The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 35-54 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. With respect to claim 35 it is not clear what constitutes “holding the entire first and second arrays of microdroplets”. Is applicant attempting to require that the arrays are held at some specific location by some specific force and/or structure, held with some specific structural relationship with respect to each other (i.e. the microdroplets are arrayed relative to each other) and/or in some sort of a container or simply held within the channels and chambers within a structure such as a microfluidic device? For examination purposes, examiner will not place any special restriction on the “array” language so that its broadest interpretation is simply a plurality of microparticles contained within the channels and chambers of a microfluidic device. With respect to claim 37, the basis for the sorting is not clear. For example is the sorting carried out based on some physical parameter of the droplets such as size, diameter, density, etc. or is based on other factors such as the presence of the biological entity, bead and/or some other component of the microdroplets? In claim 40, it is not clear whether an interdigitated array simply requires a microdroplet of the first or second array of microdroplets to be between two microdroplets of the respective second or first array of microdroplets such as when they flow through a channel of a microfluidic device or if applicant is attempting to require a specific structural relationship between the microdroplets as they are held at specific locations in for example a chamber of a microfluidic device? For the examination of claim 40, examiner will bot place any specific structural limitations of the language. With respect to claim 41, it is not clear if the further array of microdroplets is also combined with the first and/or second arrays of microdroplets or if they are just present in whatever device is being used to perform the method. Another was of looking at the issue, is the further array of microdroplets required for the detection of the change in the optical signal? If so, what steps need to be added to claim 35 and/or what steps of claim 35 need to be further defined so that the reported is present at the time any change in the optical signal is detected? In claim 43, “the time of illumination” does not have antecedent basis in claim 35. Examiner notes that it would have antecedent basis if claim 43 were dependent from claim 42. Additionally with respect to claim 43, it is not clear how the time of illumination can be varied with a single subset? Examiner notes that it makes more sense if the array of first microdroplets comprises a plurality of subsets (subset arrays) and each subset has a different time of illumination. With respect to claim 46, “the intensity of illumination” does not have antecedent basis in claim 35. Examiner notes that it would have antecedent basis if claim 46 were dependent from claim 44. Additionally with respect to claim 46, it is not clear how the intensity of illumination can be varied with a single subset? Examiner notes that it makes more sense if the array of first microdroplets comprises a plurality of subsets (subset arrays) and each subset has a different intensity of illumination. With respect to claim 47, it is not clear what splitting at least a sunset of the arrays of the first or second microdroplets entails. Are the microdroplets in the subset divided into multiple droplets or is the subset divided into smaller subsets? Also, where in the steps of claim 35 does the step of claim 47 occur? With respect to claim 48, is the determination of the concentration of molecules or the number of molecules released from the bead only performed after a predetermined threshold level as been exceeded or is claim 48 trying to claim something else? With respect to claim 51, is the claim requiring all of the microdroplets to contain a cell media or is the claim only a further limitation on one of the arrays of first or second microdroplets? With respect to claim 52, the relationship between the steps of claim 35 and the further step of claim 52 is not clear. When in the steps of claim 35 does the further step of claim 52 occur? With respect to claim 53, it is not clear which microdroplets are dispensed into a well plate of at what point in the steps of claim 35 the step of claim 53 occurs. With respect to claim 54, it is not clear which of the microdroplets of claim 35 constitute the progenitor droplet: the first microdroplet, the second microdroplet, the merged microdroplet some combination of those microdroplets or some entirely new droplet/microdroplet that is called a progenitor droplet.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 35-36, 38-40, 49 and 51-52 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Link (US 2010/0137163). With respect to claim 35, Link teaches a method (see at least paragraphs [0012], [0014] and [0015]; examples 1-12; Figure 1 with its associated description) of detecting the interactions between a biological entity and a molecule, the method comprising providing an array of first microdroplets (see at least paragraphs [0012], [0014] and [0015]) into a microfluidic chip (Figure 1); wherein each microdroplet contains at least one bead and each bead having a bound photocleavable molecule (see at least paragraphs [0183]-[0184]); providing an array of second microdroplets into the microfluidic chip; wherein each microdroplet contains at least one biological entity (see at least paragraph [0184]); holding the entire first and second arrays of microdroplets (see at least paragraph [0121] in combination with the fact that the device of figure 1 contains a plurality of cells from both the library and the cells being combined with the library); illuminating at least a subset of the first microdroplets containing at least one bead with an illumination source configured to photo-cleave the molecule (see at least paragraphs [0183]-[0184]); subsequently merging at least one subset of the first array of microdroplets with at least one subset of the second microdroplets to form an array of merged microdroplets (see the description of the coalescence module beginning at paragraph [0121] and the interdigitation of droplets of specific liquids followed by pair-wise coalescence described beginning at paragraph [0145]); and detecting a change in an optical signal from the merged microdroplets using an optical system to indicate the interactions between the biological entity and the molecule (see at least the description of the detection module in paragraph [0148]-[0169]; Figure 1: "detection module'). With respect to claim 36, Link teaches that the biological entity is a cell or part of a cell or a virus or an enzyme (see at least paragraphs [0087], cells or virons; [0091], biological/chemical material can be tissues, cells, particles, proteins, antibodies, amino acids, nucleotides, small molecules, and pharmaceuticals; [0200], biological cells, polynucleotides, polypeptides and proteins (including enzymes)). With respect to claim 38, Link teaches a further step of sorting the merged microdroplets using the detected optical signal (see at least paragraph [0170]-[0171]). With respect to claim 39, Link teaches that each bead further comprises a molecular tag on the surface of the bead, wherein the molecular tag is a nucleic acid tag, or a protein tag, or a small molecule tag, or a synthetic tag (see at least paragraph [0155]). With respect to claim 40, Link teaches that the array of first microdroplets and the array of second microdroplets are held in an interdigitated array microdroplets (see the description of the interdigitation of droplets of specific liquids followed by pair-wise coalescence described beginning at paragraph [0145]). With respect to claim 49, Link teaches that the optical signal is a fluorescence signal or is a Fluorescence Resonance Energy Transfer (FRET) signal, or a Homogeneous Time Resolved Fluorescence (HTRF) signal or a luminescence signal (see at least paragraph [0153]; optical scattering, absorption, fluorescence, or any other optical measurement technique). With respect to claim 51, Link teaches that the microdroplets contain a cell media see at least paragraph [0094]; the droplet forming liquid is typically an aqueous buffer solution, such as ultrapure, 10 mM Tris HCl and 1 mM EDTA (TE) buffer, phosphate buffer saline (PBS) or acetate buffer or any liquid or buffer that is physiologically compatible with the population of molecules, cells or particles to be analyzed and/or sorted can be used). With respect to claim 52, Link teaches the step of supplying a carrier fluid into the microfluidic chip (see at least paragraph [0094]; the fluid passing through the main channel and in which the droplets are formed is one that is immiscible with the droplet forming fluid: a non-polar solvent, most preferably decane (e.g., tetradecane or hexadecane), fluorocarbon oil or another oil (for example, mineral oil)).
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.
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.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Link as applied to claim 35 above, and further in view of Issac (WO 2020/104769). With respect to claim 37, Link clearly teaches that the device can have multiple sorting modules (see at least paragraphs [0048] and [0170]-[0171]) but does not specifically teach a step of sorting the first and/or second microdroplets prior to providing an array of the first and/or second microdroplets into the microfluidic chip.
With respect to claim 37, Isaac teaches a device having a microdroplet manipulation component that is configured to manipulate a first microdroplets using real or virtual electrowetting electrodes. A first zone is configured to arrange first microdroplets into an array for optical inspection, and to introduce a reporter system into each first microdroplet by unit of microdroplet merging. A second zone is located within or adjacent the first zone and configured to detect merged microdroplets in detection windows. A third zone is provided in which microdroplets are sub-divided and isolated for later recovery from the instrument. An optical detection system is configured to detect an optical signal from the microdroplets through the detection window. The signal arises from an interaction is provided between the reporter system and the cells or an expressed product for merged microdroplets. Page 21, lines 9-22 describe figure 1 and teach that a fluid inlet 1 admits an emulsion 2 of a mixture of empty and cell-containing first microdroplets in a fluorocarbon oil. These first microdroplets are then transferred by means of OEWOD structures (not shown) to a sorting zone 3 where they are sorted, by optical means or by other sorting means as described above, into those which are empty 4 and those which contain cells 5. Thereafter each of the cell-containing microdroplets 5 are transferred to merging zone 8, also by means of OEWOD structures, where they are held for a defined period of time under conditions which promote cell growth and division within each. At the end of this period, a second inlet 6 admits second microdroplets, containing a fluorescence reporter system selective for a cell type of interest 7 which are then merged with the cell-containing first microdroplets 5 at merging zone 8 to form merged microdroplets 9. The merged microdroplets 9 are then transferred by means of OEWOD structures to optical window 10 where a fluorescence signal characteristic of the reporter system is detected using an optical detection instrument 11 comprised of an LED light source, a photodetector and a microprocessor. Optical detection instrument 11 is partially combined with an optical manipulation projector 12. Also see the description on page 7, line 32 to page 8, line 21.
With respect to claim 37, it would have ben obvious to one of ordinary skill in the art at the time the application was filed to incorporate a sorting step for separating cell containing microdroplets from empty microdroplets as taught by Issac into the method of Link prior to merging the droplets because of a need/desire to make that separation of cell containing and empty microdroplets when one is analyzing cells contained in microdroplets as taught by Issac.
Claims 42 and 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Link as applied to claim 35 above and further in view of Heath (US 2023/0069843). With respect to claims 42 and 44-45, paragraph [0183] teaches that Link teaches that a laser of an appropriate wavelength can be used in the UV-release module. Paragraph [0216] teaches that a triazene-based photolabile linker, which is cleaved by irradiation with a 355 nm 3 w Nd-YAG laser, can be used. Paragraph [0217] teaches that if the residence time of the bead inside the UV laser is insufficient to cleave all of the compound off the substrate bead, the residence time can be increased by slowing down the flow of the bead containing drops by widening the channel. Alternatively the intensity of laser beam can be increased to ensure complete cleavage. Link does not teach the specifically claimed frequency range or give specific irradiation times or intensities.
In the patent publication, paragraph [0226] teaches a photo-labile peptide in which (S)-3-(Fmoc-amino)-3-(2-nitrophenyl)propionic acid, is the photo-labile amino acid residue. A mixture of MHC photo-labile protein (0.5 μM) and a single antigenic peptide sequence (50 μM) was exposed to 365 nm UV light for 1 hour to generate pMHC complexes.
It would have been obvious to one of ordinary skill in the art at the time the application was filed to use an appropriate laser illumination frequency such as the 365 nm frequency taught by Heath and determine the appropriate time of illumination and/or intensity to reach complete cleavage as required by Link.
Examiner notes that several claims are rejected under 35 U.S.C. 112(b) but not rejected with art. If the rejections under 35 U.S.C. 112(b) are overcome and the claims are amended to include all of the limitations of the base claim and any intervening claims, the claims not rejected with art are potentially allowable. The following is a statement of reasons for the indication of allowable subject matter: the art of record fails to teach or fairly suggest the combination of step involved in the claims which are not rejected with art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The additionally cited art is related to the type of methods being claimed in microdroplets.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Arlen Soderquist whose telephone number is (571)272-1265. The examiner can normally be reached 1st week Monday-Thursday, 2nd week Monday-Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander can be reached at (571)272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ARLEN SODERQUIST/ Primary Examiner, Art Unit 1797
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