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, 5, 6, 9, 10, and 12 are pending in the instant application. All the 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 claims filed 7/21/2025 designate the claim status for claims 1 and 12 as “currently amended”. Additionally, the response states at page 6 “As indicated above, the amended claim 1 recites…”. The claims filed 7/21/2025 have been thoroughly reviewed, however no amendments to the claims could be found. As such, the claims from 7/21/2025 and claims dated 9/30/2024 appear identical. In any future response, applicant is required to correctly designate the status of claims. Any subsequent submission that does not comply with the requirements set forth in 37 CFR 1.121 or 1.4 will be held non-compliant.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 101
Claims 1, 5, 6, 9, 10, and 12 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 recites a method of determining the need for treatment in a subject by mRNA sequencing the HPV E2, E6, and/or E7 genes to detect a splice variant, mutation, or aberrant level of transcript. This recitation is a natural correlation between the presence of a splice variant, mutation, or aberrant level of transcript of HPV E2, E6, or E7, and the need to treat a subject. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed recitation of “determination”, “determining the need for treatment”, etc are directed to abstract ideas because it encompasses conclusions and determinations which can occur entirely within the mind. 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 mRNA sequencing with molecular inversion probes. However, this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method. Although claim 10 recites “treating the disease or condition”, this step is conditional depending on the results of detecting the presence or absence of an HPV E2, E6, or E7 variant, mutation, or aberrant level. Additionally, the limitation of “treating” only sets forth generally recited elements which are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step. As such, the “treating” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
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 providing a sample from a subject is considered insignificant post solution activity. The steps of performing multiplex mRNA sequencing are generally recited. Although the claim recites the use of molecular inversion probes, these are also generally recited and do not set forth any particular reagents (eg probe SEQ ID NOS) that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). It should also be noted that the technology for molecular inversion probes is well understood, routine, and conventional. For example, the review by Wang (Wang et al; Cancer Genetics, vol 205, pages 341-355, 2012) teaches that it is used for identifying different types of genetic variations. Wang teaches that central to the technology is the use of padlock probes, which were first described in 1994. 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 claimed method recites specific technical implications of molecular inversion probe sequencing that go beyond conventional application and cites the specification at page 51, lines 36-40. This argument has been thoroughly reviewed but was not found persuasive because the structural requirements set forth in the specification are not recited in the claims.
The response quotes the specification at page 53, lines 25-29 as indicating that the claimed MIP-based technique represents an advancement in the field. This argument has been thoroughly reviewed but was not found persuasive because it appears the quote is asserting that the technology has been recently introduced to detect tumor associated mutations in DNA, not that the technology of MIPs is new or recent. It is also noted that this quote appears to show that the technique is being used to gather data by which to detect the natural correlation set forth in the claims.
The response further asserts that the claims recite a specialized gap filling step where MIP’s leave a gap that must be filled by a polymerase, as well as specific technical elements, including unique molecular identifiers, and cites to Hiatt. This argument has been thoroughly reviewed but was not found persuasive because the reference citations illustrate the fact that this technology was already known in the prior art. Furthermore, the Hiatt reference is used in the prior art rejections in this office action. The response’s arguments and the claims do not appear to be directed to an unconventional improvement in MIP technology, but rather to the use of a conventional technology to gather data. While the biomarker it is being used to detect may not have been targeted in this specific way, the use of routine and conventional technology to detect known biomarkers does not add significantly more to the judicial exceptions set forth in the claims. In the instant situation, probes used in the methods are recited in a generic way and the claimed method is recited at a high level of generality.
MPEP 2106.05(d)(II) 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.
The rejection is maintained.
Claim Rejections - 35 USC § 103
Claims 1, 5, 6, 9, 10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Sorbye (Sorbye et al; PLOS One, 2011, 6(10): e26022; pages 1-8) in view of Hiatt (Hiatt et al; Genome Research, vol 23, pages 843-854, 2013), Lin (Lin et al; BMC Genomics, 2010, vol 11, pages 1-14) and Boyle (Boyle et al; Bioinformatics, vol 30, pages 2670-2672; 2014) as evidenced by Varnai (Varnai et al; Oncology Reports, vol 19, pages 457-465, 2008).
With regard to claims 1 and 10, Sorbye teaches methods of detecting HPV E6 and E7 mRNA for detection of cervical intraepithelial neoplasia (CIN; claim 5, 12). Sorbye teaches that routine cervical cancer cytological screening is to identify and treat high grade CIN lesions before they progress to invasive cancer. Sorbye teaches that colposcopy does not have optimal sensitivity for CIN2+ (page 1). With regard to the claims, Sorbye teaches providing a sample from a patient (pap smear, colposcopy; claim 6), and performing analysis for E6 and E7 mRNA (page 2, col 2) using PreTect HPV Proofer (page 5, col 2). Although Sorbye does not explicitly state that the mRNA is converted to cDNA, as evidenced by the teachings of Varnai, the PreTect HPV Proofer test used by Sorbye involves the reverse transcription of mRNA into cDNA prior to nucleic acid testing (see page 458, col 2). Sorbye teaches that E6 and E7 mRNA was analyzed because the main cause of invasive cervical cancer is the deregulated and persistent production of E6 and E7 oncoproteins. Sorbye teaches comparing histological analysis vs mRNA testing where HPV mRNA testing showed a specificity of 92.5% (page 6, col 2). Sorbye teaches that when the HPV result is positive, the data suggest direct treatment for women above 40 years of age or for women with a concurrent cytological HSIL diagnosis, contributing to better clinical safety for these patients (claims 1, 9, 10).
Sorbye does not teach the use of molecular inversion probes for HPV mRNA analysis, however Hiatt teaches that molecular inversion probes, which hybridize to nucleic acid target of interest via an extension probe and a ligation probe, connected by a backbone leaving a 112 nt gap on the target sequence (figure 1), allows for ultrasensitive detection and precise quantitation of nucleic acid targets (page 849, col 1). Furthermore, Lin teaches the use of MIPs to detect cDNA (transcribed from mRNA) of interest is sensitive and accurate. Additionally, Boyle teaches a user friendly package, MIPgen, that simplifies the process of designing molecular inversion probes to targets. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date, to use the molecular inversion probes for mRNA analysis in the method of Sorbye in view of the teachings of Hiatt, Lin, and Boyle, for the detection of HPV E6 and E7 mRNA as taught by Sorbye with a reasonable expectation of success. The ordinary artisan would have been motivated to use the MIPs taught by Hiatt and Lin because Hiatt teaches that it allows for ultrasensitive detection and precise quantitation while Lin teaches that MIP assays targeted to cDNA are sensitive and accurate.
Response to Arguments
The response traverses the rejection. The response asserts Hiatt does not disclose or suggest that the sample RNA is converted to cDNA or that MIPs hybridize to the cDNA of interest via an extension probe and a ligation probe that are connected by a backbone sequence because Hiatt used genomic DNA. The response asserts that Lin does not remedy the deficiencies because it is focused on the detection of splice variants where both hybridization arms anneal to cDNA without a gap. This argument has been thoroughly reviewed but was not found persuasive. The generally recited structural requirements of the probe: an extension probe and a ligation robe that are connected by a backbone sequence, leaving a gap on the target upon hybridization is taught by Hiatt. Lin was cited for the teaching that probes can be used on a cDNA target as well. The fact that the target is cDNA vs genomic DNA does not alter the design of the probes. The use of the probes for detecting splice variants is a particular application taught by Lin, however it does not take away from the fact that the reference illustrates that the probes function through hybridization with a target, as also taught by Hiatt. Therefore, one of ordinary skill in the art prior to the effective filing date, would have realized that the probes taught by Hiatt could also be used on a cDNA target, transcribed from mRNA as taught by Sorbye, with a reasonable expectation of success. This is also evidenced by the recitation in the response which states “Because annotation takes place based on the nucleotide sequence of interest, there is no risk of false positives”. In this situation, the sequence of interest, HPV E6/E7 nucleic acid target, is taught by Sorbye. The HPV PreTect assay taught by Sorbye detects and genotypes (detects particular alleles) HPV target nucleic acids. It would have been obvious to use the probes taught by Hiatt to detect the target taught by Sorbye because Hiatt teaches that molecular inversion probes, which hybridize to nucleic acid target of interest via an extension probe and a ligation probe, connected by a backbone leaving a 112 nt gap on the target sequence (figure 1), allows for ultrasensitive detection and precise quantitation of nucleic acid targets (page 849, col 1), including targets that possess mutations (detects particular alleles). For these reasons and the reasons made of record above and in the previous office action, the rejection is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682