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 .
Claims 1-4 and 6-21 are currently pending and under examination. Claim 5 is cancelled. Claims 1 and 6 are amended. Claim 21 is new.
Response to Amendment
The Amendment filed 2/4/26 has been entered. Claims 1-4 and 6-21 are pending.
Response to Arguments
Applicant’s arguments, see pages 5-11, filed 2/4/26, with respect to the rejections of claims 1-4 and 6-20 under 35 USC 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Non-Final mailed 11/5/25 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments and new claim 21 are made in this Final Office Action.
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 1, 6-12, 16-18, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Klein et al. (2020; WO 2020/106889 A1; FOR citation B4 in IDS filed on 9/19/23).
This new 103 rejection, including claim 21, is necessitated by claim amendments filed 2/4/26, and addresses the amended limitation “a linking moiety comprised of nucleic acid”.
Relevant to claim 1, Klein et al. teaches "In some embodiments, each peptide sequence may be associated with a unique spatial address. For example, once the peptides are attached to the solid support in spatially separated locations, each peptide sequence can be assigned an indexed address, such as by coordinates" (paragraph 00175).
This teaching reads on claim 1 a) providing a solid support comprising an address, wherein the address is resolvable at single-analyte resolution, wherein the address comprises an analyte.
Further relevant to claim 1, Klein et al. teaches "The substrate may be any substrate capable of forming a solid support. Substrates, such as solid supports, as used herein can refer to any solid surface to which peptides can be covalently or non-covalently attached. Non-limiting examples of solid supports include particles… In some embodiments, a solid support can be composed of and may be further modified to allow or enhance covalent or non-covalent attachment of the oligonucleotides" (paragraph 00167).
Further relevant to claim 1, Klein et al. teaches “FIG. 1 illustrates an immobilized target for selection of affinity reagents” (paragraph 0026).
Further relevant to claim 1, Klein et al. teaches “In some cases, a target may be immobilized to a solid support, such as a bead, using a linker” (paragraph 0083).
Further relevant to claim 1, Klein et al. teaches “In the case of a solid support that has been functionalized with alternate moieties (e.g. a sulfhydryl, amine, or linker DNA), a crosslinking reagent (e.g. disuccinimidyl suberate, NHS, sulphonamides) may be used. In the case of a solid support that has been functionalized with linker DNA the peptides of the target may be modified with complementary DNA tags” (paragraph 00172).
These Klein et al. teachings provide for a solid support wherein the target (analyte) is coupled to the address by a linking moiety comprised of nucleic acid (linker DNA). The linking moiety couples the analyte and solid support through DNA base pair complementarity of “DNA tags.” The coupling of the linking moiety and analyte constitutes a single structure, thus reading on wherein the linking moiety comprises a first optically detectable label (DNA tags).
Further relevant to claim 1, Klein et al. teaches "In a second embodiment of the third case, affinity reagents and peptides may be contacted in solution for a period of time, then immobilized to a target such that the affinity reagent is linked or bound to the substrate. After immobilization of the affinity reagents, proteins may be unbound from the affinity reagents by an elution step. Immobilized affinity reagents may be subsequently released from the substrate for sequencing and/or amplification. Methods of contacting affinity reagents with targets pools may involve one or more rinse, wash, or separation steps to remove any unbound or weakly-bound affinity reagents or peptides before binding is measured" (paragraph 0073).
The Klein et al. "affinity reagents" that are "immobilized to a target" read on the instant probe that is bound to the analyte. The Klein et al. affinity reagent (probe) can be bound and removed from the target, thus reading on claim 1 c) removing the probe from the analyte.
Further relevant to claim 1, Klein et al. teaches "The affinity reagents may be modified. Modifications include, but are not limited to, attachment of a detection moiety. Detection moieties may be directly or indirectly attached. For example, the detection moiety may be directly covalently attached to the affinity reagent, or may be attached through a linker, or may be attached through an affinity reaction such as complementary nucleic acid tags or a biotin streptavidin pair" (paragraph 00155).
Further relevant to claim 1, Klein et al. teaches "Detection moieties include, but are not limited to, fluorophores, bioluminescent proteins (GFP), enzymatic proteins (e.g., HRP), nanoparticles (e.g., quantum dots), nucleic acid segments including a constant region and barcode region, or chemical tethers for linking to a nanoparticle such as a magnetic particle" (paragraph 00156).
These teachings read on claim 1 wherein a probe is bound to the analyte, wherein the probe comprises a second optically detectable label.
Further relevant to claim 1, Klein et al. teaches "For example, each affinity reagent may be conjugated to one of several different fluorescent moieties, each with a different wavelength of excitation or emission. This may allow multiplexing of the affinity reagents as several different affinity reagents may be combined and/or distinguished. In one example, a first affinity reagent may be conjugated to a green fluorescent protein, a second affinity reagent may be conjugated to a yellow fluorescent protein and a third affinity reagent may be conjugated to a red fluorescent protein, thus the three affinity reagents can be multiplexed and identified by their fluorescence" (paragraph 00159).
This Klein et al. teaching allows the skilled artisan to ensure that the first wavelength differs from the second wavelength, reading on claim 1 wherein the first optically detectable label produces a first optical signal of a first wavelength, wherein the second optically detectable label produces a second optical signal of a second wavelength, and wherein the first wavelength differs from the second wavelength.
The skilled artisan would find it obvious that the Klein et al. "different fluorescent moieties, each with a different wavelength" would be detected via different channels.
Further relevant to claim 1, Klein et al. teaches "In some cases, presence or absence of the affinity reagent may be determined under several different conditions - for example different stringencies of washing, which may be achieved, for example, by using different washing buffers, different times of washing, different washing temperatures, or different levels of agitation" (paragraph 00100).
This teaching reads on claim 1 d) after removing the probe from the analyte, detecting on the first channel of the sensor the presence of the first detectable signal, and detecting on the second channel an absence of the second detectable signal.
Collectively, these teachings read on the limitations of claim 1.
Relevant to claim 6, Klein et al. teaches "The substrate may be any substrate capable of forming a solid support. Substrates, such as solid supports, as used herein can refer to any solid surface to which peptides can be covalently or non-covalently attached. Non-limiting examples of solid supports include particles, beads, slides, surfaces of elements of devices, membranes, flow cells, wells, chambers, macrofluidic chambers, microfluidic chambers, channels, microfluidic channels, or any other surfaces" (paragraph 00167).
Taken with the Klein et al. teaching that the target can be linked to the support via nucleic acid (relevant to claim 1), the skilled artisan would find a nanoparticle solid support linked to a nucleic acid as reading on claim 6 wherein the nucleic acid comprises a nucleic acid nanoparticle.
As discussed within the rejection of claim 1, it is established that the Klein et al. affinity reagent reads on the instant probe.
Relevant to claims 7-8, Klein et al. teaches "In some cases, a solid support is a magnetic bead, or a plurality of magnetic beads. Each magnetic bead of a plurality of magnetic beads may be coated in multiple copies of a single, distinct, affinity reagent, such that each bead is coated with a different affinity reagent from each other bead" (paragraph 0085).
This teaching reads on claim 7 wherein the probe further comprises an affinity agent; and claim 8 wherein the probe further comprises a plurality of affinity agents.
Further relevant to claims 9-10, Klein et al. teaches "The affinity reagents may be modified. Modifications include, but are not limited to, attachment of a detection moiety. Detection moieties may be directly or indirectly attached. For example, the detection moiety may be directly covalently attached to the affinity reagent, or may be attached through a linker, or may be attached through an affinity reaction such as complementary nucleic acid tags or a biotin streptavidin pair" (paragraph 00155).
Further relevant to claims 9-10, Klein et al. teaches "Detection moieties include, but are not limited to, fluorophores, bioluminescent proteins (GFP), enzymatic proteins (e.g., HRP), nanoparticles (e.g., quantum dots), nucleic acid segments including a constant region and barcode region, or chemical tethers for linking to a nanoparticle such as a magnetic particle" (paragraph 00156).
These teachings read on claim 9 wherein the plurality of affinity agents is coupled to the second detectable label by a retaining moiety.
Taken with the Klein et al. teaching that the affinity reagent can be linked to the support via nucleic acid, the skilled artisan would find a nanoparticle solid support linked to a nucleic acid as reading on claim 10 wherein the retaining moiety comprises a nucleic acid nanoparticle.
Relevant to claims 11-12, Klein et al. teaches "Excess bound target and negative control peptide will be allowed to dissociate from aptamer beads for 15 minutes prior to labeling with fluorescent streptavidin and sorting will be gated on high target peptide signal, low negative control peptide signal, and high aptamer signal" (paragraph 00189).
This teaching of a peptide target being non-covalently bound by the aptamer probe and subsequent dissociation reads on claim 11 wherein the probe is non-covalently bound to the analyte; and claim 12 wherein removing the probe comprises dissociating the probe from the analyte.
Relevant to claims 16-17, Klein et al. teaches "In a second embodiment of the third case, affinity reagents and peptides may be contacted in solution for a period of time, then immobilized to a target such that the affinity reagent is linked or bound to the substrate. After immobilization of the affinity reagents, proteins may be unbound from the affinity reagents by an elution step. Immobilized affinity reagents may be subsequently released from the substrate for sequencing and/or amplification. Methods of contacting affinity reagents with targets pools may involve one or more rinse, wash, or separation steps to remove any unbound or weakly-bound affinity reagents or peptides before binding is measured" (paragraph 0073).
Further relevant to claims 16-17, Klein et al. teaches "In some cases, presence or absence of the affinity reagent may be determined under several different conditions - for example different stringencies of washing, which may be achieved, for example, by using different washing buffers, different times of washing, different washing temperatures, or different levels of agitation" (paragraph 00100).
The Klein et al. affinity reagents (or probes) contact the target (analyte) through sequential rounds of contact, wherein the detection can occur after each round.
These teachings read on claims 16-17 limitations.
Relevant to claim 18, Klein et al. teaches "Buffers, solutions or mixtures of the present disclosure may be provided at a particular temperature or heated and/or cooled to a particular temperature during an assay or process. The temperature of a buffer, solution or mixture may be changed to optimize a particular process, for example affinity reagent binding, washing, or affinity reagent elution" (paragraph 0080).
Relevant to claim 21, Klein et al. paragraph 0073 teaches a protein target/analyte.
Klein et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro, 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. At 1742.
Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of various disclosed elements — including analytes, probes, linking moieties, and affinity agents — for a method, to arrive at compositions "yielding no more than one would expect from such an arrangement."
Claims 2-4 are rejected under 35 U.S.C. 103 as being unpatentable over Klein et al. (2020; WO 2020/106889 A1; FOR citation B4 in IDS filed on 9/19/23), as applied to claims 1, 6-12, 16-18, and 21 above, and further in view of Williamson et al. (2020; USPat citation A in PTO-892 filed 11/5/25; US 2020/0290043 Al; publication of US application 16/874,412, which claims the priority of provisional application 61/431,429, filed on 1/10/11).
The teachings of Klein et al. are applied to instantly rejected claims 2-4 as they were previously applied to claims 1, 6-12, 16-18, and 21 as rendering obvious a method. Klein et al. is silent to specifics regarding time delay and integration mode (claim 2) and first and second channel limitations (claims 3-4). However, these limitations were known in the prior art and taught by Williamson et al.
Relevant to claim 2, Williamson et al. teaches "In other embodiments, the sample imager is a scanning time-delay integration (TDI) system" (paragraph 0097).
Relevant to claims 3-4, Williamson et al. teaches "As shown, the optical surfaces 742 and 744 may be continuously smooth and planar surfaces that extend parallel to each other such that the thickness T3 is substantially uniform" (paragraph 0235). Williamson et al. Figures 44 and 46 depict the two optical surfaces (first channel and second channel) as coplanar and spatially separated on a solid support.
Although Klein et al. is silent to the Williamson et al. limitations, they would have been prima facie obvious to the skilled artisan. It is noted that Klein et al. and Williamson et al. are analogous disclosures to the instant detection methodology.
The skilled artisan would have been motivated to combine the analogous art and include the Williamson et al. optical design within the Klein et al. methodology because Williamson et al. teaches that their optical system (with the TDI and optical surface limitations) allows for the ability to distinguish more than one type of label within imaging sessions (see paragraph 0092). Thus, the skilled artisan would have been motivated to include the Williamson et al. optical design and limitations within the methodology rendered obvious by Klein et al. in order to distinguish between multiple optical labels.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Klein et al., and further in view of Williamson et al., as discussed in the preceding paragraphs.
Claims 13-15 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable Klein et al. (2020; WO 2020/106889 A1; FOR citation B4 in IDS filed on 9/19/23), as applied to claims 1, 6-12, 16-18, and 21 above, and further in view of Marcotte et al. (2020; US 10,545,153 B2; USPat citation A58 in IDS filed 8/22/23).
The teachings of Klein et al. are applied to instantly rejected claims 13-15 and 19-20 as they were previously applied to claims 1, 6-12, 16-18, and 21 as rendering obvious a method. Klein et al. is silent to specifics regarding covalent binding (claims 13-15) and focus adjustment (claims 19-20). However, these limitations were known in the prior art and taught by Marcotte et al.
Marcotte et al. teaches "The present invention relates to the field of identifying proteins and peptides, and more specifically large-scale sequencing (including but not limited to partial sequencing) of single intact peptides (not denatured) in a mixture of diverse peptides at the single molecule level by selective labeling amino acids on immobilized peptides followed by successive cycles of labeling and removal of the peptides' amino-terminal amino acids" (column 3, lines 20-27).
Relevant to claims 13-15, Marcotte et al. teaches "In one embodiment, the peptide is attached to said solid support at its C-terminal end. In one embodiment, the method further comprises a step of treating said immobilized peptides under conditions such that each N-terminal amino acid of each peptide is removed by an Edman degradation reaction; and a step of detecting the signal for each peptide at the single molecule level. In one embodiment, said label is attached to a fluorophore by a covalent bond" (column 3, line 65 - column 4, line 6).
These teachings read on claim 13 wherein the probe is covalently bound to the analyte; claim 14 wherein removing the probe comprises chemically or enzymatically separating the probe from the analyte; and claim 15 wherein chemically separating the probe from the analyte comprises performing an Edman-type degradation reaction.
Relevant to claims 19-20, Marcotte et al. teaches "Using a motorized microscope stage with automated focus control to image multiple stage positions in the flow cell may allow millions of individual single peptides (or more) to be sequenced in one experiment" (column 46, lines 27-31). The Marcotte et al. “automated focus” would read on both claim 19 focus adjustment and claim 20 non-adjustment, as the “automated” function would allow for both based upon the experimental input/need.
Although Klein et al. is silent to the Marcotte et al. covalent binding and focus adjustment, it would have been prima facie obvious to the skilled artisan. It is noted that Klein et al. and Marcotte et al. are analogous disclosures to the instant detection mode.
The skilled artisan would have been motivated to include the Marcotte et al. limitations within the Klein et al. methodology. Marcotte et al. teaches "The most widely used reaction for the sequential analysis of N-terminal residue of peptides is the Edman degradation method… Edman degradation is a method of sequencing amino acids in a peptide wherein the amino-terminal residue is labeled and cleaved from the peptide without disrupting the peptide bonds between other amino acid residues… The advantage of the Edman method is that the rest of the peptide chain after removal of the N-terminal amino acid is left intact for further cycles of this procedure; thus the Edman method can be used in a sequential fashion to identify several or even many consecutive amino acid residues starting from the N-terminal end" (column 2, lines 9-37). As the sequential analysis proceeds, the skilled artisan would find it obvious to include the Marcotte et al. auto focus adjustment as well in order to capture the sequential signals.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Klein et al., and further in view of Marcotte et al., as discussed in the preceding paragraphs.
Conclusion
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 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 Sarah J Kennedy whose telephone number is (571)272-1816. The examiner can normally be reached Monday - Friday 8a - 5p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682