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 .
DETALED ACTION
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/3/2025 has been entered.
Applicant’s response filed 12/3/25 is acknowledged and has been entered.
2. Applicant is reminded of Applicant's election of Group I in Applicant’s response filed 1/8/19.
Claims 31, 33, 34, 37, 39, 41, 42 and 45-49 are presently being examined.
3. 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.
4. 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.
5. Claims 31, 33, 34, 37, 39, 41, 42 and 45-49 are rejected under 35 U.S.C. 103 as being obvious over US 20100168390 A1 (of record) in view of Andersen et al (Nature Protocols, 2012, 7: 891-902, of record), US 2021/0239698 A1 (priority to 2011), Brakmann, S. (Angew. Chem. Int. Ed. 2004, 43: 5730-5734), and WO 2013/137737 A1 (of record).
Claim Interpretation: instant base claim 31 recites that eight or more MHC molecules are coupled to the backbone and a nucleic acid molecule comprising the barcode with primer regions of part “iii” is coupled to the backbone; these limitations are being interpreted to mean that the MHC molecules and the nucleic acid molecule comprising the barcode with primer regions are directly or indirectly attached or coupled to the backbone. The specification does not disclose a limiting definition for “conjugating” as in “conjugating the nucleic acid label to the backbone” as is recited in instant dependent claim 46. The said limitation is therefore being interpreted as is it is known in the art to mean ‘to join together’ or ‘chemically join together’. See for example, evidentiary reference Biology Online (2024,10 pages, of record). The definition of “barcode” in the instant specification is: “In the present context, a nucleic acid barcode is a unique oligo-nucleotide sequence ranging for [from] 10 to more than 50 nucleic acids. The barcode has shared amplification sequences in the 3’ and 5’ ends, and a unique sequence in the middle. This sequence can be revealed by sequencing and can serve as a specific barcode for a given molecule.” (see page 5 at lines 21-26).
US 2010/0168390 A1 discloses peptide/MHC class I molecules or tetramers or other multimers thereof bound to fluorophore-labeled dextran carrier molecules (or other polysaccharides such as derivatized dextrans, scleroglucan (i.e., a glucan), streptavidin, streptavidin tetramers, or avidin); and when the complexes are bound to streptavidin, attachment is via biotin/streptavidin attachment chemistries. The streptavidin can also be attached to a derivatized dextran or other polysaccharide. US 2010/0168390 A1 also discloses other carriers such as magnetic or other beads, including those comprising dextran-coated beads comprising the MHC dextramers. US 2010/0168390 A1 discloses that the MHC molecule can be a recombinant molecule wherein the MHC class I heavy chain comprises a C-terminal target peptide sequence for biotinylation, and the chemically biotinylated MHC can then bind to streptavidin coupled to the carrier molecule. US 2010/0168390 A1 discloses that in making the MHC peptide molecule recombinantly, the heavy chain of MHC class I and the b2m light chain may be expressed separately and added together during in vitro refolding. US 2010/0168390 A1 discloses that peptide epitopes presented by MHC molecules can be presented to T cells and activates the T cells, wherein each T cell expresses one unique specificity of TCR which recognizes one specific MHC/peptide epitope complex. US 2010/0168390 A1 discloses that the dextran backbone can further comprise one or more than one detectable label and tags such as for example, a His tag, metal-ion tag, or other selectable tags and labels such as detectable labels. US 2010/0168390 A1 discloses that the labeling molecule many be any labeling molecule such as a nucleic acid molecule, including DNA, or nucleic acid analogs, (e.g.,[0488]) and it may be attached to the MHC multimer directly or indirectly, covalently or noncovalently; it can be attached to the MHC multimer, to the multimerization domain, or to the dextran backbone. US 2010/0168390 A1 discloses that the labelling compound can be attached via a suitable linker and that such linkers are readily known by the person skilled in the art.
US 2010/0168390 A1 discloses that the number of MHC molecules can be at least two, at least four, or at least eight, up to a plurality depending on the capacity and nature of the multimerization domain(s), and the MHC can harbor the same or a different peptide; in the latter case, the composition can be used to detect several types of MHC recognizing T cells simultaneously. US 2010/0168390 A1 discloses that one of ordinary skill in the art can determine the number of binding entities (pMHC multimers) that can be attached to the multimerization domains. US 2010/0168390 A1 discloses that the MHC multimers may be comprised of single chain MHC/peptide complexes, that the peptides that bind to MHC class | molecules are typically 8-11 amino acid residues in length.
US 2010/0168390 A1 discloses that different MHC multimers can be differently labeled enabling visualization of different target MHC-recognizing T cells; if several different MHC multimers with different labels are present, it is possible simultaneously to identify more than one specific T cell receptor, if each of the MHC multimers present a different peptide. US 2010/0168390 A1 discloses using groups of MHC multimers that are labeled with different labels together in the same preparation.
US 2010/0168390 A1 discloses that MHC multimers, including those comprising single chain MHC/peptide monomers attached to one or more multimerization domains, provide increased affinity and half-life on interaction with a cognate TCR as compared with that to the monomer MHC/peptide complex; the MHC multimers bind with high avidity to cognate T cell receptors (TCRs). US 2010/0168390 A1 discloses that the increased valences of the compounds of the invention produce surprisingly higher avidity in comparison to oligo-valent complexes such as tetramers known from the prior art, allowing for quantitative analysis of even small T cell populations, with the increased binding avidity of the MHC multimers of the invention allowing detection of MHC-recognizing T cells expressing low affinity T cell receptors. US 2010/0168390 A1 discloses that this augmented interaction also allows detection of very small MHC recognizing cell populations in blood samples without the need for in vitro expansion, and the MHC multimers of the invention are therefore useful for direct monitoring of all types of MCH recognizing cells in blood samples. US 2010/0168390 A1 discloses that these carriers are useful for binding and identifying cognate T cells comprising cognate T cell receptors on their surfaces, including for identifying low affinity binding T cells.
US 2010/0168390 A1 discloses that the MHC multimers can be labelled, for example, with one or more fluorophores and used in flow cytometry to label T cells carrying specific TCRs that bind the MHC multimers, including individual T cells or populations of T cells. US 2010/0168390 A1 discloses that the flow cytometer can also separate and collect particular types of cells, i.e., by “cell sorting’, and the MHC multimers in combination with sorting on a flow cytometer can be used to isolate antigen specific T cell populations. That is, US 2010/0168390 A1 discloses that the MHC multimers in addition to being useful for binding and identifying cognate T cells comprising cognate T cell receptors on their surfaces, are also useful for isolating the T cells for identification, further study, monitoring the antigen specific T cell response to a vaccine, or for adoptive transfer. US 2010/0168390 A1 discloses that p/MHC-specific T cells can be isolated using fluorescence activated cell sorting (FACs) when fluorescent label(s) is/are also attached to the multimer backbones. US 2010/0168390 A1 discloses that p/MHC-specific T cells can also be counted/quantified by FACs analysis (e.g., [0663], [0667], [0668], [0759], [0859], [0855], [0866], [0894]). US 2010/0168390 A1 discloses that the p/MHC I multimers of the invention also allow for better separation of specific and unspecific MHC recognizing cells ([0772]). US 2010/0168390 A1 discloses that an advantage of sorting the p/MHC specific T cells is that the relevant population of cells are selected for expansion, avoiding polyclonal expansion of T cell populations that include a multitude of irrelevant T cell specificities ([0900], [0901]). (See entire reference, especially abstract, [0003], [0013], [ [0042]-[0047], [0054], [0062],[0066]-[0086], [0094], [0095], [0134], [0145],[0161], [0195], [0196],[0200], [0207]-[0211], [(0213],[0214], [0220], [0236], [0242], [0252], [0308]-[0323],[0326], [0358],[0401 ]-[0405], [0411], [0415]-[0417], [0487], [0488], [0659], [0770], [0771], [0845], [0874]).
US 2010/0168390 A1 does not disclose that the different DNA labels are DNA barcodes comprising at least 10 nucleotides and comprised within 5’ and 3’ universal primer regions, nor wherein the composition comprises 1,000 to 10,000 different subsets of multimeric MHC, nor wherein the complexes are produced by UV peptide exchange. US 2010/0168390 A1 does not disclose wherein the coupling of the nucleic acid label to the backbone is through a streptavidin-biotin binding as is recited in instant dependent claim 49.
Andersen et al teach that producing pMHC tetramers by UV peptide exchange. Andersen et al teach that UV exchange technology enables the parallel production of large panels of peptide/MHC complexes, allowing the generation of sets of thousands of different peptide/MHC complexes within hours. Andersen et al teach that a method of using one to four dimensional fluorescent color codes (i.e., color barcodes) at the higher number of color combinations results in lower sensitivity, as the use of all possible color combinations precludes the elimination of background events that are caused by signal in only one channel or in many channels. In addition, for each additional dimension added, a consequent reduction in fluorescence intensity of each individual color takes place, and the use of four color codes and to some extent three color codes can make it difficult to distinguish antigen-specific T cells. Andersen et al teach a protocol that allows the detection of 27 different (combinatorially encoded) antigen-specific T cell populations in a single sample, wherein the protocol uses p/MHC tetramers labeled with different combinations of three QDOT fluorescent labels (color barcodes) by FACs analysis. Although Andersen et al teach that the method is more sensitive than conventional MHC multimer staining, they also teach that limitations of their method include: lower sensitivity with an often limited sample size, variation in lot to lot fluorescence, sometimes observed optical overlap in labels despite narrow emission spectra, the configuration of the flow cytometer limits the number of labels used depending upon the particular flow cytometer, differences in fluorochrome intensities exist between different labels and degradation of labels occurs over time, the QDOT fluorescent labeled-streptavidin conjugates are expensive, and structurally related peptides cannot be placed in the same panel. (See entire reference, especially page 891 at the second paragraph, sentence spanning pages 892-893, first two full paragraphs at column 1 on page 893, spanning paragraph at columns 1-2, paragraph spanning pages 893-894, first three paragraphs at the column 1 on page 894, paragraph spanning pages 894-895).
Thus, Andersen et al teach that their method of using one to four dimensional fluorescent color codes (i.e., use of color barcodes) to label MH multimers comprising MHC molecules bound to different peptides is more sensitive than conventional pMHC multimer staining (such as that disclosed by US 2010/0168390 A1), there are still limitations such as lower sensitivity with an often limited sample size, variation in lot to lot fluorescence, optical overlap in labels, dependence of limitations of the particular flow cytometer used, differences in fluorochrome intensities between different labels, label degradation over time, expense, and that structurally related peptides cannot be placed in the same panel. Andersen et al teach a protocol that allows for the parallel detection of 27 different (combinatorially encoded) antigen-specific T cell populations in a single sample. Conversely, Andersen et al teach that the UV exchange technology enables the parallel production of large panels of pMHC complexes, allowing for the generation of sets of hundreds or thousands of different pMHC complexes within hours. Thus, Andersen et al teach that they can produce hundreds to thousands of different pMHC complexes within hours, but that they can only analyze 27 different antigen-specific T cell populations in parallel, and including with the limitations they teach in such a detection assay. Andersen et al teach that there are serious limitations as to the number of different complexes that can be tested, the number of different particular p/MHC-specific TCRs that can be detected, and the sensitivity of the assay, making it difficult to identify peptide antigen/MHC-specific T cells, including wherein often the sample size is not optimal for such detection.
US2021/0239698 A1 discloses linking a peptide (that is bound to its necessary components such as b2m and MHC class I heavy chain such as in a single chain format that optionally includes flexible linker peptides between the components, e.g., [0046], [0075]-[0077]) to the said peptide’s encoding DNA through attachment of both to any suitable support carrier. US2021/0239698 A1 discloses that this is advantageous because methods that are available to sequence DNA are far more sophisticated than those available to sequence protein, it is less expensive and much more rapid, and can be successful on very small samples, both in terms of length and molar amounts. In addition DNA samples can be easily amplified to provide more DNA if needed. DNA sequencing can be undertaken by traditional Sanger based methodology or by various high throughput sequencing approaches ([0006]. US2021/0239698 A1 discloses that the aim of the invention is to provide a system to screen for ligands, in particular, to screen for ligands for cell surface receptors such as for TCRs ([0007]) that recognize and bind to a MHC molecule presenting a peptide epitope ([0008]). US2021/0239698 A1 discloses that a carrier may be advantageously be multivalent, i.e., it may carry multiple copies of each peptide/MHC complex (including single chain b2m/MHC heavy chain/peptide complex) and the peptides encoding DNA (with primer region for amplifying the templated DNA encoding the peptide), increasing the chance of its interaction with a TCR and improving the rate of recovery ([0030]). The peptide may be randomly generated or derived from a source library, and the nucleic acid may then be analyzed to determine the peptide it encodes ([0034]-[0036]). US2021/0239698 A1 discloses HLA class I molecules and that a complex thereof comprises the HLA class I heavy chain, b2m and peptide, and the complexes thereof may comprise the individual components or a single chain construct ([0039]-[0047]) and the complex and the DNA encoding the peptide are attached to a carrier (e.g., claims 1-5, 8-10). US2021/0239698 A1 discloses that a biotin moiety may be attached to the DNA when using a carrier having streptavidin disposed thereon (e.g., [0058]). Thus, US2021/0239698 A1 inherently discloses that biotin is a binding partner for streptavidin. US2021/0239698 A1 discloses that the MHC molecule may be covalently or non-covalently attached to the carrier (e.g., [0055]) including attachment to a streptavidin treated or coated carrier (e.g., [0056]). US2021/0239698 A1 discloses that preferably multiple copies of the peptide and its encoding DNA are attached to the carrier, preferably at least 10, 100, 1000 or more copies are attached ([0078]). US2021/0239698 A1 discloses that preferably each carrier comprises multiple copies of the same MHCI/peptide complex and encoding DNA, while multiple carriers may be used together and comprise different populations of carriers, each of the said carriers having a different MHC I/peptide complex/encoding DNA from one another (e.g., [0052]). See entire reference, including claims.
Thus, US2021/0239698 A1 discloses linking a peptide-b2m-MHC I single chain molecule to the peptide’s encoding DNA (i.e., a type of barcode DNA) through attachment to a same carrier, the DNA comprising a primer region, and the advantages of doing so in terms of rapid, sensitive, high throughput, parallel detection of cognate TCRs and identification of the cognate peptide ligands in the MHC molecules by isolating and sequencing the encoding DNA.
Brakmann teaches that interaction of an antibody protein disposed on a carrier that recognizes an antigen advantageously comprises one or more copies of a marker DNA [comprising PCR primer reactive sequences flanking barcode DNA, wherein the barcode DNA codes for a same particular antigen of interest), and whereby the DNA can be amplified using PCR, and wherein using multiple copies of DNA increases the sensitivity of detection of the protein of interest (for example, the ratio of recognition of the protein to marker DNA is about 1:100). Brackmann teaches that the carriers were functionalized with DNA barcodes. Brackmann teaches that if every antigen is coded by a distinct marker DNA sequence (“bio-barcodes”), parallel analysis of multiple analytes may be accomplished (see entire reference, especially barcodes for the identification of proteins section, Figure 1C).
Thus, Brakmann links a protein binding specificity to a DNA barcode sequence on a same carrier.
Likewise, WO 2013/137737 A1 cited below links a binding specificity to a DNA or other unique nucleic acid barcode. The DNA barcode is flanked by universal (i.e., same) primer regions which allow for parallel, high-throughput screening of binding region pools, including those from libraries of from 10 molecules up to one million molecules, as is enunciated below.
WO 2013/137737 A1 teaches compositions comprising library binding regions connected or covalently attached with a specific PCR-amplifiable DNA, PNA, LNA or other artificial nucleotide molecule, wherein the nucleic acid molecule can be flanked at both ends by a universal primer binding site to which primers can hybridize, serving as the starting point for amplification. WO 2013/137737 A1 teaches that the size of the unique identifier barcode is typically from 2-100 nucleotides in length, preferably 12-25 nucleotides usually being sufficient. WO 2013/137737 A1 teaches that the library may vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules. WO 2013/137737 A1 teaches that the target molecule corresponding to the target of the binding region may be a receptor, including a cell surface receptor. WO 2013/137737 A1 teaches that each binding region is attached to a specific nucleotide sequence identifier and that the constructs can be placed in pools, wherein each nucleotide sequence identifier is a pool-specific sequence identifier termed a DNA barcode. WO 2013/137737 A1 teaches that the library binding region constructs are used in a method of screening of the binding regions for potential interaction with target molecules(s) including one on a cell surface, and wherein the identifying binding comprises amplifying the DNA barcodes in parallel through the universal primal primer regions an sequencing the barcodes in parallel, preferably through high throughput sequencing. WO 2013/137737 A1 teaches that the constructs may also be labeled with a tag such as a fluorescent tag (see entire reference, especially Figure 1, abstract, [22], [24], [30], [31], [40], [41], [45], [59], [60], [63], [67], claims).
Thus, the art reference US2021/0239698 A1 teaches a different type of barcode, a DNA barcode that uniquely identifies the peptide comprised in a pMHC complex and it comprises the particular peptides encoding DNA with both the pMHC complex and the encoding DNA attached to any suitable support carrier, and that the carrier may be advantageously and preferably configured to be multivalent, carrying multiple copies of each pMHC complex, including at least 10 or more copies of the pMHC and its encoding DNA (barcode) are attached. The DNA comprises primer regions for amplifying the DNA encoding the peptide. The art reference Brakmann also links a protein binding specificity to a DNA barcode, and art reference WO 2013/137737 A1 teaches compositions comprising library binding regions attached with a specific PCR-amplifiable DNA or other nucleic acid molecule that is a unique identifier barcode that is flanked at both ends by a universal primer binding site for parallel, high throughput sequencing along with their use in screening for potential interaction with target molecules, including those on a cell surface. WO 2013/137737 A1 that the library may vary in size with a lower limit of 10 molecules up to 1,000,000 molecules, indicating the combinatorial encoding power of DNA barcodes attached to a binding specificity.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used unique DNA barcode sequences as is disclosed by US2021/0239698 A1 and taught by Brakmann, either random or corresponding to the peptide sequence, and including with 5’ and 3’ primer sequences flanking the DNA label as is taught by Brakmann, particularly those taught by WO 2013/137737 A1 having universal PCR- amplifiable 3’ and 5’ flanking primers, as the DNA label on the multimeric carriers of the primary art reference that are disclosed to have MHC class I complexes attached thereto along with a DNA label, and also a fluorescent (selectable) label.
One of ordinary skill in the art would have been motivated to do this in order to reap the aforementioned advantages of using unique barcode molecules to make a carrier that is useful and improved in identifying cognate TCRs for MHC class I/peptide complexes (e.g., sequencing DNA is far more sophisticated than protein sequencing, it is less expensive and much more rapid, it can be successful on very small samples, both in terms of length and molar amounts, and DNA samples can be easily amplified to provide more DNA if needed), and in addition, when using DNA barcodes that encode the peptide, for identifying the peptide through DNA sequences, and with a reasonable expectation of success in doing so, as the primary art reference is silent as to the identity of the different DNA labels, Brakmann and US2021/0239698 A1 teach or disclose, respectively, the advantageous use of barcode DNA labels that connect a binding specificity to its encoding DNA, while Andersen et al teach that the use of fluorescent labels to distinguish binding specificities of MHC/peptide complexes to TCRs is associated with disadvantages, (e.g., limited in the number of labels that can be used, lower sensitivity with a limited sample size, variation in lot to lot fluorescence, sometimes observed optical overlap in labels despite narrow emission spectra, differences in fluorochrome intensities exist between different labels and degradation of labels occurs over time, the QDOT fluorescent labeled-streptavidin conjugates are expensive, and structurally related peptides cannot be placed in the same panel).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used UV peptide exchange as is taught by Anderson et al in constructing the composition of the combined references.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to produce large numbers of peptide/MHC complexes quickly, as Andersen et al teach that UV exchange technology enables the parallel production of large panels of peptide/MHC complexes, allowing the generation of sets of thousands of different peptide/MHC complexes within hours.
Instant claim 42 is included in this rejection because the primary art reference discloses that peptide may be randomly generated or derived from a source library, and one of ordinary skill in the art was aware of the size of random or source libraries, the tens of thousands of human MHC class I molecules alone (see for example, evidentiary reference HLA Nomenclature 2015, of record) as well as the repertoire of peptides that can be bound from the universe of proteins, while US2021/0239698 A1 also discloses library screening and that the method of using such a carrier with attached MHC class I/peptide complexes and the barcode DNA is high-throughput. In addition, WO 2013/137737 A1 teaches that the library may vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules.
With regard to the limitation recited in instant base claim 31 “wherein the barcode comprises at least 10 nucleotides”, the instant claims are included in this rejection because the primary art reference discloses that peptides that typically bind to MHC class I molecules are 8-11 amino acid residues in length, and wherein the barcodes encode the peptide, the length of the barcode nucleotides would therefore range from 24 to 33. Wherein the barcodes are unique identifiers that don’t correspond to the actual sequence of the peptide, it would have been prima facie obvious to one of ordinary skill in the art to have used a number of nucleotides around the same size as those encoding a MHC class I binding peptide. One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, as the art teaches that encoding DNA of such lengths may be used as DNA barcodes.
Applicant’s arguments have been fully considered but are not persuasive. Applicant’s said arguments are of record in the amendment and response filed 12/3/25 on pages 5-6.
Applicant alleges hindsight reconstruction. However, this said argument has been rebutted in the prosecution history. Applicant further argues that even if each of the rejections is sufficient for a prima facie showing of obviousness, they are outweighed by the advantages of the present[ly] claimed compositions, which would have been unexpected at the time of the invention over the teachings of the cited prior art. Applicant argues that the requirement of eight or more MHC molecules per multimer heightens the sensitivity of detection by introducing a high degree of binding cooperativity, for example enabling the detection of T cell populations having a lower binding affinity for a given peptide than is possible using fewer MHC molecules per multimer.
However, as is enunciated in the instant rejection, the art reference US 2010/0168390 A1 discloses that the increased valencies of the compounds of the invention produce surprisingly higher avidity in comparison to oligo-valent complexes such as tetramers known from the prior art, allowing for quantitative analysis of even small T cell populations, with the increased binding avidity of the MHC multimers of the invention allowing detection of MHC-recognizing T cells expressing low affinity receptors, and allowing for quantitative analysis of even small cell populations by for example, flow cytometry (e.g., [0659]). In addition, said art reference discloses that the number of MHC molecules can be at least eight, up to a plurality depending on the capacity and nature of the multimerization domain(s), i.e., a teaching that an optimal number of p/MHC molecules depends upon the capacity and nature of the multimerization domains (e.g., the actual backbone and its size and/or average molecular weight, the orientation of pMHC on the backbone) (e.g., [0062], [0075]). The instant specification does not appear to disclose optimal numbers of pMHC for particular backbones from those recited in the claims, nor in the examples in the specification. Although the Examiner agrees that avidity can be increased when disposing pMHC at optimized number thereof for a particular backbone (and sensitivity can additionally be increased by choice of flurophore(s)), the art indicates that this is not unexpected. The art reference also discloses using the fluorescent label as a basis for fluorescence activated cell sorting, quantifying and/or isolating/separating cognate T cells bound to the constructs (e.g., [0663], [0667], [0668], [0759], [0859], [0855], [0866], [0894]). The art reference also discloses that the pMHC multimers can comprise more than one label or more than one type of label.
Applicant’s further argument as to an exemplary use of the multimers by attaching a fluorescent label to the backbone of only one or more specific groups of MHC multimers is not persuasive, as all of the multimers in the claimed composition must necessarily comprise one or more fluorescent labels.
Applicant argues that the combination of fluorescent labeling of the backbone with nucleic acid barcoding offers two independent levels of labeling, analysis, and isolation of cells, combined with the detection of low affinity peptide-binding cell populations resulting from the use of eight or more MHC molecules per multimer, which was not possible or even suggested by the cited references. Applicant argues that the recited combination of features provides synergistic benefits that are uniquely suited to allow the tremendous diversity of immune cell specificity to be analyzed and exploited in ways that are not disclosed or suggested by any combination of the cited references.
However, the said art reference US 2010/0168390 A1 discloses that if several different MHC multimers with different labels are present, it is possible simultaneously to identify more than one specific TCR if each of the MHC multimers presents a different peptide. The art reference also discloses that the pMHC multimers can comprise more than one label or more than one type of label, including a nucleic acid label such as a DNA label.
As is also enunciated in the instant rejection, Andersen et. al. teach that their method of using one to four dimensional fluorescent color codes (i.e., use of color barcodes) to label MH multimers comprising MHC molecules bound to different peptides is more sensitive than conventional pMHC multimer staining (such as that disclosed by US 2010/0168390 A1), there are still limitations such as lower sensitivity with an often limited sample size, variation in lot to lot fluorescence, optical overlap in labels, dependence of limitations of the particular flow cytometer used, differences in fluorochrome intensities between different labels, label degradation over time, expense, and that structurally related peptides cannot be placed in the same panel. Andersen et. al. teach a protocol that allows for the parallel detection of 27 different (combinatorially encoded) antigen-specific T cell populations in a single sample. Conversely, Andersen et. al. teach that the UV exchange technology enables the parallel production of large panels of pMHC complexes, allowing for the generation of sets of hundreds or thousands of different pMHC complexes within hours. Thus, Andersen et. al. teach that they can produce hundreds to thousands of different pMHC complexes within hours, but that they can only analyze 27 different antigen-specific T cell populations in parallel, and including with the limitations they teach in such a detection assay.
The art reference US2021/0239698 A1 teaches a different type of barcode, a DNA barcode that uniquely identifies the peptide comprised in a pMHC complex and it comprises the particular peptides encoding DNA with both the pMHC complex and the encoding DNA attached to any suitable support carrier, and that the carrier may be advantageously and preferably configured to be multivalent, carrying multiple copies of each pMHC complex, including at least 10 or more copies of the pMHC and its encoding DNA (barcode) are attached. The DNA comprises primer regions for amplifying the DNA encoding the peptide. The art reference Brakmann also links a protein binding specificity to a DNA barcode, and art reference WO 2013/137737 A1 teaches compositions comprising library binding regions attached with a specific PCR-amplifiable DNA or other nucleic acid molecule that is a unique identifier barcode that is flanked at both ends by a universal primer binding site for parallel, high throughput sequencing along with their use in screening for potential interaction with target molecules, including those on a cell surface. WO 2013/137737 A1 that the library may vary in size with a lower limit of 10 molecules up to 1,000,000 molecules, indicating the combinatorial encoding power of DNA barcodes attached to a binding specificity.
Thus, the art indicates that an increase in avidity using an optimal number of pMHC, including at least eight, is not surprising for identifying low affinity TCRs, that pMHC constructs labeled with fluorochrome(s) (including for cell sorting of populations of T cells), including using several in tandem as color barcodes, can enable the use of cell sorting but is limited in its ability to identify a large number of different pMHC constructs, but that a different type of barcode (DNA or nucleic acid barcode) has the power to identify the sequence of the different peptides comprised in different pMHC complexes and matching the ability to easily and quickly produce hundreds to thousands of different pMHC complexes in parallel, rebutting Applicant’s argument of unexpected results.
6. Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are rejected under 35 U.S.C. 103 as being obvious over US2021/0239698 A1 (of record) in view of US 2010/0168390 A1 (of record), Brakmann (of record), and WO 2013/137737 A1 (of record).
Claim Interpretation: instant base claim 31 recites that eight or more MHC molecules are coupled to the backbone and a nucleic acid molecule comprising the barcode with primer regions of part “iii” is coupled to the backbone; these limitations are being interpreted to mean that the MHC molecules and the nucleic acid molecule comprising the barcode with primer regions are directly or indirectly attached or coupled to the backbone. The specification does not disclose a limiting definition for “conjugating” as in “conjugating the nucleic acid label to the backbone” as is recited in instant dependent claim 46. The said limitation is therefore being interpreted as is it is known in the art to mean ‘to join together’ or ‘chemically join together’. See for example, evidentiary reference Biology Online (2024,10 pages, of record). The definition of “barcode” in the instant specification is: “In the present context, a nucleic acid barcode is a unique oligo-nucleotide sequence ranging for [from] 10 to more than 50 nucleic acids. The barcode has shared amplification sequences in the 3’ and 5’ ends, and a unique sequence in the middle. This sequence can be revealed by sequencing and can serve as a specific barcode for a given molecule.” (see page 5 at lines 21-26).
US2021/0239698 A1 discloses linking a peptide (that is bound to its necessary components such as b2m and MHC class I heavy chain such as in a single chain format that optionally includes flexible linker peptides between the components, e.g., [0046], [0075]-[0077]) to the peptide-encoding DNA through attachment of both to any suitable solid support carrier is advantageous because methods that are available to sequence DNA are far more sophisticated than those available to sequence protein, it is less expensive and much more rapid and can be successful on very small samples, both in terms of length and molar amounts. In addition DNA samples can be easily amplified to provide more DNA if needed. DNA sequencing can be undertaken by traditional Sanger based methodology or by various high throughput sequencing approaches ([0006]. US2021/0239698 A1 discloses that the aim of the invention is to provide a system to screen for ligands, in particular, to screen for ligands for cell surface receptors such as for TCRs ([0007]) that recognize and bind to a MHC molecule presenting a peptide epitope ([0008]). US2021/0239698 A1 discloses that a carrier may be advantageously be multivalent, i.e., it may carry multiple copies of each peptide/MHC complex (including single chain b2m/MHC heavy chain/peptide complex) and the peptides encoding DNA (with primer region for amplifying the templated DNA encoding the peptide), increasing the chance of its interaction with a TCR and improving the rate of recovery ([0030]). The peptide may be randomly generated or derived from a source library, and the nucleic acid may then be analyzed to determine the peptide it encodes ([0034]-[0036]). US2021/0239698 A1 discloses HLA class I molecules and that a complex thereof comprises the HLA class I heavy chain, b2m and peptide, and the complexes thereof may comprise the individual components or a single chain construct ([0039]-[0047]) and the complex and the DNA encoding the peptide are attached to a carrier (e.g., claims 1-5, 8-10). US2021/0239698 A1 discloses that a biotin moiety may be attached to the DNA when using a carrier having streptavidin disposed thereon (e.g., [0058]). Thus, US2021/0239698 A1 inherently discloses that biotin is a binding partner for streptavidin. US2021/0239698 A1 discloses that the MHC molecule may be covalently or non-covalently attached to the carrier (e.g., [0055]) including attachment to a streptavidin treated or coated carrier (e.g., [0056]). US2021/0239698 A1 discloses that preferably multiple copies of the peptide and its encoding DNA are attached to the carrier, preferably at least 10, 100, 1000 or more copies are attached ([0078]). US2021/0239698 A1 discloses that preferably each carrier comprises multiple copies of the same MHCI/peptide complex and encoding DNA, while multiple carriers may be used together and comprise different populations of carriers, each of the said carriers having a different MHC I/peptide complex/encoding DNA from one another (e.g., [0052]). See entire reference, including claims.
Thus, US2021/0239698 A1 teaches a DNA barcode that uniquely identifies the peptide comprised in a pMHC complex and it comprises the particular peptide’s encoding DNA with both the pMHC complex and the encoding DNA attached to any suitable support carrier, and that the carrier may be advantageously and preferably configured to be multivalent, carrying multiple copies of each pMHC complex, including at least 10 or more copies of the pMHC and its encoding DNA (barcode) are attached. The DNA comprises primer regions for amplifying the DNA encoding the peptide.
US2021/0239698 A1 does not disclose that the carrier is one of a polysaccharide, a glucan, a dextran or a streptavidin, nor does US2021/0239698 A1 disclose that the DNA label that encodes the peptide also comprises 3’ and 5’ universal primer regions, nor that the barcode DNA comprises at least 10 nucleotides. US2021/0239698 A1 does not disclose that the carrier further comprises one or more fluorescent labels. US2021/0239698 A1 does not disclose wherein the composition comprises 1,000 to 10,000 different subsets of multimeric MHC. Although US2021/0239698 A1 discloses that the carrier has at least 10 copies of the peptide and its encoding DNA, it does not disclose that the lower limit includes at least 8 pMHC molecules coupled to the carrier.
US 2010/0168390 A1 discloses similar constructs, but wherein the carrier is a dextran carrier molecule or other polysaccharides such as derivatized dextrans, scleroglucan, streptavidin, streptavidin tetramers or avidin, and wherein the construct may comprise a DNA label and a fluorescent label as is enunciated below.
US 2010/0168390 A1 discloses peptide/MHC class I molecules or tetramers or other multimers thereof bound to fluorophore-labeled dextran carrier molecules (or other polysaccharides such as derivatized dextrans, scleroglucan (i.e., a glucan), streptavidin, streptavidin tetramers, or avidin); and when the complexes are bound to streptavidin, attachment is via biotin/streptavidin attachment chemistries. The streptavidin can also be attached to a derivatized dextran or other polysaccharide. US 2010/0168390 A1 also discloses other carriers such as magnetic or other beads, including those comprising dextran-coated beads comprising the MHC dextramers. US 2010/0168390 A1 discloses that the MHC molecule can be a recombinant molecule wherein the MHC class I heavy chain comprises a C-terminal target peptide sequence for biotinylation, and the chemically biotinylated MHC can then bind to streptavidin coupled to the carrier molecule. US 2010/0168390 A1 discloses that in making the MHC peptide molecule recombinantly, the heavy chain of MHC class I and the b2m light chain may be expressed separately and added together during in vitro refolding. US 2010/0168390 A1 discloses that peptide epitopes presented by MHC molecules can be presented to T cells and activates the T cells, wherein each T cell expresses one unique specificity of TCR which recognizes one specific MHC/peptide epitope complex. US 2010/0168390 A1 discloses that the dextran backbone can further comprise one or more than one detectable labels and tags such as for example, a His tag, metal-ion tag, or other selectable tags and labels such as detectable labels. US 2010/0168390 A1 discloses that the labeling molecule many be any labeling molecule such as a nucleic acid molecule, including DNA, or nucleic acid analogs, (e.g.,[0488]) and it may be attached to the MHC multimer directly or indirectly, covalently or noncovalently; it can be attached to the MHC multimer, to the multimerization domain, or to the dextran backbone. US 2010/0168390 A1 discloses that the labelling compound can be attached via a suitable linker and that such linkers are readily known by the person skilled in the art.
US 2010/0168390 A1 discloses that the number of MHC molecules can be at least two, at least four, or at least eight, up to a plurality depending on the capacity and nature of the multimerization domain(s), and the MHC can harbor the same or a different peptide; in the latter case, the composition can be used to detect several types of MHC recognizing T cells simultaneously. US 2010/0168390 A1 discloses that one of ordinary skill in the art can determine the number of binding entities (pMHC multimers) that can be attached to the multimerization domains. US 2010/0168390 A1 discloses that the MHC multimers may be comprised of single chain MHC/peptide complexes, that the peptides that bind to MHC class | molecules are typically 8-11 amino acid residues in length.
US 2010/0168390 A1 discloses that different MHC multimers can be differently labeled enabling visualization of different target MHC-recognizing T cells; if several different MHC multimers with different labels are present, it is possible simultaneously to identify more than one specific T cell receptor, if each of the MHC multimers present a different peptide. US 2010/0168390 A1 discloses using groups of MHC multimers that are labeled with different labels together in the same preparation.
US 2010/0168390 A1 discloses that MHC multimers, including those comprising single chain MHC/peptide monomers attached to one or more multimerization domains, provide increased affinity and half-life on interaction with a cognate TCR as compared with that to the monomer MHC/peptide complex; the MHC multimers bind with high avidity to cognate T cell receptors (TCRs). US 2010/0168390 A1 discloses that the increased valences of the compounds of the invention produce surprisingly higher avidity in comparison to oligo-valent complexes such as tetramers known from the prior art, allowing for quantitative analysis of even small T cell populations, with the increased binding avidity of the MHC multimers of the invention allowing detection of MHC-recognizing T cells expressing low affinity T cell receptors. US 2010/0168390 A1 discloses that this augmented interaction also allows detection of very small MHC recognizing cell populations in blood samples without the need for in vitro expansion, and the MHC multimers of the invention are therefore useful for direct monitoring of all types of MCH recognizing cells in blood samples. US 2010/0168390 A1 discloses that these carriers are useful for binding and identifying cognate T cells comprising cognate T cell receptors on their surfaces, including for identifying low affinity binding T cells.
US 2010/0168390 A1 discloses that the MHC multimers can be labelled, for example, with one or more fluorophores and used in flow cytometry to label T cells carrying specific TCRs that bind the MHC multimers, including individual T cells or populations of T cells. US 2010/0168390 A1 discloses that the flow cytometer can also separate and collect particular types of cells, i.e., by “cell sorting’, and the MHC multimers in combination with sorting on a flow cytometer can be used to isolate antigen specific T cell populations. That is, US 2010/0168390 A1 discloses that the MHC multimers in addition to being useful for binding and identifying cognate T cells comprising cognate T cell receptors on their surfaces, are also useful for isolating the T cells for identification, further study, monitoring the antigen specific T cell response to a vaccine, or for adoptive transfer. US 2010/0168390 A1 discloses that p/MHC-specific T cells can be isolated using fluorescence activated cell sorting (FACs) when fluorescent label(s) is/are also attached to the multimer backbones. US 2010/0168390 A1 discloses that p/MHC-specific T cells can also be counted/quantified by FACs analysis (e.g., [0663], [0667], [0668], [0759], [0859], [0855], [0866], [0894]). US 2010/0168390 A1 discloses that the p/MHC I multimers of the invention also allow for better separation of specific and unspecific MHC recognizing cells ([0772]). US 2010/0168390 A1 discloses that an advantage of sorting the p/MHC specific T cells is that the relevant population of cells are selected for expansion, avoiding polyclonal expansion of T cell populations that include a multitude of irrelevant T cell specificities ([0900], [0901]). (See entire reference, especially abstract, [0003], [0013], [ [0042]-[0047], [0054], [0062],[0066]-[0086], [0094], [0095], [0134], [0145],[0161], [0195], [0196],[0200], [0207]-[0211], [(0213],[0214], [0220], [0236], [0242], [0252], [0308]-[0323],[0326], [0358],[0401 ]-[0405], [0411], [0415]-[0417], [0487], [0488], [0659], [0770], [0771], [0845], [0874]).
Brakmann teaches that interaction of an antibody protein disposed on a carrier that recognizes an antigen advantageously comprises one or more copies of a marker DNA [comprising PCR primer reactive sequences flanking barcode DNA, wherein the barcode DNA codes for a same particular antigen of interest), and whereby the DNA can be amplified using PCR, and wherein using multiple copies of DNA increases the sensitivity of detection of the protein of interest (for example, the ratio of recognition of the protein to marker DNA is about 1:100). Brackmann teaches that the carriers were functionalized with DNA barcodes. Brackmann teaches that if every antigen is coded by a distinct marker DNA sequence (“bio-barcodes”), parallel analysis of multiple analytes may be accomplished (see entire reference, especially barcodes for the identification of proteins section, Figure 1C). Thus, Brakmann link a binding specificity to a DNA barcode sequence on a same carrier.
Likewise, WO 2013/137737 A1 links a binding specificity to a DNA or other nucleic acid barcode that is flanked by universal primer regions which allows for parallel, high-throughput screening of binding region pools, including those from libraries of from 10 molecules up to one million molecules, as is enunciated below. WO 2013/137737 A1 that the library may vary in size with a lower limit of 10 molecules up to 1,000,000 molecules, indicating the combinatorial encoding power of DNA barcodes attached to a binding specificity.
WO 2013/137737 A1 teaches compositions comprising library binding regions connected or covalently attached with a specific PCR-amplifiable DNA, PNA, LNA or other artificial nucleotide molecule, wherein the nucleic acid molecule can be flanked at both ends by a universal primer binding site to which primers can hybridize, serving as the starting point for amplification. WO 2013/137737 A1 teaches that the size of the unique identifier barcode is typically from 2-100 nucleotides in length, preferably 12-25 nucleotides usually being sufficient. WO 2013/137737 A1 teaches that the library may vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules. WO 2013/137737 A1 teaches that the target molecule corresponding to the target of the binding region may be a receptor, including a cell surface receptor. WO 2013/137737 A1 teaches that each binding region is attached to a specific nucleotide sequence identifier and that the constructs can be placed in pools, wherein each nucleotide sequence identifier is a pool-specific sequence identifier termed a DNA barcode. WO 2013/137737 A1 teaches that the library binding region constructs are used in a method of screening of the binding regions for potential interaction with target molecules(s) including one on a cell surface, and wherein the identifying binding comprises amplifying the DNA barcodes in parallel through the universal primal primer regions an sequencing the barcodes in parallel, preferably through high throughput sequencing. WO 2013/137737 A1 teaches that the constructs may also be labeled with a tag such as a fluorescent tag (see entire reference, especially Figure 1, abstract, [22], [24], [30], [31], [40], [41], [45], [59], [60], [63], [67], claims).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used any suitable carrier such as the carrier disclosed by US2021/0239698 A1 (e.g., a polysaccharide, a glucan, a dextran or a streptavidin) in place of the carrier disclosed by the primary art reference, to have added universal 3’ and 5’ primer regions to the (barcode) DNA labels encoding the MHC class I binding peptide disclosed by the primary art reference as per the teaching of WO 2013/137737 A1, to have used a barcode DNA comprising at least the minimum number to encode the peptide of interest (i.e., 8-11 amino acid residues corresponds to a minimum of 24 to 33 nucleotides), and to have added a fluorescent label to the construct for cell sorting as is disclosed for the constructs disclosed by US 20100168390 A1 and WO 2013/137737 A1.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to make a composition that could be used in a high-throughput fashion to identify MHC class I/peptide ligands of cognate TCRs and to isolate the said cognate TCRs or TCRs on T cells.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made a composition comprising 1,000 to 10,000 different subsets of multimeric MHC.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to analyze a large number of MHC class I/peptide complexes in parallel, given that US 20100168390 A1 discloses that the peptide may be randomly generated or derived from a source library,
while one of ordinary skill in the art was aware of the size of random or source libraries, the tens of thousands of different human MHC class I molecules alone (as is evidenced for example by HLA Nomenclature 2015, of record), as well as the repertoire of peptides that can be bound from the universe of proteins, while US2021/0239698 A1 also discloses library screening and that the method of using such a carrier with attached MHC class I/peptide complexes and the barcode DNA is high-throughput. In addition with further regard to the number of multimeric MHCs (as recited in instant dependent claims 33 and 42), WO 2013/137737 A1 teaches that the library may vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules.
Applicant’s arguments (of record in the amendment and response filed 12/3/25 on pages 5-6) have been fully considered but are not persuasive. Applicant’s arguments are the same as presented above. See the Examiner’s rebuttal thereto as pertains to the references cited in this rejection.
7. Claim 45 is rejected under 35 U.S.C. 103 as being obvious over US2021/0239698 A1 (of record) in view of US 2010/0168390 A1 (of record), Brakmann, and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 39, 41, 42 and 46-49 above, and further in view of Andersen et al (Nature Protocols, 2012, 7: 891-902, of record).
The combination and teachings of US2021/0239698 A1 in view of US 2010/0168390 A1, Brakmann, and WO 2013/137737 A1 is enunciated above, hereafter referred to as the “combined references.”
The combined references do not teach wherein the step of providing the human class I MHC/T cell binding peptide complexes comprises UV peptide exchange as is recited in instant dependent claim 45.
Andersen et al teach labeled p/MHC tetramers Andersen et al teach that they produce their pMHC tetramers by UV peptide exchange. Andersen et al teach that UV exchange technology enables parallel production of large panels of hundreds or thousands of different peptide/MHC complexes within hours (See entire reference, especially page 891 at the second paragraph, sentence spanning pages 892-893, first two full paragraphs at column 1 on page 893, spanning paragraph at columns 1-2, paragraph spanning pages 893-894).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made the peptide/MHC complexes in the multimer composition of the combined references using the UV peptide exchange methodology taught by Andersen et al.
One of ordinary skill in the art would have been motivated to do this in order to generate large panels of different peptide/MHC complexes in a short amount of time, and with a reasonable expectation of success in doing so, as Andersen et al teach the UV methodology enables parallel production of thousands of different MHC/peptide complexes within hours.
Applicant’s arguments (of record in the amendment and response filed 12/3/25 on pages 5-6) have been fully considered but are not persuasive. Applicant’s arguments are the same as presented above. See the Examiner’s rebuttal thereto.
8. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
9. Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,585,806 (formerly Application No. 15/316,587) in view of Brakmann, and WO 2013/137737 A1 (of record).
Claim Interpretation: instant base claim 31 recites that eight or more MHC molecules are coupled to the backbone and a nucleic acid molecule comprising the barcode with primer regions of part “iii” is coupled to the backbone; these limitations are being interpreted to mean that the MHC molecules and the nucleic acid molecule comprising the barcode with primer regions are directly or indirectly attached or coupled to the backbone. The specification does not disclose a limiting definition for “conjugating” as in “conjugating the nucleic acid label to the backbone” as is recited in instant dependent claim 46. The said limitation is therefore being interpreted as is known in the art as ‘to join together’ or ‘chemically join together’. See for example, evidentiary reference Biology Online (2024, 10 pages, of record). The definition of “barcode” in the instant specification is: “In the present context, a nucleic acid barcode is a unique oligo-nucleotide sequence ranging for [from] 10 to more than 50 nucleic acids. The barcode has shared amplification sequences in the 3’ and 5’ ends, and a unique sequence in the middle. This sequence can be revealed by sequencing and can serve as a specific barcode for a given molecule.” (see page 5 at lines 21-26).
The claims of US Patent No. 11,585,806 are drawn to a composition for analysis of a cell population, the composition comprising from 5 to 1,000,000 sets of detection molecules, wherein each of the detection molecules of a set comprise:
a. at least two identical binding molecules [i.e., the limitation encompasses at least eight as it is open ended on the high end of the range],
b. a multimerization domain coupled with each of the at least two identical binding molecules, wherein each binding molecule is covalently coupled to the multimerization domain via a separate connector molecule, and wherein said multimerization domain is selected from the group consisting of polysaccharides, dextran moieties, avidins, streptavidins, and streptactin,
c. a first label, where the first label comprises at least one nucleic acid label coupled with the multimerization domain or with at least one of said at least two identical binding molecules, wherein said nucleic acid label is 30-200 nucleotides in length and comprises a 5’ first primer region and a barcode region and a 3’ second primer region, and a random nucleotide region, wherein said barcode region comprises a sequence that is common to the set but uniquely represents the set within the composition, wherein said random nucleotide region comprise a sequence that is unique within the composition; the nucleic acid label can be attached to the multimerization domain via streptavidin-biotin binding, and
d. a second recited label such as a fluorescent label, and wherein said binding molecules of each of said sets recognize and/or bind to a TCR.
The label may be a DNA label, RNA label or an artificial nucleic acid label, and the binding molecule may be an MHC molecule, and the connector molecules may comprise avidins or streptavidins, and the barcode region of the nucleic acid label consists of 3 to 30 nucleotides (a range that overlaps the recited range of at least 10 nucleotides in instant base claim 31 and anticipates it).
Although the claims of 11,585,806 do not recite that the 5’ primer and the 3’ primer are identical (and are inherently therefore configured to allow amplification of all barcode regions simultaneously in a PCR reaction), the teaching of WO 2013/137737 A1 is when using unique nucleic acid barcodes, they can be simultaneously amplified by PCR through the universal 5’ and 3’ primer regions of the nucleic acid sequences. For example:
WO 2013/137737 A1 teaches compositions comprising library binding regions connected or covalently attached with a specific PCR amplifiable DNA, PNA, LNA or other artificial nucleotide molecule, wherein the said nucleic acid molecule can be flanked at both ends by a primer binding site to which primers can hybridize, serving as the starting point for amplification, and wherein the size of the unique identifier barcode is typically from 2-100 nucleotides in length, preferably 12-25 nucleotides usually being sufficient. WO 2013/137737 A1 teaches that the library can vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules. WO 2013/137737 A1 teaches that the target molecule can be a receptor, including a cell surface receptor. WO 2013/137737 A1 teaches that each binding region is attached to a specific nucleotide sequence identifier (in essence to a barcode) and that the constructs can be placed in pools. WO 2013/137737 A1 teaches that the library binding region constructs are screened for interaction with the target molecule(s), including one on a cell surface, and that the constructs may be labeled with a tag such as a fluorescent tag, a metal tag (see entire reference, especially [22], [24], [30], [31], [40], [41], [45], [59], [60], [63]).
WO 2013/137737 A1 links a binding specificity to a DNA or other nucleic acid barcode flanked by universal primer regions for parallel, high-throughput evaluation of library binding members. Brakmann teaches that a protein can be linked to its encoding DNA binding specificity on a same carrier.
Brakmann teaches that interaction of an antibody protein disposed on a carrier that recognizes an antigen advantageously comprises one or more copies of a marker DNA [comprising flanking PCR primer reactive sequences and barcode DNA, wherein the barcode DNA codes for a same particular antigen of interest), and whereby the DNA can be amplified using PCR, and the samples are analyzed in parallel.
Therefore it would have been prima facie obvious to one of ordinary skill in the art before the time the invention was made to have used identical 3’ and 5’ primer regions in order to accomplish this goal. Although the claims of 11,858,806 are silent as to the identity of the MHC class, MHC class I molecules are an obvious variant of MHC molecules (as is evidenced for example by US 2010/0168390 A1, the disclosure of which is enunciated above in this Office Action) and therefore it would have been prima facie obvious to one of ordinary skill in the art before the time the invention was made to have used MHC class I as the MHC in the claims of 11,858,806. One of ordinary skill in the art would have been motivated to do this in order to accomplish the goal of binding to a TCR that is recited in base claim 1 of 11,858,806, wherein the TCR is restricted to MHC class I.
With regard to the recitation of peptide in the instant claims, the claims of US Patent No. 11,585,806 recite “an MHC complex” and said patent discloses that the definition of MHC complexes are MHC loaded with or bound to peptides as well as empty MHCs not loaded with peptides (par spanning cols 18-19). Claim 8 of 11,858,806 that recites CD1 molecules is also included in this rejection because only one of the sets need comprise CD1 (i.e., a MHC-like molecule), while the other set may comprise a MHC molecule.
Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are directed to an invention not patentably distinct from claims 1-26 of commonly assigned of US 11,585,806, as is enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 11,585,806, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Applicant’s comments on page 7 of the amendment and response filed 12/3/24 is acknowledged, i.e., that the presently amended claims are not obvious over the stated combinations of references for the same reasons as stated above for the rejections under 35 USC 103. However, Applicant’s arguments have been fully considered but are not persuasive. As is stated above in the instant rejection, although the claims of 11,585,806 do not recite that the 5’ primer and the 3’ primer are identical (and are inherently therefore configured to allow amplification of all barcode regions simultaneously in a PCR reaction), the teaching of WO 2013/137737 A1 is when using unique nucleic acid barcodes, they can be simultaneously amplified by PCR through the universal 5’ and 3’ primer regions of the nucleic acid sequences, and thus it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used identical 5’ and 3’ primer regions as the 5’ and 3’ primer regions of the barcodes of the constructs of the claims of 11,585,806, and with a reasonable expectation of success in doing so in order to reap the advantage of simultaneous amplification.
10. Claim 45 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,585,806 (formerly Application No. 15/316,587) in view of Brakmann and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 39, 41, 42 and 46-49 above, and further in view of Bakker et al (PNAS, 2008, 105: 3825-3830, of record).
See above for the combination of claims of ‘806 in view of the cited art reference.
The said combination does not disclose wherein a UV exchange process is used to exchange out a bound peptide from the MHC class I peptide binding site in favor of binding of a different peptide of interest.
Bakker et al teach that the use of multimeric forms of pMHC (peptide/MHC) complexes has become a core immunological technique to visualize antigen specific CD8+ T cells. Bakker et al teach that the development of high-throughput assay systems in which T cell responses against a multitude of epitopes are analyzed, has been precluded by the fact that for each T cell epitope, a separate in vitro MHC refolding reaction is required. Bakker et al teach use of conditional peptide ligands that disintegrate upon exposure to long-wavelength UV light, allowing dissociation from the MHC class I complex and allowing a rescue peptide (a peptide of interest) to be loaded into the antigen binding groove of the MHC class I, and resulting in the formation of stable pMHC complexes with a distinct T cell specificity (see entire reference, especially abstract, introduction and discussion sections).
It would have been prima facie obvious to one of ordinary skill in the art before the time the invention was made to have used the UV exchange process taught by Bakker et al to exchange in a different peptide of interest in lieu of a conditional peptide ligand in the multimeric MHCs in the claims of ‘806 in view of US Patent No. 6,489,116 or WO 2013/137737 A1.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to load MHC class I molecules with different antigen-specific peptides, particularly in light of the teaching of Bakker et al of the advantage of doing so in promoting high-throughput analysis of antigen specific CD8+ T cells.
Claims 31-35, 37, 39, 41, 42 and 45-49 are directed to an invention not patentably distinct from claims 1-26 of commonly assigned of US 11,585,806, as is enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 11,585,806, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Applicant’s comments on page 7 of the amendment and response filed 12/3/25 is acknowledged. However, Applicant’s arguments have been fully considered but are not persuasive for the reasons enunciated above in the base rejection.
11. Claims 31, 33, 34, 37, 39, 41, 42 and 46-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 21-27 and 31-36 of copending Application No. 17/279,025 in view of US 2010/0168390 A1 (of record) and WO 2013/137737 A1 (of record).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Interpretation: instant base claim 31 recites that eight or more MHC molecules are coupled to the backbone and a nucleic acid molecule comprising the barcode with primer regions of part “iii” is coupled to the backbone; these limitations are being interpreted to mean that the MHC molecules and the nucleic acid molecule comprising the barcode with primer regions are directly or indirectly attached or coupled to the backbone. The specification does not disclose a limiting definition for “conjugating” as in “conjugating the nucleic acid label to the backbone” as is recited in instant dependent claim 46. The said limitation is therefore being interpreted as is known in the art as ‘to join together’ or ‘chemically join together’. See for example, evidentiary reference Biology Online (2024, 10 pages, of record). The definition of “barcode” in the instant specification is: “In the present context, a nucleic acid barcode is a unique oligo-nucleotide sequence ranging for [from] 10 to more than 50 nucleic acids. The barcode has shared amplification sequences in the 3’ and 5’ ends, and a unique sequence in the middle. This sequence can be revealed by sequencing and can serve as a specific barcode for a given molecule.” (see page 5 at lines 21-26).
Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file 17/279,025 as an unrelated application, the instant rejection has been set forth.
Claims 1, 21-27 and 31 of copending application 17/279,025 are drawn to a method for detection of one or more antigenic peptide responsive T cells in a sample comprising:
providing loadable detection molecules comprising at least one peptide-free MHC class I molecule [i.e., includes at least eight peptide-free MHC class I molecules since the range is open ended] and at least one detectable label,
providing at least one antigenic peptide,
contacting the loadable detection molecules with the at least one antigenic peptide to provide loaded detection molecules comprising at least one peptide-MHC (pMHC) class I molecule,
contacting the loaded detection molecules with the sample, and
detecting the binding of the loaded detection molecules to the one or more antigenic peptide responsive T cells,
wherein each of the at least one antigenic peptide is represented by
at least two different detectable labels (including wherein one is a fluorescent label and at least one is a nucleic acid label that comprises a 5’ first primer region, a barcode region comprising a unique molecular identifier, and a 3’ second primer region), or
at least one detectable label which is a nucleic acid label,
wherein the peptide-free MHC class I molecule comprises a heavy chain comprising an alpha 1 domain and an alpha 2 domain connected by a disulfide bridge, said heavy chain comprising an amino acid sequence selected from SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 1, wherein a mutant cysteine residue is positioned in the alpha 1 domain at amino acid residue 84 or 85 and a mutant cysteine residue is positioned in the alpha 2 domain at amino acid residue 139 (base claim 1), and including the limitations recited in the dependent claims.
Claims 32-35 of 17/279,025 are drawn to a loadable detection molecule comprising at least one peptide free MHC class I molecule and a nucleic acid label, wherein the peptide free MHC I comprises a heavy chain comprising an alpha-1 domain and an alpha-2 domain connected by a disulfide bridge, said heavy chain comprising the recite amino acid sequence.
Claim 36 of 17/279,025 is drawn to a method for determining the interaction between a TCR or antigenic peptide responsive T cell and a library of antigenic peptides comprising, providing loadable detection molecules according to claim 32, providing a library of antigenic peptides, contacting the loadable detection molecules with the library of antigenic peptides to provide a library of loaded detection molecules comprising pMHC I molecules, contacting the TCR or T cells with the said library of loaded detection molecules and detecting binding.
The dependent claims of 17/279,025 recite wherein the MHC class I molecule is attached to a connector molecule via non-covalent interactions between the connector molecule and an affinity tag on the MHC I molecule (claim 21), wherein the connector molecule is streptavidin (SA) and the affinity tag is biotin (claim 22), wherein the loadable detection molecule comprises at least two MHC I (claim 23), or four MHC I attached to SA via non-covalent interactions between SA and a biotin tag on each MHC I (claim 24), wherein at least one detectable label is attached to the connector molecule (claim 25), wherein at least two different antigenic peptides are provided in step ii (claim 26), wherein the at least one antigenic peptide is represented by at least two different detectable labels (claim 27), wherein the at least one detectable label in claim 1 is a nucleic acid label comprising a 5” first primer region, a barcode region, and a 3’ second primer region and a unique molecular identifier region of random nucleotide bases, wherein the barcode region is a unique barcode serving as an identification tag for the detection molecule (claim 31), and loadable detection molecules thereof (comprising no peptide) (claims 32-35), and a method for determining the interaction between a TCR or antigenic peptide responsive T cell and a library of antigenic peptides comprising loading the said loadable detection molecules by contacting with a library of antigenic peptides, contacting the TCR or T cell and detecting binding (claim 36).
The claims of 17/279,075 do not recite that the detection molecules are present on a backbone, nor the components disposed thereon as is recited in the instant claims, numbers of subsets, backbone types, streptavidin-biotin linkers, numbers of identical MHC/peptide complexes. The claims of 17/279,025 do not recite the length of the nucleic acid molecules, nor the sizes of the MHC I peptides or the number of different subsets of multimeric MHCs.
US 2010/0168390 A1 (of record) does provide these limitations of backbone types, numbers of identical pMHC complexes thereon, as well as attachment of the label (i.e., the nucleic acid molecule) to the carrier or backbone. The disclosure of US 2010/0168390 A1 has been enunciated above, so will not be repeated herein.
US 2010/016390 A1 also provides disclosure of at least two identical binding molecules (and explicitly at least 8) that are one of a pair of ligand for a cell surface molecule, many of the same backbone types, and using avidin/streptavidin to couple MHC or nucleic acid label (such as different DNA labels) to the dextran or other backbone, wherein the different labels allow for identification of more than one TCR for multimers that present different peptides.
WO 2013/137737 A1 teaches a nucleic acid tag comprising the a unique barcode flanked by universal 3’ and 5’ regions to allow simultaneous identification of a number of subsets (or pools) of molecules, allowing identification of different associated binding regions, each binding region dispositive of a particular binding region. WO 2013/137737 A1 teaches the size of nucleic acid barcode nucleotides comprised by the 5’ and 3’ primers, additional tags, and the size of the different subsets of binding molecules that can be detected with such barcodes:
WO 2013/137737 A1 teaches compositions comprising library binding regions connected or covalently attached with a specific PCR amplifiable DNA, PNA, LNA or other artificial nucleotide molecule, wherein the said nucleic acid molecule can be flanked at both ends by a primer binding site to which primers can hybridize, serving as the starting point for amplification, and wherein the size of the unique identifier barcode is typically from 2-100 nucleotides in length, preferably 12-25 nucleotides usually being sufficient. WO 2013/137737 A1 teaches that the library can vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules. WO 2013/137737 A1 teaches that the target molecule can be a receptor, including a cell surface receptor. WO 2013/137737 A1 teaches that each binding region is attached to a specific nucleotide sequence identifier (in essence to a barcode) and that the constructs can be placed in pools. WO 2013/137737 A1 teaches that the library binding region constructs are screened for interaction with the target molecule(s), including one on a cell surface, and that the constructs may be labeled with a tag such as a fluorescent tag, a metal tag (see entire reference, especially [22], [24], [30], [31], [40], [41], [45], [59], [60], [63]).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have incorporated the disclosure and teachings of the art references cited herein as to the disposition of the MHC molecules on a backbone and configured as disclosed/taught therein, with the length of the unique identifier barcode that is taught by WO 2013/137737 A1, and placed in pools comprising the disclosed number of different subsets, to the detection molecules in the method claims of 17/279,025, or in the composition of the product claims of 17/279,025. Wherein in some claims of 17/279,025 the detection molecules in the method are not loaded with peptide, it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have loaded an antigenic peptide into the detection molecules as the same peptide in a particular subset (or pool) of detection molecules, including using the method of claim 36 of 17/279,025 to do so.
One of ordinary skill in the art would have been motivated to do this because the claims of 17/279,025 are silent as to these limitations, while the disclosure and teachings of the art references cited herein do provide these said limitations and that it is useful to incorporate these features in a pMHC-dextran or polysaccharide backbone, including with streptavidin-biotin and unique nucleic acid barcodes and other labels and tags for ultra-sensitive and simultaneous detection of peptide/MHC molecules and the T cells to which they bind.
Claims 31, 33, 34, 37, 39, 41, 42 and 46-48 are directed to an invention not patentably distinct from claims 1, 21-27 and 31-36 of commonly assigned of 17/279,025, as is enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 17/279,025, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Applicant’s comments on page 7 of the amendment and response filed 12/3/25 is acknowledged. However, Applicant’s arguments have been fully considered but are not persuasive, as the claims of 17/279,025 recite at least two detectable labels or at least one detectable label which is a nucleic acid label, and wherein one may be a fluorescent label, and wherein the nucleic acid label comprises a 5’ primer region, a barcode region that serves as a unique barcode for the loaded detection molecule, and a 3’ primer region.
12. Claims 45 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 21-27 and 31-36 of copending Application No. 17/279,025 in view of US 2010/0168390 A1 (of record) and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 39, 41, 42 and 46-48 above, and further in view of Bakker et al (PNAS, 2008, 105: 3825-3830, of record) and US20130336531 A1 (of record).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The combination of the claims of 17/279,025 in view of WO 2013/137737 A1 and WO 2013/137737 A1 has been enunciated above. In addition, it bears repeating that:
US 2010/0168390 A1 discloses that the MHC molecule can be a recombinant molecule wherein the MHC class I heavy chain comprises a C-terminal target peptide sequence for biotinylation, and the chemically biotinylated MHC can then bind to streptavidin coupled to the carrier molecule such as dextran. As is also stated above, US 2010/0168390 discloses that the labeling molecule many be any labeling molecule such as a nucleic acid molecule, including DNA, or nucleic acid analogs, and it may be attached to the MHC multimer directly or indirectly, covalently or noncovalently; it can be attached to the MHC multimer, to the mulltimerization domain, or to the dextran backbone. US 2010/0168390 A1 discloses that the labelling compound can be attached via a suitable linker and that such linkers are readily known by the person skilled in the art.
The combination of the claims of 17/279,025 in view of WO 2013/137737 A1 and WO 2013/137737 A1 do not recite/disclose/teach wherein a UV exchange process is used to exchange out a bound peptide from the MHC class I peptide binding site in favor of binding of a different peptide of interest. The said combination also does not disclose/teach that the step ii of claim 45 comprises coupling of the nucleic acid label to the backbone through a streptavidin-biotin binding.
Bakker et al teach that the use of multimeric forms of pMHC (peptide/MHC) complexes has become a core immunological technique to visualize antigen specific CD8+ T cells. Bakker et al teach that the development of high-throughput assay systems in which T cell responses against a multitude of epitopes are analyzed, has been precluded by the fact that for each T cell epitope, a separate in vitro MHC refolding reaction is required. Bakker et al teach use of conditional peptide ligands that disintegrate upon exposure to long-wavelength UV light, allowing dissociation from the MHC class I complex and allowing a rescue peptide (a peptide of interest) to be loaded into the antigen binding groove of the MHC class I, and resulting in the formation of stable pMHC complexes with a distinct T cell specificity (see entire reference, especially abstract, introduction and discussion sections).
It would have been prima facie obvious to one of ordinary skill in the art before the time the invention was made to have used the UV exchange process taught by Bakker et al to exchange in a different peptide of interest in lieu of a conditional peptide ligand in the multimeric MHCs in the claims of ’025 in view of WO 2013/137737 A1 and WO 2013/137737 A1.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to load MHC class I molecules with different antigen-specific peptides, particularly in light of the teaching of Bakker et al of the advantage of doing so in promoting high-throughput analysis of antigen specific CD8+ T cells.
US20130336531 A1 discloses that a solid surface that is coated with streptavidin can be coupled to a biotinylated nucleic acid (see [0690]).
It would have been prima facie obvious before the filing date of the claimed invention to have biotinylated the nucleic acid barcode labels in the multimeric MHCs in the claims of ’025 in view of US 2010/016390 A1 and WO 2013/137737 A1 and to have attached them to the dextran backbone coupled to streptavidin via streptavidin-biotin binding.
One of ordinary skill in the art would have been motivated to do this in order to attach the dextran-streptavidin carrier to biotinylated-nucleic acid barcodes because of the aforementioned disclosure of US 2010/0168390 A1 (restated below) and because US20130336531 A1 discloses an art known method to attach biotinylated nucleic acid molecules to a streptavidin coupled surface:
Claims 31, 33, 34, 37, 39, 41, 42 and 45-49 are directed to an invention not patentably distinct from claims 1, 21-27 and 31-36 of commonly assigned of 17/279,025, as is enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 17/279,025, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Applicant’s comments on page 7 of the amendment and response filed 12/3/25 is acknowledged. However, Applicant’s arguments have been fully considered but are not persuasive, as the claims of 17/279,025 recite at least two detectable labels or at least one detectable label which is a nucleic acid label, and wherein one may be a fluorescent label, and wherein the nucleic acid label comprises a 5’ primer region, a barcode region that serves as a unique barcode for the loaded detection molecule, and a 3’ primer region.
13. Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,402,373 (of record, formerly Application No. 17/668,980) in view of US 2010/0168390 A1 (of record) and WO 2013/137737 A1 (of record).
Claim Interpretation: instant base claim 31 recites that eight or more MHC molecules are coupled to the backbone and a nucleic acid molecule comprising the barcode with primer regions of part “iii” is coupled to the backbone; these limitations are being interpreted to mean that the MHC molecules and the nucleic acid molecule comprising the barcode with primer regions are directly or indirectly attached or coupled to the backbone. The specification does not disclose a limiting definition for “conjugating” as in “conjugating the nucleic acid label to the backbone” as is recited in instant dependent claim 46. The said limitation is therefore being interpreted as is known in the art as ‘to join together’ or ‘chemically join together’. See for example, evidentiary reference Biology Online (2024, 10 pages, of record). The definition of “barcode” in the instant specification is: “In the present context, a nucleic acid barcode is a unique oligo-nucleotide sequence ranging for [from] 10 to more than 50 nucleic acids. The barcode has shared amplification sequences in the 3’ and 5’ ends, and a unique sequence in the middle. This sequence can be revealed by sequencing and can serve as a specific barcode for a given molecule.” (see page 5 at lines 21-26).
Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file application serial no. 17/668,980 that issued as US 11,402,373 as an unrelated application, the instant rejection has been set forth.
The claims of U.S. Patent No. 11,402,373 are drawn to a cell detection method, including a T cell detection method, comprising the steps of combining a sample comprising cells with a composition comprising two or more different sets of detection molecules, wherein each detection molecule comprises:
i) at least two pMHC complexes (encompasses at least eight pMHC complexes as the upper end of the range is open),
ii) at least one nucleic acid label, including DNA, comprising a 5’ primer region, a random barcode region comprising 7 to 20 nucleotides that are unique to and specific for the binding molecules of a set and unique for each detection molecule, and a 3’ second primer region, wherein the primer regions are identical for all detection molecules in the composition,
iii) a multimerization domain associated with the at least two binding molecules and the at least one nucleic acid label, optionally via one or more connector molecules such as a peptide, a protein, streptactin, a polysaccharide, a dextran, an avidin and a streptavidin, and wherein the detection molecule further comprises a fluorescent label that is used for FACs (wherein biotin is the binding partner of streptavidin and avidin).
The claims of 11,402,373 do not recite that the pMHC is a pMHC class I molecule, nor do they recite the numbers of pools of a same pMHC I, nor that the dextran multimerization domain for instance is connected to the pMHC via avidin or streptavidin/biotin.
Although the claims of 11,402,373 do not recite that the pMHC is a pMHC class I molecule, human MHC class I molecules are an obvious variant of MHC molecules and therefore it would have been prima facie obvious to one of ordinary skill in the art before the time the invention was made to have used MHC class I as the MHC in the claims of 11,402,373. Alternatively, US 2010/0168390 A1 (of record, see below) discloses a pMHC class I multimer with a unique DNA or other nucleic acid label attached to the dextran or other multimerization domain, as well as numbers of pMHC I comprised thereon, numbers of pools of same pMHC I (e.g., two or more, at least 8), attachment of the p/MHC via streptavidin-biotin binding to the dextran backbone multimerization domain, while WO 2013/137737 A1 teaches binding molecules comprising a binding region, a unique DNA identifier for each specific binding region and comprised within universal 3’ and 5’ primer regions as well as numbers of pools of different unique binding regions (i.e., 10 to 1, 000,000):
US 2010/0168390 A1 discloses peptide/MHC class I molecules or tetramers or other multimers thereof bound to fluorophore-labeled dextran carrier molecules (or other polysaccharides such as derivatized dextrans, scleroglucan, streptavidin, streptavidin tetramers, or avidin); and when the complexes are bound to streptavidin, attachment is via biotin/streptavidin attachment chemistries. The streptavidin can also be attached to a derivatized dextran or other polysaccharide. US 2010/0168390 A1 discloses that the dextran backbone can further comprise a His tag, metal-ion tag, or other selectable tags and labels such as detectable labels. US 2010/0168390 A1 discloses that the labeling molecule many be any labeling molecule such as a nucleic acid molecule, including DNA, or nucleic acid analogs, and it may be attached to the MHC multimer directly or indirectly, covalently or noncovalently; it can be attached to the MHC multimer, to the mulltimerization domain, or to the dextran backbone. US 2010/0168390 A1 discloses that the number of MHC molecules can be at least two, at least 4, or at least 8, up to a plurality depending on the capacity and nature of the multimerization domain(s), and the MHC can harbor the same or a different peptide; in the latter case, the composition can be used to detect several types of MHC recognizing T cells simultaneously. US 2010/0168390 A1 discloses that one of ordinary skill in the art can determine the number of binding entities (pMHC multimers) that can be attached to the multimerization domains. US 2010/0168390 A1 discloses that the MHC multimers may be comprised of single chain MHC/peptide complexes, that the peptides that bind to MHC class | molecules are typically 8-11 amino acid residues in length. US 2010/0168390 A1 discloses that different MHC multimers can be differently labeled enabling visualization of different target MHC-recognizing T cells; if several different MHC multimers with different labels are present, it is possible simultaneously to identify more than one specific T cell receptor, if each of the MHC multimers present a different peptide. US 2010/0168390 A1 discloses using groups of MHC multimers that are labeled with different labels together in the same preparation US 2010/0168390 A1 discloses that MHC multimers, including those comprising single chain MHC/peptide monomers, provide increased affinity and half-life on interaction as compared with that to the monomer MHC/peptide complex, and are attached to one or more multimerization domains, which bind which high avidity to appropriate T cell receptors (TCRs). US 2010/0168390 A1 discloses that the increased valences of the compounds of the invention produce surprisingly higher avidity in comparison to oligo-valent complexes such as tetramers known from the prior art, allowing for quantitative analysis of even small cell populations, with the increased binding avidity of the MHC multimers of the invention allowing detection of MHC-recognizing T cells expressing low affinity T cell receptors. US 2010/0168390 A1 discloses that this augmented interaction also allows detection of very small MHC recognizing cell populations in blood samples without the need for in vitro expansion, and the MHC multimers of the invention are therefore useful for direct monitoring of all types of MCH recognizing cells in blood samples. US 2010/0168390 A1 discloses that these carriers are useful for binding and identifying cognate T cells comprising cognate T cell receptors on their surfaces, including for identifying low affinity binding T cells. US 2010/0168390 A1 discloses that the MHC multimers can be labelled, for example, with one or more fluorophores and used in flow cytometry to label T cells carrying specific TCRs that bind the MHC multimers, including individual T cells or populations of T cells. US 2010/0168390 Ai discloses that the flow cytometer can also separate and collect particular types of cells, /.e., by “cell sorting’, and the MHC multimers in combination with sorting on a flow cytometer can be used to isolate antigen specific T cell populations (see entire reference, especially abstract, [0042]-[0047], [0054], [0062],[0066]-[0086], [0095], [0145], [0195], [0196],[0200], [0211], [(0213],[0214], [0220], [0236], [0242], [0252], [0308]-[0323],[0326], [0358],[0401 ]-[0405], [0411], [0415]-[0417], [0487], [0488], [0659], [0770], [0771]).
WO 2013/137737 A1 teaches compositions comprising library binding regions connected or covalently attached with a specific PCR amplifiable DNA, PNA, LNA or other artificial nucleotide molecule, wherein the said nucleic acid molecule can be flanked at both ends by a universal primer binding site to which primers can hybridize, serving as the starting point for amplification, and wherein the size of the unique identifier barcode is typically from 2-100 nucleotides in length, preferably 12-25 nucleotides usually being sufficient. WO 2013/137737 A1 teaches that the library can vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules. WO 2013/137737 A1 teaches that the target molecule can be a receptor, including a cell surface receptor. WO 2013/137737 A1 teaches that each binding region is attached to a specific nucleotide sequence identifier and that the constructs can be placed in pools, wherein each nucleotide sequence identifier is a pool-specific sequence identifier termed a DNA barcode. WO 2013/137737 A1 teaches that the library binding region constructs are screened for interaction with the target molecule(s), including one on a cell surface, and that the constructs may be labeled with a tag such as a fluorescent tag or a metal tag (see entire reference, especially Figure 1, abstract, [22], [24], [30],[31], [40], [41], [45], [59], [60], [63]).
In addition, both Brakmann, S. (Angew. Chem. Int. Ed. 2004, 43: 5730-5734), that is of record above in this office action also teaches a carrier with a unique DNA barcode attached thereto and associating this barcode sequence with a protein specificity.
It would have been prima facie obvious to have used the human MHC class I molecule disclosed by US 2010/0168390 A1 as the MHC molecule in the pMHC molecule construct in the claims of ‘373, as well as the numbers of different pools taught by WO 2013/137737 A1.
One of ordinary skill in the art would have been motivated to do this since the claims of ‘373 are silent as to the particular species of these limitations, while US 2010/0168390 A1 discloses a similar cell detection molecule to be used in a T cell detection method that comprises a MHC class I molecule and the WO 2013/137737 A1 document teaches the number of different pools of binding molecules with the attached unique DNA identifiers that can be assessed.
Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are directed to an invention not patentably distinct from claims 1-17 of commonly assigned of 11,402,373, as is enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 11,402,373, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Applicant’s comments on page 7 of the amendment and response filed 12/3/25 is acknowledged. However, Applicant’s arguments have been fully considered but are not persuasive, as the claims of 17/279,025 recite one detectable label which is a nucleic acid label, and additionally a fluorescent label, and wherein the nucleic acid label may be a DNA molecule comprising a 5’ primer region, a random barcode region comprising 7 to 20 nucleotides that are unique to and specific for the binding molecules of a set and unique for each detection molecule, and a 3’ second primer region, wherein the primer regions are identical for all detection molecules in the composition.
14. Claim 45 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,402,373 (formerly Application No. 17/668,980, of record) in view of US 2010/0168390 A1 (of record) and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 39, 41, 42 and 46-49 above, and further in view of Bakker et al (PNAS, 2008, 105: 3825-3830, of record).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The combination of the claims of ‘373 in view of US 2010/0168390 A1 and WO 2013/137737 A1 has been enunciated above.
The said combination does not recite/disclose/teach wherein a UV exchange process is used to exchange out a bound peptide from the MHC class I peptide binding site in favor of binding of a different peptide of interest.
Bakker et al teach that the use of multimeric forms of pMHC (peptide/MHC) complexes has become a core immunological technique to visualize antigen specific CD8+ T cells. Bakker et al teach that the development of high-throughput assay systems in which T cell responses against a multitude of epitopes are analyzed, has been precluded by the fact that for each T cell epitope, a separate in vitro MHC refolding reaction is required. Bakker et al teach use of conditional peptide ligands that disintegrate upon exposure to long-wavelength UV light, allowing dissociation from the MHC class I complex and allowing a rescue peptide (a peptide of interest) to be loaded into the antigen binding groove of the MHC class I, and resulting in the formation of stable pMHC complexes with a distinct T cell specificity (see entire reference, especially abstract, introduction and discussion sections).
It would have been prima facie obvious to one of ordinary skill in the art before the time the invention was made to have used the UV exchange process taught by Bakker et al to exchange in a different peptide of interest in lieu of a conditional peptide ligand in the multimeric MHCs in the claims of ’373 in view of US 2010/0168390 A1 and WO 2013/137737 A1.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to load MHC class I molecules with different antigen-specific peptides, particularly in light of the teaching of Bakker et al of the advantage of doing so in promoting high-throughput analysis of antigen specific CD8+ T cells.
Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are directed to an invention not patentably distinct from claims 1-17 of commonly assigned of 11,402,373, as is enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 11,402,373, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Applicant’s comments on page 7 of the amendment and response filed 4/15/24 is acknowledged, i.e., that the double patenting rejection be held in abeyance until such time as the claims are otherwise allowed.
Applicant’s comments on page 7 of the amendment and response filed 12/3/25 is acknowledged. However, Applicant’s arguments have been fully considered but are not persuasive, as the claims of 17/279,025 recite one detectable label which is a nucleic acid label, and additionally a fluorescent label, and wherein the nucleic acid label may be a DNA molecule comprising a 5’ primer region, a random barcode region comprising 7 to 20 nucleotides that are unique to and specific for the binding molecules of a set and unique for each detection molecule, and a 3’ second primer region, wherein the primer regions are identical for all detection molecules in the composition.
15. Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18/304,028 in view of WO 2013/137737 A1 (of record) and Bakker et al (PNAS, 2008, 105: 3825-3830, of record).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Interpretation: instant base claim 31 recites that eight or more MHC molecules are coupled to the backbone and a nucleic acid molecule comprising the barcode with primer regions of part “iii” is coupled to the backbone; these limitations are being interpreted to mean that the MHC molecules and the nucleic acid molecule comprising the barcode with primer regions are directly or indirectly attached or coupled to the backbone. The specification does not disclose a limiting definition for “conjugating” as in “conjugating the nucleic acid label to the backbone” as is recited in instant dependent claim 46. The said limitation is therefore being interpreted as is known in the art as ‘to join together’ or ‘chemically join together’. See for example, evidentiary reference Biology Online (2024, 10 pages, of record). The definition of “barcode” in the instant specification is: “In the present context, a nucleic acid barcode is a unique oligo-nucleotide sequence ranging for [from] 10 to more than 50 nucleic acids. The barcode has shared amplification sequences in the 3’ and 5’ ends, and a unique sequence in the middle. This sequence can be revealed by sequencing and can serve as a specific barcode for a given molecule.” (see page 5 at lines 21-26).
The claims of 18/304,028 are drawn to a detection molecule comprising:
a) at least two identical bindings molecules (includes values in excess of 2), including a pMHC class I complex having binding specificity for a TCR,
b) a multimerization domain associated, optionally via one or more connector molecules, with the at least two binding molecules, wherein the multimerization domain is selected from the group consisting of a peptide, a protein, a streptactin, a polysaccharide, a dextran, an avidin and a streptavidin, and
c) at least one nucleic acid label associated with said multimerization domain, optionally via one or more connector molecules, wherein said nucleic acid label (DNA, RNA or an artificial nucleic acid label) is 30-200 nucleotides in length and comprises a 5’ first primer region a random nucleotide region of between 7 to 15 or 20 or 3 or 5 to 30 nucleotides, the said random nucleotide region being a barcode region that serves as an identification tag for the binding specificity of said at least two binding molecules, and wherein said random nucleotide region uniquely represents the nucleic acid label in which it is found. The at least one nucleic acid label comprises biotin (which is the binding partner for streptavidin or avidin); and
d) a second label selected from the group consisting of fluorophores, chromophores, and peptides, wherein the second label is couple with the multimerization domain or with at least one of said at least two identical binding molecules.
The claims of 18/304,028 do not recite wherein there are a plurality of the detection molecules in a composition, including 10 to 10,000 different subsets of the detection molecules (i.e., the multimeric pMHCs). The claims of 18/304,028 do not recite wherein MHC class I/peptide complexes are exchanged via UV exchange for a peptide of interest.
However, WO 2013/137737 A1 teaches a molecule comprising a binding region attached to a unique DNA barcode of a similar size comprised within 3’ and 5’ universal primer regions, wherein the DNA barcode represents a unique binding region, the universal primers can be simultaneously detected, and further teaches 10 to 1,000,000 different subsets (pools) of binding molecules may be comprised together and detected:
WO 2013/137737 A1 teaches compositions comprising library binding regions connected or covalently attached with a specific PCR amplifiable DNA, PNA, LNA or other artificial nucleotide molecule, wherein the said nucleic acid molecule can be flanked at both ends by a universal primer binding site to which primers can hybridize, serving as the starting point for amplification, and wherein the size of the unique identifier barcode is typically from 2-100 nucleotides in length, preferably 12-25 nucleotides usually being sufficient. WO 2013/137737 A1 teaches that the library can vary in size, with a lower limit of 10 molecules up to 1,000,000 molecules. WO 2013/137737 A1 teaches that the target molecule can be a receptor, including a cell surface receptor. WO 2013/137737 A1 teaches that each binding region is attached to a specific nucleotide sequence identifier and that the constructs can be placed in pools, wherein each nucleotide sequence identifier is a pool-specific sequence identifier termed a DNA barcode. WO 2013/137737 A1 teaches that the library binding region constructs are screened for interaction with the target molecule(s), including one on a cell surface, and that the constructs may be labeled with a tag such as a fluorescent tag or a metal tag (see entire reference, especially Figure 1, abstract, [22], [24], [30],[31], [40], [41], [45], [59], [60], [63]).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have comprised different sets (or pools) of detection molecules recited in the claims of 18,304,028 with each set comprising a same at least two pMHC class I molecule therein, up to the number taught by WO2013.
One of ordinary skill in the art before the filing date of the claimed invention would have been motivated to do this in order to make a composition to be used for simultaneous detection of T cells cognate to the different pMHC class I complexes.
Bakker et al teach that the use of multimeric forms of pMHC (peptide/MHC) complexes has become a core immunological technique to visualize antigen specific CD8+ T cells. Bakker et al teach that the development of high-throughput assay systems in which T cell responses against a multitude of epitopes are analyzed, has been precluded by the fact that for each T cell epitope, a separate in vitro MHC refolding reaction is required. Bakker et al teach use of conditional peptide ligands that disintegrate upon exposure to long-wavelength UV light, allowing dissociation from the MHC class I complex and allowing a rescue peptide (a peptide of interest) to be loaded into the antigen binding groove of the MHC class I, and resulting in the formation of stable pMHC complexes with a distinct T cell specificity (see entire reference, especially abstract, introduction and discussion sections).
It would have been prima facie obvious to one of ordinary skill in the art before the time the invention was made to have used the UV exchange process taught by Bakker et al to exchange in a different peptide of interest in lieu of a conditional peptide ligand in the multimeric MHCs in the claims of ’028.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to load MHC class I molecules with different antigen-specific peptides, particularly in light of the teaching of Bakker et al of the advantage of doing so in promoting high-throughput analysis of antigen specific CD8+ T cells.
Claims 31, 33, 34, 37, 39, 41, 42 and 46-49 are directed to an invention not patentably distinct from claims 1-17 of commonly assigned of 18/304,028, as is enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 18/304,028, discussed above, would be prior art to the noted claims under 35 U.S.C. 102(a)(2) if the patentably indistinct inventions were not commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned as of the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Applicant’s comments on page 7 of the amendment and response filed 12/3/25 are acknowledged, have been fully considered, but are not persuasive. The claims of 18/304,028 recite the nucleic acid barcodes having first and second 5’/3’ primer regions, wherein the barcode region serves as an identification tag for the binding specificity of the at least two binding molecules. The claims of 18/304,028 also recite a second label that is a fluorophore (i.e., a fluorescent label).
16. No claim is allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
Prosecution Insights