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. Applicant’s response filed 5/18/26 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, 41, 42 and 45-50 are presently being examined. Claim 31 is an independent claim.
3. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
4. This is a new ground of rejection necessitated by Applicant’s amendment filed 5/48/26. Applicant has amended instant base claim 31 to delete recitation of any backbone except for a dextran backbone.
Claim 41 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In the instant case, claim 41 recites “The composition according to claim 31, wherein said backbone is a dextran backbone”, while instant base claim 31 exclusively recites as a backbone “a dextran backbone” at line 3. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
5. 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.
6. For the purpose of prior art rejections, the filing date of the instant claims is deemed to be the filing date of PCT/DK2015/050150, i.e., 6/8/15, as Denmark PA 201470340 does not support the claimed limitations of the instant application. The said PA 201470340 does not provide support for the newly added limitation “wherein each of the multimeric MHCs of at least one subset comprises MHC molecule HLA-A*0201 bound to peptide ALIAPVHAV” because it does not disclose the said peptide. In addition, the said PA 201470340 does not provide support for the full complement of nucleic acid molecules recited in newly added claim 50 (and of the two nucleic acid sequences that are disclosed in the said foreign document lack the terminal modifications recited in instant claim 50).
7. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claims 31, 33, 34, 37, 41, 42 and 45-50 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO2015/188839 A2 (priority to at least 8/16/2014, IDS reference).
The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31, has canceled claim 39, and has added new dependent claim 50. As is enunciated above in this office action, the priority date for the purpose of prior art rejections considering the present amendment of instant base claim 31 is now 6/8/2015.
Independent claim 31 recites:
A composition comprising a plurality of multimeric MHCs, each multimeric MHC comprising:
i) a dextran backbone,
ii) eight or more MHC molecules that are human MHC class I molecules coupled to the backbone, wherein each MHC molecule is bound to a T cell binding peptide to form a human MHC class I/T cell binding peptide complex,
iii)a nucleic acid molecule coupled to the backbone, the nucleic acid molecule comprising a 5’ primer region, a barcode, and a 3’ primer region, wherein the barcode comprises at least 10 nucleotides, and wherein the 5’ primer region is identical for all nucleic acid molecules in the composition and the 3’ primer region is identical for all nucleic acid molecules in the composition, allowing amplification of all barcodes in the composition simultaneously in a PCR reaction using one primer set;
wherein the plurality of multimeric MHCs comprises 2 to 10,000 different subsets of multimeric MHCs;
wherein the backbone further comprises one or more fluorescent labels; wherein the multimeric MHCs of each subset comprise (1) an identical backbone, (2) identical two or more MHC molecules coupled to the backbone, and (3) an identical barcode whose sequence can be revealed by sequencing and uniquely represents the subset within the composition;
wherein the multimeric MHCs are produced by a method comprising the steps of (i) providing the eight or more human class I MHC/T cell binding peptide complexes and (ii) coupling the eight or more human class I MHC/T cell binding peptide complexes to the backbone; and
wherein each of the multimeric MHCs of at least one subset comprises MHC molecule HLA-A*0201 bound to peptide ALIAPVHAV (SEQ ID NO: 17).
WO2015/18839 A2 teaches a composition comprising a library of barcode labeled pMHC multimer comprised of 1,000 to 100,000 different p/MHC multimers (i.e., subsets) each having a specific nucleic acid barcode as a unique label for each pMHC specificity (e.g., Figures 3 and 4 and legends thereof, page 112 at lines 1-4, page 318 at lines 9-12). The pMHC multimers also have optional fluorescent labels to track the total pool of pMHC multimer binding cells irrespective of the pMHC multimer specificity. The nucleic acid barcodes have shared 5’ and 3’ amplification ends, enabling amplification of all nucleic acid barcodes simultaneously in a PCR reaction. These barcodes are attached to the MHC multimerization backbone, for example via a biotin linker binding to streptavidin or avidin on the multimer backbone. The MHC may be MHC class I (page 23 at lines 24-25). The carrier may be a dextran (e.g., 41 page at lines 19-24, paragraph spanning pages 53-54, page 55 at line 12, page 57 at lines 11-14, page 60 at lines 1-6, page 67 at lines 2-3). A pMHC multimer may be a dextramer with the peptide being a nonsense peptide; that is, a peptide that binds the MHC protein but expectably does not mediate efficient pMHC complex/TCR interaction with any T cell and used as a negative control for specific binding (page 55 at lines 15-20); a specific negative control dextramer is HLA-A*0201/ALIAPVHAV (page 146 at lines 14-23, page 147 at lines 4-6). The pMHCs may be coupled to the dextran backbone through a streptavidin-biotin binding or a streptavidin-avidin binding, or via the MHC heavy and/or light chain (b2m) (page 57 at lines 16-18, page 317 at lines 1-5). The multimers may comprise two or more pMHC complexes (page 60 at lines 33-35), or can comprise up to 1,000 pMHC complexes (page 4 at lines 15-16). The DNA barcodes may be those found at page 145 at lines 1-12 (that are identical to instantly recited SEQ ID NO: 5-10 recited in instant dependent claim 50). The nucleic acid barcode may comprise or consist of DNA, RNA, or artificial amino acids (e.g., page 46 at lines 17-35, page 47 at lines 1-12). The pMHC monomers are made by refolding, biotinylation and purification (e.g., Example 1). WO2015/18839 A2 teaches producing the specific pMHC by UV-exchange (Example 1). See entire reference, including claims.
Instant dependent claim 46 is included in this rejection because the instant specification does not disclose a limiting or otherwise definition for the limitation “conjugating”, while the specification throughout does discuss conjugating in the sense of through biotin-avidin or biotin-streptavidin binding.
9. 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.
10. Claims 31, 33, 34, 37, 41, 42 and 45-49 are rejected under 35 U.S.C. 103 as being obvious over US 20100168390 A1 (of record) or US 10,030,065, either in view of Andersen et al (Nature Protocols, 2012, 7: 891-902, of record), US 2021/0239698 A1 (priority to 2011, of record), Brakmann, S. (Angew. Chem. Int. Ed. 2004, 43: 5730-5734, of record), and WO 2013/137737 A1 (of record).
Independent claim 31 recites:
A composition comprising a plurality of multimeric MHCs, each multimeric MHC comprising:
i) a dextran backbone,
ii) eight or more MHC molecules that are human MHC class I molecules coupled to the backbone, wherein each MHC molecule is bound to a T cell binding peptide to form a human MHC class I/T cell binding peptide complex,
iii)a nucleic acid molecule coupled to the backbone, the nucleic acid molecule comprising a 5’ primer region, a barcode, and a 3’ primer region, wherein the barcode comprises at least 10 nucleotides, and wherein the 5’ primer region is identical for all nucleic acid molecules in the composition and the 3’ primer region is identical for all nucleic acid molecules in the composition, allowing amplification of all barcodes in the composition simultaneously in a PCR reaction using one primer set;
wherein the plurality of multimeric MHCs comprises 2 to 10,000 different subsets of multimeric MHCs;
wherein the backbone further comprises one or more fluorescent labels; wherein the multimeric MHCs of each subset comprise (1) an identical backbone, (2) identical two or more MHC molecules coupled to the backbone, and (3) an identical barcode whose sequence can be revealed by sequencing and uniquely represents the subset within the composition;
wherein the multimeric MHCs are produced by a method comprising the steps of (i) providing the eight or more human class I MHC/T cell binding peptide complexes and (ii) coupling the eight or more human class I MHC/T cell binding peptide complexes to the backbone; and
wherein each of the multimeric MHCs of at least one subset comprises MHC molecule HLA-A*0201 bound to peptide ALIAPVHAV (SEQ ID NO: 17).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended base claim 31 to recite a specific multimeric MHC/peptide of one subset and has also amended the said base claim to delete the recitation of any carrier that is not dextran. Applicant has also canceled claim 39.
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 experiments with MHC multimers require a negative control in order to determine background staining with MHC multimer (e.g., [0627]), a negative control including a nonsense peptide that binds to the MHC protein efficiently, but does not support binding of the resultant MHC/peptide complex to the desired TCR (e.g., [0628]), with the nonsense peptide having relevant anchor residues for binding to the MHC but having other residues chosen so that potential interactions with TCRs are minimized (e.g., [0628]). US 2010/0168390 A1 discloses that discloses that the negative control MHC multimer(s) can comprise a nonsense peptide(s) that interact efficiently with the MHC protein but do not support specific binding of the MHC multimer to the TCR in question, and this nonsense peptide containing MHC multimer is labeled differently from the label of the MHC multimer used for analysis (i.e., a specific peptide/MHC multimer for to which a TCR binds) (e.g., [0619]). US 2010/0168390 A1 discloses two different HLA-A*0201 MHC multimers, each comprising a specific nonsense peptide, i.e., GLAGDVSAV or ALIAPVHAV (“construct 1” and “construct 2”, the latter of which is recited in instant base claim 31) (e.g., [1067], [1073], [1328], [1331]).
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 10,030,065 contains the same disclosure as US 2010/0168390 A1. US 10,030,065 issued from application serial no. 12/644,554, while US 2010/0168390 A1 is the publication of the same application.
US 2010/0168390 A1 or US 10,030,065 does not disclose that the different DNA labels are DNA barcodes comprising at least 10 nucleotides and that are 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 although 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 primary art reference 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, the 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.
None-the-less, although Andersen et al teach a superior method for producing large panels of pMHC complexes through UV peptide exchange, Andersen et al also teach there are serious limitations using color barcodes as pertains 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, although it does not teach identical 3’ and 5’ primer regions on the peptide encoding DNA, nor a dextran 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 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. 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 included an HLA-A*0201/nonsense peptide such as ALIAPVHAV complex in the composition when analyzing HLA-A*201/peptide specific TCRs or T cells.
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). One of ordinary skill in the art would have been motivated to add the negative control(s) MHC multimers in order to provide an appropriate control for non-specific binding to TCRs as is disclosed by the primary art reference US20100168390 A1 or US 10,030,065.
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 5/18/26 on pages 6-7.
Applicant argues that none of the above-cited references, nor any combinations thereof discloses multimeric MHCs as recited in claim 31, wherein the MHC molecules of at least one subject comprise HLA-A*0201 as the MHC molecule bound to peptide ALIAPVHAV, and all of the present claims are therefore nonobvious over the combined teaches of the cited references.
However, the primary art reference does disclose the said multimeric MHC comprising HLA-A*0201/ ALIAPVHAV as a negative control multimeric MHC, and the claims are obvious over the combination of references as is enunciated in the instant rejection above.
11. Claims 31, 33, 34, 37, 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).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended base claim 31 to recite a specific multimeric MHC/peptide of one subset and has amended the said base claim to delete recitation of any carrier except for dextran. Applicant has also canceled claim 39.
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 a dextran, 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. US2021/0239698 A1 does not disclose wherein the composition comprises at least one MHC/peptide multimer subset wherein each MHC/peptide multimer comprises HLA-A*0201 bound to peptide ALIAPVHAV.
US 2010/0168390 A1 discloses similar constructs, but wherein the carrier is a dextran carrier molecule or other polysaccharides such as derivatized dextrans, 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 pMHC dextran multimers can be combined with fluorochrome labelling ([0287]).
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 experiments with MHC multimers require a negative control in order to determine background staining with MHC multimer (e.g., [0627]), a negative control including a nonsense peptide that binds to the MHC protein efficiently, but does not support binding of the resultant MHC/peptide complex to the desired TCR (e.g., [0628]), with the nonsense peptide having relevant anchor residues for binding to the MHC but having other residues chosen so that potential interactions with TCRs are minimized (e.g., [0628]). US 2010/0168390 A1 discloses that discloses that the negative control MHC multimer(s) can comprise a nonsense peptide(s) that interact efficiently with the MHC protein but do not support specific binding of the MHC multimer to the TCR in question, and this nonsense peptide containing MHC multimer is labeled differently from the label of the MHC multimer used for analysis (i.e., a specific peptide/MHC multimer for to which a TCR binds) (e.g., [0619]). US 2010/0168390 A1 discloses two different HLA-A*0201 MHC multimers, each comprising a specific nonsense peptide, i.e., GLAGDVSAV or ALIAPVHAV (“construct 1” and “construct 2”, the latter of which is recited in instant base claim 31) (e.g., [1067], [1073], [1328], [1331]).
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 dextran carrier disclosed by US 2010/0168390 A1 in place of the carrier disclosed by the primary art reference, to have used a barcode DNA comprising at least the minimum number of nucleotides to encode the peptide of interest (i.e., 8-11 amino acid residues corresponds to a minimum of 24 to 33 nucleotides), 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, 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.
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 in the composition at least one subset of multimeric MHCs that each comprise HLA-A*0201 bound to peptide ALIAPVHAV, as is disclosed by US2021/0239698 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 comprises a subset having a nonsense peptide bound to HLA-A*0201 as a negative control, as is disclosed by US2021/0239698 A1.
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 at least 8 pMHC molecules on the carrier as is disclosed by US2021/0239698 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 as US2021/0239698 A1 discloses that least 8 copies of the pMHC are attached to the carrier.
Applicant’s arguments (of record in the amendment and response filed 5/18/26 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.
13. 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 (of record), and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 41, 42 and 46-49 above, and further in view of Andersen et al (Nature Protocols, 2012, 7: 891-902, of record).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31 and has canceled claim 39.
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 5/18/26 on pages 6-7) have been fully considered but are not persuasive. Applicant’s arguments are the same as presented above. See the Examiner’s rebuttal thereto.
14. Claim 50 is rejected under 35 U.S.C. 103 as being obvious over US 20100168390 A1 (of record) or US 10,030,065, either one in view of Andersen et al (Nature Protocols, 2012, 7: 891-902, of record), US 2021/0239698 A1 (priority to 2011, of record), Brakmann, S. (Angew. Chem. Int. Ed. 2004, 43: 5730-5734, of record), and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 41, 42 and 45-49 above, and further in view of WO2015/188839 A2 (priority to at least 8/16/2014).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31, has canceled claim 39, and has added new dependent claim 50. As is enunciated above in this office action, the priority date for prior art considering present amendment of instant base claim 31 is now 6/8/2015.
The combination and teachings of US 20100168390 A1 (of record) or US 10,030,065 in view of US 2021/0239698 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 nucleic acid molecule is one of the nucleic acid sequences recited in claim 50.
WO2015/18839 A2 teaches a composition comprising a library of barcode labelled pMHC multimer comprised of 1,000 to 50,000 different p/MHC multimers each having a specific nucleic acid barcode as a unique label for each pMHC specificity (e.g., Figures 3 and 4 and legends thereof, page 112 at lines 1-4). The pMHC multimers have optional fluorescent labels to track the total pool of pMHC multimer binding cells irrespectively of the pMHC multimer specificity. The nucleic acid barcodes have shared 5’ and 3’ amplification ends, enabling amplification of all nucleic acid barcodes simultaneously in a PCR reaction. These barcodes are attached to the MHC multimerization backbone, for example via a biotin linker binding to streptavidin on the multimer backbone. The MHC may be MHC class I or class II (page 23 at lines 24-25). The carrier may be a dextran (e.g., 41 page at lines 19-24, paragraph spanning pages 53-54, page 55 at line 12, page 57 at lines 11-14, page 60 at lines 1-6, page 67 at lines 2-3). A pMHC may be a dextramer with a nonsense peptide, a peptide that binds the MHC protein but expectably does not mediate efficient pMHC complex/TCR interaction with any T cell and used as a negative control for specific binding (page 55 at lines 15-20), with a specific negative control dextramer being HLA-A*0201/ALIAPVHAV (page 146 at lines 14-23, page 147 at lines 4-6). The pMHCs may be coupled to the dextran backbone through a streptavidin-biotin binding or a streptavidin-avidin binding (page 57 at lines 16-18). The multimers may comprise two or more pMHC complexes (page 60 at lines 33-35), or can comprise up to 1,000 pMHC complexes (page 4 at lines 15-16) . The DNA barcodes may be those found at page 145 at lines 1-12 (that are identical to instantly recited SEQ ID NO: 5-10 recited in instant dependent claim 50). The nucleic acid barcode may comprise or consist of DNA, RNA, or artificial amino acids (e.g., page 46 at lines 17-35, page 47 at lines 1-12). See entire reference, including 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 the nucleic acid barcodes taught by WO2015/18839 A2 in the composition taught by 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 label specific subsets of pMHCs.
15. Claim 50 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 (of record), and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 41, 42 and 46-49 above, and further in view of in view of WO2015/188839 A2 (priority to at least 8/16/2014).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31, has canceled claim 39, and has added new dependent claim 50. As is enunciated above in this office action, the priority date for prior art considering present amendment of instant base claim 31 is now 6/8/2015.
The combination and teachings of US2021/0239698 A1 in view of US 2010/0168390 A1, Brakmann, and WO 2013/137737 A1 has been enunciated above in detail and will not be repeated herein, hereafter referred to as the “combined references”.
The combined references do not teach wherein the nucleic acid molecule is one of the nucleic acid sequences recited in claim 50.
WO2015/18839 A2 teaches a composition comprising a library of barcode labelled pMHC multimer comprised of 1,000 to 50,000 different p/MHC multimers each having a specific nucleic acid barcode as a unique label for each pMHC specificity (e.g., Figures 3 and 4 and legends thereof, page 112 at lines 1-4). The pMHC multimers have optional fluorescent labels to track the total pool of pMHC multimer binding cells irrespectively of the pMHC multimer specificity. The nucleic acid barcodes have shared 5’ and 3’ amplification ends, enabling amplification of all nucleic acid barcodes simultaneously in a PCR reaction. These barcodes are attached to the MHC multimerization backbone, for example via a biotin linker binding to streptavidin on the multimer backbone. The MHC may be MHC class I or class II (page 23 at lines 24-25). The carrier may be a dextran (e.g., 41 page at lines 19-24, paragraph spanning pages 53-54, page 55 at line 12, page 57 at lines 11-14, page 60 at lines 1-6, page 67 at lines 2-3). A pMHC may be a dextramer with a nonsense peptide, a peptide that binds the MHC protein but expectably does not mediate efficient pMHC complex/TCR interaction with any T cell and used as a negative control for specific binding (page 55 at lines 15-20), with a specific negative control dextramer being HLA-A*0201/ALIAPVHAV (page 146 at lines 14-23, page 147 at lines 4-6). The pMHCs may be coupled to the dextran backbone through a streptavidin-biotin binding or a streptavidin-avidin binding (page 57 at lines 16-18). The multimers may comprise two or more pMHC complexes (page 60 at lines 33-35), or can comprise up to 1,000 pMHC complexes (page 4 at lines 15-16) . The DNA barcodes may be those found at page 145 at lines 1-12 (that are identical to instantly recited SEQ ID NO: 5-10 recited in instant dependent claim 50). The nucleic acid barcode may comprise or consist of DNA, RNA, or artificial amino acids (e.g., page 46 at lines 17-35, page 47 at lines 1-12). See entire reference, including 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 the nucleic acid barcodes taught by WO2015/18839 A2 in the composition taught by 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 label specific subsets of pMHCs.
12. 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.
16. Claims 31, 33, 34, 37, 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 (of record), WO 2013/137737 A1 (of record) and US 2010/0168390 A1 (of record).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31 and has canceled claim 39.
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.
The disclosure of US 2010/0168390 A1 has been enunciated in detail above, and will not be repeated herein except to reiterate that the said reference teachings including a nonsense peptide such as ALIAPVHAV in an HLA-A*0201 multimer as a negative control MHC multimer.
Therefore 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 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.
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 included a subset comprising all MHC multimers having HLA-A*0201/ALIAPVHAV. 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 include a negative control MHC multimer subset as per the disclosure of US 2010/0168390 A1.
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, 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 5/18/26 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 for the reasons enunciated in the instant rejection.
17. 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 (of record) and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 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 that are present in the pMHC multimers.
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, 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 5/18/26 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 for the reasons enunciated in the instant rejection.
18. Claims 31, 33, 34, 37, 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 new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended base claim 31 to recite a specific multimeric MHC/peptide of one subset. Applicant has also canceled claim 39.
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 as defined in claim 31, 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 following 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, nor that at least one subset of multimeric MHCs each comprise HLA-A*0201/ALIAPVHAV complexes MHC multimers.
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.
US 2010/0168390 A1 further discloses that experiments with MHC multimers require a negative control in order to determine background staining with MHC multimer (e.g., [0627]), a negative control including a nonsense peptide that binds to the MHC protein efficiently, but does not support binding of the resultant MHC/peptide complex to the desired TCR (e.g., [0628]), with the nonsense peptide having relevant anchor residues for binding to the MHC but having other residues chosen so that potential interactions with TCRs are minimized (e.g., [0628]). US 2010/0168390 A1 discloses that discloses that the negative control MHC multimer(s) can comprise a nonsense peptide(s) that interact efficiently with the MHC protein but do not support specific binding of the MHC multimer to the TCR in question, and this nonsense peptide containing MHC multimer is labeled differently from the label of the MHC multimer used for analysis (i.e., a specific peptide/MHC multimer for to which a TCR binds) (e.g., [0619]). US 2010/0168390 A1 discloses two different HLA-A*0201 MHC multimers, each comprising a specific nonsense peptide, i.e., GLAGDVSAV or ALIAPVHAV (“construct 1” and “construct 2”, the latter of which is recited in instant base claim 31) (e.g., [1067], [1073], [1328], [1331]).
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.
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 included a subset comprising all MHC multimers having HLA-A*0201/ALIAPVHAV. 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 include a negative control MHC multimer subset as per the disclosure of US 2010/0168390 A1.
Claims 31, 33, 34, 37, 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 5/18/26 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 for the reasons enunciated in the instant rejection.
19. 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, 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 new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31 and has canceled claim 39.
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, 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 5/18/26 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 for the reasons enunciated in the instant rejection.
20. Claims 31, 33, 34, 37, 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).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31 and has canceled claim 39.
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, nor that the composition comprises at least one subset of multimeric MHCs wherein each one of the said multimeric MHCs comprises HLA-A*0201 bound to peptide ALIAPVHAV.
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]).
In addition, US 2010/0168390 A1 further discloses that experiments with MHC multimers require a negative control in order to determine background staining with MHC multimer (e.g., [0627]), a negative control including a nonsense peptide that binds to the MHC protein efficiently, but does not support binding of the resultant MHC/peptide complex to the desired TCR (e.g., [0628]), with the nonsense peptide having relevant anchor residues for binding to the MHC but having other residues chosen so that potential interactions with TCRs are minimized (e.g., [0628]). US 2010/0168390 A1 discloses that discloses that the negative control MHC multimer(s) can comprise a nonsense peptide(s) that interact efficiently with the MHC protein but do not support specific binding of the MHC multimer to the TCR in question, and this nonsense peptide containing MHC multimer is labeled differently from the label of the MHC multimer used for analysis (i.e., a specific peptide/MHC multimer for to which a TCR binds) (e.g., [0619]). US 2010/0168390 A1 discloses two different HLA-A*0201 MHC multimers, each comprising a specific nonsense peptide, i.e., GLAGDVSAV or ALIAPVHAV (“construct 1” and “construct 2”, the latter of which is recited in instant base claim 31) (e.g., [1067], [1073], [1328], [1331]).
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.
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 included a subset comprising all MHC multimers having HLA-A*0201/ALIAPVHAV. 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 include a negative control MHC multimer subset as per the disclosure of US 2010/0168390 A1.
Claims 31, 33, 34, 37, 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 5/18/26 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 for the reasons enunciated in the instant rejection.
21. 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 new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended base claim 31 and has canceled claim 39.
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, 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 5/18/26 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 for the reasons enunciated in the instant rejection.
22. Claims 31, 33, 34, 37, 41, 42 and 45-49 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), US 2010/0168390 A1 (of record), and Bakker et al (PNAS, 2008, 105: 3825-3830, of record).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended base claim 31 and has canceled claim 39.
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. The claims of 18/304,028 do not recite wherein the composition comprises at least one subset of multimeric MHCs that each comprise HLA-A*0201 bound to peptide ALIAPVHAV.
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.
The disclosure of US 2010/0168390 A1 has been enunciated in detail above, and will not be repeated herein except to reiterate that the said reference teachings including a nonsense peptide such as ALIAPVHAV in an HLA-A*0201 multimer as a negative control MHC multimer.
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 included a subset comprising all MHC multimers having HLA-A*0201/ALIAPVHAV. 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 include a negative control MHC multimer subset as per the disclosure of US 2010/0168390 A1.
Claims 31, 33, 34, 37, 41, 42 and 45-49 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 5/18/26 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 for the reasons enunciated in the instant rejection.
23. Claims 31, 33, 34, 37, 41, 42 and 45-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,030,065 (of record, formerly Application No. 12/644,554) in view of US2021/0239698 A1, US 20100168390 A1 (of record), Brakmann, S. (Angew. Chem. Int. Ed. 2004, 43: 5730-5734, of record), WO 2013/137737 A1 (of record), and Andersen et al (Nature Protocols, 2012, 7: 891-902, of record).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31 and has canceled claim 39.
Claims 1-8 of US 10,030,065 are drawn t o a soluble MHC multimer comprising an HLA-A*0201/ALIAPVHAV multimer that comprises a dextran carrier, and composition thereof, wherein the MHC multimers are identical or different, and a carrier, and wherein the MHC multimers further comprises one or more marker molecules carrying one or more labels.
The claims of US 10,030,065 do not recite wherein the one or more labels are nucleic acid barcodes comprising identical 5’ and 3’ primer regions, at least 8 pMHCs coupled to the backbone, the number of different subsets of different pMHCs (2 to 10,000), nor that the MHC molecules and nucleic acid barcode molecules are coupled to the dextran backbone carrier via streptavidin-biotin binding and/or avidin-biotin binding, nor wherein the backbone further comprises one or more fluorescent labels, nor wherein the pMHCs are provided by UV peptide exchange as recited in instant dependent claim 45.
The teachings/disclosures of the cited art references have been enunciated in detail above in this office action and will not be repeated herein. These said cited art references provide teachings of attaching at least 8 pMHCs to the carrier, streptavidin-biotin coupling to the dextran carrier backbone, a DNA barcode that uniquely identifies the peptide comprised in a pMHC complex with the barcode comprising the 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 8or more copies of the pMHC and its encoding DNA (barcode) are attached. The references teach/disclose that the DNA barcodes comprise identical 5’ and 3’ primer regions for simultaneously amplifying all of the DNA barcode nucleic acid sequences. The references teach and disclose the advantage of adding a fluorescent label to the backbone, as well as the use of HLA-A*0201/ALIAPVHAV pMHC complexes as a negative control when assessing binding of HLA-A*0201/peptide complexes. The Andersen et al. reference teaches the advantages of providing pMHCs via peptide exchange for quick and efficient production of large numbers of pMHCs. Therefore 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 these features into the composition recited in the claims of US 10,030,065, thereby producing a composition comprising a multiplicity of subsets, each subset comprising different HLA-A*0201 binding peptides as well as a negative control pMHC subset comprising HLA-A*0201/ALIAPVHAV.
24. Claims 31, 33, 34, 37, 41, 42 and 45-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,030,065 (of record, formerly Application No. 12/644,554) in view of WO2015/188839 A2 (priority to at least 8/16/2014, IDS reference).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/18/26. Applicant has amended instant base claim 31, has canceled claim 39, and has added new dependent claim 50. As is enunciated above in this office action, the priority date for the purpose of prior art rejections considering the present amendment of instant base claim 31 is now 6/8/2015.
Claims 1-8 of US 10,030,065 are drawn t o a soluble MHC multimer comprising an HLA-A*0201/ALIAPVHAV multimer that comprises a dextran carrier, and composition thereof, wherein the MHC multimers are identical or different, and a carrier, and wherein the MHC multimers further comprises one or more marker molecules carrying one or more labels.
The claims of US 10,030,065 do not recite wherein the one or more labels are nucleic acid barcodes comprising identical 5’ and 3’ primer regions, at least 8 pMHCs coupled to the backbone, the number of different subsets of different pMHCs (2 to 10,000), nor that the MHC molecules and nucleic acid barcode molecules are coupled to the dextran backbone carrier via streptavidin-biotin binding and/or avidin-biotin binding, nor wherein the backbone further comprises one or more fluorescent labels, nor wherein the pMHCs are provided by UV peptide exchange as recited in instant dependent claim 45.
WO2015/18839 A2 provides these said teachings.
WO2015/18839 A2 teaches a composition comprising a library of barcode labeled pMHC multimer comprised of 1,000 to 100,000 different p/MHC multimers (i.e., subsets) each having a specific nucleic acid barcode as a unique label for each pMHC specificity (e.g., Figures 3 and 4 and legends thereof, page 112 at lines 1-4, page 318 at lines 9-12). The pMHC multimers have optional fluorescent labels to track the total pool of pMHC multimer binding cells irrespective of the pMHC multimer specificity. The nucleic acid barcodes have shared 5’ and 3’ amplification ends, enabling amplification of all nucleic acid barcodes simultaneously in a PCR reaction. These barcodes are attached to the MHC multimerization backbone, for example via a biotin linker binding to streptavidin on the multimer backbone. The MHC may be MHC class I or class II (page 23 at lines 24-25). The carrier may be a dextran (e.g., 41 page at lines 19-24, paragraph spanning pages 53-54, page 55 at line 12, page 57 at lines 11-14, page 60 at lines 1-6, page 67 at lines 2-3). A pMHC multimer may be a dextramer with the peptide being a nonsense peptide, that is, a peptide that binds the MHC protein but expectably does not mediate efficient pMHC complex/TCR interaction with any T cell and used as a negative control for specific binding (page 55 at lines 15-20); a specific negative control dextramer is HLA-A*0201/ALIAPVHAV (page 146 at lines 14-23, page 147 at lines 4-6). The pMHCs may be coupled to the dextran backbone through a streptavidin-biotin binding or a streptavidin-avidin binding, or via the MHC heavy and/or light chain (b2m) (page 57 at lines 16-18, page 317 at lines 1-5). The multimers may comprise two or more pMHC complexes (page 60 at lines 33-35), or can comprise up to 1,000 pMHC complexes (page 4 at lines 15-16). The DNA barcodes may be those found at page 145 at lines 1-12 (that are identical to instantly recited SEQ ID NO: 5-10 recited in instant dependent claim 50). The nucleic acid barcode may comprise or consist of DNA, RNA, or artificial amino acids (e.g., page 46 at lines 17-35, page 47 at lines 1-12). The pMHC monomers are made by refolding, biotinylation and purification (e.g., Example 1). WO2015/18839 A2 teaches producing the specific pMHC by UV-exchange (Example 1). See entire reference, including 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 the nucleic acid barcodes, the number of pMHCs coupled to the dextran backbone, and the coupling via streptavidin-biotin binding and/or avidin-biotin binding, to have incorporated the additional one or more fluorescent labels, and to have provided the pMHCs UV peptide exchange.
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 WO2015 reference provides teachings and motivation to add these features to the pMHC multimer and composition thereof. As the composition claim 4 of US 10,030,065 recites the pMHC comprising HLA-A*0201 and the nonsense peptide ALIAPVHAV, but is silent as to the identity of the others of the plurality of pMHC multimers, in view of the WO2015 reference teachings, 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 included HLA-A*0201 pMHC multimer subsets, each subset comprising an HLA-A*0201 molecule bound to a peptide, wherein the complex could serve as a source to identify cognate T cells specific for the said pMHC. One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so since the WO2015 reference teaches such compositions comprising subsets of such T cell binding pMHCs along with a subset comprising the said nonsense peptide.
Instant dependent claim 46 is included in this rejection because the instant specification does not disclose a limiting or otherwise definition for the limitation “conjugating”, while the specification throughout does discuss conjugating in the sense of through biotin-avidin or biotin-streptavidin binding. In addition claims 7 and 8 of US 10,030,065 recite that the one or more labels are attached directly or indirectly to the pMHC multimer.
25. The following are new grounds of rejection necessitated by Applicant’s amendment filed 5/18/26.
a) Claim 50 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 (of record) and WO 2013/137737 A1 (of record) as applied to claims 31, 33, 34, 37, 41, 42 and 46-49 above, and further in view of WO2015/188839 A2 (priority to at least 8/16/2014, IDS reference).
b) Claim 50 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, 41, 42 and 46-48 above, and further in view WO2015/188839 A2 (priority to at least 8/16/2014, IDS reference).
c) Claim 50 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 WO2015/188839 A2 (priority to at least 8/16/2014, IDS reference).
d) Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,030,065 (of record, formerly Application No. 12/644,554) in view of US2021/0239698 A1, US 20100168390 A1 (of record), Brakmann, S. (Angew. Chem. Int. Ed. 2004, 43: 5730-5734, of record), WO 2013/137737 A1 (of record), and Andersen et al (Nature Protocols, 2012, 7: 891-902, of record) as applied to claims 31, 33, 34, 37, 41, 42 and 45-49 above, and further in view of WO2015/188839 A2 (priority to at least 8/16/2014, IDS reference).
None of the claims of the applications or patents listed above at “a)” through “d)” in view of their respective cited references provide for a nucleic acid molecule selected from the Markush alternatives recited in instant dependent claim 50.
WO2015/18839 A2 does provide for these said DNA barcodes (they may be found at page 145 at lines 1-12 and are identical to instantly recited SEQ ID NO: 5-10 recited in instant dependent claim 50:
WO2015/18839 A2 teaches a composition comprising a library of barcode labeled pMHC multimer comprised of 1,000 to 100,000 different p/MHC multimers (i.e., subsets) each having a specific nucleic acid barcode as a unique label for each pMHC specificity (e.g., Figures 3 and 4 and legends thereof, page 112 at lines 1-4, page 318 at lines 9-12). The pMHC multimers have optional fluorescent labels to track the total pool of pMHC multimer binding cells irrespective of the pMHC multimer specificity. The nucleic acid barcodes have shared 5’ and 3’ amplification ends, enabling amplification of all nucleic acid barcodes simultaneously in a PCR reaction. These barcodes are attached to the MHC multimerization backbone, for example via a biotin linker binding to streptavidin on the multimer backbone. The MHC may be MHC class I or class II (page 23 at lines 24-25). The carrier may be a dextran (e.g., 41 page at lines 19-24, paragraph spanning pages 53-54, page 55 at line 12, page 57 at lines 11-14, page 60 at lines 1-6, page 67 at lines 2-3). A pMHC multimer may be a dextramer with the peptide being a nonsense peptide, that is, a peptide that binds the MHC protein but expectably does not mediate efficient pMHC complex/TCR interaction with any T cell and used as a negative control for specific binding (page 55 at lines 15-20); a specific negative control dextramer is HLA-A*0201/ALIAPVHAV (page 146 at lines 14-23, page 147 at lines 4-6). The pMHCs may be coupled to the dextran backbone through a streptavidin-biotin binding or a streptavidin-avidin binding, or via the MHC heavy and/or light chain (b2m) (page 57 at lines 16-18, page 317 at lines 1-5). The multimers may comprise two or more pMHC complexes (page 60 at lines 33-35), or can comprise up to 1,000 pMHC complexes (page 4 at lines 15-16). The DNA barcodes may be those found at page 145 at lines 1-12 (that are identical to instantly recited SEQ ID NO: 5-10 recited in instant dependent claim 50). The nucleic acid barcode may comprise or consist of DNA, RNA, or artificial amino acids (e.g., page 46 at lines 17-35, page 47 at lines 1-12). The pMHC monomers are made by refolding, biotinylation and purification (e.g., Example 1). WO2015/18839 A2 teaches producing the specific pMHC by UV-exchange (Example 1). See entire reference, including claims.
It would therefore have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used the DNA barcodes taught by WO2015/18839 A2 in the compositions of “a)” through “d)” listed above.
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 WO2015/18839 A2 teaches suitable barcode nucleic acid sequences that comprise universal 3’ and 5’ primer regions for parallel PCR and detection.
26. Claim 33 is objected to because of the following informality: “10000” should be recited as ’10,000’. Appropriate correction is required.
27. No claim is allowed.
28. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
29. 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
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights