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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 15, 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. Any rejections or objections not reiterated herein have been withdrawn.
Claims 1-6, 9-13, 15, 17-18, and 21-22 are currently pending and have been examined herein.
Claim Rejections - 35 USC § 101
3. 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 1-6, 9-13, 15, and 17-18 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 a law of nature.
The claims recite a correlation between the expression level of the 55 OGFGT genes and a cancer selected from the group consisting of liver cancer, kidney cancer, breast cancer, lung cancer, and brain cancer. 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.
The instant claims recite abstract ideas.
The claims recite a step of “comparing” the expression level of each OGFGT in the sample to a reference level (clm 1). The “comparing” step broadly encompasses a mental processes. For example, one may “compare” the expression levels to reference levels by looking at data and thinking about whether the expression level is greater than or less than the reference level. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
The claims recite a step of “identifying” the subject as having cancer based on the expression levels of the 55 OGFGTs (clm 1). The “identifying” step broadly encompasses is that it may be accomplished by a mental processes. For example, one may “identify” the subject as having cancer by thinking about the subjects expression levels and the expression signature. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
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 “administering an anticancer treatment to the subject having cancer. This administration step is not particular, i.e., specifically identified so that it does not encompass all applications of the judicial exceptions. This step is merely instructions to apply the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.
In addition to the judicial exceptions the claims recite a step of “determining” the mRNA expression levels of a plurality of OGFGTs in a sample. This step is not considered to integrate the judicial exceptions into a practical application because it merely adds 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 a step of “determining” the mRNA expression levels of a plurality of OGFGTs in a sample. This step does not amount to significantly more because it simply appends well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The step is recited at a high level of generality. Determining the expression levels of a plurality of OGFGTs in a sample merely instructs a scientist to use any known technique for measuring expression levels. The claim does not require the use of any particular non-conventional reagents. 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 because it teaches that the additional elements are well known or commercially available. For example the specification teaches the following:
[0055] The disclosed methods include determining the expression levels of genes of interest (e.g., O-glycan-forming glycosyltransferases) in a sample. Various assays known in the art can be used to measure genes at the DNA, mRNA, or protein levels. Thus, OGFGTs can be measured at the mRNA level.
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);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
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
4. In the response the Applicants traversed the rejection under 35 USC 101. The Applicants argue that claim 1 requires a treatment step, not merely instructions to apply an exception in a generic way. They argue that Claim 1 as amended, requires administering an anticancer treatment to a subject identified as having cancer using the steps recited in claim 1, and specifies specific cancer types.
This argument has been fully considered but is not persuasive. A treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all limitations of a judicial exception. Herein the recitation of administering an “anti-cancer treatment” is not particular. Instead it is merely instructions to “apply” the judicial exception in a generic way. Thus, the administration step does not integrate the judicial exceptions into a practical application. It is noted that claims 21-22 have not been included in the rejection because they do recite “particular” treatments for cancer. The rejection could be overcome by amending claim 1 to recite the treatments listed in claim 21.
Claim Rejections - 35 USC § 112
5. 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 1-6, 9-13, 15, 17-18, and 21-22 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 1-6, 9-13, 15, 17-18, and 21-22 recite a step of “determining the mRNA expression levels of a plurality of the following 55 O-glycan forming glycosyltransferases (OGFGTs)”. The phrase “a plurality of the following 55 OGFGTs” would encompass any two, three, four, or all the way up to 55 of the OGFGTs. The claims further recite steps of “comparing the expression level of each OGFGT” and “identifying the subject as having cancer when the expression levels of the 55”. The “comparing” and “identifying” steps seem to require all 55 of the OGFGTs. Therefore the claims are confusing and the skilled artisan would not be able to determine the scope of the claims so as to avoid infringement.
Claims 1-6, 9-13, 15, 17-18, and 21-22 are rejected over the recitation of the phrases “liver cancer, kidney cancer, breast cancer, lung cancer, and brain cancer” and “cancer” in the same claim. A broad limitation (cancer) together with a narrow limitation (liver cancer, kidney cancer, breast cancer, lung cancer, and brain cancer) that falls within the broad limitation in the same claim is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. In the instant case it is unclear if the claims are limited only to liver cancer, kidney cancer, breast cancer, lung cancer, and brain cancer (in view of the preamble) or ANY cancer in view of the recitation of “as having cancer” (in the preamble) and “as having a cancer” (in the identifying step). Clarification is required.
Claims 1-6, 9-13, 15, 17-18, and 21-22 are rejected over the recitation of the phrase “identifying the subject as having a cancer when the expression levels of the 55 of”. This recitation renders the claim indefinite because it appears to be incomplete.
Claim 6 is rejected over the recitation of the phrase “wherein the expression signature is cancer type specific and/or the sample comprises cells, tissues, or a bodily fluid”. A “bodily fluid” sample encompasses blood, urine, saliva, CSF, sweat, tears, etc. It is noted that claim 1 has been amended to recite that the sample is a tumor sample. While cells and tissue can be obtained from a tumor sample, the following types of bodily fluids i.e., blood, urine, saliva, CSF, sweat, tears, etc. cannot.
Claim Rejections - 35 USC § 112
6. 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 1-6, 9-13, 15, 17-18, and 21-22 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 tumor sample from a human subject, wherein the tumor sample comprises liver, kidney, breast or lung tissue;
(b)determining in said sample, the mRNA levels of 55 O-glycan- forming glycosyltransferases (OGFGTs), wherein the 55 OGFGTs are: ST3GAL3, B3GNT3, CIGALTICI, B3GNT6, CHST1, B4GALT5, B4GALT1,GALNT8, B4GALT3, GCNT7, B3GNT7, B4GALT2, FUT5, FUT4, GALNT4, ST3GAL1, ST3GAL2, FUT11, FUT2, FUT7, GALNT3, B3GNT2, GCNT2, FUT1, B4GALT4, FUT3, B3GNT5, CHST2, GALNT2, FUT9, GCNT4, B3GNT8, GALNT13, GALNT7, GALNT1O, B3GNT9, GALNT6, CIGALTI, GALNT12, FUT10, B3GNT4, FUT6, B3GNT1, CHST4, ST3GAL4, GALNT5, ST3GAL6, GALNT1, GALNT9, GCNT1, GALNT14, GALNT11, ST6GALNAC1, GCNT3, and ST6GAL1;
(c) analyzing the mRNA levels of the 55 OGFGTs determined in (b) with a classifier that can distinguish between cancer and non-cancer samples based on the mRNA levels of the 55 OGFGTs in said sample;
(d) determining that the human subject has liver, kidney, breast or lung cancer based on the analysis in (c); and
(d) administering an anticancer treatment to the human subject that has been determined to have liver, kidney, breast or lung cancer.
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 for treating cancer in a human subject, comprising administering an anticancer treatment to the subject identified as having a cancer selected from the group consisting of liver cancer, kidney cancer, breast cancer, lung cancer, and brain cancer.
The claims state that the subject is identified as having cancer by a method comprising:
(a) determining the mRNA expression levels of a plurality of the following 55 O-glycan-forming glycosyltransferases (OGFGTs) in a tumor sample from the subject: ST3GAL3, B3GNT3, CIGALTICI, B3GNT6, CHST1, B4GALT5, B4GALT1, GALNT8, B4GALT3, GCNT7, B3GNT7, B4GALT2, FUT5, FUT4, GALNT4, ST3GAL1, ST3GAL2, FUT11, FUT2, FUT7, GALNT3, B3GNT2, GCNT2, FUT1, B4GALT4, FUT3, B3GNT5, CHST2, GALNT2, FUT9, GCNT4, B3GNT8, GALNT13, GALNT7, GALNT10, B3GNT9, GALNT6, C1GALT1, GALNT12, FUT10, B3GNT4, FUT6, B3GNT1, CHST4, ST3GAL4, GALNT5, ST3GAL6, GALNT1, GALNT9, GCNT1, GALNT14, GALNT11, ST6GALNAC1, GCNT3, and ST6GAL1. In view of the recitation of “a plurality of the following 55 OGFGTs”, the claims broadly encompass determining the mRNA expression level of any two, three, four, or up to all 55 OGFGTs. In view of the recitation of the phrase “a tumor sample”, the claims broadly encompass ANY type of tumor sample. The claims are NOT limited to liver, kidney, breast, lung, or brain tumor samples.
The claims recite a second step of comparing the expression level of each OGFGT in the sample to a reference level. The claims state that the reference levels are: (a) the expression levels in a non-cancerous sample from the subject OR the expression levels in a non-cancerous sample from one or more different subjects, wherein the non-cancerous sample is of the same tissue type as the sample from the subject; or (b) the expression levels in a cancerous sample from one or more different subjects, optionally wherein the cancerous sample is of the same tissue type as the sample from the subject.
The claims recite a step of “identifying the subject as having a cancer when the expression levels of the 55 of”. In view of the recitation of “a cancer” the claims broadly encompass ANY type of the cancer. This recitation is NOT limited to liver, kidney, breast, lung, or brain cancer. Here the claims also appear to encompass using the expression levels of the 55 OGFGTs to identify the subject as having cancer, but they do not set how this is accomplished.
Claim 11 states that the brain cancer is glioblastoma multiforme.
Claim 12 further states that the subject is diagnosed as having a subtype of Glioblastoma multiforme (GBM) selected from the group consisting of: (i) IDH wild type GBM, (ii) IDH mutant with 1p/19q co-deletion GBM, or (iii) IDH mutant without 1p/19q co- deletion GBM.
Claim 13 states that the subject is determined to have (a) lower expression levels of a plurality of OGFGTs selected from the list consisting of B3GNT3, ST3GAL4, GALNT6, ST3GAL1, B3GNT2, GCNT1, CHST4, GALNT12, GALNT5, CIGALTICI, B3GNT8, CHST2, B3GNT7, GALNT3, B3GNT9, B4GALT4, CIGALTI, GALNT7, FUT4, B4GALT1, GALNT2, B3GNT5, and GALNT4; and/or (b) higher expression levels of a plurality of OGFGTs selected from the list consisting of GALNT14 , GALNT9, ST6GALNAC1, B3GNT1, CHST1, GALNT13, FUT9, FUT3, FUT6, and FUT5 compared to the reference levels; and wherein the subject is diagnosed as having the IDH wild type subtype of GBM.
Claim 15 states that the subject is determined to have (a) higher expression levels of a plurality of OGFGTs selected from the list consisting of B3GNT3, ST3GAL4, GALNT6, ST3GAL1, B3GNT2, GCNT1, CHST4, GALNT12, GALNT5, CIGALTICI, B3GNT8, CHST2, B3GNT7, GALNT3, B3GNT9, B4GALT4, CIGALTI, GALNT7, FUT4, B4GALT1, GALNT2, B3GNT5, and GALNT4; and/or (b) lower expression levels of a plurality of OGFGTs selected from the list consisting of GALNT14, GALNT9, ST6GALNAC1, B3GNT1, CHST1, GALNT13, FUT9, FUT3, FUT6, and FUT5 compared to the reference levels; and wherein the subject is diagnosed as having an IDH mutant subtype of GBM.
Claim 17 states that the subject is diagnosed as having a IDH mutant with lp/19q co-deletion GBM or IDH mutant without lp/19q co-deletion GBM based on the expression levels of a plurality of OGFGTs comprising FUT5, GCNT2, B4GALT2, ST3GAL3, FUT4, and, B3GNT5.
Thus the claims encompass not only being able to identify a human subject with brain cancer, but further encompass determining the type of a brain cancer (GBM) and certain subtypes of GBM (IDH wild type GBM, IDH mutant with 1p/19q co-deletion GBM, or IDH mutant without 1p/19q co- deletion GBM). In view of the recitation of “a plurality of OGFGTs”, the claims do not require each of the recited genes to have lower/higher expression.
The nature of the invention requires a reliable correlation between the expression level of 55 OGFGTs and liver cancer, kidney cancer, breast cancer, lung cancer, and brain cancer (including subtypes of brain cancer).
Teachings in the Specification and Examples
The specification (Example 1) teaches that 55 OGFGTs were used a develop a classifier to distinguish normal and cancer tissue, cancer type and subtype, and predict likelihood of survival.
The specification (0179) teaches that the model classifier that can distinguish between cancer and non-cancer tissue samples based on the expression profiles of a curated-set of 55 GT genes was developed. To this end, RNA sequencing data from The Cancer Genome Atlas (TCGA) incorporating 6 different cancer types for which tumor and matched-normal samples were available (n=944) breast invasive carcinoma (BRCA, n=224), pan-kidney cohort (KIPAN, n=258), kidney renal cell carcinoma (KIRC, n=144), liver hepatocellular carcinoma (LIHC, n=100), lung adenocarcinoma (LUAD, n=116) and lung squamous cell carcinoma (LUSC, n=102), was used.
The specification (para 0181) teaches that unsupervised hierarchical clustering was thereby performed individually on each cancer type (FIG. 2A-F) and using the set of 55 OGFGTs, each cancer type was reliably clustered into two distinct groups of normal and tumor samples (FIG. 2G and FIGS. 1C-F). Similarly, the linear discriminant analysis (LDA) showed significant separation between the normal and tumor samples across the six cancer types. Importantly, LDA not only illustrated the ability of OGFGT genes to distinguish between normal and tumor samples in each cancer type independently (FIG. 2A-F, right), but it was also able to distinguish between the normal and tumor labels collectively regardless of the cancer type (FIG. 2H). The OGFGTs were able to distinguish between the different tissue types (i.e. liver, kidney, breast, lung) as well as between the cancer and the non-cancer samples within each tissue type.
The specification (para 0182) teaches that the relative importance of the classifying features using the area under the receiver operating characteristic (ROC) curve (AUROC) in identifying the cancer type and the normal-tumor label (FIG. 2J) showed that some OGFGTs were of relatively high importance in all cancer types while the importance of other O-glycan GTs were cancer-type-specific. For example, FUT5, B3GNT7, ST3GAL1, FUT11, GALNT3, B4GALT3, and others were of high importance across all types of tested solid tumors while B4GALT3, FUT5, FUT11, ST3GAL1 and others were of particular importance in discriminating between cancer and non-cancer samples in kidney (or liver or lung).
The specification (para 0185) further teaches that they investigated whether similar alterations in OGFGTs take place in different cancer types or whether OGFGTs alter their expression levels in a cancer-type-specific manner OGFGTs expression profiles across a wide array of 23 cancer types from the TCGA dataset was compared (FIG. 3). Unsupervised hierarchical clustering of 11015 samples was performed (FIG. 3A, FIG. 3E) and it revealed that the OGFGT genes exhibited distinct expression profiles across the different cancer types. Therefore a model classifier using these OGFGT genes was developed. The model was able to reliably classify cancer samples into distinct cancer types.
The specification (para 0187) teaches that the accuracy of predicting a specific cancer type depends on high dimensional combinations of OGFGT genes, and not simply on single OGFGT genes, in order to identify cancer-type-specific expression signatures. It is believed that this is the first study to show that this curated set of O-glycan GT genes can predict both cancer state (i.e. cancer or normal) and type.
The specification (para 0189) teaches that the inventors also investigated the ability of the OGFGT genes to classify cancer subtypes in GBM was investigated.
The specification (para 0190) teaches that the OGFGTs were able to separate the glioblastoma samples into two major groups in line with their clinical annotation (IDHwt and IDHmut) (FIG. 4A). The IDHmut cluster could be classified further into 3 clusters: two corresponding to IDHmut-non-code1 while the third corresponding to IDHmut-code1 (FIG. 4A). Using hierarchical clustering, the OGFGT genes clustered the samples into 4 clusters (G1-4) depending on OGFGT expression (FIG. 4A). Moreover, multi-dimensional scaling (MDS) using PCA and LDA analyses illustrated that the OGFGT genes were able to cluster the glioblastoma samples into their respective clinical subtypes (FIG. 6A-B).
State of the Art and the Unpredictability of the Art
While methods of measuring expression levels are known in the art, methods of correlating expression levels with a phenotype such as cancer are highly unpredictable. The unpredictability will be discussed below.
As discussed above, the claims broadly encompass determining the mRNA expression level of any two, three, four, or up to all 55 OGFGTs. However it is highly unpredictable if one could identify subjects having cancer based on detecting subcombinations of the combination of the 55 OGFGTs. In the instant case the specification does not disclose the expression level of any single OGFGT gene. The specification does not disclose the AUC, sensitivity or specificity of using any combination of two or more of the OGFGTS to detect the claimed cancers. In the absence of evidence to the contrary it is highly unpredictable which subcombinations of markers, if any could function in the method. The specification only provides support for a method wherein a classifier comprising all 55 OGFGTs is used.
To the extent that the claims are not limited to liver, kidney, breast, lung, or brain cancer, it is relevant to point out that it is highly unpredictable if one could extrapolate the findings in the specification with these cancers to other types of cancer. Xu (PloS ONE October 2010 Vol 5 Issue 10 e13696 pages 1-8) teaches that they sought out to identify genes that could be used as indictors for cancer in general or for a group of cancers. They examined differentially expressed genes with at least 2 fold changes between cancer and corresponding control tissues across seven different cancer types (breast, colon, kidney, lung, pancreas, prostate, stomach). Only 85 genes were differentially expressed across 3 cancer types, 19 genes were differentially expressed across four cancer types, and 5 genes were differentially expressed across five cancer types (page 5). Thus it is highly unpredictable as to whether the findings in the specification regarding the 55 OGFGTs with liver, kidney, breast, lung, or brain cancer could be extrapolated to any of the other greater than 100 different cancers known in the art.
The claims encompass identifying a subject having liver, kidney, breast, lung, or brain cancer based on the expression level of the OGFGT genes in ANY type of tumor sample. However the specification only provides analysis of expression levels in tumor samples and normal-matched samples comprising liver, kidney, breast, lung, or brain. The prior art of Whitehead (Genome Biology 2005 Vol 6 Issue 2 Article R13) teaches that variation in gene expression is extensive among tissues (abstract). Whitehead further teaches that many different cancers have unique tissue specific patterns of gene expression (page 1, col 2). The specification teaches that OGFGTs are differentially expressed in breast tumor tissue compared to normal breast tissue. However there is no evidence that these OGFGTs would also be differentially expressed in other tumor types of a subject with breast cancer. The specification only provides support for the analysis of tumor tissue and normal-matched samples.
Regarding Claims 13, 15, and 17 it is noted that the claims broadly encompass diagnosing glioblastoma subtypes based on having lower or higher expression levels of a plurality of recited OGFGTs. In the instant case the specification does not disclose the expression level of any single OGFGT gene in any of the glioblastoma subtypes. In the absence to evidence to the contrary it is highly unpredictable if for example, B3GNT3, ST3GAL4, GALNT6, ST3GAL1, B3GNT2, GCNT1, CHST4, GALNT12, GALNT5, CIGALTICI, B3GNT8, CHST2, B3GNT7, GALNT3, B3GNT9, B4GALT4, CIGALTI, GALNT7, FUT4, B4GALT1, GALNT2, B3GNT5, and GALNT4 all have decreased expression in subjects diagnose with the IDH wild type subtype of GBM. Further it is highly unpredictable if one only had decreased expression of one, two, three, four, or more of these markers if they would actually have the IDH wild type subtype of GBM.
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 ANY type of cancer (and particularly liver, kidney, breast, lung or brain cancer) based on the mRNA level of two, three, four, or more up to all 55 OGFGT genes in ANY type of tumor sample.
In order to practice the breadth of the claimed invention one of skill in the art would first have to gather samples from human subjects having liver, kidney, breast, lung or brain cancer plus a representative number of other cancers. The samples would need to include different types of tumor tissue. Then the mRNA levels of the 55 OGFGTs would have to be measured. Then sophisticated data analysis would need to be performed to see which subcombinations, if any, can reliably be used to identify a subject with cancer. 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
7. In the response the Applicants traversed the rejection under 35 USC 112(a). The Applicants note that claim 1 has been amended to specify that the subject is human and that the sample is a tumor sample. The Applicants argue that the enablement requirement does not preclude experimentation, so long as the experimentation is not undue.
The amendments to the claims have been fully considered but do not overcome the rejection. As discussed in the rejection above, the amended claims still contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. It would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed. Thus the rejections are maintained.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682