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 .
Office Action: Notice
Any objection or rejection of record in the previous Office Action, mailed 11/6/2025,
which is not addressed in this action has been withdrawn in light of Applicants' amendments
and/or arguments. This action is FINAL.
Claim Status
Claims 1, 3, 7, 9-11 and 13-17 have been amended (2/6/2026). No new matter was added. Claims 1-20 are under examination (2/6/2026).
Priority
Claims 1-20 receive a priority date of 11/3/2021, the effective filing date of US Provisional Patent 63/275,298.
Objections and Disclosures Withdrawn
Sequence Disclosure:
The requirement for Sequence Listing Nucleotide and/or Amino Acid Sequence Disclosures has been fulfilled for both the Specification and Drawings in view of Applicant’s amendments.
Specification:
The objections to the specification due to the use of a trademark or tradenames are withdrawn in view of Applicant’s amendments.
Claims:
The minor formality objection to claim 2 is withdrawn in view of Applicant’s amendments.
Rejections and Interpretations Withdrawn
Claim Interpretations - 35 USC § 112(f)
The claim limitations of claims 2 and 4 no longer meet the three-prong test and will no longer be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, in view of Applicant’s removal of functional language without reciting sufficient structure to perform the recited function.
Claim Rejections - 35 USC § 112(a)
The rejection of claims 2-4 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn in view of Applicant’s removal of functional language without reciting sufficient structure to perform the recited function.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 2-4 under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 2nd paragraph, is withdrawn in view of Applicant’s removal of functional language without reciting sufficient structure to perform the recited function, as well as amendments to claims 3 and 4 to address insufficient antecedent basis.
Rejections Maintained
Claim Rejections—35 U.S.C. § 102
Claims 1-20 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Pirrung et al., (US PGPub 2006/0194258 A1, published 8/31/2006).
Regarding claim 1, Pirrung teaches a composition comprising a plurality of positionally distinguishable sequence specific reagents attached to a solid substrate, which reagents are capable of specifically binding to a predetermined subunit sequence of a preselected multi-subunit length having at least three subunits, said reagents representing substantially all possible sequences of said preselected length (Paragraph 12, lines 1-5). Further, Pirrung teaches that alternatively various substrates may be individually treated differently, where different substrates may be produced, each having reagents which bind to target subsequences with substantially identical stabilities and kinetics of hybridization (Paragraph 472, lines 1-5). Further Pirrung teaches that for example, all of the high GC content probes could be synthesized on a single substrate which is treated accordingly and in this embodiment, the alkylammonium buffers could be unnecessary where each substrate is then treated in a manner such that the collection of substrates show essentially uniform binding and the hybridization data of target binding to the individual substrate matrix is combined with the data from other substrates to derive the necessary subsequence binding information and the hybridization conditions will usually be selected to be sufficiently specific such that the fidelity of base matching will be properly discriminated (Paragraph 472, lines 1-8).
Further, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes selectively removable protecting groups allow creation of well-defined areas of substrate surface having differing reactivities, where preferably, the protecting groups are selectively removed from the surface by applying a specific activator, such as electromagnetic radiation of a specific wavelength and intensity and even more preferably, the specific activator exposes selected areas of surface to remove the protecting groups in the exposed areas (Paragraph 562, lines 1-5).
Further, Pirrung teaches that after a particular sequence has been hybridized and the pattern of hybridization analyzed, the matrix substrate should be reusable and readily prepared for exposure to a second or subsequent target polynucleotides. In order to do so, the hybrid duplexes are disrupted and the matrix treated in a way which removes all traces of the original target, where the matrix may be treated with various detergents or solvents to which the substrate, the oligonucleotide probes, and the linkages to the substrate are inert and this treatment may include an elevated temperature treatment, treatment with organic or inorganic solvents, modifications in pH, and other means for disrupting specific interaction (Paragraph 481, lines 1-8). Specifically, Pirrung teaches that thereafter, a second target may actually be applied to the recycled matrix and analyzed as before (Paragraph 481, lines 1-10).
Further, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes oligonucleotide synthesis which generally involves coupling an activated phosphorous derivative on the 3'-hydroxyl group of a nucleotide with the 5'-hydroxyl group of an oligomer bound to a solid support and two major chemical methods exist to perform this coupling: the phosphate-triester and phosphonamidite methods (Paragraph 358, lines 1-5).
Regarding claim 2, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes methods for forming predefined regions on a surface of a solid support, wherein the predefined regions are capable of immobilizing receptors and that these methods make use of caged binding members attached to the surface to enable selective activation of the predefined regions, where caged binding members are liberated to act as binding members ultimately capable of binding receptors upon selective activation of the predefined regions and the activated binding members are then used to immobilize specific molecules such as receptors on the predefined region of the surface (Paragraph 320, lines 1-5). Further, Pirrung teaches that the above procedure is repeated at the same or different sites on the surface so as to provide a surface prepared with a plurality of regions on the surface containing, for example, the same or different receptors and when receptors immobilized in this way have a differential affinity for one or more ligands, screenings and assays for the ligands can be conducted in the regions of the surface containing the receptors (Paragraph 320, lines 1-10).
Regarding claim 3, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes methods and apparatus for the preparation and use of a substrate having a plurality of polymer sequences in predefined regions primarily with regard to the preparation of molecules containing sequences of amino acids, but could readily be applied in the preparation of other polymers where such polymers include, for example, both linear and cyclic polymers of nucleic acids, polysaccharides, phospholipids, and peptides having either alpha-, beta-, or omega-amino acids, hetero-polymers in which a known drug is covalently bound to any of the above, polyurethanes, polyesters, polycarbonates, polyureas, polyamides, polyethyleneimines, polyarylene sulfides, polysiloxanes, polyimides, polyacetates, or other polymers which will be apparent upon review of this disclosure (Paragraph 172, lines 1-10).
Further, Pirrung teaches that the protective group on the linker molecules may be selected from a wide variety of positive light-reactive groups preferably including nitro aromatic compounds such as o-nitrobenzyl derivatives or benzylsulfonyl; including, 6-nitroveratryloxy-carbonyl (NVOC), 2-nitrobenzyloxycarbonyl (NBOC) or alpha,alpha-dimethyl-dimethoxybenzyloxycarbonyl (DDZ) is used and in one embodiment, a nitro aromatic compound containing a benzylic hydrogen ortho to the nitro group is used, i.e., a chemical of the form: alkoxy, alkyl, halo, aryl, alkenyl, or hydrogen (Paragraph 198, lines 1-10). Specifically, Pirrung teaches that after the reaction with the active ester in the fluorophore was complete, the locations in which the fluorophore was bound could be visualized by exposing them to ultraviolet light and observing the red and the green fluorescence. (Paragraph 282, lines 1-5). Additionally, Pirrung teaches that surfaces on the solid substrate will usually, though not always, be composed of the same material as the substrate and thus, the surface may be composed of any of a wide variety of materials, for example, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, membranes, or any of the above-listed substrate materials (Paragraph 192, lines 1-5).
Regarding claim 4, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes a set of masks used for the first monomer layer and, thereafter, varied light wavelengths are used for selective deprotection and in the process discussed above, first regions are first exposed through a mask and reacted with a first monomer having a first protective group, which is removable upon exposure to a first wavelength of light (i.e., IR) and second regions are masked and reacted with a second monomer having a second protective group, which is removable upon exposure to a second wavelength of light (i.e., UV) (Paragraph 185, lines 1-5). Pirrung teaches that thereafter, masks become unnecessary in the synthesis because the entire substrate may be exposed alternatively to the first and second wavelengths of light in the deprotection cycle (Paragraph 185, lines 1-8). Additionally, Pirrung teaches that selectively removable protecting groups allow creation of well-defined areas of substrate surface having differing reactivities and preferably, the protecting groups are selectively removed from the surface by applying a specific activator, such as electromagnetic radiation of a specific wavelength and intensity and more preferably, the specific activator exposes selected areas of surface to remove the protecting groups in the exposed areas (Paragraph 562, lines 1-5).
Regarding claim 5, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes suitable chromogens which will include molecules and compounds which absorb light in a distinctive range of wavelengths so that a color may be observed, or emit light when irradiated with radiation of a particular wave length or wave length range, i.e., fluoresces (Paragraph 639, lines 1-5; Table 1).
Regarding claim 6, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes the density of reagents attached to a silicon substrate may be varied by standard procedures and the surface area for attachment of reagents may be increased by modifying the silicon surface (Paragraph 567, lines 1-5).
Regarding claim 7, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules where the polymeric substrate approach involves either of two ways of generating a polymeric substrate and the first uses a high concentration of aminopropyltriethoxysilane (2-20%) in an aqueous ethanol solution (95%) and this allows the silane compound to polymerize both in solution and on the substrate surface, which provides a high density of amines on the surface of the glass (Paragraph 603, lines 1-5).
Regarding claim 8, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes other potential labeling moieties like radioisotopes, chemiluminescent compounds, labeled binding proteins, heavy metal atoms, spectroscopic markers, magnetic labels, and linked enzymes. (Paragraph 636, lines 5-10).
Regarding claim 9, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes a second polymeric method which involves either the coating or covalent binding of an appropriate acrylic acid polymer onto the substrate surface and in particular, i.e., in DNA synthesis, a monomer such as a hydroxypropylacrylate is used to generate a high density of hydroxyl groups on the substrate surface, allowing for the formation of phosphate bonds (Paragraph 604, lines 1-5).
Regarding claim 10, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes a method in which light is directed at the surface of the substrate containing the protective groups including the use of such masking techniques as they are applied to a positive reactive group so as to activate linking molecules and expose functional groups in areas 10a and 10b (Figure 5 (10a and 10b); Paragraph 202, lines 5-10).
Regarding claim 11, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes oligonucleotide synthesis which generally involves coupling an activated phosphorous derivative on the 3'-hydroxyl group of a nucleotide with the 5'-hydroxyl group of an oligomer bound to a solid support, where two major chemical methods exist to perform this coupling: the phosphate-triester and phosphonamidite methods where protecting groups of the present invention are suitable for use in either method and a photoremovable protecting group is attached to an activated nucleotide on the 5'-hydroxyl group (Paragraph 358, lines 1-5).
Regarding claim 12, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes oxidative or reductive removal which is accomplished by exposure of the protecting group to an electric current source, preferably using microelectrodes directed to the predefined regions of the surface which are desired for activation (Paragraph 566, lines 15-20).
Regarding claims 13-16, Pirrung teaches a composition comprising a plurality of positionally distinguishable sequence specific reagents attached to a solid substrate, which reagents are capable of specifically binding to a predetermined subunit sequence of a preselected multi-subunit length having at least three subunits, said reagents representing substantially all possible sequences of said preselected length (Paragraph 12, lines 1-5). Further, Pirrung teaches
Alternatively, various substrates may be individually treated differently, where different substrates may be produced, each having reagents which bind to target subsequences with substantially identical stabilities and kinetics of hybridization and for example, all of the high GC content probes could be synthesized on a single substrate which is treated accordingly. In this embodiment, the alkylammonium buffers could be unnecessary and each substrate is then treated in a manner such that the collection of substrates show essentially uniform binding and the hybridization data of target binding to the individual substrate matrix is combined with the data from other substrates to derive the necessary subsequence binding information (Paragraph 472, lines 1-5). Further Pirrung teaches that the hybridization conditions will usually be selected to be sufficiently specific such that the fidelity of base matching will be properly discriminated and control hybridizations should be included to determine the stringency and kinetics of hybridization (Paragraph 472, lines 1-8).
Further Pirrung teaches that selectively removable protecting groups allow creation of well-defined areas of substrate surface having differing reactivities and preferably, the protecting groups are selectively removed from the surface by applying a specific activator, such as electromagnetic radiation of a specific wavelength and intensity and more preferably, the specific activator exposes selected areas of surface to remove the protecting groups in the exposed areas (Paragraph 562, lines 1-5).
Pirrung additionally teaches that finally, after a particular sequence has been hybridized and the pattern of hybridization analyze, the matrix substrate should be reusable and readily prepared for exposure to a second or subsequent target polynucleotides, where in order to do so, the hybrid duplexes are disrupted and the matrix treated in a way which removes all traces of the original target and the matrix may be treated with various detergents or solvents to which the substrate, the oligonucleotide probes, and the linkages to the substrate are inert (Paragraph 481, lines 1-8). Further, Pirrung teaches that this treatment may include an elevated temperature treatment, treatment with organic or inorganic solvents, modifications in pH, and other means for disrupting specific interaction, where thereafter, a second target may actually be applied to the recycled matrix and analyzed as before (Paragraph 481, lines 1-10).
Also, Pirrung teaches that the linker molecules and monomers used are provided with a functional group to which is bound a protective group, where preferably, the protective group is on the distal or terminal end of the linker molecule opposite the substrate and the protective group may be either a negative protective group (i.e., the protective group renders the linker molecules less reactive with a monomer upon exposure) or a positive protective group (i.e., the protective group renders the linker molecules more reactive with a monomer upon exposure) and in the case of negative protective groups an additional step of reactivation will be required(Paragraph 197, lines 1-5).
Regarding claim 17, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes that the desired repertoire of possible oligomer sequences of a given length has been synthesized, this collection of reagents may be individually positionally attached to a substrate, thereby allowing a batchwise hybridization step (Paragraph 449, lines 1-5).
Regarding claims 18-20, Pirrung teaches that the previously described method of individualized labeling of a solid support for the coupling of molecules includes one embodiment in which a substrate is shown in cross-section (Figure 1), where essentially, any conceivable substrate may be employed in the invention and may be biological, nonbiological, organic, inorganic, or a combination of any of these, existing as particles, strands (non-continuous), precipitates, gels, sheets, tubing, spheres (annular), containers, capillaries, pads, slices, films, plates, slides (continuous), etc. and where the substrate may have any convenient shape, such as a disc, square, sphere, circle, etc. (Paragraph 190, lines 1-10; Figure 1).
Specifically, Pirrung teaches methods for forming predefined regions on a surface of a solid support, wherein the predefined regions are capable of immobilizing receptors and the methods make use of caged binding members attached to the surface to enable selective activation of the predefined regions, where the caged binding members are liberated to act as binding members ultimately capable of binding receptors upon selective activation of the predefined regions and the activated binding members are then used to immobilize specific molecules such as receptors on the predefined region of the surface (Paragraph 825, lines 1-8). Further, Pirrung teaches that the density of reagents attached to a silicon substrate may be varied by standard procedures and the surface area for attachment of reagents may be increased by modifying the silicon surface, including a matte surface may be machined or etched on the substrate to provide more sites for attachment of the particular reagents (Paragraph 567, lines 1-5).
Pirrung teaches each and every limitation of claims 1-20, and therefore Pirrung anticipates claims 1-20.
Applicant’s Response: The Applicant argues that Pirrung does not anticipate amended claim 1 because it fails to disclose the complete detachment of first molecules from a first subset of surface sites such that those sites are not attached to any first molecules or derivatives. The Applicant further argues that Pirrung merely removes protecting groups or strips the entire matrix, rather than selectively ablating first molecules on a second subset. The Applicant also asserts that Pirrung does not teach the claimed differential coupling step, wherein second molecules are coupled to retained first molecules on the second subset and third molecules are coupled to the fully cleared first subset of surface sites.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully and fully considered but are not found persuasive, as discussed below.
The Applicant argues that Pirrung fails to teach (i) complete detachment of first molecules form a first subset of surface sites and (ii) differential coupling of second molecules to retained first molecules and third molecules to cleared surface sites. However, Pirrung teaches selective removal of protecting groups from predefined regions of a substrate using electromagnetic radiation of a specific wavelength and intensity, thereby generating well-defined regions of differing reactivity (Paragraphs 185, 202, 562). The selective exposure of regions to light to remove protecting groups inherently results in surface sites that are no longer attached to protected moieties and are available for subsequent coupling. Under the broadest reasonable interpretation (BRI) (MPEP 2111), the claimed detaching of first molecules encompasses Pirrung’s selective photo-deprotection and activation of defined surface regions because they result in first and second subsets of surface sites having different attachment states and being differentially coupled with additional molecules, as claimed.
Specifically, although Pirrung describes removal of protecting groups via electromagnetic radiation (Paragraph 562), this selective photo-deprotection renders defined surface regions reactive and available for subsequent coupling, thereby producing a subset of surface sites no longer functionally attached to the original protected species. Under the BRI, the claimed detaching first molecules encompasses such selective removal that generates vacant, reactive surface sites.
Further, Pirrung teaches subsequent coupling steps at the selectively activated regions, including oligonucleotide synthesis via phosphonamidite or phosphate triester chemistry (Paragraph 358), and repeated cycles of deprotection and coupling to generate distinct regions bearing differing molecules (Paragraphs 20, 449). Pirrung also teaches reuse of the substrate and treatment steps that remove prior targets (Paragraph 481), demonstrating that regions may be cleared and differentially functionalized. These teachings disclose coupling different molecules to distinct subsets of surface sites required by the amended instant claims.
Therefore, the Applicant’s argument that Pirrung merely removes protecting groups rather than first molecules is not persuasive because anticipation does not require ipissimis verbis disclosure, only that the reference teach the claimed limitations arranged as in the claim (MPEP 2131). Pirrung’s selective photochemical activation and subsequent coupling steps inherently produce first and second subsets of surface sites with different attachment states, satisfying the claimed differential coupling limitations.
Accordingly, Pirrung teaches each and every limitation of claims 1-20, and the rejection under 35 USC 102 is maintained.
Conclusions
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
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/ELIZABETH ROSE LAFAVE/ Examiner, Art Unit 1684
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684