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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/18/25 has been entered.
Claims 20-21 have been added by Applicant.
Claims 1, 2, 5-11, 13, and 19-21 are pending.
Claims 1, 2, 5, 7, and 8 have been amended by Applicant.
Claims 1, 2, 5-11, 13, and 19-21 are currently under examination.
This Office Action contains New Rejections Necessitated by Amendments.
Rejections Withdrawn
The rejection of claims under 35 U.S.C. 101 is withdrawn.
The rejections of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn.
The rejection of claims 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 112
Claims 1, 2, 5-11, 13, and 19 remain rejected and claims 20-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for administering cancer treatments and extracting, denaturing, measuring, calculating, and comparing single stranded cell free DNA fragments, does not reasonably provide enablement for methods wherein detecting recited levels of single stranded cell free DNA fragments is indicative of recited cancers (liposarcoma and cancers of the lung, liver, breast, and gastrointesine). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
The instant claims are drawn to methods wherein detecting recited levels of single stranded cell free DNA fragments is indicative of recited cancers (liposarcoma and cancers of the lung, liver, breast, and gastrointesine).
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The specification discloses administering cancer treatments and extracting, denaturing, measuring, calculating, and comparing single stranded cell free DNA fragments. However, the specification does not demonstrate methods wherein detecting recited levels of single stranded cell free DNA fragments is indicative of recited cancers (liposarcoma and cancers of the lung, liver, breast, and gastrointesine).
The level of unpredictability for using a particular marker (such as a particular ratio compared to a particular reference value) to detect any disease is quite high. The state of the prior art dictates that one of skill in the art would not predict that a marker is indicative of a particular diseased state without a demonstration that said particular diseased stated correlates with said particular marker. For example, Tockman et al (Cancer Res., 1992, 52:2711s-2718s) teach considerations necessary in bringing a cancer biomarker (intermediate end point marker) to successful application. Absent evidence demonstrating a particular marker correlating with a particular diseased state, one of skill in the art would not predict said particular marker correlates with said particular diseased state without undue experimentation. Experimentation to identify such a correlation would in itself be inventive.
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to methods wherein detecting recited levels of single stranded cell free DNA fragments is indicative of recited cancers (liposarcoma and cancers of the lung, liver, breast, and gastrointestine), and Applicant has not enabled said methods because it has not been shown that detecting recited levels of single stranded cell free DNA fragments is indicative of recited cancers (liposarcoma and cancers of the lung, liver, breast, and gastrointestine). Further, undue experimentation would be required to determine which levels of recited single stranded cell free DNA fragments are (or are not) indicative of each cancer encompassed by the claims in order to use such levels to diagnose each cancer.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require undue experimentation by one of skill in the art to determine with any predictability, that the method would function as claimed.
Response to Arguments
In the Reply of 12/18/25, Applicant submitted a Declaration by Alain Thierry. The Declaration provides the following figures of single strand DNA in various patients (with dinucleotides in enlargement windows) and argues the recited singles strand DNA sizes are diagnostic of recited cancers:
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The amendments to the claims and the Oath of 12/18/25 have been carefully considered, but are not deemed persuasive. Claim 1 recites single stranded DNA fragments having a length ranging from 88 to 240 nucleotides are diagnostic of lung cancer. As shown in Figure 1A (a comparison of single stranded DNA fragments of 6 patients with lung cancer and median healthy individuals), DNA fragments having a length ranging from 88 to 240 nucleotides are not diagnostic of lung cancer. From at least 100 to about 140 nucleotides, there is a complete overlap in frequencies of single strand DNA fragments between the 6 patients with lung cancer and median healthy individuals:
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Claim 1 recites single stranded DNA fragments having a length ranging from 168 to 240 nucleotides are diagnostic of liver cancer. Figure 1C compares single stranded DNA fragments of a single patient with liver cancer with median healthy individuals and finds a fraction of a single percent higher frequency of single stranded DNA fragments in median healthy individuals as compared to the single patient with liver cancer within the recited range. It would require unreasonable experimentation to determine whether the frequencies of single stranded DNA fragments found in the single patient with liver cancer are representative of any other patients with liver cancer in order to perform the method as claimed.
Claim 1 recites single stranded DNA fragments having a length ranging from 109 to 230 nucleotides are diagnostic of breast cancer. Figure 2A compares single stranded DNA fragments of two patient with breast cancer with median healthy individuals and finds what appears to be a complete overlap in the frequencies of single stranded DNA fragments having a length ranging from 109 to 230 with the two patient with breast cancer and median healthy individuals. Therefore, Figure 2A indicates single stranded DNA fragments having a length ranging from 109 to 230 are not indicative of breast cancer:
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Claim 1 recites single stranded DNA fragments having a length ranging from 98 and 242 nucleotides are diagnostic of liposarcoma. Figure 1B compares single stranded DNA fragments of a single patient with liposarcoma with median healthy individuals and finds no reasonable evidence of predictable differences in recited frequencies of single stranded DNA fragments having a length ranging from 109 to 230 with any other patient with liposarcoma and healthy individuals.
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Claim 1 recites single stranded DNA fragments having a length ranging from 60 and 240 nucleotides are diagnostic of gastrointestine cancer. Figure 2C compares single stranded DNA fragments of two patients with pancreatic cancer with median healthy individuals and finds slight differences in percentages of recited Single stranded DNA fragments of the two patients as compared to median healthy individuals. However, unreasonable experimentation would be required to determine whether the differences are predictable of just any other gastrointestine cancer patients in order to perform the method as broadly claimed.
Further, just any lengths of single stranded DNA fragment within a recited range is not predictably indicative of any particular recited cancer (as claimed) because all ranges of recited lengths of single stranded DNA fragments overlap.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
Claims 2, 8, 20, and 21 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.
Claims 2, 8, 20, and 21 are rejected because claim 2 recites “the ratio of predetermined reference values” and claims 20-21 both recite “the ratio.” There is a lack of antecedent basis for “the ratio of predetermined reference values” and “the ratio” in the claims.
Claim Rejections - 35 USC § 103
Claims 1, 5-7 and 19 are rejected under 35 U.S.C. 103(a) as being unpatentable over Thierry et al (WO 2012/028746 A1; 3/8/12) in view of Labianca et al (Critical Reviews in Oncology/Hematology, 2004, 51: 145-170).
Thierry et al teaches circulating DNA of healthy patients seems clearly constituted of fragment <138 bp and >300 bp with no apparent fragment between 138 bp and 300 bp (lines 13-14 on page 72, in particular). Thierry et al demonstrates a method of distinguishing colorectal cancer patients from healthy patients comprising extracting cell free DNA from a sample (a blood sample) obtained from a subject, determining levels of single stranded DNA fragment having lengths of between 145 to 185 nucleotides (including a length of 145 bp) obtained by denaturing the cell free DNA and performing PCR and demonstrating single stranded DNA of length of 145 bp is detected in samples from colorectal cancer patients (“gastrointestine cancer” patients) and not detected in samples from healthy patients (Example VI and Figure 18, in particular).
Thierry et al does not explicitly describe administering a particular cancer therapy after diagnosing a subject as having colorectal cancer and does not specifically describe a level determined in a subject as being compared with a predetermined reference value and concluding the subject suffers from cancer when the level determined in the subject is higher in the subject than the predetermined reference value when having a length ranging from 145 to 185 nucleotides. However, these deficiencies are made up in the teachings of Labianca et al.
Labianca et al teaches colorectal cancer patients are known to therapeutically benefit from chemotherapy, radiotherapy, and immunotherapy (pages 155-163, in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to perform the method of Thierry et al to screen a subject for colorectal cancer wherein cell free DNA is extracted from a sample (a blood sample) obtained from a subject, levels of single stranded DNA fragment having a length of 145 to 185 bp are determined by denaturing the cell free DNA and performing PCR, and the levels of single stranded DNA fragment having a length of 145 to 185 bp in the sample are compared to with a predetermined reference level of single stranded DNA fragment having a length of 145 to 185 bp in a corresponding sample from a healthy control, and concluding that the subject has colorectal cancer and diagnosing the subject as having colorectal cancer when levels of single stranded DNA fragments having a length of 145 to 185 bp are higher in the sample from the subject as compared to the level in the corresponding sample from a healthy control because Thierry et al teaches single stranded DNA of length of 145 to 185 bp is detected in samples from colorectal cancer patients and is not detected in samples from healthy patients (Example VI and Figure 18, in particular).
One of ordinary skill in the art would have been further motivated, with an expectation of success, to provide therapeutic benefit by diagnosing and treating a subject with colorectal cancer comprising performing said method to diagnose subjects with colorectal cancer and administering chemotherapy, radiotherapy, and/or immunotherapy of Labianca et al to those subjects diagnosed as having colorectal cancer because Labianca et al teaches colorectal cancer patients are known to therapeutically benefit from chemotherapy, radiotherapy, and immunotherapy (pages 155-163, in particular).
In particular regards to instant claim 7, one of ordinary skill in the art would have been further motivated, with an expectation of success, to perform said method wherein the screening is again performed after therapeutic treatment in order to determine whether cancer remains or there is relapse after the treatment and repeat administration of the therapeutic treatment if levels of single stranded DNA are increased after the treatment because the screening detects the presence of the cancer, an increase in single stranded DNA of the screening would indicate a relapse of the cancer, and the treatment therapeutically treats the cancer.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 112
Claims 1, 2, 5-11, 13, and 19-21 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Claim 1 recites methods wherein fragment(s) having a length from 88 to 240 nt is/are diagnostic of lung cancer, 168 to 240 nt is/are diagnostic of liver cancer, 109 to 230 nt is/are diagnostic of breast cancer, 98 to 242 nt is/are diagnostic of liposarcoma, and/or 60 to 240 nt is/are diagnostic of gastointestine cancer and administering one or more cancer treatments to a subject as having a higher or lower level within at least one range diagnostic of cancer of lung, liver, breast, gastrointestine and/or liposarcoma than at least one predetermined reference value. Descriptions of methods wherein fragment(s) having a length from 88 to 240 nt is/are diagnostic of lung cancer, 168 to 240 nt is/are diagnostic of liver cancer, 109 to 230 nt is/are diagnostic of breast cancer, 98 to 242 nt is/are diagnostic of liposarcoma, and/or 60 to 240 nt is/are diagnostic of gastointestine cancer and administering one or more cancer treatments to a subject as having a higher or lower level within at least one range diagnostic of cancer of lung, liver, breast, gastrointestine and/or liposarcoma than at least one predetermined reference value are not found in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the invention was filed, had possession of the claimed invention.
Claim 2 recites methods further measuring and calculating ratios of levels of single stranded DNA fragments having lengths ranging from 88-167 and 168-235 nt for lung cancer, 152-167 and 168-240 nt for liver cancer, 109-152 and 168-230 nt for breast cancer, 98-152 and 178-242 nt for liposarcoma, and/or 60-167 and 168-240 nt for gastrointestinal cancer. Descriptions of methods measuring and calculating ratios of levels of single stranded DNA fragments having lengths ranging from 88-167 and 168-235 nt for lung cancer, 152-167 and 168-240 nt for liver cancer, 109-152 and 168-230 nt for breast cancer, 98-152 and 178-242 nt for liposarcoma, and/or 60-167 and 168-240 nt for gastrointestinal cancer are not found in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the invention was filed, had possession of the claimed invention.
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642