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 .
Information Disclosure Statement
The information disclosure statement (IDS) submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Examiner agrees with Applicant’s response filed November 27, 2023 that the present application does not contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831 (b). Therefore, the sequence listing requirement has been withdrawn.
Claim Objections
Claim 129 is objected to because of the following informalities: Claim does not end with a period. Appropriate correction is required.
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 109, 115, 118, 128, and 129 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 109 recites the limitation "second photoresist in the second region" in step (e). There is insufficient antecedent basis for this limitation in the claim. Claim 108 in which 109 is dependent upon only mentions “a photoresist” in the first and “a photoresist” in the second region.
Claim 115 recites the limitation "second nucleic acid molecules". There is insufficient antecedent basis for this limitation in the claim. Claim 109, in which 115 is dependent upon, does not establish the nucleic acid molecules of the instant claim.
Claim 118 recites the limitation "and/or step (h)”. There is insufficient antecedent basis for this limitation in the claim. Claim 108, in which the instant claim depends one, does not possess step (h). The applicant may overcome this rejection by changing the instant claim to be dependent on claim 109.
Claim 128 recites the limitation "the attaching steps". There is insufficient antecedent basis for this limitation in the claim, as independent claim 108 does not state an attaching step.
Regarding Claim 129, the limitation “in feature(s) on the substrate in cycle I and in feature(s) on in cycle J” is indefinite as there is no previous mention of feature(s), cycle I or cycle J. Additionally, it is unclear what specific feature(s) the claim is referring to.
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 108-112, 116-126, and 128-131 is/are rejected under 35 U.S.C. 103 as being obvious over Patterson et. al. (US 20220228210 A1, IDS ref.) in view of Keefe et. al. (WO 2014012010 A1).
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2)
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Patterson teaches a method for providing an array, comprising: (a) irradiating a substrate comprising an unmasked first region and a masked second region, whereby a photoresist in the first region is degraded to render an oligonucleotide molecule in the first region available for ligation, whereas an oligonucleotide molecule in the second region is protected by a photoresist in the second region from ligation ; (b) contacting the oligonucleotide molecule in the first region with a first oligonucleotide comprising a first barcode sequence and wherein the first splint hybridizes to the oligonucleotide molecule in the first region, (c) ligating the first oligonucleotide molecule to the oligonucleotide molecule in the first region using the first splint as a template to generate a barcoded oligonucleotide molecule in the first region, wherein the oligonucleotide molecule in the second region does not receive the first barcode sequence; and (d) irradiating the first oligonucleotide, thereby crosslinking the first splint to the barcoded oligonucleotide molecule in the first region, thereby providing on the substrate an array comprising oligonucleotide molecules having different sequences in the first and second regions ([0007],[0031],[0165], instant claim 108).
Patterson teaches irradiating the substrate while the second region is unmasked, with a first or second degraded photoresist in the second region to render the oligonucleotide molecule available for ligation and the first region barcoded oligonucleotide molecule is protected from ligation, ligating the second oligonucleotide molecule to the oligonucleotide molecule in the second region using the second splint as a template to generate a barcoded oligonucleotide molecule in the second region; and irradiating the oligonucleotide molecule in the second region, thereby crosslinking the second splint to the barcoded oligonucleotide molecule in the second region ([0034], instant claim 109).
Patterson teaches the repetition of steps (a)-(d) in one or more cycles with different oligonucleotides, each cycle for one or more different regions on the substrate ([0021], instant claim 110).
Patterson teaches that the photoresist is not removed prior to, during, or between the one or more cycles ([0156], instant claim 111).
Patterson teaches in Figure 1, an example of generating an oligonucleotide array. One cycle consists of ligating a Round A cycle 1 barcode made of a splint-oligonucleotide hybridized complex to the oligo lawn, then rinsing and removing the photoresist prior to repeating N cycles for M rounds. The ligated barcode splint of the first cycle remains attached to the nucleic acid molecules within the region upon initiating subsequent ligation rounds, teaching on the limitations of instant claims 112 and 120. Patterson recites “the photoresist may be removed after each cycle of in situ array generation and re-applied prior to the next cycle of in situ array generation.” The addition of a photoresist for subsequent cycles would provide hybridization stability of the ligated barcode and splint of round 2 ([0083], instant claim 121). In paragraph [0014], Patterson recites that the plurality of functional groups of the substrate (e.g., of a lawn of oligonucleotides) do not need to be protected by a protective group, moiety, or molecule that is photo-sensitive, photo-labile, photo-degradable, acid-labile or otherwise removable in a photo-activable reaction, indicating that a moiety can be exempt from the cycle process, reading on the limitations of claim 122.
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Patterson teaches steps (a)-(d) as a part of Round 1, and a Round 2 comprising: (a') applying another photoresist to the substrate, and irradiating the substrate while the first region is unmasked and the second region is masked, whereby a photoresist in the first region is degraded to render the barcoded oligonucleotide molecule in the first region available for ligation, whereas the oligonucleotide molecule in the second region is protected by the photoresist in the second region from ligation ; (b') contacting the barcoded oligonucleotide molecule in the first region with (i) a first Round 2 oligonucleotide comprising a first Round 2 barcode sequence and (ii) a first Round 2 splint; and (c') ligating the first Round 2 oligonucleotide molecule to the barcoded oligonucleotide molecule in the first region using the first Round 2 splint as a template to generate a Round 2 barcoded oligonucleotide molecule in the first region, wherein the oligonucleotide molecule in the second region does not receive the first Round 2 barcode sequence ([0035], [0026], [0111], instant claim 119).
Patterson teaches forming a pattern of oligonucleotide molecules on the substrate prior to applying the photoresist to the substrate, wherein the forming step comprises: irradiating a substrate comprising a plurality of functional groups and a photoresist through a patterned mask, whereby the photoresist in a first region of the substrate is degraded, rendering functional groups in the first region available for reacting with functional groups in functionalized oligonucleotide molecules, whereas functional groups in a second region of the substrate are protected by the photoresist from reacting with functional groups in the oligonucleotide molecules; and contacting the substrate with the functionalized oligonucleotide molecules, wherein the functionalized oligonucleotide molecules are coupled to functional groups in the first region but not to functional groups in the second region, thereby forming a pattern of oligonucleotide molecules on the substrate ([0133] , instant claim 123).
Patterson teaches the photoresist in the first and/or second regions comprises a photoacid generator, an acid scavenger, and a barcode sequence between 4 and 25 nucleotides in length ([0092], [0022], instant claims 124, 125, and 126).
Patterson teaches wherein the method comprises N cycles, N is an integer of 2 or greater, and one of the N cycles comprises the irradiating and the attaching steps ([0028], instant claim 128).
Patterson teaches wherein the barcode sequences received by oligonucleotide molecules in feature(s) on the substrate in cycle I and in feature(s) on in cycle J ([0155], instant claim 129).
Patterson teaches de-crosslinking the first splint and the oligonucleotide molecule in the first region by irradiating the substrate with light having a wavelength of 312nm (Figure 3, instant claims 130 and 131).
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Patterson fails to teach a first splint comprising a photo-crosslinkable moiety used as a template for generating a barcoded oligonucleotide, and irradiation of the first oligonucleotide to crosslink the first splint to the barcoded oligonucleotide in the first region (limitations of instant claims 108 and 109). However, Keefe teaches unreadable linkage formation by a cross-linking oligonucleotide with a reversible co-reactive group of a cyanovinylcarbazole group (Figure 3, instant claims 116 and 117). Figure 3 of Keefe illustrates a cyanovinylcarbazole-containing cross-linkable splint that is used as a template to bind the two oligonucleotides by crosslinking at the X position at 366 nm within the first region (instant claim 118). Figure 3 of Keefe also illustrates repeat hybridization of the photocrosslinkable splint, indicating this step can be performed in a second region on the substrate.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Patterson to incorporate the teachings of Keefe by adding a 3-cyanovinylcarbazole cross-linkable moiety to a splint oligonucleotide for providing the benefit of rapid reversible photo cross-linking to the complementary barcode strand for increased specificity and structure stability on an array.
Claim(s) 115 and 127 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patterson et. al. (US 20220228210 A1, IDS ref.) and Keefe et. al. (WO 2014012010 A1) as applied to claims 108-112, 116-126, and 128-131 above, and further in view of Price et. al. (US 20220314187 A1, IDS ref.).
Patterson and Keefe fail to teach the nucleic acid molecules of the splints and the oligonucleotide comprising the barcode sequence and splint as a pre-hybridized complex.
Price teaches an embodiment in paragraph [0045] wherein the first splint and the second splint can be of the same nucleic acid sequence or different nucleic acid sequences (instant claim 115). Price further teaches hybridization complexes in the first region, wherein at least one of the hybridization complexes comprise a polynucleotide molecule immobilized in the first region hybridized to a first splint, which is in turn hybridized to a first oligonucleotide comprising a first barcode sequence, wherein the hybridization complexes are protected by a first photo-cleavable polymer that inhibits or blocks hybridization and/or ligation (instant claim 127).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Patterson and Keefe to incorporate the teachings of Price to have modified the nucleic acid molecules of the splints and the oligonucleotide comprising the barcode sequence and splint. Providing the splint barcode as a pre-hybridized complex can eliminate concerns over barcode fidelity in base-by-base in situ approach, reduce manufacturing time, cost of goods, and increase total yield.
Claim(s) 113 and 114 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patterson et. al. (US 20220228210 A1, IDS ref.) and Keefe et. al. (WO 2014012010 A1) as applied to claims 108-112, 116-126, and 128-131 above, and further in view of Maroney (Maroney et. al., Nature Publishing group, Nature Protocols, 2008) .
Patterson and Keefe fail to teach a first splint provided as a first and second nucleic acid molecule, wherein the first nucleic acid molecule comprises a first nucleotide sequence that hybridizes to the oligonucleotide molecule in the first region and a second nucleotide sequence that hybridizes to the first oligonucleotide, a second nucleic acid molecule comprising the photo-crosslinkable moiety and hybridizes to the oligonucleotide molecule in the first region, and the first and second nucleic acid molecule of the first splint are ligated together using the oligonucleotide molecule in the first region as a template.
Maroney teaches in figure 1 a splinted-ligation nucleic acid hybridization assay that uses a small RNA which equates to a first nucleic acid molecule and a 5’- end- radiolabeled ligation oligonucleotide which equates to a second nucleic acid molecule. The small RNA and ligation oligonucleotide are linked during steps 14 and 15 of Figure 1 using a bridge oligonucleotide template, reading on the limitations of instant claims 113 and 114.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Patterson and Keefe to incorporate the teachings of Maroney to provide a splint containing a first and second nucleic acid molecule because all three of the references are in the same field of endeavor and are drawn to using an oligonucleotide to join another oligonucleotide for detection in a hybridization assay. Therefore, at a minimum it would be obvious to try using the two RNA molecules of Moroney in the hybridization assays of Patterson and Keefe.
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 108, 111, 123, 128 and 129 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 53, 18, 19, and 52 of copending application number 17/565047 in view of Keefe et. al. (WO 2014012010 A1).
Claim 1 of ‘047 recites “A method for providing an array, comprising: (a) irradiating a substrate comprising an unmasked first region and a masked second region, whereby a photoresist in the first region is degraded to render oligonucleotide molecules in the first region available for hybridization and/or ligation, whereas oligonucleotide molecules in the second region are protected by a photoresist in the second region from hybridization and/or ligation” which inherently includes step (a) of instant claim 108.
Regarding instant claim 108, copending application ‘047 fails to teach the limitation of a first splint comprising a photo-crosslinkable moiety used as a template for generating a barcoded oligonucleotide. However, Keefe teaches unreadable linkage formation by a cross-linking oligonucleotide with a reversible co-reactive group of a cyanovinylcarbazole group in Figure 3 of Keefe above.
Claim 53 of ‘047 recites “The method of claim 51, wherein the photoresist is not removed prior to, during, or between one or more of the N cycles”, anticipating instant claim 111.
Claim 18 of ‘047 recites “The method of claim 1, further comprising forming a pattern of oligonucleotide molecules on the substrate prior to applying the photoresist to the substrate.” Claim 19 of ‘047 further recites “ The method of claim 18, wherein forming the pattern of oligonucleotide molecules comprises: irradiating a substrate comprising a plurality of functional groups and a photoresist through a patterned mask, whereby the photoresist in a first region of the substrate is degraded, rendering functional groups in the first region available for reacting with functional groups in functionalized oligonucleotide molecules, whereas functional groups in a second region of the substrate are protected by the photoresist from reacting with functional groups in the oligonucleotide molecules; and contacting the substrate with the functionalized oligonucleotide molecules, wherein the functionalized oligonucleotide molecules are coupled to functional groups in the first region but not to functional groups in the second region, thereby forming a pattern of oligonucleotide molecules on the substrate.” , which inherently includes the forming steps and anticipates instant claim 123.
Claim 51 of ‘047 recites “The method of claim 1, wherein the method comprises N cycles, N is an integer of 2 or greater, and one of the N cycles comprises the irradiating and the attaching steps.”, anticipating instant claim 128.
Claim 52 of ‘047 further recites “The method of claim 51, wherein the barcode sequences received by oligonucleotide molecules in a feature on the substrate in cycle I and in the feature on the substrate in cycle J are different, wherein I and J are integers and 1≤I<J≤N.”, anticipates instant claim 129, though claim 129 appears to be an incomplete statement with incorrect punctuation.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the claims of ‘047 with the addition of a 3-cyanovinylcarbazole cross-linkable moiety of Keefe to have arrived at the instantly claimed invention. The addition of the 3-cyanovinylcarbazole moiety to a splint oligonucleotide provides the benefit of rapid reversible photo cross-linking to the complementary barcode strand for increased specificity and structure stability on an array.
Conclusion
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/A.H.B./
Examiner, Art Unit 1683 /ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683