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 .
Election/Restrictions
2. Applicant's election with traverse of the species of the SNP at position 101 in SEQ ID NO: 1 in the reply filed on 06 January 2026 is acknowledged. The traversal is on the ground(s) that it would not require undue burden to search species I and species II together This is not found persuasive because the criteria for restriction under PCT Rule 13.1 and 13.2 is not based on search burden. As set forth in the restriction requirement of 21 November 2025, species I and II do not share unity of invention because the linking technical feature of methods of detecting a SNP as indicative of a metabolic syndrome was known in the prior art. Additionally, the different SNPs of species I and II have different chemical structures and thereby do not have both a common property or activity AND a common structure essential to that activity as would be required to show that the inventions are “of a similar nature.” It is also noted that a search of species I would not be fully commensurate in scope with a search of species II, and would not identify all prior art applicable to species II, and vice versa, and would require undue burden.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
3. Claims 20-25 are pending.
Claims 21 and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 20, 22 and 24-25 read on the elected invention and have been examined herein to the extent that the claims read on the elected species of methods which detect a SNP at position 101 of SEQ ID NO: 1. The claims encompass the non-elected species of methods which detect a SNP at position 101 of SEQ ID NO: 2. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
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 20, 22 and 24-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between the SNP at position 101 of SEQ ID NO: 1 (i.e., rs75397325) and metabolic syndrome. For instance, the claims recite “diagnosing metabolic syndrome in the case of the polynucleotide of step (b) in which a base at position 101 of the polynucleotide represented by SEQ ID NO: 1 is G.” As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
The claims require performing the step of “determining” the level of expression of one or more biomarkers. Neither the specification nor the claims set forth a limiting definition for "determining" and the claims do not set forth how “determining” is accomplished. The broadest reasonable interpretation of the determining step is that this step may be accomplished by reading information in a database or report to thereby ascertain the level of expression of the genes in a sample obtained from a subject. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
The claims recite “diagnosing" metabolic syndrome. Neither the specification nor the claims set forth a limiting definition for “diagnosing” and the claims do not set forth how “diagnosing” is accomplished. As broadly recited, “diagnosing” may be accomplished mentally and thus is an abstract step / process. “Diagnosing” may also be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of obtaining a sample and detecting, from the analysis of the sample, a polynucleotide are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
The claims also recite an administering step. However, this step is conditional and only occurs when the subject is diagnosed as having metabolic syndrome based on detecting the presence of a G nucleotide at position 101 of SEQ ID NO: 1. The detecting step encompasses detecting either a G or C nucleotide at position 101 of SEQ ID NO: 1. In those instances in which a C nucleotide is detected, the subject is not diagnosed as having metabolic syndrome and no administering step occurs.
Further, the claims encompass administering “an effective dose of metabolic syndrome therapeutic agent” to the subject diagnosed with the metabolic syndrome in step (c). The “metabolic syndrome therapeutic agent” is recited at a high degree of generality, covering any agent that may directly or indirectly, have any level of effect on metabolic syndrome. As broadly recited, the administering step is not a specific application of the judicial exception, but rather is merely an “apply it” limitation.
Regarding specific treatments, see MPEP 2106.04(d)(2):
When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant.
a. The Particularity Or Generality Of The Treatment Or Prophylaxis
The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead 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….
b. Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)
The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature into a practical application.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The obtaining and detecting steps are recited at a high degree of generality, covering any methods for obtaining and detecting a SNP in a sample which were well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification at e.g., para [0069] (note that paragraph numbering herein is with respect to the published application).
See also MPEP 2106.05(d) II which states 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.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
This rejection may be obviated by amendment of claim 20 to recite:
20. A method for diagnosing and treating metabolic syndrome in a subject comprising: (a) obtaining a sample comprising nucleic acids from a subject; (b) assaying the sample to detect the presence of a G allele at SNP rs75397325; (c) diagnosing the subject as having metabolic syndrome based on the detection of the G allele at SNP rs75397325; and (d) administering an effective dose of a metabolic syndrome therapeutic agent to the subject diagnosed as having the metabolic syndrome in step (c), wherein the metabolic syndrome therapeutic agent is selected from the group consisting of pitavastatin, amlodipine besylate, losartan, carvedilol, lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, fenofibrate, gemfibrozil, bezafibrate, pravafenix, ezetimibe, niacin, probucol, orlistat, lorcaserin, diethylpropion, phentermine, mazindol, phendimetrazine, lorcaserin, liraglutide, nicotinic acid and acipimox.
Improper Markush Grouping Rejection
5. Claims 20, 22 and 24-25 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 § 2117.
The Markush groupings of the SNP at position 101 of SEQ ID NO: 1 and the SNP at position 101 of SEQ ID NO: 2 and the combination 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 2117 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 2117IIA).
Herein, the recited alternative species do not share a single structural similarity, as each polymorphism has a different chemical structure in that it consists of a different nucleotide alteration that occurs at a different location in different genes (i.e., the CERS6/LASS6 gene for SEQ ID NO: 1 and the SMGS1 gene for SEQ ID NO: 2) and each polymorphism is flanked by a unique nucleotide sequence, as shown below:
Nucleotides 91-110 of SEQ ID NO: 1 catgccactt s agtaaataaNucleotides 91-110 of SEQ ID NO: 2 atttcaattt y ctacatctc
Thus, the polymorphisms do not share a single structural similarity. The only structural similarity present is that the polymorphisms comprise nucleotides. The fact that the polymorphisms comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with metabolic syndrome. Thereby, while the different polymorphisms are asserted to have the property of being diagnostic of metabolic syndrome, they do not share a single structural similarity essential to this activity.
Further, the recited polymorphisms do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that all polymorphisms 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 polymorphisms possess the common property of being diagnostic of metabolic syndrome.
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.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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 20, 22, 24 and 25 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 20, 22, 24 and 25 are indefinite over the recitation of “a polynucleotide represented by SEQ ID NO: 1” (see claim 20). This phrase is not clearly defined in the specification or the claims and there is no art recognized meaning for the phrase ‘a polynucleotide represented by.”. It is unclear as to the relationship between SEQ ID NO: 1 and the polynucleotide. For example, it is unclear as to whether the diagnosis is based on the detection of a polynucleotide consisting of 10 to 100 nucleotides that includes position 101 of SEQ ID NO: 1 and has a G nucleotide at position 101 of SEQ ID NO: 1, or if the diagnosis is based on the detection of any nucleotide at position 101 or a nearby position (e.g., position 110) of SEQ ID NO: 1, or if the diagnosis is based on detection of a polynucleotide having a G nucleotide in a sequence having an unspecified degree of identity or complementary (e.g., 10% or 20% etc.) with SEQ ID NO: 1. According, the metes and bounds of the claimed subject matter is not clear.
Claims 20, 22, 24 and 25 are indefinite over the recitation of “diagnosing metabolic syndrome in the case of” because it is not clear as to in whom or what metabolic syndrome is diagnosed. Further, the claims are indefinite over the recitation of “a subject diagnosed as the metabolic syndrome” because it is not clear as to what is intended to be meant by this phrase. This rejection may be obviated by amendment of claim 20 to recite “(c) diagnosing the subject as having metabolic syndrome…(d) administering… to a subject diagnosed as having metabolic syndrome.”
Claim 24 is indefinite over the recitation of “wherein the ceramide is” because “the ceramide” lacks proper antecedent basis. Note that claim 24 depends from claim 20 which does not recite a ceramide. It appears that claim 24 is intended to depend from (withdrawn) claim 23.
Claim 25 is indefinite over the recitation of “wherein the metabolic syndrome represents at least three symptoms” because, in the context of the claim, it is not clear as to what is meant by “represents.” That is, it is unclear as to the relationship between the metabolic syndrome and the three symptoms.
Claim Rejections - 35 USC § 112(a) - Enablement
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 20, 22, 24 and 25 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 the claimed methods comprising (in part) (a) obtaining a sample comprising nucleic acids from a subject; (b) assaying the sample to detect the presence of a G allele at SNP rs75397325; and (c) diagnosing the subject as having metabolic syndrome based on the detection of the G allele at SNP rs75397325 in step (b),
does not reasonably provide enablement for the claimed methods which encompass detecting a polynucleotide consisting of 10 to 100 consecutive DNA sequences including a single nucleotide polymorphism in which a base at position 101 is C or G in a polynucleotide represented by SEQ ID NO: 1; and diagnosing metabolic syndrome in the case of the polynucleotide of step (b) in which a base at position 101 of the polynucleotide represented by SEQ ID NO: 1 is G. 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 use the invention commensurate in scope with these claims.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
The claims are drawn to the following method:
A method for diagnosing and treating metabolic syndrome comprising: (a) obtaining an analysis sample from a subject; (b) detecting, from the analysis sample of step (a), a polynucleotide consisting of 10 to 100 consecutive DNA sequences including a single nucleotide polymorphism in which a base at position 101 is C or G in a polynucleotide represented by SEQ ID NO: 1; (c) diagnosing metabolic syndrome in the case of the polynucleotide of step (b) in which a base at position 101 of the polynucleotide represented by SEQ ID NO: 1 is G; and (d) administering an effective dose of metabolic syndrome therapeutic agent to a subject diagnosed as the metabolic syndrome in step (c).
First, the claims require detecting a polynucleotide in a sample wherein the polynucleotide consists of 10 to 100 nucleotides. At para [0068], the specification states that the sample may be “tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid or urine.” While polynucleotides consisting of short fragments of genomic DNA are sometimes present as circulating nucleic acids in fluid samples such as plasma, serum or urine, polynucleotides consisting of 10-100 nucleotides are generally not present in cellular samples, such as tissue or blood samples. The example (para [0079]) provided in the specification in which the SNPs were detected utilized a blood sample. There is no showing that the polynucleotides detected in this example consisted of only 10-100 nucleotides. The specification contemplates using primers or probes to detect target nucleic acids in a sample from the subject wherein the primers or probes may consist of 10 to 100 nucleotides. However, the claims do not recite such a limitation. Rather, the claims require that what is detected in the “analysis sample” is a polynucleotide “consisting of” 10 to 100 nucleotides. The disclosure has not established that such polynucleotides can be detected in a representative number of different sample types as diagnostic of metabolic syndrome in a subject without undue experimentation.
Secondly, the claims recite detecting “a polynucleotide consisting of 10 to 100 consecutive DNA sequences including a single nucleotide polymorphism in which a base at position 101 is C or G in a polynucleotide represented by SEQ ID NO: 1” and “diagnosing metabolic syndrome in the case of the polynucleotide of step (b) in which a base at position 101 of the polynucleotide represented by SEQ ID NO: 1 is G.” Neither the specification nor the claims provide a limiting definition for what is intended to be encompassed by polynucleotides represented by SEQ ID NO: 1. As broadly recited, such polynucleotides may have minimal sequence identity or complementarity with SEQ ID NO: 1, may be in the same gene or in a nearby gene as the sequences of SEQ ID NO: 1, and/or may include a polymorphism that share some level of linkage disequilibrium with the polymorphism at position 101 of SEQ ID NO: 1. Thus, the claims encompass detecting a significantly large genus of polynucleotides as diagnostic of metabolic syndrome, which polynucleotides are not clearly defined in terms of their complete structure or other relevant identifying characteristics.
However, the specification has not established that such a broad genus of polymorphisms can be detected in a sample from a subject as diagnostic of metabolic syndrome.
Rather, the specification teaches only that the elected species of a G allele at rs75397325 and the non-elected species of a T allele at rs12358192 were significantly correlated with the occurrence of metabolic syndrome (see Table 1). In particular, the specification (para [0090]) states:
“The 12 SNPs showed a particularly high frequency in patients with metabolic syndrome compared to a normal control, and the nucleotide sequences of the SNPs of a subject were confirmed to predict or diagnose metabolic syndrome, and a significant association with the levels of blood dihydroceramide or ceramide was confirmed to be used to predict a group at high risk of expression of blood ceramide.”
At para [0089], the specification states:
“rs75397325 was closely associated with a blood C16_ceramide concentration and a blood C20_ceramide concentration.”
The limited disclosure in the specification of SNPs correlated with metabolic syndrome is not considered to be representative of the broadly claimed genus of polynucleotides “represented by” SEQ ID NO: 1 that are to be detected as diagnostic of metabolic syndrome.
The art of identifying polymorphisms and of determining an association between polymorphism and a phenotype, such as a risk of metabolic syndrome, is highly unpredictable. Knowledge of the sequence of the CERS6 / LASS6 gene (in which the SNP at rs75397325 is present) and other genes on chromosome 2 does not allow one to predict the identity of particular polymorphisms which are diagnostic of metabolic syndrome. Polymorphisms are known to occur at a frequency of approximately 1 out of every 1000 bases in the human genome. However, there is no predictable means for distinguishing between polymorphisms which will be correlated with a given phenotype, such as risk of metabolic syndrome, and which will not be correlated with the phenotype.
It was well recognized in the art at the time the invention was made that the associations between polymorphisms and phenotypic traits are often not reproducible.
The unpredictability of establishing a correlation between a polymorphism or a haplotype and a disease is well accepted in the art.
For example, Cohen et al (Shock. 2020 March. 53(3): 256-268) teaches that recent studies suggest “that a large portion of SNP studies are not reproducible” (abstract). Cohen (p. 2) further states that:
“With approximately 4–5 million SNPs in the human genome (i.e. gene sequence variations with >1% frequency in the human population (18, 19)), the possibility of spurious SNP-disease associations is a major concern; thus, we suggest that the ultimate clinical utility of assessing particular SNPs will likely depend on validation and quality control (QC) measures. Additionally, the interplay between SNPs and pathology, physiologic responses, and pharmaceuticals all contribute to clinical outcomes.
Illustrating the crucial need for validation in SNP studies, a well-powered replication and validation study of 70 previously published studies of SNPs associated with clinical outcomes after blood or marrow transplantation found only one validated SNP of the 45 SNPs studied.”
The unpredictability in the art of detecting a polymorphism in the CERS6 gene correlated with a phenotype is further supported by the teachings of Good et al (Twin Research and Human Genetics. 2019. 22: 79-87) teaches screening for polymorphisms in chromosome 2 and particularly in the ceramide synthase 6 (CERS6) gene to identify polymorphisms correlated with type 2 diabetes. Good reports that that the T allele of rs4668106, present in intron 8 of the CERS6 gene, was significantly associated with type 2 diabetes in human subjects (p. 81, col. 2; p. 94, col. 1; and Table 1). However, Good was not able to identify any SNPs in coding or upstream sequences of CERS6 which were correlated with type 2 diabetes (p. 84, col. 1). That is, Good states:
“As the identified SNPs are intronic, we sequenced all coding regions of this gene to rule out coding polymorphisms in linkage disequilibrium with the SNPs. Sequence analysis of all 10 exons, 800 bp upstream of exon 1 and all intron/exon boundaries in four affected and four unaffected family members identified a number of genetic variations. These were screened in all pedigree members; however, none were found to be associated with T2D.”
The specification does not provide sufficient guidance as to how to predictably detect additional polymorphisms diagnostic of metabolic syndrome which are “represented by SEQ ID NO: 1.” Identification of such polymorphisms can only be accomplished by experimentation in which, for example, genome wide association studies are performed using samples from human subjects and/or a representative number of non-human subjects to screen for polymorphisms, followed by replication studies to try to identify new polymorphisms that are show a statistically significant association with metabolic syndrome. The outcome of such experimentation cannot be predicted, and such experimentation is considered to be undue.
As set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention. Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
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.
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Good et al (Twin Research and Human Genetics. 2019. 22: 79-87; cited above) teaches that the region of chromosome 2q24.3 was previously found to be strongly linked to type 2 diabetes (p. 80, col. 2). Good screened the 2q24.3 region and particularly the sequences of the ceramide synthase 6 (CERS6) gene present in this region, to identify polymorphisms correlated with type 2 diabetes. Good reports that that the T allele of rs4668106, present in intron 8 of the CERS6 gene, was significantly associated with type 2 diabetes in human subjects (p. 81, col. 2; p. 94, col. 1; and Table 1). Good also discloses other SNPs in CERS6 and their association with type 2 diabetes in Table 1. Good does not teach or suggest the presently claimed methods comprising detecting, from a sample from a subject, a polynucleotide consisting of 10 to 100 nucleotides that includes a C or G at position 101 of a polynucleotide represented by SEQ ID NO: 1 and diagnosing the subject as having metabolic syndrome when a G nucleotide is present in the polynucleotide representative by SEQ ID NO: 1.
Lee et al (KR102039529, published 01 November 2019; English translation included) teaches methods for diagnosing metabolic syndrome by detecting a polymorphism in a nucleic acid sample (e.g., p. 3 of translation). Lee teaches methods that detect a C or G nucleotide at position 1003 or position 1051 of the ADD1 gene, consisting of SEQ ID NO: 4 therein (p. 3). Lee et al identified additional SNPs in other genes that were correlated with metabolic syndrome accompanied by other risk factors including obesity, hyperglycemia, low HLD cholesterol, hypertension, hypertriglyceridemia and nonalcoholic fatty liver disease (see Tables 2-8 and p. 5 of translation). Lee et al does not teach or suggest the presently claimed methods comprising detecting, from a sample from a subject, a polynucleotide consisting of 10 to 100 nucleotides that includes a C or G at position 101 of a polynucleotide represented by SEQ ID NO: 1 and diagnosing the subject as having metabolic syndrome when a G nucleotide is present in the polynucleotide representative by SEQ ID NO: 1.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682