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 .
Status of Claims
Currently, claims 1-20 are pending in the instant application. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are reiterated. They constitute the complete set being presently applied to the instant Application. Response to Applicant's arguments follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 101
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention is directed to methods of preparing amplified DNA for identifying neoplasms in pregnant women by amplifying cell free DNA of at least 100, 1000, 10,000, or 20,000 polymorphic loci and analyzing the sequenced DNA to identify copy number variations indicative of neoplasm. This recitation is a natural correlation between the polymorphic loci and CNVs as well as the correlation between the CNVs and maternal neoplasms. With regard to the natural correlations, as in Mayo, the relationships are natural processes that exist apart from any human action. The claimed invention also recites using the sequencing reads to identify copy number variants in fetal and maternal chromosomes, determining whether there are CNVs in the maternal or fetal chromosome or chromosome segments, and identifying aneuploidy in the fetus which are directed to abstract ideas because these steps encompasses making observations (reading a report) or analyzing data which can occur entirely within the mind or with pencil and paper. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of isolating cell free DNA from a biological sample of a pregnant woman, preparing amplified DNA via targeted multiplex amplification to amplify SNP loci, and analyzing the amplified DNA by sequencing to obtain sequence reads of the SNP loci and using the sequencing reads to identify copy number variants in fetal and maternal chromosomes. However this does not integrate the JE into a practical application because the steps are mere data gathering to use the correlation and does not add a meaningful limitation to the method.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the step of isolating cell free DNA from a biological sample of a pregnant woman is considered insignificant post solution activity. The amplification and analysis steps are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. These steps are not only mere data gathering, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that the claims are directed to a method of preparation, not a judicial exception because the steps involve physical manipulation of biological materials in a laboratory and cites Illumina, Inc. v. Ariosa Diagnostics, Inc., 967 F.3d 1319, 1329 (Fed. Cir. 2020). The response asserts that the Federal Circuit reversed the district court's finding of ineligibility and held that claims reciting methods of preparing DNA fractions were patent-eligible. This argument has been thoroughly reviewed but was not found persuasive because the instant claims, unlike the claims in Illumina, Inc. v Ariosa Diagnostics, Inc, expressly recite “identifying neoplasm in the pregnant woman by the presence of two or more of CNV’s in the maternal chromosomes or chromosomal segments of interest”. which is a recitation of a natural correlation as well as an abstract mental step of “identifying” (identifying encompasses drawing a conclusion which occurs within the mind). The response asserts that under step 2B the steps in the claims constitute core physical transformations that produce a non-naturally occurring composition of amplified DNA which is a tangible product that does not exist in nature and is created through specific laboratory manipulation. This argument has been thoroughly reviewed but was not found persuasive because the steps are recited at a high level of generality, with no specific reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. The claims recite a general step of isolating cell free DNA which is insignificant post solution activity, followed by a general step of “preparing non-naturally occurring composition of amplified DNA by performing targeted multiplex amplification”. Again, no specific elements or reagents are recited. The final step, c, recites an analysis of the amplified DNA by sequencing, which is again a broad, general step. The steps of identifying CNVs and neoplasm are abstract steps which are themselves JE’s. Recitations of judicial exceptions cannot add significantly more because they are themselves, JE’s. Accordingly, even when considered as a whole, the additional steps are broadly and generally directed to isolating cell free DNA, performing multiplex amplification on the isolated DNA, and sequencing the DNA. This is well understood, routine and conventional in the field of life science arts. The data or information that these steps produce are then used to identify CNVs and neoplasm in pregnant women. The MPEP 2106.05(d)(II), which was cited in the office action, specifically states:
The courts have recognized the following laboratory techniques as well-understood, routine, 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:
i. 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);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. Ltd. 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);
iii. 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);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. 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); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Therefore, even when considering the steps in addition to the recited JE’s either alone, or in an ordered combination, the steps recited do not amount to significantly more than the JE’s recited, as evaluated with the specific guidance from the MPEP. The arguments with regard to Ex Parte Desjardins are therefore not persuasive because the office action provided an explanation as to the high level of generality and provided further guidance and citations from the MPEP. Accordingly, the rejection is maintained.
Claim Rejections - 35 USC § 103
Claims 1-6, 9-17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Bianchi (Bianchi et al; JAMA, 2015; vol 314; pages 162-169) in view of Nicolaides (Nicolaides et al; Prenatal Diagnosis, 2013; vol 33, pages 575-579).
With regard to claims 1 and 12, Bianchi teaches a method of detecting incidental maternal cancer during noninvasive prenatal testing (see whole document). Bianchi teaches obtaining plasma samples (claims 2, 3, 13, 14) from pregnant woman (page 163-164) and performing massively parallel sequencing of cell free DNA using Prenatal Test from Illumina, which necessarily requires DNA amplification prior to sequencing. Bianchi teaches that maternal plasma contains a mixture of placental DNA as a proxy for the fetus and maternal DNA. With regard to claims 10 and 11, Bianchi teaches detecting fetal aneuploidies (see whole document, discussion). Bianchi teaches that discordance between karyotypes were detected. With regard to claims 9 and 20, Bianchi teaches that genome wide bioinformatics analysis of 8 reported maternal cancers in the patient population showed extensive CNVs involving several chromosomes (see abstract, results, discussion). With regard to claims 1, 4-6, 12, and 15-17, Bianchi does not teach amplifying at least 100; 1,000; 5,000; 10,000; or 20,000 polymorphic loci, however Nicolaides teaches validation of targeted sequencing of about 20,000 SNPs (see page 576) using cf DNA from maternal plasma samples to detect CNVs and diagnose aneuploidy of chromosomes 13, 18, 21, X, and Y (see whole document). Nicolaides teaches obtaining maternal blood, targeted multiplex PCR amplification of about 20,000 SNPs, and sequencing of amplified DNA to detect CNVs (see whole document). Nicolaides teaches this method accurately detected aneuploidy in fetal DNA. Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to have used the targeted SNP sequencing method for detecting CNVs taught by Nicolaides in the method of Bianchi, including for detection of maternal cancer, for the purpose of accurately detecting CNVs as taught by Nicolaides, with a reasonable expectation of success. Additionally, the substitution of the targeted SNP sequence method to detect CNVs taught by Nicolaides for the massively parallel sequence method taught by Bianchi is considered the substitution of known method steps to achieve predictable results.
Claims 7, 8, 18, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Bianchi in view of Nicolaides as applied to claims 1-6, 9-17, and 20 above, and further in view of Kirkizler (US 2018/0148777).
The teachings of Bianchi in view of Nicolaides is set forth above. Bianchi and Nicolaides do not teach 50%, 60%, or 70% of the SNP loci are within haploblocks on the chromosome or chromosomal segments, however Kirkizler teaches methods for detecting CNVs using targeted SNP multiplex PCR amplification and sequencing in methods of detecting fetal aneuploidy or for detecting cancer (see abstract, whole document). Kirkizler teaches optimizing analysis with SNPs in haploblocks (whole document, para 0051, 0100). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to have improved upon the method of Bianchi in view of Nicolaides, to include analysis of SNPs in haploblocks as taught by Kirkizler with a reasonable expectation of success because Kirkizler teaches that doing so increases accuracy of testing.
Response to Arguments
The response traverses the rejections. The response asserts that the Bianchi is directed to NIPT using massively parallel whole genome sequencing, not targeted SNP based multiplex amplification. The response asserts that Bianchi does not teach a method for prospectively identifying neoplasm by detecting two more CNVs. This argument has been thoroughly reviewed because Bianchi specifically teaches “All 8 cases that underwent further bioinformatics analysis showed unique patterns of non-specific copy number gains and losses across multiple chromosomes.” (see abstract, results). Accordingly, the teaching that all the cases showed CNV gains and losses across “multiple chromosomes” is necessarily a teaching of “two or more CNV’s”. Arguments that Bianchi teaches whole genome counting approaches rather than targeted SNP-based multiplex amplification of at least 100 polymorphic loci and that Nicolaides is directed to detecting fetal aneuploidy and does not teach detecting maternal neoplasm is not found persuasive because one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The response also asserts that the rejection assumes that “Bianchi teaches a method of detecting maternal cancer, which it does not.”. This is not found persuasive because Bianchi teaches that discordant NIPT results were the result of maternal cancers. Bianchi literally states “When there is discordance between the fetal karyotype and NIPT result, occult maternal malignancy… may be an explanation for the findings.”. Therefore, it is immediately obvious that maternal malignancy can be detected by the method of Bianchi. The response then asserts that the rejection fails to articulate a proper motivation or reason why a person having ordinary skill in the art would have combined Bianchi and Nicolaides. This argument has been thoroughly reviewed but was not found persuasive because the rejection states: “Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to have used the targeted SNP sequencing method for detecting CNVs taught by Nicolaides in the method of Bianchi, including for detection of maternal cancer, for the purpose of accurately detecting CNVs as taught by Nicolaides, with a reasonable expectation of success. Additionally, the substitution of the targeted SNP sequence method to detect CNVs taught by Nicolaides for the massively parallel sequence method taught by Bianchi is considered the substitution of known method steps to achieve predictable results.”. Both Nicolaides and Bianchi teach methods of detecting CNV’s (aneuploidies) in maternal samples using nucleic acid analysis. Bianchi teaches that CNV’s concordant with karyotype indicated fetal aneuploidies, while discordant results showed that the CNVs (aneuploidies) can be the result of maternal neoplasm. Since both Bianchi and Nicolaides teach accurate methods of detecting aneuploidies in maternal samples using nucleic acid analysis methods, and are analogous art, the use of Nicolaides targeted SNP based multiplex amplification method for detecting aneuploidies instead of Bianchi’s massively parallel method of detecting aneuploidies is the substitution of one known method, for another which yield predictable results (see MPEP 2143I: Examples of Rationales: Examples of rationales that may support a conclusion of obviousness include …(B) Simple substitution of one known element for another to obtain predictable results…”).
The arguments that Bianchi teaches away from the method are not found persuasive. As stated in the MPEP 2145(X)(D)(1): “Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.")”. In the instant situation, Bianchi teaches that CNVs attributed to maternal neoplasms can be detected in maternal samples, even though the method sought to detect fetal aneuploidies. The claims simply require detecting two more CNVs in the maternal chromosomes, they do not require assaying for all CNV’s. Bianchi teaches that two more more CNVs can be detected in maternal samples and that these can be the result of maternal neoplasm. The targeted sequencing method of Nicolaides is another nucleic acid based method of detecting CNVs in samples. Although the references exemplifies using it for fetal aneuploidy, there is nothing in the reference to suggest that targeted sequencing of SNPs can ONLY be used for detecting fetal CNVs.
The response also asserts that the claimed methods achieved unexpected results with positive predictive value for maternal neoplasm ranging from 39% to 59% when multiple CNVs are detected. This argument has been thoroughly reviewed but was not found persuasive. At para 0039, the specification states “When maternal CNVs are identified on SNP-based NIPT, the data suggests an increased risk of maternal neoplasm ranging from 39-59%”. However, it appears that these numbers are attributed to the ability to detect multiple maternal CNVs in maternal samples. However, the prior art already teaches that multiple maternal CNVs can be detected in maternal samples and that they can be due to maternal neoplasm (see Bianchi).
The response also argues that for claims 7, 8, 18, and 19, the teachings of Kirkizler do not cure the deficiencies of Bianchi and Nicolaides. This is not found persuasive for the reasons already made of record. The arguments that Kirkizler teaches detecting chromosomal ploidy in the context of cancer and not to incidental detection of maternal neoplasm during incidental NIPT testing is not found persuasive because the rejection is based on the combination of Bianchi, Nicolaides, and Kirkizler.
For these reasons and the reasons already made of record, the rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
