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 .
Election/Restrictions
Applicant's election with traverse of MiRNA 151a-5p, L1CAM/CD171, L-serine and without traverse, ALS in the reply filed on 4/21/2023 is acknowledged. Upon further consideration and in view of the prior art, the species requirements for these specific groups are withdrawn.
Claims 1-2, 4, 7-8, 10-19 and 22 are under consideration in the instant Office Action.
Modified Rejections Necessitated by Amendment
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, 4, 7-8, 10-19 and 22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring correlation without significantly more. The claims recite a natural correlation based on the levels of micro RNA from neural-derived exosome fraction from a sample and amyotrophic lateral sclerosis. This judicial exception is not integrated into a practical application because the claimed method only observed this natural correlation. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it reads on a natural correlation of the levels of micro RNA and amyotrophic lateral sclerosis (ALS).
The subject matter eligibility under 35 U.S.C. 101 of natural products (i.e., whether the claimed product is a non-naturally occurring product of human ingenuity that is markedly different from naturally occurring products) was confirmed by the U.S. Supreme Court decisions including Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. _, 133 S. Ct. 2107, 2116, 106 USPQ2d 1972 (2013), and Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. _, 132 S. Ct. 1289, 101 USPQ2d 1961 (2012). "[L]aws of nature, natural phenomena, and abstract ideas" are not patentable. Diamond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. __, __ (2010) (slip op., at 5). "Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work." Gottschalkv. Benson, 409 U. S. 63, 67 (1972).
In brief, in Prometheus, a method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder is the focus. This method comprises a) administering 6-thioguanine to patients and b) determining the level of 6-thioguanine in the patients and c) correlate the level of 6-thioguanine, i.e. a certain level/red blood cells, with the decision whether a need for increase or decrease the amount of 6-thioguanine treatment in said patients.
In Prometheus, the Court found that "[i]f a law of nature is not patentable, neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Additionally, "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law". Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at __ (slip op., at 14) ("[T]he prohibition against patenting abstract ideas 'cannot be circumvented by’..., adding 'insignificant post-solution activity'" (quoting Diehr, supra, at 191-192)).
The Court also summarized their holding by stating "[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."
Thus, if the claim recites or involves a judicial exception, such as a law of nature/natural principle or natural phenomenon (e.g., the law of gravity, F=ma, sunlight, barometric pressure, etc.), and/or something that appears to be a natural product (e.g., a citrus fruit, uranium metal, nucleic acid, protein, etc.), then the claim only qualifies as eligible subject matter if the claim as a whole recites something significantly different than the judicial exception itself.
In the instant case, based upon an analysis with respect to the claim as a whole, claims 1, 4 7-8, 10-19 and 22 are determined to be directed to judicial exception without significantly more. The rationale for this determination is explained below in view of controlling legal precedent set forth in 2014 Interim Guidance on Patent Subject Matter Eligibility (79 FR 74618) dated December 16, 2014 and 2019 Revised Patent Subject Matter Eligibility Guidance (84 FR 50) dated January 07, 2019.
The instant claims 1, 4, 7-8, 10-19 and 22 encompass a process. (Step 1: Yes).
Next, Step 2, is the two-part analysis from Alice Corp. (also called the Mayo test) to determine whether the claim is directed to laws of nature, natural phenomena, and abstract ideas (the judicially recognized exceptions). (In Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014) the Supreme Court sets forth a two-step test for determining patent eligibility. First, determine if the claims encompass a judicial exception (a natural phenomenon/law of nature/abstract idea). If so, then ask whether the remaining elements/steps, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to ‘“transform the nature of the claim’ into a patent-eligible application.” Id. at 2355 (quoting Mayo, 132 S. Ct. at 1297). Put another way, there must be a further “inventive concept” to take the claim into the realm of patent eligibility. Id. at 2355. In the recent Myriad v Ambry case, the CAFC found claims (drawn to methods comprising obtaining tissue samples, analyzing sequences of cDNA and comparing germline sequences of a gene to wild-type sequences) to encompass the abstract mental processes of ‘comparing’ and ‘analyzing’. Recitation of specific techniques (in Myriad claims 7 and 8 further recited hybridization and PCR) were deemed not “enough” to make the claims patent-eligible since the claims contained no otherwise new process. The elements/steps recited in addition to the judicial exception did nothing more than spell out what practitioners already knew). The instant claims encompass the human micro RNA and changes in the levels of these micro RNA levels in the pathology of ALS, the process that is governed by a law of nature, and thus is a judicial exception. The human micro RNA are naturally occurring factors, which, as evidenced by the claims and the specification as filed, are present naturally within the samples obtained from the subjects suffering from ALS. Thus, the relation between the presence and levels of micro RNA and pathology of ALS exists in principle and is a consequence of the ways these factors are metabolized by the body, entirely natural process, a natural phenomenon, and thus a judicial exception (Step 2A/1: Yes). Next, prong two of Step 2A requires identifying whether there are additional elements recited in the claim beyond the judicial exception(s) and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. “Integration in to a practical application” requires an additional element or combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such as the claim is more than a drafting effort designed to monopolize the exception. In the instant case, the claims do not recite any additional elements to integrate the judicial exception into a practical application because all the steps of the claimed methods are limited to only those that measure naturally occurring factors during a naturally occurring pathology. (Step 2A/2: No). The second step is determining if the claims recite or involve judicial exceptions, such as laws of nature, natural phenomena, or natural products. In this case, the claims involve a natural correlation: the human micro RNA and natural correlation of these miRNA and ALS. In the next step, it must be determined if the claim as a whole amounts to something significantly more than the judicial exception. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Claims 1, 4, 7-8, 10-19 and 22 fail to include any limitations which would distinguish the method because they do not recite any elements, or combinations of elements to ensure that the claim as a whole amounts to significantly more than the judicial exception because the active steps of the claims – collecting biological samples, measuring the amount miRNA − represent routine steps that are recited at a high level of generality and encompass well-understood and purely conventional routine techniques in the art, as shown by the prior art, such as Katsu et al., 2019 (11/1/2023, IDS), Chou US2018/0356405 (5/24/2023, PTO-892), Mitsuhashi US2019/0361037 (5/24/2023, PTO-892) and Viswambharan et al., 2017 (5/24/2023, PTO-892) and JP641049 (9/23/2021, IDS) teaches that the claimed miRNA occur naturally in nature and are effective in diagnosing neurodegenerative and motor disease including ALS. The claims encompass diagnosing or monitoring ALS by determining the levels of specific miRNA. This is the judicial exception itself. There are no steps in addition to the judicial exception, as the comparing and diagnosing steps can be mental processes and are simply drawn to the observance of nature. There is no indication of particular levels to detect and the steps do no more than describe the correlation with the instructions to “apply it” when they recite the step of administering a therapeutic ALS drug. There are no elements that include a particular machine or transformation as no specific machine is required and the information obtained is not transformed into anything useful for a different purpose, i.e., the claim amounts to data gathering. There are no features in addition to the exception that are more than purely conventional or routine in the art. On the other hand, there is a high level of generality, which also supports the conclusion that in order to use the judicial exception (the correlation) others are required to somehow detect these miRNA and ALS and draw a conclusion about their correlation.
The instant claims only require the naturally occurring correlation to be observed by applying the known methods in the art. The instantly rejected claims do not recite any elements in addition to the natural correlation that impose meaningful limits on the claim scope and would substantially foreclose others from using this natural correlation of the levels of miRNA and ALS without significantly more. The intended use of this method does not further limit or apply any significant action once the natural correlation has been observed using the claimed method. The natural correlation is found in nature whether it is observed or not and would be present and act quite independently of any effort of the patentee.
Note that recited miRNA for the natural correlation are natural products and as such cannot add significantly more to satisfy step 2B (Step 2B: No).
Thus, for reasons fully explained above, claims 1, 4, 7-8,10-19 and 22 do not satisfy the requirement of 35 U.S.C. 101 and are therefore rejected.
Response to Arguments
Applicant's arguments filed 11/3/2025 have been fully considered but they are not persuasive. Applicant argues that the new amendments to the instant claims that now require obtaining miRNA from a neuronal-derived exosome fraction from non-ALS subjects with L1CAM antibody and performing PCR no longer reads on a natural correlation. Applicant argues that since they have to manipulate and detect certain specific miRNA that this no longer reads on natural correlation since they are not using a signal from a sample with no manipulation. The applicant argues that this is more than the recitation of a natural correlation. This is not found persuasive because the 101 rejection is dependent on a natural correlation. The active steps of determining the natural correlation does not overcome the 101 rejection. The act of obtaining baseline levels of miRNA in non-ALS subjects and potential ALS subjects is still part of observing the natural correlation since it is just providing a baseline of what occurs in nature when the disease is not present and then compare it to the levels in a potential ALS subject to make the determination of the disease presence by using the natural correlation of the changes of in non-ALS to ALS subjects. The new claim limitations only go into further details for the methods of observing the natural correlation and the methods used are all routine and conventional as attested by all of the references set forth above as prior art. Claims 1, 4, 7-8, 10-19 and 22 fail to include any limitations which would distinguish the method from routine and conventional methods of measuring miRNA in ALS subjects. The instant claims do not recite any elements, or combinations of elements, to ensure that the claim as a whole amounts to significantly more than the judicial exception because the active steps of the claims – collecting biological samples, isolating miRNA from a neural-derived exosome fraction from subjects, measuring the amount of miRNA − represent routine steps that are recited at a high level of generality and encompass well-understood and purely conventional routine techniques in the art, as shown by the prior art, such as Katsu et al., 2019 (11/1/2023, IDS), Chou US2018/0356405 (5/24/2023, PTO-892), Mitsuhashi US2019/0361037 (5/24/2023, PTO-892) and Viswambharan et al., 2017 (5/24/2023, PTO-892) and JP641049 (9/23/2021, IDS). These references teach that the claimed miRNA occur naturally in nature and when observed or detected are effective in diagnosing neurodegenerative and motor disease including ALS. The claims encompass diagnosing or monitoring ALS by determining the levels of specific miRNA. This is the judicial exception itself. There are no steps in addition to the judicial exception, as the comparing and diagnosing steps can be mental processes and are simply drawn to the observance of nature. The issue is that the rejected claims only call forth the natural correlation and do actually apply the natural correlation in a practical application that is not already routine and conventional in the prior art. A practical application is not a specific method of observing the natural application but what one of ordinary skill in the art would apply after determining if natural correlation is present, like administering certain treatments or modifying the treatment to the identified patient population.
Therefore, the applicant’s arguments are not found persuasive and the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4, 7-8, 10-19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Mitsuhashi US2019/0361037 (5/24/2023, PTO-892), Katsu et al., 2019 (11/1/2023, IDS), Ricci et al., 2018 (IDS) and JP641049 (IDS) in view of Viswambharan et al., 2017 (5/24/2023, PTO-892).
Mitsuhashi teaches methods of quantifying subpopulations of exosomes and using them as a diagnostic and prognostic methods for neurodegenerative disorders that include amyotrophic lateral sclerosis (ALS, see paragraphs 3, 5-6). Mitsuhashi teaches that the exosomes are obtained from a human plasma biological sample and detecting one of more biomarkers in the biological sample wherein the biomarkers is the level of one or more micro RNA (see paragraphs 9, 12 and 92) as in instant claims 1, 4, 10 and 22. Mitsuhashi teaches that the exosomes are neural-derived exosomes (aka neuron-derived, astrocyte-derived, microglia derived exosomes, see paragraphs 6, 8-9, 12, 36-37, 43) as in instant claims 1, 4, 7 and 22. Mitsuhashi teaches using their methods to identify a subject at risk of a neurodegenerative disorder and prescribing a therapeutic regimen (see beginning of paragraph 11 and 12) as in instant claims 1-2, 11, 17-19, 22. Mitsuhashi teaches using exosome biomarkers that include CD81, CD63 and CD9 (see paragraphs 6, 8) which encompasses the tretraspanin of claims 14 and 15. Mitsuhashi teaches that the exosome surface markers include CD81, CD63, CD9 and CD171 to isolate neural-derived exosomes (see paragraphs 9, 13 and 45) as in instant claims 14-16. Mitsuhashi teaches using PCR to quantify gene expression changes (see paragraph 52) as now required in instant claims 1 and 22. While Mitsuhashi teaches neural-derived exosomes and that they contain micro RNA, Mitsuhashi fails to specifically teach the specific miRNA of claims 1 and 22.
Katsu teaches isolated neuron-derived extracellular vesicles (EVs) in plasma by immunoaffinity purification and comprehensively analyzed their miRNA expression profiles using microarray as biomarkers for early diagnosis and monitoring of disease progression in ALS subject (see abstract) as in instant claims 1 and 22. Katsu teaches that these sample come from blood (see page 1, 1st column) as in instant claim 4. Katsu teaches using anti-human CD171 (L1CAM) antibodies to capture EVs and also teaches using CD63 and CD81 EV specific markers to confirm the capture of the target EVs (see section 2.2 Isolation od neuron-derived EVs in plasma) as in instant claims 1, 4, 7, 14-16 and 22. Katsu teaches that miRNA in neuron-derived EVs are very useful diagnostic biomarkers and should be validated by PCR (see page 6, 1st column) as in instant claims 1 and 22.
Ricci teaches using microRNAs as biomarkers in Amyotrophic Lateral Sclerosis (ALS) since miRNA are remarkably stable in human body fluids and reflect physiological and pathological process for ALS (see Abstract and page 3). Ricci teaches that the only approved drug treatment for ALS is riluzole (see page 2, section 1.2) as required in instant claim 2. Ricci teaches that the miRNA can be obtained from human biological samples in blood found in serum exosomes, extract miRNA and used different tools to detect miRNA to determine the clinical biomarkers in ALS (see Figure 1, page 5: page 7, section 4.2 and page 9, 4th paragraph) as required in instant claims 1, 4, 10, 14 and 22. Ricci teaches that the exosomes are double lipid vesicles secreted by a variety of cells and reflect physiological and pathological process for ALS (see page 9, 4th paragraph) as in instant claim 4. Ricci teaches that there are many miRNA levels are altered in the ALS populations and that the miRNA include miR-146a, miR-146a-3p, miR-151a-5p, miR-10b-5p, miR-199a (see table 1; table 2, page 8; table 4 and table 5) as in instant claims 1 and 22. Ricci further teaches that using multiple biomarker combinations for miRNA for ALS will produce a better signature for the ALS disease (see page 11, 1st paragraph) which would motivate one of ordinary skill in the art to use multiple miRNAs to identify ALS subjects as required in instant claims 1, 8, 12-13, 17.
JP641049 teaches using micro RNA (miRNA) to detect the presence of ALS as in instant claims 1 and 22. JP641049 teaches monitoring the levels of different miRNA, including miRNA-151-3p, before and after drug administration and determining the levels of miRNA in ALS patients and control (human patients) in their example 1 and reads on instant claims 1-2, 10, 12-13 and 22. JP641049 fails to teach obtaining the miRNA from neural-derived exosomes.
Viswambharan teaches early treatment is crucial for neurodegenerative diseases including ALS and therefore, there is an urgent need for specific and sensitive biomarkers for early diagnosis for these neuro degenerative disorders (see abstract). Viswambharan teaches that ALS subjects have miR-146a, one of claimed miRNA is elevated in ALS subjects (see page 156, 2nd column, 2nd paragraph) as in instant claims 1 and 22. Viswambharan teaches that other neurodegenerative disease like Alzheimer’s, Parkinson’s and Huntington’s diseases also express aberrant miRNA which include miR-146a-5p, miR-151-3p, miR-151-5p, miR-146a, miR29a/b, miR-199a-3p, miR-199a-5p and miR-10b-5p (see Tables 1-3) as in instant claims 1 and 22.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Mitsuhashi, Katsu, Ricci, JP641049 and Viswambharan. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Mitsuhashi, Katsu, Ricci, JP641049 and Viswambharan all teach the ability of miRNA extracted from exosomes as good biomarkers for neurovegetative diseases like Alzheimer’s disease, Parkinson’s disease and ALS. Katsu teaches the method of isolating the EVs with L1CAM antibodies. Ricci specifically teaches that miRNA extracted from exosomes as good biomarkers for ALS subjects. Therefore, one of ordinary skill who would wish to identify ALS early on before deleterious effects would be motivated to use these known protein miRNA, derived from neuronal exosomes, to determine the status of a ALS patient population. All prior art references provide guidance on what specific miRNA to quantify to be able to determine ALS status in possible patient population since Ricci, Viswambharan and JP641049 have already shown that there are altered miRNA levels such as, miR-146a and miRNA-151-3p, in ALS subjects. The teachings of Ricci provide many other miRNA proteins have been shown to be altered in ALS and use these levels to monitor the progression of ALS over time and treatment plans. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because one of ordinary skill in the art would be motivated to treat ALS subjects once diagnosed to treat and alleviate symptoms and one would use the known treatments for ALS such as the treatment taught by Ricci. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4, 7-8, 10-19 and 22 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18/974,425 in view of Katsu et al., 2019 (IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘425 claims a method of identifying a subject with ALS by measuring the amount of micro-RNA in a subjects blood sample but measuring two or more miRNA of miR-199a-3p, miR-4454, miR-10b-5p, miR-151a-5p, miR-199a-5p, miR-151a-3p, miR-146a-5p, and miR-29b-3p, and treating it with L-serine and riluzole. ‘425 fails to teach the specific method of isolating the EVs as set forth in the instant claims. This is remedied by the disclosure of Katsu. Katsu teaches isolated neuron-derived extracellular vesicles (EVs) in plasma by immunoaffinity purification and comprehensively analyzed their miRNA expression profiles using microarray as biomarkers for early diagnosis and monitoring of disease progression in ALS subject (see abstract) as in instant claims 1 and 22. Katsu teaches that these sample come from blood (see page 1, 1st column) as in instant claim 4. Katsu teaches using anti-human CD171 (L1CAM) antibodies to capture EVs and also teaches using CD63 and CD81 EV specific markers to confirm the capture of the target EVs (see section 2.2 Isolation od neuron-derived EVs in plasma) as in instant claims 1, 4, 7, 14-16 and 22. Therefore, the claims limitations of ‘425 are obvious over Katsu’s teaching. One of ordinary skill would use the well-known methods taught in the prior art by Katsu to specifically determine the miRNA of the ‘425. Therefore, the instant claims are obvious over the ‘425 claims in view of Katsu.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 11/3/2025 have been fully considered but they are not persuasive. Applicant argues that the Mitsuhashi reference while teaching the claimed diagnostic method that it is only limited to Alzheimer’s disease. Applicant argues that the JP6541049 while teaching the miRNA-151-3p in ALS subjects fails to teach that this was obtained from exosomes or that it fails to teach the miRNA as being upregulated. Applicant also argues that the Viswambharan does not teach ALS biomarker mi-RNA from neural derived exosomes. Applicant argues that the Ricci reference does not add anything new and while teaching many miRNA for ALS, they do not overlap.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is pointed out that while the Mitsuhashi reference is not specifically directed to the ALS subjects, this reference is in the same field of endeavor. ALS and Alzheimer’s are both neurodegenerative diseases and provide a clear guide to one of ordinary skill in the art to look to these types of analysis for new biomarkers in these types of diseases. This point is further supported by the Ricci et al., 2018 which clearly states that ALS mi-RNA biomarkers are known to be extracted from neural derived exosomes. It is also pointed out that the JP641049 and Viswambharan along with the Ricci reference, that these types of assay have been considered and performed in the prior art with reasonable success. Further, the newly added reference to the 103 obvious rejection, Katsu et al., 2019, also teaches the miRNA levels extracted from neural derived exosomes are also proper biomarkers for ALS subjects. Therefore, the combination of the references of record clearly show that the instantly claimed methods are obvious over the teachings in the prior art.
In response to Applicant’s argument that the references fails to teach the miRNA as being upregulated to a certain degree is not found persuasive. Routine optimization is comprised of methods that are well-understood and conventional activities previously known to the industry. See MPEP 2145(II): “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)” (“The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”). “(W)here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation” In re Aller, 220F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Therefore, just because the applicant was able to recognized the correlation of miRNA to ALS with specific folds of increase or decrease does not make it unobvious.
Applicant argues that while these biomarkers are found in different diseases like Alzheimer’s disease, they are not specific for ALS and would teach away from the instant invention to distinguish ALS from other diseases. This is not found persuasive because biomarkers can be found in different diseases and still be capable of being using in a diagnostic analysis to determine what disease is present. As set forth in the instant claims, no single miRNA biomarker is an indicator of ALS but rather require a combination of biomarkers, like miRNAs, to achieve a diagnostic of a disease. Therefore, just because some of the miRNA are also present in AD does not mean they cannot be indicative of other diseases, like ALS. Routine optimization can easily identify what specific miRNA and either their increase of decrease are indicative of specific disease when present in a specific combination of biomarkers.
Finally, the double patenting rejection is maintained in view of the newly amended rejection over Katsu which now teaches the new claim limitations of how to determine the levels of miRNA.
Therefore, the arguments are not found persuasive and the rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675