Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 1 of 26 PageID #: 878
`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 1 of 26 PageID #: 878
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`EXHIBIT 20
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`EXHIBIT 20
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 2 of 26 PageID #: 879
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`Docket No.: RA V-34298
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Ravinder S. DHALLAN
`
`Confirmation No.: 8885
`
`Application No.:
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`11/212,812
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`Art Unit:
`
`1634
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`Filed:
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`For:
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`August 26, 2005
`
`Examiner:
`
`Ethan C. Whisenant
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`METHODS FOR DETECTION OF
`GENETIC DISORDERS
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`CERTIFICATION UNDER 37 CFR 1.8(a) and I.IO
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`I hereby certify that, on the date shown below, this correspondence is being transmitted via the Patent Electronic Filing
`System (EFS) addressed to the U.S. Patent and Trademark Office.
`
`Dato
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`c_,/9,,
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`,2009 ~ - /
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`AMENDMENT IN RESPONSE TO NON-FINAL OFFICE ACTION
`
`Mail Stop Amendment (via EFS)
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Sir:
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`INTRODUCTORY COMMENTS
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`This is in response to the non-final Office Action mailed December 4, 2008 (Part of
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`Paper No./Mail Date 20081125), for which a response was due on March 4, 2009. Applicant hereby
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`requests, with payment, a three-month extension of time, thereby extending the deadline for
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`response to June 4, 2009. Accordingly, this response is timely filed. Reconsideration and
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`allowance of the pending claims, as amended, in light of the remarks presented herein are
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`respectfully requested.
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`Amendments to the claims begin on page 2 of this paper.
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`Remarks/Arguments begin on page 8 of this paper.
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`

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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 3 of 26 PageID #: 880
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`Application No.: 11/212,812
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`2
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`Docket No.: RA V-34298
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`AMENDMENTS TO THE CLAIMS
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`This listing of claims will replace all prior versions, and listings, of claims
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`in the application:
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`1. (Currently amended) A method for detecting a free nucleic acid, wherein said
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`method comprises: (a) isolating free nucleic acid from a non-cellular fraction of a sample, wherein
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`said sample comprises an agent that impedes cell lysis, if cells are present, and wherein said agent is
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`selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor; and
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`(b) detecting the presence or absence of the free nucleic acid.
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`2. (Original) The method of claim 1, wherein said sample is obtained from a source
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`selected from the group consisting of bacteria, viruses, fungi, mycobacteria, protozoa, molds, yeasts,
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`plants, humans, non-humans, multi-cellular parasite, animals, and archeabacteria.
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`3. (Original) The method of claim 2, wherein the sample is obtained from a human
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`source.
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`4. (Previously presented) The method of claim 1, wherein the sample is obtained from a
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`source selected from the group consisting of: tissue, blood, serum, plasma, saliva, urine, tear,
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`vaginal secretion, umbilical cord blood, chorionic villi, amniotic fluid, embryonic tissue, lymph
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`fluid, cerebrospinal fluid, mucosa secretion, peritoneal fluid, ascitic fluid, fecal matter, and_body
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`exudates.
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`5. (Original) The method of claim 4, wherein said sample is blood.
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`6. (Original) The method of claim 5, wherein said sample is obtained from plasma from
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`said blood.
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 4 of 26 PageID #: 881
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`Application No.: 11/212,812
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`3
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`Docket No.: RA V-34298
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`7. (Original) The method of claim 1, wherein said nucleic acid contains at least one
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`mutation.
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`8. (Original) The method of claim 7, wherein said mutation is selected from the group
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`consisting of: single point mutation, multiple point mutations, an insertion, a frameshift, a
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`truncation, a deletion, a duplication, and a transversion.
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`9. (Previously presented) The method of claim 7, wherein said mutation is in a gene
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`selected from the group consisting of: BRCAl, BRCA2, MSH6, MSH2, MLHl, RET, PTEN,
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`ATM, H-RAS, p53, ELAC2, CDHl, APC, AR, PMS2, MLH3, CYPlAl, GSTPl, GSTMl, AXIN2,
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`CYP19, MET, NATI, CDKN2A, NQOl, trc8, RAD51, PMS1, TGFBR2, VHL, MC4R, POMC,
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`NROB2, UCP2, PCSKI, PPARG, ADRB2, UCP3, glurl, cart, SORBS1, LEP, LEPR, SIMI, TNF,
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`IL-6, IL- 1, IL-2, IL-3, ILIA, TAP2, THPO, THRB, NBS1, RBM15, LIF, MPL, RUNXI, Her-2,
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`glucocorticoid receptor, estrogen receptor, thyroid receptor, p21, p27, K-RAS, N-RAS,
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`retinoblastoma protein, Wiskott-Aldrich (WAS) gene, Factor V Leiden, Factor II (prothrombin),
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`methylene tetrahydrofolate reductase, cystic fibrosis, LDL receptor, HDL receptor, superoxide
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`dismutase gene, SHOX gene, genes involved in nitric oxide regulation, genes involved in cell cycle
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`regulation, tumor suppressor genes, oncogenes, genes associated with neurodegeneration, and genes
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`associated with obesity.
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`10. (Previously presented) The method of claim 1, wherein said free nucleic acid is
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`from a species different from the species from which the sample was taken.
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`11. (Original) The method of claim 10, wherein said different species is from a group
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`consisting of bacteria, viruses, fungi, mycobacteria, protozoa, molds, yeasts, plants, humans, non(cid:173)
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`humans, multi-cellular parasite, animals, and archeabacteria.
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`12. (Original) The method of claim 11, wherein said different species is a bacteria.
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 5 of 26 PageID #: 882
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`Application No.: 11/212,812
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`4
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`Docket No.: RA V-34298
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`13. (Original) The method of claim 12, wherein said bacterial species is a gram-positive
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`or gram-negative bacteria.
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`14. (Previously presented) The method of claim 13, wherein said bacteria is selected
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`from the group consisting of: Acidaminococcus, Acinetobacter, Acinetobacter Iwoffi, Aeromonas,
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`Alcaligenes, Bacteroides, Bordetella, Branhamella, Brucella, Calymmatobacterium, Campylobacter,
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`Cardiobacterium, Chromobacterium, Citrobacter, Citrobacter freundii, Coliform group,
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`Edwardsiella, Enterobacter, Enterobacter sakazaki, Enterobacter aerogenes, Enterobacter cloacae,
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`Enterobacter agglomerans, Enterococcus, Enterococcus faecalis, Enterococcus faecium,
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`Escherichia, Escherichia coli, Escherichia coli-0157, Flavobacterium, Francisella, Fusobacterium,
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`Haemophilus, Hafuia alvei, Klebsiella, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella,
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`Moraxella, Morganella, Morganella morganii, Neisseria, Pasturella, Plesiomonas, Proteus,
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`Providencia, Proteus mirabilis, Pseudomonas, Pseudomonas aeruginosa, Salmonella, Salmonella
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`typhimurium, Serratia, Serratia marcescens, Shigella, Shigella flexneri, Streptobacillus, Veillonella,
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`Vibrio, Vibrio cholera, Y ersinia, Yersinia entercolitica, Xanthomanas maltophiia, Staphylococcus,
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`Staphylococcus albus, Staphylococcus aureus, Streptococcus, Streptococcus dysgalacticae,
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`Micrococcus, Peptococcus, Peptostreptococcus, Bacillus, Bacillus cereus, Clostridium,
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`Lactobacillus, Listeria, Listeria monocytogenes, Erysipelothrix, Propionibacterium, Eubacterium,
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`and Corynebacterium.
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`15. (Original) The method of claim 11, wherein said different species is a virus.
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`16. (Original) The method of claim 15, wherein said virus is a DNA virus or an RNA
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`virus.
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`Application No.: 11/212,812
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`5
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`Docket No.: RA V-34298
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`17. (Original) The method of claim 15, wherein said virus is selected from the group
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`consisting of: retrovirus, pathogenic virus, non-pathogenic virus, drug-resistant virus, drug(cid:173)
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`sensitive virus, adeno-associated virus, bird flu virus, cauliflower mosaic virus, cytomegalovirus
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`(CMV), dengue virus, Epstein-Ban· virus, feline leukemia virus, flavivirus, haemophilus influenza,
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`hemorrhagic fever viruses, hepatitis virus including hepatitis A, B, C, and E, viruses, herpes simplex
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`virus, human herpesvirus type A and B, human immunodeficiency virus (HIV), human papilloma
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`virus, human T-cell lymphotrophic virus, HTL V Type I, HTL V Type II, influenza virus, Japanese
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`encephalitis virus, moraxella catarrhalis, non-typeable haemophilus, reovirus, parainfluenza,
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`parvovirus, papova virus, Respiratory syncytial virus, Rubella virus, rotavirus, SARS, tomato bushy
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`stunt virus, varicella-zoster virus, and vaccinia virus.
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`18. (Original) The method of claim 11, wherein said different species is a fungus.
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`19. (Original) The method of claim 18, wherein said fungus is a drug-sensitive fungus
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`or a drug-resistant fungus.
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`20. (Original) The method of claim 18, wherein said fungus is selected from the group
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`consisting of: Candida, Candida albicans, Candida tropicalis, Candida parapsilosis, Candida
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`stellatoidea, Candida krusei, Candida parakrusei, Candida lusitanae, Candida pseudotropicalis,
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`Candida guilliermondi, Candida glabrata, Aspergillus, Aspergillus fumigatis, Aspergillus flavus,
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`Aspergillus niger, Aspergillus nidulans, Aspergillus terreus, Aspergillus sydowi, Aspergillus
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`flavatus, Aspergillus glaucus, Cryptococcus, Histoplasma, Coccidioides, Paracoccidioides,
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`Blastomyces, Basidiobolus, Conidiobolus, Rhizopus, Rhizomucor, Mucor, Absidia, Mortierella,
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`Cunninghamella, Saksenaea, Pseudallescheria, Sporotrichosis, Fusarium, Trichophyton,
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`Trichosporon, Microsporum, Epidermophyton, Scytalidium, Malassezia, Actinomycetes,
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`Sporothrix, Penicillium, Saccharomyces and Pneumocystis.
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`21. (Previously presented) The method of claim 1, wherein isolation of free nucleic acid
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`comprises a centrifugation step.
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`Application No.: 11/212,812
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`Docket No.: RA V-34298
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`22. (Original) The method of claim 21, wherein the centrifugation step is performed
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`with the centrifuge braking power set to zero.
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`23. (Original) The method of claim 21, wherein the centrifugation step is performed at
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`a speed selected from the group consisting of 0-50 rpm, 50-100 rpm, 100-200 rpm, 200-300 rpm,
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`300-400 rpm, 400-500 rpm, 500-600 rpm, 600-700 rpm, 700-800 rpm, 800-900 rpm, 900-1000 rpm,
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`1000-2000 rpm, 2000-3000 rpm, 3000-4000 rpm, 4000-5000 rpm, 5000-6000 rpm, 6000-7000 rpm,
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`7000-8000 rpm, and greater than 8000 rpm.
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`24. Cancelled.
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`25. Cancelled.
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`26. (Original) The method of claim 1, wherein said method is used to detect, diagnose,
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`or monitor a disease.
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`27. (Original) The method of claim 26, wherein said disease is cancer.
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`28. (Original) The method of claim 27, wherein said cancer is selected from the group
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`consisting of: carcinoma of the bladder, breast, bronchial, colon, kidney, liver, lung, esophagus,
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`gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin; small cell lung cancer,
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`squamous cell carcinoma, hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic
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`leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's
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`lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, hematopoietic
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`tumors of myeloid lineage, acute and chronic myelogenous leukemias, myelodysplastic syndrome
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`and promyelocytic leukemia, tumors of mesenchymal origin, fibrosarcoma and rhabdomyosarcoma,
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`tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma and
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`schwannomas, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
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`keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 8 of 26 PageID #: 885
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`Application No.: 11/212,812
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`Docket No.: RA V-34298
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`29. (Original) The method of claim 1, wherein said method is used to monitor response
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`to treatment.
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`30. (Original) The method of claim 29, wherein the treatment is selected from the group
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`consisting of surgery, radiation, lifestyle change, dietary protocol, supplementation and
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`administration of a drug.
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`31. (Original) The method of claim 30, wherein the treatment is administration of a
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`drug.
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`3 2. (Previously presented) The method of claim 31, wherein said drug is selected from
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`the group consisting of: chemotherapeutic agents, anti-bacterial agents, anti-viral agents, anti(cid:173)
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`fungal agents, targeted-cancer drugs, cytoxoic agents, cytostatic agents, anti-proliferative agents,
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`A vastin, altretamine, busulfan, chlorambucil, cyclophosphamide, Erbitux, Rituxan, ifosfamide,
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`mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine,
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`thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine,
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`streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM2 l 6, JM335,
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`fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone
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`acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone,
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`bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone,
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`mitomycin-c, plicamycin, paclitaxel, docetaxel, CPT-11, epothilones , topotecan, irinotecan, 9-
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`amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine,
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`vinorelbine, procarbazine, asparaginase, pegaspargase, methoxtrexate, octreotide, estramustine, and
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`hydroxyurea.
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`33. (Cancelled)
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 9 of 26 PageID #: 886
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`Application No.: 11/212,812
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`8
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`Docket No.: RA V-34298
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`REMARKS
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`Claims 1-32 are pending in the present application. Claims 24 and 25 previously have
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`been withdrawn, and claim 33 previously has been cancelled. By virtue of this response, claim 1
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`has been amended and claims 24 and 25 have been cancelled. Accordingly, claims 1-23 and 26-32
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`are currently under consideration. Allowance of the pending claims is respectfully requested.
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`With respect to all amendments and cancelled claims, Applicant has not dedicated or
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`abandoned any unclaimed subject matter and, moreover, has not acquiesced to any rejections and/or
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`objections made by the Patent Office. Applicant reserves the right to pursue prosecution of any
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`presently excluded claim embodiments in future continuation and/or divisional applications.
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`Claim Amendments
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`Claim 1 has been amended to recite "non-cellular fraction." Support for the amendment to
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`claim 1 can be found at least at page 107, paragraph [0504]; at least at page 202, paragraph [0812],
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`and at least at page 246 at paragraphs [0978]-[0979]. No new matter has been added by virtue of
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`this amendment.
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`Claims Rejections Under 35 U.S.C. § 102
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`Claims 1-5, 10-11, 15-17, 21, and 23: The Office has rejected claims 1-5, 10-11, 15-17,
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`21, and 23 under 35 U.S.C. §102(b) as being anticipated by Kiessling [US 5,618,664 (1997)].
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`Applicant respectfully traverses this rejection.
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`Amended claim 1 recites a method for detecting free nucleic acid comprising: (a)
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`isolating free nucleic acid from a non-cellular fraction of a sample, wherein said sample comprises
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`an agent that impedes cell lysis, if cells are present, and wherein said agent is selected from the
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`group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor; and (b) detecting the
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`presence or absence of the free nucleic acid. Claims 2-5, 10-11, 15-17, 21, and 23 all depend
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`(directly or indirectly) from independent claim 1, and therefore, incorporate all elements of
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`independent claim 1.
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 10 of 26 PageID #: 887
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`Application No.: 11/212,812
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`Docket No.: RA V-34298
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`To anticipate a claim, a prior art reference must teach or suggest each and every element
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`of the claim. Applicant respectfully submits that Kiessling does not anticipate claims 1-5, 10-11,
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`15-17, 21, and 23 because the reference fails to teach or suggest all elements of claims 1-5, 10-11,
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`15-17, 21, and 23. By contrast to the method of claims 1-5, 10-11, 15-17, 21, and 23, which all
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`involve isolating free nucleic acid from a non-cellular fraction of a sample, the methods disclosed
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`by Kiessling involve analysis of fixed cells. Kiessling fails to teach or suggest a method
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`comprising, inter alia, isolating free nucleic acid from a non-cellular fraction of a sample, wherein
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`said sample comprises an agent that impedes cell lysis, if cells are present, and wherein said agent is
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`selected from the group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor; and
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`(b) detecting the presence or absence of the free nucleic acid.
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`Kiessling discloses methods and kits for reducing the transmission of infectious agents
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`contained in biological fluid samples. The methods disclosed in Kiessling involve contacting the
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`biological sample with a fixative solution containing a fixative present at a concentration sufficient
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`to fix analytes contained therein. The methodology disclosed in Kiessling "fixes'' leukocytes, and
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`subsequently DNA is isolated from the fixed leukocytes (see col. 10, lines 43-49). Thus, Kessling
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`teaches isolation of DNA from a cellular fraction, i.e, cells. Nowhere does Kiessling teach or
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`suggest a method for detecting free nucleic acid comprising, inter alia, isolating free nucleic acid
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`from a non-cellular fraction of a sample.
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`At col. 9, lines 40-45, Kiessling states "Thefu:ed blood cells were recovered from the
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`formaldehyde-blood solution free of hemoglobin and red blood cell membranes by overnight
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`settling or by repeated routine centrifugation and resuspension in fresh fixative containing reduced
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`formaldehyde concentrations. ( emphasis added). Kiessling recovers the fixed blood cells either by
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`overnight settling or centrifugation. Kiessling recovers DNA from a cellular fraction of the sample.
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`The non-cellular fraction, in this case the supernatant, was not isolated or analyzed by Kiessling.
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`The Kiessling methods do not involve the isolation of free nucleic acid from a non-cellular fraction
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`of a sample, and therefore, do not teach methods for detection of free nucleic acid from a non(cid:173)
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`cellular fraction, let alone the use of a fixative in such methods.
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`Furthermore, Kiessling's disclosure that fixatives may used to reduce the transmission of
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`infectious agents would be of no value to one ordinary skill in the art working with free nucleic
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`10
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`Docket No.: RA V-34298
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`acid. Absent Applicant's teachings (e.g., Example 4), the advantage of adding an agent that
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`impedes cell lysis to a sample when isolating free nucleic acid from a non-cellular fraction would
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`not have been apparent to one of ordinary skill in the art.
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`Since Kiessling does not teach or suggest each and every element of claims 1-5, 10-11,
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`15-17, 21, and 23, Applicant respectfully requests that the rejection of claims 1-5, 10-11, 15-17, 21,
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`and 23 under 35 U.S.C. § 102(b) be withdrawn.
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`Claims Rejections Under 35 U.S.C. § 103
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`A. Claims 1-8, 21-23, and 26: The Office has rejected claims 1-8, 21-23, and 26 under
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`35 U.S.C. § I03(a) as being unpatentable over Amicucci et al. (Clinical Chemistry 46(2): 301-302,
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`2000) or Saito et al. (The Lancet 356:1170 (2000)) in view of Kiessling (U.S. Patent No.
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`5,618,664). Applicant respectfully traverses this rejection.
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`Amended claim 1 recites a method for detecting free nucleic acid comprising: (a)
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`isolating free nucleic acid from a non-cellular fraction of a sample, wherein said sample comprises
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`an agent that impedes cell lysis, if cells are present, and wherein said agent is selected from the
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`group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor; and (b) detecting the
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`presence or absence of the free nucleic acid. Claims 2-8, 21-23 and 26 all depend (directly or
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`indirectly) from independent claim 1, and therefore, incorporate all elements of independent claim
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`1.
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`The factors a Court considers when determining obviousness and non-obviousness in the
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`United States were outlined by the Supreme Court in Graham et al. v. John Deere Co. of Kansas
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`City et al., 383 U.S. 1 (1966) and are commonly referred to as the "Graham factors." The Court
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`held that obviousness should be determined by looking at: (1) the scope and content of the prior art;
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`(2) the level of ordinary skill in the prior art; (3) the difference between the claimed invention and
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`the prior art; and (4) objective evidence of non-obviousness. In addition, the Court outlined several
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`factors that show "objective evidence of non-obviousness" and include commercial success, long(cid:173)
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`felt need but unsolved needs, and failure of others. In a recent Supreme Court decision, KSR v.
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`Teleflex, the Court re-affirmed the continuing validity of its decision in Graham as the touchstone
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`for an obviousness analysis, stating "there is no necessary inconsistency between the idea
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`underlying the TSM [teaching, suggestion, motivation] test and the Graham analysis" (slip opinion
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`at 15).
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`Moreover, the Patent and Trademark Office published in the Federal Register on October 10,
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`2007 Examination Guidelines for Determining Obviousness under 35 U.S.C. § 103 in view of the
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`Supreme Court Decision KSR International Co. v. Teleflex, Inc. (72 Federal Register 57526). The
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`Examination Guidelines state that the key to supporting any rejection under 35 U.S.C. § 103 is the
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`clear articulation of the reasons why the claimed invention would have been obvious and identifies
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`seven rationales that can be used to support the legal conclusion of obviousness (see page 57528).
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`One rationale identified in the Federal Register Examination Guidelines at page 57534 is as follows:
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`G. Some Teaching, Suggestion or Motivation in the Prior Art That Would Have Led
`One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior
`Art Reference or To Combine Prior Art Reference Teachings To Arrive at the
`Claimed Invention.
`
`To reject a claim based on this rationale, Office personnel must resolve the Graham
`factual inquiries. Office personnel must then articulate the following: (1) a finding
`that there was some teaching, suggestion, or motivation, either in the references
`themselves or in the knowledge generally available to one of ordinary skill in the art,
`to modify the reference or to combine reference teachings; (2) a finding that there
`was reasonable expectation of success; and (3) whatever additional findings based on
`the Graham factual inquiries may be necessary, in view of the facts of the case under
`consideration, to explain a conclusion of obviousness.
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`Methods for detecting free nucleic acid serve a long felt need in the medical community,
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`including as a method for the detection of cancer. As discussed in Example 7, paragraph [0626] of
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`the present application, which should not be construed to limit the scope of the invention in any
`
`manner, non-invasive methods for the detection of various types of cancer have the potential to
`
`reduce morbidity and mortality from the disease. For instance, several techniques for the early
`
`detection of colorectal tumors have been developed including colonoscopy, barium enemas, and
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`sigmoidoscopy; however the techniques are limited in use because they are invasive, which causes a
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`low rate of patient compliance.
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`Application No.: 11/212,812
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`12
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`Docket No.: RA V-34298
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`Methods for detecting free nucleic acid as claimed in claims 1-8, 21-23, and 26 may be
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`useful in identifying early stage diseases, including, but not limited to, detecting tumors. Thus, the
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`methods encompassed within claims 1-8, 21-23, and 26 provide a solution to a long-felt need in the
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`medical community.
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`Applicant has discovered that the addition of a cell lysis inhibitor to a sample prior to
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`detecting the presence of free nucleic acid can significantly and unexpectedly increase the
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`proportion of free nucleic acid obtained from the non-cellular fraction of a sample. One
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`representative example, which should not be construed to limit the scope of the invention in any
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`manner, demonstrating the impact of using an agent to impede cell lysis is provided in Example 4 of
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`Applicant's specification. In this example, free nucleic acid is fetal nucleic acid but the principal
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`applies to any free nucleic acid. Blood samples were obtained from pregnant women, and each
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`sample was split into two aliquots: one was treated with an agent to impede lysis of cells (formalin)
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`and the other was left untreated. As shown in Example 4, the amounts of fetal DNA isolated from
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`maternal blood samples were significantly, and unexpectedly, higher for samples treated with
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`formalin. As indicated in paragraph [0515] in Example 4, in one set of experiments, the percentage
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`of fetal DNA present in the sample without formalin was 1.56%, whereas the percentage of fetal
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`DNA in the sample treated with formalin was 25%. The high percentage of fetal DNA, which can
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`be obtained from the plasma of maternal blood to which a cell lysis inhibitor (e.g. formalin) has
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`been added, is further demonstrated in Example 15 of Applicant's specification (see, e.g., Table
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`XXI and XXII).
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`Furthermore, the Manual for Patent Examining Procedure states that "greater than
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`expected results are evidence of non-obviousness." See MPEP 716.02(a). As discussed above,
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`prior to the Applicants' work, small amounts of free nucleic acid could be obtained from samples.
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`However, using the methods encompassed within claims 1-8, 21-23, and 26, the mean percentage of
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`free nucleic acid obtained from a sample is unexpectedly and significantly increased. Thus, the
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`methods encompassed within claims 1-8, 21-23, and 26 produce unexpected results, and therefore,
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`the claimed methods would not have been obvious to one of ordinary skill in the art.
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`WHD\6493207. I
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 14 of 26 PageID #: 891
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`Application No.: 11/212,812
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`13
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`Docket No.: RA V-34298
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`Amicucci et. al discloses a method using maternal plasma for prenatal diagnosis of
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`myotonic dystrophy (DM) by monitoring the pregnancy of an unaffected woman whose husband
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`was affected by DM. Saito et al. disclose a method of detecting free DNA in plasma. Amicucci et
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`al. and Saito et al. fail to teach or suggest a method for detecting free nucleic acid comprising, inter
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`alia, isolating free nucleic acid from a non-cellular fraction of a sample, wherein an agent that
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`impedes cell lysis has been added. This element is neither taught nor suggested by Amicucci et al.
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`or Saito et al. either alone or in combination with Kiessling. For a more detailed explanation of the
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`deficiencies of the Kiessling reference, please see pages 8-10 of the present response.
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`The Examiner asserts that one of ordinary skill in the art would have been motivated to
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`combine the teachings of Amicucci et al. or Saito et al. with the teachings of Kiessling. Applicant
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`respectfully submits that there is no motivation to combine the teachings of the reference Kiessling
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`with the teachings of the reference Amicucci et al. or Saito et al. The methods disclosed in
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`Amicucci et al. and Saito et al. encompass free nucleic acid from a non-cellular fraction of a sample
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`while the methods disclosed in Kiessling encompass fixing cells and then lysing cells to analyze the
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`analytes therein (a cellular fraction), which would be of no utility to one of ordinary skill in the art
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`working with free DNA from a non-cellular fraction. Thus, there is no motivation to combine the
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`disclosures of Kiessling with Amicucci et al or Saito et al.
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`The Examiner asserted that one of ordinary skill in the art would be motivated to
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`combine the teachings of Amicucci et al. or Saito et al. with the teachings of Kiessling to protect
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`laboratory personnel from accidental exposure to infectious agents. However, there are numerous
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`methods available to achieve this goal, and there is no motivation to choose the method disclosed by
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`Kiessling. For example, U.S. Patent No. 5,985,260 discloses a method of disinfecting blood and
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`blood components comprising preparing and immediately adding active albumin-iodine complex to
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`the material to be disinfected. In addition, Moreton and Delves report that the addition ofVirkon,
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`which is a viral disinfectant, to clinical samples can reduce the likelihood of infection (Moreton and
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`Delves, J. Anal. At. Spectrom, 1999, 14:893-894). Thus, if one of ordinary skill in the art was
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`concerned with reducing the risk of exposure to infections agents, there are numerous methods
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`available and there is nothing that would lead one of ordinary skill to the disclosure of Kiessling.
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 15 of 26 PageID #: 892
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`Application No.: 11/212,812
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`14
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`Docket No.: RA V-34298
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`The methods disclosed in claims 1-8, 21-23, and 26 serve a long-felt need in the medical
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`community, and provide unexpected results, and are therefore non-obvious. In addition, there is no
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`motivation to combine the disclosures of Amicucci et al. or Saito et al. with Kiessling, and thus,
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`Applicant respectfully requests that the rejection of claims 1-8, 21-23, and 26 under 35 U.S.C. § 103
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`be withdrawn.
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`B. Claims 1-9, 21-23 and 26-28: The Office has rejected claims 1-9, 21-23, and 26-28
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`under 35 U.S.C. § 103(a) as being unpatentable over Ankar et al. (Gastroenterology l 12:1114-1120,
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`1997) in view of Kiessling (US 5,618,664 (1997)). Applicant respectfully traverses this rejection.
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`Amended claim 1 recites a method for detecting free nucleic acid comprising: (a)
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`isolating free nucleic acid from a non-cellular fraction of a sample, wherein said sample comprises
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`an agent that impedes cell lysis, if cells are present, and wherein said agent is selected from the
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`group consisting of membrane stabilizer, cross-linker, and cell lysis inhibitor; and (b) detecting the
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`presence or absence of the free nucleic acid. Claims 2-9, 21-23 and 26-28 all depend (directly or
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`indirectly) from independent claim 1, and therefore, incorporate all elements of independent claim
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`1. The methods recited within claims 1-9, 21-23, and 26-28 serve a long-felt need in the medical
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`community and provide unexpected results as discussed above with respect to the rejection of
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`claims 1-8, 21-23, and 26 under 35 U.S.C. § 103.
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`To establish a prima facie case of obviousness, the cited references must teach or suggest
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`each and every claim limitation. The factors a Court considers when determining obviousness and
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`non-obviousness in the United States were outlined by the Supreme Court in Graham et al. v. John
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`Deere Co. of Kansas City et al., 383 U.S. 1 (1966) and are commonly referred to as the "Graham
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`factors." The Court held that obviousness should be determined by looking at: (1) the scope and
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`content of the prior art; (2) the level of ordinary skill in the prior art; (3) the difference between the
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`claimed invention and the prior art; and (4) objective evidence of non-obviousness. In addition, the
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`Court outlined several factors that show "objective evidence of non-obviousness" and include
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`commercial success, long-felt need but unsolved needs, and failure of others. In a recent Supreme
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`Court decision, KSR International Co. v. Teleflex, Inc., the Court re-affirmed the continuing
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`validity of its decision in Graham as the touchstone for an obviousness analysis, stating "there is no
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`WHD\6493207.1
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`Case 1:20-cv-01644-RGA Document 1-20 Filed 12/03/20 Page 16 of 26 PageID #: 893
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`Application No.: 11/212,812
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`Docket No.: RA V-34298
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`necessary inconsistency between the idea underlying the TSM [teaching, suggestion, motivation]
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`test and the Graham analysis" (slip opinion at 15).
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`Moreover, the Patent and Trademark Office published in the Federal Register on October 10,
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`2007 Examination Guidelines for Determining Obviousness under 35 U.S.C. § 103 in view of the
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`Supreme Court Decision KSR International Co. v. Teleflex, Inc. (72 Federal Register 57526). The
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`Examination Guidelines state that the key to supporting any rejection u