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 .
DETAILED ACTION
Status of the Claims
Claims 1-25 are pending and the subject of this NON-FINAL Office Action. This is the first action on the merits.
Subject-matter eligibility under Section 101 cannot be determined at this time due to the lack of clarity as to the claims, as explained below. Clarity as to the assay and/or analysis used to analyze the cfDNA is critical to a proper application of the Alice test as it is the additional element (JE=presence of cfDNA in all AI diseases, recited at a very high level of generality) capable of yielding eligibility under step 2B.
Claim Rejection - 35 USC § 112- Written Description
The following is a quotation of the first paragraph of 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 1-25 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, 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.
The Specification fails to reasonably convey to one having ordinary skill in the art at the time of filing that Applicants were in possession of (A) “increasing peak number” of cfDNA; and (B) “estimating a [] level of [] auto-immune disease in [a] subject based upon the amount [of cell-free DNA molecules having sizes below the threshold value].”
“when the size is below the threshold value, increasing a peak number to
measure an amount of the cell-free DNA molecules having sizes below the threshold value”
First, the specification never mentions or hints at “increasing a peak number,” much less in response to a cfDNA size below a threshold, even less any threshold value. This description is simply missing from the specification. At most, the specification discusses “diagnosing . . . systemic lupus erythematosus (SLE) based on the sizes, methylation levels, and/or genomic characteristics of circulating DNA molecules” (Abstract). This involves “[a] level of SLE can be estimated based on: the amount of molecules having sizes below a threshold value” (Abstract). “Compared with a healthy patient, an SLE patient presents a higher percentage of DNA molecules with sizes less than the threshold value, or a higher ratio of shorter DNA molecules to longer DNA molecules” (para. 0006). “Samples with higher abundances of short molecules, as indicated by the portion of molecules having sizes within a range or below a threshold value, can indicate a higher level of the disease” (para. 0068). “The threshold value can be chosen as desired and is 115 bp in some embodiments, as discussed above. Other possible threshold values include, but are not limited to, 90, 95, 100, 105, 110, 120, and 125 bp” (para. 0076). Data to support this specific threshold is shown in Figures 2, 5 and 7. Figure 2 is representative:
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However, in none of these descriptions or data is there anything about “increasing a peak number to measure an amount of the cell-free DNA molecules having sizes below the threshold value.” Instead, sequencing read frequency data from two ranges of DNA sizes are analyzed based on a cutoff around 115bp; if percentage of <115bp cfDNA exceeds 20%, then some form of SLE (active or inactive) is likely present. In other words, a threshold of ~115bp is used to distinguish SLE-informative cfDNA from general cfDNA. Again, this is not “increasing a peak number to measure an amount of the cell-free DNA molecules having sizes below the threshold value.” Rather, the peak number is merely a measure of cfDNA at a particular size, not an active step of analysis. Thus, the specification does not demonstrate possession of actively “increasing a peak number to measure an amount of the cell-free DNA molecules having sizes below the threshold value.”
“estimating a [] level of [] auto-immune disease in [a] subject based upon the amount [of cell-free DNA molecules having sizes below the threshold value]”
In addition, this threshold-based peak size analysis is only provided for SLE. No other auto-immune disease data is found in the specification. Autoimmune diseases encompass hundreds if not thousands of specific diseases. Among them, various forms of arthritis, HIV/AIDS, alopecia, acne, dermatitis, bullous, psoriasis, Hashimoto’s, diabetes, Addison’s, Grave’s, myositis, celiac, multiple sclerosis, vasculitis, colitis, Crohn’s, and many others. Each disease presents specific molecular characteristics. Yet, Applicants provide data for one. The genus of autoimmune disease is clearly not supported by the specification.
Instead, Applicants extrapolate from SLE that “[t]hese findings provide interesting insights into the biology of plasma DNA in an autoimmune disease and have potential implications for the development of new molecular markers for SLE” (para. 0215). Yet, at the same time, Applicants recognize that “Systemic lupus erythematosus (SLE) is a prototype autoimmune disease” (para. 0217; emphasis added). This is why Applicants are guarded in their assertions that “[o]ur study also highlights the possibility that the study of plasma nucleic acids would be a valuable venue for research for other autoimmune diseases” (para. 0243; emphases added). In other words, even Applicants recognize from their own data that they have not demonstrated possession of diagnosing other autoimmune diseases. Rather, they have only shown proof of principle for SLE.
In sum, the breadth of the claimed invention is not supported by the specification species.
Claim Rejections - 35 USC § 112- Indefiniteness
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.
Claims 1-25 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
“[I]ncreasing a peak number” is too ambiguous to apply prior art without conjecture as to its meaning. When the claims become so ambiguous that one of ordinary skill in the art cannot determine their scope absent speculation, such claims are invalid for indefiniteness. see In re Steele, 305 F.2d 859, 862 (CCPA 1962). As explained above, the specification never describes, defines or explains “increasing a peak number.” As also explained above, it is not clear if this means actively increasing a number of cfDNA reads at a specific size, or a size range. In addition, it is unclear how “increasing a peak number” “measures an amount of the cell-free DNA molecules having sizes below the threshold value.” For example, if a threshold value is 115bp, then, first merely increasing any peak number because the cfDNA molecule is below 115bp makes no sense; and second, this does not measure anything because it is only data collection. The measurement is provided by the computer or human determining amount of cfDNA below the 115bp threshold based on plotted data. In other words, the first step is plotting, the second step is measuring. Nor is it clear from the prior art what all this means. The Examiner cannot find this phrase in the prior art.
Applicants are strongly encouraged to amend the claims to require the specific threshold-based bifurcation of cfDNA shown for example in Figure 2. Specifically, sequencing read frequency data from two ranges of DNA sizes are analyzed based on a cutoff around 115bp; if percentage of <115bp cfDNA exceeds 20%, then some form of SLE (active or inactive) is likely present. In other words, a threshold of ~115bp is used to distinguish SLE-informative cfDNA from general cfDNA.
Double Patenting- Obvious Type
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Instant claims 1-25 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over conflicting claims 1-65 of U.S. 10,174,375.
The instant claims are obvious over the conflicting claims because the conflicting claims anticipate the instant by teaching the same threshold-based cutoff for auto-immune diagnosis, with an additional treatment step. Specifically, the conflicting claims teach:
1. A method of analyzing a biological sample of an organism, the biological sample including nucleic acid molecules, wherein at least some of the nucleic acid molecules are cell-free, the method comprising:
sequencing a plurality of cell-free DNA molecules from the biological sample to obtain sequence data from both ends of each cell-free DNA molecule of the plurality of cell-free DNA molecules from the biological sample, wherein the biological sample is extracted from a bodily fluid sample from the organism;
analyzing the sequence data of the plurality of cell-free DNA molecules from the biological sample, wherein analyzing the sequence data of a cell-free DNA molecule comprises:
aligning, by a computer system, the sequence data of the cell-free DNA molecule to a reference genome,
determining, by the computer system, a size of the cell-free DNA molecule from the aligned portion of the sequence data of the cell-free DNA molecule, and
comparing the size of the cell-free DNA molecule with a threshold value;
determining, with the computer system, an amount of the cell-free DNA molecules having sizes below the threshold value;
estimating a first level of an auto-immune disease in the organism based upon the amount;
using the first level of the auto-immune disease in the organism to design a treatment regimen for the organism or determine a dose of a medication; and
providing treatment for the auto-immune disease to the organism according to the treatment regimen or with the dose of the medication.
2. The method of claim 1, wherein the amount is a percentage.
3. The method of claim 1, further comprising:
designating a first peak size of cell-free DNA molecules, wherein the first peak size is less than the threshold value;
designating a second peak size of cell-free DNA molecules, wherein the second peak size is greater than the threshold value;
determining a first peak number, wherein the first peak number is the number of the cell-free DNA molecules having sizes within a specified range of the first peak size;
determining a second peak number, wherein the second peak number is the number of the cell-free DNA molecules having sizes within a specified range of the second peak size;
calculating a ratio of the first peak number to the second peak number; and
estimating a second level of an auto-immune disease in the organism based upon the ratio.
4. The method of claim 3, wherein
the first peak size is equal to the mean, median, or mode size of the cell-free DNA molecules having sizes less than the threshold value, and
the second peak size is equal to the mean, median, or mode size of the cell-free DNA molecules having sizes greater than the threshold value.
Thus, as is clear from the conflicting claims, they anticipate the instant claims.
Prior Art
The following prior art teaches that cfDNA is increased in SLE, including certain sizes based on DNA ladder analysis using e.g. LM-PCR: Galeazzi et al, Dosage and characterization of circulating DNA: present usage and possible applications in systemic autoimmune disorders, February, 2003Autoimmunity Reviews 2(1):50-5; Rumore et al., Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone, J Clin Invest. 1990 Jul;86(1):69–74. doi: 10.1172/JCI114716; US 20100297710; US 20130224740; US 20120178918.
Conclusion
No claims are allowed.
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/YUNG-SHENG M TSUI/ Primary Examiner, Art Unit 1743