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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 28, 2025 has been entered. The three month suspension ended on January 28, 2025.
Applicant's election of the normalizers hsa-let-7a, hsa-miR-103, and hsa-miR-125a-5p, and the discriminator hsa-miR-146b in the reply filed on March 16, 2022 is reiterated for the record.
Claims 17, 19-21, 23-29, and 31-34 are currently pending.
Claims 20, 24, 28, and 32-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter (nonelected miRNAs), there being no allowable generic or linking claim.
The claims have been examined to the extent that the claims read on the elected miRNAs (the normalizers hsa-let-7a, hsa-miR-103, and hsa-miR-125a-5p and the discriminator hsa-miR-146b). The additionally recited miRNAs have been withdrawn from consideration as being directed to a non-elected invention. 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.
Any rejections or objections not reiterated herein have been withdrawn.
NON COMPLIANT AMENDMENT
3. It was previously noted in the prior Office Action that the claims were non compliant because the current status of each of the claims in the application, including any previously canceled or withdrawn claims, was not given. Applicants were asked to correct this but they did not. Claims 20, 24, 28, and 32-34 still have the wrong status identifiers. Technically this makes the amendment Non-Compliant. However in order the advance prosecution, the amendment has been entered but correction is required.
Claim Objections
4. Claim 21 is objected to because of the following informalities: the claim recites a typographical error. The recitation of “the data normalizing value obtained in c)” should say
“the data normalizing value obtained in d)”. Appropriate correction is required.
Claim 29 is objected to because of the following informalities: the claim recites “classifying the thyroid sample as benign as benign”. Appropriate correction is required.
Claim 29 is objected to because of the following informalities: the claim recites a typographical error. The recitation of “the data normalizing value obtained in c)” should say
“the data normalizing value obtained in d)”. Appropriate correction is required.
Claim Rejections - 35 USC § 101
5. 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 17, 19, 25-27, 29, and 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
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 abstract ideas.
The claims recite the following limitations:
- measuring a data normalizing value of the discriminating microRNAs using the formula: Normalization value = 2(N-D), wherein N is the expression level of the normalizing microRNAs when only one of the microRNAs is measured, and N is the mean expression level of normalizing microRNAs when two or three of the microRNAs are measured, and D is the expression level of the discriminating microRNAs when only one of the microRNAs is measured, and D is the mean expression level of discriminating microRNAs when two or three of the microRNAs are measured (see claims 17, 25, 29)
- diagnosing a malignancy in the thyroid nodule sample by using an algorithm selected from the group consisting of RandomForest, ExtraTrees, C4.5, DecisionJungle, and Boosted DecisionTrees to classify the samples by comparison with the data normalizing value measured in d); and measuring fold change in the one to three discriminating microRNAs when compared to the fold change in the normalizing microRNA; and wherein the malignancy in the thyroid nodule sample is diagnosed when at least one of the discriminating microRNAs has a fold change of 2.5 or greater (see claim 17)
-comparing the data normalizing value obtained in d) with validation samples using an algorithm selected from the group consisting of RandomForest, ExtraTrees, C4.5, DecisionJungle, and Boosted DecisionTrees so as to screen the previously obtained thyroid nodule sample based on the comparison of the data normalizing value obtained in d) (see claim 25)
- classifying the thyroid nodule sample as benign by using an algorithm selected from the group consisting of RandomForest, ExtraTrees, C4.5, DecisionJungle, and Boosted DecisionTrees to classify the samples by comparison with the data normalizing value obtained in c); and wherein comprising measuring fold change in the one to three discriminating microRNAs when compared to the fold change in the normalizing microRNA; and wherein the malignancy in the thyroid nodule sample is diagnosed when at least one of the discriminating microRNAs has a fold change of 2.5 or greater
These limitations recite mathematical relationships, mathematical formulas or equations and/or mathematical calculations. These mathematical concepts are abstract ideas. The courts have found that algorithms for calculating parameters indicating an abnormal condition are abstract ideas (In re Grams).
The claims recite the following limitation:
-measuring fold change in the one to three discriminating microRNAs when compared to the fold change in the normalizing microRNA
The “measuring” step broadly encompasses a mental processes. For example, one may “measure” the fold changes by comparing the expression levels of the discriminating miRNA and normalizing miRNA by looking at data side by side and thinking about the result of the comparison. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
Additionally the instant claims recite a law of nature.
The claims recite a correlation between the level of hsa-miR-146b and whether a thyroid nodule is benign or malignant. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
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.
In addition to the judicial exceptions the claims recite the following limitations:
- extracting nucleic acids from a punctured thyroid nodule cytology sample previously obtained from said patient undergoing thyroid fine-needle aspiration (FNA) cytology testing wherein said previously obtained sample resulted in an indeterminate test result (claim 17, 25, 29)
-measuring the expression level of three normalizing microRNAs in said sample, wherein the three normalizing microRNAs hsa-let-7a, hsa-miR-103, and hsa-miR- 125a-5p (claim 17, 25, 29)
-measuring the expression level of a discriminating microRNA in said sample, wherein the discriminating microRNA is hsa-miR-146b (claim 17, 25, 29)
These additionally recited steps are not considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims recite the following limitations:
- extracting nucleic acids from a punctured thyroid nodule cytology sample previously obtained from said patient undergoing thyroid fine-needle aspiration (FNA) cytology testing wherein said previously obtained sample resulted in an indeterminate test result (claim 17, 25, 29)
-measuring the expression level of three normalizing microRNAs in said sample, wherein the three normalizing microRNAs hsa-let-7a, hsa-miR-103, and hsa-miR- 125a-5p (claim 17, 25, 29)
-measuring the expression level of a discriminating microRNA in said sample, wherein the discriminating microRNA is hsa-miR-146b (claim 17, 25, 29)
The additional steps/elements do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
The steps are recited at a high level of generality. Obtaining a sample and extracting RNA in order to perform tests is well understood, routine, and conventional activity for those in the field of diagnostics. Measuring the expression level of miRNA merely instructs a scientist to use any detection technique. The claim does not require the use of any particular non-conventional reagents (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.
Additionally the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements. For example in the background section, the specification discloses various patent documents where miRNA expression is used to classify thyroid tumors (see paras 0019-0022).
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available.
Kennedy (US 2012/0220474 Pub 8/30/2012) teaches a method for distinguishing malignant thyroid nodules from benign (para 0018). Kennedy teaches methods of obtaining suitable samples of thyroid are known in the art and are further described in the ATA Guidelines for thyroid nodule management (Cooper et al. Thyroid Vol. 16 No. 2 2006), herein incorporated by reference in its entirety. Generic methods for obtaining biological samples are also known in the art and further described in for example Ramzy, Ibrahim Clinical Cytopathology and Aspiration Biopsy 2001 which is herein incorporated by reference in its entirety. In one embodiment, the sample is a fine needle aspirate of a thyroid nodule or a suspected thyroid tumor. In some cases, the fine needle aspirate sampling procedure may be guided by the use of an ultrasound, X-ray, or other imaging device (para 0081). Kennedy discloses performing cytological analysis on the sample (paras 0113-0115). Kennedy teaches that cytological assays mark the current diagnostic standard for many types of suspected tumors including for example thyroid tumors or nodules. In some embodiments of the present invention, samples that assay as indeterminate may be subjected to subsequent assays to obtain more information. In the present invention, these subsequent assays comprise the steps of molecular profiling of genomic DNA, gene expression product levels or gene expression product alternative splicing (para 0125). Kennedy teaches that methods of measuring gene expression product levels includes methods of measuring miRNA levels (para 0144). Kennedy teaches the general methods for determining gene expression product levels are known to the art and may include but are not limited to one or more of the following: additional cytological assays, assays for specific proteins or enzyme activities, assays for specific expression products including protein or RNA or specific RNA splice variants, in situ hybridization, whole or partial genome expression analysis, microarray hybridization assays, SAGE, enzyme linked immuno-absorbance assays, mass-spectrometry, immuno-histochemistry, or blotting (para 0168).
Nikiforova (J Clin Endocrinol Metab May 2008 93(5) 1600-1608) teaches detection of miRNA expression levels in 62 FNA samples by RT-PCR. Nikiforova teaches that miR-146b is one of the most overexpressed miRNAs in thyroid tumors vs. hyperplastic nodules (abstract). Nikiforova also teaches that miR-146b was normalized against the expression of an endogenous control (let7-a miRNA) (page 1601, col 1).
Chen (Modern Pathology 2008 21, 1139-1146) teaches the analysis of miRNA in FNA specimens by RT-PCR. Chen teaches that miR-146b is overexpressed in papillary thyroid carcinoma (abstract). Chen teaches miRNAs were normalized using U6 values (page 1141, col 1).
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);
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
6. In the response the Applicants traversed the rejection under 35 USC 101. In the response the Applicants argue that the present claims clearly go beyond mere mental activities and require positive steps used to obtain the practical applications to detect, diagnosis, classify and treat a particular condition, and further provide a practical method that will curtail unnecessary operations which would otherwise have severe consequences for the patient being diagnosed. Applicants argue that the claims are eligible in view of Example 29 (relating to methods of diagnosing and treating Julitis) because the amended claims contain precisely the same type of elements. Specifically, the claims as presently amended relate to diagnosis and treatment, and they include the same positive steps relating to active elements for obtaining the sample and several non-routine steps in order to analyze the nucleic acid expression in the sample so as to be able to determine if the condition to be detected is present based on the active steps. Additionally the Applicants argue that the claims do not relate to a natural product. Finally they argue that methods of screening which include many of the types of method elements as in the present claims have commonly been issued as patents under the present eligibility guidelines.
These arguments have been fully considered but are not persuasive. As explained in the rejection above, the claims recite a law of nature and abstract ideas. The steps/elements recited in addition to the judicial exceptions have been fully considered but they do NOT integrate the judicial exceptions into a practical application because they merely recite insignificant extra-solution activity (data gathering) to the judicial exceptions. Additionally the steps/elements recited in addition to the judicial exceptions have been fully considered but they do NOT provide an inventive concept because they merely append well known, routine, and conventional activity that is recited at a high level of generality to the judicial exceptions (see prior art cited in the rejection). It is noted that Applicants state that the claims recite non-routine steps but the response to does not specifically point out which steps in addition to the judicial exception they consider to be non-routine. The Applicants argue that the claims are analogous to those in the Julitis Examples but they do not state which claim(s) in the Julitis Example is analogous to the pending claims. After reviewing the claims in the Julitis Example, none of the claims appear to be analogous to pending claims. Further it is noted that the rejection does not say that the claims are ineligible for reciting natural products. The claims are rejected for reciting abstract ideas and a law of nature. Finally each case is examined on its own merits and the prosecution and allowance of the cited cases have no bearing on the case currently under examination. The rejection is maintained.
Claim Rejections - 35 USC § 112(b)
7. 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 17, 19, 21, 23, 25-27, 29, and 31 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.
Claims 17, 19, 21, 23, 29, and 31 are rejected over the recitation of “measuring the expression level of one to three discriminating microRNAs in said sample, wherein the one to three normalizing microRNAs are structurally similar, and wherein the one to three normalizing microRNAs are selected from the group consisting of hsa-miR-146b, hsa-miR-181b, hsa-miR-152, hsa-miR-200b, hsa-miR-155 and hsa-miR-375” (see claims 17, 21, 29). The recitation of both discriminating and normalizing in this limitation is confusing because it is unclear if the elected miRNA (hsa-miR-146b) is a discriminating miRNA or normalizing miRNA. Clairification is requested.
Claims 17, 19, 21, and 23 are rejected over the recitation of “diagnosing a malignancy in the thyroid nodule sample by using an algorithm selected from the group consisting of RandomForest, ExtraTrees, C4.5, DecisionJungle, and Boosted DecisionTrees to classify the samples by comparison with the data normalizing value measured in d); and measuring fold change in the one to three discriminating microRNAs when compared to the fold change in the normalizing microRNA; and wherein the malignancy in the thyroid nodule sample is diagnosed when at least one of the discriminating microRNAs has a fold change of 2.5 or greater” (see claims 17, 21). This recitation is confusing because it is unclear how the diagnosing is actually accomplished. First the limitation states that it is accomplished using an algorithm to classify the samples. However later the claims state that it is accomplished based on a fold change of 2.5 or greater. Thus it is unclear if the claims require both or one or the other. Clairification is required.
Claim 19 is rejected as being indefinite because it depends from the method according to claim 18 and claims 18 has been canceled. For examination purposes this claim will be treated as if it depended from claim 17.
Claim 23 is rejected as being indefinite because it depends from the method according to claim 22 and claims 22 has been canceled. For examination purposes this claim will be treated as if it depended from claim 21.
Claims 29 and 31 are rejected over the recitation of “classifying the thyroid nodule sample as benign by using an algorithm selected from the group consisting of RandomForest, ExtraTrees, C4.5, DecisionJungle, and Boosted DecisionTrees to classify the samples by comparison with the data normalizing value measured in c); and comprising measuring fold change in the one to three discriminating microRNAs when compared to the fold change in the normalizing microRNA; and wherein the malignancy in the thyroid nodule sample is diagnosed when at least one of the discriminating microRNAs has a fold change of 2.5 or greater” (see claim 29). This recitation is confusing because it is unclear how the classifying is actually accomplished. First the limitation states that it is accomplished using an algorithm to classify the samples. However later the claims state that it is accomplished based on a fold change of 2.5 or greater. Thus it is unclear if the claims require both or one or the other. Clairification is required.
Claim 31 is rejected as being indefinite because it depends from the method according to claim 30 and claim 30 has been canceled. For examination purposes this claim will be treated as if it depended from claim 29.
Claim Rejections - 35 USC § 112(a)
8. 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.
9. Claims 17, 19, 21, 23, 25-27, 29 and 31 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
In the instant case the specification does not appear to provide support for obtaining a data normalizing value of the discriminating miRNA using the formula: Normalization value =2(N-D).
The specification teaches the following:
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It is noted that the specification teaches that there is a “^” symbol after the number 2. Thus while the specification provides support for obtaining a data normalizing value of the discriminating miRNA using the formula: Normalization value = 2(N-D) the specification does not provide support for obtaining a data normalizing value of the discriminating miRNA using the formula: Normalization value =2(N-D). These two different formulas are not equivalent and would produce very different results. This rejection can be overcome by amending the claims to recite the correct formula.
Response To Arguments-New Matter
10. In the response the Applicants traversed the new matter rejection. The Applicants argue that all of the aspects of the present claims are clearly supported in the original application, and no new matter has been entered. Applicant argue that the rejection should be withdrawn.
This argument has been fully considered but is not persuasive. The Applicants argue that the claim limitations are clearly supported in the original application, yet they do not point out any specific teachings in the specification (by page number or paragraph number) where the support is located. Thus the rejections are maintained.
Enablement
11. Claims 17, 19, 21, 23, 25-27, 29, and 31 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 of diagnosing a malignancy in a thyroid nodule from a patient, said method comprising:
(a) extracting nucleic acids from a punctured thyroid nodule cytology sample previously obtained from said patient undergoing thyroid fine-needle aspiration (FNA) cytology testing wherein said previously obtained sample resulted in an indeterminate test result;
b) measuring the expression level of three normalizing microRNAs in said sample, wherein the three normalizing microRNAs are hsa-let-7a, hsa-miR-103, and hsa-miR- 125a-5p;
c) measuring the expression level of a discriminating microRNA in said sample, wherein the discriminating microRNA is hsa-miR-146b;
d) obtaining a data normalizing value of the discriminating microRNAs using the formula:
Normalization value = 2(N-D),
wherein N is the mean expression level of said three normalizing microRNAs, and D is the expression level of the discriminating microRNA;
e) correlating the data normalizing value obtained in d) with validation samples using an algorithm selected from the group consisting of RandomForest, ExtraTrees, C4.5, DecisionJungle, and Boosted DecisionTrees; and
f) diagnosing a malignancy in the thyroid nodule sample based on the correlation of the data normalizing value obtained in e).
does not reasonably provide enablement for (i) subcombinations of the recited miRNA and (ii) using the formula Normalization value=2(N-D). 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 methods for diagnosing a malignancy in a thyroid nodule from a patient, diagnosing and treating a malignancy in a thyroid nodule from a patient, screening a punctured thyroid nodule cytology sample previously obtained from a patient undergoing thyroid FNAP cytology testing and determining if a thyroid nodule sample obtained from a patient is benign.
The claims recite a step of extracting nucleic acids from the previously obtained sample. The claims recite a step of measuring the expression level of one to three normalizing miRNAs selected from: hsa-let-7a, hsa-miR-103, and hsa-miR-125a-5p and measuring the expression level of a discriminating miRNA, wherein the discriminating miRNA is hsa-miR-146b.
Thus the claims encompass measuring the expression level of 7 different combinations of miRNA
(i) mir-146b + let-7a
(ii) mir-146b + miR-103
(iii) mir-146b + miR-125a-5p
(iv) mir-146b + let-7a + miR-103
(v) mir-146b + let-7a + miR-125a-5p
(vi) mir-146b + miR-103 + miR-125a-5p
(vii) mir-146b + let-7a + miR-103 + miR-125a-5p
The claims recite a step of measuring a data normalizing value of the discriminating miRNA using the formula: Normalization value = 2(N-D)
The claims recite steps of using an algorithm, selected from the group consisting of Random Forest, Extra Trees, C4.5, Decision Junglee, and Boosted Decision Trees to classify the samples by comparison with the data normalizing value measured and measuring fold change in the one to three discriminating microRNAs when compared to the fold change in the normalizing microRNA; and wherein the thyroid nodule sample is malignant or benign based on the fold change.
The nature of the invention requires a reliable correlation between discriminator miR-146b and malignant thyroid nodules.
Teachings in the Specification and Examples
The specification (Example 2) teaches that the inventors initially considered 96 miRNAs. The expression of these 96 initial candidate microRNAs in 80 indeterminate thyroid nodules (40 benign and 40 malignant--postoperative tissues) was analyzed and then only those microRNAs that expressed in at least 95% of the samples were selected. This analysis selected 65 microRNAs, being 10 candidates for normalizers and the remaining 55 candidates for discriminators. The selection of the 10 candidates for normalizers was carried out by analyzing the standard deviation. The 10 microRNAs with expression values (Ct) having a smaller standard deviation among all samples (benign and malignant) were preselected. The 10 normalizers (including hsa-let-7a, hsa-miR-103, and hsa-miR-125a-5p) are listed in Table 10. The 55 discriminators (including hsa-miR-146b) are listed in Table 9.
The specification (Example 3) teaches that the inventors generated normalizing values. To generate unique values that will be used as normalizers, they made all possible combinations among the 10 candidates for normalizers, so that the final value was the average between the values. At the end, all possible combinations come to a total of 175 combinations, therefore 175 single values to be used as normalization values. Then each of the 55 candidates for discriminator (D) is normalized by each of the 175 normalization values (N) generated above.
Normalization formula=2˄(N-D)
Each discriminator generates 175 normalized values. Each of these values is called a feature. A feature is a value used in machine-learning to separate classes. The concept used in the invention was to identify a set of features that have distinct values between benign and malignant. Then filter-based metaheuristic methods were used to know which features best separate the benign and malignant classes. The results allowed us to observe which microRNAs make up the best features, to then analyze a smaller panel of microRNAs in new samples (validation samples). After applying the described selection methods, the present inventors observed that the top-10 features (i.e., with the highest discriminating power between classes) were made of these 17 microRNAs. We then analyzed the expression of these microRNAs in a new set of patients (other than those previously used) of 95 samples (validation samples), being 37 malignant and 58 benign, this time directly on the FNAP cytology slides. It is noted that “Feature A” comprises the following normalizing miRNA: hsa-let-7a, hsa-miR-103, and hsa-miR-125a-5p and the following discriminating miRNA: hsa-miR-146b.
State of the Art and the Unpredictability of the Art
While methods of measuring miRNA are known in the art, methods of correlating miRNA with a phenotype such as thyroid cancer are highly unpredictable. The unpredictability will be discussed below.
As discussed above the claims encompass measuring the expression level of 7 different combinations of miRNA
(i) mir-146b + let-7a
(ii) mir-146b + miR-103
(iii) mir-146b + miR-125a-5p
(iv) mir-146b + let-7a + miR-103
(v) mir-146b + let-7a + miR-125a-5p
(vi) mir-146b + miR-103 + miR-125a-5p
(vii) mir-146b + let-7a + miR-103 + miR-125a-5p
Regarding these combinations the specification teaches that combination (vii) (which is also known as Feature A) was one of the best features and had the highest discriminating power between the classes. However there is no data or information provided in the specification on the ability of any of these additional features (i-vi) to discriminate between the classes. The specification teaches that 9625 features were generated and ranked with respect to their ability to discriminate. The specification is silent with respect to where features (i-vi) ranked within the 9625 tested features and if they even worked. In the absence of evidence to the contrary it is highly unpredictable which, if any, of these additionally recited features will work in the claimed methods.
Finally it is highly unpredictable if the method would work using the normalization value that is recited in the claims (normalization value = 2(N-D)). It is noted for the record that this formula is NOT the same as the formula disclosed in the specification for the normalization value. The specification teaches that the normalization value used was normalization formula=2˄(N-D) (which can also be represented by 2(N-D)). These different formulas are expected to produce very different results and it is highly likely if one were to use the claimed formula if they would get the same results that were obtained using the formula in the specification.
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 to diagnose a malignant thyroid nodule based on seven different combinations of miRNAs
(i) mir-146b + let-7a
(ii) mir-146b + miR-103
(iii) mir-146b + miR-125a-5p
(iv) mir-146b + let-7a + miR-103
(v) mir-146b + let-7a + miR-125a-5p
(vi) mir-146b + miR-103 + miR-125a-5p
(vii) mir-146b + let-7a + miR-103 + miR-125a-5p
In order to practice the breadth of the claimed invention one of skill in the art would have to obtain a large number of benign and malignant thyroid samples. Then one would have to measure the level of the four recited miRNAs in the samples. Then one would have to calculate 7 different data normalization values. Then those would have to be correlated with validation samples using an algorithm. While this type of experimentation is disclosed in the specification, the data is not provided so it would need to be repeated to see if each of the 7 combinations would work in the claimed methods. 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
12. In the response the Applicants traversed the rejection under 35 USC 112(a). It is noted that the rejections have been modified to address the claims as amended. Applicants arguments will be addressed to the extent that they still apply to the modified rejection.
The Applicants argue that normalizers Let 7a, miR-103 and miR-125a-5p all have expression values shown in the specification and are all extremely close to each other. The Applicants argue that it has been observed that whether or not the discriminator was the miR-146b, when normalizers miR-103 and miR-125a-5p alone or in combination, this confidently showed results wherein everything above 2.5 in fold change was evidenced to be malignant. As a result, any of the normalizing values obtained in the claims via the specific normalizers used have values that are very close and which repeatedly has shown that 2.5 or greater in fold change using the claimed method has proved to be highly predictable with regard to showing the presence or absence of a malignancy.
This argument has been fully considered but is not persuasive. The claimed methods encompass being able to diagnose a malignant thyroid nodule based on seven different combinations of miRNAs
(i) mir-146b + let-7a
(ii) mir-146b + miR-103
(iii) mir-146b + miR-125a-5p
(iv) mir-146b + let-7a + miR-103
(v) mir-146b + let-7a + miR-125a-5p
(vi) mir-146b + miR-103 + miR-125a-5p
(vii) mir-146b + let-7a + miR-103 + miR-125a-5p
Regarding these combinations the specification teaches that combination (vii) (which is also known as Feature A) was one of the best features and had the highest discriminating power between the classes. However there is no data or information provided in the specification on the ability of any of these additional features (i-vi) to discriminate between the classes. The specification teaches that 9625 features were generated and ranked with respect to their ability to discriminate. The specification is silent with respect to where features (i-vi) ranked within the 9625 tested features and if they even worked. It is noted that the the Applicants state that the normalizers all have similar values but they do not point to any specific teaching of this in the specification. If Applicants have data showing that these additional features (i-vi) do in fact work, they could submit this data by filing a declaration. Otherwise, in the absence of evidence to the contrary the rejection is maintained.
Further it is noted the rejection is maintained because Applicants did not address the issue with respect to the formula that is being used to detect the normalization value.
Improper Markush Rejection
13. Claims 17, 19, 21, 23, 25-27, 29, and 31 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 Groups:
(i) one to three normalizing microRNAs selected from the group consisting of hsa-let-7a, hsa-let-7b, hsa-let-7e, hsa-miR-103, has-miR-145, RNU48, and hsa-miR-125a-5p
(ii) at least one discriminating microRNA selected from the group consisting of: hsa-miR-146b, hsa-miR-181b, hsa-miR-152, hsa-miR-200b, hsa-miR-155, and has-miR-375
The Markush groupings 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 miRNAs comprise nucleotides. The fact that the miRNAs 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 used in a method of classifying thyroid nodules. Accordingly, while the different normalizing microRNAs are asserted to have the property of being equally expressed between benign and malignant thyroid samples, they do not share a substantial structural similarity essential to this activity. Accordingly, while the different discriminating microRNAs are asserted to have the property of being differentially expressed between benign and malignant thyroid samples, 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 normalizing miRNAs possess the common property of being equally expressed between benign and malignant thyroid samples. There is no evidence of record to establish that it is clear from their very nature that the recited discriminating miRNAs possess the common property of being differentially expressed between benign and malignant thyroid samples.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Response To Arguments-Improper Markush Group
14. In the response the Applicants state that the improper Markush rejection has been overcome by the present amendments. The amendments have been considered but do not overcome the rejection. This rejection could be overcome by amending the claims to recite i.e., measuring the expression level of three normalizing miRNAs, wherein the normalizing miRNAs are has-let-7a, has-miR-103 and has-miR-12a-5p and measuring the expression level of a discriminating miRNA, wherein the discriminating miRNA is has-miR-146b.
Closest Prior Art
15. The closest prior art is that of Dos Santos (Thyroid Vol 28 No 12, Epub 11/22/2018). This reference discloses a method of classifying thyroid nodules with indeterminate cytology using let-7a, miR-103, and miR-125a-5p as normalizers and miR-146b as a discriminator. Dos Santos teaches normalizing the Ct value of the discriminator candidate to the average of Ct values for the normalizers using the formula (ΔCt) = 2^(Ct average normalizers – Ct discriminator)(page 1621, col 1). This is distinct from the instant claims that require obtaining a data normalizing value of the discriminating miRNA using the formula: Normalization value= 2(N-D). As noted above, the recitation of the claimed formula is New Matter because the specification teaches using the formula: Normalization value = 2(N-D). If the claims are amended to recite the formula taught in the specification, then the claims will be rejected over 35 USC 102/103 in view of this reference. It is further noted that this reference is considered to be prior art because it was published before 2/22/2019 (the filing date of PCT/BR2019/050053). Acknowledgment is made of applicant's claim for foreign priority based on applications filed in Brazil on 2/23/2018. It is noted, however, that the foreign priority date is the effective filing date of the claimed invention IF
-the foreign application supports the claimed invention under 112(a), AND
-the applicant has perfected the right of priority by providing
-a certified copy of the priority application, and
-a translation of the priority application (if not in English).
In the instant case Applicant has submitted a certified copy of the priority application but it is not in English and the Examiner cannot determine if it supports the claimed invention. The effective filing date of the Application is considered to be 2/22/2019 which is the filing date of PCT/BR2019/050053. Further it is noted that the 102(b)(1)(A) exception would not apply because there is no evidence explaining the involvement of David Livingstone Alves Figueiredo.
16. 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