NATIONAL CANCER CENTER et al.

Patent Trials and Appeals Board

Jan 31, 2022

2021002178 (P.T.A.B. Jan. 31, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/287,121 10/06/2016 Toshikazu USHIJIMA Q229241 1071 23373 7590 01/31/2022 SUGHRUE MION, PLLC 2000 PENNSYLVANIA AVENUE, N.W. SUITE 9000 WASHINGTON, DC 20006 EXAMINER WHALEY, PABLO S ART UNIT PAPER NUMBER 3619 NOTIFICATION DATE DELIVERY MODE 01/31/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): PPROCESSING@SUGHRUE.COM USPTO@sughrue.com sughrue@sughrue.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ________________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ________________ Ex parte TOSHIKAZU USHIJIMA and SATOSHI YAMASHITA1 ________________ Appeal 2021-002178 Application 15/287,121 Technology Center 3600 ________________ Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and JOHN G. NEW, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 We use the term “Appellant” to refer to the “applicant” as defined in 37 C.F.R. § 1.142. Appellant identifies the National Cancer Center and Sysmex Corporation as the real parties-in-interest. App. Br. 3. Appeal 2021-002178 Application 15/287,121 2 SUMMARY Appellant files this appeal under 35 U.S.C. § 134(a) from the Examiner’s Final Rejection of claims 1-18 and 20 as unpatentable under 35 U.S.C. § 101 as being directed to nonstatutory subject matter. Claims 1-18 and 20 also stand rejected as unpatentable under 35 U.S.C. § 112(a) as lacking written descriptive support (see Final Act. 11).2,3 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellant’s claimed invention is directed to a method for detecting a rare DNA mutation. Spec., Abstr. REPRESENTATIVE CLAIM Independent claim 1 is representative of the claims on appeal and recites: Claim 1. A method for detecting a rare mutation, the method comprising the steps of: 2 The Examiner also rejected claims 1-18 and 20 as lacking utility under 35 U.S.C. § 101 and being indefinite under 35 U.S.C. § 112(b). Non-Final Act. 9, 14. The Examiner has withdrawn these rejections. Ans. 3. 3 Appellant also argues that the Examiner rejected claims 1-18 and 20 as unpatentable under 35 U.S.C. § 112(a) as lacking enablement, on the ground that the claims are not supported by a specific, substantial and credible utility. App. Br. 20. We can discern no such lack of enablement rejection in the Non-Final Office Action of November 7, 2019. See Non- Final Act. 11. Appeal 2021-002178 Application 15/287,121 3 preparing a sample comprising not more than 1,000 copies of template DNA; amplifying the template DNA to prepare a library, and analyzing a nucleotide sequence of the library; calculating a ratio of variants in a base at a predetermined position, from the analysis result; comparing the calculated ratio of variants with a predetermined cut-off value; and determining that the sample has a rare mutation in the base at the predetermined position when the calculated ratio of variants is not less than the predetermined cut-off value, wherein in the analysis step, the nucleotide sequence of the library is determined by a next generation sequencer. App. Br. 27. ISSUE AND ANALYSIS We agree with and adopt the Examiner’s findings, reasoning, and conclusion that the claims are directed to nonstatutory subject matter. We decline, however, to adopt the Examiner’s conclusion that the claims lack written descriptive support. We address below the arguments raised by Appellant. A. Nonstatutory subject matter The Examiner’s Findings and Conclusions The Examiner, employing the two-step analytical framework set forth in Alice Corp. Pty. Ltd. v. CLS Bank Intern., 573 U.S. 208, 217-18 (2014), first finds that the language of the analyzing and executing steps is so Appeal 2021-002178 Application 15/287,121 4 generically written that it encompasses observation or evaluation, which is an act that can be performed in the human mind, similar to mental thought processes. Final Act. 4. The Examiner finds that there is nothing in the language of the claims that forecloses these steps from being performed by a human, mentally or with pen and paper. Id. Specifically, the Examiner finds that the comparing, executing, and determining steps require using a ratio (in order to determine a ratio of variants) and comparing the ratios to cut-off values. Final Act. 5. This type of observation or evaluation is an act that can be practically performed in the human mind, similar to mental thought processes. Id. The Examiner reasons that such mental observations or evaluations fall within the “mental processes” grouping of abstract idea. Id. Turning to the second step of the analysis, the Examiner finds that the preparing, amplifying, dividing, and executing the amplifying steps merely obtain data for use by the abstract idea (i.e. pre-solution activity). Final Act. 5. Therefore, the Examiner reasons, these steps amount to insignificant extra-solution activity and are not indicative of integration into a practical application. Id. (citing MPEP § 2106.05(g). As such, the Examiner finds, none of the non-abstract steps apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Id. at 6. With respect to the next generation sequencer recited in the claims, the Examiner finds that this feature is not being used in a positive process step (i.e., it has no limiting effect on the method as claimed). Final Act. 6. The Examiner reasons that, even if the sequencer was used in a positive process step, it is recited so generically that it can be viewed as nothing more insignificant extra-solution activity and is not indicative of integration into a Appeal 2021-002178 Application 15/287,121 5 practical application. Id. (citing MPEP § 2106.05(g)). The Examiner therefore concludes that the claim as a whole does not integrate the recited judicial exception into a practical application. Id. The Examiner also takes official notice that the preparing, dividing, amplifying, and executing steps were well known in the art of genomics, and that this notice is supported by Appellant’s Specification at page 2, as well as the prior art reference T. Shimizu et al., Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection, 147(2) GASTROENTEROL. 407-17 (2014) (“Shimizu”). Final Act. 6. The Examiner also cites additional references to show that the recited steps of preparing, dividing, amplifying, and executing steps were well known in the art of genomics at the time of invention. Id. The Examiner therefore concludes that these steps remain insignificant extra-solution activity and do not amount to significantly more. Id. Issue Appellant argues that the Examiner erred in concluding that the claims are directed to an abstract idea without reciting significantly more elements sufficient to raise the claimed invention to patent-eligible subject matter. App. Br. 10. Analysis Appellant first argues that although a “mathematical concept” may, at some level, underpin the calculating step, that alone does not make it a judicial exception. App. Br. 10. Appellant notes that the Supreme Court has acknowledged that all inventions, “at some level[,] embody, use, reflect, rest Appeal 2021-002178 Application 15/287,121 6 upon, or apply laws of nature, natural phenomena, or abstract ideas” but that this does not automatically make them directed to a judicial exception. Id. (quoting Mayo Collaborative Srvcs. v. Prometheus Labs., Inc., 566 U.S. 66. 70 (2012). Appellant also points to the USPTO’s 2019 Subject Matter Eligibility Examples: Abstract Ideas, available at: https://www.uspto.gov/sites/default/files/documents/101_examples_37to42_ 20190107.pdf, (last visited January 12, 2019) (the “2019 Examples”), which advises that “mathematical concepts” must be expressly recited in the claims to be considered a judicial exception. Id. (quoting 2019 Examples at 7 (Example 38)). Appellant accordingly contends that the claimed calculating steps do not constitute a judicial exception. Id. Similarly, argues Appellant, the claimed “analyzing” steps cannot be considered a mental step (i.e., one that may “reasonably be performed by the human mind”) because these steps require discerning the actual sequence of an amplified polynucleotide molecule. App. Br. 10-11. According to Appellant, this is not something that can be done purely in the mind but, rather, some technology must be used to “sequence,” i.e., read and output, the nucleotide sequence of the polynucleotide molecule. Id. at 11. Appellant asserts that independent claims 1, 11, and 20 embody the use of nucleic acid sequencing technology to perform the analyzing step. Id. Appellant argues that independent claims 1, 11, and 20 recite the step of “amplifying the template DNA … to prepare a library, and analyzing a nucleotide sequence of the library … wherein in the analysis step, the nucleotide sequence of the library is determined by a next generation sequencer.” App. Br. 12. Appellant asserts that a polynucleotide library is therefore first produced through the tangible process of amplifying template Appeal 2021-002178 Application 15/287,121 7 DNA (which is unquestionably not a process that can be practically performed in the mind); and then a nucleotide sequence within that polynucleotide library is determined (“sequenced”) by a next-generation sequencer, i.e., through a next-generation sequencing technique. Id. Therefore, argues Appellant, contrary to the Examiner’s findings, the “next generation sequencer” recited in the claims is not “merely directed to how the sequence data … for preparing the library was determined.” App. Br. 12. Appellant contends that it is after creation of the polynucleotide library that a nucleotide sequence within that library is determined by a next- generation sequencer, i.e., through a next-generation sequencing technique. Id. These steps, Appellant argues, go beyond the Examiner’s finding that the analyzing step of the claims embodies only data manipulation. Id. Appellant next argues that, even if the claims could be construed to recite a judicial exception, the claims as a whole are directed to specific improvements over prior sequencing techniques and result in improved differentiation between a low-frequency mutation in, e.g., a sample from an individual; and an error introduced by the amplification and sequencing process itself. App. Br. 13 (citing Spec. ¶¶ 18-24). Appellant particularly points to paragraph [0021] of the Specification, which discloses that, unlike conventional techniques, Appellant’s claimed invention “can distinguish whether the variation detected by sequencing is derived from the rare mutation or derived from the [amplification or sequencing] error.” Id. Appellant notes that a judicial exception can be “integrated” into a practical application such that the claim is directed to patent-eligible subject matter if the claim improves a technology. App. Br. 13 (citing Alice, 573 U.S. 208; also citing Diamond v. Diehr, 450 U.S. 175 (1981); Finjan Inc. v. Appeal 2021-002178 Application 15/287,121 8 Blue Coat Systems, Inc., 879 F.3d 1299 (Fed. Cir. 2018)). Appellant contends that, 2018). Appellant contends that, to the extent that the present claims may be construed, arguendo, to recite a judicial exception, any judicial exception is sufficiently integrated into a tangible sequencing method to thereby improve a specific technology (i.e., next generation sequencing), and are patent-eligible for at this reason. Id. at 14. Appellant notes that MPEP § 716.02, upon which the Examiner relies, relates only to evidence proffered to rebut an obviousness rejection under 35 U.S.C. § 103 on a theory of unexpected results, and is irrelevant to demonstrating a technological improvement to rebut a rejection under § 101. App. Br. 14. Appellant also argues that the Examiner’s position here is at odds with the USPTO’s own guidance that, to establish an improvement, the specification need only provide “sufficient details such that one of ordinary skill in the art would recognize the claimed invention as providing an improvement.” Id. (quoting USPTO, October 2019 Update: Subject Matter Eligibility, 12 available at: https://www.uspto.gov/sites/default/files/ documents/peg_oct_2019_update.pdf (last visited January 13, 2022)). Finally, Appellant argues that the claims on appeal are patent-eligible because the step of “preparing a sample comprising not more than 1,000 copies of template DNA,” when considered with the subsequent amplification and sequencing steps as part of an ordered combination, together constitute an “inventive concept.” App. Br. 15. Appellant asserts that it is well settled that the presence of non-routine and non-conventional activity in a claimed method otherwise directed to recite a judicial exception, is one way of establishing a patent-eligible “inventive concept.” Id. Appeal 2021-002178 Application 15/287,121 9 Appellant points to paragraphs [0018]-[0020] of the Specification, which disclose that conventional sequencing assays typically require, and use, 50-100 ng of genomic DNA (corresponding to more than 15,000 copies of the genomic DNA) per reaction. App. Br. 15-16. In contrast, Appellant argues, in the claimed invention, the sample requires, unconventionally, “not more than 1,000 copies of template DNA.” Id. at 16. Appellant asserts that Paragraphs [0018]-[0020] of the Specification discloses that the higher amount of template DNA used in conventional sequencing assays precludes the ability to accurately elucidate whether a different base at a particular position reflects a mutation in the original sample; or whether it reflects an error introduced during the amplification and sequencing reactions. Id. Therefore, argues Appellant, the use of samples containing such low template copy number for sequencing, as presently claimed, is non-routine and nonconventional activity that constitutes a patent-eligible inventive concept. Id. Appellant notes that the Examiner rejects the assertion that the step of “preparing a sample comprising not more than 1,000 copies of template DNA,” and the subsequent amplification and sequencing steps, together constitute an “inventive concept,” citing Hindson et al. (US 2012/0252015 A1, October 4, 2020) (“Hindson”) and A.S. Whale et al., Methods for Applying Accurate Digital PCR Analysis on Low Copy DNA Samples, 8(3) PLOS ONE, e58177 (2013) (“Whale”) show these features to be routine and conventional. App. Br. 16 (citing Final Act. 9). Appellant contends, however, that Hindson and Whale are deficient as evidence. According to Appellant, the Examiner cites to paragraphs [0508]-[0511] of Hindson, but this teaching of Hindson has nothing to do with sequencing (much less the Appeal 2021-002178 Application 15/287,121 10 fidelity of sequencing); it relates only to ddPCR, and is unconcerned with sequencing any of the amplified products. Id. Appellant therefore argues that Hindson does not establish that, in conventional sequencing methods, it was routine to use “not more than 1,000 copies of template DNA.” Id. at 16-17. Appellant asserts that Whale is similarly deficient in this regard, again pertaining only to PCR amplification of low-copy number samples - and having nothing to do with sequencing. Id. at 17. We are not persuaded by Appellant’s arguments. In performing an analysis of patentability under Section 101, we follow the framework set forth by the Supreme Court in Mayo. We are also mindful of, and guided by, the United States Patent and Trademark Office’s 2019 Revised Patent Subject Matter Eligibility Guidance, 84(4) Fed. Reg. 50-57 (January 7, 2019) (the “2019 Guidance”). Appellant’s claim 1 recites: “A method for detecting a rare mutation, the method comprising….” Independent claims 11 and 20 similarly recite a method for detecting a rare mutation. Following the first step of the Mayo analysis, we find that the claims are directed to a process, or method, and therefore fall into one of the broad statutory categories of patent-eligible subject matter under 35 U.S.C. § 101. In the next step of the Mayo analysis, we determine whether the claims at issue are directed to a nonstatutory, patent-ineligible concept, i.e., a law of nature, a phenomenon of nature, or an abstract idea. Mayo, 566 U.S. at 70-71. If the claims are so directed, we next consider the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. Id. at 78-79; see also Ariosa Diagnostics, Inc. v. Appeal 2021-002178 Application 15/287,121 11 Sequenom, Inc., 788 F.3d 1371, 1375 (Fed. Cir. 2015). Specifically, the Supreme Court considered this second step as determining whether the claims recite an element or combination of elements that is “sufficient to ensure that the patent in practice amounts to significantly more than a patent upon the [ineligible concept] itself.” Mayo, 566 U.S. at 72-73. More specifically, in this second step of the Mayo analysis, we look to whether the claim recites one of the judicially-created exceptions to Section 101, i.e., an abstract idea, a law of nature, or a natural phenomenon. See 2019 Guidance 54 (step 2A, prong 1). If we determine that the claim recites a judicial exception, we then determine whether the limitations of the claim reciting the judicial exception are integrated into a practical application. Id. (Step 2A, Prong 2). Finally, if we determine that the claim is directed to a judicially- created exception to Section 101 and is not integrated into a practical application, we evaluate the claim under the next step of the Mayo analysis, considering the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. Mayo, 566 U.S. at 78-79; 2019 Guidance at 56 (Step 2B). Claim 1 is directed to a “method for detecting a rare mutation” and recites the following steps: (1) preparing a sample comprising not more than 1,000 copies of template DNA; (2) amplifying the template DNA to prepare a library, and (3) analyzing a nucleotide sequence of that library using a next generation sequencer; (4) calculating a ratio of variants in a base at a predetermined position, from the analysis result; (5) comparing the calculated ratio of variants with a predetermined cut-off value; and (6) Appeal 2021-002178 Application 15/287,121 12 determining that the sample has a rare mutation in the base at the predetermined position when the calculated ratio of variants is not less than the predetermined cut-off value, Put more succinctly, the claims are directed to using a small number of template DNA samples and amplifying them to prepare and sequence a library using a next-generation sequencer. Base variation is then measured at a given locus to construct a ratio of variants, which is then compared to a pre-determined value to determine whether there is a rate mutation at that locus. See Spec. ¶ 7. We agree with the Examiner that the claims are directed to an abstract idea and, more specifically, to the mental step of comparing the ratio of the variants at a given locus on the DNA sequences in the library with a predetermined cut-off value to “determin[e] that the sample has a rare mutation in the base at the predetermined position.” This step is a process that is performed in the mind of the operator of the claimed method and consequently falls within the abstract idea category. See Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (holding that “analyzing information by steps people go through in their minds, or by mathematical algorithms, without more, as essentially mental processes within the abstract-idea category”). However, the predecessor to our reviewing court recognized that the presence of a mental step is not necessarily fatal to § 101 eligibility. See Application of Prater, 415 F.2d 1393, 1402 n.22 (C.C.P.A. 1969). We therefore move on to the next step of our analysis. Having determined that the claims recite a mental process, we next look to see whether the claims are integrated into a practical application. Appeal 2021-002178 Application 15/287,121 13 2019 Guidance 54 (step 2A, prong 2). The 2019 Guidance provides additional context for this analysis, stating that: “A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the judicial exception.” Id. at 53. In the claims on appeal, we are not persuaded that the recited abstract idea is integrated into a practical application. There are no limitations in the claims reciting what is done with the information that is derived from the mental step, e.g., a treatment or any other practical steps by which the information gained by the claimed method is somehow put to a practical use. The claim recites only a method of determining, by comparing a ratio to a predetermined cut-off value, whether a rare mutation exists in a biological sample. We can thus distinguish the claims on appeal from the claims in Vanda Pharms. Inc. v. West-Ward Pharms., 887 F.3d 1117 (2018). In Vanda, the patent-eligible claims recited a method of: (1) determining the patient’s CYP2D6 metabolizer genotype by (a) obtaining a biological sample and (b) performing a genotyping assay; and (2) administering specific dose ranges of iloperidone depending on the patient’s CYP2D6 genotype. 887 F.3d 1134. As our reviewing court stated: [T]he ’610 patent claims recite the steps of carrying out a dosage regimen based on the results of genetic testing. The claims require doctors to “internally administer[ ] iloperidone to the patient in an amount of 12 mg/day or less” if the patient has a CYP2D6 poor metabolizer genotype; and “internally administer[ ] iloperidone to the patient in an amount that is greater than 12 Appeal 2021-002178 Application 15/287,121 14 mg/day, up to 24 mg/day” if the patient does not have a CYP2D6 poor metabolizer genotype. These are treatment steps. Id. (internal citation omitted). The “treatment steps” in Vanda added a practical application to the mental process by which the genotyping assay was evaluated. No such practical application is recited in the claims presently before us. Rather, the claims on appeal pose a similar problem to eligibility as the claims at issue in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013). As the Supreme Court stated in Myriad: [T]his case does not involve patents on new applications of knowledge about the BRCA1 and BRCA2 genes. Judge Bryson aptly noted that, “[a]s the first party with knowledge of the [BRCA1 and BRCA2] sequences, Myriad was in an excellent position to claim applications of that knowledge. Many of its unchallenged claims are limited to such applications.” 569 U.S. 595 (quoting Association for Molecular Pathology v. U.S. Patent and Trademark Office, 689 F.3d 1303, 1349 (Fed. Cir. 2012)). We similarly find that the claims in the appeal presently before us do not recite a new application of the knowledge obtained from practicing the claimed method, and we therefore conclude that the claims are not integrated into a practical application. Under the final step of the Mayo analysis, we evaluate the claims considering the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. Mayo, 566 U.S. at 78-79; 2019 Guidance at 56 (Step 2B). In the claims at issue, the additional Appeal 2021-002178 Application 15/287,121 15 elements include preparing a sample comprising not more than 1,000 copies of template DNA, amplifying the template DNA to prepare a library, and analyzing a nucleotide sequence of the library using a next generation sequencer. We find that none of these steps, all of which were well known in the art, are sufficient to transform the nature of the claim into a patentable invention. Appellant’s Specification acknowledges that the basic steps of sampling, amplifying, and sequencing using a next-generation sequencer were all well known in the art. The Specification discloses: While it has been considered that the genome sequence of an individual is single, it has been revealed that there exists much genomic DNA having slightly different nucleotide sequences in an individual, based on the research using a next-generation sequencer. …. It is known that an individual cancer cell does not have a single genome sequence, but has various variations, by analyzing genomic DNA obtained from a tumor tissue by a next-generation sequencer. Shimizu T. et al., Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection, Gastroenterology, 2014, vol. 147, No. 2, p. 407- 417 discloses that whole exome sequencing and deep sequencing are performed for genomic DNA in a tumor tissue of stomach and a non-tumor tissue of stomach, and a somatic mutation is accumulated in various genes of gastric cancer tissue in which inflammation is caused. Spec. ¶¶ 2-3. With respect to the sampling step, the Specification discloses: The DNA extraction method is not particularly limited. When genomic DNA is extracted from a biological sample, it can be extracted by a known method in the art such as phenol/chloroform method. A commercially available DNA extraction kit and the like may be used. The fragmentation, size Appeal 2021-002178 Application 15/287,121 16 selection, terminal smoothing and the like of the extracted template DNA may be performed, as necessary. …. The means of adjusting the copy number of the template DNA in the sample to 1,000 copies or less is not particularly limited. It is known in the art that 1 ng of genomic DNA corresponds to 300 copies. Accordingly, the concentration of the genomic DNA extracted from the biological sample is measured by a spectrophotometer, and a sample containing not more than 1,000 copies, i.e., not more than 3.33 ng of the genomic DNA may be prepared by dilution based on the concentration. Spec. ¶¶ 27, 29. With regard to the amplification step, the Specification discloses: The amplification of the template DNA is preferably performed by PCR-based method. A primer pair capable of amplifying a region to be analyzed in the template DNA is designed, and the template DNA is amplified by PCR method using this primer pair, whereby an amplicon can be obtained. The region to be analyzed is concentrated from the fragmented genomic DNA by sequence capture method, and an amplicon may be obtained using this region as template DNA. Spec. ¶ 31. With regard to the sequencing step, Appellant’s Specification discloses: In this embodiment, the nucleotide sequence should be analyzed by a sequencing method known in the art for the library as described above. The sequencing method is not particularly limited, but the analysis by a next-generation sequencer is preferred. The “next-generation sequencer” is a term used as compared to a “first-generation sequencer” that is a sequencer by capillary electrophoresis using Sanger’s method, and means a device that determines nucleotide sequences by treating several tens of millions to several hundred millions of DNA fragments simultaneously in parallel. In this embodiment, the next- Appeal 2021-002178 Application 15/287,121 17 generation sequencer is not particularly limited, but examples thereof include HiSeq 2500 (Illumina, Inc.), MiSeq (Illumina, Inc.), Ion Proton (Thermo Fisher Scientific Inc.), Ion PGM (Thermo Fisher Scientific Inc.), and the like. Spec. ¶ 40. All of these disclosures demonstrate that these sampling, amplifying, and sequencing steps are applications of devices and techniques that are well understood, routine, and conventional in the art. See Berkheimer v. HP Inc., 881 F.3d 1360, 1368 (2018). The Examiner has also provided a substantial list of references to demonstrate that these techniques are well known in the art. See Final Act. 6-7. Our reviewing court’s analysis in Cleveland Clinic Foundation v. True Health Diagnostics LLC, 859 F.3d 1352 (2017) is instructive here. In its “additional elements” analysis, the court found that: Indeed, Cleveland Clinic has not created a new laboratory technique; rather, it uses well-known techniques to execute the claimed method. The specifications of the testing patents confirm that known testing methods could be used to detect MPO, and that there were commercially available testing kits for MPO detection. …. The ’552 patent and ’581 patent contain a “determining” step that requires analyzing MPO levels. Cleveland Clinic does not purport to have invented colorimetric-based assay, flow cytometry, or ELISA. …. The claims of the testing patents also contain a “comparing” step where MPO levels are compared to statistically derived control or predetermined values. Here too, Cleveland Clinic does not purport to derive new statistical methods to arrive at the predetermined or control levels of MPO that would indicate a Appeal 2021-002178 Application 15/287,121 18 patient’s risk of cardiovascular disease. Known statistical models can be employed, as described. …. The claims, whether considered limitation-by-limitation or as a whole, do not sufficiently transform the natural existence of MPO in a bodily sample and its correlation to cardiovascular risk into a patentable invention. The process steps here merely tell those “interested in the subject about the correlations that the researchers discovered.” Mayo, 566 U.S. at 78, 132 S.Ct. 1289. 859 F.3d 1361-62. We quote these passages at length because we find that the same reasoning applies to our step 2B analysis of the claims presently before us. As in Cleveland Clinic, the additional elements recited in the present claims, i.e., the sampling, amplifying, and sequencing using a next-generation sequencer, are all routine, conventional, and well-understood in the art and are insufficient to transform the abstract idea of measuring the derived ratios of single base variances against a predetermined cut-off value into a patent- eligible invention. We consequently affirm the Examiner’s rejection upon this ground. B. Lack of Written Descriptive Support The Examiner’s Findings and Conclusions The Examiner finds that the claims are not limited to any specific diagnostic markers or diseases (i.e. the generic recitation of “rare mutation” does not impose sufficient bounds on disease) for performing the claimed functions. Final Act. 11. The Examiner finds that a review of Appellant’s Specification does not provide sufficient evidence or examples sufficient to teach a person skilled in the art what specific diagnostic markers, Appeal 2021-002178 Application 15/287,121 19 predetermined positions, ratios of variants, and cut-off values are used to accomplish the claimed functions and achieve the invented result. Id. at 11- 12. The Examiner similarly finds that a review of the Specification does not provide sufficient evidence that applicant has actually disclosed the requisite “predetermined positions,” “ratios of variants,” or “cut-off values” for the broad scope of genes and conditions associated with “rare mutations” embraced by the claims. Final Act. 12. The Examiner notes that the Specification does provide a limited disclose of conditions such as cancer. Id. (citing Spec. ¶ 16, Fig. 3). The Examiner finds, however, this is narrower in scope than what is being claimed, and notes that narrowing limitations found in the Specification cannot be read into the claims. Id. (citing In re Philips Inds. v. State Stove & Mfg. Co, Inc., 186 USPQ 458 (CA6 1975); MPEP § 2111.01). With respect to the analyzing step (in which the nucleotide sequence of the library is determined by the next generation sequencer), the Examiner finds that this step is not limited to any particular algorithms, equations, or techniques for performing the claimed function, i.e., it generically reads on “doing math” to achieve the intended result. Final Act. 12. The Examiner finds that the Specification discloses “analyzing genomic DNA obtained from a tumor tissue by a next-generation sequencer,” as taught by Shimizu. Id. (citing Spec. ¶ 3). However, the Examiner finds that this is not commensurate in scope with what is being claimed; the claim does not require performing analysis using a next generation sequencer but suggests that sequencing was performed at some previous time period using a next generation sequencer. Id. Appeal 2021-002178 Application 15/287,121 20 The Examiner notes that the Specification is also silent as to how the inventor intends this analysis step to be performed. Final Act. 12. The Examiner reasons that it is not enough that one skilled in the art could write a program to achieve the claimed analysis functions. Id. Furthermore, the Examiner finds, it would be readily apparent to one of ordinary skill in the art that different mutations require analysis of different predetermined positions, and that determining different mutations requires knowledge of different ratios and cut-off values. Id. The Examiner finds that this position is supported by Shimizu, which teaches mutational analysis for specific genes and mutations associated with specific disease. Id. (citing Shimizu, 7- 9). The Examiner therefore finds that Appellant’s Specification fails to support a “broad genus claim that covers all ways of performing the claimed functions when the specification provides only one method and there is no evidence that a more generic way is contemplated” and also fails to support a “claim that defines the invention in functional language specifying a desired result when the specification does not sufficiently identify how the invention achieves the claimed function.” Final Act. 12-13. As such, the Examiner concludes, Appellant’s Specification fails to disclose the requisite information that must be practiced in order to realize the subsequently recited functionality. Id. at 13. Analysis Appellant argues that the Examiner has not adequately explained why the Specification requires additional disclosure in order for a person of skill in the art to recognize possession of the claimed generic invention. App. Br. Appeal 2021-002178 Application 15/287,121 21 21 (citing Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc)). Appellant contends that the state of the art already recognized a vast number of nucleotide sequences (of known function and significance) that could be used in the claimed invention, and that a skilled artisan would have understood, without a needless re-description in the Specification, that the presently claimed invention could be used with any of these known sequences. App. Br. 22. Appellant also argues that the Examiner’s position in this regard is in conflict with Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). App. Br. 22. According to Appellant, the claims at issue in Capon were directed to a genus of chimeric genes, comprising a first segment encoding a variable region of an antibody capable of binding an antigen, and a second segment encoding a protein expressed on cells of the immune system. Id. (see Capon, 418 F.3d at 1352-53). Appellant argues that, despite the claims being generic to the variable region, the Federal Circuit nevertheless noted that the structures of exemplary genetic sequences that could function as the first and second segments were known in the art as of the filing date of the application, as were techniques for linking the two segments, and that such description in the prior art was sufficient to meet the written description requirement. Id. Appellant notes that the Federal Circuit stated that “[t]he chimeric genes here at issue are prepared from known DNA sequences of known function. The Board’s requirement that these sequences must be analyzed and reported in the specification does not add descriptive substance.” Id. (quoting Capon, 418 F.3d at 1358). Appeal 2021-002178 Application 15/287,121 22 Appellant argues that, in the present appeal, simply reciting large lists of different known sequences of known function, in which a rare mutation could be detected, does not add any “descriptive substance” to the disclosure, and is therefore unnecessary for an adequate written description. App. Br. 23. The Examiner responds that the Capon claims were directed to a chimeric DNA encoding a membrane bound protein and a chimeric protein, which are categorically different from Appellant’s claimed method. Ans. 9. The Examiner finds that Capon is therefore not informative with respect to the Appellant’s claims beyond the general discussion of the written description requirement, and that the descriptive disclosures required to meet this requirement necessarily varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence. Id. (see Capon, 418 F.3d at 1360) (holding that, in a written description analysis “the facts of the specific case must be evaluated”). The Examiner notes that the written description requirement requires the inventor to describe the claimed invention in sufficient detail so that one of ordinary skill in the art can reasonably conclude that the inventor had possession of the claimed invention. Ans. 9 (see Ariad Pharms., Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1351 (Fed. Cir. March 2010)). The Examiner finds that, in the claims presently on appeal, the claims are directed to a method for detecting “rare mutations” (which generically encompasses all known genetic mutations and/or diseases). Id. The Examiner finds, however, that Appellant’s Specification discloses, at most, a limited example of mutations including cancer. Id. (citing §pec. ¶¶ 16, 88). The Examiner similarly finds that the Specification does not disclose evidence that Appeal 2021-002178 Application 15/287,121 23 Appellant has actually disclosed specific diagnostic markers, predetermined positions, ratios of variants, or cut-off values that are used to accomplish the full scope of the “rare mutations” encompassed by the claims and necessary for performing the claimed functions. Id. at 9-10. The Examiner also points to Shimizu as teaching that mutational analysis requires knowledge of specific genes and mutations associated with a specific disease or condition. Ans. 10 (citing Shimizu, 7-9). The Examiner finds that it would therefore have been readily apparent to one of ordinary skill in the art that the full scope of “rare mutations” being claimed in combination with the functional limitations being claimed would require knowledge of different predetermined positions, ratios, and cut-off values, depending upon the specific type of mutation being investigated. Id. The Examiner therefore concludes that Appellant’s Specification fails to support a “broad genus claim that covers all ways of performing the claimed functions when the specification provides only one method and there is no evidence that a more generic way is contemplated.” Ans. 10. The Examiner further concludes that the Specification also fails to support a “claim that defines the invention in functional language specifying a desired result when the specification does not sufficiently identify how the invention achieves the claimed function.” Id. We agree with Appellant that the Specification provides sufficient written support for the claims. The claims are directed to a “method for detecting a rare mutation,” comprising, inter alia, “calculating a ratio of variants in a base at a predetermined position.” The scope of the latter limitation encompasses virtually any base, in any location, on any DNA sample: a truly vast genus. Despite the size of the genus, however, and the Appeal 2021-002178 Application 15/287,121 24 generality of the method recited in the claims, we conclude that Appellant’s Specification discloses sufficient written descriptive support. The Examiner finds that the Specification fails to disclose sufficient examples or explanation with respect to specific genes or disease or condition markers. We do not find that the requirement imposed by the Examiner is a necessary one to meet the written description requirement. On the contrary, the claimed method is a general one that can be used to differentiate genetic mutations at a given locus in a given sample from potential transcription errors occurring during the amplification step: When variation recognized at very low frequency in genomic DNA is detected by analysis of nucleotide sequence (hereinafter, also referred to as “sequencing”), a sufficient amount of genomic DNA is usually used as a template such that a genomic DNA molecule having the variation is surely contained in a sample.… However, in the present technology, an error occurs at a predetermined frequency during nucleic acid amplification of a template DNA and during sequencing, thus variation derived from the error may be contained in the analyzed nucleotide sequence of the genomic DNA. Therefore, it is difficult to distinguish whether the variation of genomic ON A detected by sequencing is mutation or variation due to an error. The present inventors have surprisingly found that it is possible to distinguish whether variation detected in a template DNA is mutation or variation due to an error, by sequencing using DNA in an amount much less than usual as a template. This finding has led to the completion of the present invention. Spec. ¶¶ 5-6. In other words, the claimed method is not meant to act as a means of characterizing a specific mutation correlating to a disease or condition, but rather as a general mechanism for distinguishing between Appeal 2021-002178 Application 15/287,121 25 mutations occurring at a given locus and transcriptional errors introduced in the amplification step. The Examiner also argues that the Specification fails to disclose necessary knowledge of, e.g., cut-off values. We disagree. Appellant’s Specification discloses: [T]he predetermined cut-off value may be the ratio of variants derived from an error. The distribution of an error due to nucleic acid amplification and sequencing is considered to follow the Poisson distribution that is a distribution of random events at a low frequency. Therefore, the predetermined cut-off value can be determined from the Poisson probability obtained from the Poisson distribution based on the Phred scores of the analyzed nucleotide sequence and the number of reads. The predetermined cut-off value may be set for each one base in the region to be analyzed, but it is preferred to set a single cut-off value based on the average value of the Phred scores of the analyzed nucleotide sequence and the average number of reads because of convenience. The “Phred” refers to a base calling program used in a DNA sequencer, and is known in the art. Phred enables to execute base calling (determination of base) from the trace data (graph image such as waveform data of signals obtained from sequencing reaction) acquired by a DNA sequencer. At this time, a Phred score (also called as “Phred quality score”) is calculated for each designated base. The Phred score is an index representing accuracy of the nucleotide sequence analyzed by a sequencer, and widely spread in the art. The relationship between the Phred score (or the average value thereof) and the frequency of errors in the analyzed nucleotide sequence is represented by the following expression. (Frequency of errors) = 10-a/10(/base) wherein a is a Phred score or an average value thereof. Appeal 2021-002178 Application 15/287,121 26 Spec. ¶¶ 48-50. Appellant’s Specification discloses similar methods for determining variance ratios. See Spec. ¶¶ 42-46. Furthermore, a predetermined position can be any position that is of interest to an investigator intending to apply this general technique. See, e.g., Spec. ¶ 29. Again, we emphasize that the claimed method is not to detect mutations at a given gene location connected with a specific disease, but rather a general method to differentiate variants at a given locus in a DNA sample from errors that are introduced by the process of amplification. We conclude that the disclosures of Appellant’s Specification “reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” Ariad, 598 F.3d at 1351. We consequently reverse the Examiner’s rejection of claims 1-18 and 20 upon this ground. CONCLUSION The rejection of claims 1-18 and 20 as unpatentable under 35 U.S.C. § 101 is affirmed. The rejection of claims 1-18 and 20 as unpatentable under 35 U.S.C. § 112(a) is reversed. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Claim(s) Rejected 35 U.S.C. § Reference(s)/ Basis Affirmed Reversed 1-18, 20 101 Eligibility 1-18, 20 Appeal 2021-002178 Application 15/287,121 27 Claim(s) Rejected 35 U.S.C. § Reference(s)/ Basis Affirmed Reversed 1-18, 20 112(a) Written Description 1-18, 20 Overall Outcome 1-18, 20