a biological sample of the subject; (d) performing a multiplex amplification reaction to amplify the at least 50 target loci encompassing the tumor-specific SNV mutations using the PCR primers designed in (b), from cell-free DNA isolated from a biological sample of the subject, wherein the biological sample is a blood, serum, plasma, or urine sample, wherein the target loci are amplified together in the same reaction volume; and (e) determining the sequences of the amplified target loci for the presence or absence of the tumor-specific SNV mutations, wherein the sequences of the amplified target loci are determined by high-throughput sequencing, and wherein the depth of read for each of the target loci is at least 50,000.
Re: claims 1, 3, 11, and 21 Diehn employs WES to genotype tumor from solid tumor of an individual (cancer) subject identifying mutations in the individual (Diehn [0015][0270][0271][0012][0559] [0785]).
Diehn then uses this information, identifies the regions with mutations [0270] and enriches for tumor specific mutations by hybrid selection for cfDNA (ctDNA) (also claim 3) that is amplified and sequenced, to determine which selected mutations are present (used in diagnosis or for monitoring) [0015], from blood plasma ([0046][0016] [0443] [0702]), high throughput sequencing (claim 12 [0053][0137]). Diehn further disclosed that as an alternative to affinity-based hybrid capture of ct/cf DNA, amplicons specific to the corresponding region could be interrogated by PCR, with fragments selectively indexed [0915]. The cell-free sample is compared to tumor DNA from the individual [0022]. Initial comparison can also be made with individual’s germline and tumor biopsy to distinguish ctDNA from germline DNA [0015].
Diehn used hybrid selection and probes [0021] to enrich, and did not disclose much detail on multiplexed PCR and targeted primers. Re: claim 11: Diehn uses sequence information to determine the presence/absence of mutations in the selected region ([0092] [0476] [0770], monitoring [0015] [0029]).
Zheng also conducted whole exome sequencing and identified a plurality of tumor-specific mutations from a subject’s lung cancer tissue biopsy (Abstract ln 7; tumor tissue: Pg 756, left col para 2 one patient; para 3), one 55-year-old male patient’s tumor and normal tissue whole exome sequencing (Pg 756, left col para 3, final 3 lines).
Zheng confirmed the SNVs by PCR amplification with primers designed to specific SNVs (Pg 756, left col, penult para; Pg 756 last para – 757 left col, first para).
Zheng did not mention using one volume for multiplexed samples.
Prior to the effective filing date of the instant application, it would have been prima facie obvious to one of ordinary skill in the art to have used the primers design of Zheng in the method of Diehn in lieu of Diehn’s probe hybridization method, given the benefit as discussed by Mertes, who also did disclose single volume multiplex:
Mertes teach selection and enrichment of sequences used in next generation sequencing (NGS). Mertes depicts multiplex PCR in a single tube, explicitly distinguishing it from traditional PCR with one tube per fragment assay, and multiple PCR with up to 50 fragments (Pg 376 FIG 1) (re: instant claim 21). Mertes et al. particularly teach that selection and enrichment of sequences to be used in next generation sequencing (NGS) can be performed using one of three methods: hybrid capture, selective circularization and PCR (page 375, fourth paragraph; Fig. 1; page 379, last two paragraphs; page 380, paragraphs 1-3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used single tube multiplex amplification as suggested by Mertes et al. in the method of whole exome sequencing of Diehn et al. as modified by Zheng for PCR, as further modified and motivated by Mertes to multiplex in a single tube with the motivation to do so provided by Mertes et al. (page 379, fifth paragraph):
“Enrichment by PCR (Figures 1.3a–c) is in terms of methodology, a more straightforward method compared with the other genome partitioning techniques. It takes advantage of the great power of PCR to enrich genome regions from small amounts of target material. Just as for circularization methods, if the PCR product sizes fall within the sequencing length of the applied NGS platform (maximum read length for SOLiD: 110 bp, Illumina: 240 bp and 454: 1000 bp) PCR-based enrichment can allow one to bypass the need for shot-gun library preparation by using suitably 50-tailed primers in the final amplification steps.”
Reasonable expectation of success is provided by the references of Nguyen-Dumont et al. and Wang et al. Nguyen-Dumont et al. disclosed successful amplification of 60 different target in a single PCR reaction (Abstract; page 70, third paragraph; page 72, paragraphs 4 and 5).
Re: claim 2, 13, 21 Diehn disclosed tumor alleles sequencing depth, 100X or more, ([0429]).
Re: claims 4, 5, 6, 15,16, 17: Diehn detects SNVs and CNV, (clonal) and subclonal mutations ([0024]; Fig. 4A-D; [0446]; [0804]).
Re: claim 8, 19, Diehn disclosed amplification of 50+ loci from cell-free DNA (claim 43; [0015]; [0398]; [0485]; [0492]-[0493]; [0523]; [0915])
Re: claim 9, 20 the cancer is lung cancer, Diehn ([0027] [0449] [0063] [0088] [0785]).
Re: claim 10, 12 Diehn disclosed repeated testing of biological samples obtained at multiple timepoints to monitor progression (Abstract, Fig. 4A-C; Fig. 6; [0015]; [0020]; [0029]; [0328]; [0765] [0915]; [0800] pre and post radiotherapy plasma cfDNA evaluation).
Re: claim 14, Diehn disclosed cell-free DNA comprises ctDNA, Diehn ([0804] [0807]; for multiple time points, multiple samples, second patient, cfDNA contained ctDNA pre and post radiation [0800]).
Claims 7 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Diehn et al. (US 2016/0032396 A1; filed March 12, 2014) and Peterson et al (hereafter, Peterson, 2014, BMC Bioinformatics, 15(Suppl 11): S9).
Diehn et al. teach detection of cancer-specific mutations and detection of (clonal and) subclonal mutations, but do not specifically teach determining clonal heterogeneity of the tumor biopsy.
Peterson addressed tumor heterogeneity for multiple myeloma, a bone marrow cancer, with bone marrow samples, obtained at three time points (Pg 2, left col, para 2 and right col, para 2). Whole exome capture libraries were constructed from 100ng of tumor (and normal DNA samples), multiplexed and sequenced at a depth of 100X (Pg 2, right col, Para 3). Intraclonal heterogeneity at the level of SNVs was depicted (Pg 3, right col, para 2); clonal populations were visualized by calculating percent mutant variant reads for all acquired mutations and adjusting for copy number (Pg 4, Left col, para 1, Fig 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the methods of Peterson into the methods of Diehn et al. to determine clonal heterogeneity of tumor sample from tumor sample, Peterson directly used a marrow sample and WES for a bone marrow cancer analysis, and developed a methodology (CloneViz) to identify clonal heterogeneity in the samples. Use of the methodology would have aided Peterson in determining clonal heterogeneity from WES.
Conclusion
All claims rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lisa Horth whose telephone number is (703)756-4557. The examiner can normally be reached Monday-Friday 8-4 EST.
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/LISA HORTH/ Examiner, Art Unit 1681
/GARY BENZION/ Supervisory Patent Examiner, Art Unit 1681