DETAILED ACTION
Status of the Claims
Claims 28-33, 37-46, 48, 50-51, and 53 are currently pending and are examined herein.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 02/20/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections – 35 U.S.C. 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Weissleder et al. and Fan et al.
Claims 28-33, 37-46, 51, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Weissleder et al. (WO 2014/200767 A1, cited in IDS of 02/20/2024) in view of Fan et al. (WO 2014/031997 A1).
Regarding claim 28, Weissleder discloses a method comprising contacting cells that comprise protein targets with at least two conjugates (e.g., single cell labeling as per Example 2), each conjugate comprising an antibody linked to a nucleic acid reporter strand through a cleavable linker, wherein the antibody binds specifically to a protein target interest (e.g., antibodies specific to cellular targets conjugated to DNA reporter barcodes via a photocleavable linker as per Fig. 2, Example 2, and/or ¶¶0007-0009), to produce modified cells comprising target-conjugate complexes (e.g., as per Example 2).
However, Weissleder does not disclose the limitation of “loading modified cells of step (a) on a base substrate containing microwells, to produce a loaded base substrate”, as set forth in claim 28.
Fan discloses methods of high-throughput, multiplexed detection of single cells loaded into individual microwells (e.g., as per the “Microwell array” section on pp. 28-31, Fan claim 17, and/or the “Single cell trapping with PDMS microwell array” section on p. 56).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to load the antibody-DNA conjugates as per Weissleder into the microwell arrays as per Fan. One of ordinary skill in the art would have been motivated to do so since this would allow for the high-throughput multiplexing molecular analysis of cells as per Weissleder while retaining single cell and spatial information of the individual cells as per Fan. In accordance with MPEP 2141 citing KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385,1395 (2007), "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results”, and as per MPEP 2143(I)(A), the rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. In the present case, all of the elements of the high-throughput, multiplexed single cell molecular analysis were well known in the art, as per Weissleder and Fan, the mere combining of the individual elements in one embodiment in the manner of the claimed invention results in no change in the elements respective functions, and the combination yields nothing more than predictable results.
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since the cells of Weissleder were already stably labeled with the antibody-barcode conjugates prior to loading into the microwell arrays as per Fan.
Regarding claim 29, Fan further discloses contacting the loaded base substrate with a cover substrate comprising at least two sets of at least two immobilized nucleic acid capture probes, each capture probe comprising a nucleotide sequence complementary to a nucleotide sequence of a nucleic acid reporter strand of step (a), to produce at least two enclosed microwells, each of the at least two enclosed microwells containing a set of at least two different capture probes of the cover substrate (e.g., as per the “Capture agent array” section on pp. 31-41).
Regarding claim 30, Weissleder further discloses cleaving the cleavable linkers of the conjugates to release the nucleic acid reporter strands (e.g., as per ¶¶0018, 0023, 0084-0085, and/or Example 1).
Regarding claim 31, Fan further discloses maintaining the enclosed microwells under nucleic acid hybridization conditions to produce reporter-capture complexes immobilized on the cover substrate (e.g., sealed microwells as per Example 1 and/or Fig. 1 and/or 6).
Regarding claim 32, Fan further discloses dissociating the cover substrate containing the immobilized reporter-capture complexes from the base substrate and visualizing at least one reporter-capture complex immobilized on the cover substrate (e.g., using fluorescent labels as per the “System for multiplex detection” section on pp. 41-43 and/or the “Fluorescence detection and analysis” section on p. 57).
Regarding claim 33, Weissleder further discloses identifying at least one protein target of interest of (e.g., Example 2).
Regarding claim 37, Weissleder further discloses contacting cells that comprise protein targets with at least three, at least five, at least ten, or at least fifty conjugates (e.g., as per Example 2).
Regarding claim 38, Weissleder further discloses wherein the cells are permeabilized (e.g., as per ¶¶0041 and/or 0083).
Regarding claim 39, Weissleder further discloses wherein the cells are fixed (e.g., fixed as per ¶¶0025 and/or 00316).
Regarding claim 40, Weissleder further discloses wherein the antibody is a monoclonal antibody (e.g., such as Herceptin as per ¶00327).
Regarding claim 41, Weissleder further discloses wherein the antibody is a humanized and/or chimeric antibody (e.g., as per ¶00319).
Regarding claim 42, Weissleder further discloses wherein the cleavable linker is selected from photocleavable linkers and enzyme-cleavable linkers (e.g., photocleavable linkers as per ¶¶0018 and/or 0022-0023).
Regarding claims 43-44, Fan further discloses wherein the nucleic acid reporter strand is linked to a detectable label and wherein the detectable label is a fluorescent label (e.g., using fluorescent labels as per the “System for multiplex detection” section on pp. 41-43 and/or the “Fluorescence detection and analysis” section on p. 57).
Regarding claims 45-46, 51, and 53, Fan further discloses wherein the base substrate is a PDMS microchip, wherein the base substrate contains 2-20,000 microwells and wherein the cover substrate forms a seal with the base substrate to prevent fluid communication among the enclosed microwells (e.g., as per Example 1 and/or Fig. 1 and/or 6).
Weissleder et al., Fan et al., and Love et al.
Claims 28-33, 37-46, 48, 50-51, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Weissleder et al. (WO 2014/200767 A1, cited in IDS of 02/20/2024) in view of Fan et al. (WO 2014/031997 A1) further in view of Love et al. (U.S. PGPub 2011/0111981 A1).
Weissleder in view of Fan is relied on as above, however, the references are silent regarding the limitations of each microwell having a volume of 1-10 or 1-999 nanoliters, as set forth in claims 48 and 50.
Love discloses forming PDMS microwell arrays for capture of single cells wherein each microwell has a volume of 0.1-1 nanoliters (e.g., as per the “Microengraving for Single-Cell Study and its Advantages” section on pp. 6-7 and/or Example 1).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to fabricate microwell arrays with each microwell being on the order of 1 nanoliter as per Love for the multiplexed, single-cell assay of Weissleder in view of Fan. One of ordinary skill in the art would have been motivated to do so since Love and Fan are drawn to the capture and analysis of single cells and Love explicitly discloses that the microwells of ~1 nanoliter are effective in the capture of single cells (e.g., as per the “Microengraving for Single-Cell Study and its Advantages” section on pp. 6-7 and/or Example 1).
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since Love discloses how to fabricate such arrays and shows that they are effective for single cell capture.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEREMY FLINDERS whose telephone number is (571)270-1022. The examiner can normally be reached M-F 10-6:00 EST.
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/JEREMY C FLINDERS/
Primary Examiner, Art Unit 1684
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