Diagnostic assay for cancer

The group of patents falling in this category is more numerous than the other groups.  To the extent that any of the assays for detecting cancerous conditions use one of the assays for telomerase activity or for nucleic acids encoding telomerase, the claims of these patents are dominated by the patents in the two groups discussed above.

One of the leaders in this area is the University of Texas.  It owns the first three patents in the table, US 5,639,613US 5,648,215; and US 5,693,474.  In patents US ‘613 and US ‘474, the lead claims are both directed to a method for making a prognosis of cancer; in the ‘613 patent the method is practiced for humans, whereas the ‘474 patent doesn’t have a limitation for the type of organism.  Both methods comprise:

  • analyzing a sample for telomerase activity; and
  • correlating high activity with an unfavorable prognosis and low activity with a favorable prognosis.

Dependent claims recite additional steps for the analyzing step, such as extending a telomerase substrate and amplifying the extended substrate.  Other dependent claims recite a variety of tumor types.

The US ‘215 patent claims a method for detecting cancerous cells in a human breast, prostate, colon or lung tissue sample (claim 1) as well as a method for determining prognosis of a cancer patient by detecting cancerous cells in a tissue sample.  The steps of the method for each of these claims comprises:

  • incubating an aliquot of a cell extract with a telomerase substrate;
  • determining whether the substrate has been extended; and
  • correlating addition of repeat sequences to the substrate with the presence of cancerous cells.

Patents US 5,989,807 and US 6,391,554 claim a method for diagnosis of a cancerous or precancerous condition through detection of an elevated level of telomerase activity in cells (US ‘807) or mammalian cells (US ‘554) that are classified as normal by pathology (US ‘807).  Dependent claims recite a laundry list of cancers and particulars about the assay method.

Patent Data Title and relevant claims Family Data
US 5,639,613

Assignee:

University of Texas

Earliest priority:

13 May 1993

Filed:

18 Apr 1995

Granted:

17 June 1997

Expiry date:

17 Jun 2014

Methods for cancer diagnosis and prognosis

Claim 1:  A method for prognosing cancer in humans, said method comprising: (a) collecting a sample suspected of containing tumor cells; (b) analyzing said sample for telomerase activity; (c) correlating said activity with a standard level of telomerase activity; and (d) correlating a high telomerase activity with an indication of unfavorable prognosis and a low telomerase activity with a favorable prognosis.

See Appendix 2
US 5,648,215

Assignee:

University of Texas

Earliest priority:

13 May 1992

Filed:

28 Sep 1994

Granted:

15 Jul 1997

Expiry date:

06 Feb 2013

Telomerase diagnostic methods

Claim 1:  A method for detecting whether a human breast, prostate, colon, or lung tissue sample contains cancerous cells, said method comprising (a) preparing a cell extract from said tissue sample; (b) incubating an aliquot of said cell extract in a reaction mixture comprising a telomerase substrate and a buffer in which telomerase can catalyze the extension of said telomerase substrate; (c) determining whether said telomerase substrate has been extended in step (b) by addition of telomeric repeat sequences; and (d) correlating presence of cancerous cells in said sample with the addition of telomeric repeat sequences to said telomerase substrate and absence of cancerous cells in said sample with no addition of telomeric repeat sequences to said telomerase substrate.

See Appendix 2
US 5,693,474

Assignee:

University of Texas

Earliest priority:

13 May 1992

Filed:

07 Jun 1995

Granted:

02 Dec 1997

Expiry date:

02 Dec 2014

Methods for cancer diagnosis and prognosis

Claim 1:  A method for prognosing cancer, said method comprising: (a) collecting a sample suspected of containing cancer cells; (b) analyzing said sample for telomerase activity; (c) correlating said activity with a standard level of telomerase activity; and (d) correlating a high telomerase activity with an indication of unfavorable prognosis and a low telomerase activity with a favorable prognosis.

See Appendix 2
US 5,989,807

Assignee:

Geron Corp. and Board of Regents

University of Texas

Earliest priority:

13 May 1992

Filed:

07 Jun 1994

Granted:

23 Nov 1999

Expiry date:

23 Nov 2016 *

Detecting cancerous conditions by assaying for telomerase activity

Claim 3:  Method for detection of a cancerous or precancerous condition in a patient comprising assaying for telomerase activity in cells classified as non-cancerous by pathology, wherein a detectable level of telomerase activity is indicative of said condition.

See Appendix 2
US 6,391,554

Assignee:

Geron Corp. and Board of Regents

University of Texas

Earliest priority:

13 May 1992

Filed:

23 Nov 1999

Granted:

21 May 2002

Expiry date:

13 May 2012 *

Detecting cancerous conditions by assaying for telomerase activity

Claim 3:  A method for detection of a cancerous or precancerous condition in a mammal, the method comprising assaying for telomerase activity, wherein a detectable level of telomerase activity is indicative of a cancerous or precancerous condition.

See Appendix 2

The next group of patents discussed claim methods that detect nucleic acids encoding telomerase.

US 6,664,046, owned by Roche Molecular Systems, determines the quantity of hTERT mRNA in a test sample compared to a normal control and concludes that cancerous cells are present if the amount of hTERT mRNA is greater in the test sample than in the normal control.  The method used to quantify hTERT mRNA is amplification using a primer pair in which one primer hybridizes within exon 8 and the other primer hybridizes either upstream of exon 7 or downstream of exon 8.  The b region, which is present in wild-type telomerase is encoded by exons 7 and 8.  Therefore, this method detects the presence of the b region.

The rest of the U.S. patents and applications contain claims that are specific for the source of the nucleic acids encoding telomerase and relatively non-specific as to the particulars of assay.  US 6,821,726 amplifies mRNA coding for telomerase from tumor cells that are isolated by centrifugation of a body fluid sample layered over a cell separation medium of 1.060-1.065 g/mL and removal of cells at the interface.  This is how lymphocytes are commonly isolated from a blood sample.  The patent applications US 2004/0132019 and US 2006/0204956 claim analyses of RNAs encoding telomerase that are present in blood plasma or serum.  In its lead claim, US ‘956 further specifies analysis by amplification.

Patent Data Title and relevant claims Family Data
US 6,664,046

Assignee:

Roche Molecular Systems

Filed:

16 Dec 1999

Granted:

16 Dec 2003

Expiry date:

16 Dec 2019

Quantitation of hTERT mRNA expression

Claim 1:  A method for identifying the presence of cancerous cells in a human sample wherein said method comprises: (a) determining the quantity of hTERT mRNA comprising β-region coding sequence in said sample and in a control sample of non cancerous cells by: (1) contacting RNA from said sample and said control sample with a pair of primers, wherein said pair of primers consists of a first primer which hybridizes within exon 8 of the hTERT gene and a second primer which hybridizes upstream of exon 7 or downstream of exon 8 of the hTERT gene; (3) measuring the generation of amplification products; (4) determining the quantity of hTERT mRNA comprising β-region coding sequence in said sample from the results obtained in step (3); and (b) identifying the presence of cancerous cells in said sample if the quantity of hTERT mRNA comprising β-region coding sequence in said sample is greater than the quantity of hTERT mRNA comprising β-region coding sequence in said control sample.

EP 1108789 A3
JP 2001204483 A2

US 6,821,726

Assignee:

Inventors –

Dahm, M

Phelps, R

Brockmeyer, C

Earliest priority:

04 Feb 1998

Filed:

04 Aug 2000

Granted:

23 Nov 2004

Expiry date:

04 Feb 2018

Method for quantitatively analyzing tumor cells in a body fluid and test kits suited therefore

Claim 1:  A method for the quantification of tumor cells in a body fluid, comprising: (a) concentrating tumor cells in a sample of a body fluid by covering a cell separation medium with a density in the range of from 1.060-1.065 g/ml with a layer of the body fluid, centrifuging the cell separation medium covered with the body fluid and collecting the tumor cells at the interface of the cell separation medium and the supernatant body fluid; (b) specifically amplifying, from the tumor cells, mRNA coding for the catalytic subunit of telomerase; (c) quantitatively determining the amount of amplified nucleic acid; and (d) correlating the amount of amplified nucleic acid with the number of tumor cells in the body fluid.

AU 756814 B2
BR PI9910193 A
CA 2319709 AA
DE 19804372 A1
EP 1051522 A2
JP 2002503454 T2
WO 99/40221 A3

US 2004/132019

Assignee:

Inventors –

Chen, X

Stroun, M

Anker, P

Earliest priority:

26 May 2000

Filed:

16 May 2001

Cancer diagnosis method

Claim 1:  Method for diagnosis and/or follow-up of the development of cancers comprising analysis of the RNAs of the telomerase enzyme present in the blood plasma or serum, characterized in that the telomerase RNAs analyzed are the hTR RNA matrix, the catalytic part of the hTERT enzyme or the TEP1 RNA coding for the associated protein, and in that the RNAs are analyzed in relation to a reference RNA corresponding to the expression of a coding gene.

AU 200155021 A5

EP 1158055 B1
EP 1283907 A1
WO 0190409 A1

US 2006/204956

Assignee:

OncoMEDx Inc.

Earliest priority:

22 Sep 1998

Filed:

09 Jun 2003

Method for detection of hTR and hTERT telomerase-associated RNA in plasma or serum

Claim 1:  A method for detecting extracellular human telomerase reverse transcriptase protein (hTERT) RNA in blood plasma or serum for detecting, diagnosing, monitoring, treating or evaluating neoplastic disease comprising cells that express hTERT, the method comprising the steps of:

a) extracting mammalian, heterogeneous extracellular RNA from human blood plasma or serum;

b) amplifying a portion of the extracted extracellular RNA or cDNA produced therefrom wherein said portion comprises hTERT RNA to produce an amplified product, and wherein amplification is performed qualitatively or quantitatively using primers or probes that target hTERT RNA or the corresponding cDNA; and

c) detecting qualitatively or quantitatively the amplified product produced from hTERT RNA or corresponding cDNA.

AU 200185157 A5
AU 200188442 A5
AU 722476 B2
CA 2250118 AA
CA 2421007 AA
EP 0938320 A4
EP 1354060 A2
US 2002/106684 A1
US 2002/155469 A1
US 2003/036068 A1
US 2004/014079 A1
US 2005/003440 A1
US 2005/069906 A1
US 2005/260594 A1
US 2006/166229 A1

US 2006/204989 A1
US 2006/228729 A1
US 2006/228732 A1
US 2006/286578 A1
US 6,329,179 B1
US 6,607,898 B1
US 6,759,217 B2
US 6,794,135 B1
US 6,916,634 B2
US 6,939,671 B2
WO 02/18645 A3
WO 02/18652 A3
WO 03/028531 A3
WO 97/35589 A1

Two additional patent applications, exemplified by the PCT filing, claim diagnosis of bladder tumor in a urine sample (WO 01/86288) by detecting mRNA for hTERT, b-actin (to verify the quality of the RNA), and either a cytokeratin family member or a marker indicative of inflammatory cells.  Finally, WO 02/15770 claims a method for detection of cell transformation by measuring total and mature hTERT mRNA expression levels and diagnosing hyperplasia or dysplasia if the ration is from 3-10.  Mature hTERT encodes wild-type telomerase; total hTERT mRNA encodes both wild-type telomerase and splice variant telomerase.

Patent Data Title and relevant claims Family Data
WO 01/86288

Assignee:

Macrochip S.R.L.

Earliest priority:

08 May 2000

Filed:

04 May 2001

Method and apparatus for early diagnosis of bladder tumor in urine samples

Claim 1. A method for early diagnosis of bladder tumor in a urine sample, characterized in that it comprises the determination, on the RNA extracted from the cells present in the urine, of: –a marker for the messenger RNA of the catalytic component of telomerase (hTRT) and a marker for B-actin, to demonstrate RNA accessibility and as standard for quantitative estimation, in association with at least one additional molecular marker chosen from the group that comprises: –a marker for a protein of the cytokeratin family; –a lymphocyte marker which is suitable to detect inflammatory cells associated with neoplastic infiltration.

AU 200170505 A5
EP 1281087 A2
IT 1318504 B1

WO 02/15770

Assignee:

Digene Corporation

Earliest priority:

18 Aug 2000

Filed:

17 Aug 2001

Methods of cancer prognosis and assessment

A method of detecting cell transformation in a patient comprising the steps of:

–              measuring total hTERT mRINA expression level in a sample collected from the patient;

–              measuring mature hTERT mRNA expression level in the sample; and

–              determining a ratio of total hTERT mRNA expression level to m[1]i.ture hTERT expression level, wherein a ratio of between about 10 and about 3 is indicative of hyperplasia and/or dysplasia or an increased risk thereof.

AU 200187192 A5