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, 3, 4, 6-11, 13-18, 21, 26, 28, and 40-42 are pending in the instant application. Claim 28 is withdrawn from consideration as being drawn to a non-elected invention and claims 40-42 are newly added. Claims 1, 3, 4, 6-11, 13-18, 21, 26, and 40-42 are currently under examination. 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 either newly applied, as necessitated by amendment, or 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 Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.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, 3, 4, 6-11, 13-18, 21, 26, and 40-42 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 informing urgent care decisions for a subject, as well as classifying a subject (newly added claim 40-42) by determining a risk score based on the expression levels of TGFB1, DEFA4, LY86, BATF, and HK3. This recitation is a natural correlation between expression levels of genes and a risk score as well as urgent care decisions. 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 invention also recites “informing urgent care decisions” as well as “classifying a subject” which encompasses mental activity as it reads on making decisions while the recitation of determining a risk score is directed to a mathematical formula and calculation. Although the claims have been amended to recite the use of a generic machine learning model using generic processors, merely performing mathematical calculations that could be performed by a human, using a generic computer model and processors, is directed to an abstract idea (see MPEP 2106.04(a)(2). As such, these are considered recitations of abstract ideas. The same analysis holds for steps such as “comparing the score” and “classifying the subject”. 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 detecting gene expression of a combination of specific genes of TGFB1, DEFA4, LY86, BATF, and HK3, 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 the claims have been amended to recite “outputting the given risk category” to a display, merely presenting the results of a process otherwise unpatentable under section 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., (Fed. Cir. Oct. 11, 2016) (claim unpatentable despite recitation of the step: "providing notification if [an] event has occurred").
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 receiving a sample is considered insignificant post solution activity. The steps of detecting expression levels 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. This includes the general recitation of qRT-PCR and QRT-LAMP. 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)). Additionally, the use of generic machine learning models using generic processors to analyze data is also well understood, routine, and conventional. In the instant claims, the recitation of “applying a machine learning model to the biomarker expression levels” is written at a high level of generality such that nor particular elements are recited that could be considered to transform the nature of the claims into a patent eligible exception. 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 not directed to abstract ideas. This argument has been thoroughly and carefully considered but was not found persuasive for the reasons made in the rejection above, regarding the newly amended claim limitations to generic processors and a generic machine learning model. The arguments that the determining step may involve a mathematical calculation but that the claim does not recite any mathematical formula is not found persuasive because the “risk score” is a generic representation of a mathematical concept. Arguments that under step 2A prong 2, the claims have been amended to recite improved risk stratification is not found persuasive because these elements are directed to the natural correlation, that is the expression levels of the biomarkers determine a risk score that is associated with a risk category. As such, this is not considered a practical application because it is directed to a JE itself. Arguments that under step 2B, the claims include substantial meaningful steps is not found persuasive because the added limitations are generic and simply instruct practitioners on how to apply the natural correlation in the claims. The rejection is maintained and applied to the newly added claims.
Claim Rejections - 35 USC § 112
Claims 1, 3, 4, 6-11, 13-18, 21, 26, and 40-42 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claims recite “determining a risk score based on the biomarker expression levels” and “the score corresponding to a risk of mortality…”, however the metes and bounds of the terms “based on” and “corresponding to” are unclear. The relationship between the risk score and the biomarker expression levels cannot be determined by the phrase “based on” because it is not clear if the score is entirely calculated using the expression levels or if additional parameters are used in determining the risk score. Additionally, the term “corresponding” in the context used is unclear because the relationship between the score and risk of mortality [or need for ICU care] is unclear. It is not clear if the score indicates the risk of mortality [or need for ICU care] or if additional parameters are used to indicate what the risk of mortality [or need for ICU care] is. The same analysis holds for “corresponding to one or more discreet levels…”.
Response to Arguments
This rejection is maintained from the previous office action. The response asserts that the claims have been amended to address the rejection, however the claim amendments do not address this issue raised in the previous office action.
Claim Rejections - 35 USC § 103
Claims 1, 3, 4, 6-11, 13-18, 21, 26, and 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Khatri (Khatri et al; US 2018/0274031) in view of Tsalik I (Tsalik et al; US2018/0245154), Tsalik II (Tsalik et al; WO2018/140256: reference will be made to US Patent 11,286,525 which is the US equivalent document of the WO document and contains the same disclosure), and Hancock (Hancock et al; US 2017/0073734).
Khatri teaches diagnosing critically ill patients (eg sepsis) with viral infections by measuring the gene expression levels (eg q RT-PCR) of particular genes, including DEF4A and LY86 (para 0083, para 0079). Khatri teaches determining a mortality gene score (para 0080) to assess mortality risk within 30 days based on the expression levels of the genes. Khatri teaches that a higher mortality gene score compared to a reference value for control subjects indicates that the subject is at high risk of mortality within 30 days (para 0080). Khatri teaches that the methods can be used to indicate patients at “low risk” for further monitoring (para 0081). Khatri teaches that both patients and clinicians can benefit from better estimates of mortality risk, and their choices for live saving measures (para 0081). Khatri teaches analysis within 24 hours of diagnosis. Khatri teaches determining the risk score using machine learning, including performing LDA, PCA, csSAM, etc (para 0136). Khatri teaches the computer processor analyzes and compares the data, establishes a risk category (determining mortality risk) for the patient, and displays the information (para 0135-0136). This necessarily requires some sort of threshold value to establish high risk vs low risk, as taught by Khatri. Although Khatri does not teach determining an intermediate risk or classifying a patient into an intermediate category, Khatri does teach that both patients and clinicians can benefit from better estimates of mortality risk, therefore it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to include different risk categories, such as intermediate risk, so as to stratify patients into appropriate treatment groups for the best possible outcome for the patient.
Khatri does not teach detecting expression of HK3, BATF, or TGFB1, however Tsalik I teaches diagnosis and treatment of acute respiratory infection, including viral infections, by assessing gene expression levels (eg quantitative RT-PCR) of specific genes including BATF. Tsalik II teaches gene expression signatures for predicting and diagnosing sepsis in critically ill patients which include DEFA4, TGFB1 and LY86 (supplementary table 7). Additionally, Hancock teaches gene expression signatures for assessing critically ill patients which include LY86, BATF, and HK3 (table 4). Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have included detection of expression levels of HK3, BATF, and TGFB1, as taught by Tsalik I, Tsalik II, and Hancock in the method of determining a risk score in the method of Khatri. All of the references are in the same field of diagnosis and assessment of critically ill patients using gene expression levels. The ordinary artisan would have been motivated to include the genes taught in each of the references to establish a risk score and classify patients into different risk categories for the purpose of stratifying patients according to need and treatment modalities and to obtain a comprehensive list of all genes useful for the method.
Response to Arguments
The response traverses the rejection and asserts that methods disclosed in the cited references are not “specifically” designed for subjects having a “diagnosis of a viral infection”. This argument has been thoroughly reviewed but was not found persuasive because Khatri specifically teaches a “critically ill patient diagnosed with a viral infection” (para 0083). While that is not the primary focus of the teachings of Khatri, Khatri does teach, and at the very least strongly suggests, to perform the methods on patients diagnosed with viral infection. Additional arguments pertaining to each of the references individually is not found persuasive because one cannot show nonobviousness 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 rejection is maintained and applied to the newly added and amended claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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
