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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/19/2025 has been entered.
Claim Status and Formal Matters
This action is in response to papers filed 5/19/2025.
The instant response is non-compliant with 37 CFR 1.121 as claim 7 has been amended to recite
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However, this is not underlined in the claim as required by the statue. However to promote compact prosecution and customer service the instant response will be examined. However, future amendments that are not compliant with 37 CFR 1.121 may not be entered or examined.
Claims 1, 7 and 10 have been amended.
Claim 18 has been added by amendment.
Applicant’s election of group 1, claims 1-10 and 14-15 in the reply filed on 4/15/2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant's election with traverse of cells and plasma in the reply filed on 4/15/2024 is acknowledged. The traversal is on the ground(s) that the response asserts there is not a search burden. This is not found persuasive because searching cells will not inherently provide art on blood or plasma or tissue. Thus searching both would place a serious search burden to the Office.
Claims 11-13, 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/15/2024.
Claims 1-7, 9-10, 14-15 and 18 are being examined.
The previous objection to the specification has been withdrawn in view of the amendment.
The previous objection to the claims has been withdrawn in view of the amendment.
Priority
The instant application was filed 06/09/2021 and is a national stage entry of PCT/EP2019/087005 with an international filing date: 12/24/2019 and claims foreign priority to EP18382992.8, filed 12/26/2018
Claim Rejections - 35 USC § 112
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.
Claims 1-7, 9-10, 14-15 and 18 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 IB New or amended claims section II
With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04 which provides that a "simple statement such as ‘applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation ‘___’ in the application as filed’ may be sufficient where the claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported."); see also MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure."); and MPEP § 2163.04
Claim 1 has been amended to recite, “ performing TAV analysis by correlating interchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug.” The response provides no indication where support for the amendment can be found. Review and searching of the specification revealed, “interchromosmal variance” recited once on page 4, which provides no teachings with respect to correlating with terchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug. Thus the amendment appears to introduce new matter.
As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851:
The written description requirement of 35 U.S.C. § 112, ¶ 1, is straightforward: “The specification shall contain a written description of the invention ….” To satisfy this requirement, the specification must describe the invention in sufficient detail so “that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought.” Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. v. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein v. Frank, 52 F.3d 1035, 1039 [34 USPQ2d 1467] (Fed. Cir. 1995).
Alonso at 1852:
A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its “relevant identifying characteristics,” such as “complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” Enzo, 323 F.3d at 964.
In applying the test as set forth in Alonso, it is noted that applicant is claiming * “performing TAV analysis by correlating interchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug.” Thus the claims broadly encompass correlating any interchromosomal variance of reference or control sample of any subject of any species with anything that can be considered measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug. This encompasses an enormous genus of any measure of health, genus of any risk of any pathological conditions, genus of any telomeric disease or genus of responsiveness to any drug.
Nucleic Acid Based Tests (https://www.fda.gov/medical-devices/in-vitro-diagnostics/nucleic-acid-based-tests#:~:text=This%20is%20a%20list%20of%20nucleic%20acid%2Dbased,deoxyribonucleic%20acid%20(DNA)%20and%20ribonucleic%20acid%20(RNA) (downloaded 9/16/2025) demonstrates health measure is an enormous genus. Drugbank (https://go.drugbank.com/stats), downloaded 916/2025) demonstrates there are at least 18,494 known drugs. Smith (iScience (25, 104698, August 19, 2022) teaches there are over 10,000 diseases (pathologies), another genus.
Thus while the claims encompass an enormous genus of measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug, the specification does not provide a representative number of species.
Further claims 4, 5, have been amended to recite, “known threshold length.” Review and searching of the specification did not reveal antecedent basis for limitation. Thus this limitation appears to be new matter.
Response to Arguments
This is a new grounds of rejection necessitated by amendment.
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 1-7, 9-10, 14-15 and 18 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 has been amended to recite, “ performing TAV analysis by correlating interchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug.” The metes and bounds are unclear how ,” performing TAV analysis by correlating interchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug” is done. Further it is unclear what is required of a telomeric disease, as what is included or excluded as this does not appear to be an art accepted term.
Claim 4 has been amended to recite, “wherein the percentage of telomeric length value TLu, is determined by the formula:TLu=100-TSU wherein the percentage of short telomeres TSu in the isolated biological test sample Mt,for a known threshold length it is determined as
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The metes and bounds are unclear how the observations are used in the claims. The claim equation appears to merely characterize a possible outcome of the data. Further the claim is unclear of what is required of known threshold length. It is unclear if previously determined threshold length is calculated, determined empirically, etc. Further it is unclear how this relates to the independent claim.
Claim 5 has been amended to recite, “: wherein the percentage of cells having short telomeres (CSC) in the isolated biological test sample M for a known threshold length i is determined by the formula:
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The metes and bounds are unclear how the observations are used in the claims. The claim equation appears to merely characterize a possible outcome of the data. Further the claim is unclear of what is required of known threshold length. It is unclear if previously determined threshold length is calculated, determined empirically, etc. Further it is unclear how this relates to the independent claim.
Claim 7 recites, “MAD-I2.” The metes and bounds are unclear as the specification does not specifically define what is required of MAD-I2. Review and searching of the art did not reveal that MAD-I2 is an art accepted term. Thus the metes and bounds are unclear.
Claim 7 is indefinite as it requires:
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The metes and bounds are unclear as the claim does not previously recite “complete set.” Thus it is unclear what this requires or is referencing. Further the metes and bounds are unclear how the observations are used in the claims. The claim equation appears to merely characterize a possible outcome of the data. Further the claim is unclear or circular in view of u.
Response to Arguments
The response traverses the rejections of claims 4-5 and 7-8 in view of the amendments. This argument has been thoroughly reviewed but is not considered persuasive as the amendment to claims 4-5 have raised new issues. Further the amendment claims 7-8 provide a name for what is required of MAD-12, but does not define what is required by all the limitations as m is defined generically and it is unclear if this m is relative to cell, nucleus, chromosome, etc.
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 1-7, 9-10, 14-15 and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step without significantly more. The claim(s) recite(s) the abstract idea or mental step of providing and calculating . This judicial exception is not integrated into a practical application because no steps depend from or otherwise integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the independent claim encompasses mental steps of providing data and analyzing data by calculation..
Claim analysis
The instant claim 1 is directed towards method in vitro for calculating [[T]]telomere [[A]]associated [[V]]variables (TAVs) in an isolated biological test sample of a subject, wherein the method uses a set of standard isolated biological samples of known telomere length, and comprises the following steps: measuring a first set of intensity values of known telomere length, by using a [[H]]high-[[T]]throughput [[Q]]quantitative [[F]]fluorescent in situ hybridization (HT Q-FISH) methodology in the set of standard isolated biological samples; generating a standard curve correlating the first set of intensity values with the known telomere length from the set of standard isolated biological samples; measuring a second set of intensity values, by using a HT Q-FISH methodology, from the isolated biological test sample; calculating the telomere lengths within the isolated biological test sample of a subject by interpolating the second set of intensity values into the standard curve; and calculating, in the isolated biological test sample, at least one of the TAVs selecting from the list consisting of: telomere length percentiles from 1st percentile to 99th percentile, percentages of telomeric length values that can be specified to a particular base pair or range or number, percentages of cells with specific telomere median or average value that can be specified to a particular base pair value, median absolute deviation of the intensities of a sample, difference between the 99th and 1st percentile of the telomere length of the sample, interquartile of the telomere length of a sample, standard deviation of the median telomere length values, or any combinations thereof, performing TAV analysis by correlating interchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug..
The measuring step is considered to be an active of analyzing a sample to providing data. The calculating steps and performing TAV analysis are mental steps or abstract ideas.
Dependent claims set forth further limitations to how to obtain data, the types of samples, and further mental steps.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea or mental steps. .
With regards to claim 1, the claim recites, “calculating, in the isolated biological test sample, at least one of the TA~s selecting from the list consisting of: telomere length percentiles from1st -percentile to 99th percentile, percentages of telomeric length values that can be specified to a particular base pair or range or number, percentages of cells with specific telomere median or average value that can be specified to a particular base pair value, median absolute deviation of the intensities of a sample, difference between the 99th and 1st percentile of the telomere length of the sample, interquartile of the telomere length of a sample, standard deviation of the median telomere length values, or any combinations.” This is a mental step or abstract idea.
Further claim 1 recites, “performing TAV analysis by correlating interchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug.” This is a mental step and/or abstract idea.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as the claim requires no additional steps, which require, depend or otherwise integrate or apply the judicial exception.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, the claims merely set forth mental steps or abstract ideas. The claims provide no steps which require specific reagents which provide for significantly more.
The specification teaches:
The TVAs are determined, for example, by using standard hybridization techniques, such as fluorescence in situ hybridization (FISH), Quantitative Fluorescent in situ hybridization (Q-FISH), or High Throughput Quantitative Fluorescent in situ hybridization (HT Q- FISH). In a more preferred embodiment, the TVAs are determined by HT Q-FISH. The term HT-Q-FISH as used herein refers to any technique that allows the processing of tens or hundreds of samples in a high-capacity multiwell plate, using high resolution fluorescence microscopy. The image data obtained by the high- resolution fluorescence microscopy can include the intensities of one or more colours at pixels that comprise an image of a nucleus or nuclei. The image data can also be grey level image data of a nucleus that has been appropriately stained to highlight telomeres and/or chromosomes. Several images, preferably at least 75 are obtained corresponding to slices along a particular axis.(page 4)
Thus the claim does not provide additional steps which are significantly more.
Canela (Proceedings National Academy of Sciences (2007) volume 104, pages 5300-5305), Vera (Aging (2012) volume 4, no 9 pages 379-382), Epel (Aging (2009) volume 1, no 1 pages 81-.88), Jiang (Assessing Telomerase Activities in Mammalian Cells Using the Quantitative PCR-Based Telomeric Repeat Amplification Protocol (qTRAP), (2017) demonstrate the active steps of the claims are routine and conventional.
Response to Arguments
The response traverses the rejection asserting, “mended claim 1 defines a step of performing TAV analysis by correlating interchromosomal variance in the TAVs with the value of at least one of the same TAVs obtained in a reference or control sample with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug. Thus, the method of the invention has a practical application on informing the user regarding the health of a patient. The method of the invention obtains a specific set of TAVs from measurements of fluorescence made by using a high-Throughput quantitative fluorescent in situ hybridization (HT Q-FISH) methodology. A interchromosomal variance in the specific set of TAVs is correlated with a measure of health, a risk of a pathological condition, a telomeric disease or responsiveness to a drug, thus, integrating the mathematical calculations into a practical application. “ This argument has been thoroughly reviewed but is not considered persuasive as this is an additional abstract idea or mental step thus is not a practical application which integrates the judicial exception.
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.
Claim(s) 1-4, 9, 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Canela (Proceedings National Academy of Sciences (2007) volume 104, pages 5300-5305) and Epel (Aging (2009) volume 1, no 1 pages 81-.88)
With regards to claim 1, Canela teaches HT- Q FISH (abstract, throughout). Canela teaches sample preparation for HT-Q FISH, HT microscopy and analysis to convert to kb length based on length of cells with known telomere length (HT Microscopy (5305).
Thus Canela teaches obtain data by HT- Q-FISH and calculating lengths by interpolating lengths and determining telomere length distribution.
With regards to claim 2, Canela teaches use of L5178Y-S and L5178Y-R cells (5305, HT microscopy).
With regards to claim 3, Canela teaches determining intensities for 1st and 2nd intensity using high resolution microscopy (5305, HT microscopy).
With regards to claim 4, Canela does not specifically teach determining the percentage of long telomeres compared to short telomeres or the specific formula.
However, Epel teaches determining the Tshort and T long as well as determining threshold ((table 3 and page 87). Epel teaches using Tshort and Tlong to examine correlations with mortality rate and cardiovascular aging.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to determine the percentage of long telomeres and short telomeres and correlate with mortality from cardiovascular disease. The artisan would be motivated to examine the ability of short or long telomeres to correlate with risk of mortality or risk of disease. The artisan would have a reasonable expectation of success as the artisan is merely using known method to correlate with different diseases.
With regards to claim 9, Canela teaches the use of human lymphocyte samples (5304).
With regards to claim 14-15, Canela teaches the use of human lymphocyte samples (5304).
Response to Arguments
The response traverses the rejection asserting, “"calculating, in the isolated biological test sample, at least one of the TAVs selecting from the list consisting of: telomere length percentiles from 1st percentile to 99th percentile, percentages of telomeric length values that can be specified to a particular base pair or range or number, percentages of cells with specific telomere median or average value that can be specified to a particular base pair value...” This argument has been thoroughly reviewed but is not considered persuasive as the claim recites, “calculating, in the isolated biological test sample, at least one of the TA~s selecting from the list consisting of: telomere length percentiles from ith 1st -percentile to99th percentile, percentages of telomeric length values that can be specified to a particular base pair or range or number, percentages of cells with specific telomere median or average value that can be specified to a particular base pair value, median absolute deviation of the intensities of a sample, difference between the 99th and 1st percentile of the telomere length of the sample, interquartile of the telomere length of a sample, standard deviation of the median telomere length values, or any combinations thereof.” Thus the broadest reasonable interpretation is determining length in view of “telomeric length values that can be specified to a particular base pair or range or number.” Canela teaches, “. Telomere fluorescence intensity values were normalized between plates, using the mean for intensity values of L5178Y-S cells that had been included as calibration standard in each plate. Telomere fluorescence values were converted into kb by using L5178Y-S and L5178Y-R cells with stable and known telomere lengths of 10.2 and 79.7 kb, respectively (30). When fluorescence intensities of major satellite repeats (centromeres) were used as internal control to normalize telomere length values (Fig. 2), images were captured in the DAPI channel (excitation, 380/10 nm; epifluorescence dichroic, Fura/FITC; and emission, 435LP) for nucleus staining, in the Cy3 channel (excitation, 548/20 nm; epifluorescence dichroic, Fura/TRITC; emission, Fura/ TRITC) for centromere staining, and in the FITC channel (excitation, 480/10 nm; epifluorescence dichroic, Fura/FITC; emission, Fura/FITC) for telomere detection. Images of samples that had been hybridized with either Cy3- or FITC-labeled PNA probes were captured in each channel to confirm negligible spectral bleeding between Cy3 and FITC. The DAPI image was used to define a nuclear area or ROI for each cell to measure centromere and telomere fluorescence intensities in the Cy3 and FITC image, respectively, within each predefined ROI. Telomere fluorescence values were normalized by dividing individual telomere fluorescence intensities of each nucleus (FITCi) by the corresponding centromere fluorescence intensity in the same nucleus (Cy3i), and multiplying these values by the mean centromere fluorescence intensity obtained for the total number of nuclei analyzed in the same well (Cy3i). Fluorescence intensities were converted into kb by using L5178Y-S and L5178Y-R cells as calibration standards, with stable and known telomere lengths of 10.2 and 79.7 kb (30), respectively.” Which anticipates this limitation.
The response further asserts, “Canela discloses an analysis method where telomeres are measured in interphase. This is a characteristic of key importance since measuring the telomere length in interphase is a simplified technique wherein cells are not synchronized by the use of chemicals to stop cell cycle. Instead, chemicals are used to freeze the cell in time. Therefore, there is no chromosome condensation, allowing a simple measurement and measuring a greater number of cells. It should be noticed that Jian and Epel do not even mention the possibility of using HT Q-FISH nor measuring in interphase to determine the intensity values of the biological samples. Also, these references do not allow to measure individual telomere length in absolute base pairs in a biological test sample. Thus, these references are not considered to be close to the present invention.” This argument has been thoroughly reviewed but is not considered persuasive as the response appears to be arguing limitations not specific to the claims.
The response continues traversing the rejection by asserting, “it is important to note that the present invention relates to a method in vitro for measuring and determining Telomere Associated Variables (TAVs), wherein these TAVs are obtained as absolute telomere length values (base pairs) of individual telomeres due to the specific method of the invention by which they are obtained. Specifically, the TAVs, as absolute telomere length values (base pairs)obtained by the method of the invention, are achieved by the standard curve built from a set of intensity values of known telomere lengths in base pairs from a set of isolated biological samples, preferably as it is mentioned in the application from a standard isolated biological samples, which are analyzed by the HT Q-FISH.” This argument has been thoroughly reviewed but is not considered persuasive as these are limitations encompassed by the claim but not required. Further, the breadth of the claims appear to be encompassed by the cited portions of Canela and Figures 1-4. Further the response concedes, “Canela discloses that telomere fluorescence values are converted into kb by using L5178Y-S and L5178Y-R cells with stable and known telomere lengths of 10.2 and 79.7 kb, respectively.” Thus this encompasses the broadest reasonable interpretation of the claims.
Claim(s) 1-3, 5-6, 9, 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Canela (Proceedings National Academy of Sciences (2007) volume 104, pages 5300-5305) and Vera (Aging (2012) volume 4, no 9 pages 379-382)
With regards to claim 1, Canela teaches HT- Q FISH (abstract, throughout). Canela teaches sample preparation for HT-Q FISH, HT microscopy and analysis to convert to kb length based on length of cells with known telomere length (HT Microscopy (5305).
Thus Canela teaches obtain data by HT- Q-FISH and calculating lengths by interpolating lengths and determining telomere length distribution.
With regards to claim 2, Canela teaches use of L5178Y-S and L5178Y-R cells (5305, HT microscopy).
With regards to claim 3, Canal teaches determining intensities for 1st and 2nd intensity using high resolution microscopy (5305, HT microscopy).
With regards to claim 5, Canal does not specifically teach determining the percentage of long telomeres and short telomeres or the specific formula.
However, Vera teaches, “More recently, we have developed an automated HT quantitative telomere FISH platform, which we named HT quantitative FISH (HT Q-FISH), that allows high throughput quantification of both mean telomere length and the percentage of short telomeres per cell in large human population studies.” (380, 2nd, column). Vera teaches, “A recently improved HT QFISH methodology now allows quantification of individual telomere spots within single nucleus (Figure 3, 4 and 5b and e) [21, 40]. Importantly, the HT Q-FISH method is the only high throughput telomere quantification methodology that allows the calculation of the frequency of short telomeres per cell in large cell populations (Table 2 and Figure 1).”
Vera teaches, “For this reason, the frequency of short telomeres, rather than the mean telomere length (TL), is proposed to be a better imdicator of telomere dysfunction and, consequently, of cell and tissue dysfunction. This highlights the relevance of measuring the frequency of short telomeres in addition to mean telomere length in human population studies. However, the vast majority of human population — studies performed to date only rely on the mean telomere length of a given tissue sample, usually blood cells. These studies have uncovered an association between lower values of mean telomere length and an increase risk to develop several-age related diseases, such as cardiovascular pathologies [13-15] (Figure 2) and even with lifespan and mortality [16-18]. In this regard, a recent publication described that telomere length early in life is a strong predictor of lifespan in zebra finches [18]. Having shorter telomeres than normal has been also related to an increased risk of different cancers [19, 20]. More recently, the measurement of the percentage of cells with short telomeres or the abundance of short telomeres per nuclei has also been introduced to human population studies revealing new associations between higher frequency of short telomeres and cognitive impairment [5] or even with mood disorders.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to determine the percentage of long telomeres and short telomeres and correlate with lifespan, age related disease, etc. The artisan would be motivated to examine the ability of short or long telomeres to correlate with risk of mortality or risk of disease. The artisan would have a reasonable expectation of success as the artisan is merely using known method to correlate with different diseases.
With regards to claim 6, Vera teaches different telomere lengths from 5 to 20 KB.
With regards to claim 9, Canela teaches the use of human lymphocyte samples (5304).
With regards to claim 14-15, Canela teaches the use of human lymphocyte samples (5304).
Response to Arguments
The response traverses the rejection for the reasons of record with respect to the independent claim. These arguments are not persuasive for the reasons of record. The response further alleges the secondary reference does not teach HT-Q FISH. This argument has been thoroughly reviewed but is not considered persuasive as the dependent claim does not require HT-Q-FISH.
Claim(s) 1-3, 9-10, 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Canela (Proceedings National Academy of Sciences (2007) volume 104, pages 5300-5305) and Jiang (Assessing Telomerase Activities in Mammalian Cells
Using the Quantitative PCR-Based Telomeric Repeat Amplification Protocol (qTRAP), (2017).
With regards to claim 1, Canela teaches HT- Q FISH (abstract, throughout). Canela teaches sample preparation for HT-Q FISH, HT microscopy and analysis to convert to kb length based on length of cells with known telomere length (HT Microscopy (5305).
Thus Canela teaches obtain data by HT- Q-FISH and calculating lengths by interpolating lengths and determining telomere length distribution.
With regards to claim 2, Canela teaches use of L5178Y-S and L5178Y-R cells (5305, HT microscopy).
With regards to claim 3, Canal teaches determining intensities for 1st and 2nd intensity using high resolution microscopy (5305, HT microscopy).
With regards to claim 9-10, Canal does not specifically teach measuring telomerase activity or Q-Trap.
However, Jiang teaches, “Telomerase expression and activity appear elevated in >80% of human cancers. The activity of the telomerase may serve as a diagnostic marker for malignancy, and an indicator of the proliferative potential of somatic and stem cells. The telomeric repeat amplification protocol (TRAP) is a sensitive and accurate PCR-based assay for telomerase detection and measurement. Here, we describe a quantitative PCR-based TRAP assay (qTRAP) that is more convenient and amenable to high-throughput applications compared to traditional gel-based TRAP assays. qTRAP can not only facilitate drug screening processes for compounds that regulate telomerase activities but also enable the measurement of total telomerase activities of cultured cells or clinical specimens; the latter should prove particularly valuable to investigators of malignancies and diseases that are associated with telomerase and telomere dysfunction.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to examine telomerase activity by Q-TRAP and correlate with malignancy. The artisan would be motivated to determine if the length of telomeres in the sample are correlated with telomerase activity and/or diseases. The artisan would have a reasonable expectation of success as the artisan is merely using known methods to detect telomere length and telomerase activity and correlate with a known diesease.
With regards to claim 14-15, Canela teaches the use of human lymphocyte samples (5304).
Response to Arguments
The response traverses the rejection for the reasons of record with respect to the independent claim. These arguments are not persuasive for the reasons of record. The response further alleges the secondary reference does not teach HT-Q FISH. This argument has been thoroughly reviewed but is not considered persuasive as the dependent claim does not require HT-Q-FISH.
Summary of Claims
No claims are allowed.
Conclusion
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/Steven Pohnert/Primary Examiner, Art Unit 1683