Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of the Claims
Claims 1-20 are pending and the subject of this FINAL Office Action.
Large IDS With Multiple Irrelevant References
Applicants filed 80 pages of IDS with over 1,000 listed references. First, it is impossible to search in detail through all 1,000-plus references in any reasonable amount of time. Second, this is not the first application in this family of applications; in fact, there are over 100 others. Applicants have had ample opportunity to winnow their IDS down to only claim-relevant references. Furthermore, after a random skim of the references within the incredibly limited time allotted to the Examiner, the Examiner determines that many of the references are irrelevant to the claimed subject matter, having nothing to do with the allele-frequency system claimed. Which leads to the larger problem: which references are relevant, and why were these seemingly irrelevant references filed? Before filing an IDS, Applicants have a duty to examine the references themselves and determine which references are reasonably pertinent to the claimed invention. If any particular preference(s) is/are directly pertinent to the claimed invention, then Applicants are encouraged to point this out in the form of a new IDS.
Yet more references were filed in IDSs on 03/11/2026 and 07/07/2026. The fecund filings continue.
Claim interpretations
Claim 1 is directed to a composition (i.e. product) with the following generic structure:
Plurality (i.e. two or more) of DNA molecules each comprising an amplicon that spans polymorphic cite (e.g. indel, SNP, deletion, etc.) and a generic universal priming sequence.
All other claim language merely recite intended uses of the composition, or product-by-process language; thus, they fail to distinguish the composition over the prior art. For example, “amplicons derived from a first individual and amplicons derived from a second individual” fails to necessarily yield any different compositional features because this encompasses the same sequences. “[O]batined from obtained from targeted multiplex amplification of 50-20,000 polymorphic loci” similarly fails to necessarily require the presence of those loci; rather, only the attempt to amplify them, whether successful or not. “[P]erformed on cell-free DNA isolated from a biological sample of the second individual or DNA derived therefrom” again only recites a type of DNA, which can have sequence added to it (e.g. primer tails), or fall within standard sequence sizes (e.g. 50-300bp). Finally, “wherein at least 80% of all amplicons in the composition map to the polymorphic loci” only states that 80% of the amplicons map (whatever this generic term means here) to amplified polymorphic loci, which can be 0-20,000, based on the success of the amplification. Even if all of these processes yielded physical features, yet they only yield generic, well-known physical features, as demonstrated by the art cited below. Thus, the broad claims encompass much prior art.
Claim Rejections - 35 USC § 112- Indefiniteness - Withdrawn
The claim amendments now make clear that the sample is from a second individual, and that second individual has nucleic acids from a first individual (e.g. pregnant woman, transplant recipient, blood transfusion, etc.).
Claim Rejections - 35 USC § 102 - Maintained
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) A person shall be entitled to a patent unless –
(1)the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention; or
(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.
Claims 1-20 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by MAY (US20100273219).
As to claim 1, MAY teaches a composition comprising a plurality of DNA molecules (e.g. in multiplex amplification, or pooled for sequencing after separate reactions of 50-1,000,000; paras. 0039, 0059-60, 0127, 0164, 0173, 0175, 0203, 0267-70) each comprising an amplicon and a universal priming sequence 454 (Abstract; Figs. 10, 15 & 18; paras. 0129, 0137, 0151, 0222), wherein the DNA molecules comprise a mixture of amplicons derived from a first individual and amplicons derived from a second individual, wherein the amplicons derived from the first individual and the amplicons derived from the second individual are obtained from targeted multiplex amplification of 50-20,000 polymorphic loci (50-1,000,000 loci; id.) performed on cell-free DNA isolated from a biological sample of the second individual or DNA derived therefrom, wherein at least 80% of all amplicons in the composition map to the polymorphic loci (Figs. 14 & 16, showing all polymorphic loci amplicons with at least one read).
As to claim 2, the source is immaterial to the resulting amplicon, yet MAY teaches the biological sample is a blood, serum, plasma, or urine sample (para. 0143, for example).
As to claim 3, the purpose is merely an intended use, yet MAY teaches the composition is a sequencing library (Figs. 14 & 16, for example).
As to claim 4, the purpose is merely an intended use, yet MAY teaches the DNA molecules each comprises a sequencing tag for high-throughput sequencing (Figs. 10, 15 & 18).
As to claim 5, the purpose is merely an intended use, yet MAY teaches the DNA molecules each comprises a sample index for multiplex sequencing (Figs. 10, 15 & 18; Abstract; paras. 0061, 0086, 0107, 0127-29)
As to claim 6, MAY teaches the DNA molecules each comprises a molecular barcode (id.) A generic “molecular barcode” is indistinguishable from any other “barcode” in MAY. Regardless, MAY in paragraphs 0127-29 discusses multiple barcodes, “a number (J) of first barcode primers can be combined with a number (K) of second barcode primers to create J×K unique amplification products.”
As to claim 7, the source is immaterial to the resulting amplicon, yet MAY teaches the first individual is a fetus (para. 0143).
As to claim 8, the source is immaterial to the resulting amplicon, and does not change the resulting amplicon of DNA.
As to claim 9, MAY teaches the polymorphic loci comprise SNP loci (para. 0105, for example).
As to claim 10, MAY teaches the polymorphic loci comprise indel loci (para. 0104).
As to claim 11, the intended targets and their successful amplification are immaterial to the actual amplicons, yet MAY teaches the amplicons are obtained from targeted multiplex amplification of 50-5,000 polymorphic loci (50-1,000,000 loci; paras. 0129, 0137, 0151, 0222).
As to claim 12, the intended targets and their successful amplification are immaterial to the actual amplicons, yet MAY teaches the amplicons are obtained from targeted multiplex amplification of 100-2,000 polymorphic loci (id.)
As to claim 13, the intended targets and their successful amplification are immaterial to the actual amplicons, yet MAY teaches the amplicons are obtained from targeted multiplex amplification of 200-1,000 polymorphic loci (id.)
As to claim 14, the intended results are immaterial to the actual amplicons, yet MAY teaches at least 90% of all amplicons in the composition map to 50-5,000 polymorphic loci (e.g. Figs. 14 & 16, showing all polymorphic loci amplicons with at least one read).
As to claim 15, the intended results are immaterial to the actual amplicons, yet MAY teaches, at least 90% of all amplicons in the composition map to 100-2,000 polymorphic loci (id.)
As to claim 16, the intended results are immaterial to the actual amplicons, yet MAY teaches at least 90% of all amplicons in the composition map to 200-1,000 polymorphic loci (id.)
As to claim 17, the intended results are immaterial to the actual amplicons, yet MAY teaches at least 95% of all amplicons in the composition map to 50-5,000 polymorphic loci (id.)
As to claim 18, the intended results are immaterial to the actual amplicons, yet MAY teaches at least 95% of all amplicons in the composition map to 100-2,000 polymorphic loci (id.)
As to claim 19, the intended results are immaterial to the actual amplicons, yet MAY teaches at least 95% of all amplicons in the composition map to 200-1,000 polymorphic loci (id.)
As to claim 20, the intended results are immaterial to the actual amplicons, yet MAY teaches one or more of the polymorphic loci are located on one or more chromosomes expected to be disomic (e.g. para. 0246).
Response to Arguments
The rejection is maintained because the claimed composition is anticipated. The simple fact is that the composition need only contain double or single-stranded DNA, one from a first individual (mouse, human, rat, fly, worm, fish, etc.) and another from a second individual, the DNA including a “universal priming sequence,” all in a single volume. Applicants fail to explain how a cell-free DNA is structurally different from any other DNA such that the resulting DNA amplicon is any different (e.g. in sequence). Further, nothing in the claim requires any particular structural feature of the amplicon that sets it apart from any other DNA (e.g. size/length). Nor does the claim require any particular number of loci to actually be amplified in either the first or second individual DNA. Applicants simply mischaracterize their claim scope, which broadly encompasses two DNA amplicons of any length and sequence with a generic “universal priming sequence” and generic “polymorphic locus.”
To this end, MAY very clearly teaches multiplex amplification, or pooled for sequencing after separate reactions of 50-1,000,000 (paras. 0039, 0059-60, 0127, 0164, 0173, 0175, 0203, 0267-70) each comprising an amplicon and a universal priming sequence 454 (Abstract; Figs. 10, 15 & 18; paras. 0129, 0137, 0151, 0222), wherein the DNA molecules comprise a mixture of amplicons derived from a first individual and amplicons derived from a second individual (e.g. fetus in pregnant woman; para. 0143); and even teaches wherein the amplicons derived from the first individual and the amplicons derived from the second individual are obtained from targeted multiplex amplification of 50-20,000 polymorphic loci (50-1,000,000 loci; id.) performed on cell-free DNA isolated from a biological sample of the second individual or DNA derived therefrom, wherein at least 80% of all amplicons in the composition map to the polymorphic loci (Figs. 14 & 16, showing all polymorphic loci amplicons with at least one read).
Double Patenting- Obvious Type - Maintained
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 obviousness-type 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); 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) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
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).
Instant claims 1-20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over conflicting claims of US 8682592, US 9430611, US 9695477, US 10227652, US 10061890, US 10061889, US 11111543, US 11111544, US 9163282, US 10017812, US 10174369, US 12020778, US 12270073, US 9228234, US 10216896, US 10522242, US 11306357, US 11408031, US 11746376, US 10526658, US 10538814, US 10557172, US 10655180, US 10731220, US 10793912, US 11519035, US 12110552, US 10590482, US 10774380, US 11339429, US 11332785, US 12152275, US 11312996, US 12410476, US 11332793, US 11939634, US 11326208, US 18/227224, US 18/243581, US 18/220183, US 18/585708, US 16/803782, US 17/529536, US 19/029107, US 18/931842, US 18/126344, US 18/243593, US 19/028937, US 16/734814, US 16/817117, US 17/868141, US 18/751175, US 18/751153, US 18/751083, US 19/327646, US 17/196659, US 18/733471, US 18/678417, US 18/733659, US 17/545881, US 17/196722, US 18/792372, US 18/747138, US 17/842118, US 18/812696, US 18/885063.
There are hundreds of Natera-assigned, and common-inventor applications and patents. If prosecution continues, not only will the claims change because it is clear they are anticipated, even more it would take an inordinate amount of time to produce detailed rejections for each of the applications and patents. Thus, the Examiner has simplified the rejections in the interest of time.
The instant claims are obvious over the conflicting claims each of the conflicting claims teaches compositions of amplicons with the same universal primer-SNP amplicon structure, or methods of making them. More specifically, demonstrative conflicting claims teach:
1. A method for nested PCR amplification, comprising:
isolating cell-free DNA from a biological sample and ligating adaptors to the isolated cell-free DNA, wherein the adaptors each comprise a universal priming sequence;
performing a first PCR to simultaneously amplify at least 10 target loci using a first universal primer and at least 10 target-specific primers in a first reaction volume; and
performing a second, nested PCR to simultaneously amplify the at least 10 target loci using a second universal primer and at least 10 inner target-specific primers in a second reaction volume to obtain amplified DNA, wherein primer binding sites of the inner target-specific primers of the second PCR are internal to primer binding sites of the target-specific primers of the first PCR, wherein at least 80% of the amplified DNA maps to the target loci.
2. The method of claim 1, wherein the biological sample is a blood, plasma, serum, or urine sample.
3. The method of claim 1, wherein the adaptors each comprise a molecular barcode.
4. The method of claim 1, wherein at least one of the primers comprises a sequencing tag.
5. The method of claim 1, wherein the adaptors each comprise a molecular barcode, and wherein at least one of the primers comprises a sequencing tag.
6. The method of claim 1, wherein the first PCR comprises simultaneously amplifying between 100 and 5,000 target loci using the first universal primer and between 100 and 5,000 target-specific primers in the first reaction volume.
7. The method of claim 6, wherein the second PCR comprises simultaneously amplifying between 100 and 5,000 target loci using the second universal primer and between 100 and 5,000 inner target-specific primers in the second reaction volume.
8. The method of claim 1, wherein the first PCR comprises simultaneously amplifying between 100 and 1,000 target loci using the first universal primer and between 100 and 1,000 target-specific primers in the first reaction volume.
9. The method of claim 8, wherein the second PCR comprises simultaneously amplifying between 100 and 1,000 target loci using the second universal primer and between 100 and 1,000 inner target-specific primers in the second reaction volume.
10. The method of claim 3, wherein the isolated cell-free DNA are tagged with up to 1024 different molecular barcodes.
11. The method of claim 3, wherein the isolated cell-free DNA are tagged with 1024-65536 different molecular barcodes.
12. The method of claim 1, wherein the concentration of each target-specific primer of the first and/or second PCR is less than 20 nM.
13. The method of claim 1, wherein the concentration of each target-specific primer of the first and/or second PCR is less than 10 nM.
14. The method of claim 1, wherein the length of the annealing step of the first and/or second PCR is at least 3 minutes.
15. The method of claim 1, wherein the length of the annealing step of the first and/or second PCR is at least 5 minutes.
16. The method of claim 1, wherein at least 90% of the amplified DNA maps to the target loci.
17. The method of claim 1, wherein the target loci are SNP loci.
18. The method of claim 1, wherein the cell-free DNA comprises DNA from a fetus.
19. The method of claim 1, wherein the cell-free DNA comprises DNA from a tumor.
20. The method of claim 1, wherein the cell-free DNA comprises DNA from a transplant.
21. The method of claim 1, wherein amplified DNAs of multiple samples are pooled and sequenced in a single sequencing lane.
Thus, the conflicting claims teach the same resulting composition as claimed here.
Response to Arguments
The rejections are maintained because Applicants have been put on proper notice of their own claim sets that are subject to double patenting rejections. Each one of the claim sets includes compositions with the same subject matter (multiplex loci amplification in single volumes from pregnant woman, transplant recipient, etc.). Applicants have created their own mess by filing an enormous number of applications and expecting the Office to make individual obvious-type double patenting rejection for each, which would require hours, if not days of work, which Applicants would then merely ask for an abeyance, or amend the claims. Applicants are well-aware of their own claims. If any particular claims listed above are not anticipatory of render obvious the instant claims, then Applicants are welcome to point this out. Applicants have been put of reasonable notice of which claim sets of which patents and applications are subject to double patenting rejections.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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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/AARON A PRIEST/Primary Examiner, Art Unit 1681
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