FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Amendment filed 27 January 2026. Claim 1 has been amended, claims 5-6 have been canceled, and claims 10-12 have been added. It is noted that all rejections of claims 5-6 are moot in view of the cancelation of those claims. Claims 1-4 and 7-12 are now pending and under consideration. Applicant’s amendments and arguments have been thoroughly reviewed, and have overcome the following objections/rejections set forth in the prior Office action:
The objection to the specification related to hyperlinks/browser-executable code, in view of applicant’s amendments (although it is again noted that the objection could have been overcome by simply deleting the recitation of “https://”;
The rejection of claims under 35 USC 112(b) in view of Applicant’s clarifying amendments (although it is noted that the claims remain indefinite for the reasons given below); and
The rejection of claims under 35 USC 103 in view of Applicant’s amendment of independent claim 1 to require that the “depositing” occur “onto a surface containing defined areas, wherein each defined areas contains at least a portion of one amplified sample”.
Claims 1-4 and 7-12 remain/are rejected for the reasons set forth below, which include new grounds of rejection necessitated by Applicant’s amendments. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(b)/second paragraph
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 1-4 and 7-12 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.
Claims 1-4 and 7-12 are indefinite over the recitation in independent claim 1 of the limitation “detecting the amplicon length distribution is distinct from the corresponding amplicon length distribution which is indicative of a length polymorphism in the target region of the DNA sample”, because it is unclear how the language “which is indicative of a length polymorphism in the target region of the DNA sample” further limits what is claimed. One possible reasonable interpretation of this language is that the claim is referencing ‘the corresponding amplicon length distribution which is indicative of a length polymorphism in the target region of the DNA sample”, with the claim language simply further limiting a characteristic/property of ‘the corresponding amplicon length distribution”, but in a manner that lacks clear antecedent basis. Alternatively, the language “which is indicative of a length polymorphism in the target region of the DNA sample” could reasonably be interpreted as modifying the intended purpose and/or outcome of the “detecting”. As there are multiple reasonable interpretations of the claim language that impart different meanings and boundaries on what is being claimed, further clarification is required.
Claim Rejections - 35 USC § 112(a)/first paragraph
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.
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 1-4 and 7-12 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. This is a new matter rejection.
Independent claim 1 (from which claims 2-4 and 7-12 depend) has been amended to recite the limitation “depositing the plurality of amplified samples onto a surface containing defined areas, wherein each defined area contains at least a portion of one amplified sample”. While the examiner agrees that (as is discussed by Applicant on page 5 of their Remarks) page 11, lines 8-19 of the specification discloses use of a gridded mica substrate and deposition of sample “into each grid square”, the application as filed did not in fact provide a disclosure of any type of “surface containing defined areas” (which is broader and more general in nature that the disclosed “grid”). The application as filed - while disclosing surfaces/substrates for deposition of samples, including the preferred embodiment of mica (as discussed on page 11), and the use of mica subdivided into sample regions via the printing of a grid (again as discussed on page 11) – does not refer to “defined areas” in general or provide any equivalent disclosure of such “defined areas”; rather, one type of such “defined areas” (a grid/grid pattern/a square substrate subdivided into a grid/etc.) is described. Thus, claim 1 as amended fails to find basis in the application as filed, and Applicant’s amendments add new matter to the claims.
Claim Rejections - 35 USC § 103
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.
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claim(s) 1-4 and 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Reed et al (WO2018/129226A1 [12 July 2018]; previously cited) in view of Watanabe et al (Clinical Cancer Research 21(15):3552 [Aug 2015]; previously cited) and Liu et al (Microscopy Research and Technique 66:156-162 [2005]; cited herein).
Reed et al disclose methods in which optical pickup unit (OPU) high-speed atomic force microscopy (HS-AFM) is employed to collect information regarding DNA, including information such as distances between markers (see entire reference, particularly paragraphs 9-17); it is particularly noted that Reed et al disclose that their methods may be practiced on PCR amplicons (see, e.g., paragraph 12), and applied to detection of length polymorphisms, with the use of digital PCR in such methods being taught as a preferred embodiment (see, e.g., paragraph 62). Additionally, it is noted that Reed et al clearly disclose the new claim 1 limitation of high-speed ASM (see, e.g., page 11, paragraph 48).
With regard to the particular steps of independent claim 1, Reed et al teach and exemplify methods in which a target region of DNA – for example, a Cas9-labeled BRCA1 amplicon, as depicted in Fig. 2A and Fig. 9, or a TERT amplicon labeled with two Cas9 proteins, as depicted in Fig. 5C - is so amplified, deposited onto a surface, and imaged by HS-AFM, with Reed et al teaching that their methods directed at BRCA1 allow differentiation of numbers of naturally occurring Alu repeats – which result in amplicons of different lengths (see in particular Figure 2 and the description thereof at paragraphs 52-55; 66-69). Reed et al provided detailed guidance regarding imaging using high-speed AFM and comparisons of length distributions with regard to reference DNA sample products so as to allow for successful detection of length difference/polymorphisms (see paragraphs 85-92); further, with regard to a more particular type of physical/manipulative comparing “to a corresponding amplicon length distribution obtained from a reference DNA sample that does not contain a length polymorphism”, Reed et al also disclose co-amplification of mutated and wild-type DNA (paragraph 79), which also meets the requirements of dependent claim 3. Regarding the final “detecting” of a length polymorphism as set forth in claim 1, it is reiterated that the language of the claim is indefinite (as discussed above); as Reed et al also teach the use of distributions of lengths in achieving detection of a length difference/polymorphism (see, e.g., paragraphs 10 and 92, and Figure 15B), they teach at least one type of ‘detecting” embraced by this claim language to the extent that it is presently understood.
While Reed et al suggests the use of digital PCR as a preferred embodiment (as noted above), Reed et al do not teach dilution “to provide a plurality of amplified samples in which 0 or 1 target DNA strand is amplified in each amplified sample and wherein at least one amplified sample includes 1 target DNA strand”, as set forth in the “amplifying” of claim 1. Further, amended claim 1 now requires the depositing of amplified samples “onto a surface containing defined areas, wherein each defined area contains at least a portion of one amplified sample”; Reed et al do not teach such a surface.
With regard to the provision of “a plurality of amplified samples in which 0 or 1 target DNA strand is amplified in each amplified sample and wherein at least one amplified sample includes 1 target DNA strand”, Watanabe et al describe the implementation of droplet digital PCR (ddPCR) in “ultra-sensitive detection” of a cancer associated mutation (see entire reference). Watanabe et al also teach (more generally) that digital PCR ‘is a highly sensitive gene mutation detection method that is based on the compartmentalization and amplification of single DNA molecules”, that their ddPCR method allowed for accurate, ultrasensitive, quantitative detection of a cancer-associated mutation, and that implementation of their method requires compartmentalizing the target-DNA containing sample into droplets containing 0 or 1 copy of target DNA prior to amplification (see entire reference, particularly Figure 1 and the description thereof). In view of the teachings of Watanabe et al, 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 modified the methods of Reed et al so as to have employed ddPCR as the dPCR suggested by Reed et al, and in doing so (i.e., when implementing the method), to have prepared a target-containing sample for amplification via dilution into drops containing 0 or 1 target copies (as taught by Watanabe et al), thereby meeting the requirements of the “amplifying” of instant claim 1 (at least to the extent that it is presently understood). Reed et al teach that dPCR is a preferred embodiment of their methods (thereby providing motivation to employ this particular type of PCR), and Watanabe et al’s teaching that their ddPCR allows for accurate, ultrasensitive quantitative amplification/detection of a target of interest would have motivated an ordinary artisan to have employed this particular type of dPCR for any/all of these benefits taught by Watanabe et al. Additionally, given the detailed guidance provided by both Reed et al and Watanabe et al, an ordinary artisan would have had a reasonable expectation of success in so-modifying the methods of Reed et al.
With regard to the depositing of amplified samples “onto a surface containing defined areas, wherein each defined area contains at least a portion of one amplified sample”, it is noted that Reed et al disclose and exemplify the use of a flat mica surface (i.e., a surface type corresponding to a preferred embodiment disclosed by Applicant) in their methods (see, e.g., paragraphs 15, 17, and 73 of Reed et al); however, neither Reed et al nor Watanabe et al explicitly teach use of a surface containing such “defined areas”. Liu et al disclose creation of an “easily identifiable” pattern – which inherently constitutes a type of “defined areas” - on a mica surface employed in AFM to facilitate re-location and re-imaging of specific samples (see entire reference, particularly the Abstract). In view of the teachings of Liu et al, it would have been 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 modified the methods suggested by Reed et al in view of Watanabe et al so as to have deposited samples onto a “surface containing defined areas”, as set forth in amended claim 1. An ordinary artisan would have been motivated to have made such a modification for the advantages taught by Liu et al of facilitating re-location and re-imaging of any particular sample of interest. Furthermore, given Liu et al’s disclosure of and guidance regarding their use of a mica surface – i.e., the same type of substrate taught by the primary reference Reed et al – an ordinary artisan would have had a reasonable expectation of success in performing such methods.
With further regard to dependent claims 2-3, it is reiterated that Reed et al teach the use of digital PCR, and the combining of test and reference DNA, as noted above.
Regarding claim 4, this claim sets forth an instructional limitation lacking any required functional relationship to other method steps, such that these claims add only nonfunctional descriptive material; however, it is also noted that Reed et al do suggest determining percentage frequencies of polymorphisms (see, e.g., paragraph 105).
Regarding claim 7, Reed et al further teach and suggest computer-implemented methods including the recited activities; see, e.g., paragraphs 86-97.
Regarding claim 8, Reed et al’s teachings of Alu repeats causing length polymorphisms (as discussed above) meets the requirements of the claim.
Regarding claim 9, the use of Cas9 in target region labeling is also discussed above.
Regarding new claim 10, independent claim recites “amplifying a target region of the DNA in the sample”, such that the claim requires amplifying a target region that is “not labeled with a labeling molecule”. Watanabe et al disclose the use in their methods of unlabeled “input DNA” extracted from FFPE samples, such that the combined teachings of the cited art teach and exemplify the use of an initial input “target region” not labeled with a labeling agent.
Regarding new claims 11-12, Reed et al teach that all “genetic alterations resulting in change of DNA size can be visualized directly”, and refer to “short insertions and deletions” as examples of such variations (paragraph 79); Reed et al thus disclose length polymorphisms of the type set forth in these new claims.
It is noted that Applicant’s arguments of 27 January 2026 regarding the prior rejection of claims under 35 USC 103 have been reviewed and considered, but these arguments are non-persuasive with regard to the present rejection (which addresses the new limitations and claims added via Applicant’s amendments of the same date).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DIANA B JOHANNSEN whose telephone number is (571)272-0744. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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