DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status Summary
Claims 1- 20 are pending.
Claims 1- 20 are considered on the merits.
Claims 1- 20 are rejected.
No Claims are allowed.
Applicant’s election without traverse of Group I, "methods of diagnosing a disease after drug treatment," drawn to Claims 1-20. in the reply filed on 2026 June 8 is acknowledged.
Claim Rejections - 35 USC § 112
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, 2, 9, 10, 14, 15 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the disease … stage" in line 5 and again in line 7. There is insufficient antecedent basis for this limitation in the claim. The “disease stage” is unclear because “a disease stage” has not been introduced previously in the claim or in a prior claim and therefore it is unclear as to what is “the disease stage.”
Furthermore, regarding, Claim 1 recites “whereby the disease state/stage is …” It is unclear what is meant by “state/stage” because the use of the backslash is interpreted to indicate there is a difference between a disease state and disease stage. However, the specification provides no further guidance as to clarify the difference and consequently, the overlapping meanings of disease state and disease stage within the broadest reasonable interpretation makes the boundary of the claim unclear.
Furthermore, regarding, Claim 1, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “systemic fibrosis,” and the claim also recites “and includes skin fibrosis, interstitial lung disease (ILD) and /or idiopathic pulmonary disease (IPF), renal and liver fibrosis” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 2 recites “wherein the gene expression or protein expression pattern is identified among cxcl13, Csf2, Il33, IL6, Cxcl2 and the inflammasome NLRP-3 including IL-18, tLr-2, Il1r1, Il1r2, wnt10b or Edn1” This is unclear because the claim states a “pattern” is “identified” among a list of several genes/proteins. However, the list does not provide any indication of what is the “pattern” nor how the pattern is supposed to be “identified” from merely a list.
Regarding claim 9, the claim uses parentheses in lines 2, 3, and 4. These parentheses are used for the same purpose as the phrase “for example.” The phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Furthermore, regarding claim 9, the claim recites “the drug or therapeutic prevents or suppresses protein expression of extracellular matrix organization (R-MMU-1474244), assembly of collagen fibrils and other multimeric structures (nectin-2, pecam-1, fibromodulin), laminin interactions (a3, a5, b3, c2) and collagen formation (R-MMU-1474290).” It is unclear what is meant by “protein expression of extracellular matrix organization;” “protein expression of assembly of collagen fibrils and other multimeric structures;” “protein expression of laminin interactions;” and “protein expression of collagen formation” because the terminology used in this manner is not consistent with the art and the specification does not provide any further clarification.
Furthermore, regarding claim 9, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 recites the broad recitation “ECM-associated proteins,” and the claim also recites “including laminin (lam)a5, lama3, lamb3, lamc2, nectin-2, pecam-1, and fibromodulin.” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding, Claim 10 recites “the drug or therapeutic alters the protein expression and gene expression of either or all in combination CCN1, CCN2, CCN3, and CCN4.” This is unclear because the claim language “either or all in combination” makes unclear whether the list is in the alternative (only one selection from the list), or in multiple combinations (two or more selections from the list), or the entire list (all selected). Because it is unclear, this examiner is unable to determine the boundary of the claim.
Regarding, Claim 14 recites “wherein the drug or therapeutic decreases the expression of keratinocyte activation, myofibroblast contraction…” It is unclear what is meant by “decreases the expression of keratinocyte activation;” and “decreases the expression of myofibroblast contraction” because the terminology used in this manner is not consistent with the art and the specification does not provide any further clarification.
Claim 15 recites the limitation "the inflammatory fibroblast subpopulation" in line 2. There is insufficient antecedent basis for this limitation in the claim. “The inflammatory fibroblast subpopulation” is unclear because “an inflammatory fibroblast subpopulation” has not been introduced previously in the claim or in a prior claim and therefore it is unclear as to what is “the inflammatory fibroblast subpopulation.”
Claim 20 recites the limitation "the optimal dosing" in line 1. There is insufficient antecedent basis for this limitation in the claim. “The optimal dosing” is unclear because “an optimal dosing” has not been introduced previously in the claim or in a prior claim and therefore it is unclear as to what is “the optimal dosing.”
Furthermore, regarding claim 20, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 20 recites the broad recitation “another drug based on amino acid sequences found in CCN3,” and the claim also recites “including the IGF-binding domain of CCN3, or an IGF-binding protein” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1- 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding claim 1:
Breadth of the Claim
The claims are directed to a method of diagnosing disease state or condition based on gene expression patterns. Claim 1 generally recites a “gene expression pattern” which is a genus because it is not limited to any particular genes or pattern of expression. In addition, the rejection that the gene expression pattern is used to determine “early onset of a diseased state”, “progression of the disease state”, or “regression of the disease state/state in response to a therapeutic treatment” are interpreted as functional limitations of the claimed gene expression pattern. The claim further recites embodiments for the disease state/stage. Accordingly, possession of the claimed method of diagnosing as broadly claimed requires possession of the genus of gene expression patterns that have the corresponding function of being diagnostic for early onset of diseases state, progression of disease state, or regression of diseased state/stage in response to a therapeutic treatment.
Support Provided by Specification
Most importantly, the specifications do not provide any instructions of what steps are to be taken to transform any gene expression pattern into a diagnosis of any sort.
Furthermore, regarding cancer, fibrosis, autoimmune, scleroderma, and systemic fibrosis, the specification does not disclose any pattern that leads to a diagnosis, nor does the specification demonstrate a diagnosis of any of these diseases. The specification provides lists of differentially expressed genes in fibrosis, autoimmune, scleroderma (SSc) (also known as systemic fibrosis) models, however, it is merely a list, not a pattern. Furthermore, as noted above, the specification fails to provide instructions how to transform this list of differentially expressed genes into a disease diagnosis.
Regarding differentiating “stages” of disease, the application does not provide any pattern.
When discussing the early inflammatory stage of bleomycin-induced fibrosis, the specification merely suggests “markers of keratinocyte activation (keratin 1, 14, 15, 6) were prevented by BLR-200 treatment” [0228].
Regarding cancer gene expression pattern and diagnosis, the specification is silent.
Regarding fibrosis gene expression (list, not a pattern) and diagnosis, the specifications discloses an embodiment, “The diagnosis for fibrotic conditions comprises the expression and contribution of CCN proteins in dermal fibrosis, representing or modeling scleroderma (Ssc) and systemic fibrosis,) and determining if therapeutic peptides based on CCN3 represent a novel anti-fibrotic strategy… Thus, targeting the activity and regulation of CCN1 and CCN2 indirectly, for example, by using BLR-200, may represent a novel therapeutic and diagnostic approach for SSc” [0070].
Regarding gene expression patterns for scleroderma (also known as systemic fibrosis), the instant specification uses the same bleomycin treated mice to model fibrosis [Example 1, Fig 4], autoimmune [scleroderma] [Figs 3A-D, 0024], scleroderma [Figs 3A-D, 0024], and systemic fibrosis [Figs 3A-D, 0024]. Additionally, the specification does not present any different gene pattern for autoimmune [scleroderma] versus SSc.
Regarding autoimmune gene expression (list, not a pattern) and diagnosis, the specifications discloses, “Figures 3A-3D are graphs showing the changes in key genes in autoimmune/inflammatory SSc modeled skin disease and the positive drug effect of BLR-200 on the mRNA expression of fibrosis related genes” [0024]. Figures 3A- D lists the differentially expressed genes YAP1, TNC, PLOD2 and SOX2.
Regarding lung fibrosis gene expression and diagnosis, the specifications discloses, “FIGS. 28D-28F show the Effect of BLR-200 on Tissue H&E staining in PBS (FIG. 28D), Bleomycin + Scrambled (FIG. 28E) and Bleomycin + BLR200 (FIG. 28F) showing A: Air spaces of alveolus, B: Respiratory Bronchiole, BV: Blood vessel. These FIGS. 28A-28F show that in the lung disease that not all of the same genes and proteins that are associated with fibrosis that are increased in the skin disease are also increased in the lung.” [0250]. Lung tissues samples list differential gene expression of TGFβ1, MMP7, TNC, PAI-1, IL-33, CCN1, CCN4, FN1, THBS1, ACTA2, IL1 beta, TNF-alpha, COL3A1, and CxCL2 [Figs 29A-D and Figs 30A- J].
Regarding liver gene expression pattern and diagnosis, the specifications discloses, [0173, line 24]; ” As exhibited by UMAPs (Figure 18A- 18C) and violin plots, BLR-200-treated mice had impaired expression of interleukin-18 (Ill8), toll-like receptor 2 (Tlr2), interleukin-I receptor type I (Illrl), and interleukin-I receptor type 2 (Illr2) (Figures 18D-18F; 18G-18I; 18J-18L; lSM-18O). This impairment was most obvious in the IFI inflammatory subpopulation. This genetic signature is associated with activation of the NLRP3 inflammasome, which has been implicated in fibrogenesis in the liver, kidney, and lung” [Figs 18A- O, 0212].
Regarding the “gene expression pattern,” the applicant identifies a pattern for inflammatory fibroblasts, “inflammatory fibroblast subpopulations expressed high levels of inflammatory markers C-X-C motif chemokine ligand 13 (Cxcl13), colony stimulating factor 2 (Csf2), and interleukin-33 (Il33) (Figures 16D-16F)” [0201]. The applicant provides markers for NLRP3 inflammasome [0214] and mesenchymal markers [0223] and UMAP data sets of fibrotic markers of non-specific fibroses [Fig 23A-C].
The specification does not provide working examples of gene expression patterns sourced from progenitor cells or stem cells. The application provides working examples of biopsied cells from mouse models after therapy demonstrating: reduction in collagen deposition [Figures 1A-G]; suppressed myofibroblast differentiation [Figures 2A-J]; reduced gene expression of YAP1, tenasin C, PLOD2, and SOX2 [Figures 3A-D]. Similarly, treatment of dermal fibrosis is demonstrated [Example 2]. The specifications indicate these data were collected from a collagen-lineage fibroblasts and later identified as “a specific myofibroblast subpopulation” [0038].
State of Prior Art and Determination of Possession of Invention
There are multiple references citing the ability to diagnose a disease based on gene expression patterns.
One model example is Beerelli (Beerelli US 20050142119 A1) “Yet another embodiment of the present invention provides a method for diagnosing a disease state by: a) establishing gene expression patterns” [0205].
Selman (Selman et al. Am J Respir Crit Care Med. 2006 Jan 15;173(2):188-98.) specifically discusses fibrosis diagnosis via gene expression “We identified statistically significant gene expression signatures that characterize HP [hypersensitivity pneumonitis] and IPF [idiopathic pulmonary fibrosis”; and “Our results underscore the value of gene expression signatures to classify the interstitial lung diseases and to understand pathogenic mechanisms, and suggest new ways to improve the diagnosis and treatment of patients with these diseases” (Abstract).
Axelsen (Axelsen et al. Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13122-7.), similarly discusses cancer diagnosis via gene expression patterns “The overlap between these two gene groups identified 1,340 tissue-selective genes that are overexpressed in cancers. Different types of cancers, including different brain cancers arising from the same lineage, showed differences in the tissue-selective genes they overexpressed.” (Abstract).
Despite the prior art’s claims to its ability to diagnose disease from gene expression patterns, the state of the art remains highly unpredictable as noted below.
Pearce (Pearce JM. Disease, diagnosis or syndrome? Pract Neurol. 2011 Apr;11(2):91-7.) demonstrates the imprecision and unpredictability of disease diagnosis in general, “medical terminology of diseases, diagnoses and syndromes is inherently imprecise… Such medicalisation (sic) of non-specific aggregations of symptoms should be avoided. The defining characteristics of diseases and diagnoses should be validated and agreed.” (Abstract).
Piccolo (Piccolo et al. PLoS Comput Biol. 2022 Mar 11;18(3):e1009926) demonstrates the technological imprecision and unpredictability of diagnosis based on gene expression patterns, “high-throughput technologies generate thousands of measurements per patient, and complex dependencies exist among genes, so it may be infeasible to classify patients using traditional statistical models… hundreds of classification algorithms exist—and most support diverse hyperparameters—so it is difficult for researchers to know which are optimal for gene-expression biomarkers.” (Abstract). Piccolo provides emphasis by stating, “even the top-performing algorithms performed poorly in some cases” (Abstract).
Furthermore, Bravo (Bravo et al. BMC Bioinformatics. 2012 Oct 22;13:272) describes cancer’s unpredictable diagnosis via gene expression “progress has been slowed by heterogeneity in cancer [genetic signature] profiles” (Abstract).
Even as recently as 2026, Freyberg (Freyberg et al. Sci Rep. 2026 Feb 27;16(1):7831.) describes the unpredictability toward the claimed method regarding fibrosis, “Among CF [cystic fibrosis] patients, total CFTR [cystic fibrosis transmembrane conductance regulator] transcript levels showed greater variability than in non-CF individuals, although both groups exhibited a broad range of transcript expression… These findings reveal important aspects to be considered for … and emphasize previously unappreciated aspects of mRNA expression during pathogenesis.” (Abstract).
Freyberg’s claim to unpredictability is evidenced by Gu (Gu et al. Front Genet. 2021 Jan 15;11:627396.) . Gu identifies gene expression profiles associated with different fibroses “There were 954 genes that were associated with at least one of the eight fibrotic diseases.” (page 2, 2nd column, 1st paragraph, supplementary Table 1). However, the gene profile mapped by Gu is significantly differs from any of the gene profiles noted above within the instant application (see Index A below and Gu supplementary Table 1). For example, Gu recites dozens of genes associated with skin fibrosis whereas the instant application only recites a few (see Index A below and Gu, supplementary Table 2). Furthermore, Gu similarly teaches a similarly different gene profile for lung fibrosis, and liver fibrosis compared to the instant application (see Index A below and Gu, supplementary Table 2).
Index A: Index of Gene Patterns
Gu 954 gene pattern: A1CF AARS ABCA3 ABCA4 ABCC8 ACACB ACE2 ACKR2 ACP1 ACTA2 ADAMTS2 ADCY5 ADH7 ADIPOQ ADIPOR2 ADM ADORA1 ADORA2A ADORA3 ADRB1 ADRB3 AFP AGER AGT AGTR1 AGTR1A AGTR2 AGTRAP AHCYL1 AHI1 AHR AIM2 AKP3 AKT1 ALB ALDH2 ALOX12 ALOX15 ALOX5 ANGPT1 ANGPT2 ANO1 ANRIL ANXA1 AOC3 APC APLN APLNR APOA1 APOE AQP1 AREG ARPC2 ATF4 ATF6 ATG16L1 ATG16L2 ATG7 ATP2A2 ATP8B1 AZGP1 BAK1 BARD1 BAX BBC3 BCHE BCL2L1 BDKRB1 BDKRB2 BDNF BGN BICC1 BID BLMH BMP1 BMP2 BMP3 BMP4 BMP6 BMP7 BMPR1A BNIP3 BRCA1 BRCA2 BTNL2 C1B1 C5 C6 C8ORF4 CACNA1H CAMK2D CAMK2G CAPN3 CAPN5 CARD8 CASP1 CASP3 CASP8 CASQ2 CAST CAT CAV1 CBS CCL17 CCL18 CCL19 CCL2 CCL21 CCL21C CCL25 CCL3 CCL4 CCL5 CCL7 CCN2 CCNA2 CCNT1 CCR1 CCR2 CCR5 CCR6 CCR7 CCR9 CD109 CD163 CD19 CD226 CD247 CD248 CD274 CD4 CD40 CD40LG CD44 CD69 CD8A CDC42 CDH-11 CDH1 CDH11 CDH16 CDH2 CDKN1A CDKN2A CEBPA CFTR CHAER CHAST CHIL1 CHRF CHUK CLCN2 CLDN1 CLDN5 CLDN7 CLIC2 CLOCK CLU CNR1 CNR2 COL1A1 COL1A2 COL3A1 COL4A3 COL7A1 COLLAL COMMD1 COMP CPT1A CR1 CREB1 CREBBP CRH CRNDE CRP CRYAB CSF1 CSF2 CSF2RA CSF3 CSRP3 CTGF CTLA4 CTNNB1 CTNND1 CTRC CTSB CTSD CUBN CUL3 CX3CL1 CX3CR1 CXCL10 CXCL13 CXCL16 CXCL6 CXCL8 CXCL9 CXCR3 CXCR4 CXXC5 CYBB CYLD CYP11B2 CYS1 DCK DCN DCRF DCTN4 DDAH1 DDAH2 DDR1 DDX5 DEFA1 DEFA3 DEFA4 DGAT1 DGKA DKC1 DKK1 DKK4 DLG5 DMBT1 DMD DNASE1 DNM3OS DNMT1 DPP4 DPT DSP DUOX2 DUSP5 EDN1 EDNRA EDNRB EFNB2 EGFR EGLN1 EGLN2 EGR1 EHMT2 ELAVL1 ELMOD2 ELOVL6 EN1 ENG ENPP1 ENTPD1 EPAS1 EPHX1 EPHX2 EPHX3 EPHX4 EPO ERBB4 ERG EZH2 F10 F11R F2RL1 F5 FAAH FABP1 FAF FAN1 FAP FAS FASL FASLG FBN1 FBRS FCER1G FENDRR FERMT2 FGF1 FGF15 FGF19 FGF21 FGF23 FGF7 FGF9 FHIT FIS1 FIZZ1 FIZZ2 FLI1 FMOD FN1 FOSL1 FOSL2 FOXD1 FOXF1 FOXO1 FOXO3 FOXO4 FOXP3 FYN GALNT2 GAS5 GATA1 GATA4 GFER GJA1 GJC1 GLI1 GLI2 GLIS2 GLIS3 GLT8D2 GNA11 GNA12 GNA13 GNAI2 GNAS GNMT GP1BA GPR19 GPX1 GRB2 GREM1 GSK3B GSN GT(ROSA)26SOR GTF2H2 H19 HABP2 HADHAP1 HAND2 HAS2 HAVCR1 HAX1 HBB HBEGF HC HDAC2 HDAC3 HDAC7 HFE HFIB1 HGF HIF1A HIPK2 HK2 HLA-B HLA-DPA1 HLA-DPB1 HLA-DQB1 HLA-DRA HLA-DRB1 HMGB1 HMOX1 HNF1B HNF4A HNRNPF HNRNPK HOPX HOXB13 HPRT HPS1 HPS4 HPS5 HSP1 HSP47 HSP90AB1 HSPA1A HSPA1B HSPA1L HSPB1 HSPD1 HTR2B HYAL2 IAPP IBD5 IBD7 ICAM1 ICOS ICOSLG ID1 IFNAR1 IFNG IFNGR2 IFNL3 IFNL4 IFT140 IFT20 IGF1 IGFBP5 IHH II27 II4RA IKBKB IKBKG IL-17A IL10 IL10RA IL12B IL13 IL13RA2 IL15 IL17A IL18 IL1A IL1B IL1R1 IL1RL1 IL1RN IL21 IL22 IL23 IL2RG IL33 IL34 IL36R IL4 IL4RA IL6 IL9 ILK INS2 INVS IRF5 IRS1 IRS2 ISI1 ITGA1 ITGA3 ITGAM ITGAV ITGB1 ITGB3 ITGB6 ITPR1 JAG1 JAK2 JAK3 JUN JUND JUP KAT5 KCNE2 KCNJ1 KCNMA1 KCNN4 KCP KDR KIF1A KIF21A KIF3A KIF5A KIR2DL2 KIR2DL3 KL KLF2 KLF5 KLF6 KLHL3 KLRK1 KRAS KRT12 KRT18 KRT8 KSR1 LAMP1 LCLAT1 LCN2 LDHA LDLR LEP LEPR LGALS7 LIF LINC01508 LNCR-30245 LOX LOXL2 LRP2 LRP5 LSP1 LTA LTB LTBP4 LTBR LTC3S LYZ2 MAGI2 MALAT1 MAML1 MAOA MAP1B MAP2K1 MAP3K5 MAP3K7 MAPK1 MAPK14 MAPK3 MAPK7 MAPK8 MAPK9 MCL1 MDM2 MECP2 MEF2C MEF2D MEG3 MEOX2 MERTK MET MFAP5 MGAT4D MHRT MICA MIF MIR-138 MIR-199A-3P MIR-199A-5P MIR-19A-3P MIR-19B-3P MIR-200 MIR-200A MIR-214-3P MIR-29 MIR-7E MIR-7F MIR1 MIR101 MIR124-1 MIR125B MIR126 MIR130A MIR130B MIR132 MIR133A MIR1343 MIR142 MIR143 MIR145 MIR145A MIR15 MIR150 MIR154 MIR155 MIR17 MIR192 MIR199A-1 MIR199B MIR200A MIR200B MIR200C MIR208A MIR21 MIR214 MIR215 MIR216B MIR21A MIR22 MIR221 MIR222 MIR25 MIR26A-1 MIR29A MIR29B1 MIR302A MIR30C MIR30E MIR324 MIR34 MIR34A MIR34B MIR34C MIR367 MIR382 MIR489 MIRLET7A1 MKL1 MMP1 MMP10 MMP12 MMP13 MMP14 MMP19 MMP2 MMP3 MMP7 MMP8 MMP9 MPZ MRC2 MSN MST1 MT1 MT2 MTHFR MTOR MUC2 MUC5AC MUC5B MYBPC3 MYC MYD88 MYH10 MYH6 MYH7 MYHC MYL2 MYLK MYOD1 MYOG MYPN N4BP2L2 NCF1 NCF2 NCR1 NCR2 NDUFS6 NEAT1 NEFM NF1 NFAT NFE2L2 NFKB1 NGF NGFR NKX2-5 NLRC4 NLRP10 NLRP12 NLRP3 NLRP6 NOD2 NOS2 NOS3 NOTCH1 NOTCH3 NOX1 NOX4 NOX5 NPHP3 NPPA NPPB NPR1 NPSR1 NR0B2 NR1D1 NR1H2 NR1H3 NR1H4 NR1I2 NR2E3 NR3C1 NR3C2 NR4A1 NRG1 NRON NRP1 NT5E NTRK1 OGR1 OLFM4 OPRM1 P2RX7 P2RY6 P53 PAI1 PANX1 PARD3 PARK2 PARN PARP1 PAX6 PAX8 PCFL PDE5A PDGFA PDGFB PDGFD PDGFRA PDGFRB PDPK1 PDPN PDZK1 PF4 PFAL PFAR PFL PFRL PHEX PHOX2A PIK3R1 PINK1 PIRB PKD1 PKD1L1 PKHD1 PLAT PLAU PLAUR PLCZ1 PLOD2 PNPLA2 PNPLA3 PON2 POSTN PPARA PPARD PPARG PPARGC1A PPP1R13L PPP2R5E PPP3R1 PRDX3 PRKAA1 PRKCA PRKCB PRKCG PRKCZ PRKD1 PRKG1PROC PROM1 PRSS1 PRSS23 PRSS3 PTEN PTF1A PTGDR PTGDR2 PTGER1 PTGER2 PTGER3 PTGER4 PTGFR PTGIR PTGIS PTGS2 PTK2 PTPN2 PTX3 PVT1 PYCARD RAC1 RAC2 RAF1 RAG1 RAG2 RAMP2 RASAL1 RASSF1A RBFOX RBPJ RELA RELM-Β REN REST RETNLB RHOA RICTOR RLN1 RMRP RNF7 ROCK1 ROCK2 RORA RP11-982M15 RPS5 RPTOR RRP9 RT1-CE13 RTEL1 RTN1 RTN4 RUNX2 RXFP3 RYR1 RYR2 S100A12 S100A4 S100A8 S100A9 SAFE SCN5A SCNN1A SDC1 SDC4 SEC23B SELP SENCR SEPP1 SERPINE1 SERPINF2 SFRP1 SFRP2 SFTPA1 SFTPA2 SFTPC SGK1 SGPL1 SHH SHROOM3 SIRT1 SIRT3 SIRT7 SIX2 SLC11A1 SLC22A4 SLC22A5 SLC26A5 SLC26A6 SLC3A2 SLC4A4 SMAD1 SMAD2 SMAD3 SMAD4 SMAD7 SMO SMURF1 SMURF2 SNAI1 SNAI2 SOCS1 SOCS3 SOD2 SPARC SPHK1 SPHK2 SPI1 SPINK1 SPP1 SPRY1 SQSTM1 SREBF1 SRSF3 STAT1 STAT3 STAT4 STAT6 STC1 STK11 STX1A SYT7 TACR1 TAK1 TAZ TBX21 TBX5 TBXA2R TCAP TCF21 TCRA TDGF1 TERRA TERT TET3 TFAM TGFB1 TGFB2 TGFB3 TGFBR1 TGFBR2 TGIF1 TGIF2 TGM2 THBD THBS1 THG1L THY1 TIMP-1 TIMP1 TIMP2 TIMP3 TINF2 TL1A TLE1 TLR1 TLR2 TLR4 TLR6 TLR7 TLR8 TLR9 TM4SF1 TMBIM6 TNC TNF TNFRI TNFRSF18 TNFRSF1A TNFRSF1B TNFRSF8 TNFSF12 TNFSF13 TNFSF14 TNFSF15 TNNT2 TNPO3 TNS1 TNS2 TNT TOLLIP TOM1 TP53 TPH1 TPMT TRAF6 TRB3 TREM2 TRIB3 TRIM33 TRIM7 TRIM72 TRL4 TRP53 TRPC3 TRPV4 TSC1 TSLP TTC7A TTN TUBB3 TUG1 TUKLS TULP1 TWIST1 TXN1 TXN2 UCP2 UMOD USP13 VDR VEGFA VEGFB VEGFC VHL VIM VLDLR WFDC2 WISP1 WISPER WNK1 WNK4 WNT10B WNT4 WNT5A WT1 XBP1 XIAP XPNPEP1 XRIP2 XYLT2 YAP1 YB1 ZBTB46 ZEB1-AS1 ZNF467.
Gu gene pattern for skin fibrosis: AGT, AGTR1, AKT1, ALOX12, ALOX15, BLMH, BRCA1, BRCA2, CASP1, CASP3, CAV1, CCL2, CCL7, CCR2, CD109, CD19, CD226, CD247, CD40, CNR1, COL1A1, COL7A1, CSF3, CTGF, CTNNB1, CX3CL1, CX3CR1, CXXC5, DGKA, DKK1, DPT, DSP, EN1, FAAH, FBN1, FBRS, FGF7, FLI1, FN1, FOSL2, FOXP3, GATA1, GNAS, GSK3B, HAX1, HIF1A, HOXB13, HPS1, HPS4, HPS5, HSP90AB1, ICAM1, IL13, IL17A, IL1A, IL1RN, IL22, IRF5, ITGAV, ITGB1, ITGB3, JUN, KLF5, LAMP1, LEP, LOXL2, LSP1, MFAP5, MMP1, MMP14, MMP2, MMP9, NOTCH1, NOX4, NR1H2, NR4A1, PANX1, PDGFRA, PDGFRB, PDPK1, PDZK1, PLAUR, PLOD2, PNPLA2, PPARD, PPARG, PTEN, PTK2, RBFOX2, REST, RLN1, RRP9, S100A8, S100A9, SCNN1A, SDC1, SERPINF2, SFRP1, SHH, SIRT1, SMAD1, SMAD2, SMAD3, SMAD7, SMO, SPARC, SPI1, SPP1, STAT3, STAT4, SYT7, TBX21, TGFB1, TIMP1, TLR8, TNF, TNFSF13, TNFSF14, TNPO3, TPH1, TRIB3, TSLP, VDR, VEGFB, WNK1 (supplementary Table 2).
Gu gene pattern for lung fibrosis: ABCA3, AGER, AGT, AKT1, ALOX5, APOA1, ARPC2, ATF4, ATF6, BAK1, BARD1, BAX, BDKRB1, BDNF, BMP4, BMP7, CAV1, CCL17, CCL19, CCL2, CCL21, CCL7, CCNA2, CCR2, CCR5, CD19, CD44, CDH11, CFTR, CLDN5, CLOCK, COL1A2, COMP, CR1, CREBBP, CRP, CRYAB, CSF1, CTGF, CTNNB1, CXCL10, CXCL13, CXCL6, CXCL9, CXCR4, DCK, DDAH1, DDR1, DEFA1, DEFA3, DEFA4, DKC1, DKK1, DKK4, EDN1, EGR1, ELMOD2, ELOVL6, F10, F2RL1, FAP, FAS, FASLG, FHIT, FN1, FOXF1, FYN, GSN, GTF2H2, HAS2, HDAC2, HDAC3, HFE, HIF1A, HLA-B, HLA-DQB1, HLA-DRB1, HMOX1, HSPA1A, HSPA1B, HSPA1L, HSPB1, IFNG, IGF1, IL10, IL12B, IL13, IL13RA2, IL17A, IL1A, IL1B, IL1R1, IL1RL1, IL1RN, IL33, IL4, IL6, ITGA3, ITGAV, ITGB1, ITGB6, JUP, KLRK1, LCLAT1, LDHA, LOX, LOXL2, LRP5, LTA, MEOX2, MICA, MKL1, MMP1, MMP10, MMP12, MMP19, MMP3, MMP7, MUC5B, NFE2L2, NGF, NOX1, NOX4, NR3C1, P2RX7, PARK2, PARN, PDGFA, PINK1, PON2, PTEN, PTGDR, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, PTGS2, PTK2, PTX3, REN, RTEL1, SEPP1, SERPINE1, SFTPA1, SFTPA2, SFTPC, SGPL1, SMAD2, SMAD3, SMAD4, SPHK1, SPHK2, STAT3, STAT6, STC1, TBXA2R, TERT, TGFB1, TGFBR1, TGFBR2, TGM2, THY1, TIMP3, TINF2, TLR9, TM4SF1, TMBIM6, TNC, TNF, TNFRSF1B, TNFSF14, TOLLIP, TOM1, TRIM33, TRPV4, TSLP, USP13, VHL, WISP1, WNT5A, WT1, XBP1, ZNF467 (supplementary Table 2).
Gu gene pattern for liver fibrosis: ADAMTS2, ADH7, ADRB3, AFP, AHR, AKT1, ALDH2, ANGPT1, ANXA1, AOC3, AQP1, AREG, ATP8B1, BCHE, BCL2L1, BMP6, C5, CASP8, CBS, CCL2, CCL21, CCL25, CCL5, CCR1, CCR5, CCR6, CCR9, CD163, CD40LG, CD44, CDKN2A, CLDN1, CNR1, CNR2, COL1A1, CPT1A, CSF1, CTGF, CTSB, CTSD, CX3CR1, CXCL10, CXCL9, CXCR3, CXCR4, CYBB, CYLD, DDX5, DKK1, ELAVL1, ELOVL6, ENPP1, EZH2, F5, FABP1, FAS, FGF19, FGF21, FMOD, FOSL1, FOXO1, GATA4, GFER, GLIS3, GLT8D2, GNMT, GP1BA, HABP2, HBB, HDAC7, HFE, HGF, HLA-DPA1, HLA-DPB1, HMOX1, HNF4A, HTR2B, ID1, IFNAR1, IFNG, IFNGR2, IFNL3, IL13, IL13RA2, IL17A, IL1B, IL1RL1, IL22, IL33, IL34, IL4, ILK, IRS1, ITGAM, ITGAV, JAK2, JUND, KLF2, KLRK1, KRT18, KRT8, LEP, LGALS7, LTB, LTBR, MAP3K7, MAPK1, MAPK14, MAPK3, MAPK8, MAPK9, MCL1, MDM2, MECP2, MEF2D, MERTK, MET, MMP2, MMP7, MTHFR, MYOD1, NCR1, NFKB1, NGFR, NLRP3, NOS2, NPHP3, NR0B2, NR1D1, NR1H2, NR1H4, NR1I2, NRP1, PARP1, PDGFA, PDGFB, PF4, PIK3R1, PKD1L1, PNPLA3, PPARA, PPARG, PPP1R13L, PRKCZ, PROM1, RAC1, RAG1, RNF7, RORA, RPS5, RTN4, SELP, SIRT1, SLC11A1, SMAD2, SMAD3, SMAD7, SPP1, SRSF3, STAT1, STAT3, TGFBR2, TIMP1, TIMP3, TLR2, TLR7, TLR9, TNFRSF1A, TNFRSF1B, TP53, TPH1, TULP1, VDR (supplementary Table 2).
Similarly, Rajalingam (Rajalingam et al. Genomics Inform. 2024 Jul 2;22(1):10.) identifies gene profiles associated with autoimmune disorders that significantly differ from the gene profiles noted above within the instant application “We employed differential gene expression … with five different autoimmune disorders [ADs] (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Crohn’s disease, and type 1 diabetes) to get nine key genes—EGR1, RUNX3, SMAD7, NAMPT, S100A9, S100A8, CYBB, GATA2, and MCEMP1 … confirming its role in immune-related pathways. Combined with biological interpretations … our current study sheds light on the in-depth research on early detection, diagnosis, and prognosis of different ADs.” (Abstract).
The differential gene expression patterns of Gu and Rajalingam demonstrate a single disease may have multiple expression patterns and therefore in combination with the unpredictability of disease diagnosis cited by Pearce, Piccolo, Bravo, and Freyberg, the differential gene expression patterns would inevitably lead to differential disease diagnoses.
Specifically, regarding cancer, the instant specification fails to provide any gene pattern for diagnosing cancer, making it impossible to diagnose any cancerous disease based on a gene expression pattern.
As noted above, the claim recites a broad genus of using a gene expression pattern to diagnose disease. However, considering the various gene expression-based diagnoses in the art due to the unpredictability in the art, the application fails to show a proper sampling of gene expression patterns that are indicative of the broad claimed.
Furthermore, the application fails to provide instructions how to interpret the differential gene expression profiles in the working examples, such that a person having ordinary skill in the art would recognize the applicant was in possession of the claimed invention at the time of filing.
Therefore, for the reasons stated above, the specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claim 1.
Furthermore, regarding claim 2, the claim attempts to further describe a gene expression pattern involving cxcl13, Csf2, 1133, IL6, Cxcl2, NLRP-3, IL-18, tLr-2, Illr1, IlIr2, wnt10b, and Edn1.
However, as described above, the specification fails to show a proper sampling of gene expression patterns and instructions how to interpret the patterns that are representative of the gene set claimed, such that a person having ordinary skill in the art would recognize the applicant was in possession of the claimed invention at the time of filing.
Therefore, for the reasons stated above, the specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claim 2.
Regarding claim 3:
Breadth of the Claim
The claim attempts to interpret the gene expression pattern and disease diagnosis of claim 1 and further interpret the diagnosis into selecting a patient. Claim 3 recites “utilizing the diagnostic [of claim 1] to select a patient” which is a genus because it is limited to the broad range of diagnoses provided by claim 1 and another genus of any patient. The patient is further described to “have a therapeutic effect from a drug.” This examiner interpretates the clause to mean to have a beneficial reaction to a drug. However, the reaction of the patient is not a step in the method of the claim, but merely a description of the patient. An exemplary embodiment interpretation is a patient is selected such that they may receive a prescription.
Support Provided By Specification
The application provides no working examples demonstrating selecting a patient. Furthermore, the specification provides no instructions how to select a patient based on the gene expression pattern and diagnosis as described above. The extent of the specification’s “utilizing the diagnostic” is described above.
Regarding the “therapeutic effect from a drug,” the specification provides disclosure of only BLR-200 treatment and the specification does not describe any other drug or therapy. The specifications describe administration of the drug BLR-200 to bleomycin-induced dermal fibrosis mouse models [Example 1, 2, 3]. The details of the structure of BLR-200 are limited to the following, “BLR-200 includes a peptide sequence found in CCN3” [0071]. The specification does not describe what specific sequence of CCN3 is included in BLR-200. Furthermore, the specification does not describe whether BLR-200 includes any other structural elements. The specification provides no further disclosure regarding the effect of BLR-200 on any other disease model.
State of Prior Art and Determination of Possession of Invention
As recently as 2023, Lazar (Lazar et al. Ther Adv Med Oncol. 2023 Mar 31;15:17588359231156382) described patients could be selected based on gene expression patterns, “As example, high mRNA expression in tumor tissue compared to analogous normal tissue of c-MET and its ligand HGF correlated in silico with shorter overall survival (OS; p < 0.0001) and may constitute an independent prognostic marker for outcome of patients with metastatic solid tumors, suggesting a strategy to identify patients most likely to benefit from MET-targeted treatments.”(Abstract). However, as noted by Pearce, Piccolo, Bravo, and Freyberg above, disease diagnosis based on gene expression is unpredictable. The unpredictability would be exacerbated to select a patient based on an unpredictable diagnosis.
Furthermore, regarding the “therapeutic effect from a drug,” the state of the art includes multitudes of drugs. However, Lin demonstrates the unpredictability with drug therapy “Patients vary considerably in their response to drug therapy. A drug that proves to be pharmacologically effective in some patients at a given dose may be ineffective or even toxic in others” (Abstract).
As noted above, the claim recites a broad genus of interpreting the diagnosis of claim 1 into selecting a patient but in light of the unpredictability in the art, fails to show a proper sampling of patient selections based on a proper sampling of diagnoses, and further fails to provide instructions how to interpret the diagnosis such that a person having ordinary skill in the art would recognize the applicant was in possession of the claimed invention at the time of filing.
Therefore, for the reasons stated above, the specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claim 3.
Furthermore, regarding claims 4- 18, the claims attempt to further describe gene expression targets of the “drug or therapeutic” of claim 3.
However, as described above, the specification fails to show a proper sampling drugs or therapeutics that are representative of the generic drug or therapy genus claimed, such that a person having ordinary skill in the art would recognize the applicant was in possession of the claimed invention at the time of filing.
Therefore, for the reasons stated above, the specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claims 4- 18.
Regarding claim 19, the claim attempts to further describe a narrower set of diseases subject to the diagnosis of claims 1 and 3, specifically “fibrotic disease, scleroderma and systemic sclerosis, interstitial lung fibrosis, idiopathic pulmonary fibrosis.”
While this instant listing of diseases is narrower than the broad genus of “disease state or condition” in claim 1, the method of diagnosing any of the diseases from this list from a gene expression pattern remains insufficiently described in the specifications as noted above.
Therefore, for the reasons stated above, the specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claim 19.
Regarding claim 20:
Breadth of the Claim
Claim 20 depends from claim 1 and further limits clause 3) embodiment “a regression of the disease state/stage in response to a therapeutic treatment.” The instant claim describes administration of a therapeutic drug, “delivering a therapeutic amount of BLR-200 or another drug based on amino acid sequences found in CCN3…“ Furthermore, the instant claim allows “optimal dosing … is determined after a period of initial drug treatment.” The claim makes no restriction whether the drug of the initial treatment is necessarily the same or different as the drug of optimal dosing treatment.
Support Provided By Specification
The specification is silent regarding dosage instructions for “initial drug treatment” versus “optimal dosing… after initial drug treatment.”
Furthermore, the specification does not provide any working examples toward “another drug based on amino acid sequences found in CCN3, including the IGF-binding domain of CCN3, or an IGF-binding protein.”
Additionally, as described above, the specification does not provide adequate description of a gene expression pattern (a diagnostic readout of changes in the pattern of gene and protein biomarker expression).
The specification cites 21 days and 14 days of BLR-200 treatment “mice were subjected to … BLR200 (intraperitoneal injection 10μg/kg every other day) for 21 days. For a reversal of fibrosis experiment,BLR200 treatment was started at d14 of bleomycin treatment and continued until d28.” [Example 1]. The specification further cites “mice… were injected intraperitoneally 3 times per week with either scrambled peptide (10 μg/kg) or BLR-200 (10 μg/kg). At the end of the treatment period” [Example 2]; and “Mice were subjected, for 21 days, to bleomycin-induced skin fibrosis in the presence or absence of BLR-200” [0166]. Another dosage working example describing 10 days of treatment is provided, “which were injected intraperitoneally 3 times per week with either scrambled peptide (10 μg/kg) or BLR-200 (10 μg/kg).” [Example 3]; and “Ten days after the initiation of bleomycin [and BLR200] injection, protein was extracted from full skin and subjected to tandem mass-tag spectrometry” [0197].
State of Prior Art and Determination of Possession of Invention
Resovi (Resovi et al. Cells. 2020 Apr 13;9(4):952.) describes the dosage of BLR200 “murine orthotopic PDAC model, the two peptides [BLR200], administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis…” (Abstract).
Once again however, Lin (Lin et al. Curr Drug Metab. 2007 Feb;8(2):109-36.) demonstrates the unpredictability with drug therapy, in particular toward “another drug” of the instant claim, “Patients vary considerably in their response to drug therapy. A drug that proves to be pharmacologically effective in some patients at a given dose may be ineffective or even toxic in others” (Abstract).
As noted above, the claim recites a broad genus of delivering a therapeutic amount of BLR-200 or another drug based on amino acid sequences found in CCN3 to treat a broad genus of diseases but in light of the unpredictability in the art, fails to show a proper sampling of diseases treated with BLR-200 or another drug based on amino acid sequences found in CCN3; and furthermore, in light of the unpredictability in the art, the specification fails to provide a broad sampling of dosages of BLR-200 or another drug based on amino acid sequences found in CCN3 such that a person having ordinary skill in the art would recognize the applicant was in possession of the claimed invention at the time of filing.
Therefore, for the reasons stated above, the specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claim 20.
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- 19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim(s) 1 recite(s) “A method of diagnosing a disease state or condition comprising: using a gene expression pattern or a protein expression pattern in a fibroblast cell, a progenitor cell, a stem cell, a myofibroblast cell, or a specific myofibroblast population with specific markers to determine 1) early onset of a diseased state, 2) a progression of the disease state, or 3) a regression of the disease state in response to a therapeutic treatment…” This amounts to a judicial exception because “using an expression pattern to determine a disease state” is merely the mental process (abstract idea) of an evaluation that can be performed in the human mind. The claim further recites the clause, “whereby the disease state/stage is cancer, fibrosis, autoimmune, scleroderma, or systemic fibrosis…” This clause merely a listing and narrowing of the “disease state” recited previously in the claim and is not an additional element.
This judicial exception is not integrated into a practical application because there are no additional elements.
Under Step 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements.
Claim 2 recites the limitation “wherein the gene expression or protein expression pattern is identified among cxcl13, Csf2, Il33, IL6, Cxcl2 and the inflammasome NLRP-3 including IL-18, tLr-2, Illr1, IlIr2, wnt10b or Edn1” is simply a law of nature.
This judicial exception is not integrated into a practical application because there are no additional elements.
Under Step 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements.
Claim 3 recite(s) “The method of Claim 1, further comprising utilizing the diagnostic to select patients…” This amounts to a judicial exception because “utilizing the diagnostic to select patients” is merely a mental process (abstract idea) because this is an evaluation of selecting patients that can be performed in the human mind.
The claim further recites the clause “to have a therapeutic effect from a drug or therapeutic based on the mechanism of action of the drug or therapeutic and the gene and protein biomarkers from the patient samples.” This clause merely describes the selected patient and is not an active step in the method.
This judicial exception is not integrated into a practical application because there are no additional elements.
Under Step 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements.
Regarding claims 4- 18, each of these claims recites “wherein the drug or therapeutic [has intended use].” The instant limitations are additional elements that do not amount to a practical application because it merely recites a generic prophylaxis of drug administration with intended use language.
Under Step 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it merely recites a generic prophylaxis of drug administration with intended use language.
Claim 19 recites the limitation “wherein the disease is a fibrotic disease, scleroderma and systemic sclerosis, interstitial lung fibrosis, idiopathic pulmonary fibrosis” is simply a law of nature.
This judicial exception is not integrated into a practical application because there are no additional elements.
Under Step 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Beerelli (Beerelli US 20050142119 A1).
Regarding claim 1, Beerelli teaches their method, “isolated MPCs [mesenchymal progenitor cells] from a patient are assayed for expression of a large number of genes. The gene expression profile is projected into a profile of gene set expression values ... A reference database … is also created from the isolated MPCs of patients with known states, such as normal and various leukemic disease states. The projected profile is then compared with the reference database ... If the projected profile of the patient matches best with the profile of a particular disease state in the database, the patient is diagnosed as having such disease state.”[0081]; and “The methods of the present invention can also be useful for monitoring the progression of diseases and the effectiveness of treatments” [0082]. This quote from paragraph [0082] reads on embodiment 2), and therefore reads on alternative embodiments 1) and 3). Furthermore, “leukemic disease” reads on the embodiment disease state is cancer and therefore also reads on alternate embodiments (fibrosis, autoimmune, scleroderma, or systemic fibrosis, and includes skin fibrosis, interstitial lung disease (ILD) and /or idiopathic pulmonary disease (IPF), renal and liver fibrosis).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beerelli (Beerelli US 20050142119 A1) as applied to claim 1 above, and further in view of Anand (Anand WO 2021096929 A1).
Claim Interpretation
The instant claim’s recitation “to have a therapeutic effect from a drug or therapeutic based on the mechanism of action of the drug or therapeutic and the gene and protein biomarkers from the patient samples” is merely a statement of a drug performing as a drug performs. Therefore, the broadest reasonable interpretation of the limitation is the patient is administered a therapeutic based on their gene/protein expression profile.
Regarding claim 3, Beerelli teaches all of the elements of claim 1.
Beerelli does not teach the limitation, “isolated their method, “further comprising utilizing the diagnostic to select patients to have a therapeutic effect from a drug or therapeutic based on the mechanism of action of the drug or therapeutic and the gene and protein biomarkers from the patient samples.”
Anand teaches “Methods for using gene expression changes and mutations in neural organoids to identify neural networks that predict the onset of Alzheimer's disease” [Abstract]; and further teaches “the inventive processes disclosed herein provide neural organoid reagents produced from an individual's induced pluripotent stem cells (iPSCs) for identifying patient-specific pharmacotherapy, predictive biomarkers, and developmental and pathogenic gene expression patterns and dysregulation thereof in disease onset and progression, and methods for diagnosing prospective and concurrent risk of development or establishment of Alzheimer’s disease (and comorbidities) in the individual” [0001]; and “administering a therapeutic agent for Alzheimer’s disease to treat the human” [0005]. Here, Anand’s clause “for identifying patient-specific pharmacotherapy” teaches the instant claimed clause “to select patients to have a therapeutic effect from a drug.”
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the invention to have utilized the diagnostic method of Beerelli to identify a patient for pharmacotherapy as taught by Anand because it is simply combining prior art elements according to known methods to yield predictable results. Both Beerelli and Anand utilized gene expression profiles to diagnose and subsequently treat disease. Similarly, both of their gene expression profiles were based on stem cells or derived stem cells. Furthermore, a PHOSITA would have recognized a targeted therapeutic will affect its target as it is intended and select a therapeutic based on the gene expression pattern of interest. Therefore, a PHOSITA would have predicted the use of Beerelli’s diagnostic with Anand’s patient selection.
Claim(s) 4, 5, and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beerelli (Beerelli US 20050142119 A1), and Anand (Anand WO 2021096929 A1) as applied to claim 3 above, and further in view of Koudelka (Koudelka et al. Redox Biol. 2022 Apr;50:102226.).
Regarding claim 4, Beerelli and Anand teach all of the elements of claims 1 and 3.
Beerelli and Anand do not teach the limitation, “wherein the drug or therapeutic suppresses myofibroblast differentiation.”
Koudelka teaches they are in the same field of endeavor, fibrotic disease treatment, “The present study was designed to test whether a small molecule electrophilic nitroalkene, nitro-oleic acid (NO2-OA), could reverse established pulmonary fibrosis; ” and further teaches “NO2-OA suppressed … myofibroblast differentiation” (Abstract).
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the invention to have used Koudelka’s NO2-OA myofibroblast differentiation suppressant with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy because it is simply combining prior art elements according to known methods to yield predictable results. A PHOSITA of fibrotic disease treatment would look for an ideal method of therapy, leading them to the teachings of Beerelli-Anand and Koudelka. Furthermore, a PHOSITA would recognize Koudelka’s NO2-OA molecule would function as it is intended within Beerelli-Anand’s method. Therefore, a PHOSITA would have predicted the combination of Koudelka’s NO2-OA myofibroblast differentiation suppressant with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy.
Regarding claim 5, Beerelli and Anand teach all of the elements of claims 1 and 3.
Beerelli and Anand do not teach the limitation, “wherein the drug or therapeutic suppresses or reverses excessive collagen deposition.”
Koudelka further teaches, “NO2-OA … reversed key indices of fibrosis (… collagen 1A1 and 3A1…)” (Abstract).
Regarding claim 7, Beerelli and Anand teach all of the elements of claims 1 and 3.
Beerelli and Anand do not teach the limitation, “wherein the drug or therapeutic decreases the number of αSMA-expressing myofibroblasts.”
Koudelka further teaches, “NO2-OA … limited the differentiation of FB into α-smooth muscle actin (α-SMA) positive myoFB” (page 2, 2nd column, 1st paragraph).
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beerelli (Beerelli US 20050142119 A1), and Anand (Anand WO 2021096929 A1) as applied to claim 3 above, and further in view of He (He et al. Fundam Res. 2021 Dec 23;2(1):37-47.).
Regarding claim 8, Beerelli and Anand teach all of the elements of claims 1 and 3.
Beerelli and Anand do not teach the limitation, “wherein the drug or therapeutic prevents or suppresses activation of highly contractile myofibroblasts in the fibrotic lesion.”
He teaches they are in the same field of endeavor, disease treatment, “Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis.” He further teaches “we have shown that (-)-blebbistatin (Ble), a non-muscle myosin II inhibitor, displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo;” and “Ble reduced mechanical [myofibroblast] contraction,” (Abstract).
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the invention to have used He’s Ble myofibroblast activation suppressant with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy because it is simply combining prior art elements according to known methods to yield predictable results. A PHOSITA of fibrotic disease treatment would look for an ideal method of therapy, leading them to the teachings of Beerelli-Anand and He. Furthermore, a PHOSITA would recognize He’s Ble molecule would function as it is intended within Beerelli-Anand’s method. Therefore, a PHOSITA would have predicted the combination of He’s Ble myofibroblast activation suppressant with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beerelli (Beerelli US 20050142119 A1), and Anand (Anand WO 2021096929 A1) as applied to claim 3 above, and further in view of Kang (Kang et al. Nanoscale. 2020 Mar 21;12(11):6385-6393.).
Regarding claim 10, Beerelli and Anand teach all of the elements of claims 1 and 3.
Beerelli and Anand do not teach the limitation, “wherein the drug or therapeutic alters the protein expression and gene expression of either or all in combination CCN1, CCN2, CCN3, and CCN4.”
Kang teaches they are in the same field of endeavor, fibrotic disease treatment, “we examine the anti-fibrotic activity of RNAi therapy utilizing siRNA against CTGF with a new drug delivery system (DDS), ‘DegradaBALL’…;” and “siCTGF, named ‘LEM-S401’, showed highly durable and effective CTGF [CCN2] gene-silencing”(Abstract).
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the invention to have used Kang’s LEM-S401 CCN2 gene-silencer with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy because it is simply combining prior art elements according to known methods to yield predictable results. A PHOSITA of fibrotic disease treatment would look for an ideal method of therapy, leading them to the teachings of Beerelli-Anand and Kang. Furthermore, a PHOSITA would recognize Kang’s LEM-S401 molecule would function as it is intended within Beerelli-Anand’s method. Therefore, a PHOSITA would have predicted the combination of Kang’s LEM-S401 CCN2 gene-silencer with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beerelli (Beerelli US 20050142119 A1), and Anand (Anand WO 2021096929 A1) as applied to claim 3 above, and further in view of Lu (Lu et al. Acta Pharmacol Sin. 2021 Nov;42(11):1808-1820.).
Regarding claim 12, Beerelli and Anand teach all of the elements of claims 1 and 3.
Beerelli and Anand do not teach the limitation, “wherein the drug or therapeutic biologically alters YAP I-gene expression and or YAP activity.”
Lu teaches they are in the same field of endeavor, fibrotic disease treatment, “we investigated the effects of pantoprazole (PPZ), a PPI [proton pump inhibitor], against liver fibrosis in a bile duct ligation (BDL) rat model, human hepatic stellate cell (HSC) line LX-2 and mouse primary HSCs (pHSCs);” and “transcriptome analysis and … validation in PPZ-treated LX-2 cells, … revealed that PPZ inhibited the expression of Yes-associated protein (YAP)”(Abstract).
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the invention to have used Lu’s PPZ YAP1 regulator with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy because it is simply combining prior art elements according to known methods to yield predictable results. A PHOSITA of fibrotic disease treatment would look for an ideal method of therapy, leading them to the teachings of Beerelli-Anand and Lu. Furthermore, a PHOSITA would recognize Lu’s PPZ molecule would function as it is intended within Beerelli-Anand’s method. Therefore, a PHOSITA would have predicted the combination of Lu’s PPZ YAP1 regulator with Beerelli-Anand’s method of utilizing the diagnostic to select patients for drug therapy.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beerelli (Beerelli US 20050142119 A1), and Anand (Anand WO 2021096929 A1) as applied to claim 3 above, and further in view of Nie (Nie et al. J Ovarian Res. 2021 Sep 3;14(1):115.) and Allahyari (Allahyari et al. Nanomedicine. 2021 Jun;34:102384.) as evidenced by Tsekrekou (Tsekrekou, et al. In: Srivastava, R., Shankar, S. (eds) Stem Cells and Human Diseases. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2801-1_25).
Regarding claim 15, Beerelli and Anand teach all of the elements of claims 1 and 3.
Beerelli and Anand do not teach the limitation, “wherein the drug or therapeutic prevents the increase in IL6 and Cxcl2 expression in the inflammatory fibroblast subpopulation.”
Nie teaches they are in the same field of endeavor, cancer disease treatment, “This study was designed to reveal the important role of CXCL2 in platinum resistance in epithelial ovarian cancer (EOC).” (Abstract). Nie then teaches their method of preventing the increase in Cxcl2 “knocking down CXCL2 or co-culturing with neutralizing antibody to CXCL2” (Abstract). Nie further teaches their therapies were performed within stem cells “CXCL2 overexpressing maintained cell stemness” (Abstract).
Allahyari teaches they are in the same field of endeavor, cancer disease treatment, “High concentrations of adenosine and interleukin (IL)-6 in the tumor microenvironment have been identified as one of the leading causes of cancer growth. Thus, we decided to inhibit the growth of cancer cells by inhibiting the production of adenosine and IL-6 in the tumor environment at the same time” (Abstract). Allahyari then teaches their method of preventing the increase in Cxcl2 “we used chitosan-lactate-PEG-TAT (CLP-TAT) nanoparticles (NPs) loaded with siRNA molecules against CD73, an adenosine-producing enzyme, and IL-6.” (Abstract). Furthermore, Allahyari provides motivation to explore additional variations in their research “These findings suggest that combination therapy using siRNA-loaded CLP-TAT NPs against CD73 and IL-6 molecules could be an effective treatment strategy against cancer that needs further study” (Abstract); and “… may have good potential in use along with traditional radiotherapy, chemotherapy, and dendritic cell-based cancer immunotherapy to achieve maximum tumoricidal activities” (page 11, 1st column, 3rd paragraph). Tsekrekou provides evidence Allayhari’s therapy is withing stem cells “Continuously increasing evidence has shown that most primary tumours contain subpopulations of cells with stem-like characteristics ... This is further supported by the identification of several common key pathways and genes between cancer and normal stem cells involved mainly in proliferation, differentiation and de-differentiation steps” (Abstract).
It would have been obvious for a person having ordinary skill in the art (PHOSITA) before the effective filing date of the invention to have used the expression reducing drug or therapies taught by Nie (Cxcl2) and Allahyari (Il-6) with the method taught by Beerelli-Anand because Allahyari provided the teaching and motivation to further combine their therapy with other known methods such Nie’s and Beerelli-Anand’s. As cited above, Allahyari suggested exploring their therapeutic method further and combining it with other therapies and methods. Furthermore, Allahayari’s Il-6 therapy showed successful results in limiting increase in Il-6 expression in stem cells. Nie also demonstrated success reducing increased expression of Cxcl2 in stem cells. Therefore, in view of the success of Nie and Allahyari, a PHOSITA would have similarly had a reasonable expectation of success selecting a patient according to Beerelli-Anand’s method and further combining the drug or therapies of Nie and Allahyari.
Conclusion
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/AARON DUREL WARD/ Examiner, Art Unit 1636
/NEIL P HAMMELL/ Supervisory Patent Examiner, Art Unit 1636
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