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 .
Election/Restrictions
Applicant’s election without traverse of the species (I)(b), (II)(c), (III)(b), and (IV)(c) in the reply filed on April 29, 2026 is acknowledged.
The elected species are free of prior art, however, and therefore, the species requirement of April 29, 2026 is hereby withdrawn and rejoined herein.
Effectively claims 2, 4, 5, and 7 are rejoined.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Information Disclosure Statement
The IDS received on February 1, 2024; May 1, 2024; August 1, 2024; November 4, 2024; February 7, 2025; May 6, 2025; August 13, 2025; and April 29, 2026 are proper and are being considered by the Examiner.
Drawings
The drawings received on January 22, 2024 are acceptable.
Claim Rejections - 35 USC § 112
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 2-21 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 3 is indefinite because the claim recites that the extension of “a 3’ end of the cDNA molecule” is performed to “include a second adaptor sequence.” However, the claim does not recite any antecedent basis for the second adaptor sequence, nor any recitation as to how a simple extension of a 3’ end of a cDNA molecule can result in the addition of a second adaptor sequence.
Claim 18 depends from claim 3.
Claim 3 recites that the cDNA is generated “within the biological sample” (see step (a)). Claim 18 recites that this step comprises introducing a reverse transcriptase, dNTP, and RT primer into the biological sample. However, for claim 3 to occur, that is, for cDNA to be generated within the biological sample itself, the necessary substrates/reagents, RT, dNTP, and RT primer are necessarily required to be present into the biological sample. Therefore, the step recited in claim 18 doesn’t appear to further limit, nor add additional limitation to the parent claim 3 as the step is inherent.
Claims 2 and 4-21 are indefinite by way of their dependency on claim 3.
Double Patenting
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 2-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,891,654 (herein, “the ‘654 patent”).
Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
With regard to instant claim 3, the ‘654 patent also claims a method of associating a spatial barcode with a target nucleic acid from a biological sample comprising the steps of:
generating a cDNA molecule comprising a sequence that is substantially complementary to the target nuclei acid using a reverse transcription primer comprising: (i) a sequence that is substantially complementary to a portion of the target nucleic acid and (ii) a first adapter sequence, wherein the step of generating the cDNA molecule occurs within the biological sample (see claim 1, step (a));
extending a 3’ end of the cDNA molecule to include a second adaptor sequence, thereby generating an extended cDNA molecule, wherein the step is performed within the biological sample (see claim (1)(b));
releasing the extended cDNA molecule from the target nucleic acid, such that the extended cDNA molecule contacts an array, wherein the array comprises an affixed capture probe comprising in a 5’ to a 3’ direction: (i) a spatial barcode and (ii) a capture domain that binds to the second adaptor sequence of the extended cDNA molecule (see claim 1(c)); and
extending the 3’ end of the capture probe using the extended cDNA molecule as a template, thereby associating the spatial barcode with the target nucleic acid from the biological sample (see claim 1(d), also because step (c) of the ‘654 patent already recites that the capture probe comprises a spatial barcode, the spatial barcode would necessarily be “associated” in an extended construct).
With regard to instant claim 2, the second adapter is ligated (see claim 1(b)).
With regard to instant claim 4, steps (a)-(c) are performed when the biological sample is disposed on the array (see claim 3).
With regard to instant claim 5, step (a) is performed when sample is not disposed on the array and step (b) is performed when the sample is disposed on the array, and between steps (a) and (b), the sample is disposed on the array (see claim 4).
With regard to instant claim 6, the step (a) and (b) are performed on the sample not disposed on the array, and disposed between steps (b) and (c) (see claim 5).
With regard to instant claim 7, the sequence that is substantially complementary to a portion of the target is poly-T (see claim 6).
With regard to instant claim 8, the sequence that is substantially complementary to a portion of the target nucleic acid present in the reverse transcription primer comprises a random sequence (see claim 7).
With regard to instant claim 9, the second adaptor sequence is a TSO (see claim 8).
With regard to instant claim 10, the capture probe comprises UMI (see claim 9).
With regard to instant claims 11 and 12, the further determining of (i) all or a portion of the sequence of the target nucleic acid or a complement thereof, and (ii) the sequence of the spatial barcode, or a complement thereof, and using the determined sequences of (i) and (ii) to identify the location of the target nucleic acid in the biological sample is performed (see claim 10).
With regard to instant claim 13, the sequencing is high throughput (see claim 11).
With regard to instant claim 14, the sequencing is SBH (see claim 12).
With regard to instant claim 15, the target nucleic acid is RNA (see claim 13).
With regard to instant claim 16, the RNA is mRNA (see claim 14).
With regard to instant claim 17, the method further comprises prior to (a), permeabilizing the biological sample (see claim 1 preamble, “permeabilized tissue sample”).
With regard to instant claim 18, the method comprises introducing RT, dNTP, and RT primer into the biological sample (see claim 16).
With regard to instant claim 19, the sample is a tissue section (see claim 1 preamble, discussed above).
With regard to claims 20 and 21, the capture probe comprises a region that anneals to the adapter region of the extended cDNA construct, as well as a spatial barcode that is functional, and the releasing of the cDNA molecule is performed in step (c) of claim 1. While the means of the releasing cDNA molecules prior to their annealing to an array is not explicitly claimed, use of heat denaturation, and or reagents that produces condition to release the cDNA molecules from the sample so they could be annealed to the capture probes of the array would have been an obvious conclusion rendered by the ordinarily skilled artisan, utilizing well-known, conventional means in the art of nucleic acid hybridization, yielding no more than a predictable outcome.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Therefore, the claims of the instant application are obvious over the claims of the ‘654 patent.
Conclusion
No claims are allowed.
West et al. (US 2019/0262831 A1, published August 29, 2019) teach a method of capturing template sample nucleic acids in a spatially specific manner of the sample. The artisans teach a method that provides a sample (e.g., tissue) on a substrate, preparation of the sample, capture of the nucleic acid from the sample on to a solid substrate, and generation of cDNA molecules thereon (see Figure 3, also below):
“Prepare sample to release sample templates to allow for hybridization” (section [0049])
“Ability to combine, through active means, the genetic material in a sample with an array of barcoded oligonucleotides in a spatially specific manner” (section [0050])
“In order to maintain a spatial resolution of a genetic sequence within a tissue, methods are disclosed to combine a sample template molecule with a primer through complimentary base pairing of DNA or RNA to maintain the location of this genetic material in a sample.” (section [0054])
“the disclosed technology provides the ability to barcode each gene or genetic element in a given cell in a spatially specific manner … further allows the amplification of each barcoded genetic sequences to allow preparation of the sample for sequencing analysis. In this way, each gene of each cell can be identified and mapped back to the original location within the sample, using the spatially defined barcode oligonucleotide.” (section [0055])
“a first step in preparing the tissue or cell sample for this imaging step is the mounting of the sample upon a substrate that allows the sample to be affixed to the substrate … the substrate will be porous to allow both tissue adherence to the surface of the substrate combined with the ability to perform downstream steps that include delivering reagents through this substrate to the tissue sample or cell aggregate sample” (section [0068])
“To enable detection of genetic material in a sample, analytes of interest may be liberated from the tissue sample or cell aggregate sample to allow hybridization through complimentary base pairing with the barcoded oligonucleotides placed upon the array surface.” (section [0078])
West et al., however, prepare the sample, and releases the nucleic acids from the tissue sample onto the solid substrate on which the cDNA is generated. The present claims require that the cDNA be generated within the sample, during which a second adapter sequence is appended, and then released onto the array comprising a capture probe that anneals to this second adapter sequence of the cDNA. West et al. therefore, do not provide a sufficient motivation to tag cDNA molecules with a second adapter sequence, as well as releasing the generated cDNA from the sample onto the solid after the cDNA has been generated within the sample.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 June 5, 2026
/YJK/
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