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 1-7 and 9-11 are pending in the instant application. 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 newly applied and constitute the complete set being presently applied to the instant Application. 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Any rejection not reiterated is withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 103
Claims 1 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Wang et al; Scientific Reports, 5:9522; pages 1-9; 2015) in view of Surges (Surges et al; Biochemical and Biophysical Research Communications, vol 481, 2016, pages 13-18) and Brodie (Brodie et al; The Lancet; vol 345, 1995, pages 476-479), further in view of Karsten (Karsten et al; Neurosci Lett; vol 497, pages 213-217; 2011), Wang II (Wang et al; Experimental and Therapeutic Medicine, vol 18, pages 373-383; 2019), Costa (Costa et al; Journal of Biomedicine and Biotechnology, doi:10.1155/2010/853916; pages 1-19; 2010), and Koch (Koch et al; Am J Respir Cell Mol Biol, vol 59, pages 145-157, 2018).
Regarding claim 1, Wang teaches obtaining RNA from whole blood samples of patients with epilepsy (extracting a whole blood sample) and control patients, as well as preparing an RNA library from the sample and sequencing the RNA library. Wang teaches ligating adaptors, converting the RNA into cDNA (see Methods) where the amplified cDNA is sequenced in the RNA library using Illumina HiSeq2000 sequencing (see abstract, and methods). Wang teaches determining differential expression of a plurality of RNA sequences within the library (see figure 1; whole document). Wang teaches creating a blood transcriptome profile based on the differential expression and comparing the blood transcriptome profile to a reference profile of normal control subjects, and using a prediction algorithm to identify miRNAs as biomarkers in epilepsy (see Bioinformatics and Statistical analysis on page 8, Discussion on page 7, figures 1-5). With regard to claim 1, Wang does not teach comparing the blood transcriptome profile to a reference blood transcriptome profile from a subject after an epileptic seizure, or obtaining a whole blood sample from a subject after a suspected epileptic seizure, however Surges teaches changes in circulating miRNA were found following generalized convulsive seizures in humans with epilepsy. Surges teaches that it is of high clinical interest to identify biomarkers that predict seizure and that allow for distinguishing people with epilepsy from those without (page 13, col 2). With regard to claim 1, Surges teaches obtaining blood samples from patients prior to seizure as well as 30 min, 3-6 hours, 20-28 hours, and 3-6 days after epileptic seizure onset (page 14, col 1, para 4). With regard to claims 9-11, these time points are taken meet the limitations of “within six hours”, “within twenty four hours”, and “within seventy two hours”. Surges teaches using mixed linear modeling approach (prediction algorithm) to assess statistical significance. Surges teaches that a number of miRNAs were found to be differentially expressed in the 30 min post seizure period, as well as some transcripts in the 3-6 hour and 20-28 hour range (see figure 3), including in seizures occurring during sleep. Surges teaches that these transcripts can be used as biomarkers for seizures.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art prior to the effective filing date, to modify the method of differential RNA expression analysis of Wang, to include analysis of patients following epileptic seizure (blood RNA transcriptome profile of a subject after an epileptic seizure), as taught by Surges, so as to provide biomarkers indicative of seizures, as taught by Surges. The ordinary artisan would have been motivated to arrive at a method of confirming seizure, post event, by obtaining a blood sample from a subject after a suspected seizure and to compare it to the transcriptome profile of a subject after an epileptic seizure for the benefit of determining whether the subject had suffered a seizure because Surges teaches that expression profiling of miRNA can provide a profile of transcripts as biomarkers for seizure.
With regard to claim 1, Wang and Surges do not teach treatment of epilepsy with lamotrigine, however Brodie teaches that lamotrigine has a wide range of efficacy for all seizure types and that it is better tolerated than carbamazepine (see Summary, Introduction, page 476). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to treat patients with epilepsy as taught by Wang and Surges, with lamotrigine because Brodie teaches it is an effective monotherapy for seizures in patients with epilepsy and that it is better tolerated than carbamazepine.
With regard to claim 1, Wang, Surges, and Brodie do not teach preparing a whole blood RNA transcriptome profile wherein the RNA transcriptome is the set of all RNA molecules found in the whole blood sample, however the prior art teaches the importance of whole transcriptome analysis including all RNA molecules found in the sample:
Karsten teaches that recent publications and data point to the presence of global gene expression changes in the peripheral blood transcriptome in response to underlying epileptogenic processes (page 5, first para).
Wang II teaches RNA seq analysis of whole blood of valproic acid responsive and non-responsive patients with epilepsy (see page 374, col 1).
Costa teaches next generation sequencing applications, such as RNA-Seq, allows for the analysis of the RNA transcriptome (page 2). Costa teaches that the discovery of endogenous small interfering RNA (siRNA) and microRNA (miRNA), long interspersed noncoding RNA (lincRNA), and many others represent part of the pieces of a complicated transcription puzzle. Costa teaches that discovering and interpreting the complexity of a transcriptome by analyzing the molecular constituents of cells and tissues, will allow for more complete knowledge of many biological issues such as the onset of disease and progression (page 2). Costa teaches: sample isolation allowing for enriched factions of mRNA and regulatory molecules such as miRNA, siRNA, small ncRNA, etc,; library preparation (see pages 4-5); sequencing the RNA library (page 6; figure 2); and computational analysis leading to differential expression data for transcripts (figure 3, pages 6-11).
Koch provides a review of RNA sequencing and teaches that transcriptome libraries can be constructed from total RNA, RNA enriched for mRNA, or RNA depleted of rRNA.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have modified the method of Wang, Surges, and Brodie, to include analysis of the entire RNA transcriptome in whole blood as taught by Wang II, Karsten, Costa, and Koch for the expected benefit of arriving at a more complete transcriptome profile. Costa and Koch teach the ability to analyze transcripts from particular cell populations using RNA-Seq allows practitioners to arrive at a more complete assessment of biological issues such as the onset of disease and progression.
Claims 2-7 are rejected under 35 U.S.C. 103 as being unpatentable over Wang, Surges, and Brodie, further in view of Karsten, Wang II, Costa, and Koch, as applied to claims 1 and 9-11 above, and further in view of Anney (Anney et al; Lancet Neurol. 2014, vol 13, pages 893-903).
The teachings of Wang, Surges, Brodie, Karsten, Wang II, Costa, and Koch are set forth above and are fully incorporated herein.
Wang, Surges, Brodie, Karsten, Wang II, Costa, and Koch do not teach wherein the subject has identified genetic descent of the patient being African, European, and Asian and the identified gender of the patient being male or female. Regarding claims 2-7, Anney teaches that epilepsies are a clinically heterogeneous group of disorders. Anney reports doing meta-analysis 12 epilepsy case/control cohorts comprising 8,696 cases and 26,157 controls. Anney teaches cases included Caucasian from the United Kingdom, Western Europe, Finland, USA and Australia, as well as African-American and Han Chinese subjects, with controls being ethnically matched (pg. 893, abstract). Anney teaches doing analysis for each of the pre-selected phenotypic categories of epilepsy 1) all epilepsy, 2) GGE, 3) focal epilepsy, where gender (male/female) was included as a covariate (pg. 4, statistical analysis).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the method of Wang, Surges, Brodie, Karsten, Wang II, Costa and Koch to include a step to conduct analysis in subjects of African, European and Asian descent as taught by Anney, as well as in male and female subjects. A person of ordinary skill in the art would have recognized that Epilepsy effects all population and does not discriminate among backgrounds and therefore, one of ordinary skill would have been motivated to apply the teachings of Koh, Surges, and Brodie in studying genetic determinants of epileptic seizures in male and female patients of African, European and Asian descent.
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 1-7 and 9-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-18 of copending Application No. 18/539,603 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are both directed to creating RNA transcriptome profiles comprising non coding RNA diagnostic of seizures to arrive at diagnosing and treating epilepsy in a subject following a suspected epileptic seizure.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Winston Shen, can be reached on (571) 272-3157. The fax phone number for organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682