DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 11, 2025 has been entered. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance.
Applicant’s election of the combination of miRNAs no. 2008 from Table 25 (hsa-miR-4732-5p, hsa-miR-3613- 3p, hsa-miR-103a-2-5p, hsa-miR-5481, hsa-miR-192-5p, hsa-miR-12136, hsa-miR-598-3p, hsa-miR-19a-3p, hsa-miR-590-3p, hsa-miR-500a-5p) is reiterated for the record.
Claims 1-19 and 21-22 are currently pending.
Claims 3-12, 16-18, and 21-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected subject matter (either a non-elected invention or species), there being no allowable generic or linking claim.
Applicants are reminded that the current status of all of the claims in the application, including any previously canceled or withdrawn claims, must be given. It is noted that claim 22 has the wrong status identifier. Correction is required.
The claims have been examined to the extent that the claims read on the elected combination of miRNAs (hsa-miR-4732-5p, hsa-miR-3613- 3p, hsa-miR-103a-2-5p, hsa-miR-5481, age, hsa-miR-192-5p, hsa-miR-12136, hsa-miR-598-3p, hsa-miR-19a-3p, hsa-miR-590-3p, hsa-miR-500a-5p). The additionally recited miRNAs and combinations thereof have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Objections
3. Claim 14 is objected to because of the following informalities: the claim recites “phenotypic character”. It is assumed that this is meant to say “phenotypic characteristic”. Additionally the claim is missing a period at the end. Appropriate correction is required.
Claim Rejections - 35 USC § 101
4. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 13-15, and 19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature.
The claims are drawn to a method to determine if a renal mass is benign or malignant based on the expression level of miRNA in a sample. Thus the claims recite a correlation between (i) the level of the recited miRNAs and malignant renal masses and (ii) the level of the recited miRNAs and benign renal masses. These types of correlations are a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas.
Claim 1 recites a method to determine if a renal mass present in a subject is a benign or malignant renal mass (see preamble). The claim is considered to encompass “determining”, even if this step is not recited in the active tense. The broadest reasonable interpretation of the “determining” step is that it may be accomplished by a mental process. For example, one may “determine” if the mass is benign or malignant by reading a laboratory report containing the outcome of the classification.
The claims recite a step of “comparing” the measured level to a reference level (clms 1, 13). The broadest reasonable interpretation of the “comparing” step is that it may be accomplished by a mental processes. For example, one may “compare” the levels by reading a laboratory report comprising the levels side by side.
The claims recite a step of “applying a machine learning supervised classification of samples” (clm 1). Machine learning falls within the category of mathematical concepts because it often relies on mathematical algorithms. Mathematical concepts are abstract ideas.
The claims recite a step of “determining” the genotype of UMOD SNPs (clm 2). Neither the specification nor the claims set forth a limiting definition for “determining” and the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the “determining” step is that it may be accomplished by a mental processes. For example, one may “determine” the genotype by reading sequencing data in a report.
The claims recite a step of “analysis” of phenotypic characteristics (clm 14). Neither the specification nor the claims set forth a limiting definition for “analyzing” and the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the “analyzing” step is that it may be accomplished by a mental processes. For example, one may “analyze” the phenotypic characteristics by reading the subjects medical chart.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 1 as amended recites a method to determine if a renal mass present in a human subject is benign or malignant and treating the human with a renal mass that is malignant (preamble). Claim 1 further recites “wherein the treating step comprises surgically removing the malignant renal mass from the human subject or comprises oncological therapy of the human subject. First of all there is no active process step of “treating” recited in the claims. The “treating” is only recited in the preamble and is considered to be an intended purpose of the claimed process. Even if the treating was recited as an active process, it is noted that the “treating” is conditional and would only occurs when the renal mass is malignant. The claims broadly encompass determining that the renal mass is benign and in those situations the treating is not performed. Further treatment limitations must be particular, i.e., specifically identified so that they do not encompass all applications of the judicial exception. In the instant case “oncological therapy” is not particular. It is merely instructions to apply the exception in a generic way. For these reasons claim 1 does not recite any steps or elements that integrate the judicial exception so as to practically apply the judicial exception.
In addition to the judicial exceptions, the claims recite a step of measuring miRNA. This step is not considered to integrate the judicial exception into a practical application because it merely adds insignificant extra-solution activity (data gathering) to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions, the claims recite a step of measuring miRNA. Additionally claim 13 further requires measuring uromodulin. These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The steps are recited at a high level of generality. Measuring miRNA in a biological sample merely instructs a scientist to use any detection technique. The claim does not require the use of any particular non-conventional reagents (i.e., primers or probes). When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicants invention and at the time the application was filed.
The teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available.
The specification (para 0065) teaches “miRNA expression may be detected by any suitable method for RNA detection including, but not limited to, microarray, reverse transcriptase polymerase chain reaction (RT-PCR) or other PCR-based assays (e.g. quantitative or real time RT-PCR) or mass spectrometry”.
The prior art demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known.
Nakuda (Journal of Pathology 2008 Vol 216 pages 418-427) teaches that they investigated expression profiles of microRNA (miRNA) in renal cell carcinoma [clear cell carcinomas (CCC) and chromophobe renal cell carcinomas (ChCC)] and in normal kidneys by using a miRNA microarray platform which covers a total of 470 human miRNAs. They found that 43 miRNAs were differentially expressed between CCC and normal kidney, of which 37 were significantly down-regulated in CCC and the other 6 were up-regulated. They also found that 57 miRNAs were differentially expressed between ChCC and normal kidney, of which 51 were significantly down-regulated in ChCC and the other 6 were up-regulated (abstract).
Wang (Scientific Reports 1/5/2015 Vol 5 No 7610) that the levels of 754 serum miRNAs were initially determined using a TaqMan Low Density Array in two pooled samples from 25 RCC and 25 noncancer controls. Markedly dysregulated miRNAs in RCC cases were subsequently validated individually by qRT-PCR in another 107 patients and 107 controls arranged in two sets. The serum levels of miR-193a-3p, miR-362 and miR-572 were significantly increased whereas the levels of miR-28-5p and miR-378 were markedly decreased in patients with RCC, even in those with stage I disease, compared with the noncancer controls (P , 0.01) (abstract).
Further it is noted that 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.
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);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. 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);
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);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
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)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Response To Arguments
5. In the response the Applicants traversed the rejection under 35 USC 101. The Applicants argue that the claims have not been considered as whole. They argue that the aim of the invention is to improve the treatment of a renal mass by first determining if the renal mass is malignant. Applicants that here, as in the facts developed by the Vanda Court, the measurements are not taken to gather data about the recited phenomenon, but the measurements are taken to more safely treat the human subject. They argue that claim 1, taken as a whole, applies a natural relationship to improving the treatment of a human subject presenting with renal mass.
These arguments and the amendments have been fully considered but do not overcome the rejection. The Examiner does not agree that the claims are analogous to those in Vanda. First of all it is noted that in Vanda, the claims recited active process steps of treating.
“if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and
if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day”
The instant claims do not recite an active process step of treating. The treating is only recited in the preamble of the claim and has been interpreted as a intended use of the claimed method. Secondly, in Vanda, the treatment is required. In other words, everyone is treated with iloperidone and the dosage is given based on whether the patient has the CYP2D6 poor metabolizer genotype. However in the instant claims the treatment is NOT required. The treatment is conditional and only given when the renal mass is malignant. The claims encompass determining that the renal mass is benign and in those situations the treatment would not be given. Additionally, in Vanda, the treatment with iloperidone is “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exception. While surgically removing a malignant renal tumor mass is considered to be a particular treatment for malignant renal mass, “oncological therapy” is NOT particular. The recitation of “oncological therapy” is general and non-specific. It merely instructions one to “apply” the exception in a generic way. The claims do not recite any steps or elements that integrate the judicial exception so as to practically apply the judicial exception and the rejection is maintained.
Claim Rejections - 35 USC § 112
6. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 13-15, and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding Claims 1-2, 13-15, and 19 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method to determine if a renal mass present in a human is benign or malignant and treating the human subject determined to have a renal mass that is malignant. However the claims only recite active process steps of “measuring”, “comparing”, and “applying”. The claims are incomplete because there is no active process steps of determining if the renal mass is benign or malignant as required by the preamble. It is noted that the of “applying a machine learning supervised classification of samples” is not necessarily equivalent in scope to determining if a renal mass is benign or malignant. Further the claims are incomplete because there is no active process step of treating the human subject determined to have a renal mass that is malignant, as required by the preamble.
Claims 1-2, 13-15, and 19 are rejected over the recitation of the phrase “the human subject determined to have a renal mass that is malignant” in claim 1 (preamble). There is insufficient antecedent basis for this limitation in the claim because while the claim previously refers to a “human subject” it does NOT refer to a “human subject determined to have a renal mass that is malignant”.
Claims 1-2, 13-15, and 19 are rejected over the recitation of the phrase “the treating step comprises surgically removing…” in claim 1. There is insufficient antecedent basis for this limitation in the claim because there is no active process step of treating recited in the claim. “Treating” is only recited in the preamble of claim and has been interpreted as an intended use of the claimed method, rather than an active process step.
Claims 1-2, 13-15, and 19 are rejected over the recitation of the phrase “the malignant renal tumor mass” in claims 1 and 19. There is insufficient antecedent basis for this limitation in the claim. While the claims are drawn to a method to determine if a renal mass is benign or malignant, they claims do not previously refer to a “malignant renal tumor mass”.
Claim Rejections - 35 USC § 112
7. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 13-15, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method comprising:
(a) obtaining a biological sample from a human subject with a renal mass, wherein the biological sample is selected from the group consisting of: blood, serum, plasma, urine, and kidney tissue;
(b) measuring the level of hsa-miR-4732-5p, hsa-miR-3613- 3p, hsa-miR-103a-2-5p, hsa-miR-5481, hsa-miR-192-5p, hsa-miR-12136, hsa-miR-598-3p, hsa-miR-19a-3p, hsa-miR-590-3p, and hsa-miR-500a-5p in said biological sample;
(c) using supervised machine learning to analyze the levels measured in (b) and determine that the human subject has a malignant renal mass;
(d) treating the human subject having the malignant renal mass by surgically removing the malignant renal mass.
does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims are drawn to a method to determine if a renal mass present in a human subject is benign or malignant and treating the human subject determined to have a renal mass that is malignant.
The claims recite a first step of “measuring” the levels of hsa-miR-4732-5p, hsa-miR-3613- 3p, hsa-miR-103a-2-5p, hsa-miR-5481, hsa-miR-192-5p, hsa-miR-12136, hsa-miR-598-3p, hsa-miR-19a-3p, hsa-miR-590-3p, hsa-miR-500a-5p in a biological sample selected from the group consisting of blood, blood cells, serum, plasma, urine, saliva, sputum, tears, and kidney tissue. Claim 15 states that the biological sample is selected from the group consisting of blood, serum, plasma, and urine.
The claims recite a second step of comparing the measured levels to a reference level. The claims do not set forth what the reference level is. Therefore the claims encompass comparing the measured levels of the recited miRNAs to the level of any biomarker in any type of biological sample obtained from any type of subject.
The claims recite a third step of applying a machine learning supervised classification of samples. This step encompasses using supervised machine learning to classify anything. For example this step encompasses classifying benign or malignant renal masses, classifying different types of benign renal masses (leiomyomas, angiomyolipomas, oncocytomas), classifying different types of malignant renal masses (renal cell carcinoma, Wilms tumor, renal sarcomas), classifying different stages of renal cancer (stages I-IV).
The claims recite “wherein” the treating step comprises surgically removing the malignant renal tumor mass from the human subject or comprises oncological therapy of the human subject. However it is noted that there is no treating step.
The nature of the invention requires a reliable correlation between the miRNA levels and the presence of a benign or malignant renal mass.
Teachings in the Specification and Examples
The specification (para 0088) teaches that the present predictive model based on circulating miRNAs can predict the presence of RCC, defined as a renal malignancy. In the model, the inventors compared the markers in patients diagnosed with any RCC histological subtype (ccRCC, p1RCC, p2RCC, chRCC) relative to patients diagnosed with a benign renal mass (oncocytoma, angiomyolipoma, benign cyst or other benign histotype). The clinical implication of this information is the selection or identification of patients with high risk of RCC and of patients with low risk of RCC to be inserted in specific treatment or surveillance protocol.
The specification (paras 0110-0111) teaches that total RNA was isolated from 200 μL of plasma. miRNAs were assayed by TaqMan microRNA profiling using the QuantStudio 12K Flex Real-Time PCR System with OpenArray.
The specification (para 0158) teaches that the inventors identified unique sets of miRNAs (miRNA signatures) leading to a significant increase in sensitivity, specificity, accuracy and predictive power for diagnosing RCC patients by using machine learning algorithms.
The specification (para 0160) discloses a list of the best 29 mRNA selected by the algorithm sorted by importance for diagnosis outcome: hsa-miR-550a-3-5p, hsa-miR-132-3p, hsa-miR-1180-3p, hsa-miR-590-5p, hsa-miR-590-3p, hsa-miR-500a-5p, hsa-miR-374a-5p, hsa-miR-99a-3p, hsa-miR-130b-5p, hsa-miR-337- 5p, hsa-miR-4732-5p, hsa-miR-374a-3p, hsa-miR-3613-3p, hsa-miR-103a-2-5p, hsa-miR-548l, hsa-miR-1277-3p, hsa-miR-29c-Sp, hsa-miR-181b-5p, hsa-miR-192-5p, hsa-miR-433-3p, hsa-miR-12136, hsa-miR-598-3p, hsa-miR-628-3p, hsa-miR-19a-3p, hsa-miR-122-5p, hsa-miR-196b- 5p, hsa-miR-215-5p, hsa-miR-491-5p, and hsa-miR-153-3p. The inventors combined these miRNAs, together or not with age and UMOD SNP variant, creating unique combinations leading - to a further significant increase in sensitivity, specificity, accuracy and predictive power for diagnosis (Table 25). It is noted for the record that the claimed combination of miRNAs appears in Table 25 as combination N 2008.
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State of the Art and the Unpredictability of the Art
The level of skill in the art with regard to measuring miRNA in biological samples is high. However correlations between miRNA levels and cancer are highly unpredictable. The unpredictability will be discussed below.
The claims require “applying” a machine learning supervised classification of samples. As discussed above, the claims broadly encompass classifying benign or malignant renal masses, classifying different types of benign renal masses (leiomyomas, angiomyolipomas, oncocytomas), classifying different types of malignant renal masses (renal cell carcinoma, Wilms tumor, renal sarcomas), classifying different stages of renal cancer (stages I-IV). However the breadth of the claims is not supported by the teachings in the specification. The specification teaches that the inventors identified unique sets of miRNAs (miRNA signatures) leading to a significant increase in sensitivity, specificity, accuracy and predictive power for diagnosing RCC patients by using machine learning algorithms. While the specification is enabled for using supervised machine learning to analyze the levels of the recited miRNAs and determine that a human subject has a malignant renal mass (RCC), the specification does not provide enablement for ANY type of classification. In the absence of evidence to the contrary the specification is not enabled for using supervised machine learning to analyze the levels of the recited miRNAs and determine what subtype of benign renal mass a subject has, what subtype of malignant renal mass a subject has, what stage a renal mass is etc.
The claims recite comparing the measured levels to a reference level. The claims encompass comparing the measured levels of the recited miRNAs to the level of any biomarker in any type of biological sample obtained from any type of subject. However it is highly unpredictable if any reference level could be used in the claimed method. It is noted that the specification (para 0088) teaches that the inventors compared the markers in patients diagnosed with any RCC histological subtype (ccRCC, p1RCC, p2RCC, chRCC) relative to patients diagnosed with a benign renal mass (oncocytoma, angiomyolipoma, benign cyst or other benign histotype). The miRNAs that were identified were those differentially expressed between these two groups. Thus the specification is only enabled for methods which compare miRNAs levels in a sample from a subject to reference levels, wherein the reference levels are of the same miRNAs in the same sample type obtained from subjects with RCC or benign renal masses.
The claims as amended recite that the biological sample selected from the group consisting of blood, blood cells, serum, plasma, urine, saliva, sputum, tears, and kidney tissue. It is relevant to point out that it is highly unpredictable as to whether the results obtained with plasma could be extrapolated to other sample types encompassed by the claims. The specification teaches the analysis of miRNAs in plasma samples of subjects with malignant and benign renal masses. The prior art of Ignaz (Experientia Supplementum 106 2015 pages 254-252) teaches that similarly to blood-borne circulating miRNA, further studies on large cohorts with uniform methodological approaches are warranted to reliably establish the clinical utility of fecal, salivary, biliary, and urinary miRNAs. Being absolutely noninvasive (except for biliary miRNAs), if the utility of these miRNAs were established, this could represent a major advance in current disease management (page 249) In the absence of evidence to the contrary it is highly unpredictable if the differential expression of claimed miRNAs in plasma samples will also occur in blood cells, saliva, sputum, and tears and that such changes will be correlated with RCC.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able perform any type of classification of samples based on the level of 10 miRNA in a biological sample selected from the group consisting of: blood, blood cells, serum, plasma, urine, saliva, sputum, tears, and kidney tissue.
In order to practice the breadth of the claimed invention one of skill in the art would first have to recruit human subjects with benign and malignant renal masses. Then one would have to obtain blood, blood cells, serum, plasma, urine, saliva, sputum, tears, and kidney tissues from those subjects. Then additional experimentation would need to be conducted to measure the claimed 10 miRNAs in each of the sample types. The machine learning models would have to be trained to determine if it is possible to determine what subtype of benign renal mass a subject has, what subtype of malignant renal mass a subject has, what stage a renal mass is etc. based on the level of the 10 miRNAs in each sample type. The specification has merely provided an invitation for further experimentation. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Response To Arguments
8. In the response the Applicants traversed the rejection under 35 USC 112(a). The Applicants argue that the claims have been amended to overcome the rejection.
The amendments have been fully considered but do not overcome the rejection. The rejection is maintained because the teachings in the specification do not support the breadth of the claims. The claims are not enabled for methods which broadly encompass (i)performing any classification using supervised machine learning, (ii) any reference level, or (iii) samples comprising blood cells, saliva, sputum, and tears. The rejection is maintained.
Improper Markush Grouping Rejection
9. Claims 1-2, 13-15, and 19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The claims recite the following Markush grouping:
wherein the at least one miRNA is selected from the group consisting of: hsa-miR-99a-3p, hsa-miR-1180-3p, hsa-miR-192- 5p, hsa-miR-4286, hsa-miR-103a-2-5p, hsa-miR-215-5p, hsa-miR-590-3p, hsa-miR-500a- 5p, hsa-miR-590-5p, hsa-miR-382-5p, hsa-miR-30e-3p, hsa-miR-545-5p, hsa-miR-5481, hsa-miR-20b-5p, hsa-miR-193b-3p, hsa-miR-450a-5p, hsa-miR-410-3p, hsa-miR-433-3p, hsa-miR-221-5p, hsa-miR-331-5p, hsa-miR-181c-3p, hsa-miR-451a, hsa-miR-491-5p, hsa-miR-501-5p, hsa-miR-4732-5p, hsa-miR-485-3p, hsa-miR-335-5p, hsa-miR-1290, hsa-miR-132-3p, hsa-miR-337-5p, hsa-miR-550a-3-5p, hsa-miR-132-3p, hsa-miR-1180- 3p, hsa-miR-590-5p, hsa-miR-590-3p, hsa-miR-500a-5p, hsa-miR-374a-5p, hsa-miR-99a- 3p, hsa-miR-130b-5p, hsa-miR-337-5p, hsa-miR-4732-5p, hsa-miR-374a-3p, hsa-miR-3613-3p, hsa-miR-103a-2-5p, hsa-miR-5481, hsa-miR-1277-3p, hsa-miR-29c-5p, hsa-miR-181b-5p, hsa-miR-192-5p, hsa-miR-433-3p, hsa-miR-12136, hsa-miR-598-3p, hsa-miR-628-3p, hsa-miR-19a-3p, hsa-miR-122-5p, hsa-miR-196b-5p, hsa-miR-215-5p, hsa-miR-491-5p, and hsa-miR-153-3p
The miRNA and combinations thereof are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 706.03(y) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 706.03(y)IIA).
Herein, the recited alternative species do not share a single structural similarity, as each miRNA has a different chemical structure in that it consists of a different nucleotide sequence. The only structural similarity present is that all of the miRNA comprise nucleotides. The fact that the miRNA comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common activity of being correlated with renal tumors. Accordingly, while the different miRNAs are asserted to have the property of being correlated with renal tumors, they do not share a substantial structural similarity essential to this activity.
Further, the recited miRNAs do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that genes behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited miRNAs possess the common property of being correlated with renal tumors.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response To Arguments
10. In the response the Applicants traversed the improper Markush group rejection. The Applicants argue that the specification provides ample evidence that the recited miRNAs do indeed share a common function by correlating with the level of malignancy of renal tumors.
This argument has been fully considered but is not persuasive. A Markush grouping is proper if the alternatives defined by the Markush group share a “single structural similarity” and a common use. While the miRNA’s share the common use of being associated with renal tumors, they do not share a single structural similarity. Thus the rejection is maintained. This rejection could be overcome by amending claim 1 so that it no longer recites miRNAs in the alternative. For example “measuring the levels of hsa-miR-4732-5p, hsa-miR-3613- 3p, hsa-miR-103a-2-5p, hsa-miR-5481, hsa-miR-192-5p, hsa-miR-12136, hsa-miR-598-3p, hsa-miR-19a-3p, hsa-miR-590-3p, and hsa-miR-500a-5p in a biological sample of the human subject”.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682