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 .
Election/Restrictions
Applicant’s election without traverse of Group I, species SOD2 and nucleic acid analysis, in the reply filed on 3/24/2026 is acknowledged.
Claims 1, 42, 46-48, 50-55, 57-63, 65, 66, 68-72, 79, and 85-88 are currently pending. Claims 72, 79, and 85 are withdrawn from consideration as being directed to a non-elected invention. Claims 57-60, 62, 87, and 88 are withdrawn from consideration as being directed to non-elected species.
An action on the merits of claims 1, 42, 46-48, 50-55, 61, 63, 65, 66, 68-71, and 86 is set forth herein.
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, 42, 46-48, 70 and 71 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena 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.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites methods of evaluating the efficiency of FXN replacement therapy, monitoring treatment of a subject with FXN replacement therapy, as well as methods of treating an FXN deficiency by comparing gene expression profiles. The claims recite “evaluating”, “monitoring”, “determining a baseline FXN expression profile” prior to and after FXN replacement therapy, “comparing … expression profile”, “determining efficacy… based on the comparison”, “determining a first [second] FXN replacement expression profile”, “comprising the second FXN replacement profile with the first…”, “classifying the FXN expression profile…”, etc. However these steps are directed to abstract ideas because they encompass making observations (determining encompasses reading a report), making comparisons, drawing conclusions, and making mathematical correlations. All of these steps can be conducted via reading reports, thinking about the results, and making mathematical correlations which can occur entirely within the mind or using pencil and paper. It is therefore determined that the claims are directed to a judicial exception.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
While claims 1, and 42 only recite abstract steps, claim 46 recites a step of “initiating or modulating an FXN replacement therapy”. However, these ambiguous terms appear to encompass making therapy decisions, or giving instructions, which does not integrate the JE into a practical application because it is a directed to nothing more than instructions to apply the JE. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, none of the steps add significantly more to the JE because they are directed to the JE themselves. While some of the steps could be broadly construed to encompass performing gene expression analysis, these are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. The general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then 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." Further "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.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than multiple abstract steps which at most use elements which are well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
112(a)
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.
Claims 1, 42, 46, 47, 48, 50, 51, 70, and 71 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for:
I) A method of treating an FXN deficiency in a subject comprising: a) detecting increased expression of LY96, LRRK2, Adgre1, Timp1, Xpo6, CD44, BASP1, PSMB8, C3ar1, TFRC, SOD2, PLCL2, S100a4, Mapre1, CFH, Tmem70, and PSMB9, and detecting decreased expression of Lgals3, Ube2v2, Sec61g, Zdhhc13, Yipf5, Tpp2, Ybx2, and Ptms in a biological sample from the subject as compared to the expression level in healthy control subjects, and b) administering FXN replacement therapy to the subject;
II) A method of evaluating the efficacy of FXN replacement therapy in a subject in need thereof, comprising: a) performing sequencing, hybridization, or amplification of RNA in a sample from a subject prior to treatment with FXN replacement therapy and detecting the gene expression levels of Timp1, LRRk2, BASP1, CD44, Xpo6, Lgals3, SOD2, and PSMB9; b) performing sequencing, hybridization, or amplification of RNA in a sample from the subject after treatment with FXN replacement therapy and detecting the gene expression levels of Timp1, LRRk2, BASP1, CD44, Xpo6, Lgals3, SOD2, and PSMB9; c) detecting increased expression of Timp1, LRRk2, BASP1, CD44, Xpo6, SOD2, and PSMB9, and detecting decreased expression of Lgals3 in the subject after treatment with FXN replacement therapy; and d) determining that the FXN replacement therapy is efficacious;
does not reasonably provide enablement for the claims as broadly recited.
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 or use the invention commensurate in scope with these claims. There are many factors to be considered when determining whether there is sufficient evidence to support determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The claims are broadly drawn to methods of monitoring and evaluating efficacy of frataxin (FXN) replacement therapy using the gene expression levels of the genes listed in Table 1. The claims additionally encompass “modulating” FXN replacement therapy “based” on the gene expression levels of the genes in table 1. The invention is in a class of inventions which the CAFC has characterized as 'the unpredictable arts such as chemistry and biology" (Mycolgen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Federal Circuit 2001)).
The specification teaches gene expression analysis using nanostring identified genes differentially expression in healthy subjects vs patients with FRDA (Friedreich’s Ataxia) (see table 1A, page 142). However, when evaluating the same genes for expression analysis in patients undergoing FXN replacement therapy, the specification teaches that only a subset of those genes were differentially expressed in patients before and after FXN replacement therapy (table 5, page 144). Furthermore, it is noted that when compared to the expression levels in normal healthy subjects, the expression levels were differently modulated (see table 5), either more or less than the levels in normal healthy subjects. While the specification contemplates that all of the biomarkers in table 1A could be modulated by FXN replacement therapy, the specification teaches that lack of correlation between the genes in table 1A and table 5 could be due to the time of sampling relative to dosing, dosage and/or administration schedule of the FXN replacement therapy, the tissue being sampled (as genes may be differentially expressed in different tissues), and/or the sensitivity of the experimental technique used to measure the gene expression (e.g., Nanostring or qPCR), the specification provides no guidance as to how or what specific factors could be changed to detect differential expression of all of the genes in table 1A as biomarkers for the efficacy and monitoring of FXN replacement therapy. Zhang (Zhang et al; rends Pharmacol Sci, 2019, vol 40, pages 1-9) teaches that defining robust and reliable biomarkers of for FRDA and therapy as well as defining a context of use is challenging for rare and heterogenous conditions like FRDA (see conclusion).
To practice the invention as broadly as it is claimed, the skilled artisan would be required to perform extensive unpredictable trial and error analysis on different patients, and different FXN replacement therapies to determine if and how all of the biomarkers in table 1A could be used to monitor and determine FXN replacement therapy. Given the lack of guidance in the specification as to which of the many parameters affecting gene expression levels would need to be changed or altered to arrive at a reliable diagnostic test using any or all of the genes in table 1A to practice the invention as broadly claimed.
112(b)
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.
Claims 1, 42, 46-48, 50-55, 61, 63, 65, 66, 68-71, and 86 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claims are rejected for being incomplete because they refer to a table. As set forth in the MPEP 2173.05(s):
Reference to Figures or Tables
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Additionally, the claims refer to table 1, however the specification teaches table 1A at page 142, but no table 1. It is not clear if the reference to table 1 is a typographical error or if it refers to the genes listed at page 142 of the specification.
The recitation of “based on” in claimed steps 1(d), 46(d), and 50(b) is indefinite because the relationship between the expression levels and performing the indicated step is unclear. The claims do not define which expression profile conditions are required for the step to be carried out. Additionally, it is not clear if the step only requires using the expression analysis or if additional information or analysis is required to carry out the step.
Claim 69 is confusing in the recitation of “obtained 15 to 45 days following the last administration of the FXN replacement therapy” because it is not clear if the claim means to require sample collection for each of the days from 15 to 45 days following the last administration or if the sample can be obtained on any day between day 15 and 45 following the last administration.
Claim Rejections - 35 USC § 102
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.
Claims 52, 54, 55, 61, 63 and 86 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Coppola (Coppola et al; Ann Neurol; 2011, 70:790-804 and Supplementary methods).
It is noted that the instant claims only require contacting a biological sample with detection reagents that are able to detect one or more of the genes listed in the claims. The claims do not require any particular gene expression for any of the genes listed.
Coppola teaches analysis of gene expression in patients with Friedreich’s Ataxia (see abstract). Coppola teaches microarray analysis (see supplementary methods) using Illumina RefSeq-8 Beachchip Expression v. 1.0 arrays and Illumina Human V4-HT12 arrays. These arrays possess oligonucleotides that are complementary to SOD2. Accordingly, since the prior teaches all of the active steps and limitations required by the claims, the claims are not distinguished over the prior art.
Claims 52, 54, 55, 61, 63, 65, 66, and 86 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Napierala (Disease Models & Mechanisms, 2017, 10:1353-1369; cited in the IDS dated 2/2/2024).
It is noted that the instant claims only require contacting a biological sample with detection reagents that are able to detect one or more of the genes listed in the claims. The claims do not require any particular gene expression for any of the genes listed.
Napierala teaches analysis of gene expression in patients with Friedreich’s Ataxia (see abstract). Napierala teaches RNA sequencing via microarray analysis using Illumina HiSeq2000 platform (page 1354, col 1), which necessarily possess oligonucleotides that are complementary to SOD2. With regard to claims 65 and 66, Napierala teaches obtaining and detecting in fibroblasts isolated from skin samples from patients with Friedreich’s ataxia and control individuals (page 1354, col 1). Accordingly, since the prior teaches all of the active steps and limitations required by the claims, the claims are not distinguished over the prior art.
Claims 50, 51, 54, 55, 61, 65, 66, and 86 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bettoun (US 2020/0377951; 12/2020; cited in the IDS filed 2/2/2024).
It is noted that the instant claims only require contacting a biological sample with detection reagents that are able to detect one or more of the genes listed in the claims. The claims do not require any particular gene expression for any of the genes listed.
Bettoun teaches RNASeq analysis from skin samples from subjects with FXN deficiency to detect FXN biomarkers (abstract, claims). Bettoun teaches using the Illumina Platforms KR1151-v4.16 which necessarily (para 0351) which necessarily possess oligonucleotides that are complementary to SOD2. Bettoun teaches administering FXN replacement therapy (see abstract, claims). Accordingly, since the prior teaches all of the active steps and limitations required by the claims, the claims are not distinguished over the prior art.
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 50-55, 61, 63, 65, 66, 68-69, and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Bettoun.
Bettoun teaches RNASeq analysis from skin samples from mice with FXN deficiency to detect FXN biomarkers (abstract, claims). Bettoun teaches using the Illumina Platforms KR1151-v4.16 which necessarily (para 0351) which necessarily possess oligonucleotides that are complementary to SOD2. Bettoun teaches gene expression analysis using RT-PCR of particular genes in patients with Friedreich’s Ataxia, but not SOD2. However, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have also performed Illumina microarray analysis on patients with Friedreich’s Ataxia undergoing frataxin replacement therapy for the obvious benefit of detecting all genes associated with Friedreich’s ataxia or associated with FXN replacement therapy efficacy. With regard to claims 68 and 69, the ordinary artisan would have been motivated to analyze samples following the last treatment, including 15 days after the last treatment for the purpose of providing a comprehensive analysis of gene expression prior to, during, and following treatment.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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/JEHANNE S SITTON/ Primary Examiner, Art Unit 1682