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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-6) in the reply filed on 03/13/2026 is acknowledged.
Claims 7-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/13/2026.
Claim Objections
Claim 2 is objected to because of the following informalities: additional space(s) are present in line 6 between “cancers,” and “provided”. 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:
(1st) 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 1-6 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.
Specifically, the Applicant has failed to demonstrate possession, or put the public in possession, of examination reagents for analyzing the degree of methylation in cancers other than those explicitly disclosed by the specification (colon, pancreatic, hepatocellular, bile duct, and ovarian) or examination reagents for methylation markers other than those specifically described in Table 1-11.
Claim 1, as well as dependent claims 2-6, are generic with regard to the types of cancer analyzed by the examination reagents as well as the methylation markers that could be associated with (even the disclosed) cancers. MPEP 2163(II)(A)(3)(a)(ii) discusses the situation of claims drawn to a genus. In particular:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021).
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
In the case of the instant application, considerable variation is expected within the genus of examination reagents used to analyze the degree of methylation as they relate to different cancers such that one could not predict, based upon the examination reagents developed for the assessment of methylation degree in colon, pancreatic, hepatocellular, bile duct, and ovarian cancers, which examination reagents would be useful for performing the same analysis on wholly different cancers.
Additionally, the data used to generate the Applicant’s selected methylation markers (e.g., from the Cancer Genome Atlas) was obtained from various studies which would have used specific patients or cell lines. Therefore, there remains the possibility that additional methylation markers exist in the human genome that are indicative of a particular cancer but have not yet been associated as such either due to insufficient study parameters to date, or simply because they were not included in the data sets used by the Applicant.
See Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004): “[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”
Therefore, the applicant has not demonstrated possession of the invention as so broadly claimed.
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 1-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon (including a product of nature) without significantly more.
The claims recite reagents for analyzing the degree of methylation of CpG site sets. The specification defines these reagents as “a reagent designed so that the degree of methylation…can be comprehensively analyzed” and provides primers as an example (¶0030-31, 0041-42). Primers are nothing more than strands of nucleic acids whose characteristics are innate to naturally occurring DNA, thus lacking markedly different characteristics from nature (see MPEP 2106.04(C).II.C.2; Ambry Genetics, 774 F.3d at 760-61, 113 USPQ2d at 1244).
This judicial exception is not integrated into a practical application because merely placing two products of nature together in a set does nothing more than attempt to generally link the products of nature to a technological environment, and is therefore considered to be insignificant extra-solution activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements limit what the reagents are analyzing, leaving the products of nature themselves unchanged. As no additional limitations exist which would modify the products of nature in a meaningful way, claims 1-6 do not contain eligible subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6 are rejected under 35 U.S.C. 102(a)1 as being anticipated by Nunes (Nunes SP et al. Cancers. 2018 Sep 26;10(10):357) as evidenced by Pan (Pan S et al. Biomedicine & pharmacotherapy. 2009 Aug 1;63(7):463-8) and Zhang (Zhang W et al. Cancer research. 2008 Apr 15;68(8):2764-72)
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Nunes teaches assessing the methylation level of the promoters of various genes (APC, FOXA1, RASSF1A, SCGB3A1, SEPT9, and SOX17) to simultaneously screen circulating, cell-free DNA (ccfDNA) samples for the presence of breast (BrC), colorectal (CRC), and lung (LC) cancer (abstract). Figure 4 provides an overview of this two-step process in which three genes are evaluated for the presence or absence of one of the three cancers generally (the PanCancer assay). Specifically, methylation of the APC, FOXA1, or RASSF1A promoters would indicate the presence of either breast, colorectal, or lung cancer. A positive result at this stage would then lead to a second round of testing in which three additional genes are used to determine which specific cancer is present (the CancerType assay). Methylation of the SCGB3A1 promoter would differentiate BrC vs CRC and BrC vs LC; methylation of the SEPT9 promoter would differentiate CRC vs BrC and CRC vs LC; and methylation of the SOX17 promoter would differentiate LC vs BrC and LC vs CRC.
The relative methylation levels of each promoter was assessed using a multiplex qMSP assay for which Nunes developed promoter-specific primers and probes (section 4.3). Therefore, the primers/probes used in the PanCancer assay can be considered equivalent to the primary examination reagent of the instant application; and the primers/probes used in the CancerType assay can be considered equivalent to the secondary examination reagent of the instant application.
Regarding claims 3-6, Nunes does not specifically discuss the number of CpG sites evaluated in their method. Rather, they report the relative methylation levels of each protomer using β-actin as a normalizer (i.e., (gene methylation/β-actin methylation) x 1000) (Figure 1). However, Pan teaches that promoter 1A of the APC gene has 31 CpG sites (Pan, p463); therefore, CpG site set 1 (aka the PanCancer assay) has at least 30 CpG sites. Additionally, Zhang investigated the methylation status of over 30 CpG sites in the SOX17 promoter (p2767; fig 3); therefore, since the CancerType assay evaluates methylation status of the SOX17 promoter, it can be assumed that the CpG site set 2 (aka the CancerType assay) has at least 30 CpG sites.
Claims 1-6 are further rejected under 35 U.S.C. 102(a)1 as being anticipated by Illumina (Illumina. Infinium® HumanMethylation450 BeadChip. 2012 March 09) as evidenced by Xia (Xia D. Modern Pathology. 2020 Oct 1;33(10):1874-88).
Xia describes the development of a “minimalist” methylation-based test for classifying 28 cancers using a combination of publicly available data (e.g., the Cancer Genome Atlas) and internal data (Xia abstract).
Xia examined different biomarker panels to determine which classification method below would be the most informative using the least number of biomarkers (Xia p1876):
X vs All: biomarkers were chosen for their ability to differentiate one cancer from all other cancers. As is shown in Supplementary Table 6, Xia identified anywhere from 10 to 18,620 highly informative CpG sites that were capable of differentiating between 27 of the 28 cancer types using this method, excluding lung squamous cell carcinoma.
Pairwise differential: biomarkers were chosen for their ability to differentiate one cancer from a second cancer. As is shown in Supplementary Table 7, Xia identified anywhere from 96 to 84,700 highly informative CpG sites capable of differentiating between each pairwise differential for 25 of the 28 cancer types, excluding three types of squamous cell carcinomas which proved difficult to distinguish from one another. That the pairwise differential analysis resulted in identification of a larger number of CpG sites as compared to “X vs All” was not surprising, as markers that work well for differentiating cancer 1 from cancer 2 may fail to differentiate cancer 1 from all other cancers (p1879).
Hybrid approach: a combination of the “X vs All” and the pairwise differential biomarkers.
The results from these analyses showed that many of the top-ranking probes in each method were approximately 100% capable (AUC at or near 1) of performing their assigned differentiation task. From this Xia concluded that a small number of the identified probes would be sufficient to accurately diagnose cancer and proceeded to assess multiple models of each classification method using varied numbers of probes (Xia p1879). Xia’s goal was to obtain the smallest, accurate panel possible; however, figure 2 shows the range at which each model was tested and the corresponding accuracy of those panels.
The TCGA data used by Xia was originally obtained using the Illumina® Infinium® HumanMethylation450 BeadChip, which contains probes for over 450,000 methylation sites (Xia p1875; Illumina data sheet). As multiple datasets were used for Xia’s analyses, probes which were not present in every dataset were removed (Xia p1875). Therefore, a skilled artisan could assume that all of the CpG sites used by Xia can be analyzed by the probes on Illumina’s BeadChip.
With all of this in mind, and with the knowledge that the data used by the Applicant for their own invention was obtained from the TCGA (instant specification, 0097), the probes used to identify the CpG sites of the “X vs All” method could be considered equivalent to the primary examination reagent of the instant application and the probes used to identify the CpG sites of the pairwise differential method could be considered equivalent to the secondary examination reagent of the instant application. Additionally, as a large number of probes were identified by Xia in all methods, it would have been within the capabilities of the skilled artisan to select different probes for each reagent.
In summary, the primary and secondary examination reagents are anticipated by the Illumina® Infinium® HumanMethylation450 BeadChip used by both Xia and the Applicant.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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