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 .
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 3 and 9 have been canceled. Claims 1, 7, 11, 13, 26-27, 30-32, 49, 51, 55, and 57-60 are pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/17/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Applicant’s Amendments and Arguments
Claims 1, 3, 7, 9, 11, 13, 26-27, 30-32, 49, 51, 55, and 57-60 were rejected under 35 U.S.C. 103 as being unpatentable over Fodor et al. (US 2016/0253584 A1) and various combinations of references.
Regarding the 35 USC 103 Rejections presented in the Non-Final Rejection mailed 8/18/2025, Applicant argues that Fodor, the primary reference used, does not teach newly amended steps (d)-(h) of instant claim 1, as the reference allegedly only teaches using beads with stochastic barcodes to capture analytes from lysed cells, according to paras. 326-328 of the reference (Remarks, pages 7-8). Furthermore, Applicant argues that the changes to Fodor proposed by the Examiner change the principle of operation of the reference, and that there is no motivation to modify Fodor so that a bead encapsulated in a droplet with a tagged cell would hybridize to the capture probe released from the substrate (Remarks, pages 8-10).
Firstly, in Fodor paras. 326-328, particularly in the portions recited by Applicant, the reference states that the cells can be “lysed, stochastically labeled, amplified, and/or digitally counted” (in para. 326, emphasis added) and that the cells can be, “crosslinked, physically separated, lysed, stochastically labeled with the distinct groups of spatial labels 1110/1111/1112/1113, amplified, and/or digitally counted,” (in para. 328, emphasis added). The “and/or” indicates that any one or more of the cited manipulations may occur, and that every listed manipulation need not occur. Therefore, while cells may be lysed, they do not have to be lysed, and cells can be stochastically labeled without being lysed.
Regarding step (d) of claim 1, in the teachings of Fodor presented in the Non-Final Rejection, the stochastic barcodes remain attached to the substrate until the sample/bead/barcode is placed into a microfluidic device and encapsulated into a droplet (para. 25 of the Non-Final Rejection). However, the stochastic barcodes of Fodor generally can be removed from the substrate – the pre-spatial label on the stochastic barcodes can be associated with a solid support or substrate and can be cleaved (paras. 311-312), para. 214 specifically mentions that nucleic acids can be removed from the substrate using chemical cleavage, and para. 202 states “The labeled targets from a plurality of cells (or a plurality of samples) (e.g., target-barcode molecules) can be subsequently pooled, for example by retrieving the stochastic barcodes and/or the beads to which the target-barcode molecules are attached. The retrieval of solid support-based collections of attached target-barcode molecules can be implemented by use of magnetic beads and an externally-applied magnetic field. Once the target-barcode molecules have been pooled, all further processing can proceed in a single reaction vessel. Further processing can include, for example, reverse transcription reactions, amplification reactions, cleavage reactions, dissociation reactions, and/or nucleic acid extension reactions. Further processing reactions can be performed within the microwells, that is, without first pooling the labeled target nucleic acid molecules from a plurality of cells.” Thus, the reference teaches the removal of the stochastic barcodes from the solid substrate, along with further processing of the labeled targets in the microwells. This is incorporated into the new grounds of rejection presented below.
It is noted that Applicant has canceled claim 9 and incorporated the limitation of the claim directly into claim 1, where it is now step (h). Regarding the teachings of previous claim 9 and current step (h), this is addressed in para. 20 of the Non-Final Rejection, where a particular motivation and reasonable expectation of success were provided (“By allowing the beads and stochastic barcodes to hybridize to each other in the manner described in para. 357 (which involves encoding the beads), separate microarrays would not have to be created in order to encode the beads. Additionally, by creating the beads and stochastic barcodes with complementary sequences, this would allow for their hybridization both when the target analyte is and is not present in the microwell. As the beads contain the optical labels, this would allow for easier imaging, and therefore locating, of the target, when present. Since the creation of stochastic barcode and bead sequences that hybridize to one another is well-known in the art, as evidenced by Fodor, there would be a reasonable expectation of success.”). Applicant’s arguments against this rationale focus on the teachings of para. 357 of Fodor, and state that utilizing such a method would result in Figure 28 of the reference, as explained in para. 456.
The teachings of Figure 28 and para. 456 result from a very specific embodiment of Fodor taught in Example 4, which demonstrates “a combinatorial method to generate large libraries of at least 963 unique synthetic particles with both DNA barcodes such as stochastic barcodes and spectrally resolvable barcodes such as optical barcodes.” Though this method describes an encoding method similar to that described in para. 357, these are not the same embodiment, and the encoding method of para. 357 is not limited to the embodiment described in Example 4. Furthermore, the principle of operation of Fodor is not limited to the teachings/advantages of a single embodiment or working example. The reference is generally drawn to “methods, compositions, systems, devices, and kits for determining the number of distinct targets in distinct spatial locations within a sample,” (Abstract), and though the creation of libraries is recited in the general teachings of the reference (e.g. paras. 7, 19, and 27), the libraries of Example 4 are not central to the principle of operation of the reference. Para. 357 is recited under the general methods of encoding solid supports within Fodor, where the teachings are broad and non-limiting in nature (para. 357 utilizes the language “such as,” and “can be,” for example), and nowhere in para. 357 or nearby paragraphs is the creation of large libraries recited. The combination of teachings of Fodor recited in the Non-Final Rejection still results in the ability to spatially tag and detect targets in a sample, and so are not considered to alter the principle of operation of the reference or render the reference inoperable for its intended purpose.
Additionally, it is generally noted that MPEP 2141.03 I states, “‘A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.’ KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.” Thus, the Examiner argues that the ordinary artisan would be capable of combining the teachings of Fodor, along with ordinary skill, creativity, and knowledge in the art, to arrive at the previously claimed invention. Furthermore, MPEP 2143.01 V states, “…in Allied Erecting v. Genesis Attachments, 825 F.3d 1373, 1381, 119 USPQ2d 1132, 1138 (Fed. Cir. 2016), the court stated "[a]lthough modification of the movable blades may impede the quick change functionality disclosed by Caterpillar, ‘[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine’" (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165, 77 USPQ2d 1865, 1870 (Fed. Cir. 2006).” Thus, though combining the teachings of Fodor in the manner suggested by the Examiner could potentially lead to disadvantages, this alone does not mean it is not proper to combine the teachings. This is particularly in view of the motivations, rationale, and reasonable expectations of success provided by the Examiner in the Non-Final Rejection (see paras. 18, 20-22, and 25). Applicant does not directly address these obviousness combinations (except in the case of para. 20 of the Non-Final Rejection, which is addressed in the paragraph above), and so these rejections are considered proper.
It is noted that previous claim 3 has been canceled, and this limitation has been moved to instant claim 1, step (b). This limitation was rejected as unpatentable over Fodor in view of Chee, and Applicant has not provided any arguments against this specific rejection.
Thus, Applicant’s arguments as applied to the previous version of the claims are not considered persuasive. In light of Applicant’s amendments to the claims submitted 12/17/2025, new grounds of rejection are required below to address each claim limitation. The relevant portions of the previous rejections are reiterated below. The previous rejections for claims 1, 7, 11, 13, 26-27, 30-32, 49, 51, 55, and 57-60 have been withdrawn. Claims 3 and 9 have been canceled, and so these rejections have been rendered moot.
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.
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.
Claims 1, 7, 11, 13, 26-27, 30-32, 51, and 57-60 are rejected under 35 U.S.C. 103 as being unpatentable over Fodor et al. (US 2016/0253584 A1) in view of Chee et al. (US 2016/0138091 A1).
Fodor teaches methods for determining the number of distinct targets in distinct spatial locations within a sample (Abstract). The sample analyzed can be a tissue section (para. 22). Specifically, tissue pieces can be fixed in formalin and embedded in paraffin wax (instant claim 27) or frozen before analysis (para. 262; instant claim 26). The sample can also include a plurality of cell types, where the specific target can be RNA (para. 10; instant claims 31-32). In the method, stochastic barcodes are placed on a solid support (para. 11). Said stochastic barcodes act as the capture probes taught in the instant invention, and can include a spatial label, a molecular label, a universal label and a cellular label (paras. 6-8 and 11-12). Stochastic barcodes can also include a target recognition region, which can attach to a target sequence, thus corresponding to the first hybridization domain of the instant invention (para. 200). The universal label can act as a primer binding site, thus corresponding to the priming domain of the instant invention (para. 101). The spatial label can aid in determining the spatial location of targets in the sample, and thus correlates with the spatial barcode of the instant invention (para. 8). A stochastic barcode can also include an affinity property, such as an antibody (para. 116; instant claim 51). This antibody can be specific for a certain cell type or molecule, and can bind to a receptor on a target (para. 116). Target nucleic acids can comprise affinity tags as well, allowing for binding of the antibody to the target (para. 79). Thus, this affinity property act as a portion of the cell-tagging agent taught in the instant invention. Fodor teaches that the substrates which comprise the stochastic barcodes can be microwells that entrap additional solid supports, such as beads (para. 139). These bead solid supports can have multiple attached sequences, called anchor regions (para. 344). Anchor regions can include optical labels that can be included on optical barcodes (paras. 346 and 349). Fodor teaches that optical labels can comprise two or more oligonucleotides with the same sequence.
It would therefore be prima facie obvious to include multiple anchor regions with the same optical labels on a single bead. These optical labels would act as the cellular barcodes taught by the instant invention. Beads can also comprise universal sequences, which are regions that are common to two or more nucleic acid molecules (paras. 72 and 350). Cellular labels and linker sequences can also be included (e.g. para. 353). Fodor teaches that these beads can hybridize with oligonucleotides in microwells (e.g. para. 357), thus containing a region acting as the second hybridization domain of the instant invention. Beads that can be used in the invention of Fodor can be oligo(dT) beads (para. 125). This reference also teaches that oligo(dT) sequences can interact with poly(A) tails of mRNAs (e.g. paras. 100 and 114), though this is in reference to target binding regions of stochastic barcodes. This reference also teaches sequencing of the entire stochastic barcode (thus including the spatial label; para. 8), as well as the target (para. 194; instant claim 7). Fodor also teaches decoding of solid supports, such as the beads with optical labels, in order to determine the location of said particles (para. 376). This decoding can include sequencing-by-synthesis (para. 383).
However, though Fodor teaches that beads can hybridize to oligonucleotides in microwells (para. 357), this reference does not specifically teach that these oligonucleotides can be the stochastic barcodes. Fodor also does not teach that beads not containing the stochastic barcodes can contain capture regions, or that all the oligonucleotides on these beads can be sequenced. Fodor also does not teach that the cell-tagging antibody can be coupled to a polynucleotide that binds to the priming domain of the stochastic barcode.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to use the teachings of Fodor to have the capture probe and bead hybridize to one another. Specifically, it would be obvious that the beads could bind to the stochastic barcodes as these barcodes are already provided on a solid support (e.g. para. 10), and can be provided in a microwell with beads (para. 139). By allowing the beads and stochastic barcodes to hybridize to each other in the manner described in para. 357 (which involves encoding the beads), separate microarrays would not have to be created in order to encode the beads. Additionally, by creating the beads and stochastic barcodes with complementary sequences, this would allow for their hybridization both when the target analyte is and is not present in the microwell. As the beads contain the optical labels, this would allow for easier imaging, and therefore locating, of the target, when present. Since the creation of stochastic barcode and bead sequences that hybridize to one another is well-known in the art, as evidenced by Fodor, there would be a reasonable expectation of success.
Regarding the bead containing a capture region for the target, as noted above, Fodor teaches that the beads used can be oligo(dT) beads, and that oligo(dT) sequences can bind to poly(A) tails of mRNAs. It would be prima facie obvious to use mRNA targets (which are already taught by Fodor, e.g. para. 10), and thus the oligo(dT) sequences of the beads would be able to hybridize to the target mRNA, becoming the capture domain taught in the instant invention. Fodor distinctly teaches that stochastic barcodes may be attached to beads (para. 119) and that oligo(dT) beads may be used (para. 125). More generally, Fodor teaches that multiple probes (which are oligonucleotides) can exist on a single substrate – particularly gene-specific probes and oligo(dT) probes (para. 184). This arrangement can be useful for bridge amplification, and the two probes can be provided in a 1:1 ratio (para. 184). Bridge amplification can be used before sequencing occurs, where the sequencing itself (and the identification of the stochastic barcodes) determines the number of targets (para. 27). Thus, Fodor contemplates embodiments in which multiple probes are used, where one probe is a oligo(dT) probe, and where these probes serve a specific amplification function, allowing for the counting of target molecules through sequencing. This combination would simply amount to including these two types of oligonucleotides on a bead for the examination of mRNA targets. As Fodor teaches that bridge amplification can occur with these two probe types, and that this amplification can allow for sequencing and identification of targets, there would be a motivation and a reasonable expectation of success for the ordinary artisan.
Regarding the sequencing of all of the sequences present on the bead, as Fodor teaches sequencing-by-synthesis of at least the optical labels of the beads (paras. 376 and 383), and the other sequences present on the beads are connected to said optical labels, it would follow that the entirety of the oligonucleotide connected to the bead can be sequenced, including the second hybridization region and the capture region. As Fodor teaches that sequencing methods are well-known, there would be a reasonable expectation of success.
Concerning the limitation of step (e) (dissociating the cell from a tissue section), it is first noted that regarding the use of the term “tissue section,” Application does not provide a specific definition. In the instant specification, page 36, paras. 4-5 describe that a tissue section can be directly harvested from a subject or grown as a population of cells, and that tissue sections can be as thin as the diameter of a cell (i.e. when the section is a single cell thick). “Dissociation” similarly has no specific definition, and so can be the simple separation of single cells from the tissue section (page 233, paras. 1-2 and 236, para. 2).
As noted above, Fodor teaches that a sample can be a tissue sample (para. 22). Para. 27 of Fodor notes that a tissue section can be a plurality of cells, and states that said cells can be distributed across the wells of a well array, where each well contains at most a single cell. Fodor then goes on to discuss that samples can be physically separated into different containers (para. 286). For tissue samples in particular, this cutting can preserve the physical relationship of the sections of the tissue (para. 290). The microwells of the invention can be arranged in a grid (para. 153), and when separating samples, a blade grid can be used so that the separation occurs when a sample is in contact with the substrate (para. 286). “A blade grid can simultaneously separate and physically isolate the parts of the samples,” (para. 286). Thus, in the method of Fodor described above, the tissue samples can undergo this blade grid separation to result in isolated cells in the individual grid sections of the microwell.
Fodor also teaches that droplets may be used as physical partitions in their invention (para. 106) and that single cells and beads can be encapsulated within droplets (para. 167). Sections of sample can be taken on a sampling device and then placed on a microfluidic chip and encapsulated in droplets that can then be placed in a container of a substrate, where the location on the substrate can be indicative of a location in a sample (para. 298). The stochastic barcodes can also be in said droplets (para. 298). Thus, it would be prima facie obvious to the ordinary artisan that the microwell sectioning and droplet methods of Fodor could be combined – wherein a sample is sectioned into single cells, encapsulated into droplets with beads, and then placed on a secondary substrate where downstream analyses may be performed as described above (e.g. the hybridizing of bead oligonucleotides, amplification, and sequencing). MPEP 2143 I (A) states, “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.” This combination would not change the sample sectioning, encapsulating, or downstream procedures, and would still result in target nucleic acids that can be identified in terms of number and location, and thus, would be predictable.
Concerning the limitation of step (d), as well as claims 11 and 60, Fodor teaches that the stochastic barcodes generally can be removed from the substrate. Cleavable sequences can be added to spatial label blocks (para. 312), which form the spatial labels on the stochastic barcodes (para. 308), para. 214 specifically mentions that nucleic acids can be removed from the substrate using chemical cleavage, and para. 202 states “The labeled targets from a plurality of cells (or a plurality of samples) (e.g., target-barcode molecules) can be subsequently pooled, for example by retrieving the stochastic barcodes and/or the beads to which the target-barcode molecules are attached. The retrieval of solid support-based collections of attached target-barcode molecules can be implemented by use of magnetic beads and an externally-applied magnetic field. Once the target-barcode molecules have been pooled, all further processing can proceed in a single reaction vessel. Further processing can include, for example, reverse transcription reactions, amplification reactions, cleavage reactions, dissociation reactions, and/or nucleic acid extension reactions. Further processing reactions can be performed within the microwells, that is, without first pooling the labeled target nucleic acid molecules from a plurality of cells.” Thus, it would be prima facie obvious that the capture probes could be released from the substrate via their cleavable domains before the dissociating and encapsulating steps of the method of Fodor described above, and that this cleavage could be a release mechanism in itself. This release would prevent the attachment of the capture probes to the substrate from interfering with the dissociating, and particularly the encapsulating, methods, as the capture probes would be more free to be further manipulated and could more readily be grouped with target cells and beads. Though Fodor does not specifically state that cleavable domain could be used for substrate release, the ordinary artisan would recognize that by cleaving the cleavable domain, the rest of the stochastic barcode, which is still attached to the target, would be free for downstream methods. Utilizing the cleavage domain, which Fodor clearly teaches as being present on the stochastic barcode, as the release mechanism from the substrate would prevent the need for additional release materials or protocols (such as the use of a magnetic field as suggest by para. 202 of Fodor). There would be a reasonable expectation of success as Fodor clearly teaches the use of cleavable domains on the stochastic barcodes, and this falls in line with the typical use of cleavage domains for oligonucleotides attached to substrates.
However, Fodor does not teach that the cell-tagging antibody can be coupled to a polynucleotide that binds to the priming domain of the stochastic barcode.
Chee teaches methods for use in spatially encoded biological assays (Abstract). This can involve a probe that binds to a biological target (e.g. para. 12), and said probe may be bound to an antibody (paras. 45 and 125). Figure 7a shows the structure of a DNA-labeled antibody probe. The antibody is bound to a target, and the DNA label contains spatially addressed DNA probes. These address tags can be bound to universal priming sites (para. 180).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Fodor and Chee to arrive at the invention of instant claim 1. Specifically, this would involve using the antibody/oligonucleotide conjugate structure taught by Chee in place of the antibody affinity property taught by Fodor. Because this conjugate can bind to a universal sequence, it would be able to bind to the universal label on the stochastic barcodes of Fodor, which is a priming site and corresponds to the priming domain of the instant invention (Fodor para. 101). MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” The creation of antibody/oligonucleotide conjugates and universal sequences is known in the art, as evidenced by Chee and Fodor, and this substitution would still allow the antibody to bind to the target, producing predictable results.
Thus, claims 1, 7, 11, 26-27, 31-32, 51, and 60 are prima facie obvious over Fodor in view of Chee.
Regarding claim 13, Fodor teaches that cell membrane permeability can be increased when staining tissue in order to increase the quality of the staining, therefore providing better visualization (para. 266).
Regarding claim 30, Fodor teaches means of imaging the sample (e.g. paras. 20-21).
Regarding claim 57, Fodor teaches that sequencing can be done via fluorescent in situ sequencing (para. 236).
Regarding claim 58, Fodor teaches performing amplification reactions (para. 213). The primers can be entirely custom and can bind to label sequences on the stochastic barcode (paras. 212-213). Thus, the target recognition sequence of the stochastic barcode could be targeted, which in the embodiment of Fodor in view of Chee taught in the rejection of claim 1, is bound to an oligonucleotide present on the bead (i.e. the first and second hybridization domains). It would be prima facie obvious to use the bead oligonucleotide hybridized to the stochastic barcode as a primer, thereby using the capture probe as an amplification template. This would allow for amplification of the labels present on the stochastic barcode, such as the spatial label. By providing more spatial labels in the reaction mixture, the sequencing and target locating/detecting in the method of Fodor would have increased accuracy and rates of detection. As methods of amplification are well-known in the art, as evidenced by Fodor, there would be a reasonable expectation of success, as amplification reagents and conditions would simply need to be provided.
Regarding claim 59, Fodor teaches performing amplification reactions (para. 213). Specifically, many of these amplification reactions are designed to amplify a target nucleic acid, such as the target mRNA of Fodor in view of Chee in the rejection of instant claim 1 discussed above (paras. 206 and 212). Because the oligo(dT) of the bead bound oligonucleotide is the capture region designed to attach to the poly(A) tail of the target mRNA, it would be prima facie obvious to extend the bead bound oligonucleotide using the target mRNA as a template to ensure the entirety of the target region is copied. By amplifying the target mRNA, more targets can be bound to stochastic barcodes and beads, allowing for increased accuracy and rates of detection. As methods of amplification are well-known in the art, as evidenced by Fodor, there would be a reasonable expectation of success, as amplification reagents and conditions would simply need to be provided.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Fodor et al. (US 2016/0253584 A1), in view of Chee et al. (US 2016/0138091 A1), and further in view of Monaghan et al. (Nat Cell Biol, 2015).
Regarding claim 49, Fodor in view of Chee teaches the method of claim 1, as described above. This reference also teaches that their method can be used to identify cellular organelles, such as mitochondria or nuclei (para. 248), and that cellular organelles can be imaged (para. 106). Given that the cell-tagging agent of the invention of Fodor in view of Chee is an antibody that can bind to a specific molecule (para. 116), and the fact that known antibodies can bind to targets in specific organelles such as the mitochondria (as evidenced by Monaghan, see Figure 1a and the anti-COXIV antibody listed on page 9 under “Antibodies”), it would have been prima facie obvious for the ordinary artisan to use an antibody specific to mitochondria in the method of Fodor in view of Chee. By targeting and imaging mitochondrial analytes, mechanisms of mitochondrial dysfunction can be targeted, which Monaghan teaches as “a hallmark of ageing and alterations in mitochondrial activity” that can affect lifespans of organisms (page 2, para. 2). Therefore, these targets would be of interest to researchers and clinicians.
Thus, claim 49 is prima facie obvious over Fodor, in view of Chee, and further in view of Monaghan.
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Fodor et al. (US 2016/0253584 A1), in view of Chee et al. (US 2016/0138091 A1), and further in view of Kozlov et al. (US 2016/0291007 A1).
Fodor in view of Chee teaches the method of claim 1, as described above. Chee teaches that when oligonucleotides are coupled to proteins (e.g. antibodies) via conjugation, this can specifically be done via cross-linking groups (para. 126). Fodor also mentions using cross-linking linkers (para. 318). However, the specific linkers described in claim 55 are not taught by either reference.
Kozlov teaches polynucleotide conjugates for use in assays to detect analytes (Abstract). In particular, they teach that when cross-linking an antibody to a polynucleotide conjugate, a bifunctional cross-linking reagent, such as an NHS moiety, can be used. Additional reagents for connecting the antibody and conjugate can also be used, such as an azide molecule (para. 189).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the specific cross-linking reagent described by Kozlov in the method of Fodor in view of Chee. As Chee specifically teaches that cross-linking can be used to attach antibodies and oligonucleotides, and in the method of claim 3 as taught by Fodor in view of Chee above, an antibody/oligonucleotide conjugate is made, it would be simple substitution to use the cross-linking agents described by Kozlov to achieve said antibody/oligonucleotide conjugate. MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” As Kozlov teaches that NHS linkers can be used for cross-linking along with azide moieties, this provides both evidence that these are well-known elements and that their use as cross-linkers would yield predictable results (i.e. linking the antibody and oligonucleotide of Fodor in view of Chee).
Thus, claim 55 is obvious over Fodor, in view Chee, and further in view of Kozlov.
Conclusion
No claims are currently allowable.
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.
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/F.F.G./Examiner, Art Unit 1681
/GARY BENZION/Supervisory Patent Examiner, Art Unit 1681
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