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 .
Status of Claims
Currently, claims 44 and 85-113 are pending in the instant application. Claims 91-94 and 98-99 are withdrawn from consideration as being drawn to non-elected species. Claims 44, 85-90, 95-97, and 100-113 are currently under examination. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant Application. Response to Applicants arguments follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Priority
The instant application claims priority to provisional application 62/840,878, filed 4/30/2019. However, the sequences of SEQ ID NOS: 2-12 are not supported by the ‘878 provisional application. Therefore, the effective filing date of claims 86-90 and 106-107 is 4/30/2020.
Claim Rejections - 35 USC § 103
Claims 44, 85-86, 100-105 and 110-113 are rejected under 35 U.S.C. 103 as being unpatentable over Coppola (Coppola et al; Ann Neurol; 2011, 70:790-804 and Supplementary methods) in view of Vyas (Vyas et al; Human Molecular Genetics, vol 21, 2012, pages 1230-1247).
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 and detecting the expression level. The claims do not require detection of any particular gene expression level for any of the genes listed.
With regard to claims 44, 100, and 103, Coppola teaches analysis of gene expression in patients with Friedreich’s Ataxia (FRDA) (see abstract). With regard to claims 44, 100, and 102, 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 (claim 100) to BTG2, PTGS2, CTSS (claim 44), and EGR1 (claim 102). Coppola teaches that gene expression changes are associated with frataxin deficiency in FRDA patients. Coppola teaches identification of the expression level of CTSS (see table 1 at page 798). With regard to claim 44 and 103, Coppola teaches that gene expression levels were also assessed prior to and after cells were treated with HDACi therapy (see page 799 and Supplementary methods) which are compounds able to raise frataxin levels in vitro and in vivo. Coppola teaches that gene expression levels changed towards normal after HDACi treatment (see para bridging pages 800-801). Coppola does not teach assessing gene expression levels of patients being treated with FXN replacement therapy. However, Vyas teaches that enzymatic replacement therapy with a TAT-fusion protein delivering FXN significantly increased both mitochondrial and cytosolic enzyme activities in vivo in mice and increased mean lifespan by 53% (see abstract). With regard to claim 86 and 105, the instant specification teaches that SEQ ID NO: 1 is the full length FXN protein taught by Vyas. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have modified the method of Coppola to include analysis in patients undergoing FXN replacement therapy as taught by Vyas because Vyas teaches that FXN replacement therapy increased both mitochondrial and cytosolic enzyme activities in vivo in mice and increased mean lifespan by 53% in mice, and Coppola teaches that gene expression levels changed upon treatment with compounds able to raise frataxin levels in vitro and in vivo. The ordinary artisan would have been motivated to assess gene expression levels in FXN deficient subjects being treated with FXN replacement therapy for the purpose of monitoring gene expression changes in subjects undergoing therapy for FXN deficiency.
Claims 95-97 and 108-109 are rejected under 35 U.S.C. 103 as being unpatentable over Coppola in view of Vyas, as applied to claims 44, 85-86, 100-105, and 110-113 above, and further in view of Napierala (Disease Models and Mechanisms, 2017, vol 10, pages 1353-1369).
The teachings of Coppola and Vyas are set forth above. Coppola and Vyas do not teach analysis in fibroblasts from skin samples, however Napierala also teaches methods of assessing gene expression in patients with Friedreich’s Ataxia. Napierala teaches that “although not directly involved in FRDA pathogenesis, peripheral tissues from patients are deficient of frataxin and can serve as models to collect data associated with stable molecular features of the disease”. Napierala teaches that an advantage of fibroblast cells is that their physiology is not likely perturbed by acute changes in daily living activities, which make them a suitable model for defining persistent gene expression patterns of FRDA. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to conduct the method of Coppola and Vyas, in fibroblast cells from skin samples because Napierala teaches that they are a suitable model for defining persistent gene expression patterns of FRDA.
Claims 86-90 and 106-107 are rejected under 35 U.S.C. 103 as being unpatentable over Coppola, and Vyas as applied to claims 44, 85-86, 100-105, and 110-113 above, and further in view of Payne, R. (US Patent 11,459,363).
The teachings of Coppola and Vyas are set forth above. Coppola in view of Vyas do not teach FXN replacement therapy comprising SEQ ID NO: 2, 4 or 12. However, Payne teaches an FXN replacement therapy that comprises SEQ ID NO: 12, as well as comprising SEQ ID NOS 2 and 4 (SEQ ID NO 1 of Payne is identical to instantly recited SEQ ID NO: 12, and SEQ ID NO: 5 of Payne is identical to instantly recited SEQ ID NO: 2). Payne teaches that the TAT-FXN demonstrates solubility and activity (see example 9; also in provisional application 62/880,073[ filed 7/29/2019]-which the ‘363 patent claims priority to). Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to substitute the use the FXN fusion protein taught by Payne in the method of Coppola and Vyas because Payne teaches the TAT-FXN demonstrates solubility and activity (see example 9).
Response to Arguments
The response traverses the rejections made in the previous office action.
The response asserts that Coppola does not teach subjects being treated with FXN replacement therapy or detecting the expression level of genomic markers in subjects being treated with FXN replacement therapy. The response also asserts that Vyas does not teach identification of the claimed biomarkers. These arguments have been thoroughly reviewed but were not found persuasive. First, it is pointed out that 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). Second, given that Coppola teaches that gene expression levels changed towards normal after treatment (see para bridging pages 800-801) with compounds that are able to raise frataxin levels in vitro and in vivo and Vyas teaches that enzymatic replacement therapy with a TAT-fusion protein delivering FXN significantly increased both mitochondrial and cytosolic enzyme activities in vivo in mice and increased mean lifespan by 53% (see abstract), the ordinary artisan would have been motivated to assess gene expression levels in FXN deficient subjects being treated with FXN replacement therapy for the purpose of monitoring gene expression changes in subjects undergoing therapy for FXN deficiency.
The response further asserts that Coppola does not teach detecting the expression level of the specific genomic markers BTG2, PTGS2, and CTSS. This argument has been thoroughly reviewed but was not found persuasive because all the claim requires is detecting expression levels of the markers, it does not require that the detected expression levels be any particular level, or that the expression levels of those biomarkers be reported. The term “detecting” has been given it’s broadest reasonable interpretation to encompass performing an assay that discovers the gene expression of the claimed biomarkers. The microarray based gene expression assay taught by Coppola achieves this because it discovers the gene expression levels of all of the biomarkers targeted by the oligonucleotides on the array.
The response also asserts that Coppola does not identify CTSS as a marker that is contrary regulated by FXN deficiency followed by an FXN replacement therapy. The response also asserts that the combination of Coppola and Vyas fail to provide an identification of the claimed biomarkers as being contrary regulated nor recognize their utility as markers of FXN replacement. This argument has been thoroughly reviewed but was not found persuasive. First, the fact that the biomarkers are contrarily regulated is a property of the biomarkers themselves, it is not a claim limitation. The claims do not require detecting a particular expression level
of any of the recited biomarkers either before or after FXN replacement therapy, let alone before and after. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
For these reasons and the reasons already made of record, the rejections are maintained and applied to the newly added claims.
Claim Rejections - 35 USC § 101
Claims 103-113 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and 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 a method of detecting genomic markers and comparing the expression level of one or more genomic markers to expression levels in a control sample. However, the recitation of the comparison step is a directed to an abstract idea because it encompasses an abstract mental step.
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)].
The claims recite steps of administering a FXN replacement therapy, followed by contacting the biological sample with detection reagents for detecting one or more genomic markers and detecting expression of the genomic markers. However, these steps do not integrate the JE into a practical application because they are directed to mere data gathering. Although the first step is directed to the administration of therapy, it merely informs practitioners who to gather data from, and does not integrate the JE into a practical application.
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, the steps of contacting a biological sample with one or more detection reagents that detect one or more of the genes listed in the claims 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. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). It is additionally noted that the prior art teaches and provides detection reagents capable of functioning as claimed. 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 data gathering followed by using mental activity to compare the date. Any additional element consists of using 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.
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.
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