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 .
DETAILED ACTION
Pursuant to a preliminary amendment filed February 26, 2026, claims 1-6, 12, 14, 15, 20, 22, 24, 28-32, 34, 35, 41 and 42 are currently pending in the instant application.
Response to Election/Restriction
Applicant's election of Group I, claims 1-5, directed to a method for identifying target multiple myeloma associated surface antigens; and Applicant’s election of Species with traverse as follows:
Species (A): wherein the first multiple myeloma sample is a nucleic acid pool of expressed genes from MM patients and the second multiple myeloma sample represents proteins expressed in MM cell lines (claim 3); and
Species (B): wherein the target multiple myeloma associated surface antigen has an expression level in a normal tissue sample…of the normal tissue sample (claim 4), in the reply filed February 26, 2026 is acknowledged.
Claims 6, 12, 14, 15, 20, 22, 24, 28-32, 34 and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 2 and 5 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement is still deemed proper and is therefore made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1, 3, 4, 41 and 42 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed September 21, 2022, claims the benefit of a 35 U.S.C. 371 national stage filing of International Application PCT/US2021/024431, filed March 26, 2021, which claims the benefit US Provisional Patent Application 63/0000694, filed March 27, 2020.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on September 21, 2022; February 28, 2024; June 11, 2024; March 12, 2025; January 21, 2026; and February 20, 2026 have been considered. Initialed copies of the IDSs accompany this Office Action.
Claim Objections/Rejections
Claim Objections
Claims 1, 3 and 42 are objected to because of the following informalities: Claims 1 recites the term "mass spec,” “MM cell lines,” “CCR1,” “IL12RB1,” “FCRL3,” “LRRC8D,” “SEMA4A” and “LILRB4” where an abbreviation should be spelled out in the first encounter of the claims.
Appropriate correction is required.
(2) Claims 1, 3, 4, 41 and 42 are objected to because of the following informalities: Claims 1, 3, 4, 41 and 42 recite a mixture of pronouns including “the” and “said” within each claim, such that for consistency, a single pronoun reciting either “the” or “said” should be used.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 4, 41 and 42 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is indefinite for the recitation of the term “the protein” such as recited in claim 1, line 6. There is insufficient antecedent basis for the term “the proteins” in the claim because claim 1, line 3 recites the term “cell-surface proteins”. The Examiner suggests that Applicant amend the claim to recite, for example, “identifying the cell surface proteins corresponding to.”
Claim 1 is indefinite for the recitation of the term “a control gene unrelated to hematopoietic cells” such as recited in claim 1, line 6 because it is unclear how the control gene is related to the plurality of genes expressing cell-surface protein, and whether the plurality of genes are also “not related to hematopoietic cells” and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “the detected elevated expressed nucleic acids” such as recited in claim 1, line 7. There is insufficient antecedent basis for the term “the detected elevated expressed nucleic acids” in the claim because claim 1 does not recite that the nucleic acids are detected, elevated, and/or that they are expressed and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “conducting mass spec analysis on proteins isolated from said second myeloma sample” such as recited in claim 1, line 9 because claim 1 does not recite that proteins have been isolated from the second myeloma sample and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term ”said second multiple myeloma” such as recited in claim 1, line 10. There is insufficient antecedent basis for the term “said second multiple myeloma” in the claim because claim 1, line 4 recites the term “a second multiple myeloma sample.”
Claim 1 is indefinite for the recitation of the term ”excluding proteins with high expression” in claim 1, line 12 because it is unclear what pool, sample, analysis, concentration level, etc. the proteins are being excluded from. Moreover, it is unclear what species the proteins expressed in the brain, spinal cord, gut, liver, etc. belong to. Additionally, the term “high” is a relative term that renders the claim indefinite. The as-filed Specification does not provide a standard for ascertaining the requisite protein expression in brain, spinal cord, guts, etc. as compared to some other value, such that the expression qualifies as a “high expression” and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term ”said first and second pools” such as recited in claim 1, line 13. There is insufficient antecedent basis for the term “said first and second pools” in the claim because claim 1, lines 7-8 and 11 recites the term “a first pool of selected proteins” and term “a second pool of selected proteins.”
Claim 3 is indefinite for the recitation of the terms “MM patients” and “MM cell lines” such as recited in claim 3, lines 2-3 because the term “MM” is undefined. It is unclear whether the term “MM” refers to multiple myeloma, mitochondrial myopathies, meningomyelocele, malignant melanoma, etc. and, thus, the metes and bounds of the claim cannot be determined.
Claim 4 is indefinite for the recitation of the term “more than about one standard deviation” such as recited in claim 4, lines 2-3 because the term “more than about” recites overlapping ranges. For example, the term “about” encompasses values above and below a reference point, while the term “more than” encompasses values above the reference point. Therefore, the combination of both terms (“more than about”) is confusing, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention.
Claim 4 is indefinite for the recitation of the terms “expression level in a normal tissue sample;” “standard deviation below the normal peak;” and “protein expression level distribution of the normal tissue sample” such as recited in claim 4, lines 2-4 because claim 4 depends from instant claim 1, where claim 1 does not recite expression levels in a normal tissue sample, standard deviations, normal peaks, distributions of protein expression in normal tissue, etc. It is completely unclear what components, measurements, assay, etc. the claim is referring and, thus, the metes and bounds of the claim cannot be determined.
Claim 4 is indefinite for the recitation of the term ”the normal peak” such as recited in claim 4, line 3. There is insufficient antecedent basis for the term “the normal peak” in the claim.
Claim 4 is indefinite for the recitation of the term ”the protein expression level distribution” such as recited in claim 4, line 3. There is insufficient antecedent basis for the term “the protein expression level distribution” in the claim.
Claim 41 is indefinite for the recitation of the term “mRNA is measured” and “identify proteins for the first pool of selected proteins” such as recited in claim 41, lines 1-2 because claim 41 depends from claims 1 and 4, where claims 1 and 4 do not recite mRNA, measuring mRNA, and/or identifying proteins for the first pool of selected proteins and, thus, the metes and bounds of the claim cannot be determined.
Claim 42 is indefinite insofar as it ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 112(d)
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.
Claims 4 and 41 are rejected under 35 U.S.C. 112(d) 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.
Claim 4 recites (in part): “wherein the target multiple myeloma associated surface antigen has an expression in normal tissue…of the normal tissue sample” such as recited in claim 4, lines 1-4 because claim 4 depends from instant claim 1, where claim 1 does not recite expression levels in a normal tissue sample, a normal tissue sample, standard deviations, normal peaks, distributions of protein expression in normal tissue, etc. Thus, claim 4 is an improper dependent claim 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.
Claim 41 recites (in part): “wherein mRNA is measured to determine the expression level of the nucleic acids used to identify proteins…form the first multiple myeloma sample” such as recited in claim 41, lines 1-3 because claim 41 depends from instant claims 1 and 4, where claims 1 and 4 do not recite mRNA, measuring mRNA, and/or identifying proteins for the first pool of selected proteins. Thus, claim 41 is an improper dependent claim 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.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3, 4, 41 and 42 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/ fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at http://www.uspto.gov/patents/law/exam/mdc_examples_nature-based_products.pdf (“Nature-Based Products Examples”). This rejection is proper.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2) whether the claim recites or involves a judicial exception (i.e., abstract idea, a law of nature, natural phenomenon, or natural product); and (3) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. In this case, the claims as a whole are directed to an abstract idea. Therefore, they must each be considered to determine whether, given their broadest reasonable interpretation, they amount to significantly more than the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claim(s) 1, 3, 4 , 41 and 42 do not recite something significantly different than the judicial exception. The rationale for this determination is explained below:
In the instant case, the claims broadly directed to a method comprising: identifying a plurality of genes that express cell-surface proteins in a first multiple myeloma sample and a second multiple myeloma sample; selecting nucleic acids from said first multiple myeloma sample that have expression levels higher than a control gene; and identifying the proteins corresponding to the detected elevated expressed nucleic acids to designate a first pool of selected proteins; conducting mass spec analysis on proteins isolated from said second myeloma sample to identify proteins that are present in higher concentration in said second multiple myeloma relative to normal tissues, wherein such proteins represent a second pool of selected proteins; excluding proteins with high expression in brain, spinal cord, gut, liver and kidney from said first and second pools to produce a modified first and second pool of proteins; and identifying proteins common to said first and second modified pool of proteins as target multiple myeloma associated surface antigens.
Beginning with Step I of the analysis, which asks whether the claimed invention falls within a statutory category, such that the instant claims are directed to a process, thus, the instant claims are directed to a statutory category. Step I: [YES].
Proceeding to revised Step IIA – Prong One of the analysis, which asks if the claimed invention is directed to a judicial exception, such that claims 1, 3, 4, 41 and 42 are directed to a natural phenomenon in the form of a natural correlation between the expression and/or amount of naturally occurring antigens such as proteins on the surface of patient cells as compared to a control, and the presence of multiple myeloma; and to an abstract idea including: (a) mathematical concepts such as mathematical relationships, formulas or equations, and/or calculations in the form of mass spectrometry analysis; determining protein expression levels; determining concentrations, etc.; as well as, (b) mental processes such as concepts performed in the human mind, such as observation, evaluation, judgement and opinion in the form of identifying genes, selecting nucleic acids, identifying proteins, excluding proteins, etc. The claims recite the judicial exception of a natural phenomenon, and an abstract idea that fall within the groupings of abstract ideas enumerated in the 2019 PEG including encompassing mathematical concepts, mental processes that can be carried out in the human mind, and/or by using a generic computer that performs routine and conventional functions including concepts including executing mathematical concepts, such as mathematical relationships, formula, equations, calculations. Thus, under the revised Step IIA analysis, the claims are directed to an abstract idea. Step IIA – Prong One [YES].
Step IIA - Prong Two asks whether the claim recites additional elements that integrate the exception into a practical application of the exception. In the instant case, the claims are directed to a judicial exception in the form of a natural phenomenon and an abstract idea. Claim 1 recites: “identifying a plurality of genes that express cell-surface proteins in a first multiple myeloma sample and a second multiple myeloma sample” in lines 3-4; “selecting nucleic acids from said first multiple myeloma sample that have expression levels higher than a control gene” in lines 5-6; “identifying the proteins corresponding to the detected elevated expressed nucleic acids” in lines 6-7; “conducting mass spec analysis on proteins isolated from said second myeloma sample to identify proteins that are present in higher concentration in said second multiple myeloma relative to normal tissues” in lines 9-11; “excluding proteins with high expression in brain, spinal cord, gut, liver and kidney from said first and second pools to produce a modified first and second pool of proteins” in lines 12-13; and “identifying proteins common to said first and second modified pool of proteins as target multiple myeloma associated surface antigens” in lines 14-15. These limitations simply describe a process of collecting and analyzing information, which is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); as well as, “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)). Moreover, many of Applicant’s process steps can be practiced as a mental process performed in the human mind, by pen and paper, or through the use of a generic computer, for example, “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Additionally, the dependent limitations of claims 3, 4, 41 and 42 also suffer from the same issue. In other words, the dependent limitations do not rectify the rejection of the independent claim. By way of example, the limitations of claim 4 provides, “wherein the target multiple myeloma associated surface antigen has an expression level in a normal tissue sample that is more than about one standard deviation below the normal peak of the protein expression level distribution of the normal tissue sample;” which clearly resembles “organizing information through mathematical correlations” (i.e. Digitech Image Techs., LLC v Electronics for Imaging, Inc., 758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)); and is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). The claims do not provide other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment, e.g., an immunization step that integrates an abstract idea of data comparison into a specific process of immunizing that lowers the risk that immunized patients will later develop chronic immune-mediated diseases, as discussed in Classen Immunotherapies Inc. v. Biogen IDEC, 659 F.3d 1057, 1066-68, 100 USPQ2d 1492, 1499-1502 (Fed. Cir. 2011) (see MPEP § 2106.05(e)). Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Proceeding to Step IIB of the analysis: the question then becomes what element or what combination of elements is sufficient to amount to significantly more than the abstract idea?
The instant independent claim is recited at a high level of generality, such that substantially all practical applications of the judicial exception are covered. For instance, claim 1 is recited without any specificity as to the method of identifying a plurality of genes; the expressed cell-surface proteins; the identity of the first myeloma sample; the identity of the second myeloma sample; the method of selecting nucleic acids; how much higher the concentration of the proteins in the myeloma samples is compared to the control; the identity of the control; how the expressed nucleic acids are pooled; the method of conducting mass spectrometry; the mass spectrometry apparatus; the method of excluding proteins; what expression level is considered to be “high”; the species from which the sample is taken; the specific section, tissue, cells, fluid, etc. obtained from the brain, spinal cord, gut, liver, and kidney; the method of identifying proteins common to the modified pool of proteins; the identity of the proteins within the modified pool of proteins; the proteins that are associated with multiple myeloma, etc., wherein the steps of the method are well-known, purely conventional or routine in the art.
For example, plasma membrane profiling (PMP) is a novel proteomic technique known in the art that overcomes previous limitations and enables the identification and quantification of hundreds to thousands of PM proteins across multiple samples, wherein this technique is adopted to characterize the whole cell surface proteome in myeloma and to identify a novel antibody-drug conjugate (ADC) target, wherein PMP uses eight primary samples and ten human myeloma cell lines which are profiled by mass spectrometry, such that a total of 2,077 proteins were identified with high confidence across all samples of which at least 1,319 were PM proteins, wherein the aim of the analysis is to employ PMP to identify and quantify plasma membrane protein expression in both human myeloma cell lines (HMCLs) and myeloma patient samples; as well as, gene expression profiling (GEP) to obtain mRNA abundance as a surrogate for protein expression; and that HMCL quantitative transcriptomics data (mRNAseq) and preliminary mutations list (generated using exome sequencing) were downloaded from the Keats Lab data repository (www. keatslab.org/data-repository) and RNA abundance was expressed as FPKM values as evidenced by Anderson (Dissertation, 2018, 1-228; Abstract, first and second full paragraphs; pg. 33, second full paragraph; pg. 61, last partial paragraph; and pg. 69, last partial paragraph); and wherein a method as depicted in Figure 1A (below) is known in the art.
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wherein genetically modified immuno-responsive cells (e.g., T cells, Natural Killer (NK) cells, cytotoxic T lymphocytes (CTL) cells and regulatory T cells) comprising one or more antigen recognizing receptor
(e.g., TCR or CAR) that binds to an antigen of interest and can optionally further comprise a co-stimulatory receptor (CCR), and methods of using such cells for treating and/or preventing myeloid disorders and other pathologies where an antigen-specific immune response is desired, wherein an algorithm shows the steps, which identify surface molecules in AML and molecules, which are overexpressed in AML compared to normal HSPCs; the quality control; the step, which identifies targets with minimal expression in a large panel of normal tissues and flow-cytometric analysis, wherein a heatmap shows the expression profile of 24 selected candidates in a large panel of normal tissues as well as previously identified CAR targets in AML and CD19. Figure 14 depicts the expression profile of CAR targets in normal tissues, wherein a heatmap shows the expression profile of selected candidates with no high (3) expression in a large panel of normal tissues, except blood, bone marrow and spleen as evidenced by Sadelain (US20180348227, published December 6, 2018; paragraphs [0036]; [0043]; [0046]; and Figure 1A). Moreover, the use of an ion intensity-based label-free protein quantification technology to analyze global protein expression profiles of plasma cells from multiple myeloma (MM) patients and healthy controls was known in the art, wherein this high-throughput method is sensitive enough to detect and quantify thousands of proteins in complex biological samples, allowing potential MM protein biomarkers with high discriminate ability to be identified, such that plasma cells were isolated from BMNCs based on the cell surface antigen expression, either by flow cytometric analysis or Magnetic-Activated Cell Sorting (MACS) after staining with magnetic conjugated antibodies; and that protein mixtures were digested with modified trypsin and filtered through spin filters (0.45 µm) before being applied to the high performance liquid chromatography (HPLC) system and injected onto an Agilent 1100 nano-HPLC system for LC/MS/MS as evidenced by Suvannasankha (J. Proteomics & Bioinformatics; 2018; pg. 8, col 1, first and third full paragraphs; and pg. 9, last full paragraph and last partial paragraph). Thus, the claims as a whole simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality to the judicial exception, wherein the steps are well-understood, routine and conventional activities previously known to the industry, as discussed in Alice Corp., 134 S. Ct. at 2359-60, 110 USPQ2d at 1984 (see MPEP § 2106.05(d)). Step IIA [YES].
In sum, when the relevant factors are analyzed, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself. Accordingly, claim 1 DOES NOT qualify as eligible subject matter.
Dependent claims 3, 4, 41 and 42 when analyzed as a whole are held to be patent ineligible under 35 U.S.C. 101 because they do not add anything that makes the natural phenomenon in claim 1, significantly different. For example, claim 41 encompasses the method of claim 1, wherein mRNA is measured to determine the expression level of the nucleic acids used to identify proteins for the first pool of selected proteins from the first multiple myeloma sample, but it does not add anything that makes the natural phenomenon and abstract idea in claim 1 significantly different.
In light of the above consideration and the new guidance, claims 1, 3, 4, 41 and 42 are non-statutory. This rejection is newly recited as necessitated by the new Guidance set forth in the Memorandum of July 30, 2015 updating the June 25, 2014 guidance (see June 25, 2014 memorandum from Deputy Commissioner for Patent Examination Policy Andrew Hirshfeld titled Preliminary Examination Instructions in view of the Supreme Court Decision in Alice Corporation Pty. Ltd. v. CLS Bank International, et al. (Alice Corp. Preliminary Examination Instructions) and the Revised Patent Subject Matter Eligibility Guidance (See, Federal Register, vol. 84, No. 4, January 7, 2019).
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claims 1, 3, 4, 41 and 42 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Georgina Suzanne Ferrier Anderson (hereinafter “Anderson”) (Dissertation, University of Cambridge, November 2018).
Regarding claim 1, Anderson teaches plasma membrane profiling of multiple myeloma and the identification of novel monoclonal antibody targets (interpreted as MM; and the identification of target antigens, claim 1) (Title). Anderson teaches that plasma membrane profiling (PMP) is a novel proteomic technique that overcomes previous limitations and enables the identification and quantification of hundreds to thousands of PM proteins across multiple samples, wherein this technique is adopted to characterize the whole cell surface proteome in myeloma and to identify a novel antibody-drug conjugate (ADC) target (Abstract, first full paragraph). Anderson teaches that eight primary samples and ten human myeloma cell lines were profiled by mass spectrometry using PMP, such that a total of 2,077 proteins were identified with high confidence across all samples of which at least 1,319 were PM proteins (interpreted as identifying target surface antigens for MM; a first myeloma sample expressing cell surface proteins; and a second myeloma sample are proteins expressed in MM cell lines, claim 1) (Abstract, second full paragraph, lines 1-3). Anderson teaches that the aim of Chapter 3 is to employ PMP to identify and quantify plasma membrane protein expression in both human myeloma cell lines (HMCLs) and myeloma patient samples; and as the cell surface proteome of primary myeloma cells has not yet been quantitatively analyzed, a comprehensive dataset would provide an invaluable tool for the myeloma community (interpreted as cell surface protein expression; quantification of plasma membrane expression; first MM sample is nucleic acid pool of expressed genes from MM patients; second MM sample is proteins expressed in MM cell lines, claims 1, 3 and 4) (pg. 69, last partial paragraph, lines 1-4). Anderson teaches that the understanding of myeloma cell biology and the downstream sequelae of specific mutations can be improved by comparing cell surface protein expression with the underlying genotype; and that the abundance of any protein can be predicted from transcript expression using a RNA-to-protein (RTP) conversion factor (interpreted as comparing to a control, claims 1 and 41) (pg. 70, first full paragraph, lines 5-6 and 15-16). Anderson teaches that Figure 3.16 shows a heatmap of the relative protein expression of the top 100 proteins across the 10 human myeloma cell lines (HMCLs) including CCR1 (interpreted as protein expression; selecting; identifying a plurality of genes that express cell-surface proteins including CCR1; and expression level higher than a control, claims 1 and 41) (pg. 92, first full paragraph, lines 5-6; and pg. 93, Figure 3.16). Anderson teaches a comparison of protein expression between HMCLs and primary samples, wherein the top five (5) proteins upregulated as ranked by fold change were CTAG1A, EFNB2, RANBP2, and LRFN4; and the top five (5) downregulated proteins were LRRC16A, SBF1, OSBP, GRK6 and ITGB3 (interpreted as identifying proteins common to the first and second modified pool of proteins as target MM associated surface antigens; and interpreting upregulated genes to include levels higher than a control gene unrelated to hematopoietic cells, claim 1) (pg. 94, Title; and pg. 95, first full paragraph, lines 6-8). Anderson teaches that the first criteria was exposure at the cell surface and therefore proteins without an annotated extracellular domain were excluded from the starting list of 2,077 proteins, wherein proteins were then ranked according to a combination of (a) high and ubiquitous on-tumor expression, (b) low off-tumor expression; and (c) the size of the extracellular domain; and healthy tissue expression was predicted using the publicly available whole-cell proteomics database (The Human Proteome Map) were used as a guide for a threshold for tolerable off-tumor expression (interpreted as excluding proteins and/or selecting expression levels, claim 1) (pg. 97, first full paragraph, lines 1-10). Anderson teaches that Figure 3.19 compares the median expression of each ‘extracellular plasma membrane’ protein against normalized length of extracellular domain, which was used as an approximation of antigenicity, wherein proteins were color-coded by their maximal expression in the lung, liver, heart or kidney, wherein a final extensive literature review revealed that six proteins had already been identified as therapeutic targets for multiple myeloma and, therefore, were excluded from our list of top candidates (CD38, SLAMF7, LY75, ITGA4, MERTK and IFNAR1 (interpreted as excluding proteins, claim 1) (pg. 97, first full paragraph, lines 11-19). Anderson teaches that the expression of these targets across all healthy tissue is summarized in Figure 3.20, where importantly there was no high expression in the heart, kidney, liver or lung (interpreted as excluding proteins with high expression in liver or kidney to give a first and second modified pool of proteins, claim 1) (pg. 97, last second paragraph; and Figure 3.20). Anderson teaches that using PMP, 3,131 and 4,962 unique proteins were identified in HMCLs and primary samples respectively, of which 2,714 were common to both datasets (Figure 3.8); and although thresholds setting the FDR are applied to peptide identification in mass spectrometry, such that to reduce the number of false identifications, proteins identified by only one unique peptide were excluded, thus, removing a total of 637 common proteins (interpreted as mass spectrometry analysis of proteins isolated from samples; and identifying proteins common to the first and second modified pool of proteins as target MM associated surface antigens, claim 1) (pg. 102, first full paragraph). Anderson teaches that Figure 5.13 shows that SEMA4A off-tumor expression across 44 normal human tissues shows medium expression in lymph nodes, but shows no expression in brain, spinal cord, intestine, liver, kidney, etc. (interpreted as excluding proteins with high expression in brain, gut, etc.; and a gene unrelated to hematopoietic cells, claim 1) (pg. 144, Figure 5.13). Figure 5.13A-B is shown below:
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Regarding claim 3, Anderson teaches that eight primary samples and ten human myeloma cell lines were profiled by mass spectrometry using PMP, such that a total of 2,077 proteins were identified with high confidence across all samples of which at least 1,319 were PM proteins (interpreted as identifying target surface antigens for MM; a first myeloma sample expressing cell surface proteins; and a second myeloma sample are proteins expressed in MM cell lines, claims 1 and 3) (Abstract, second full paragraph, lines 1-3). Anderson teaches that the aim of Chapter 3 is to employ PMP to identify and quantify plasma membrane protein expression in both human myeloma cell lines (HMCLs) and myeloma patient samples; and as the cell surface proteome of primary myeloma cells has not yet been quantitatively analyzed, a comprehensive dataset would provide an invaluable tool for the myeloma community (interpreted as cell surface protein expression; quantification of plasma membrane expression; first MM sample is nucleic acid pool of expressed genes from MM patients; second MM sample is proteins expressed in MM cell lines, claims 1 and 3) (pg. 69, last partial paragraph, lines 1-4).
Regarding claim 4, Anderson teaches narrowing down a list of >2,000 potential targets based on the following criteria to rank proteins: high on-tumor expression, low off-tumor expression, and the length of the extracellular domain (pg. 104, first full paragraph). Anderson teaches that normal tissue distribution of several MM therapeutic antibody targets have off-tumor expression profiles within a similar range as known therapeutic targets (interpreted as the surface antigen expression level in normal tissue sample is >1 standard deviation below the normal peak of the protein expression level distribution of the normal tissue sample, claim 4) ( pg. 100, Figure 3.20; and pg. 105, last full paragraph). Figure 3.20 is shown below:
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Anderson teaches that high expression alone does not necessarily translate to a good target because a number of high ranked proteins were observed to be also highly expressed in normal tissues, such that to avoid targets that would exhibit unacceptable off-tumor toxicity, proteins were also ranked according to their off-tumor expression as determined by whole-cell proteomics, such that as a threshold for off-tumor expression, the distribution was examined for several MM therapeutic antibody targets that have either been FDA-approved or are currently in clinical trials (interpreted as expression levels of MM surface antigens in normal tissue sample; and protein expression level distribution, claim 4) (pg. 104, last full paragraph). Anderson teaches that Figure 5.2 shows the predicted normal tissue expression from the Human Proteome Map (interpreted as an expression level in a normal tissue sample, claim 4) (pg. 129, Figure 5.2). Anderson teaches that unless otherwise specified, all data is presented as the median ± standard deviation (interpreted as more than about 1 standard deviation, claim 4) (pg. 61, second full paragraph, lines 5-7).
Regarding claim 41, Anderson teaches that a common technique for gene expression profiling (GEP) is the use of mRNA abundance as a surrogate for protein expression (interpreted as mRNA is measured to determine expression level, claim 41) (pg. 33, second full paragraph, lines 1-3). Anderson teaches that HMCL quantitative transcriptomics data (mRNAseq) and preliminary mutations list (generated using exome sequencing) were downloaded from the Keats Lab data repository (www. keatslab.org/data-repository) and RNA abundance was expressed as FPKM values, wherein a gene-specific RNA-to-protein (RTP) conversion factor for each cell line was determined by calculating the ratio between mRNA and protein abundance following normalization of the PMP datasets as described above and log10 transformation of the RNA dataset (interpreting gene expression profiling of transcripts as measuring mRNA to determine the expression level of the nucleic acids, claim 41) (pg. 61, last partial paragraph).
Regarding claim 42, Anderson teaches that one target, SEMA4A, which was rapidly internalized and exhibited restricted healthy tissue expression, was taken forward to test for in vitro killing activity; and that an anti-SEMA4A ADC induced cell death exclusively in high SEMA4A-expressing cell lines in vitro and demonstrated potent activity in an in vivo xenograft model of myeloma (interpreted as SEMA4A, claim 42) (Abstract, last partial paragraph). Anderson teaches that Figure 3.16 shows a heatmap of the relative protein expression of the top 100 proteins across the 10 human myeloma cell lines (HMCLs) including CCR1 (interpreted as protein expression; selecting; identifying a plurality of genes that express cell-surface proteins including CCR1; and expression level higher than a control, claims 1 and 42) (pg. 92, first full paragraph, lines 5-6; and pg. 93, Figure 3.16). Anderson teaches that the top 20 novel target candidate proteins including LRRC8D and SEMA4A (interpreted as MM surface antigens include LRRC8D and SEMA4A, claim 42) (pg. 99, Table 3.5).
Anderson meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Conclusion
Claims 1, 3, 4, 41 and 42 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684