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 .
Status of the Application
Claims 1,4,5,7,19,20,25-27,35,37,38,41,42,44,50,51,54,55,58,65-71, 86 and 139-142 are under examination.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Seelig et al. and Fodor et al.
Claim(s) 1,4,5,7,19,20,25,26,35,37,38, 50,51,54,55,58,65-68, 86 and 139-142 are rejected under 35 U.S.C. 103 as being unpatentable over Seelig et al. (US20170233722), as evidenced by Liu et al. (Liu, Qingyang, and Alexander Deiters. "Optochemical control of deoxyoligonucleotide function via a nucleobase-caging approach." Accounts of chemical research 47.1 (2014): 45-55.) in view of Fodor et al. (US20050079529).
Prior to the effective filing date of the claimed invention, Seelig et al. teach methods are known comprising providing an array comprising a plurality of cells, i.e. cell samples in each well of a multiwell plate (e.g. para 0104,pg. 10), comprising target polynucleotides; coupling one photo-controlled adapter to each polynucleotide; exposing a first portion of cells to light to activate the photo-controlled adapter; providing a plurality of primary nucleic acid tags ; coupling the primary tags to the activated adapters; exposing a second portion of cells to light to activate photo-controlled adapters and/ or primary nucleic acid tags within the second portion; providing secondary nucleic acid tags to the second portion and coupling the secondary tags to the activated adapters and/ or primary nucleic acid tags. Furthermore, Seelig et al. teach the methods are repeated 1 to 100 or more times. Furthermore, Seelig et al. teach the primary tags are different barcodes (e.g. Entire Seelig reference and especially para 0038-0046, pg. 2-3; para 0079-0082, pg. 7-8; para 0085, pg. 8; Example 1, pg. 9-10; Fig. 1-3, Fig. 6, 7).
Furthermore, Seelig et al. teach barcodes are DNA oligonucleotides (e.g. Entire Seelig reference and especially barcoded oligonucleotides in Table 1, pg. 9-10; DNA sequences as in SEQUENCE LISTING). Furthermore, Seelig et al. teach barcodes comprise 1-25 nucleotides (e.g. para 0053, pg. 4).
Furthermore, Seelig et al. teach barcodes are coupled to adapters by hybridization followed by ligation (e.g. Entire Seelig reference and especially para 0048, pg. 3; para 0059, pg. 5; Fig.5,15A).
Furthermore, Seelig et al. teach barcode sequences comprising blocking moieties, i.e. hairpin structures (e.g. para 0079-0082, pg. 7-8; Fig. 3; para 0077, pg. 7; Fig. 5).
Furthermore, Seelig et al. teach exposure to UV light (e.g. Entire Seelig reference and especially para 0085, pg. 8; Fig.5, 6, 15A).
Furthermore, Seelig et al. teach photo-controlled adapters are photocleavable adapters comprising photocleavable linkers or photolabile protecting groups (e.g. Entire Seelig reference and especially para 0051, para 0054-0057, pg. 4-5).
Furthermore, Seelig et al. teach photo-controlled adapters are photocaged adapters comprising inhibitory chemical moieties, i.e. NPOM, that are released upon exposure to light, allowing hybridization of barcoded sequence. Seelig et al. teach NPOM-coupled thymidine (e.g. Entire Seelig reference and especially para 0049-0052,pg. 3-4; photocaged moieties as in para 0070-0072, pg. 6; photolabile group, 6-nitropiperonyloxymethyl (NPOM), may be coupled to the N3 position of thymidine, impairing base-pairing properties and thus hindering hybridization of complementary oligonucleotides…Upon exposure to near-UV light of 365 nm, the NPOM group may be detached, permitting hybridization of an oligonucleotide containing a complementary sequence. For optimal masking properties, NPOM groups should generally be attached every five to six bases apart …This group may also be attached to a guanidine… One or several NPOM-caged bases may be incorporated into the 5' end of the photocaged adapter sequence, which may permit hybridization of linker and barcode strands upon photonic energy exposure at near UV wavelength. Following hybridization, a ligation or click reaction may couple the barcoded strands to the photo-controlled adapter... as in para 0072,pg. 6; featuring four evenly spaced NPOM-caged dT residues... as in para 0111, Example 3,pg. 11; Fig. 16).
Furthermore, Seelig et al. teach other embodiments wherein photo-controlled adapters are exposed to UV light to permit attachment of barcoded sequences (e.g. Example 2, pg. 10-11; Example 5, pg. 11; Fig. 15A; Fig. 18).
Furthermore, Seelig et al. teach embodiments comprising providing two regions comprising samples containing nucleic acid molecules comprising adapters comprising structure that block hybridization, i.e. hairpin structures; exposing a first region to light but not the second region, resulting in the cleavage of the blocking moiety in the first region; adding a barcode sequence comprising a blocking moiety and a sequence that is complementary to the adapter as well as ligase and ligating the barcoded sequence to exposed nucleic acid molecules in the first region prior to repeating the method. Seelig et al. teach that nucleic acid molecules in the second region are not capable of hybridizing and ligating barcoded sequences as they have not been cleaved. Seelig et al. teach another round of barcoding is initiated with selective light exposure (e.g. Entire Seelig reference and especially repeated rounds of tagging as in para 0074, pg. 6-7; para 0079-0082,pg. 7-8;Fig. 3; para 0077, pg. 7; Fig. 5; Example 2, pg. 10-11; Fig. 15).
Furthermore, Seelig et al. teach multiple embodiments comprising selective light exposure to arrays of cells comprising target molecules (e.g. Entire Seelig reference and especially Example 1, pg. 9-10; Fig. 6-8, 12 and 13).
Furthermore, Seelig et al. teach their method comprises exposing multiple regions of cells to light, wherein first and second portions of cells are different, overlapping, or identical regions (e.g. Entire Seelig reference and especially para 0058, pg. 5; para 0084, pg. 8).
Furthermore, considering the Seelig teaching as a whole, Seelig et al. teach embodiments wherein cells are fixed and/or permeabilized prior to the first step of their method and wherein fixed cells are lysed, allowing the release of cellular molecules. Furthermore, Seelig et al. teach methods are known wherein fixed cells are also prepared to allow immobilization of cellular components(e.g. (e.g. para 0037,pg. 2; para 0059, pg. 5; In some embodiments, methods of labeling molecules within one or more portions of a plurality of cells may include fixing and/or permeabilizing at least a portion of the plurality of cells prior to step (a). The methods may also include lysing at least a portion of the plurality of cells. Such lysing may release one or more of the molecules from within the plurality of cells... as in para 0059; components of a cell may be fixed or cross-linked such that the components are immobilized or held in place... as in para 0063, pg. 5). Furthermore, Seelig et al. teach oligonucleotide arrays are known in the art (e.g. para 0005, pg. 1).
Furthermore, Seelig et al. teach target molecules comprise DNA and RNA (e.g. para 0067-68, para 0073, pg. 6).
Therefore, Seelig et al. teach methods are known comprising providing arrays of polynucleotides comprising chemical -based photocleavable polymers(e.g. photocaged oligonucleotide adapters)that inhibit or block hybridization or ligation, i.e. sequestered polynucleotides; selectively exposing regions of the arrays to light to remove blocking moieties , yielding cleaved polynucleotides in those regions; and adding barcoded sequences and ligase to the array, wherein the barcoded sequences are hybridized to cleaved polynucleotides but do not interact with polynucleotides which comprise photocleavable polymers that inhibit or block hybridization or ligation, i.e. sequestered polynucleotides, in regions of the array that have not been exposed to UV light. Furthermore, Seelig et al. teach it is known to repeat the process to yield a different set of polynucleotides comprising primary barcodes as well as polynucleotides comprising secondary and tertiary barcodes, resulting in a differentially barcoded array of target polynucleotides.
Furthermore, Seelig et al. teach oligonucleotide arrays are known in the art (e.g. para 0005, pg. 1). However, Seelig et al. do not expressly teach target polynucleotides that are immobilized to a substrate.
Prior to the effective filing date of the claimed invention, Fodor et al. teach methods are known comprising providing an array of immobilized molecules, wherein molecules are attached in rows and columns and wherein the molecules are polynucleotides(e.g. Fig. 1; rows and columns as in para 0327-0362, pg. 20-23;especially para 0329-0330; para 0340-0341; oligonucleotide synthesis as in para 0465-0469, pg. 31-32),wherein each polynucleotide comprises a light-sensitive protecting group at the unattached end, and selectively exposing regions of the array to UV or IR light which causes the cleavage of the protective groups. Fodor et al. teach selective exposure comprises applying masks to some regions to retain the protective groups. Fodor et al. teach this is an iterative process which yields combinatorial pools of polynucleotide sequences and patterning of immobilized molecules on a substrate (e.g. Entire Fodor reference and especially para 0012,pg, 1; para 0020,pg. 2; para 0128,pg. 5; … a strategy in which a switch matrix for a masking strategy halves regions that were previously illuminated, illuminating about half of the previously illuminated region and protecting the remaining half (while also protecting about half of previously protected regions and illuminating about half of previously protected regions). It will be recognized that binary rounds may be interspersed with non-binary rounds and that only a portion of a substrate may be subjected to a binary scheme. A combinatorial "masking" strategy is a synthesis which uses light or other deprotecting or activating agents to remove protecting groups from materials for addition of other materials… as in para 0137,pg. 6; para 0142, pg. 6; On the substrate or a distal end of the linker molecules, a functional group with a protecting group PO is provided. The protecting group P0 may be removed upon exposure to radiation, electric fields, electric currents, or other activators to expose the functional group…In a preferred embodiment, the radiation is ultraviolet (UV), infrared (IR), or visible light as in para 0146-0147,pg. 7; para 0162-0164,pg. 8; selective masking strategies as in para 0363-0372,pg. 23-24;oligonucleotide synthesis as in para 0465-0469, pg. 31-32; para 0509-0521,pg. 35-36; Fig. 1; Fig. 25-27;Fig. 38).
Furthermore, Fodor et al. teach immobilized polynucleotides comprise caged entities which inhibit interaction with prospective binding partners and which are released upon selective UV light exposure (e.g. Entire Fodor reference and especially para 0532-0536,pg. 37).
Furthermore, Fodor et al. teach other types of protecting groups , include glycol polymers ( e.g. para 0166,pg. 8; para 0171,pg. 9; monodimethoxy-tritylpentaethyleneglycol groups as in para 0518, pg. 36).
Furthermore, Fodor et al. teach methods of preparing an array by contacting a substrate with linker molecules prior to irradiation, wherein the substrate is functionalized with silane molecules to which linker molecules are subsequently bonded. Fodor et al. teach the bonded linker molecules may comprise a photocleavable protecting group and are deprotected by irradiation prior to bonding with monomers that are used to build the oligonucleotide array (e.g. Entire Fodor reference and especially para 0170—194, pg. 9-11; slide preparation as in para 0205-0210, pg. 12; para 0218-0221, pg. 12-13).
Therefore, as Seelig et al. And Fodor et al. both teach methods comprising light-mediated removal of blocking groups, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Seelig et al. comprising selectively barcoding target polynucleotides comprising photocleavable polymers(e.g. photocaged adapters), i.e. sequestered polynucleotides, wherein the target polynucleotides become reactive by light -mediated cleavage of blocking groups to include providing an array of immobilized polynucleotides and using a combinatorial masking technique comprising selectively exposing regions of the array to UV or IR light which causes the cleavage of the protective groups, which includes glycol polymers and caged blocking entities that are responsive to light, while masking protected regions as taught by Fodor et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method of removing protective groups from an array comprising polynucleotides using light.
Therefore, the combined teachings of Seelig et al. and Fodor et al. render obvious a method comprising selectively masking regions of an array of immobilized polynucleotides comprising a light-sensitive protecting groups at the unattached ends, yielding an array comprising a first group of polynucleotides that hybridize with a barcoded nucleic acid sequence and a second group of polynucleotides that remain protected, wherein the method is repeated to yield a differentially barcoded array.
Regarding the requirement of hybridization or ligation for attaching a barcode:
As Seelig et al. teach hybridization followed by ligation to attach barcodes, this teaching meets the requirement.
Therefore, the combined teachings of Seelig et al. and Fodor et al. render obvious the limitations: a method for providing an array of polynucleotides, comprising: irradiating a first polynucleotide immobilized on a substrate with a first light while a second polynucleotide immobilized on the substrate is not irradiated with the first light, wherein the first polynucleotide is bound to a first photo-cleavable polymer that inhibits or blocks hybridization and/or ligation to the first polynucleotide, and the second polynucleotide is bound to a second photo-cleavable polymer that inhibits or blocks hybridization or ligation to the second polynucleotide, thereby cleaving the first photo-cleavable polymer such that the inhibition or blocking of hybridization or ligation to the first polynucleotide is reduced or eliminated, whereas hybridization or ligation to the second polynucleotide remains inhibited or blocked by the second photo-cleavable polymer, wherein a first barcode is attached to the first polynucleotide via hybridization or ligation, thereby providing on the substrate an array comprising the first and second polynucleotides, wherein the first polynucleotide is barcoded with the first barcode and the second polynucleotide is not barcoded with the first barcode as recited in claim 1.
Furthermore, as Seelig et al. teach the method is repeated multiple times in different and/or overlapping regions to yield differentially barcoded polynucleotides (e.g. para 0038-0046, pg. 2-3; para 0079-0082,pg. 7-8; para 0085, pg. 8; Example 1, pg. 9-10; Fig. 1-3, Fig. 6,7), the combined teachings of Seelig et al. and Fodor et al. render obvious claims 4, 5 and 7.
Furthermore, as Seelig et al. teach embodiments comprising providing barcoded sequences comprising blocking moieties, i.e. hairpin structures(e.g. para 0079-0082,pg. 7-8;Fig. 3; para 0077, pg. 7; Fig. 5) , the combined teachings of Seelig et al. and Fodor et al. render obvious claims 19 and 20.
Furthermore, as Seelig et al. teach photo-controlled adapters are photocleavable adapters comprising photocleavable linkers or photolabile protecting groups (e.g. Entire Seelig reference and especially para 0051, para 0054-0057, pg. 4-5; hairpin structure as in Fig. 5, 15A) or photocaged adapters comprising inhibitory moieties that are released the upon exposure to light, allowing hybridization of barcoded sequence, such as NPOM-caged deoxythymidine (e.g. Entire Seelig reference and especially para 0049-0052,pg. 3-4; para 0072,pg. 6; ; featuring four evenly spaced NPOM-caged dT residues... as in para 0111, Example 3,pg. 11; Fig. 16), the combined teachings of Seelig et al. and Fodor et al. render obvious claims 25,26, 65, 66 and 68.
Regarding claim 67:
Seelig et al. teach photo-controlled adapters are photocaged adapters comprising inhibitory chemical moieties, i.e. NPOM, that are released upon exposure to light, allowing hybridization of barcoded sequence. Seelig et al. teach NPOM-coupled thymidine (e.g. Entire Seelig reference and especially para 0049-0052,pg. 3-4; photocaged moieties as in para 0070-0072, pg. 6; photolabile group, 6-nitropiperonyloxymethyl (NPOM), may be coupled to the N3 position of thymidine, impairing base-pairing properties and thus hindering hybridization of complementary oligonucleotides…Upon exposure to near-UV light of 365 nm, the NPOM group may be detached, permitting hybridization of an oligonucleotide containing a complementary sequence. For optimal masking properties, NPOM groups should generally be attached every five to six bases apart …This group may also be attached to a guanidine… One or several NPOM-caged bases may be incorporated into the 5' end of the photocaged adapter sequence, which may permit hybridization of linker and barcode strands upon photonic energy exposure at near UV wavelength. Following hybridization, a ligation or click reaction may couple the barcoded strands to the photo-controlled adapter... as in para 0072, pg. 6; featuring four evenly spaced NPOM-caged dT residues... as in para 0111, Example 3, pg. 11; Fig. 16).
As evidenced by Liu et al., the structure of claim 67 is an NPOM coupled deoxythymidine (e.g. Entire Liu reference and especially item 11 of Figure 1, pg. 47; ... its corresponding hydroxymethylene analog (NPOM) on guanine (7), thymine (11), and uracil (18).2... as in 1st para, pg. 47).
Therefore, the combined teachings of Seelig et al., as evidenced by Liu et al., and Fodor et al. render obvious claim 67.
Furthermore, as Seelig et al. teach differentially barcoded array of target polynucleotides and Fodor et al. teach methods are known comprising providing an array of immobilized molecules, wherein the molecules are polynucleotides, the combined teachings of Seelig et al. and Fodor et al. render obvious claim 35.
Furthermore, as Fodor et al. teach combinatorial masking techniques are known, wherein some regions of an array of polynucleotides are exposed to light that cleaves blocking moieties and some regions are protected by masks, the combined teachings of Seelig et al. and Fodor et al. render obvious claim 37.
Furthermore, as Seelig et al. teach embodiments comprising attaching barcoded sequences by hybridization and ligation (e.g. Entire Seelig reference and especially para 0048,pg. 3; para 0059, pg. 5; para 0079-0082,pg. 7-8;Fig. 3; para 0077, pg. 7; Fig. 5; Example 2, pg. 10-11; Fig. 15), the combined teachings of Seelig et al. and Fodor et al. render obvious claim 38.
Furthermore, as both Seelig et al. and Fodor et al. teach methods comprising repeated rounds of masking and addition of other entities, such as tags, the combined teachings of Seelig et al. and Fodor et al. render obvious claims 50, 51, 54, 55 and 58.
Furthermore, as Seelig et al. teach their methods comprise providing polynucleotides in each well of multi-well plates comprising rows and columns (e.g. Example 1, pg. 9-10; Fig. 6-8, 12 and 13) and Fodor et al. teach methods are known comprising providing an array of immobilized molecules , wherein molecules are attached in rows and columns and wherein the molecules are polynucleotides(e.g. Fig. 1; rows and columns as in para 0327-0362, pg. 20-23;especially para 0329-0330; para 0340-0341; oligonucleotide synthesis as in para 0465-0469, pg. 31-32), the combined teachings of Seelig et al. and Fodor et al. render obvious claim 86.
Furthermore, as Fodor et al. teach preparation of substrates comprise providing silanized substrates that are contacted with linker molecules comprising photocleavable protecting groups which are deprotected by irradiation prior to bonding with monomers that are used to build the oligonucleotide array (e.g. Entire Fodor reference and especially para 0170—194, pg. 9-11; slide preparation as in para 0205-0210, pg. 12; para 0218-0221, pg. 12-13) and that combinatorial masking techniques are known, wherein some regions of an array of polynucleotides are exposed to light that cleaves blocking moieties and some regions are protected by masks, the combined teachings of Seelig et al. and Fodor et al. render obvious claims 139-142.
Seelig et al., Fodor et al. and Ramachandran Iyer et al.
Claim(s) 26, 68 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Seelig et al. , as evidenced by Liu et al., and Fodor et al., as applied to claims 1,4,5,7,19,20,25,26,35,37,38, 50,51,54,55,58,65-68, 86 and 139-142 above, and further in view of Ramachandran Iyer et al.(WO2020123309; filed 06 December 2019).
The combined teachings of Seelig et al., as evidenced by Liu et al., and Fodor et al. as applied above are incorporated in this rejection.
The combined teachings of Seelig et al. , as evidenced by Liu et al., and Fodor et al. render obvious a method comprising selectively masking regions of an array of immobilized polynucleotides comprising a light-sensitive protecting groups at the unattached ends, yielding an array comprising a first group of polynucleotides that hybridize with a barcoded nucleic acid sequence and a second group of polynucleotides that remain protected, wherein the method is repeated to yield a differentially barcoded array.
Furthermore, Seelig et al. teach photo-controlled adapters are photocaged adapters comprising inhibitory chemical moieties, i.e. NPOM, that are released upon exposure to light, allowing hybridization of barcoded sequence. Seelig et al. teach NPOM-coupled DNA (e.g. Nucleic acid species in both wells of a petri dish insert on the microscope stage: an 8 base pair adapter featuring four evenly spaced NPOM-caged dT residues and a terminal phosphate ... as in Example 3, pg. 11).
Furthermore, Seelig et al. teach barcode sequences comprising blocking moieties, i.e. hairpin structures (e.g. para 0079-0082, pg. 7-8; Fig. 3; para 0077, pg. 7; Fig. 5).
However, the combined teachings of Seelig et al. and Fodor et al. do not expressly teach a photocaged 3’hydroyl group as recited in claim 69.
Prior to the effective filing date of the claimed invention, Ramachandran Iyer et al. teach the structure of claim 69 is an ortho-nitrobenzyl (ONB) linker moiety (e.g. Entire Ramachandran Iyer reference and especially lines 4-25, pg. 81- lines 1-3, pg. 84; wherein: X is selected from O and NH; R1 is selected from H and C1-3 alkyl; R2 is selected from H and C1-3 alkoxy; n is 1, 2, or 3 as in lines 13-17, pg. 81; linker structure in line 9, pg. 82 and below):
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Therefore, as Seelig et al. and Ramachandran Iyer et al. both teach methods comprising providing hairpin structure moieties, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Seelig et al. , as evidenced by Liu et al., and Fodor et al. to include ONB linkers as taught by Ramachandran Iyer et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for providing an array of polynucleotides.
Furthermore, claim 69 depends from claim 68, which recites an embodiment of a photocleavable hairpin. Furthermore, claim 26 recites a photocleavable hairpin.
Therefore, the combined teachings of Seelig et al. , as evidenced by Liu et al., Fodor et al. and Ramachandran Iyer et al. render obvious claims 26, 68 and 69.
Seelig et al., Fodor et al. and Liu et al.
Claim(s) 27,65-67, 70 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Seelig et al. , as evidenced by Liu et al., and Fodor et al., as applied to claims 1,4,5,7,19,20,25,26,35,37,38, 50,51,54,55,58,65-68, 86 and 139-142 above, and further in view of Liu et al.(Liu, Qingyang, and Alexander Deiters. "Optochemical control of deoxyoligonucleotide function via a nucleobase-caging approach." Accounts of chemical research 47.1 (2014): 45-55.).
The combined teachings of Seelig et al., as evidenced by Liu et al., and Fodor et al. as applied above are incorporated in this rejection.
The combined teachings of Seelig et al. , as evidenced by Liu et al., and Fodor et al. render obvious a method comprising selectively masking regions of an array of immobilized polynucleotides comprising a light-sensitive protecting groups at the unattached ends, yielding an array comprising a first group of polynucleotides that hybridize with a barcoded nucleic acid sequence and a second group of polynucleotides that remain protected, wherein the method is repeated to yield a differentially barcoded array.
Furthermore, Seelig et al. teach photo-controlled adapters are photocaged adapters comprising inhibitory chemical moieties, i.e. NPOM, that are released upon exposure to light, allowing hybridization of barcoded sequence. Seelig et al. teach NPOM-coupled DNA ( e.g. Nucleic acid species in both wells of a petri dish insert on the microscope stage: an 8 base pair adapter featuring four evenly spaced NPOM-caged dT residues and a terminal phosphate ... as in Example 3, pg. 11).
However, the combined teachings of Seelig et al. and Fodor et al. do not expressly teach a photocaged 3’hydroyl group as recited in claims 27, 70 and 71.
Prior to the effective filing date of the claimed invention, Liu et al. teach the structure of claim 71 is an NPOM light removable caging moiety that can be linked to different residues (e.g. Entire Liu reference and especially item 11 of Figure 1, pg. 47; The light-removable caging groups are shown in red as in Fig. 1 caption; ... its corresponding hydroxymethylene analog (NPOM) on guanine (7), thymine (11), and uracil (18).... as in 1st para, pg. 47).
Therefore, as Seelig et al. and Liu et al. both teach methods comprising providing photo-caged residues, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Seelig et al. , as evidenced by Liu et al., and Fodor et al. to include NPOM coupled residues as taught by Liu et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for providing an array of polynucleotides.
Furthermore, claim 71 depends from claim 70, which recites an embodiment of a photocaged 3’ hydroxyl group. Furthermore, claim 27 recites a photocaged 3’ hydroxyl group.
Therefore, the combined teachings of Seelig et al., as evidenced by Liu et al., Fodor et al. and Liu et al. render obvious claims 27,65-67, 70 and 71.
Seelig et al., Fodor et al. and Hindson et al.
Claim(s) 41 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Seelig et al. , as evidenced by Liu et al., and Fodor et al., as applied to claims 1,4,5,7,19,20,25,26,35,37,38, 50,51,54,55,58,65-68, 86 and 139-142 above, and further in view of Hindson et al. (US20140378345).
The combined teachings of Seelig et al., as evidenced by Liu et al., and Fodor et al. as applied above are incorporated in this rejection.
The combined teachings of Seelig et al. , as evidenced by Liu et al., and Fodor et al. render obvious a method comprising selectively masking regions of an array of immobilized polynucleotides comprising a light-sensitive protecting groups at the unattached ends, yielding an array comprising a first group of polynucleotides that hybridize with a barcoded nucleic acid sequence and a second group of polynucleotides that remain protected, wherein the method is repeated to yield a differentially barcoded array.
However, the combined teachings of Seelig et al. and Fodor et al. do not expressly teach a splint as recited in claims 41 and 42.
Prior to the effective filing date of the claimed invention, Hindson et al. teach methods are known comprising providing an array of polynucleotides , i.e. a multi-well plate comprising a bead comprising polynucleotides in each well, wherein the unattached end of the target polynucleotide is capable of interacting with another nucleic acid sequence. Furthermore, Hindson et al. teach methods wherein the interaction comprises splint-mediated ligation comprising hybridization of an oligonucleotide sequence comprising a barcode with the target polynucleotide (e.g. Entire Hindson reference and especially para 0017-0030,pg.3-4 ; para 0183-0184,pg. 20-21; a multi-well plate comprising a bead comprising polynucleotides in each well as in para 0197-0201,pg. 23; splint-mediated ligation as in para 0212-0218,pg. 25-26; Example 4, pg. 59; Example 15,pg. 62; Fig. 4, Figs. 23-26).
Furthermore, Hindson et al. teach splints comprise 5-10 nucleotides with 1-10 nucleotides in overhang sequences (e.g. para 0219, pg. 26).
Therefore, as Seelig et al. and Hindson et al. both teach methods comprising hybridization of a target sequence with a barcoded sequence, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Seelig et al. , as evidenced by Liu et al., and Fodor et al. comprising removing blocking groups from selected groups of target polynucleotides attached to an array using light and a combinatorial masking technique, followed by hybridizing unblocked target polynucleotides with a barcoded sequence to include hybridizing target polynucleotides with barcoded oligonucleotides through splint-mediated ligation as taught by Hindson et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for providing an array of polynucleotides.
Therefore, as Hindson et al. teach splint-mediated ligation comprising hybridization and ligation of a barcoded oligonucleotide sequence with a target polynucleotide, the combined teachings of Seelig et al., as evidenced by Liu et al., Fodor et al. and Hindson et al. render obvious claims 41 and 42.
Seelig et al., Fodor et al., Hindson et al. and Rothberg et al.
Claim(s) 44 is rejected under 35 U.S.C. 103 as being unpatentable over Seelig et al., as evidenced by Liu et al., Fodor et al. and Hindson et al., as applied to claims 41 and 42 above, and further in view of Rothberg et al. (US7,264,929).
The combined teachings of Seelig et al , as evidenced by Liu et al.., Fodor et al. and Hindson et al.as applied above are incorporated in this rejection.
The combined teachings of Seelig et al. , as evidenced by Liu et al., Fodor et al. and Hindson et al. render obvious a method comprising selectively masking and exposing to light different regions of an array of immobilized polynucleotides comprising light-sensitive protecting groups, yielding an array comprising a first group of polynucleotides that hybridize with a barcoded nucleic acid sequence and a second group of polynucleotides that remain protected, wherein the barcodes are attached by splint-mediated ligation and wherein the method is repeated to yield a differentially barcoded array.
However, the combined teachings of Seelig et al., as evidenced by Liu et al., Fodor et al. and Hindson et al. do not expressly teach claim 44.
Prior to the effective filing date of the claimed invention, Rothberg et al. teach methods are known comprising annealing polynucleotide sequences to complementary sequences of a different polynucleotide molecule, i.e. a splint, wherein the splint complementary sequences are spaced apart, and subsequently subjecting to extension using a DNA polymerase in a “gap filling” reaction followed by ligation ( e.g. Sequences at the 5'and 3' ends of the open circle molecule are complementary to two regions of adjacent nucleotides in a second nucleic acid molecule, e.g., an adapter region of an anchor primer, or to two regions that are nearly adjoining in a second DNA molecule. Thus, the ends of the open-circle molecule can be … extended by DNA polymerase in a gap-filling reaction. …. An open circle can be converted to a closed circle in the presence of a DNA ligase (for DNA) or RNA ligase following, e.g., annealing of the open circle to an anchor primer as in lines 16-27, col. 11).
Therefore, as Hindson et al. and Rothberg et al. both teach methods comprising hybridization and ligation mediated with a splint, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Seelig et al., as evidenced by Liu et al., Fodor et al. and Hindson et al. to include hybridizing target polynucleotides and barcoded oligonucleotides with a splint, wherein the splint complementary sequences are spaced apart and subsequently subjecting to extension using a DNA polymerase in a “gap filling” reaction followed by ligation as taught by Rothberg et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for providing an array of polynucleotides.
Therefore, the combined teachings of Seelig et al. , as evidenced by Liu et al., Fodor et al., Hindson et al. and Rothberg et al. render obvious claim 44.
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.
U.S. Patent No. 12,497,654 (formerly Application No. 17/312,625)
Claims 1,4,5,7,19,20,25-27,35,37,38,41,42,44,50,51,54,55,58,65-71, 86 and 139-142 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,497,654 in view of Seelig et al. (US20170233722); Fodor et al. (US20050079529); Ramachandran Iyer et al.(WO2020123309; filed 06 December 2019); Liu et al.(Liu, Qingyang, and Alexander Deiters. "Optochemical control of deoxyoligonucleotide function via a nucleobase-caging approach." Accounts of chemical research 47.1 (2014): 45-55.); Hindson et al. (US20140378345); and Rothberg et al. (US7,264,929).
Claims 1-20 of U.S. Patent No. 12,497,654 teach a method comprising providing polynucleotides and attaching barcodes do not expressly teach all the features of the claimed invention, such as providing polynucleotides comprising photocleavable protecting groups.
However, these features are known in art. As noted in the current rejections, the combined teachings of Seelig et al. and Fodor et al. render obvious instant claims 1,4,5,7,19,20,25,26,35,37,38, 50,51,54,55,58,65-68, 86 and 139-142. Furthermore, the combined teachings of Seelig et al., Fodor et al. and Ramachandran Iyer et al. render obvious instant claims 26, 68, 69. Furthermore, the combined teachings of Seelig et al., Fodor et al. and Liu et al. render obvious instant claims 27, 65-67, 70 and 71. Furthermore, the combined teachings of Seelig et al., Fodor et al. and Hindson et al. render obvious instant claims 41 and 42. Furthermore, the combined teachings of Seelig et al., Fodor et al., Hindson et al. and Rothberg et al. render obvious instant claim 44.
Therefore, as claims 1-20 of U.S. Patent No. 12,497,654, Seelig et al., Fodor et al., Ramachandran Iyer et al., Liu et al., Hindson et al., and Rothberg et al. all disclose methods comprising attaching barcodes to polynucleotides, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of claims 1-20 of U.S. Patent No. 12,497,654 and to include the teachings of Seelig et al., Fodor et al., Ramachandran Iyer et al., Liu et al., Hindson et al., and Rothberg et al. as discussed in the rejections above because a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for providing an array of polynucleotides.
U.S. Patent No. 12,624,392 (formerly Application No. 17/565,047)
Claims 1,4,5,7,19,20,25-27,35,37,38,41,42,44,50,51,54,55,58,65-71, 86 and 139-142 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,624,392 in view of Seelig et al. (US20170233722); Fodor et al. (US20050079529); Ramachandran Iyer et al.(WO2020123309; filed 06 December 2019); Liu et al.(Liu, Qingyang, and Alexander Deiters. "Optochemical control of deoxyoligonucleotide function via a nucleobase-caging approach." Accounts of chemical research 47.1 (2014): 45-55.); Hindson et al. (US20140378345); and Rothberg et al. (US7,264,929).
Claims 1-24 of U.S. Patent No. 12,624,392 teach a method comprising providing polynucleotides, masking selected regions and attaching barcodes do not expressly teach all the features of the claimed invention, such as providing polynucleotides comprising photocleavable protecting groups.
However, these features are known in the art. As noted in the current rejections, the combined teachings of Seelig et al. and Fodor et al. render obvious instant claims 1,4,5,7,19,20,25,26,35,37,38, 50,51,54,55,58,65-68, 86 and 139-142. Furthermore, the combined teachings of Seelig et al., Fodor et al. and Ramachandran Iyer et al. render obvious instant claims 26, 68, 69. Furthermore, the combined teachings of Seelig et al., Fodor et al. and Liu et al. render obvious instant claims 27, 65-67, 70 and 71. Furthermore, the combined teachings of Seelig et al., Fodor et al. and Hindson et al. render obvious instant claims 41 and 42. Furthermore, the combined teachings of Seelig et al., Fodor et al., Hindson et al. and Rothberg et al. render obvious instant claim 44.
Therefore, as claims 1-24 of U.S. Patent No. 12,624,392, Seelig et al., Fodor et al., Ramachandran Iyer et al., Liu et al., Hindson et al., and Rothberg et al. all disclose methods comprising attaching barcodes to polynucleotides, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of claims 1-24 of U.S. Patent No. 12,624,392 and to include the teachings of Seelig et al., Fodor et al., Ramachandran Iyer et al., Liu et al., Hindson et al., and Rothberg et al. as discussed in the rejections above because a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for providing an array of polynucleotides.
Response to Arguments
Any rejection not reiterated or specifically addressed has been overcome by amendment. New rejections are set forth to address the amended claims.
However, previously cited references teach art relevant to the amended claims and therefore are included in the new rejections.
Regarding Applicants’ arguments that the previously cited art does not meet the requirements of the amended claims: these arguments are not persuasive.
Applicants’ arguments regarding combining the teachings of Seelig and Fodor are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
As discussed in the current rejections, the teaching of Seelig is applied because Seelig et al. teach methods are known comprising providing arrays of polynucleotides comprising chemical -based photocleavable polymers(e.g. photocaged oligonucleotide adapters)that inhibit or block hybridization or ligation, i.e. sequestered polynucleotides; selectively exposing regions of the arrays to light to remove blocking moieties , yielding cleaved polynucleotides in those regions; and adding barcoded sequences and ligase to the array, wherein the barcoded sequences are hybridized to cleaved polynucleotides but do not interact with polynucleotides which comprise photocleavable polymers that inhibit or block hybridization or ligation, i.e. sequestered polynucleotides, in regions of the array that have not been exposed to UV light. Furthermore, Seelig et al. teach it is known to repeat the process to yield a different set of polynucleotides comprising primary barcodes as well as polynucleotides comprising secondary and tertiary barcodes, resulting in a differentially barcoded array of target polynucleotides.
Furthermore, considering the Seelig teaching as a whole, Seelig et al. teach embodiments wherein cells are fixed and/or permeabilized prior to the first step of their method and wherein fixed cells are lysed, allowing the release of cellular molecules. Furthermore, Seelig et al. teach methods are known wherein fixed cells are also prepared to allow immobilization of cellular components(e.g. (e.g. para 0037,pg. 2; para 0059, pg. 5; In some embodiments, methods of labeling molecules within one or more portions of a plurality of cells may include fixing and/or permeabilizing at least a portion of the plurality of cells prior to step (a). The methods may also include lysing at least a portion of the plurality of cells. Such lysing may release one or more of the molecules from within the plurality of cells... as in para 0059; components of a cell may be fixed or cross-linked such that the components are immobilized or held in place... as in para 0063, pg. 5). Furthermore, Seelig et al. teach oligonucleotide arrays are known in the art (e.g. para 0005,pg. 1). Therefore, a skilled artisan would appreciate that such embodiments would allow analysis using arrays of immobilized oligonucleotides as taught by Fodor.
Furthermore, regarding the assertion that Seelig et al. do not teach the instant claims because the preferred embodiments taught by the cited art do not teach the claimed invention, Applicants’ arguments are not persuasive. The cited art is considered as a whole and is not limited to its preferred embodiments. See MPEP 2123.
I. PATENTS ARE RELEVANT AS PRIOR ART FOR ALL THEY CONTAIN
“The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also > Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); < Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”).
II. NONPREFERRED AND ALTERNATIVE EMBODIMENTS CONSTITUTE PRIOR ART
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have “relatively acceptable dimensional stability” and “some degree of flexibility,” but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since “Gurley asserted no discovery beyond what was known in the art.” 27 F.3d at 554, 31 USPQ2d at 1132.). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
As also discussed in the current rejections, the teaching of Fodor is applied because Fodor et al. teach preparation of substrates comprise providing silanized substrates that are contacted with linker molecules comprising photocleavable protecting groups which are deprotected by irradiation prior to bonding with monomers that are used to build the oligonucleotide array (e.g. Entire Fodor reference and especially para 0170—194, pg. 9-11; slide preparation as in para 0205-0210, pg. 12; para 0218-0221, pg. 12-13) and that combinatorial masking techniques are known, wherein some regions of an array of polynucleotides are exposed to light that cleaves blocking moieties and some regions are protected by masks.
Therefore, as Seelig et al. and Fodor et al. both teach methods comprising light- mediated removal of blocking groups, such as release of caged moieties, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to combine the teachings of Seelig et al. and Fodor et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method of removing protective groups from an array comprising polynucleotides using light.
Regarding Applicants’ arguments in reference to the teachings of Ramachandran Iyer, Liu, Hindson, and Rothberg, the additional arguments rely on the position that a prima facie case was not established in previous rejections. However, this was not found persuasive and is not persuasive for the other rejections. The rejections are reiterated.
Regarding the rejection of the instant claims on the grounds of non-statutory double patenting, Applicants‘ arguments and the amendment have been fully considered and deemed unpersuasive for the reasons that follow. Applicants have submitted additional arguments that rely on the position that a prima facie case was not established in previous rejections. However, this was not found persuasive and is not persuasive for these rejections.
Furthermore, Applicants have not submitted documentation (i.e. terminal disclaimer) in response to the double patenting rejection. Therefore, rejections of non-statutory double patenting are applied to address the amended claims.
Conclusion
No claims are allowable.
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 SAHANA S KAUP whose telephone number is (571)272-6897. The examiner can normally be reached M-F 7-10 EST.
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/SAHANA S KAUP/ Supervisory Primary Examiner, Art Unit 1612
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