DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16/826,010 has been entered.
Application Status
This action is written in response to applicant’s correspondence received on 4/27/2026. Claims 1-2, 4-9, 11-18, 20, and 23-24 are pending. Claims 1-2, 13, and 24 have been amended. All pending claims are currently under examination.
Oath/Declaration
The Declaration filed 4/27/2026 has been considered but is not persuasive to place the claims in condition for allowance. The Declaration is specifically addressed in the “Response to Arguments” section following the 103 rejection, below.
Claim Rejections - 35 USC § 103 – Maintained/Updated
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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 2, 11-13, 17-18, and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012). The rejection is further evidenced by Mercer (Mercer TR et al. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21).
As an initial matter, the presently claimed invention is drawn to a general exploratory method of measuring lncRNAs in the context of an epileptic patient’s brain tissue. As such, the method itself is not drawn to a specific lncRNA for treatment, but is rather drawn to simply a method of measuring lncRNAs in epileptic brain samples. The following 103 rejection is therefore made in light of the facts that the tissue sampling method was already known in the art, as well as a motivational teaching in the art which implicates lncRNAs having an association with epilepsy, thereby motivating a practitioner to measure, in general, lncRNA expression in the context of epilepsy (see 103 rejection below for further explication).
Regarding claim 1, Rakhade is a research article which examines activity-dependent gene expression and its correlation with interictal spiking in epilepsy patients (Title, Summary, and throughout). Rakhade teaches that:
“we explore this further by comparing the expression of these genes within human epileptic neocortex to both ictal and specific electrical parameters of interictal spiking from subdural recordings prior to surgical resection in order to determine the electrical properties of the human neocortex that correlate best to the expression of these genes,”(Summary).
Rakhade therefore teaches that their methods are performed with neocortex tissue samples (Summary).
Rakhade also teaches that:
“together with deafferented regions of nearby control tissue, seizure onset zones were removed along with deafferented seizure-spread tissue in an enbloc resection” ( see Methods, e.g., second paragraph).
Rakhade therefore teaches a method of obtaining pair samples from the neocortex from a human brain, where the human is a patient with epilepsy, where each sample has a different level of brain electrical brain activity (i.e., control tissue versus seizure onset zones”). Furthermore, Rakhade teaches and focuses on the correlation of gene expression profiles with human epilepsy, and teaches that:
“we have recently identified a common group of genes induced in human epileptic foci, including EGR1, EGR2, c-fos, and MKP-3. We found that the expression levels of these genes correlate precisely with the frequency of interictal activity and can thus serve as markers of epileptic activity,” (Summary).
Rakhade further teaches that:
“In this study we have further refined the link between the expression of these genes and quantitative measures of interictal epileptiform activity in human neocortex by showing that the expression of 3 of these genes (c-fos, EGR1, EGR2) is highly correlated with a number of interictal spike parameters including spike amplitude, frequency, and area,” (page 92, left column, first paragraph).
Therefore Rakhade teaches not only sampling paired brain tissue with different electrical properties in epilepsy patients, but also teaches that gene expression profiling is critical to elucidating differentially expressed genes in epileptic brain tissue, where the differential expression was evaluated in paired brain sample tissues from the neocortex in epileptic patients by measuring interictal epileptiform spike parameters (Summary, Methods second paragraph, and page 92, left column, first paragraph).
Additionally, Rakhade teaches that “electricocography (ECoG) using subdural grids of electrodes are often used to delineate…epileptic activity at each electrode,” (page 86, left column, first paragraph). Furthermore, Rakhade teaches the use of ECoG in their methods, where electrodes are surgically implanted in the epilepsy patient brain to monitor electrical activity of the brain to monitor interictal epileptiform spikes, and also teaches excising pairs of tissue samples displaying different interictal spiking patterns (see Methods, page 87, right column, and also page 88, left column final paragraph into the right column, first paragraph).
Furthermore, Rakhade also teaches the use of microarrays to measure differential gene expression profiles designed to identify differentially expressed genes in epileptically active versus inactive neocortex, and therefore teaches transcriptome wide profiling using a microarray (page 91, right column, first paragraph).
Rakhade also teaches that:
“Understanding the potential roles of interictal spike activity and the genes that are induced together with that spiking should offer us further clues on both the causes of focal neocortical epilepsy as well as potential therapeutic treatments for the future,” (page 94, left column, first paragraph).
Rakhade therefore teaches that elucidating genes which are upregulated and coupled to spiking is important to understanding causes of epilepsy and to identify therapeutic targets (page 94, left column, first paragraph). Rakhade therefore teaches a motivation to further explore differentially expressed genes in the context of epilepsy, specifically within the neocortex by using paired tissue sample microarray profiling.
Rakhade, while teaching a method of comparing expression profiles of neocortical tissue to elucidate molecular mechanisms of epilepsy based on interictal spiking, does not tech lncRNAs, or the identification of paired lncRNA/mRNA differentially expressed gene pairs.
Qureshi 2 is a research article that focuses on non-coding RNAs and their association with cognitive disorders (Title, Abstract, and throughout). Qureshi 2 teaches the non-coding RNA (ncRNA) HAR1, that this ncRNA is coexpressed with the glycoprotein reelin, a critical developmental factor implicated in cognitive function and the pathogenesis of diverse cognitive disorders including epilepsy (page 2 final paragraph into page 3, first paragraph). Furthermore, Qureshi 2 teaches that:
“additional lncRNAs are associated with epilepsy and stroke,” (page 8, final two lines). Thus, Qureshi 2 teaches that lncRNAs are associated with epilepsy, and therefore teaches a motivation to include lncRNAs in expression profiling of epilepsy tissues. Furthermore, Qureshi 2 and Rakhade directly overlap in subject matter because both focus on underlying mechanisms of epilepsy (Title, Abstract, and see both documents).
Bennett discloses a method for identifying putative therapeutic targets (page 38, lines 20-24) comprising: identifying long non-protein-coding RNA (IncRNA) molecules (page 27, lines 6-10) and protein-coding messenger RNA (mRNA) molecules (mRNAs) (page 38, lines 20-24) that are differentially expressed in association with a disease or disorder (page 27, lines 6-10); linking a first differentially expressed IncRNA with a differentially expressed mRNA and/or a second differentially expressed IncRNA (linking an expressed IncRNA with an expressed mRNA or second RNA, such as an RNAi (page 23, lines 8-18; page 24, line 26 to page 25, line 2) when the gene encoding the first differentially expressed IncRNA overlaps with, or is adjacent to, the gene encoding the differentially expressed mRNA and/or the gene encoding the differentially expressed second IncRNA along the human genome the IncRNA overlaps with, or is adjacent to (i.e., “cis”) the gene encoding the paired mRNA (“Non-coding RNA” section, pages 23-28), thereby identifying an IncRNA/ mRNA gene pair and/or an IncRNA/IncRNA gene pair (an IncRNA/mRNA gene pair and/or an IncRNA/IncRNA gene pair; page 27, lines 6-10) as putative therapeutic targets (page 24, lines 5-6) (page 38, lines 20-24); Bennett therefore teaches differentially expressed lncRNAs and mRNAs to elucidate lncRNA/mRNA gene pairs in the context of disease, and that it was known that lncRNA and mRNA expression are coupled (above). Bennett further teaches that lncRNA are known to be implicated in various diseases of the brain (page 27, second paragraph). Bennett teaches large-scale transcriptomic analysis to characterize ncRNAs (page 24, lines 1-5, and furthermore the references taught on page 24, first paragraph).
Furthermore, Bennett teaches that lncRNA and their target mRNAs can occur in cis or trans (page 24, first paragraph). By teaching cis-acting lncRNA/mRNA pairings, Bennett teaches the known association of lncRNAs with mRNAs, where lncRNAs are known to act on target mRNAs (page 24, first paragraph). Bennett lists known lncRNA and mRNA pairings, including reference to Mercer. Mercer teaches that specific lncRNAs are expressed in the mouse brain (Title, Abstract, and throughout). Mercer further teaches that lncRNAs are known to be associated with and paired with mRNAs, as lncRNAs are known to regulate the expression of protein coding genes via mechanisms such as cis-antisense, bidirectional, and intronic (page 717 final paragraph to page 718, Figure 2). Thus, as Bennett teaches cis ncRNA, and offers Mercer as a reference and example of such lncRNA/mRNA (protein coding gene), where furthermore Bennett teaches cis-acting lncRNA operating on protein coding genes (mRNA), Bennett teaches cis-acting lncRNA pairings on page 24, first paragraph, as referenced by Mercer. In other words, Bennett clearly teaches that lncRNAs are functionally paired with nearby mRNA/protein coding genes (acting in “cis”). Thus, it was known in the art that lncRNAs are paired with mRNAs, where the investigation of lncRNAs is paired with the mRNAs that they affect (Bennett page 24, as evidenced by Mercer page 717 final paragraph to page 718, Figure 2). Bennett therefore provides motivation to explore lncRNA and mRNA pairings, as well as their expression profiles, as taught by Bennett and evidenced by Mercer (page 24).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the presently claimed invention to modify the paired sampling method of Rakhade to include lncRNAs as taught by both Qureshi 2 and Bennett because lncRNAs, as taught by Qureshi 2, are associated with epilepsy, the stated focus of the method of Rakhade. A practitioner would therefore be motivated to include lncRNAs as part of the investigatory method of Rakhade because Qureshi 2 directly teaches that lncRNAs are associated with epilepsy. Furthermore, Bennett teaches that lncRNA/mRNA pairs can be targeted as therapeutics, and that such gene pairs can be coupled/overlap/are “cis.” This is further evidenced by Mercer; it was thus clear in the art that it was known that ncRNAs influence mRNA in cis-acting mechanisms, where furthermore transcriptomic analysis is a known method of exploring such RNA expression levels (e.g., Bennett, page 24, first paragraph). Thus, a practitioner would be motivated to include lncRNAs with the microarray profiling method of Rakhade, as it was already known that such molecules are associated with epilepsy and can be targeted as therapeutics, and furthermore, it was known that lncRNAs and paired with mRNAs in cis fashion.
Regarding claim 2, Rakhade teaches interictal spike detection wherein amplitude is a component in measuring the interictal spike in Figure 2. Figure 2 also depicts seizure spikes compared with control spikes, and therefore teaches the classification of high (“seizure onset”) and low (“control”) electrical brain activity (Figure 2).
Regarding claim 11, all of these claim limitations are addressed in the rejection of claim 1 (see rejection of claim 1, above). The combination of Rakhade, Qureshi 2, and Bennett renders obvious the recited method of identifying putative therapeutic targets by obtaining at least a pair of brain tissue samples from a human brain, wherein each sample has a different level of electrical activity from the other, and measuring the expression of lncRNAs and mRNAs in the samples to determine differentially expressed lncRNAs and mRNAs in the samples (see claim 1 rejection, above). Furthermore, the rejection of claim 1 addresses the broadest reasonable interpretation of claim 11, which includes linking a differentially expressed lncRNA with a differentially expressed mRNA when the gene encoding the differentially expressed lncRNA overlaps with or is adjacent to the gene encoding the differentially expressed mRNA and identifying the pair as a cis-encoded target because Bennett teaches that lncRNA can act on “cis” encoded targets (page 24, line 5).
Regarding claim 12, Rakhade teaches observed gene expression in more than one brain sample pair (page 91, column 2 paragraph 1; page 92, column 1, paragraph 1). Additionally, Rakahde teaches the collection of multiple brain tissue samples/pairs per patient (page 87, right column, final paragraph). Thus, Rakhade teaches the collection of multiple brain tissue pairs (page 87, right column, final paragraph). Rakhade also teaches each pair having a low electrical brain member and a high electrical brain activity member (page 92, column 2, and Figure 5).
Regarding claim 13, Rakhade teaches interictal spike detection wherein amplitude is a component in measuring the interictal spike in Figure 2. Figure 2 also depicts seizure spikes compared with control spikes, and therefore teaches the classification of high (“seizure onset”) and low (“control”) electrical brain activity (Figure 2).
Regarding claim 17, Rakhade teaches that:
“understanding the potential roles of interictal spike activity and the genes that are induced together with that spiking should offer us further clues on both the causes of focal neocortical epilepsy as well as potential therapeutic treatments for the future,” (page 94, left column, first paragraph).
Thus, Rakahde teaches that their method can be used to identify potential therapeutic treatments. It is inherently obvious that a therapeutic target would be a site of effective intervention because if the site were not a site of effective intervention it would offer no benefit to target as a therapy.
Regarding claim 18, the methods of Rakhade, Qureshi 2, and Bennett are directed to identifying lncRNAs and/or mRNAs which could be used as putative therapeutic targets (see the rejection of claim 1).
Regarding claim 23, Rakhade teaches correlation of gene expression patterns of activity-dependent genes in their methods (Title, Abstract), and teaches expression patterns of known activity-dependent coding genes (Abstract, e.g., c-fos, EGR1, and EGR2). Furthermore, as discussed above, Rakhade in combination with Qureshi 2 and Bennett render obvious determining differentially expressed lncRNA, where such lncRNA would be activity-dependent as taught by Rakhade (Abstract). Additionally, Rakhade teaches microarray profiling, which, in combination with lncRNA profiling rendered obvious by Qurshi 2 and Bennett, would yield correlation data between lncRNAs and activity-dependent coding gene expression (see rejection of claim 1). Furthermore, Bennett also teaches that it is known that ncRNAs correlate with gene expression profiles (e.g., page 24, first paragraph, and section entitled “Non-coding RNA,” pages 23-31). It would therefore be obvious to correlate lncRNA expression with the expression patterns of genes (Bennet, page 24 first paragraph and “Non-coding RNA,” pages 23-31).
Claim 4 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer (Mercer TR et al. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21) and Zhang (Zhang X et al. Neurobiol Dis. 2012 Oct;48(1):1-8, published online 6/16/2012), as applied to claims 1, 2, and 23 and further in view of Lippa (Lippa KA et al. BMC Res Notes. 2010 Dec 28;3:349).
The teachings of Rakhade, Qureshi 2, and Bennett are discussed above with regards to independent claim 1.
Regarding claim 4, as discussed above, the combination of Rakhade, Qureshi 2, Bennett, and Zhang renders obvious the invention of claim 1. Furthermore, Zhang teaches the use of microarrays for the profiling of lncRNAs and mRNAs (“Data sets characteristics” section” and “LncRNA expression profiles on Affymetrix HG-U133 Plus 2.0 arrays”, section, and Discussion).
The above prior art does not teach the use of correlating the fold-change of a protein-coding control gene that is common to both arrays.
Lippa is a research article focused on the use of internal and external controls when using microarrays (Title and throughout). Lippa teaches that:
“whole-array metrics and information from a standard mixture of external spike-in and endogenous internal controls. Spike-in controls were found to carry the same information about technical performance as whole-array metrics and endogenous "housekeeping" genes. These results support the use of spike-in controls as general tools for performance assessment across time, experimenters and array batches, suggesting that they have potential for comparison of microarray data generated across species using different technologies,” (Background, first paragraph).
Thus, Lippa teaches that, when comparing data from multiple microarrays, positive controls to control for consistency of data can be used to generate comparable datasets across microarrays, including endogenous protein-coding genes common to the arrays (“housekeeping” genes, Background, first paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Rakhade, Qureshi 2, Bennett, Zhang and Lippa, to include a protein-coding gene control common to both the lncRNA and mRNA arrays, because, as taught by Lippa, this is simply the use of a known technique to improve a similar method in the same way. In the present case, the use of an endogenous control when comparing microarray data is a known technique taught by Lippa which would be applied to the known method of microarray analysis of lncRNA and mRNA taught by Zhang. A practitioner would be motivated to include a positive control across the data to ensure that the results of the data are consistent.
Claims 5, and 9 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer (Mercer TR et al. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21), as applied to claims 1, 2, and 23 above, and further in view of Zhang (Zhang X et al. Neurobiol Dis. 2012 Oct;48(1):1-8, published online 6/16/2012, previously supplied). Claims 5 and 9 are further evidenced by Thermo (Product insert for Affymetrix HG-U133 Plus 2.0 arrays, published 2007, previously supplied).
The teachings of Rakhade, Qureshi 2, and Bennett are discussed above with regards to independent claim 1.
Regarding claim 5, Rakhade teaches a method to identify differentially expressed genes between two paired brain tissue samples (Summary, and throughout, see rejection of claim 1,above). Rakhade also teaches the use of microarray profiling/probes to identify differentially expressed genes (page 91, right column, first paragraph). Qureshi 2 teaches a motivation to identify differential expression of lncRNAs in diseased versus control tissue in epilepsy patients (page 8, final two lines).
Rakhade, Qureshi 2, and Bennett do not teach that measuring the expression of lncRNAs and mRNAs comprises contacting the sample with at least 1000 lncRNA probes and at least 4000 mRNA probes.
Zhang is a research article focused on lncRNA expression profiles, and how these expression profiles can predict glioma phenotypes (Title, Abstract, and throughout). Zhang teaches obtaining brain tissue samples and also performing lncRNA expression profiling using Affymetrix microarrays to determine lncRNA expression levels (“Data sets characteristics” section” and “LncRNA expression profiles on Affymetrix HG-U133 Plus 2.0 arrays”, section). Zhang also teaches that:
“in this study, we re-annotated the HG-U133 Plus 2.0 probe sets and developed a lncRNA classification pipeline to identify the lncRNAs represented on this array. This method is feasible and attractive in its accuracy and low cost. It also allows the analysis of mRNA and lncRNA expressions at the same time and is easier to follow than transcript sequencing analysis,” (Discussion, second paragraph).
Thus, Zhang teaches lncRNA expression profiling of human brain tissue, that such a method can be coupled with mRNA expression profiling, and that such a method is attractive because of its low cost and accuracy (Discussion, second paragraph). Zhang overlaps with the research scope of Qureshi 2 and Rakhade because these research efforts concern expression profiling of human brain tissue. Zhang teaches that “2448 lncRNA probe sets” were analyzed (page 3, left column, third paragraph). Furthermore, Zhang teaches the use of Affymetrix HG-U133 Plus 2.0 arrays (Results, second paragraph). As evidenced by Thermo, the Affymetrix HG-U133 Plus 2.0 arrays target up to 14,500 genes/mRNAs (page 2, middle column, first paragraph). Furthermore, the fact that Thermo, a commercial supplier of molecular biology reagents and supplies, has a product insert concerning array chip probes is evidence in the industry that such tests are routine.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the presently claimed invention to modify the microarray/lncRNA expression methods rendered obvious by Rakhade, Qureshi 2, and Bennett to include at probes for at least 1000 lncRNAs and at least 4000 mRNAs because such a combination is the simple combination of known prior art elements to yield predictable results. Furthermore, Zhang teaches that such testing is cost effective and simple. Additionally, as evidenced by Thermo, such probe arrays are commercially available and therefore routine and predictable in the art.
Regarding claim 9, Zhang teaches the use of Affymetrix HG-U133 Plus 2.0 arrays and, as evidenced by Thermo, these arrays comprise 11 probe pairs per sequence (Zhang, “Data sets characteristics” section” and “LncRNA expression profiles on Affymetrix HG-U133 Plus 2.0 arrays”, section, Thermo page 4, top table).
Claim 6 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer (Mercer TR et al. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21), as applied to claims 1, 2, and 23 above, and further in view of Lu (Lu R et al. BMC Bioinformatics. 2008 Jul 19;9:314).
Regarding claim 6, the limitations of claims 1 and 5 are addressed above. The above prior art does not teach contacting the pair of samples with dyes before contacting the samples with probes, wherein each member of the paired samples is contacted with a different dye than the other member.
Lu is a research article which focuses on probe-specific dyes and slide biases in two-color microarrays (Title and throughout). Lu teaches that:
“a primary reason for using two-color microarrays is that the use of two samples labeled with different dyes on the same slide, that bind to probes on the same spot, is supposed to adjust for many factors that introduce noise and errors into the analysis,” (Abstract).
It would have been obvious to a person of ordinary skill in the art, before the time of the effective filing date, to combine the teachings of Rakhade, Qureshi 2, and Bennett with the teachings of Lu because such a combination is the simple combination of known prior art elements to yield predictable results. As discussed above, Rakhade teaches the use of microarrays, and Lu teaches that it is a known method to use different dyes for different samples to adjust for background noise and errors in the analysis. Thus, a practitioner would be motivated to use different dyes for the different samples to yield more accurate data and to differentiate the samples.
Claim 7 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer (Mercer TR et al. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21), as applied to claims 1, 2, and 23 above, and further in view of Yuan (Yuan DS et al. Nucleic Acids Res. 2005 Jul 1;33(12):e103).
Regarding claim 7, as discussed above the limitations of claim 1 are rendered obvious by the combination of Rakahde, Qureshi 2, and Bennett. Rakhade teaches the use of microarrays (see above rejection of claim 1). These prior art references do not teach the use of a dye flip microarray.
Yuan is a research article focused on the improvement of microarray methods (Title and throughout). Yuan teaches that:
“microarrays are fundamentally an assay methodology for detecting specific nucleic acids. A foremost concern of any assay is to determine its sensitivity and specificity. This is a potentially complex problem in the case of microarrays, not only because of the multiplexed nature of the assay but also because of the diverse range of experimental variables that come into play during the assay procedure. As a control for these variables, we performed a ‘dye-flip’ experiment in which matched samples were hybridized on consecutive days by the same person to the same slides using the same reagents, but with labels that were in reversed order on the second day,” (section entitled “A dye-flip experiment for microarray diagnostics”, first paragraph).
Thus, Yuan teaches that performing dye flip experiments when using microarrays offers better control of experimental variables (section entitled “A dye-flip experiment for microarray diagnostics”, first paragraph).
It would have been obvious to a person of ordinary skill in the art, before the time of the effective filing date, to combine the teachings of Rakhade, Qureshi 2, and Bennett with the dye flip microarray teachings of Yuan because performing a dye flip microarray confers better control of experimental variables, as taught by Yuan. Thus, a practitioner using the microarrays taught by Rakhade would be motivated to do a dye flip microarray taught by Yuan, for better experimental results.
Claim 8 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer (Mercer TR et al. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21), as applied to claims 1, 2, and 23 above, and further in view of Kaposi-Novak (Kaposi-Novak P et al. Biotechniques. 2004 Oct;37(4):580, 582-6, 588).
As discussed above, the combination of Rakhade, Qureshi 2, and Bennett, render obvious to claim limitations recited in claim 1. These prior art references do not teach generating aminoally-aRNA from RNA in the samples before measuring expression.
Kaposi-Novak is a research article focused on microarray analysis of aminoally-labeled oligonucleotides from RNA amplification (Title and throughout). Kaposi-Novak teaches aRNA synthesis during microarray analysis, and also that their methods yielded highly reproducible results (Abstract).
It would have been obvious to a person of ordinary skill in the art, before the time of the effective filing date of the claimed invention, to combine the teachings of Rakhade, Qureshi 2, Bennett, and Kaposi-Novak to arrive at the invention claimed in claim 8 because such a combination is the simple combination of known prior art elements to yield predictable results. The results are predictable because the methods taught by Rakhade use microarrays, and Kaposi-Novak’s methods also use microarrays in combination with aRNA, wherein Kaposi-Novak teaches that their method is “highly reproducible” (Abstract) The combination of the teachings would therefore produce predictable results, where a practitioner would be motivated to combine the teachings of Kaposi-Novak because such methods are highly reproducible.
Claims 20 and 24 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer (Mercer TR et al. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21), as applied to claims 1, 2, and 23 above, and further in view of Jia (Jia H et al. RNA. 2010 Aug;16(8):1478-87, provided in the IDS filed 4/28/2020).
Regarding 20, as discussed above, the combination of Rakhade, Qureshi 2, and Bennett, render obvious to claim limitations recited in claim 1. Rakhade teaches the use of microarrays/probes (see above rejection of claim 1). Qureshi 2 teaches that lncRNAs are associated with epilepsy and therefore teaches a motivation to target and measure lncRNAs to determine their mechanistic role in epilepsy (see rejection of claim 1).
The prior art references cited do not teach that the plurality of lncRNA genes are 6736 lncRNA genes.
Jia is a research article that teaches genome-wide identification and annotation of lncRNA genes (Title, Abstract, and throughout). Jia teaches that they have identified 5446 lncRNA genes, and that they combined this dataset with other published work to derive 6736 lncRNA genes (Abstract). Thus, Jia teaches known pools of lncRNAs of 6736 genes which have been manually annotated/curated and verified (Abstract and Title). Jia further teaches that lncRNAs are widely unexplored, and may have great biological relevance (page 1478, right column, first paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the microarray methods of Rakhade to measure lncRNAs and associated lncRNA/mRNA pairs in the context of epilepsy as taught by Qureshi 2 and Bennett with the lncRNA pools taught by Jia, and to measure 6736 lncRNAs because Jia has already taught a manually curated set of 6736 lncRNAs which are useful for exploring lncRNAs using microarrays. A practitioner would be motivated to use Jia’s dataset of 6736 lncRNAs because they have been manually curated for accuracy.
Regarding claim 24, the method claim of 24 appears to be identical to the method of claim 1, the rejection of which is incorporated herein, with the exception that claim 24 recites specific probes for lncRNAs. For instance, claim 24 recites a probe for lncRNA AF086035 (SEQ ID NO: 3). It is further important to note that the high density microarray as claimed is not limited to one or more of the lncRNAs recited, but that such one or more probes are simply a part of the microarray.
As discussed above, Jia teaches lncRNA panel. Furthermore, the supplemental data of Jia teaches that AF086035 is one of the lncRNAs used in microarray profiling (see the supplemental data set attached at the end of Jia, where the supplemental data was pulled from the online publication and lists each of the lncRNAs). As seen in the supplemental data, AF086035 is one of the lncRNAs identified as part of the annotated set of Jia (see the 16th page of the listed lncRNAs, line 30, “AF086035”). As Jia teaches this lncRNA, they furthermore inherently teach its sequence (i.e., SEQ ID NO: 3). Therefore, a practitioner using the lncRNA set taught by Jia would be using a probe for microarray analysis for AF086035. Thus, the combination of Rakhade/Quereshi 2/Bennett/Jia renders obvious the limitations of claim 24.
Claims 14, and 15 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer, as applied to claims 1-2, 11, 12, 13, 17, 18, and 23, above, and further in view of Zhang (Zhang X et al. Neurobiol Dis. 2012 Oct;48(1):1-8, published online 6/16/2012, previously supplied).
The teachings of Rakhade, Qureshi 2, and Bennett are discussed above with regards to independent claim 11.
Regarding claims 14 and 15, Zhang is a research article focused on lncRNA expression profiles, and how these expression profiles can predict glioma phenotypes (Title, Abstract, and throughout). Zhang teaches obtaining brain tissue samples and also performing lncRNA expression profiling using Affymetrix microarrays to determine lncRNA expression levels (“Data sets characteristics” section” and “LncRNA expression profiles on Affymetrix HG-U133 Plus 2.0 arrays”, section). Zhang also teaches that:
“in this study, we re-annotated the HG-U133 Plus 2.0 probe sets and developed a lncRNA classification pipeline to identify the lncRNAs represented on this array. This method is feasible and attractive in its accuracy and low cost. It also allows the analysis of mRNA and lncRNA expressions at the same time and is easier to follow than transcript sequencing analysis,” (Discussion, second paragraph).
Thus, Zhang teaches lncRNA expression profiling of human brain tissue, that such a method can be coupled with mRNA expression profiling, and that such a method is attractive because of its low cost and accuracy (Discussion, second paragraph). Zhang overlaps with the research scope of Qureshi 2 and Rakhade because these research efforts concern expression profiling of human brain tissue. Zhang teaches that “2448 lncRNA probe sets” were analyzed (page 3, left column, third paragraph). Furthermore, Zhang teaches the use of Affymetrix HG-U133 Plus 2.0 arrays (Results, second paragraph). As evidenced by Thermo, the Affymetrix HG-U133 Plus 2.0 arrays target up to 14,500 genes/mRNAs (page 2, middle column, first paragraph). Furthermore, the fact that Thermo, a commercial supplier of molecular biology reagents and supplies, has a product insert concerning array chip probes is evidence in the industry that such tests are routine. Regarding claims 14 and 15, Zhang teaches the use of Affymetrix microarrays to detect lncRNAs and mRNAs, and therefore teaches quantifying lncRNA and mRNA and a microarray capable of quantifying lncRNA and mRNA (“Data sets characteristics” section and “LncRNA expression profiles on Affymetrix HG-U133 Plus 2.0 arrays”, section, and Discussion).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Rakhade, Quereshi 2 and Bennett with those of Zhang to arrive at a microarray capable of quantifying lncRNA and mRNA, as such a combination is the simple combination of known prior art elements to arrive at predictable results. In the present case, Zhang teaches that such microarrays can quantify lncRNA and mRNA; as such a practitioner would be motivated lncRNA and mRNA simply because of such a requirement to quantify and measure target variables/RNAs rendered obvious by Rakhade, Qureshi 2, and Bennett.
Claim 16 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rakhade (Rakhade SN et al. Epilepsia. 2007;48 Suppl 5:86-95) in view of Qureshi 2 (Qureshi et al. Trends Mol Med. 2011 June ;17(6):337-346), and Bennett (WO 2012/012467 A2, published 1/26/2012) as evidenced by Mercer, and Zhang (Zhang X et al. Neurobiol Dis. 2012 Oct;48(1):1-8, published online 6/16/2012), as applied to claims 11, 14, and 15 and further in view of Lippa (Lippa KA et al. BMC Res Notes. 2010 Dec 28;3:349).
The teachings of Rakhade, Qureshi 2, and Bennett are discussed above with regards to independent claim 11.
Regarding claim 16, as discussed above, the combination of Rakhade, Qureshi 2, Bennett, and Zhang renders obvious the invention of claim 11. Furthermore, Zhang teaches the use of microarrays for the profiling of lncRNAs and mRNAs (“Data sets characteristics” section” and “LncRNA expression profiles on Affymetrix HG-U133 Plus 2.0 arrays”, section, and Discussion).
The above prior art does not teach the use of correlating the fold-change of a protein-coding control gene that is common to both arrays.
Lippa is a research article focused on the use of internal and external controls when using microarrays (Title and throughout). Lippa teaches that:
“whole-array metrics and information from a standard mixture of external spike-in and endogenous internal controls. Spike-in controls were found to carry the same information about technical performance as whole-array metrics and endogenous "housekeeping" genes. These results support the use of spike-in controls as general tools for performance assessment across time, experimenters and array batches, suggesting that they have potential for comparison of microarray data generated across species using different technologies,” (Background, first paragraph).
Thus, Lippa teaches that, when comparing data from multiple microarrays, positive controls to control for consistency of data can be used to generate comparable datasets across microarrays, including endogenous protein-coding genes common to the arrays (“housekeeping” genes, Background, first paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Rakhade, Qureshi 2, Bennett, Zhang and Lippa, to include a protein-coding gene control common to both the lncRNA and mRNA arrays, because, as taught by Lippa, this is simply the use of a known technique to improve a similar method in the same way. In the present case, the use of an endogenous control when comparing microarray data is a known technique taught by Lippa which would be applied to the known method of microarray analysis of lncRNA and mRNA taught by Zhang. A practitioner would be motivated to include a positive control across the data to ensure that the results of the data are consistent.
Response to Arguments
The Applicant’s arguments filed 4/27/2026 have been considered but are not persuasive.
As an initial matter, the presently claimed invention is drawn to a general exploratory method of measuring lncRNAs in the context of an epileptic patient’s brain tissue. As such, the method itself is not drawn to a specific lncRNA for treatment, but is rather drawn to simply a method of measuring lncRNAs in epileptic brain samples. The 103 rejection (above) is made in light of the facts that the tissue sampling method was already known in the art, as well as a motivational teaching in the art which implicates lncRNAs having an association with epilepsy, thereby motivating a practitioner to measure, in general, lncRNA expression in the context of epilepsy. It is the position of the Office that Qureshi 2 provides sufficient motivation to measure lncRNAs in the context of exploring therapeutic targets using a method such as that taught by Rakhade because Qureshi 2 states “Additional lncRNAs are associated with epilepsy and stroke,” (page 8, final line). Thus, lncRNAs and their association with epilepsy was known, thereby providing a motivation to measure lncRNAs in the context of therapeutic identification assays in epileptic tissue sampling screenings such as those taught by Rakhade.
Regarding the Remarks, the Applicant argues that Rakhade does not provide a motivation to look at lncRNAs because Rakhade was concerned with measuring proteins, arguing that Rakhade provides other proteins to explore as potential targets. The Applicant references the Declaration filed 4/27/2026, where the inventors state that lncRNAs were not explored because they do not encode proteins. This argument is not persuasive because, for the purposes of the rejection, Qureshi 2 is relied upon for teaching a motivation to measure lncRNAs, not Rakhade. The mere fact that Rakhade used the sampling method of the independent claims 1 to investigate proteins does not preclude a practitioner from using the same brain tissue sampling method to extract tissue to be used to measure lncRNAs. Furthermore, the practitioner is motivated to measure lncRNAs in epilepsy samples because Qureshi 2 teaches that lncRNAs are associated with epilepsy (see 103 rejection). The Applicant’s argument does not address the motivational teachings of Qureshi 2, who teaches that lncRNAs are in fact associated with epilepsy.
Thus, the Office reiterates that such analysis is piecemeal analysis. The Applicant quotes MPEP 2145 IV, in part stating that “where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate.” This argument is not persuasive because in the present case, the applied references do teach the limitations of the claims, where furthermore the applicant has not addressed the combined teachings and suggestions of the applied art. Thus, the Applicant’s arguments attack the references individually, as the argument relies on the fact that Rakhade measured RNA expression profiles of proteins and not lncRNAs, but does not address the fact that it was known in the art that lncRNAs are also associated with epilepsy, thus motivating a practitioner to measure lncRNAs using the tissue sampling method of epileptic patients taught by Rakhade.
Furthermore, it should be stated for the sake of clarity and the record that the methods of Rakhade teach the use of microarrays (page 91, right column, first paragraph) and RNA isolation (page 88, left column final paragraph into right column paragraphs 1-2). The methods of Rakhade therefore rely on measuring gene expression by measuring RNA, and not proteins directly. Given that Rakhade teaches RNA isolation and the use of microarrays (which measure RNA), measuring lncRNAs (which are also RNA) is compatible with the basic sample preparation methodologies of Rakhade, where different probes would be used to measure lncRNA.
The Applicant argues that Rakhade only teaches a motivation to measure proteins, and not other genes that are differentially expressed. This argument is not persuasive because it does not take into consideration the totality of what the combined teachings of the art would motivate a practitioner to measure. A practitioner would be motivated to measure lncRNAs (i.e., other differentially expressed genes) based on the known fact that they are associated with epilepsy, as taught by Qureshi 2.
The Applicant argues that “obvious to try” is not equated with obvious. This argument is not persuasive. As an initial point, the rejection of the independent claims is not based upon the KSR rationale of “obvious to try,” but is instead based on the motivational teachings of Qureshi 2 to investigate lncRNAs, who teaches that lncRNAs are associated with epilepsy. The arguments presented by the Applicant with regards to the “obvious to try” rationale are therefore moot. However, the points of the argument shall be addressed. The Applicant cites MPEP 2143, stating that “obvious to try” is not equated with obviousness where what would be obvious to try would be to vary all parameters to eventually arrive at a solution with no clear indication of what parameters are critical. This is not persuasive because Qureshi 2 provides an exact parameter to measure/vary: lncRNAs, and furthermore a motivation to measure lncRNAs. With regards to the prior art only giving general guidance on what is claimed or how to achieve it, this argument is not persuasive because the prior art gives a specific method of sampling (Rakhade) where Qureshi 2 gives a specific target to measure (lncRNAs). Furthermore, such measurements using microarrays/RNA isolation/quantification are routine in labs (e.g., see rejection of claims 20 and 24, and Rakhade, page 91 right column, “microarray,” and Thermo, which is a commercially available product for such arrays).
The Applicant argues that Qureshi 2 does not cure the deficiencies of Rakhade because Qureshi 2 teaches another protein for exploration, where such a teaching would not suggest lncRNAs as there is a lack of specific information in Qureshi 2. This argument is not persuasive because it mischaracterizes the totality of what Qureshi 2 teaches. Qureshi 2 directly states that “Additional lncRNAs are associated with epilepsy
and stroke,” (page 8, final line). This statement is not lacking in specific information with regards to lncRNAs and epilepsy, and would furthermore motivate a practitioner to measure lncRNAs and make associations with epilepsy, as suggested by Qureshi 2. Thus, Qureshi 2 makes a clear statement which implicates lncRNAs and their association with epilepsy. This is a clear motivational teaching to measure lncRNAs in the context of epilepsy.
The Applicant argues that Qureshi 2 and Bennet do not teach exploring different portions of a patient’s brain, where the combination of Qureshi 2 and Rakhade would yield “an entire universe” of things to explore. This argument is not persuasive because Qureshi 2 is only modifying Rakhade in one aspect, namely, in the measurement of lncRNAs versus RNA for genes expressing protein, as taught by Rakhade. The sampling method, including sampling from different parts of the brain from the same patient and measuring interictal spikes, has already been taught by Rakhade, who teaches that the sampling method is useful for identifying therapeutics:
“Understanding the potential roles of interictal spike activity and the genes that are induced together with that spiking should offer us further clues on both the causes of focal neocortical epilepsy as well as potential therapeutic treatments for the future,” (page 94, left column, first paragraph).
Rakhade therefore teaches that it is important to measure and understand genes that are differentially expressed (“induced”) using their method to identify therapeutic targets (above). It is therefore irrelevant that either Qureshi 2 or Bennet do not disclose sampling different regions of the same person’s brain/interictal spiking correlations, because Rakhade already teaches this as part of their method, as well as the benefits of using such a sampling method. Qureshi 2 is relied upon as simply teaching a category of genes which are already known to be associated with epilepsy (i.e., lncRNAs). A practitioner is therefore motivated to apply the useful method of Rakhade to a known family of genes associated with epilepsy, as taught by Qureshi 2. The fact that Rakhade focused on protein-coding genes is in no way a final statement on potential biomarkers or therapeutic targets which could be explored by a practitioner. Given that Qureshi 2 teaches that lncRNAs are associated with epilepsy, it is the position of the Office that a practitioner would be motivated to measure such genes as lncRNAs using a sampling method specific for the identification of therapeutic targets in epilepsy as taught by Rakhade.
The Applicant argues that there is no mention of epilepsy in Bennett. This argument is not persuasive because Bennett is not relied upon to teach epilepsy and its association with lncRNA, where Qureshi 2 is relied upon for such a teaching. Instead, given that Rakhade/Qureshi 2 already teach a motivation to perform sampling on epileptic patient brains, and to specifically measure lncRNA, Bennett is relied upon to teach how to interpret such lncRNAs for identifying therapeutic targets and mRNA associations. Bennett teaches that it is known that lncRNAs are associated with mRNA pairings; therefore, given that a practitioner would be motivated to measure lncRNAs using the method of Rakhade, and given that is was known in the art that lncRNAs are associated with cis-mRNA targets as taught by Bennett to affect gene expression changes, the practitioner would furthermore be motivated to investigate functional lncRNA/mRNA pairings because they would be armed with the knowledge that lncRNAs are functionally paired with nearby mRNA, per Bennet. The fact that Bennet is not directed to epilepsy is irrelevant because Bennet teaches underlying mechanistic functions of lncRNA, and that it is useful to identify mRNA pairs with lncRNAs. In other words, Rakhade/Qureshi 2 already render obvious measuring lncRNA in the context of epilepsy, where Bennett teaches that when measuring lncRNAs it is also useful to identify an mRNA paired with the lncRNA, as lncRNAs are known to function with nearby mRNAs. The Applicant argue that Engstrom teaches significant differences between mouse and human non-coding RNA, but does not recite a specific passage to support this claim. Furthermore, the fact that there are differences between mouse and human genes does not render the claimed invention non-obvious, as Engstrom does not support a conclusion that lncRNAs are not paired with mRNA, which is taught by Bennett and relied upon for the rejection.
The Applicant argues that it is impermissible to pick and choose material from a given set of references to arrive at a rejection. The Applicant argues that Rakhade is directed to proteins and uses a different sampling method than Qureshi 2 and Bennett. This argument is not persuasive. Rakhade is relied upon for teaching the tissue sampling method, where the method is taught to be useful for identifying therapeutic targets. Thus, the practitioner is not picking and choosing form different methods, but is starting with and applying the method of Rakhade as a primary reference. Furthermore, Rakhade is in no way limited to only proteins, as such a statement would preclude any additional measurements being taken from a given sampling method. Given that Qureshi 2 teaches new information, that lncRNAs are associated with epilepsy, a practitioner is motivated to look outside of just proteins as taught by Rakhade, in light of the additional information known in the field. Furthermore, Rakhade relies on quantifying and characterizing protein expression by measuring RNA levels, where measuring RNA levels and their expression is also how one would evaluate lncRNA expression using known techniques outlined in the 103 rejection above. Rakhade therefore teaches a useful sampling technique to identify therapeutic targets in epileptic patients where Qureshi 2 teaches the target to measure (lncRNAs). The Applicant argues that Qureshi 2 teaches proteins associated with epilepsy, and a diverse class of non-coding RNAs. This argument is not persuasive because it does not include a key teaching of Qureshi 2: “Additional lncRNAs are associated with epilepsy and stroke,” (page 8, final line). Thus, Qureshi 2 teaches unequivocally that lncRNAs are associated with epilepsy, as they state this directly. The fact that Qureshi 2 also teaches other information does not detract from this teaching relating lncRNAs to epilepsy.
The Applicant argues that a practitioner is choosing from a large list of parameters in order to arrive at the claimed invention by using the combination of Rakahde, Qureshi 2, Bennett, and Mercer. This argument is not persuasive. Rakhade teaches the sampling method steps of the independent claims. Starting with Rakhade, the limitations not recited in Rakhade is that the target is lncRNA, where lncRNA is paired with an mRNA. However, a practitioner is motivated to measure lncRNA, per Qureshi 2, who states clearly that lncRNA is associated with epilepsy. Given that such a motivation to measure lncRNA already exists using the useful method of Rakhade, it is furthermore obvious to pair such lncRNA with an mRNA, as lncRNAs were already known to be paired with mRNAs per Bennett. The fact that the sited references also teach other proteins is irrelevant in light of the clear motivation taught by Qureshi 2 to measure lncRNA. The Applicant’s argument that no clear choices or guidance is provided, which echoes the “obvious to try” argument, is not persuasive for the reasons discussed (bottom of page 26 into page 27 of this office action), namely, that sufficient guidance and parameters are defined by the cited references.
The Applicant argues that the office provides no reason to create an assay for anything aside from proteins. This argument is not persuasive because it does not address the merits of the rejection. Qureshi 2 clearly teaches a motivation to create an assay for something other than proteins by directly stating that lncRNAs are associated with epilepsy, as discussed above. The office action is therefore not relying on hindsight reasoning or the Applicant’s own specification but is instead relying on a direct motivational teaching which is combinable with the teachings of Rakhade.
The Applicant argues that the remaining prior art references do not cure the deficiencies of the dependent claims. This argument is not persuasive because, as discussed above, the combination of Rakhade, Qureshi 2, Bennett, and Merce is sufficient to render the claimed subject matter non-obvious.
In summary, the presently recited invention can be characterized as follows: the independent claims recite a known tissue sampling technique for brain tissue of epileptic patients for the discovery of therapeutic targets, as taught by Rakhade. The claims recite that lncRNAs are a target to be measured. It is obvious to measure lncRNAs because it was already known that lncRNAs are associated with epilepsy, per Qurehsi 2. Furthermore, given that it is obvious to measure lncRNAs in the context of epilepsy, it is furthermore obvious to pair lncRNAs with mRNA pairings, as lncRNAs are known to function with mRNAs/be paired with mRNAs, per Bennett. Thus, the Applicant has not offered a new sampling method with respect to sampling epileptic patient brain tissue, nor have they originated the concept that lncRNAs are associated with epilepsy. In addition, they have not originated the concept of lncRNA/mRNA pairing because lncRNAs were already known to be functionally associated with cis-mRNA. Thus, the present claims do not comprise an inventive concept.
Response to Declaration
The following are responses to positions addressed in the Declaration filed 4/27/2027 which were not addressed in the response to the arguments above.
The Applicant’s Declaration filed 4/27/2026 has been considered but is not persuasive to place the claims in condition for allowance.
The Declarants state that lncRNAs were not well-characterized at the time of Rakhade. This argument is not persuasive because, following the publication of Rakhade, Qureshi 2 implicates lncRNAs as being associated with epilepsy, which is a motivational teaching to measure lncRNAs in an epileptic patient.
The Declarants state that Rakhade is focused on measuring transcription factors which are already known to be linked with epilepsy, and not any gene. This argument is not persuasive because there is nothing in Rakhade which would limit the basic tissue sampling method only to transcription factors already known to be associated with epilepsy. Given the publication of Qureshi 2, published after the method of Rakhade was published, a practitioner would be motivated to also include the measurement of lncRNAs with the method of Rakhade, as Qureshi 2 teaches that lncRNAs are associated with epilepsy which was the disease of focus in the Rahade study. Thus, the fact that the Rakhade paper was not looking at lncRNAs at the time does not preclude the measurement of lncRNAs using the method of Rakhade, where furthermore a later publication (Qureshi 2) implicates lncRNAs and their association with epilepsy. The fact that the teachings of Rakhade do not encompass all potential therapeutic targets but only transcription factors does not mean that the sampling method of Rakhade can not be modified to accommodate new discoveries (e.g., the association of lncRNAs with epilepsy, as later taught by Qureshi 2).
The Declarant states that there are no methods of discovery in Qureshi 2. This argument is not persuasive because Qureshi 2 simply provides the target (lncRNAs) to be evaluated using a method of discovery such as that of Rakhade in combination with known assays such as microarrays, also taught by Rakhade.
The Declarant states that the teachings of Rakhade are directed to protein coding genes that have known roles in signaling and plasticity, and that lncRNAs are not genes and do not encode proteins, where Rakhade would not lead a practitioner to look at lncRNAs (see paragraph 17 of Declaration filed 4/27/2026). This argument is not persuasive. As an initial matter, lncRNAs are in fact genes, although they are not protein encoding genes (see Title and Abstract of Jia, of record). Furthermore, expression of lncRNAs can be evaluated using transcriptomic analysis similar to methods of record, and can therefore be measured with predictable success (microarrays are taught by Rakhade, and the methods of Jia). Additionally, the fact that Rakhade is directed to proteins, specifically transcription factors, does not mean that Rakhade is the final investigation of biomarkers and therapeutic target discovery for epilepsy, or that no other therapeutic targets could be investigated. Rakhade is not relied upon to motivate a practitioner to measure lncRNAs; Qureshi 2 addresses this limitation. As such, a practitioner is reasonably encouraged to measure lncRNAs using the method of Rakhade, who teaches that such a method is useful in the context of therapeutic identification in epilepsy. Further, Rakade teaches that it is important to understand differentially regulated (“induced”) genes (page 94, left column). This statement does not exclude genes such as lncRNAs, which are implicated in association with epilepsy per Qureshi 2 and therefore would motivate the measurement of such genes as lncRNAs.
The Declarant argues that Qureshi 2 teaches brains from different people, and not sampling brain tissue from the same person at different locations. This argument is not persuasive because the method of Rakhade is used as the primary reference, where Rakhade teaches sampling the same brain in different places to understand underlying mechanisms of epilepsy. Thus, Qureshi 2 is not required to teach sampling the same brain from different places, as this is a component of the sampling method of Rakhade.
The Declarant states that Mercer teaches that specific lncRNAs are expressed in mouse brains and that lncRNAs are known to be associated with paired mRNAs, but that Mercer does not teach the limitations of the tissue sampling method presently recited. This argument is not found to be persuasive, as Rakahde teaches these claim limitations (e.g., sampling a live patient, comparing electrical activity in two samples, etc.). The Declarant states that Engstrom teaches that mouse and human lncRNAs differ substantially and can not be assumed to be equivalent. This argument is not persuasive. As an initial matter, no specific teaching of Engstrom is referenced in the Declaration or Applicant’s Remarks filed 4/27/2026. Secondly, the Applicant does not show that Engstrom teaches that lncRNAs from mice are not paired with mRNA targets, as taught by Mercer. In short, the teachings of Mercer/Bennett, which teach that lncRNA and mRNAs are paired and can be used as therapeutic targets, is not contradicted by the alleged teachings of Engstrom.
Conclusion
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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