DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of group I, Alzheimer’s and SYNPO in the reply filed on 8/14/26 is acknowledged.
Claims 8-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/14/26.
Claim Rejections - 35 USC § 101
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 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) a method of determining a type of neurodegenerative disease comprising measuring a naturally occurring marker and correlating it to a disease state. This judicial exception is not integrated into a practical application because the claims do not require any additional steps. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Analysis, step 1: The claims are directed to a method, which is a statutory category of invention.
Analysis, step 2A, prong 1: The claims recite a judicial exception, a natural phenomenon. The claims are directed to assaying for a naturally gene-associated cfRNA in a biological sample and correlating it with the presence of a neurodegenerative disease. This is a natural correlation, and it existed in the body before people had discovered it. It is a natural phenomenon. The claims recite determining the presence of any neurodegenerative disease by mere detection of one of any naturally occurring gene-associated cfRNAs. This limitation sets forth a judicial exception because 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. Additionally, the correlation could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams). Thus, the claim is directed to at least one exception, which may be termed a law of nature, an abstract idea, or both.
Analysis, step 2A, prong 2: In instant case, the method steps of (a) obtaining a sample from a subject, and (b) detecting the presence of a gene associated cfRNA consist of well understood, routine, conventional activity already engaged in by the clinical community (see Ibanez et al. (Alzheimer’s Dement. 2020;16(Suppl. 4):e043273, page 1) that teaches detection of cfRNA in a biological sample and correlation to Alzheimer’s). Collecting a sample and detecting the presence of the naturally occurring marker are insignificant and amounts to mere data gathering.
Finally, the claims do not recite any additional method steps. Thus, the claims as a whole do not integrate the recited judicial exception into practical application.
Analysis, step 2B: The claims recite detection at a high level of generality of a naturally occurring marker and correlation to a disease state, which amount to mere data gathering and routine laboratory techniques. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claims as a whole do not amount to significantly more than a generic instruction to “apply” the judicial exception. Thus ,the instant claims do not amount to significantly more than the judicial exception itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 112
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 1-7 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.
Claim 1 requires determining the type of neurodegenerative disease “based on” the level of the at least one gene-associated cfRNA. The metes and bounds of the limitation “based on” are not definite because it does not set forth any specific method step. It is unclear what method step is required to determine the type of neurodegenerative disease that is vaguely “based on” any possible level of the gene-associated cfRNA.
Claim 6 requires for the determining not to be based on a level of amyloid beta in the subject. It is unclear what specific method step is being excluded for the determining not to be “based on” any level of amyloid beta.
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 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to a method of determining any type of neurodegenerative disease in a subject comprising providing any biological sample from the subject and measuring a level of at least one of any “gene-associated” cfRNA in the biological sample and determining the type of neurodegenerative disease “based” on the level of the gene-associated cfRNA.
The specification does not adequately describe the structure required for the function of the cfRNA that has any association to any gene. Without further description of the structure required for the function, one would not be able to readily envision which cfRNAs have any possible association to any possible gene and meet the limitation of being a “gene-associated cfRNA”.
Additionally, the specification does not adequately describe the step required for determination of the disease type “based on” the level of the gene-associated cfRNA. The specification does not adequately describe if the level of the cfRNA needs to be above or below any specific value or amount to result in determination of the type of neurodegenerative disease.
The specification does not adequately describe what specific step is excluded by recitation of the determining not being “based on” any level of amyloid beta in the subject.
The specification does not adequately describe what is meant by the subject has an “APOE genotype risk factor for AD”. The specific genotype required has not been adequately described.
Bruno et al. (Brazilian Journal of Medical and Biological Research (2020) 53(10): e9881, 1-15) teach: cfRNAs can be classified as protein-coding (mRNAs) or non-coding RNAs. Non-coding RNAs are further classified according to size as small non-coding RNAs (sncRNAs), including microRNAs and lncRNAs (35,36). The most recent studies that investigated the application of cfRNAs as biomarkers in plasma and serum have focused on non-coding RNAs, especially microRNAs (page 6).
Bruno et al. is evidence that “cfRNA” encompasses an enormous possible genus of possible RNAs including miRNAs. The specification does not adequately describe which species have been associated to any gene in any manner and have the structure to function as any neurodegenerative disease determinant.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To achieve the desired function, it appears that the structure is required to be specific cfRNAs wherein the expression of the specific cfRNA has been shown to have specific parameters of expression to be correlated to a specific disease state. These species are not representative of the entire claimed genus.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for within the instant enormous genus that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 1-7 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 determining Alzheimer’s disease comprising detecting specific cfRNAs of the specification, does not reasonably provide enablement for a method of determining nay possible type of neurodegenerative disease via measuring any level of any gene associated cfRNA and making the determination based upon any level. 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.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method of determining nay possible type of neurodegenerative disease via measuring any level of any gene associated cfRNA and making the determination based upon any level.
The specification does not draw an adequate nexus between measuring any level of any possible cfRNA with any possible association to any gene and the predictable outcome of determination of any type of neurodegenerative disease.
The specification demonstrates detection of minimal species of cfRNAs that have been correlated to Alzheimer’s disease, which is not commensurate in scope with a method of determining nay possible type of neurodegenerative disease via measuring any level of any gene associated cfRNA and making the determination based upon any level.
The claims are directed to a method of determining any type of neurodegenerative disease in a subject comprising providing any biological sample from the subject and measuring a level of at least one of any “gene-associated” cfRNA in the biological sample and determining the type of neurodegenerative disease “based” on the level of the gene-associated cfRNA.
The claims encompass detection of any possible cfRNA, for example a specific cfRNA that has been correlated with Alzheimer’s disease, and the determination of another type of neurodegenerative disease. The claims are not limited to detection of any specific cfRNA and the determination of any specific neurodegenerative disease. The specification is not enabling for measuring any possible cfRNA with any association to any gene and the predictable determination of any type of neurodegenerative disease.
For example, Ibanez et al. (Alzheimer’s Dement. 2020;16(Suppl. 4):e043273, page 1) teaches detection of specific cfRNAs in a biological sample and correlation to Alzheimer’s (instant claims 1 and 2), which is not commensurate in scope with measuring any level of any cfRNA with any association to any gene and the predictable outcome of determining any type of neurodegenerative disease.
Bruno et al. (Brazilian Journal of Medical and Biological Research (2020) 53(10): e9881, 1-15) teach that cfRNA may show specific expression profiles in different biofluids and distinct bio logical states and/or disorders (page 6). Bruno et al. is evidence that detection of any possible cfRNA associated to any possible gene is not substantial enough to determine any neurodegenerative disease. Bruno et al. teaches that specific cfRNAs “may” have a specific expression pattern in a specific disease state. The instant claims are not directed to detection of any specific cfRNA expression pattern and the presence of any specific disease state that has been enabled.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of measuring any cfRNA associated in any manner to any gene and predictably determining any type of neurodegenerative disease.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether measuring any possible cfRNA associated in any manner to any gene by the broadly disclosed methodologies of the specification would predictably determine any type of neurodegenerative disease. Without further guidance, one of skill in the art would have to practice a substantial amount of trial-and-error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ibanez et al. (Alzheimer’s Dement. 2020;16(Suppl. 4):e043273, page 1).
Ibanez et al. teaches detection of cfRNA in a biological sample and correlation to Alzheimer’s (instant claims 1 and 2).
Ibanez et al. teaches: Background: Alzheimer’s disease (AD) is inexorable, incurable, and in many cases very difficult to diagnose before symptom onset. Thus, there is a clear need to develop tools to detect the pathological changes that occur before clinical symptoms onset. Historically, proteins have been the preferred biomarker. However, biofluids also contains ribonucleic acid in its free form (cfRNA). The source of cfRNA in plasma is not fully understood, but it is thought to be the result of normal cell death throughout the body, thus providing a mirror of the status of a normal functioning body. Therefore, if some organs are functioning incorrectly, we can detect it by changes in cfRNA. To date, several species of cfRNA have been investigated as biomarkers for cancer, fetal development and AD. In here we tested plasma cell-free RNA species as biomarker for AD diagnostic (instant claims 1, 2, and 7).
Ibanez et al. teaches: Method: We generated cfRNA-Seq data from a discovery dataset (ten pathologically confirmed AD cases and ten sex, age and APOE genotype matched controls) and a replication dataset containing samples at different stages of the disease and controls (N=80) not matched by sex or APOE. Standard quality control and alignment pipeline for RNA seq data was used. Gene expression was quantified with Salmon and corrected by library complexity and log transformed prior to analysis. Predictive models were built using the wrapper algorithm Boruta and the machine learning tool Tensorflow to define the optimal number of RNA transcripts (instant claims 3).
Ibanez et al. teaches: Results: Transcriptome-wide principal component analyses show that cfRNA reflect significant differences between cases and controls (46% of variance explained, p=0.001). Using machine learning, we identified a set of 24 genes that perfectly predicts cases in the discovery dataset. In the replication dataset, the area under the ROC curve for the model with APOE and sex was 0.84 for advanced clinical stage (CDR=1), 0.82 for early stages (CDR=0.5) and 0.86 for presymptomatic. Exclusion of APO E genotype in the predictive model drastically affected the predictive power (instant claim 4).
Ibanez et al. does not teach measuring amyloid beta (instant claims 5 and 6).
Ibanez et al. teaches: Conclusion: Cell-free RNA is a promising biomarker for AD with an accuracy comparable to the one obtained using CSF biomarkers. This non-invasive approach can provide new biomarkers or screening tool for AD.
Therefore, the claims are anticipated by Ibanez et al.
Conclusion
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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