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 .
Election/Restrictions
Applicant’s election of species without traverse of “all of the regions of Table 1” in the reply filed on 05/11/2026 is acknowledged.
Upon further consideration, the requirement for species election between elected species directed to “all of the regions of Table 1” and following non-elected species chr10:72080814-72080990, chr10:72084046-72084426, chr14:74573813-74573962, and chr19:56840344-56740644, is withdrawn.
Claims 1-8, 11, 14, 17, and 19-27 are pending.
Claim(s) 11, 14, 17, and 19 is/are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 11, 2026.
Claims 1-8 and 20-27 are currently under examination on their merits.
Priority
It is acknowledged that the instant application is a continuation of international PCT Application No. PCT/US2022/016769, filed February 17, 2022, and that it claims benefit of provisional 63/150,207, filed February 17, 2021. Note that while PCT Application No. PCT/US2022/016769 disclosed the target genomic regions as recited in the instant application, the provisional application 63/150,207 recited a Table 1 which enumerated target genes for methylation analysis (PRO: specification, pg. 15-17). The effective filing date of the claim set filed on 05/11/2026, including the target genomic regions in Table 1, is determined to be 02/17/2022, the filing date of PCT/US2022/016769, because provisional 63/150,207 filed 02/17/2021 does not support the specific chromosomal locations in the context of limitation “the target genomic regions in Table 1”
Claim Objections
Claims 1-8, 20-27 are objected to because of the following informalities: improper grammar and/or typographical errors.
‘a subject’ is recited twice in the preamble in claim 1
‘the plurality of target genomic region” in claim 1b (lines 1 and 2) should read ‘the plurality of target genomic regions’
‘…subject is like to have…’ should read ‘…subject is likely to have…’ in claim 1c, line 1
‘…the methylation levels of the target genomic is determined…’ in claim 5. There is a lack of subject-verb agreement (levels…is), and the word ‘regions’ appears to be erroneously omitted (‘the target genomic’)
‘probes comprises and affinity tag’ in claim 8, line 2 should read ‘probes comprise an affinity tag’
The final comma in claim 22 should precede the word ‘and’ so that the claim reads ‘…, and administering…’
‘…fallopian tubes samples’ in claim 25, line 3 should read ‘fallopian tube samples’
‘…is examined’ in claim 25, line 4 should read ‘…are examined’
In claim 27, ‘the plurality of target genomic region in the sample’ should read ‘the plurality of target genomic regions in the sample.’ This error is present in step a (lines 1-2) and step b (lines 1-2)
Claim 27b uses a period as well as a semicolon ‘.;’ in line 3 and should just end with a ‘;’
Appropriate correction is required.
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 1-8 and 20-27 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 some combinations of the target genomic regions of Table 1 as elaborated below, does not reasonably provide enablement for all possible combinations regarding a method for determining whether a subject is likely to have or develop epithelial ovarian cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
Claims 1-8 and 20-25 are drawn to a method of determining whether a subject is likely to have or develop epithelial ovarian cancer in a subject. In view of the recitation of “epithelial ovarian cancer,” the claims broadly encompass ANY type of epithelial ovarian cancer. Claim 2 limits the cancer to stage I-IV epithelial ovarian cancers. Claim 3 limits the epithelial histological subtypes to endometrioid, mucinous, clear cell, and serous ovarian cancers. In view of the recitation of "subject", the claims encompass both human and non-human subjects.
The claims recite a first step of measuring the level of nucleic acid methylation of a plurality of target genomic regions in Table 1 from a cell-free nucleic acid sample from the subject. In view of the recitation of a plurality of target genomic regions in Table 1, the claims broadly encompass the measurement of ANY two or more genomic regions from Table 1. It is noted that Table 1 lists 1,677 genomic regions. Any combination of two or more of those regions amounts to >10504 combinations of regions. In view of the recitation of cell free nucleic acid sample, the claims encompass ANY type of cell-free nucleic acid sample (lymph, serum, plasma, blood, breast milk, etc.). Claim 21 limits the sample to whole blood, plasma, serum, or urine.
The claims recite a second step of comparing the level of nucleic acid methylation of the plurality of target genomic regions in the sample to those of a sample isolated from a cancer-free subject, a cancer-free reference standard, or a cancer-free reference cut-off value. This encompasses comparison to ANY cancer-free subject, a cancer-free reference standard, or a cancer-free reference cut-off value (including samples isolated from humans, non-human animals, and standards or cut-offs obtained from epidemiological or clinical studies or in silico modeling).
The claims recite a third step of determining that the subject is likely to have or develop epithelial ovarian cancer based on whether the subject’s sample has a greater OR lower level of nucleic acid methylation than the cancer-free subject or reference. This encompasses ANY degree of difference and ANY type of difference (hyper- or hypo-methylation) between the sample and the cancer-free subject or reference.
Claim 26 is drawn to a method of detecting high grade serous epithelial ovarian cancer in a subject. Claim 27 is drawn to a method for differentiating high grade serous epithelial ovarian cancer from non-high grade serous epithelial ovarian cancer in a subject. The claims encompass both human and non-human subjects, ANY type or ANY degree of methylation, ANY two or more genomic regions from Table 1, ANY type of cell-free nucleic acid sample, and ANY degree and type of difference between the sample and cancer-free reference, as discussed for claim 1 above. Claim 26 additionally encompasses ANY type of cancer-free subject, a cancer-free reference standard, or a cancer-free reference cut-off value, as discussed for claim 1 above.
The nature of the invention requires reliable correlations between the nucleic acid methylation level of ANY combination of two or more of the target genomic regions of Table 1 and the diagnosis or differentiation of epithelial ovarian cancers.
Teachings in the Specification and Examples
The specification describes the development of the DNA methylation testing method involving the 1,677 differentially methylated target genomic regions (DMRs) listed in Table 1 (par. 148-152). In short, 1,677 DMRs were identified between high grade serous epithelial ovarian cancer (HGSOC) and normal fallopian/ovarian samples (par. 148). Without evidence to the contrary, it is assumed that fallopian and ovarian samples are not cell free nucleic acid samples. Hybrid probes were designed for the DMRs and used for target enrichment of bisulfite-treated plasma-derived cfDNA of patients with benign and malignant adnexal masses. Libraries were quantified and sequenced (par. 149). The specification does not discuss the performance of any combination of the 1,677 target genomic regions in determination of whether subjects were likely to have or develop epithelial ovarian cancer, nor detecting high grade serous epithelial ovarian cancer, nor differentiating high grade serous epithelial ovarian cancer from non-high-grade serous epithelial ovarian cancer. However, by virtue of being differentially methylated between samples having high grade serous epithelial ovarian cancer, the 1,677 target regions are (together) potential indicators of the likelihood of having or developing high grade serous epithelial ovarian cancer. Note that in another experiment, a different set of DMRs was identified (10,972 total DMRs) and validated (35 DMRs) for specific uses in epithelial ovarian cancer (EOC) diagnosis and differentiation (including stratification between stages I-III of epithelial ovarian cancer – par. 146), but it is not clear whether or how these 10,972/35 DMRs overlap with the target genomic regions listed in Table 1 (see par. 142-147).
From the information given in the specification, it is unclear the degree to which any combination of the 1,677 target genomic regions from Table 1 is predictive of diagnosis of EOC or predictive of subtype of EOC. The specification states that preliminary clustering analysis of RRBS data across the 1,677 regions showed that there may be at least 3 epigenetic subtypes of EOC with undetermined clinical significance (Fig. 1; 152). However, this data is identified alternately as originating from the larger 10,972/35 target region dataset (par. 142) and as originating from the 1,677 target region dataset relevant to the claims (par. 21). While the specification states the intention of using DMRs to differentiate histological subtypes (par. 151), such data does not appear to be present in the disclosure. Sensitivity and specificity data are shown only for the large 10,972/35 target region dataset and for diagnosis of grade of epithelial ovarian cancer (Fig. 2-4, par. 23-24, 146-147).
State of the Art and the Unpredictability of the Art
While methods of measuring methylation levels are known in the art, methods of correlating methylation levels with a phenotype such as epithelial ovarian cancer of various subtypes are highly unpredictable. The unpredictability will be discussed below.
The claims broadly encompass epithelial ovarian cancer diagnosis/determination using differential methylation patterns of ANY two or more genomic regions of Table 1. Table 1 lists 1,677 genomic regions. Any combination of two or more of those regions amounts to an astronomically large number of combinations. While the specification provides support that the full set of 1,677 target genomic regions of Table 1 may be indicators of the likelihood of having or developing at least one type of epithelial ovarian cancer, the specification does not provide evidence regarding reliable use of ANY combination of two or more target genomic regions of Table 1 to diagnose or differentiate epithelial ovarian cancer. The prior art teaches that certain sets of differentially methylated regions may be associated with the likelihood of having or developing epithelial ovarian cancer (Gloss et al., published April 17, 2014: US 20140106354 A1). In Gloss, at least the following set of differentially methylated regions may be used for the diagnosis of epithelial ovarian cancer (in bold are regions overlapping with those listed in Table 1 of the instant application):
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However, it is highly unpredictable as to whether any given combination of two or more target genomic regions of Table 1 would be associated with epithelial ovarian cancer or any subtype of epithelial ovarian cancer.
The claims are drawn to methods of predicting the development of and diagnosing ANY epithelial ovarian cancer. Claims 26 and 27 are drawn to methods of detecting high grade serous epithelial ovarian cancer or differentiating high-grade from non-high-grade serous epithelial ovarian cancer. In view of the recitation of epithelial ovarian cancer, the claims broadly encompass being able to predict ANY type of epithelial ovarian cancer based on expression of the target genomic regions of Table 1. However, the specification does not teach the association between any combination of target genomic regions and ANY type of epithelial ovarian cancer. For a different dataset (10,972/35), the specification provides evidence only that the 35 region set of DMRs was capable of stratifying samples by stage (par. 146). The art (Gloss et al., published April 17, 2014: US 20140106354 A1) teaches that methylation levels of some of the Table 1 target genomic regions may be used to differentiate ovarian cancers into clear cell or serous carcinomas (par. 34, 64; Fig. 4A – PEG3, LTBP2, and SPOCK2). However, the prior art also teaches that there is a large amount of unpredictability regarding methylation patterns between different types of epithelial ovarian cancer. For example, Earp et al. (Earp & Cunningham. DNA methylation changes in epithelial ovarian cancer histotypes. Genomics. 2015 Dec;106(6):311-21) shows that local patterns of hypo- and hypermethylation (of specific sets of genomic regions/genes) are histological type specific (Table 1) and that global patterns of methylation are distinct between different stages and grades of epithelial ovarian cancer. Thus, it is highly unpredictable as to whether correlations between the presence or any given type of epithelial ovarian cancer and differential methylation using any given combination of one or more target genomic regions of Table 1 could be extrapolated to any of the other stages or grades of epithelial ovarian cancer. The specification provides no evidence regarding the relationship between differential methylation of any combination of the 1,677 target genomic regions of Table 1 and epithelial ovarian cancer of any type.
The instant claims broadly encompass diagnosis/determination in a human subject or a nonhuman subject. However, the specification’s data regarding methylation as it related to epithelial ovarian cancer is based on the analysis of samples from human subjects. The prior art teaches that there is a large amount of unpredictability with regard to comparing results from epigenetic modifications (such as methylation patterns) in humans to animals. For example, Woo et al. (Woo & Li. Evolutionary conservation of histone modification in mammals. Mol Biol Evol. 2012 Jul; 29(7):1757-67) found that a particular methylation pattern of regulatory sites which was shared between cell types in humans was not highly shared between mice and humans. Only ~20% of regulatory sites with H3K4me1 modifications which were shared between cell types in humans were also shared between mice and humans (pg. 1759: col. 2, last par.). This supports the finding that there is no predictable means for determining whether differential methylation which is diagnostic of epithelial ovarian cancer in humans will also be predictive in a representative number of non-human subjects. The specification only provides support for human subjects.
The instant claims broadly encompass epithelial ovarian cancer diagnosis/determination using any cell-free nucleic acid sample. Claim 21 restricts sample types to whole blood, plasma, serum, or urine. The specification only provides examples of differential methylation expression levels for the target genomic regions of Table 1 measured from fallopian/ovarian samples (par. 148). As discussed above (Teachings in the Specification and Examples), cfDNA was isolated, enriched, and sequenced from plasma samples, but the specification does not provide any data related to determinations of epithelial ovarian cancer in these samples. The art, as evidenced by Peng et al. (Peng et al. Non-blood circulating tumor DNA detection in cancer. Oncotarget. 2017 Aug 4;8(40):69162-69173), teaches that even in non-urothelial carcinoma patients, cfDNA analysis from urine be concordant with analysis of plasma (pg. 69164, col. 2). While this is evidence of concordance between plasma and urine, there is no evidence that ovarian cancer-related epigenetic modifications would be the same between all possible sample types (i.e. stool, lymph, cerebrospinal fluid, etc.). Woo et al. (Mol Biol Evol. 2012 Jul; 29(7):1757-67) demonstrates that the fraction of genomic sites which experience the same epigenetic modification in multiple cell types even in the same species is relatively low (Fig. 2). Therefore, it is not clear if nucleic acid methylation levels observed in plasma or urine (or serum/whole blood) could be extrapolated to other sample types such as lymph or cerebrospinal fluid, as encompassed by the claims. Absent evidence to the contrary, it is highly unpredictable if cfDNA present in urine or blood samples which is useful for determination and differential of epithelial ovarian cancer would also be found in other sources of cfDNA (such as cerebrospinal fluid, saliva, sputum, lymph, etc.). The specification itself provides support only for the use of the target genomic regions of Table 1 in fallopian/ovarian samples.
The instant claims broadly encompass epithelial ovarian cancer diagnosis/determination using comparison to ANY cancer-free subject, reference standard, or reference cut-off value. However, it is highly unpredictable if the claimed method can be practiced using ANY of these comparisons. The claims do not set forth what the subject is or what the reference standard or cut-off values are. The subject could be any organism and the reference standard or cut-off values could come from any source (in silico predictive modeling, mouse models, clinical data, etc.). The teachings in the specification are limited to comparison of the large 10,972/35 dataset high grade serous epithelial cancer samples to normal fallopian/ovarian samples (par. 142, 148). There is no support for comparisons to any other kind of reference. It is highly unpredictable if target genomic regions which are differentially methylated between epithelial ovarian cancer human subjects and normal fallopian/ovarian samples will also be differentially expressed between epithelial ovarian cancer human subjects and ANY other type of cancer-free reference level encompassed by the claims.
The instant claims broadly encompass epithelial ovarian cancer diagnosis/determination using ANY degree and ANY type of difference (‘greater or less’) between the sample of interest and a cancer-free subject or reference. The specification does not teach any particular level of degree of difference – merely that the target genomic regions represent differentially methylated regions. However, the art teaches that hypermethylation of some regions and hypomethylation of other regions are associated with the development of epithelial ovarian cancer (Earp: pg. 312 – ‘Methylation patterns in ovarian cancer’). Therefore, it is highly unpredictable if any degree of either or both hyper- and hypomethylation of the same target genomic region(s) would be indicative of the development or presence of epithelial ovarian cancer or be useful for differentiation between subtypes of epithelial ovarian cancer.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to determine whether ANY type of subject (human or non-human animals) is likely to have or develop ANY type of epithelial ovarian cancer using ANY degree and ANY type of methylation difference of ANY combination of two or more target genomic regions from Table 1 between a subject and ANY cancer-free subject, a cancer-free reference standard, or a cancer-free reference cut-off value.
In order to practice the breadth of the claimed invention one of skill in the art would first have to gather samples from human and non-human subjects having a representative number of epithelial ovarian cancer types. The methylation levels of a representative number of combinations of two or more of the target genomic regions from Table 1 would have to be determined and then compared to a representative number of any cancer-free subjects, cancer-free reference standards, or cancer-free reference cut-off values. Then, sophisticated data analysis would have to be conducted to determine which combinations of target genomic regions would be predictive of epithelial ovarian cancer development or type. The specification has merely provided an invitation for further experimentation. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even "a considerable amount of experimentation is permissible," as long as it is "merely routine" or the specification "provides a reasonable amount of guidance" regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360- 61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is "not without bounds." Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation "would be excessive, e.g., that it would involve testing for an unreasonable length of time." 707 F .3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a "diverse and relatively poorly understood group of microorganisms," with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years' work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a "predictable" factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
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 1-8 and 20-27 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 1-8, 11, 14, 17, and 19-27 are rejected for referring to specific figures and/or tables in the specification. MPEP 2173.05(s) states that “Where possible claims are to be complete in themselves. Incorporation by reference to a specific table or figure ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicated a drawing or table into a claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.”
Claims 1-8, 11, 14, 17, and 19-27 are rejected for the references to chromosomal locations in Table 1 in claims 1,11, 14, 17, 19, and 25-27 and recitation of chromosomal locations in claim 20 because it is unclear from the claims which genome(s) are being described or are required. For example, the designation “Chr2: 38323997-38324203” could indicate different sequences in different human genome builds as well as in non-human animals. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 1-8, 11, 14, 17, and 19-27 are rejected for the recitation of “change” in claims 1, 26, and 27. Neither the claims nor the specification provide a clear limiting definition for the term and the plain meaning of the term ‘change’ is ‘to become different.’ The claims recite a step of comparing the methylation levels between a subject’s sample and the levels from a cancer-free subject or between the subject’s sample and a normal reference standard or cut-off value. None of these comparisons would involve a level which ‘became different,’ and therefore it is unclear whether the claim is intended to require a change in the subject’s methylation levels over time or something else. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. If what was intended was a that there be a non-zero ‘difference’ between the subject’s sample and another sample or reference, the claim must be amended to reflect that meaning.
Claims 4-8 are rejected for the recitation of “post whole genome library hybrid probe capture” in claim 4. Neither the claims nor the specification provide a clear limiting definition for the term. While methylation determination methods involving ‘whole genome’ or ‘hybrid probe capture’ are known, it is not clear what is meant by “post whole genome library hybrid probe capture” in the context of the claims. For example, does the claim require whole genome sequencing of each sample in order to generate hybrid probes for sequence enrichment, or can a shared set of hybrid probes or baits developed from a single instance of whole genome sequencing be used instead? As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 5-8 are rejected for the recitation of ‘the target genomic’ in claim 5, and ‘one or more target genomic regions’ in claims 6 and 7. There is insufficient antecedent basis for these limitations in the claims. Claim 1, on which claim 5 depends, recites only ‘a/the plurality of target genomic regions,’ which requires multiple target genomic regions, while claim 5 requires only a single region. It is therefore unclear which of the plurality of regions from claim 1 are determined in claim 5. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 5-8 are rejected for the recitation of ‘hybrid probe capture’ in claim 5, because it is unclear whether ‘hybrid probe capture’ is the same or different than ‘post whole genome library hybrid probe capture,’ as recited in claim 4. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 6-8 are rejected for the recitation of ‘one or more target genomic regions’ in claims 6 and 7. There is insufficient antecedent basis for this limitation in the claims. Claims 1 and 5, on which claims 6-8 depend, recite only ‘a/the plurality of target genomic region’ (claim 1) and ‘the target genomic is’ (claim 5). It is unclear what the ‘one or more’ regions of claims 6 and 7 refer to and if the region(s) are the same or different from the regions of claims 1 or the region of claim 5. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 6-8 are rejected for the recitation of ‘the DNA molecule’ in claim 6, as lacking antecedent basis. Claims 1, 4, and 5, on which claim 6 depends, do not recite ‘a DNA molecule.’ While Claim 1 implicitly requires that the measured nucleic acid be DNA (by referring to target genomic regions defined by chromosomal location), probes are also present which may be either DNA or RNA. It is therefore unclear what DNA molecule is being referred to in claim 6: the target nucleic acid, the hybrid probe DNA, or some other DNA molecule present in the sample? As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 23-25 are rejected because the recitation of ‘the use of’ in claim 23 renders the claims indefinite. The claim merely recites a use without any active, positive steps delimiting how this use is actually practiced (see MPEP 2173.05(q): “Use” Claims). As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 25 is rejected because it is unclear whether what the samples are required to be comprised of. The claim requires ‘known epithelial ovarian cancer samples,’ ‘known cancer-free ovarian and/or fallopian tube samples,’ but also examination of ‘each of the cell-free nucleic acid samples.’ Claim 1 requires only a single ‘cell-nucleic acid sample.’ It is not clear whether the cell-free nucleic acid samples of claim 25 are the same as the single cell-free nucleic acid sample from claim 1, or if they’re a further limitation on either of the known cancer/cancer-free samples recited earlier in claim 25, or if they’re something else. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. Clarification is requested.
Improper Markush Rejection
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim(s) 1-8, and 20-27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 1-8, 11, 14, 17, and 19-27 are rejected on the basis that it/they contain(s) an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The claims recite the following Markush groups:
Claims 1, 26, and 27: “a plurality of target genomic region listed in Table 1”
Claim 11: “the plurality of target genomic regions comprises at least 30% of the target genomic regions of Table 1”
Claim 14: “the plurality of target genomic regions comprises at least 60% of the target genomic regions of Table 1”
Claim 17: “the plurality of target genomic regions comprises at least 90% of the target genomic regions of Table 1”
Claim 19: “the plurality of target genomic regions comprises at least 95% of the target genomic regions of Table 1”
These Markush groupings are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”. Herein, the members of the Markush grouping are all genomic loci. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited loci would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP § 2117(II)(B) states that “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again, the members of the Markush grouping are all chromosomal loci. While they are all made up of nucleic acids, the structure of comprising nucleic acids is not essential to any asserted common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 1-8, and 20-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4, Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite a correlation between the methylation level of target genomic regions and epithelial ovarian cancer. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. Claims 1-8 and 20-25 recite ‘determining’ whether a subject is likely to have or develop epithelial ovarian cancer. Claim 26 recites ‘detecting’ high grade serous epithelial ovarian cancer. Claim 27 recites ‘differentiating’ high grade serous epithelial ovarian cancer from non-high-grade serous epithelial ovarian cancer. Neither the specification nor the claims set forth active processes for ‘determining’, detecting’, or ‘differentiating.’ Some of the claims allow that ‘determining’ may be accomplished through the ‘use’ of a machine learning algorithm (claims 23-25), but no active steps for determination are recited, and otherwise the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the “determination” step is that it may be accomplished by a mental process. For example, one may ‘determine’ the likelihood of having or developing epithelial ovarian cancer by thinking about the subject’s methylation levels relative to the reference level or by thinking about the output of the machine learning algorithm. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
The claims recite a step of “comparing” the methylation levels of target genomic regions in a subject with those of a reference. Neither the specification nor the claims set forth a limiting definition for “comparing” and the claims do not set forth how this step is accomplished. The “comparing” step broadly encompasses mental processes. For example, one may “compare” the methylation levels by looking at data and thinking about whether the expression level is higher than a reference level. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claims 23-25 recite ‘the use of’ a trained machine learning algorithm. Neither the specification nor the claims set forth criteria for ‘the use of’ the algorithm and the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the ‘use of’ an algorithm is that it may be accomplished by a mental process. For example, one may make ‘use of’ a trained machine learning algorithm by thinking about the algorithm’s output and deciding if a subject is likely to develop epithelial ovarian cancer. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exception(s) into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or a technological field;
An additional element that applies or used a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing;
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, the claims recite a step of ‘measuring’ methylation of target genomic regions from a cell-free nucleic acid sample from a subject. Claims 4-8 recite limitations of the ‘measurement’ step. The measurement steps are not considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Claims 20 recites a step of treating epithelial ovarian cancer. This administration step is not particular, i.e., specifically identified so that it does not encompass all application of the judicial exceptions. The steps is merely instruction to apply the exception in generic ways. Furthermore, the administering step is conditional and only occurs when the subject is determined to have epithelial ovarian cancer. The claims broadly encompass situations where the subject is found to NOT to have epithelial ovarian cancer. In those situations, the treatment would not be administered. Thus, the administration steps do not integrate the mental analysis step into a practical application.
In addition to the judicial exceptions, the claims recite wherein clauses including limitations to the target genomic regions (claim 20), limitations of the machine learning algorithm (claims 24, 25), limitations to the type of sample (21), and intended uses of the method (claims 2 and 3). These do not integrate the judicial exceptions into practical application because they are merely instruction to apply the exception in generic ways.
Step 2B: Evaluate Whether the Claim Provides and Inventive Concept
In addition to the judicial exceptions, the claims recite steps of ‘measuring’ and ‘treating.’ In addition to the judicial exceptions, the claims recite wherein clauses limiting the target genomic regions, machine learning algorithm, type of sample, and intended use. These steps and limitations do not amount to significantly more because they simply append well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The additional steps are recited a high level of generality. Determining the methylation levels of genomic regions and treating a subject are merely instructions to a scientist to use any known technique for measuring methylation levels or treating a subject with cancer. The claims do not require the use of any particular non-conventional reagents or equipment or methodology. When recited at this high level of generality, there is no meaningful limitation that distinguishes these steps from well-understood, routine, and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well-understood, routine, and conventional nature of additional elements because it teaches that the additional elements are well-known or commercially available. For example, the specification teaches the following:
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Further, it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, and conventional activity in the life science arts when they are claimed in a merely generic manner (e.g. at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 1-7, 20-23, 26, and 27 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Gloss et al. (published April 17, 2014; US 20140106354 A1).
Regarding claims 1, 26, and 27, Gloss recites a method for determining whether a subject is likely to have or develop epithelial ovarian cancer (par. 11). Gloss recites that the method comprises measuring the level of nucleic acid methylation of a plurality of target genomic regions, as listed in Table 1. These loci comprise one or more of SPOCK2, LTBP2, and PEG3 (par. 114), which are located at chr10:72059034-72089032, chr14:74498183-74612378, and chr19:56810077-56840728 in human genome build hg38, respectively. These loci overlap the claimed target genomic regions (chr10:72080814-72080990, chr10:72084046-72084426, chr14:74573813-74573962, and chr19:56840344-56740644) with sufficient specificity that the limitation is considered to have been anticipated.
Gloss recites measuring methylation in cell-free nucleic acid samples (par. 11), and comparing the level of nucleic acid methylation in the sample to the level of nucleic acid methylation of the plurality of target genomic regions in a sample isolated from a cancer-free subject, a cancer-free reference standard, or a cancer-free reference cutoff value (par. 235). Gloss recites determining that the subject is likely to have or develop epithelial ovarian cancer based on a change in the level of nucleic acid methylation in the plurality of target genomic regions in the sample derived from the subject compared to that from a cancer-free subject, a normal reference standard, or a normal reference cutoff value (par. 242). Regarding claims 26 and 27, Gloss recites determining the stage or grade of cancer (par. 252), as well as the determination of histological subtype (par. 11). Gloss recites comparing the sample of interest to a control sample with a specific stage or grade of cancer for identification of stage or grade of cancer in the subject (par. 252). Therefore, the additional limitations of claims 26 and 27 are considered to have been met.
Regarding claims 2 and 3, Gloss recites determining the presence of cancer of any stage (par. 228) and various histological types, including endometrioid, mucinous, clear cell, and serous ovarian cancer (par. 119).
Regarding claim 4, Gloss recites determination of methylation level using various methods, including: enzymatic treatment (par. 132), bisulfite treatment of DNA (par. 151), methylation-sensitive PCR (par. 169), bisulfite amplicon sequencing (par. 153), and bisulfite conversion combined with bisulfite restriction analysis (par. 157).
Regarding claim 5, Gloss recites determination of methylation levels using hybrid probe capture (par. 184). In this case, the hybrid probe capture is used to enrich or isolate methylated DNA from a sample and the recited embodiment of probe is a recombinant protein (par. 185).
Regarding claim 6, Gloss recites that the one or more target genomic regions comprise a uracil at each position corresponding to an unmethylated cytosine in the DNA molecule (par. 151).
Regarding claim 7, Gloss recites that one or more probes is configured to hybridize to a nucleotide sequence of the one or more target genomic regions comprising cytosine at each position, corresponding to a cytosine of a CpG site of the nucleic acid molecule (par. 185).
Regarding claim 20, Gloss is silent regarding target genomic regions comprising Chr2: 38323997-38324203, Chr2:113712408-113712611, Chr3:20029245-20029704, Chr8:58146211-58146673, Chr8:124995553-124995624, Chr9:89438825-89439085, Chr11:63664463-63664769, Chr11:120496972-120497256, or Chr20:5452392-5452552, and recites target genomic regions which do not fall within those chromosomal locations (PEG3, LTBP2, and SPOCK2, among others). Therefore, the limitations of claim 20 are considered to have been met.
Regarding claim 21, Gloss recites samples from whole blood or plasma (par. 11), as well as urine and serum (par. 47).
Regarding claim 22, Gloss recites treatment comprised of surgery to remove cancer or administering a therapeutic agent to the patient (par. 268).
Regarding claim 23, Gloss recites the use of a trained machine learning algorithm to determine whether a subject is likely to have or develop epithelial ovarian cancer (par. 243, 246).
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claim 8 is rejected under 35 U.S.C. 103 as unpatentable over Gloss et al. (published April 17, 2014; US 20140106354 A1), as discussed for claims 1 and 4-6 above, and further in view of Gnirke et al (published Feb 2009; Gnirke et al. Nat Biotechnol. 2009 Feb;27(2):182-9).
The teachings of Gloss et al. have been stated in the rejection of claims 1-7, 20-23, 26, and 27 under 35 U.S.C. 102(a)(1) documented above.
Regarding claim 8, Gloss does not explicitly recite hybrid probe capture using a hybrid probe comprised of ribonucleic acid and biotin or streptavidin. However, Gloss does teach the use of hybridization probes for the purposes of enrichment (par. 134, 184-185).
Gnirke teaches hybrid probe capture using a hybrid probe comprised or ribonucleic acid and biotin or streptavidin (pg. 3: ‘Hybrid selection method’).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Gloss and Gnirke with reasonable expectation of success because Gnirke demonstrates that hybrid probe capture using biotinylated RNA probes is reproducible (pg. 6, last par.; Figure 5a). One would have been motivated to do so in order to enrich target genomic regions using a method shown to be flexible, scalable, and efficient (pg. 8, 1st par.).
Claims 24 and 25 are rejected under 35 U.S.C. 103 as unpatentable over Gloss et al. (published April 17, 2014; US 20140106354 A1), as discussed for claims 1 and 23 above, and further in view of Haghshenas et al. (published Nov 22, 2020; Haghshenas et al. Int J Mol Sci. 2020 Dec 6;21(23):9303).
The teachings of Gloss et al. have been stated in the rejection of claims 1-7, 20-23, 26, and 27 under 35 U.S.C. 102(a)(1) documented above
Regarding claim 24, Gloss does not explicitly disclose the use of random forest, support vector machine, neural network, or deep learning machine learning algorithms.
Haghshenas et al. teach the use of support vector machines (SVM) and random forests (RF) with methylation data (pg. 8, 1st par.).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Gloss and Haghshenas with reasonable expectation of success because support vector machines (SVM) and random forests (RF) are commonly implemented for the purpose of differentiating cases and controls based on methylation data (pg. 8, 1st par). One would have been motivated to do so in order to process data using methods suitable for datasets with low numbers of samples and high dimensionality (pg. 8, 1st par.).
Regarding claim 25, Gloss does not explicitly disclose machine learning algorithms trained using samples comprising known cancer samples and known cancer-free samples. However, Gloss does teach machine learning algorithms used to classify subjects normal (cancer-free) or at risk of having cancer, and which are derived based on biomarker results in the ‘relevant training population’ (par. 250). In this context, the ‘relevant training population’ would include samples known to have epithelial ovarian cancer (par. 11) and known to be cancer-free (par. 235). Therefore, the limitations of claim 25 are considered to have been met.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine M Jones whose telephone number is (571)272-2585. The examiner can normally be reached Monday - Friday, 8AM - 4PM.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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