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 .
2. This action is in response to papers filed 8/01/2025.
3. Applicant’s election without traverse of Group I in the reply filed on 4/20/22 is acknowledged.
4. Claims 1, 3-14, 77, 79-80, 82-83, 85-95 are pending. Claims 2,15-76, 78, 81,84 have been cancelled.
5. Claims 83, 85-91 has been withdrawn as being drawn to a nonelected invention.
6. The following rejections for claims 1,3-14,78-80,82,92-95 are newly applied or modified. Response to arguments follows.
7. This action is FINAL.
Claim Interpretation
The specificiaotn teaches jagged ends could not be revealed in previous studies because the process of DNA end repair which commonly precedes library construction for massively parallel sequencing would convert the jagged ends into blunt ends.
Newly Applied Claim Rejections - 35 USC § 112
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 1,3-14,78-80,82,92-95 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.
Claims 1,3-14,78-80,82,92-95 are indefinite over in claim 1. The claim states determining a jagged end value using the measured degrees of the plurality of nucleic acid molecules. The claims state that the measured degrees are (1) the length that the first strand overhangs the second strand or (2) a methylation status at one or more sites of each an end portion of the first strand, a complementary portion hybridized to the end portion of the first strand or a combination. The claims further states “wherein the jagged end value proves a collective average measure that a strand overhangs another strand in the plurality of nucleic acid molecules”. The claim further states “the collective average measure is proportional to an average length that the first strands overhang the second”. As such the wherein clauses appear to be drawn to lengths and it is not clear how methylation status is correlative to length. The claim further has a third wherein of “when the measured degree is determining using (2). As such it appears that the claims require a degree of either (1) or (2), then the wherein clauses require (2). As such it is unclear how to perform this measurement.
Further, the term “methylation status” is unclear as it is not clear what the term is intending to encompass. It is not clear if the claim is intending to encompass the presence or methylation, the presence or absence of methylation, the expression of methylation, or further, that there are sites at those positions that can be methylated. Therefore the metes and bounds are not clear.
Modified 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 1,3-14,77-80,82,92-95 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.
The claims are drawn to a method determining the existence of cancer or SLE based upon the comparison of the jagged end value to a reference value wherein the reference value is of one or more samples of subjects that have a condition and one or more samples that do not have the condition.
Therefore the claims claim a functionality of detection of cancer, SLE based upon the comparing of the jagged end value to a reference value.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure.
The claims are drawn to the analysis of any cfDNA. The specification teaches methylated regions were used or regions with polymorphic regions of interested (para 129-132). As such the specificiaotn appears to measure regions that have some correlation to cancer or SLE, however, the claims are drawn to any cfDNA regions. The specification has not provided guidance as how to perform the functionality of detection of cancer, SLE based upon the determination of jagged end values in any cfDNA samples. In particular the claims are drawn to a plurality of nucleic acid molecules comprising at least 10000 nucleic acid molecules whereas, the specification does not provide a correlation with this plurality. Rather, figure 50 does a different between overhang indices of plasma DNA between healthy, inactive SLE and active SLE (para 54). Figure 54 provides overhang indices across different size ranges (para 59-60). The specification asserts that there was significant elevation of overhang index seen in active SLE compared to healthy and inactive SLE subjects and as such the overhang index could be used to inform likelihood of having SLE (para 252). The sequencing was performed on 129.5 million paired reads for likelihood of SLE. However, this does not provide guidance of existence of SLE (interpreted as diagnosis) based upon the analysis of 10000 nucleic acid molecules. The specification does not describe a correlation to existence of SLE based upon the comparisons provided in the claims. Further, it does not appear that the specification provides support to any methylation status measurement and existence of SLE.
One embodiment of the claims is existence of cancer. Figure 45, 52B asserts the difference between cancer and noncancer with regard to jagged index ratios. The specification discloses jagged index ratios across cancer (para 245). However, although there appears to be a difference in the type of cancer used in the specification the specification has not provided critical guidance to detection of existence any cancer based upon jagged index values in cfDNA. There is a comparison step, but the specification has not provided which comparisons would be associated with a particular cancer. Further it is not clear if one has to compare each sample to every possible cancer type or do all cancer types have the same jagged end values as compared to patients without out cancer? In other words if the comparison is to a reference with breast cancer and non-breast cancer, would the sample have breast cancer or would the sample have cancer (with no type determination).
Figure 46 provides jagged index ratio of healthy controls, cirrhotic subjects, HBV carriers, early state HCC, intermediate state HCC and advanced stage HCC (p. 50). Further the specification asserts that methylation levels may depend on cancer stages (para 248). The specification has not provided guidance as to what is the critical requirements for the comparison of methylation status in any cancer. Nor has the specification provided determination of existence of cancer based upon a measured degree that is a methylation status used in a jagged edge value. Although the specification appears to provide a difference in jagged end values in HCC vs healthy controls, the specification has not provided jagged edge provided for diagnosis. The specification appears to provide functionality of HCC risk.
The specification provides an analysis of hypermethylation and jagged index ratio (para 248). However, hypermethylation is not the same scope as methylation status. Further, the specification does not provide that the status is at the end portion, a complementary portion hybridized to the end but rather the specification identified CpG sites in the genome that are “stably unmethylated” in healthy organs and so that these sites may become methylated in cancer patients (para 248). The specification further asserts that the methylation is based upon CPG methylation in particular tissues (para 248).
In analysis of the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note regarding genus/species situations that "Satisfactory disclosure of a ``representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed." (See: 'Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.) In the instant case, the specification fails to teach the necessary common attributes or features of the jagged end value to functionality detect cancer, or SLE in view of the species disclosed. As such, one of skill in the art would not recognize that applicant was in possession of the genus of markers, encompassed by the broadly claimed invention.
Response to arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments following.
The reply asserts that the nucleic acid molecules are not cancer biomarker specific (p 12). However, it is noted that the issue is that the plurality of nucleic acid molecules used (at least 10000) have not been described in the specification to functionally provide existence of active SLE or cancer. Rather, the specification uses a large number of nucleic acid molecules (a screening of plasma cfDNA) for analysis of active SLE. It is not clear based upon the description in the specification if the plurality of nucleic acid molecules would functionally provide existence of active SLE or cancer. The reply asserts that the measured degree has been amended to clarify the particular characteristics (p. 12). However, as noted in the 35 USC 112b the measuring a degree, determining jagged end values is unclear based upon the language in claim 1. The reply asserts that there is guidance for determining existence of cancer and active SLE based upon the specification on page 91, 106, Figure 46 and 48 (p. 13). These arguments have been reviewed but have not been found persuasive. As noted in the rejection above the specification has not provided guidance for “determining existence”. Furthermore as noted in the rejections above the measuring a degree and determining a jagged end value is indefinite and as such the specification has not provided guidance for the steps of the claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/ Primary Examiner, Art Unit 1682