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 .
Priority
The present application, filed on October 27, 2023, claims priority to U.S. Provisional Patent Application No. 63/420,436, filed on October 28, 2022.
Claim Status
Claims 68-87 are currently pending and under examination. Claims 1-67 were canceled by applicant prior to this action.
Drawings
It is noted that a petition to accept color drawings under 37 CFR 1.84(a)(2) was granted in this application on March 7, 2024. The drawings filed on October 27, 2023 are acceptable.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
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.
Claims 78, 79, and 87 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The term “about” in claim 78 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The specification defines: “The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field.” (paragraph 0265).
This special definition does not provide any meaningful insight as to the “usual” error range for any particular value “readily known to the skilled person in this technical field”, much less the error range for a length of a nucleic acid linking a primer sequence to a substrate. It appears that this definition may encompass any linker length at which the primer sequences are capable of functioning in the amplification of their target sequences.
In claim 78, the recitation of “the flexible linker is a nucleic acid sequence of between about 5 and about 100 nucleotides in length between the primer sequence and an immobilized end…” does not appear to impose any meaningful limitation to the minimum or maximum requisite length of the “linker” (i.e. the length of the oligonucleotide sequence 5’ to the primer sequence necessarily located at the 3’ end of the immobilized oligonucleotide). It is unclear whether the claim encompasses embodiments wherein the “primer sequence”: is directly immobilized to the substrate (i.e. 0 nucleotide length linker), requires a linker of at least one nucleotide (i.e. 1 nucleotide length linker; 80% error relative to 5 nucleotide length), is limited to some unspecified minimum length (i.e. 4 nucleotides; 20% error relative to 5 nucleotide length), and/or is limited to some unspecified maximum length (i.e. 101 nucleotides; 1% error relative to 100 nucleotides in length; 120 nucleotides, 20% error; 180 nucleotides, 80% error; etc.).
The term “the flexible linker is at least 75 nucleotides in length” in claim 79, which depends from claim 78, appears to broaden the range of linker lengths encompassed by claim 78. Claim 78 limits the linker length to “between about 5 and about 100 nucleotides”, whereas claim 79 limits the linker length to “at least 75 nucleotides” (i.e. encompassing 75 nucleotide linkers and any linker length greater than 75 nucleotides, including those greater than the previously recited range of “about 5 to about 100 nucleotides”). It is unclear whether this limitation is intended to be limited to the previously recited upper bound of the range recited in claim 78, or is broader than the previously recited range.
Claim 87 recites “The method of claim 54, wherein the detecting in e)…”. Claim 54 was canceled prior to this action and the only pending independent claim is claim 68. It is unclear whether this claim is meant to depend from independent claim 68, which recites a step “e) detecting…”, is meant to depend from one claims presently depending from claim 68, or something else.
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.
Claims 76, 79, and 87 are rejected under 35 U.S.C. 112(d) 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 76 recites, “The method of claim 68, wherein the primer sequence is at the 3’ end of the immobilized oligonucleotide molecules.”
However, claim 68 already requires “a plurality of oligonucleotide molecules immobilized on the substrate, wherein at least a portion of the immobilized oligonucleotide molecules comprise a primer sequence, and wherein the primer sequence is bound to the primer binding sequence of the circularized probe”. Furthermore, the specification defines: “A “primer” used herein can be an oligonucleotide… that is capable… of acting as a point of initiation of nucleic acid synthesis and being extended from its 3’ end along the template…” (paragraph 0259) (i.e. a primer, by applicant’s definition, must comprise a 3’ end).
Therefore, the structure recited by claim 68 requires the primer sequence must be at the 3’ end of the immobilized oligonucleotide molecules. As such, claim 76 merely restates a limitation already required by the claim from which it depends. Claim 76 is therefore not in proper dependent form, as it fails to further limit the subject matter of the claim upon which it depends.
Claim 79 recites a “flexible linker is at least 75 nucleotides in length” (i.e. 75 nucleotides or greater). However, claim 78, upon which claim 79 depends, recites the “flexible linker is between about 5 and about 100 nucleotides in length” (i.e. has an upper bound of about 100 nucleotides in length). Claim 79 does not clearly include the upper bound limitation of the range recited by the claim upon which it depends.
Therefore, claim 79 is not in proper dependent form, as it fails to include all of the limitations of the claim upon which it depends.
Claim 87 depends on canceled claim 54. Therefore, claim 87 is not in proper dependent form.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Claim Interpretation
Regarding claim 74, the claims and the specification do not define “a pattern of discrete features”. However, the specification provides “the immobilized oligonucleotide molecules may but do not need to be distributed in a pattern of discrete features on the capture area. In some embodiments, the substrate is prepared by dipping a functionalized substrate (e.g., an NHS-coated substrate, such as a slide) in an oligonucleotide solution to form a lawn of immobilized on the substrate” (paragraph 0013). Given its broadest reasonable interpretation, the limitation “the immobilized oligonucleotide molecules are not distributed in a pattern of discrete over the capture area” has been interpreted as excluding embodiments wherein the capture area comprises patterned arrays of oligonucleotides (e.g. “capture spots” contained within a larger “capture area”).
For the purposes of prior art search and the rejections that follow, claim 87, which further limits a step “e) compris[ing] detecting… rolling circle amplification product[s]” has been treated as dependent upon independent claim 68, which claims a method comprising a step e) of detecting a rolling circle amplification product.
Claim Rejections - 35 USC § 102
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)(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.
(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.
Claims 68-74, 76-81, 83, 84, and 87 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Witters et al., WO 2021/231263 A2 (published November 18, 2021).
Regarding claim 68, Witters et al. teach methods for analyzing biological samples comprising in situ spatial sequencing using hybrid amplification (Witters et al., paragraph 0180). Witters et al. teach methods comprising in situ ligation of padlock probes (i.e. a circularizable probe or probe set) targeting cellular nucleic acids (Witters et al., paragraphs 0180-0181). Witters et al. teach subsequently transferring the circularized probe(s) to a substrate comprising immobilized oligonucleotide primers and using a polymerase to perform rolling circle amplification (RCA) to generate extension products from the immobilized primers such that the RCA products are tethered (i.e. immobilized) at a location on the substrate (Witters et al., paragraph 0182). Finally, Witters et al. teach that the RCA products are detected at the location on the substrate (Witters et al., 0184-0188).
Regarding claim 69, Witters et al. teach the contacting step comprises contacting the sample with a pool of circularizable probes or probe sets that bind to targeted nucleic acid sequences (Witters et al., paragraph 0181), the ligating step comprises ligating the circularizable probes at two or more locations in the sample (Witters et al., paragraph 0181), the transferring step comprises transferring circularized probes from the sample to the substrate (Witters et al., paragraph 0181-0182), the rolling circle amplification step generates RCA products that are immobilized at multiple loci on the substrate (Witters et al., paragraph 0182-0185), and the detecting step comprises detecting RCA products at the loci on the substrate (Witters et al., paragraph 0182-0185).
Regarding claim 70, Witters et al. teach hybrid amplification of circularized target nucleic acids (i.e. ligated padlock probes, removed from a first substrate) wherein circularized targets are transferred to and hybridized to a solid support (i.e. a second substrate) (Witters et al., paragraph 0160-0163).
Regarding claim 71, Witters et al. teach the hybridization may be performed by hybridizing separated circularized target nucleic acids to a second substrate (i.e. the sample does not come into direct contact with the second substrate) (Witters et al., paragraph 0160-0163).
Regarding claim 72, Witters et al. teach the substrate may be uniformly silanized for attachment of primers (i.e. the immobilized oligonucleotides are uniformly distributed on a surface of the substrate (Witters et al., paragraph 0152).
Regarding claim 73, Witters et al. teach in some embodiments the immobilized oligonucleotides are arrayed on a solid support (i.e. a capture area) to which the cell is immobilized (i.e. the capture area is aligned with the sample) (Witters et al., paragraph 0121).
Regarding claim 74, Witters et al. teach the primers (i.e. the immobilized oligonucleotides) can be randomly distributed on a solid surface (i.e. are not distributed in a pattern of discrete features) OR can be distributed on a patterned surface (i.e. are distributed in a pattern of discrete features) (Witters et al., paragraph 0154).
Regarding claim 76, Witters et al. teach the primer sequence is at the 3’ end of the immobilized oligonucleotides (Witters et al., paragraph 0013).
Regarding claim 77, Witters et al. teach the primer sequence at the 3’ end of the immobilized oligonucleotide is connected to the substrate by a 5’-end nucleotide that comprises a linker group (i.e. a flexible linker) (Witters et al., paragraph 0140-0142).
Regarding claims 78 and 79, Witters et al. teach the flexible linker in the immobilized oligonucleotide comprises spacer moieties of sufficient length to allow amplification of the nucleic acid bound to the matrix, and that the amplification primer (i.e. the immobilized oligonucleotide) ranges in length between 17-30, at least 17, at least 18, at least 19,…, at least 30 nucleotides, or at least 50 nucleotides or at least 75 nucleotides, or alternatively at least 100 nucleotides (i.e. between about 5 and about 100) OR (i.e. at least 75 nucleotides) (Witters et al., paragraph 0141).
Regarding claim 80, Witters et al. teach the biological sample is a tissue section (Witters et al., paragraph 0120, 0131-0132).
Regarding claims 81, Witters et al. teach a target nucleic acid is RNA (Witters et al., paragraph 0042).
Regarding claim 83 and 84, Witters et al. teach compositions for rolling circle amplification comprising PEG or glycerol (Witters et al., paragraphs 0150-0151).
Regarding claim 87, Witters et al. teach the detecting step comprises detecting detectably labeled probe(s) bound to the RCA product(s) (Witters et al., paragraph 0162-0163).
Claims 68-81, and 83-87 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Bava et al., US 2021/0262018 A1 (filed February 19, 2021 and published August 26, 2021).
Regarding claim 68, Bava et al. teach methods of analyzing biological samples comprising contacting the sample with a circularizable probe that binds to a target sequence in the sample, ligating the circularizable probe comprising a primer binding sequence, transferring the probe to a surface comprising immobilized oligonucleotide primers, performing rolling circle amplification from the immobilized primers using the circularized probe as a template, and detecting the amplification product on the substrate (Bava et al., figures 1 and 3 and paragraphs 0108 and 0111, see figures below).
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Regarding claim 69, Bava et al. teach the circularizable probe or probe set comprises a pool of probes or probe sets that bind to a plurality of different target sequences “a targeted assay for between 100 and about 1000 genes and/or mRNA transcripts (Bava et al., paragraph 0108). Bava et al. further teach the ligating occurs in-situ in the biological sample (i.e. at two or more locations) (Bava et al., paragraph 0108). Bava et al. teach the transferring step comprises migrating (i.e. transferring) the in situ probes or products thereof (i.e. ligated padlock probes) to a substrate comprising capture probes (i.e. immobilized oligonucleotides comprising primer sequences) (Bava et al., paragraph 0108). Finally, Bava et al. teach the performing rolling circle amplification step comprises using the immobilized primer and a polymerase to generate immobilized rolling circle products at two or more locations on the substrate (Bava et al., paragraph 0111) and detecting the amplification products at the locations on the substrate (Bava et al., figure 3 and paragraph 0111).
Regarding claim 70, Bava et al. teach the biological sample is on a first substrate in the contacting step, and the substrate comprising the immobilized oligonucleotides is a second substrate (Bava et al., figures 1 and 3).
Regarding claim 71, Bava et al. teach the biological sample does not directly contact the second substrate (Bava et al., figures 1 and 3 and paragraphs 0111 and 0185).
Regarding claim 72, Bava et al. teach the second substrate comprises a lawn of immobilized oligonucleotides (i.e. are uniformly distributed on the surface) (Bava et al., paragraph 0413).
Regarding claim 73, Bava et al. teach the immobilized oligonucleotides are distributed over a capture area aligned with the biological sample (Bava et al., paragraph 0257-0259).
Regarding claim 74, Bava et al. teach that the surface of the substrate can be modified so that discrete sites are formed that accommodate a single feature OR the surface of the substrate can be modified so that features adhere to random sites (i.e. the immobilized oligonucleotide molecules are not distributed in a pattern of discrete features over the capture area) (Bava et al., paragraph 0395).
Regarding claim 75, Bava et al. teach the primer sequence comprises a common sequence among a plurality of the immobilized oligonucleotide molecules (Bava et al., paragraph 0300-0303).
Regarding claim 76, Bava et al. teach the primer sequence is at the 3’ end of the immobilized oligonucleotide molecules (Bava et al., paragraph 0300).
Regarding claim 77-79, Bava et al. teach the primer is connected to the substrate by a linker comprising additional oligonucleotide sequences such as flow cell attachment sequences, sequencing primer sequences, a spatial barcode, a UMI, and/or additional functional sequences (Bava et al., paragraph 0294-0295, 0570, or 0582) (i.e. a flexible linker that is a nucleic acid sequence of about 5 to about 100 nucleotides in length or; a flexible linker that is at least 75 nucleotides in length).
Regarding claim 80, Bava et al. teach the biological sample is a tissue section (Bava et al., paragraph 0269).
Regarding claim 81, Bava et al. teach the target nucleic acid sequence is an RNA (Bava et al., paragraph 0269).
Regarding claims 83-84, Bava et al. teach migrating analytes and probes (Bava et al., paragraph 0108) through a diffusion-resistant medium comprising a hydrogel (Bava et al., paragraph 0185) prior to the capture and rolling circle amplification (Bava et al., paragraph 0108). Bava et al. further teach such diffusion-resistant media are sandwiched between a sample on a substrate and an oligonucleotide array on a second surface (Bava et al., paragraph 0471) and the diffusion resistant media (i.e. the crowding agent) can be poly(ethylene glycol) or dextran (Bava et al., paragraph 0164).
Regarding claim 85, Bava et al. teach the biological sample can be stained with hematoxylin and eosin (H&E) (Bava et al., paragraph 0152).
Regarding claim 86, Bava et al. teach correlating the locations the rolling circle amplification products (i.e. the extended capture probes) with a location or location on the surface of the substrate using optical markers on the surface (Bava et al., paragraph 0398).
Regarding claim 87, Bava et al. teach detecting the rolling circle amplification products with detectably labeled probes (Bava et al., paragraph 0217).
Claim Rejections - 35 USC § 103
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.
Claims 68 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Bava et al., US 2021/0262018 A1 (filed February 19, 2021 and published August 26, 2021).
Regarding claim 68, as described in the 102(a)(1) and 102(a)(2) rejection above, Bava et al. teach methods of analyzing biological samples comprising contacting the sample with a circularizable probe that binds to a target sequence in the sample, ligating the circularizable probe comprising a primer binding sequence, transferring the probe to a surface comprising immobilized oligonucleotide primers, performing rolling circle amplification from the immobilized primers using the circularized probe as a template, and detecting the amplification product on the substrate (Bava et al., figures 1 and 3 and paragraphs 0108 and 0111, see figures below).
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Regarding claim 82, Bava et al. teach transferring steps comprising passive migration of analytes and probes from the biological sample to the immobilized capture probes by diffusion (Bava et al., paragraph 0478-0482). Bava et al. further teach conditions for transferring analytes or probes to the capture array can be modified (i.e. optimized) to enhance the transfer/capture step. Bava et al. teach that such modifications to the transfer/capture steps include adjusting conditions for contacting the substrate with a biological sample (e.g. time, temperature, orientation, pH, pre-treating) and can be further facilitated by treatment with permeabilization reagents. Finally, Bava et al. teach methods of preparing biological samples to facilitate transfer are known in the art and can be modified depending on the sample type and how the sample is prepared (Bava et al., paragraphs 0476-0477).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have determined a duration of time necessary for sufficient transfer of the analytes/probes (i.e. ligated padlock probes) from the biological sample to the array of immobilized oligonucleotides by passive diffusion through a diffusion-resistant medium as taught by Bava et al., (see in particular Bava paragraph 0475). The ordinary artisan would therefore have reached the claimed passive diffusion duration (at least 60 minutes) by routine optimization following the guidance of Bava et al.
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.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16 of U.S. Patent No. 12,195,790 (herein referred to as ‘790) in view of Bava et al., US 2021/0262018 A1. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 1, the claims of ‘790 recite a method for analyzing nucleic acids in a tissue sample placed on a first substrate, the method comprising: contacting the “permeabilized tissue sample” (i.e. the biological sample) with one or more nucleic acid probes that hybridize to a set of nucleic acids in the tissue sample (i.e. target nucleic acids), coupling the nucleic acid probes (i.e. ligating the ends of the one or more probes), migrating the connected probe from the permeabilized tissue sample on the first substrate to an array comprising capture probes on a second substrate (i.e. transferring… to a substrate comprising immobilized oligonucleotides… (’790, claim 1). Claim 16 of ‘790 further recites that the “one or more nucleic acid probes” comprises a padlock probe, a circular probe, or a circularized probe.
The claims of ‘790 do not recite steps of performing rolling circle amplification of the ligated padlock probes using the immobilized capture oligonucleotides as primers and subsequently detecting the resulting amplification product on the capture array.
However, Bava et al. teach methods comprising contacting tissue samples on a first substrate with padlock probes, ligating padlock probes bound to complementary nucleic acid targets in the tissue sample, transferring the ligated padlock probes to a second substrate comprising immobilized capture oligonucleotides, and amplifying the captured ligated padlock probes on the capture array using the capture oligonucleotides as primers (Bava et al., figures 1 and 3 and paragraphs 0108 and 0111).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art to have combined the cited claims of ‘790 with the teachings of Bava et al. to arrive at the presently claimed invention because of the predictable enhancement in detectable signal (i.e. number of probe binding sites) generated by the rolling circle amplification of the ligated padlock probe immobilized to the capture probe.
Conclusion
No claim is allowed.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682