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 .
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because:
The lettering is not of proper size, uniform density, and well-defined in Figure(s) 1A - 9. See 37 CFR 1.84(p)(1) – (5) and 37 CFR 1.84(l). (“Numbers, letters, and reference characters must measure at least .32 cm (1/8 inch) in height.”)
The lines, numbers and lettering are not clean, well-defined, sufficiently dense and dark, and uniformly thick and well defined in Figure(s) 5A and 6A. See 37 CFR 1.84(l) and (q).
The margins are not of proper size in Figure(s) 1A - 14. See 37 CFR 1.84(g).
In Figure(s) 1A - 9 the reference characters, sheet numbers, and view numbers are not all oriented in the same direction so as to avoid having to rotate the sheet. See 37 CFR 1.84(p)(1).
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
INFORMATION ON HOW TO EFFECT DRAWING CHANGES
Replacement Drawing Sheets
Drawing changes must be made by presenting replacement sheets which incorporate the desired changes and which comply with 37 CFR 1.84. An explanation of the changes made must be presented either in the drawing amendments section, or remarks, section of the amendment paper. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). A replacement sheet must include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of the amended drawing(s) must not be labeled as “amended.” If the changes to the drawing figure(s) are not accepted by the examiner, applicant will be notified of any required corrective action in the next Office action. No further drawing submission will be required, unless applicant is notified.
Identifying indicia, if provided, should include the title of the invention, inventor’s name, and application number, or docket number (if any) if an application number has not been assigned to the application. If this information is provided, it must be placed on the front of each sheet and within the top margin.
Annotated Drawing Sheets
A marked-up copy of any amended drawing figure, including annotations indicating the changes made, are required by the examiner. The annotated drawing sheet(s) must be clearly labeled as “Annotated Sheet” and must be presented in the amendment or remarks section that explains the change(s) to the drawings.
Timing of Corrections
Applicant is required to submit acceptable corrected drawings within the time period set in the Office action. See 37 CFR 1.85(a). Failure to take corrective action within the set period will result in ABANDONMENT of the application.
If corrected drawings are required in a Notice of Allowability (PTOL-37), the new drawings MUST be filed within the THREE MONTH shortened statutory period set for reply in the “Notice of Allowability.” Extensions of time may NOT be obtained under the provisions of 37 CFR 1.136 for filing the corrected drawings after the mailing of a Notice of Allowability.
Response to traversal
At page 5 of the response of 05 February 2026, hereinafter the response, applicant’s representative traverses the grounds of objection to the figures filed 12 June 2025.
As stated at page 5 of the response:
Regarding Figures 1A-9, the Office alleges that "[t]he lettering is not of proper size, uniform density, and well-defined". Applicant respectfully disagrees and submits that the drawings do comply with 37 CFR 1.84.
Regarding Figures 5A and 6A, the Office alleges that "[t]he lines, numbers, and lettering are not clean, well-defined, sufficiently dense and dark, and uniformly thick and well defined".
Applicant respectfully disagrees and submits that the drawings do comply with 37 CFR 1.84.
Regarding Figures 1A-14, the Office alleges that "[t]he margins are not of proper size". Applicant respectfully disagrees and submits that the drawings do comply with 37 CFR 1.84.
Regarding Figures 1A-9, the Office alleges that "[t]he reference characters, sheet numbers, and view numbers are not all oriented in the same direction so as to avoid having to rotate the
sheet".
Applicant respectfully disagrees and submits that the drawings do comply with 37 CFR 1.84.
Applicant’s traversals have been considered and have not been found persuasive. With regard to lettering, 37 CFR 1.84(p)(3) specifies that lettering needs to e at least .32 cm (1/8 inch) in height. A review of the figures finds that in FIG. 1A – 8B, the letters o, n, and a in the word “optional” are 1/16 inn height. In Fig. 1A – 2B, 8A and 8B the letters a, s, and e in “ligase” are also 1/16 in height, which is one half of the required size (1/8).
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It is further noted that in FIG. 5A and 5B there are lines crossing through the lettering.
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As specified in 37 CFR 1.84(p)(3):
Numbers, letters, and reference characters must measure at least .32 cm. (1/8 inch) in height. They should not be placed in the drawing so as to interfere with its comprehension. Therefore, they should not cross or mingle with the lines. (Emphasis added)
In using FIG. 1A and 1B as an example, it is clear that the sheet numbering, “1/14” is not oriented in the same direction as the lettering of the figures.
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It is further noted that the margin on the side where sheet numbering is placed needs to be at least 1 inch, and that sheet numbering is not to occur within the margin. After printing out the different sheets and using a ruler to measure the margins, it became obvious that all sheet numbering was placed within the 1 inch margin.
In view of the above analysis and in the absence of convincing evidence to the contrary, the objections are maintained.
Claim Interpretation
Attention is directed to MPEP 904.01 [R-08.2012].
The breadth of the claims in the application should always be carefully noted; that is, the examiner should be fully aware of what the claims do not call for, as well as what they do require. During patent examination, the claims are given the broadest reasonable interpretation consistent with the specification. See In re Morris, 127 F.3d 1048, 44 USPQ2d 1023 (Fed. Cir. 1997). See MPEP § 2111 - § 2116.01 for case law pertinent to claim analysis.
It is noted with particularity that narrowing limitations found in the specification cannot be inferred in the claims where the elements not set forth in the claims are linchpin of patentability. In re Philips Industries v. State Stove & Mfg. Co, Inc., 186 USPQ 458 (CA6 1975). While the claims are to be interpreted in light of the specification, it does not follow that limitations from the specification may be read into the claims. On the contrary, claims must be interpreted as broadly as their terms reasonably allow. See Ex parte Oetiker, 23 USPQ2d 1641 (BPAI, 1992). In added support of this position, attention is directed to MPEP 2111 [R-11.2013], where, citing In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550-51 (CCPA 1969), is stated:
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.
Additionally, attention is directed to MPEP 2111.01 [R-01.2024], wherein is stated:
II. IT IS IMPROPER TO IMPORT CLAIM LIMITATIONS FROM THE SPECIFICATION
“Though understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment.” Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875, 69 USPQ2d 1865, 1868 (Fed. Cir. 2004).
Attention is also directed to MPEP 2111.02 II [R-07.2022]. As stated herein:
II. PREAMBLE STATEMENTS RECITING PURPOSE OR INTENDED USE
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The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "'extraneous' limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020) (The court found that the preamble in one patent’s claim is limiting but is not in a related patent); Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation")… (Emphasis added)
Attention is directed to MPEP 2111 [R-10.2019]. As stated therein:
During patent examination, the pending claims must be "given their broadest reasonable interpretation consistent with the specification." The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) expressly recognized that the USPTO employs the "broadest reasonable interpretation" standard:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1). (Emphasis added).
Attention is directed to MPEP 2173.04 [R-10.2019]. As stated therein:
Breadth of a claim is not to be equated with indefiniteness. In re Miller, 441 F.2d 689, 169 USPQ 597 (CCPA 1971); In re Gardner, 427 F.2d 786, 788, 166 USPQ 138, 140 (CCPA 1970) ("Breadth is not indefiniteness."). A broad claim is not indefinite merely because it encompasses a wide scope of subject matter provided the scope is clearly defined. But a claim is indefinite when the boundaries of the protected subject matter are not clearly delineated and the scope is unclear. For example, a genus claim that covers multiple species is broad, but is not indefinite because of its breadth, which is otherwise clear. But a genus claim that could be interpreted in such a way that it is not clear which species are covered would be indefinite (e.g., because there is more than one reasonable interpretation of what species are included in the claim). (Emphasis added)
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Standard for Obviousness.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Attention is directed to In re Jung, 98 USPQ2d 1174, 1178 (Fed. Cir. 2011) wherein is stated:
There has never been a requirement for an examiner to make an on-the-record claim construction of every term in every rejected claim and to explain every possible difference between the prior art and the claimed invention in order to make out a prima facie rejection. This court declines to create such a burdensome and unnecessary requirement. “[Section 132] does not mandate that in order to establish prima facie anticipation, the PTO must explicitly preempt every possible response to a section 102 rejection. Section 132 merely ensures that an applicant at least be informed of the broad statutory basis for the rejection of his claims, so that he may determine what the issues are on which he can or should produce evidence.” Chester, 906 F.2d at 1578 (internal citation omitted). As discussed above, all that is required of the office to meet its prima facie burden of production is to set forth the statutory basis of the rejection and the reference or references relied upon in a sufficiently articulate and informative manner as to meet the notice requirement of § 132. As the statute itself instructs, the examiner must “notify the applicant,” “stating the reasons for such rejection,” “together with such information and references as may be useful in judging the propriety of continuing prosecution of his application.” 35 U.S.C. § 132.
Attention is directed to the decision in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007):
When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
It is further noted that prior art is not limited to the four corners of the documentary prior art being applied. Prior art includes both the specialized understanding of one of ordinary skill in the art, and the common understanding of the layman. It includes “background knowledge possessed by a person having ordinary skill in the art. . . [A] court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1396.
Suggestion, teaching or motivation does not have to be explicit and “may be found in any number of sources, including common knowledge, the prior art as a whole or the nature of the problem itself’” Pfizer, Inc. v. Apotex, Inc. 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007) citing Dystar Textilfarben GMBH v. C. H. Patrick Co., 464 F.3d 1356 (Fed. Cir. 2006).
Holding and Rationale
Claim(s) 1-30 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0126825 A1 (Nagendran et al.).
Nagendran et al., teach:
[0007] In some instances, the analyte derived molecule is a ligation product. In some instances, the method further includes, prior to step (b): contacting a plurality of first probes and second probes to the biological sample on the array, wherein the plurality of first probes and second probes target a plurality of nucleic acids in the biological sample, wherein a first probe and a second probe of the plurality comprise sequences that are substantially complementary to the analyte, wherein the analyte is a target nucleic acid, and wherein the second probe comprises a capture probe capture domain sequence that is complementary to all or a portion of the capture domain; hybridizing the first probe and the second probe to the target nucleic acid; generating a ligation product by ligating the first probe and the second probe; and releasing the ligation product from the target nucleic acid. (Emphasis added)
[0008] In some instances, the first probe and the second probe are substantially complementary to adjacent sequences of the target nucleic acid. In some instances, the first probe and the second probe hybridize to sequences that are not adjacent to each other on the target nucleic acid, and wherein the first probe is extended with a DNA polymerase, thereby (i) filling in a gap between the first probe and the second probe and (ii) generating an extended first probe. In some instances, the first probe further comprises a primer sequence. In some instances, the first probe and/or the second probe is a DNA probe. In some instances, the releasing the ligation product from the target nucleic acid comprises contacting the biological sample with an endoribonuclease, optionally wherein the endoribonuclease is an RNase H enzyme. (Emphasis added)
[0009] In some instances, the analyte derived molecule is an analyte capture agent. In some instances, the methods further include, prior to step (b): contacting the biological sample with a plurality of analyte capture agents, wherein the analyte capture agent comprises an analyte binding moiety and an oligonucleotide comprising an analyte binding moiety barcode and an analyte capture sequence, wherein the analyte capture sequence comprises a sequence complementary to the capture domain; and binding the analyte binding moiety of the analyte capture agent to the analyte, wherein the analyte is a protein. In some instances, step (b) comprises hybridizing the analyte capture sequence to the capture domain. (Emphasis added)
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[0031] In some embodiments, determining the mislocalization of the analyte includes measuring the signal intensity of the plurality of detection probes and comparing the signal intensity to a first image of the biological sample. In some embodiments, signal intensity in the image of the biological sample includes a single cell or cell type that expresses a biomarker that is detected when the biological sample is stained.
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[0039] In some embodiments, the biological sample includes a tissue section. In some embodiments, the tissue section is about 2.5 μm to about 20 μm in thickness.
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[0041] In some embodiments, the analyte is RNA. In some embodiments, the RNA is mRNA. In some embodiments, the analyte is a protein. In some embodiments, the protein is a cell surface marker. In some embodiments, the protein is an immune cell receptor. (Emphasis added)
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[0043] In some embodiments, the method also includes determining abundance and/or location of an analyte in the second biological sample, wherein the determining includes: (a) contacting a spatial array with the second biological sample, wherein the spatial array includes a plurality of spatial capture probes, wherein a spatial capture probe of the plurality of spatial capture probes includes a capture domain and a spatial barcode; (b) hybridizing the analyte to the spatial capture probe; and (c) determining (i) all or a part of the sequence of the analyte, or a complement thereof, and (ii) the sequence of the spatial barcode… (Emphasis added)
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[0071] Spatial analysis methodologies and compositions described herein can provide a vast amount of analyte and/or expression data for a variety of analytes within a biological sample at high spatial resolution, while retaining native spatial context. Spatial analysis methods and compositions can include, e.g., the use of a capture probe including a spatial barcode (e.g., a nucleic acid sequence that provides information as to the location or position of an analyte within a cell or a tissue sample (e.g., mammalian cell or a mammalian tissue sample) and a capture domain that is capable of binding to an analyte (e.g., a protein and/or a nucleic acid) produced by and/or present in a cell. Spatial analysis methods and compositions can also include the use of a capture probe having a capture domain that captures an intermediate agent for indirect detection of an analyte. For example, the intermediate agent can include a nucleic acid sequence (e.g., a barcode) associated with the intermediate agent. Detection of the intermediate agent is therefore indicative of the analyte in the cell or tissue sample. (Emphasis added)
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[0073] Some general terminology that may be used in this disclosure can be found in Section (I)(b) of WO 2020/176788 and/or U.S. Patent Application Publication No. 2020/0277663. Typically, a “barcode” is a label, or identifier, that conveys or is capable of conveying information (e.g., information about an analyte in a sample, a bead, and/or a capture probe). A barcode can be part of an analyte, or independent of an analyte. A barcode can be attached to an analyte. A particular barcode can be unique relative to other barcodes. For the purpose of this disclosure, an “analyte” can include any biological substance, structure, moiety, or component to be analyzed. The term “target” can similarly refer to an analyte of interest. (Emphasis added)
[0074] Analytes can be broadly classified into one of two groups: nucleic acid analytes, and non-nucleic acid analytes. Examples of non-nucleic acid analytes include, but are not limited to, lipids, carbohydrates, peptides, proteins, glycoproteins (N-linked or O-linked), lipoproteins, phosphoproteins, specific phosphorylated or acetylated variants of proteins, amidation variants of proteins, hydroxylation variants of proteins, methylation variants of proteins, ubiquitylation variants of proteins, sulfation variants of proteins, viral proteins (e.g., viral capsid, viral envelope, viral coat, viral accessory, viral glycoproteins, viral spike, etc.), extracellular and intracellular proteins, antibodies, and antigen binding fragments. In some embodiments, the analyte(s) can be localized to subcellular location(s), including, for example, organelles, e.g., mitochondria, Golgi apparatus, endoplasmic reticulum, chloroplasts, endocytic vesicles, exocytic vesicles, vacuoles, lysosomes, etc. In some embodiments, analyte(s) can be peptides or proteins, including without limitation antibodies and enzymes. Additional examples of analytes can be found in Section (I)(c) of WO 2020/176788 and/or U.S. Patent Application Publication No. 2020/0277663. In some embodiments, an analyte can be detected indirectly, such as through detection of an intermediate agent, for example, an analyte derived molecule such as a connected probe (e.g., a ligation product) or an analyte capture agent (e.g., an oligonucleotide-conjugated antibody), such as those described herein. (Emphasis added)
[0075] A “biological sample” is typically obtained from the subject for analysis using any of a variety of techniques including, but not limited to, biopsy, surgery, and laser capture microscopy (LCM), and generally includes cells and/or other biological material from the subject. In some embodiments, a biological sample can be a tissue section. In some embodiments, a biological sample can be a fixed and/or stained biological sample (e.g., a fixed and/or stained tissue section). Non-limiting examples of stains include histological stains (e.g., hematoxylin and/or eosin) and immunological stains (e.g., fluorescent stains).
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[0078] A “capture probe” refers to any molecule capable of capturing (directly or indirectly) and/or labelling an analyte (e.g., an analyte of interest) in a biological sample. In some embodiments, the capture probe is a nucleic acid or a polypeptide. In some embodiments, the capture probe includes a barcode (e.g., a spatial barcode and/or a unique molecular identifier (UMI)) and a capture domain). In some embodiments, a capture probe can include a cleavage domain and/or a functional domain (e.g., a primer-binding site, such as for amplification, or a flow cell attachment sequence, such as for next-generation sequencing (NGS)). (Emphasis added)
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[0085] In some embodiments, more than one analyte type (e.g., nucleic acids and proteins) from a biological sample can be detected (e.g., simultaneously or sequentially) using any appropriate multiplexing technique, such as those described in Section (IV) of WO 2020/176788 and/or U.S. Patent Application Publication No. 2020/0277663. (Emphasis added)
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[0086] In some embodiments, detection of one or more analytes (e.g., protein analytes) can be performed using one or more analyte capture agents. As used herein, an “analyte capture agent” refers to an agent that interacts with an analyte (e.g., an analyte in a biological sample) and with a capture probe (e.g., a capture probe attached to a substrate or a feature) to identify the analyte. In some embodiments, the analyte capture agent includes: (i) an analyte binding moiety (e.g., that binds to an analyte), for example, an antibody or antigen-binding fragment thereof; (ii) analyte binding moiety barcode; and (iii) a capture handle sequence. As used herein, the term “analyte binding moiety barcode” refers to a barcode that is associated with or otherwise identifies the analyte binding moiety. As used herein, the term “analyte capture sequence” or “capture handle sequence” refers to a region or moiety configured to hybridize to, bind to, couple to, or otherwise interact with a capture domain of a capture probe. In some embodiments, a capture handle sequence is complementary to a capture domain of a capture probe. In some cases, an analyte binding moiety barcode (or portion thereof) may be able to be removed (e.g., cleaved) from the analyte capture agent. (Emphasis added)
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[0115] Thus, disclosed herein are methods of determining analyte mislocalization within a biological sample, the method including: (a) obtaining a first image of the biological sample; (b) hybridizing the analyte or analyte derived molecule to a capture probe on an array, wherein the array includes a plurality of capture probes, wherein a capture probe of the plurality of capture probe includes a capture domain; (c) optionally extending the capture probe using the analyte as a template, thereby generating an extended capture probe; (d) hybridizing a padlock probe or a snail probe to the analyte derived molecule or extended capture probe; (e) circularizing the padlock probe or the snail probe; (f) amplifying the padlock probe or the snail probe, thereby generating an amplified circularized padlock probe or an amplified circularized snail probe; (g) hybridizing a plurality of detection probes to the amplified circularized padlock probe or the amplified circularized snail probe, wherein a detection probe from the plurality of detection probes comprises: a sequence that is substantially complementary to a sequence of the padlock probe or the snail probe, or a complement thereof, and a detectable label; (h) obtaining a second image of the biological sample and detecting a signal from the plurality of detection probes in the second image; and (i) determining mislocalization of the analyte within the biological sample by comparing the first image of the biological sample to the second image of the biological sample. (Emphasis added)
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[0125] In other embodiments, probes can be designed so that one of the probes of a pair is a probe that hybridizes to a specific sequence. Then, the other probe can be designed to detect a mutation of interest. (Emphasis added)
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[0130] In some embodiments, proteins in a biological sample can be detected using analyte capture agents, as described herein. In some embodiments, the analyte capture agents are contacted with the biological sample before the biological sample is contacted with an array. In some embodiments, the analyte capture agents are contacted with the biological sample after the biological sample is contacted with the array. In some embodiments, an analyte binding moiety of the analyte capture agent interacts (e.g., binds) with an analyte (e.g., protein) in a biological sample. In some embodiments, the analyte binding moiety is an antibody, aptamer or antigen-binding fragment. (Emphasis added)
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[0134] In some embodiments, analyte capture agents are capable of binding to analytes present inside a cell. In some embodiments, analyte capture agents are capable of binding to cell surface analytes that can include, without limitation, a receptor, an antigen, a surface protein, a transmembrane protein, a cluster of differentiation protein, a protein channel, a protein pump, a carrier protein, a phospholipid, a glycoprotein, a glycolipid, a cell-cell interaction protein complex, an antigen-presenting complex, a major histocompatibility complex, an engineered T-cell receptor, a T-cell receptor, a B-cell receptor, a chimeric antigen receptor, an extracellular matrix protein, a posttranslational modification (e.g., phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation or lipidation) state of a cell surface protein, a gap junction, and an adherens junction. In some embodiments, the analyte capture agents are capable of binding to cell surface analytes that are post-translationally modified.
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[0160] In some embodiments, the detecting step includes contacting the amplified circularized padlock probe or snail probe with a plurality of detection probes. In some embodiments, a detection probe of the plurality of detection probes includes a sequence that is substantially complementary to a sequence of the padlock probe or snail probe, circularized padlock probe or snail probe, or amplified circularized padlock probe or snail probe and a detectable label. For example, the detection probe of the plurality of detection probes can include a sequence that is substantially complementary to a sequence of amplified circularized padlock probe or snail probe and a detectable label. (Emphasis added)
[0162] In some embodiments, a detection probe of the plurality of detection probes includes a nucleotide sequence that is different from other detection probes, thereby enabling detection of signals from two or more detection probe sequences (e.g., two or more different amplified circularized padlock probe or snail probe).
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[0166] In some embodiments, the method includes repeating the detecting step with a second plurality of detection probes. In such cases, the method includes removing the detection probes from the first detecting step (e.g., via enzymatic digestion) and contacting the amplified circularized padlock probe or snail probe with a second plurality of detection probes. A detection probe of the second plurality of detection probes includes a sequence that is substantially complementary to a sequence of the padlock probe or snail probe and that is non-overlapping, partially overlapping, or completely overlapping with the sequence to which a detection probe from the first plurality of detection probes is substantially complementary.
[0172] In some embodiments, the methods are applied to analyte, or analyte derived molecules (e.g., an mRNA molecule, a gDNA molecule, a product of reverse transcription (e.g., an extended capture probe), and an analyte binding moiety barcode (e.g., a binding moiety barcode that identifies that analyte binding moiety (e.g., an antibody))). In some embodiments, the analyte or analyte derived molecules comprise RNA and/or DNA. In some embodiments, the analyte or analyte derived molecules comprise one or more proteins. (Emphasis added)
[0174] In some instances, the biological sample is a section of a tissue (e.g., a 10 μm section). (Emphasis added)
In view of the above presentation, Nagendran et al., is deemed to at least render obvious, if not anticipate, the claimed method of “detecting analytes in a sample” which can be both nucleic acids and proteins, using a plurality of probes, which can be nucleic acid probes and/or antibodies or fragments of same.
In view of the above showing of the prior art, claims 1-30 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0126825 A1 (Nagendran et al.).
Response to traversal
Applicant’s representative, at page 14 of the response of 5 February 2026 traverses the rejection of claims under 35 USC 103(a). As asserted to therein:
For example, the relied-upon portions of Nagendran do not state: "wherein said first probe comprises: (i) a first binding site configured to couple to a first analyte at a first portion; (ii) a second binding site configured to couple to said first analyte at a second portion, wherein said first portion is adjacent to said second portion; (iii) a third binding site configured to couple to said second probe", as recited in claim 1.
The above cited argument has been considered and has not been found persuasive towards the withdrawal of the rejection. While Nagendran et al., may not use the exact phrase of applicant, it is noted that Nagendran et al., does of embodiments where such is taken into consideration. In support of this position attention is directed to paragraph [0127] of Nagendran et al. As stated therein:
In instances where probe sets are designed to cover an entire genome (e.g., the human genome), the methods disclosed herein can detect analytes in an unbiased manner. In some instances, one probe oligonucleotide pair is designed to cover one analyte (e.g., transcript). In some instances, more than one probe oligonucleotide pair (e.g., a probe pair comprising a first probe and a second probe) is designed to cover one analyte (e.g., transcript). For example, at least two, three, four, five, six, seven, eight, nine, ten, or more probe sets can be used to hybridize to a single analyte. Factors to consider when designing probes is presence of variants (e.g., SNPs, mutations) or multiple isoforms expressed by a single gene. In some instances, the probe oligonucleotide pair does not hybridize to the entire analyte (e.g., a transcript), but instead the probe oligonucleotide pair hybridizes to a portion of the entire analyte (e.g., transcript). (Emphasis added)
The aspect of detecting a point mutation speaks to probes that bind not only to the point mutation, but also bind to adjoining sequence(s), therein confirming the location of that particular nucleotide. Such speaks to a first probe that binds to a first and second binding site.
In view of the above analysis and in the absence of convincing evidence to the contrary, claims are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0126825 A1 (Nagendran et al.).
Conclusion
Objections and/or rejections which appeared in the prior Office action and which have not been repeated hereinabove have been withdrawn.
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.
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/Bradley L. Sisson/Primary Examiner, Art Unit 1682
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