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 .
Application Status
Applicant’s response filed January 22, 2026, and supplemental response filed January 26, 2026 are acknowledged. In the response filed January 22, 2026, claims 25, 28-29, and 33 were amended, claims 30, 34, and 37 were cancelled, and claims 38-39 were introduced. No further claim amendments were made in the response filed January 26, 2026. Accordingly, claims 25-29, 33, and 38-39 are pending.
Restriction/Election
Newly submitted claims 38-39 are directed to inventions that are related, but distinct, from the invention originally claimed. Original claims 25-29, and 33 (Group I) are directed to a synthetic double-stranded RNA (dsRNA) targeting MB3 lincRNA having an RNA sequence corresponding to SEQ ID NO: 1, or a vector encoding the dsRNA, wherein the dsRNA comprises a sense strand comprising the sequence set forth in SEQ ID NO: 2, and an antisense strand comprising the sequence set forth in SEQ ID NO: 3, as well as a composition comprising the dsRNA, and methods of treating medulloblastoma in a subject using the synthetic dsRNA of claim 25. Claim 38 (Group II) is directed to a method for reducing at least one of THSD7A expression or Focal Adhesion Kinase (FAK) phosphorylation in medulloblastoma cells of a subject, by administering the synthetic dsRNA of claim 25, or a composition or vector comprising the dsRNA. Claim 39 (Group III) is directed to a method of treating a subject with medulloblastoma, by classifying the medulloblastoma by detecting a level of MB3 lincRNA having an RNA sequence corresponding to SEQ ID NO: 1, and administering an inhibitory nucleic acid targeting the MB3 lincRNA, wherein the inhibitory nucleic acid is an siRNA, ASO, shRNA, or vector encoding the same.
Group I lacks unity of invention with Group II, because even though these groups share the technical feature of the synthetic dsRNA of claim 25, this is not a special technical feature because it does not make a contribution over the prior art in view of Collard and Nanjing (each of record). As described in paragraph 12 below, a dsRNA with the features of claim 25 is obvious in view of Collard and Nanjing. Thus, Groups I and II lack unity of invention a posteriori.
Group III lacks unity of invention with Group I, because even though these groups share the technical features of an MB3 lincRNA having an RNA sequence corresponding to SEQ ID NO: 1, and an inhibitory nucleic acid targeting MB3 lincRNA, these are not special technical features because they do not make a contribution over the prior art in view of Collard and Nanjing (each of record). As described in paragraphs 11-12 below, Nanjing teaches an MB3 lincRNA 100% identical to instant SEQ ID NO: 1 (i.e., COL1A2-AS1), and Collard and Nanjing render obvious an inhibitory nucleic acid targeting MB3 lincRNA. Thus, Groups I and III lack unity of invention a posteriori.
Group III lacks unity of invention with Group II, because even though these groups share the technical feature of an inhibitory nucleic acid targeting MB3 lincRNA, this is not a special technical feature because it does not make a contribution over the prior art in view of Collard and Nanjing (each of record). As described in paragraph 12 below, an inhibitory nucleic acid targeting MB3 lincRNA is obvious in view of Collard and Nanjing. Thus, Groups II and III lack unity of invention a posteriori.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 38-39 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03. Claims 25-29, and 33 are under consideration hereinafter, accordingly.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Withdrawn Rejections
Applicant’s amendments to claims are sufficient to overcome the claim objections, and § 112(b) and § 112(d) rejections raised in the prior action. These rejections are withdrawn, accordingly.
Applicant’s remarks and amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. Any rejection or objection not reiterated herein has been overcome by amendment.
Priority
Applicant’s priority claims to Application Nos. 62/810,981, 62/810,984, and PCT/IL2020/050229 are acknowledged. Claims 25-29, and 33 find support in Application No. 62/810,981, filed February 27, 2019. The effective filing date of the claims under examination is February 27, 2019.
Notice to Joint Inventors
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim Rejections - 35 USC § 103 – Collard in view of Nanjing
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Collard (Collard et al., 16 March 2017, US 2017/0073680 A1; of record) in view of Nanjing (Li, CN106282184A, published 4 January 2017, with attached machine translation; of record). The rejections that follow are maintained and modified as necessitated by Applicant’s amendments to the claims.
Claim 25 encompasses a synthetic dsRNA comprising a sense strand set forth in SEQ ID NO: 2 and an antisense strand set forth in SEQ ID NO: 3, wherein each strand is between 19-25 nucleotides in length. The claim also encompasses a vector, e.g., plasmid, viral vector, and the like (pg. 16, lines 28-31), encoding a polynucleotide comprising the sense and antisense strands of the dsRNA. The dsRNA targets the MB3 lincRNA encoded by the nucleic acid sequence set forth in SEQ ID NO: 1. SEQ ID NO: 1 has 100% identity to the “predicted mRNA from genomic sequences” corresponding to the GRCh37/hg19 entry for TCONS_00013888 (see pgs. 2-3 of Appendix of record, and the alignment of record between the predicted TCONS_00013888 sequence and SEQ ID NO: 1). TCONS_00013888 is also known as COL1A2-AS1 (see GenBank NR_147206.1, of record).
The claim also recites properties of the dsRNA: “said dsRNA is effective in reducing at least one of THSD7A expression or Focal Adhesion Kinase (FAK) phosphorylation in medulloblastoma cells.” The specification teaches that inhibiting MB3 lincRNA using a combination of siRNAs (“siRNA SEQ ID NOs: 2-7”), one of which is encompassed by the instant claims (i.e., “siRNA1” or “si1,” corresponding to SEQ ID NOs: 2-3), reduces THSD7A expression and Focal Adhesion Kinase (FAK) phosphorylation in medulloblastoma cells (Example 7; Figs. 7, and 10-11). As evidenced by the specification, the properties recited in instant claim 25 are achieved by a dsRNA having the structure recited in instant claim 25. Therefore, the recited properties are presumed to be inherent to the structure required of claim 25. See MPEP 2112.
Regarding claim 25, Collard teaches dsRNAs targeting COL1A2-AS1 (“SEQ ID NO: 5: Natural COL1A2 antisense sequence”, [0021], [0063]; “the antisense oligonucleotides are specific for natural antisense sequences of a Collagen gene wherein binding of the oligonucleotides to the natural antisense sequences of a Collagen gene modulate expression and/or function of a Collagen gene”, [0113]; “antisense compounds include… siRNA compounds… double-stranded RNA interference (RNAi) compounds”, [0137], claim 14 pg. 45). Collard also teaches vectors encoding the dsRNA ([0222]-[0225]). Collard teaches that natural antisense transcripts interfere with expression of the corresponding sense gene, and accordingly, antisense compounds targeting the natural antisense transcript increase expression of the corresponding sense transcript ([0004]; [0134]-[0135]). Indeed, Collard demonstrates that administration of antisense compounds targeting COL1A2-AS1 increases the levels of the corresponding sense transcript in cells, COL1A2 mRNA (Fig. 2; [0018]). Collard teaches methods of treatment using siRNAs targeting COL1A2-AS1 (at least claim 14, pg. 45).
The antisense compounds used by Collard in working examples which increased the levels of COL1A2 mRNA in cells have a sense and antisense strand which forms a double-stranded molecule, in which each strand is 20-21 nts in length and 100% complementary to COL1A2-AS1. However, Collard does not teach the specific sense and antisense strand sequences recited in instant claim 25, or the specific COL1A2-AS1 sequence set forth in instant SEQ ID NO: 1.
However, Nanjing teaches a COL1A2-AS1 sequence, which is 100% identical to instant SEQ ID NO: 1 as shown in the alignments of record (“The nucleotide sequence of the transcript of the lncRNA is located at the upstream position of the 5’ end of the COL1A2 gene on human chromosome 7, and has a relationship with COL1A2 as a natural antisense”; “The sequence of said SEQ ID NO. 1 is: ….”, pg. 2/9 of machine translation). As shown in the attached alignments in Appendix I (of record), instant SEQ ID NOs: 2 and 3 are 100% identical and complementary, respectively, to the COL1A2-AS1 sequence disclosed by Nanjing.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the COL1A2-AS1 inhibitory dsRNAs (i.e., siRNAs) taught by Collard, to comprise a sequence complementary to a 20-21nt region of the COL1A2-AS1 sequence disclosed by Nanjing, to arrive at a synthetic dsRNA comprising the sense strand of SEQ ID NO: 2 and the antisense strand of SEQ ID NO: 3. It would have amounted to adapting the target sequence of known dsRNA compounds, by known means, to yield predictable results. Collard states that “Targeting an antisense compound to a particular nucleic acid molecule, in the context of this invention, can be a multistep process… The targeting process usually also includes determination of at least one target region, segment, or site within the target nucleic acid for the antisense interaction to occur such that the desired effect… will result” ([0109-110]). Indeed, Collard demonstrates that different antisense compounds targeting COL1A2-AS1 have differing levels of effectivity in increasing sense transcript expression (Fig. 2).
Nanjing teaches a COL1A2-AS1 sequence 100% identical to instant SEQ ID NO: 1. The skilled artisan would have had a reasonable expectation of success in adapting the target sequence of the dsRNA compounds because as evidenced by Nanjing, the sequence was known, and therefore, the skilled artisan could easily prepare dsRNAs targeting Nanjing’s sequence. The skilled artisan would have been motivated to target the COL1A2-AS1 target sequence of Nanjing because it is known, naturally-occurring COL1A2-AS1 sequence, and Collard strongly suggests that targeting COL1A2-AS1 sequences may provide effective treatments for treating collagen gene-related diseases.
The COL1A2-AS1 taught by Nanjing is 352 nts in length. There are 332 dsRNAs 20 nts in length, and 331 dsRNAs 21 nts in length, each with a sense sequence 100% identical to COL1A2-AS1, and an antisense sequence 100% complementary thereto. Among these solutions are dsRNAs comprising the limitations of instant claim 25. A skilled artisan would have had a reasonable expectation of success in pursuing these finite, predictable solutions because as evidenced by Collard I) it is well within the capabilities of the skilled artisan to design and prepare dsRNAs to a known target sequence and test their effectivity in cells ([0037]-[0038]), and II) it was known that antisense compounds targeting a COL1A2-AS1 sequence increase COL1A2 mRNA expression in cells. A skilled artisan seeking effective treatments for treating collagen gene-related diseases would have been motivated to adapt the target sequence of the compounds of Collard, because Nanjing teaches a naturally-occurring COL1A2-AS1 target sequence, and Collard strongly suggests that a suitable target site with a COL1A2-AS1 sequence must be empirically determined.
As described in paragraph 8 above, based on the evidence in the specification, the properties recited in claim 25 (i.e., “effective in reducing at least one of…”) are achieved by the structure required of claim 25. Each structural element of the dsRNA of claim 25 has been rendered obvious over Collard and Nanjing, and therefore, the properties are presumed to be inherent to the obvious structure. See MPEP 2112.
Regarding claim 26, Collard teaches pharmaceutical compositions comprising the dsRNA and a pharmaceutically acceptable carrier ([0216]).
Regarding claim 27, Collard teaches a method of treating medulloblastoma comprising administering the dsRNA (claims 35-36, pg. 45; wherein ““cancer” refers to all types of cancer or neoplasm or malignant tumor… including… medulloblastoma,” [0058]).
Claim Rejections - 35 USC § 103 – Collard and Nanjing, in view of Su, Anderton, and Ivanov
Claims 28 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Collard (Collard et al., 16 March 2017, US 2017/0073680 A1; of record) and Nanjing (Li, CN106282184A, published 4 January 2017, with attached machine translation; of record) as applied to claims 25-27, in view of Su (Su et al., 2010, Biochemical and Biophysical Research Communications, 396(2010), p. 177-181; of record), Anderton (Anderton et al., 2008, Neuro-Oncology, 10, p. 981-994; of record), and Ivanov (Ivanov et al., 2016, Journal of Biotechnology, 236(2010), p. 10-25; of record). The rejections that follow are maintained and modified as necessitated by Applicant’s amendments to the claims.
The teachings of Collard and Nanjing are described above and applied as to claims 25-27 therein. As stated above, Collard teaches a method of treating medulloblastoma comprising administering a dsRNA targeting COL1A2-AS1 to the subject, or a composition comprising the same (claims 35-36, pg. 45; wherein ““cancer” refers to all types of cancer or neoplasm or malignant tumor… including… medulloblastoma,” [0058]; [0216]). Collard teaches the inhibitor is an siRNA (“the antisense oligonucleotides are specific for natural antisense sequences of a Collagen gene wherein binding of the oligonucleotides to the natural antisense sequences of a Collagen gene modulate expression and/or function of a Collagen gene”, [0113]; “antisense compounds include… siRNA compounds… double-stranded RNA interference (RNAi) compounds”, [0137], claim 14 pg. 45; Fig. 2, [0018]). Finally, for the reasons described in paragraph 12 above, Collard and Nanjing render obvious an siRNA targeting the COL1A2-AS1 sequence disclosed by Nanjing which is 100% identical to instant SEQ ID NO: 1, wherein the siRNA comprises a sense strand as set forth in SEQ ID NO: 2 and an antisense strand as set forth in SEQ ID NO: 3.
However, neither Collard nor Nanjing teach the “classifying” limitations of claim 28, which requires detecting a level of COL1A2-AS1 (i.e., SEQ ID NO: 1) above a predefined threshold in a medulloblastoma tumor sample from the subject, or the “measuring… detecting” limitations of claim 33, which require measuring a level of COL1A2-AS1 (i.e., SEQ ID NO: 1) in a medulloblastoma tumor sample from the subject, and detecting a level of COL1A2-AS1 above a control level.
Su, like Collard, teaches that natural antisense transcripts interfere with the expression of the corresponding sense transcript, such that the antisense transcript and sense transcript may have inverse expression patterns (sections 3-4, pg. 178). Su teaches that antisense transcripts can promote methylation of CpG islands within the sense gene, which leads to sense gene inactivation (section 4, pg. 178-179; Fig. 1). Su teaches that DNA methyltransferase inhibitors, which relieve methylation of CpG islands in diseases or disorders associated with aberrant gene silencing, are not well tolerated by some patients (section 5, pg. 179). Su strongly suggests targeting natural antisense transcripts could be an effective, alternative strategy to increase the expression of sense genes which are aberrantly silenced in diseases or disorders (section 5, pg. 180). Su also teaches that the levels of natural antisense transcripts could “serve as molecular markers for monitoring tumor development” (section 5, pg. 180).
Anderton teaches that the sense gene to COL1A2-AS1, COL1A2, is frequently methylated and epigenetically silenced in medulloblastoma (pg. 982, left col.). Anderton evaluated levels of COL1A2 CpG methylation in normal tissue, various medulloblastoma cell lines, and in primary medulloblastoma samples (Figs. 2-3, pg. 986-988). Anderton shows that in contrast to normal tissue samples (“Normal Cerebella” and two cell lines (“DAOY” and “UW228-3”), many medulloblastoma cell lines and 77% (46/60) primary medulloblastoma samples were methylated, typically across every analyzed COL1A2 CpG site (pg. 988; Fig. 2). Anderton demonstrates that COL1A2 expression levels correlate with methylation status; in contrast to unmethylated cell lines and samples, methylated medulloblastoma cell lines and primary medulloblastoma samples have less COL1A2 expression (Fig. 4). Anderton demonstrates that treatment of COL1A2-methylated cell lines with the DNA methyltransferase inhibitor 5-azaCdR increases COL1A2 expression (Fig. 1B, 4A).
Finally, Ivanov teaches that 6/7 COL1A2-methylated cell lines taught by Anderton (“D425”, “MEB-MED8A,” “D283,” “D341,” “D384,” “D556”) are classified as either Group 3 subtype, or in one case (“D283”) Group 3/Group 4, owing to the similarities between the two Groups (Fig. 1; Table 1; pg. 13, right col.). The remaining cell line has not been molecularly classified (“MHH-MED1”). In contrast, the COL1A2-unmethylated cell lines (“DAOY” and “UW228-3”) correspond to SHH subtype (Fig. 1; Table 1). Ivanov reports that the evidence supporting the affiliation of many of Anderton’s COL1A2-methylated cell lines with the Group 3 subtype is “strong,” based on transcriptional profiling and array data compared to patient tumors (Table 1, “D425”, “MEB-MED8A,” “D341,” “D384”).
Taken together, Su and Collard both teach that natural antisense transcripts (e.g., “MB3 lincRNA”/COL1A2-AS1), have inverse expression patterns to their corresponding sense genes (e.g., COL1A2). Collard specifically demonstrates such an inverse relationship, by using antisense compounds to knockdown COL1A2-AS1 expression, and concomitantly, increase COL1A2 expression. Su teaches that natural antisense transcripts can directly impact CpG methylation of their corresponding sense gene, leading to sense gene inactivation. Finally, together, Anderton and Ivanov illustrate that COL1A2 is hypermethylated and inactivated in medulloblastoma cell lines and primary medulloblastoma samples, and provide strong support that COL1A2 hypermethylation is associated with Group 3 subtype medulloblastoma.
Regarding the “classifying” limitations of claim 28, and the “measuring…detecting” limitations of claims 33, in view of the above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted hypermethylation and/or decreased expression of COL1A2, for a level of COL1A2-AS1 corresponding to instant SEQ ID NO: 1 over a predefined threshold in a subject’s medulloblastoma tumor sample, as a means to classify a subject’s medulloblastoma as Group 3. It would have amounted to a simple substitution of a known marker associated with Group 3 medulloblastoma, for a second marker which is mechanistically linked thereto, by known means to yield predictable results. The prior art establishes a relationship between Group 3 medulloblastoma, and hypermethylation and decreased expression of COL1A2 in medulloblastoma samples. The prior art also establishes an inverse relationship between COL1A2 and COL1A2-AS1 expression, which Su strongly suggests could be mediated by COL1A2-AS1 epigenetic inactivation. Thus, the skilled artisan would have reasonably predicted that substituting hypermethylation and reduced expression of COL1A2, for a level of COL1A2-AS1 over a predefined threshold in a subject’s medulloblastoma tumor sample would identify the subject’s medulloblastoma as Group 3 subtype. The skilled artisan would have had a reasonable expectation of success in performing the claimed method following the substitution because Nanjing teaches the exact sequence of a naturally-occurring COL1A2-AS1 sequence, thereby enabling its detection and quantification, and teaches that COL1A2-AS1 may be amplified from human tissue samples. A skilled artisan would have been motivated to substitute the two biomarkers because Su teaches that the levels of natural antisense transcripts (i.e., COL1A2-AS1) could “serve as molecular markers for monitoring tumor development” (section 5, pg. 180).
Regarding combining the aforementioned “classifying” limitations of claim 28, or “measuring … detecting” limitations of claim 33, with administering an siRNA targeting COL1A2-AS1 to the subject, it would have been obvious to one of ordinary skill in the art to have administered the siRNA rendered obvious in paragraph 12 above, to treat a subject’s Group 3 medulloblastoma. It would have amounted to combining an obvious classification/measuring and detecting step, with a known method of treatment for medulloblastoma, by known means to yield predictable results. Collard teaches that the expression of COL1A2 is increased by administering antisense compounds which knock down expression of COL1A2-AS1. Collard teaches that administration of the antisense compounds is applicable to diseases associated with defective Collagen gene expression, including cancer and specifically, medulloblastoma. Anderton demonstrates that COL1A2 hypermethylation and diminished COL1A2 expression is prevalent in medulloblastoma cell lines and primary patient medulloblastoma samples. Because Collard and Su both strongly suggest that targeting antisense transcripts is an effective strategy to treat diseases associated with aberrant sense gene silencing, and Anderton demonstrates that medulloblastoma is associated with aberrant silencing of COL1A2, a skilled artisan would have reasonably expected that administering a COL1A2-AS1 inhibitor, to subjects having COL1A2-AS1 levels over a threshold/control value would increase expression of COL1A2 and exert some therapeutic effect. Anderton demonstrates that a DNMT inhibitor alleviates COL1A2 inactivation in medulloblastoma cell lines, but Su teaches that DNMT inhibitors are not well-tolerated by some subjects. Thus, a skilled artisan would have been motivated to administer a COL1A2-AS1 inhibitor instead of a DNMT inhibitor because Su suggests that this may be an effective, alternative strategy to restore expression of aberrantly silenced sense genes.
Claim Rejections - 35 USC § 103 – Collard, Nanjing, Su, Anderton, and Ivanov, in further view of Li
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Collard (Collard et al., 16 March 2017, US 2017/0073680 A1; of record), Nanjing (Li, CN106282184A, published 4 January 2017, with attached machine translation; of record), Su (Su et al., 2010, Biochemical and Biophysical Research Communications, 396(2010), p. 177-181; of record), Anderton (Anderton et al., 2008, Neuro-Oncology, 10, p. 981-994; of record), and Ivanov (Ivanov et al., 2016, Journal of Biotechnology, 236(2010), p. 10-25; of record) as applied to claims 25-28, and 33, and in further view of Li (Li et al., 2016, Cellular Physiology and Biochemistry, 2016;40:326-334; of record). The rejection that follows is maintained and modified as necessitated by Applicant’s amendments to the claims.
The teachings of Collard, Nanjing, Su, Anderton, and Ivanov are described above and applied as to claims 25-28, and 33.
None of Collard, Nanjing, Su, Anderton, or Ivanov teach that the level of MB3 lincRNA is measured by extracting RNA from the sample, reverse transcribing the RNA to cDNA, and subjecting the resultant cDNA to quantitative amplification.
However, Li teaches detecting COL1A2-AS1 (“lncRNA8975-1”) in patient samples and cell lines by extracting RNA from the sample, reverse transcribing the RNA, and subjected the resultant cDNA to quantitative amplification (“Quantitative reverse transcription PCR assay”, pg. 327-328; Figs. 1-2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have detected the levels of COL1A2-AS1 in the methods rendered obvious above using quantitative reverse transcription PCR as taught by Li. It would have amounted to applying a well-known technique to detect RNA levels, to obvious methods, by known means to yield predictable results. Li teaches a specific quantitative reverse transcription PCR assay to detect the levels of COL1A2-AS1 in RNA extracted from patient samples and cell lines. Thus, a skilled artisan would have been motivated to apply Li’s method of detecting COL1A2-AS1 to the methods rendered obvious above, with a reasonable expectation of detecting COL1A2-AS1 in patient tumor samples.
Response to Remarks - 35 USC § 103
Applicant’s remarks regarding the § 103 rejections raised in the prior action have been reviewed. First, Examiner acknowledges Applicant’s description of the legal standard for establishing a prima facie case of obviousness.
Regarding the § 103 rejections raised over Collard and Nanjing, Applicant asserts that the “fundamental teachings of Collard and Nanjing are contradictory: while Collard is interested in upregulating collagen and teaches inhibiting natural antisense transcripts of collagen genes including a natural antisense of COL1A2… Nanjing is interested in downregulating collagen… and teaches over-expressing the natural antisense of COL1A2 that it discloses.” Applicant asserts that the skilled artisan would “find no reason or motivation to combine these opposed teachings of Collard and Nanjing.”
Examiner acknowledges that Nanjing is interested in administering a natural antisense transcript of COL1A2 which is 100% identical to instant SEQ ID NO: 1, in an effort to reduce collagen, for the purposes of preventing hypertrophic scar formation. The skilled artisan would have recognized that the applications of Collard and Nanjing differ, but would have easily understood that Collard and Nanjing both leverage the inverse relationship between COL1A2 and its natural antisense transcript to treat diseases or disorders associated with COL1A2. The skilled artisan would have recognized that Nanjing teaches the sequence of a COL1A2 natural antisense transcript, and that Collard teaches preparing dsRNA targeting the COL1A2 natural antisense transcript. There is no evidence in either of Collard or Nanjing, that the skilled artisan would not have been able to prepare a dsRNA molecule targeting the natural antisense transcript of COL1A2 as taught by Collard, using the known sequence of the natural antisense transcript of COL1A2 taught by Nanjing. Examiner notes that motivation to combine the references was provided in the prior rejection, which is maintained herein (“The skilled artisan would have been motivated to target the COL1A2-AS1 target sequence of Nanjing because it is known, naturally occurring COL1A2-AS1 sequence, and Collard strongly suggests that targeting COL1A2-AS1 sequences may provide effective treatments for treating collagen gene-related diseases”).
Applicant also asserts that “[m]aintaining the outstanding obviousness rejections… would amount to hindsight reconstruction.” Applicant appears to allege that the obviousness rejections of record “stitch together… discrete portions of the prior art references without considering the references as a whole.” Applicant also asserts that the Office Action provides no basis for why one of skill in the art would have been motivated to select a dsRNA comprising the claimed sense and antisense strands, and no basis that would lead the skilled artisan to target the RNA sequence corresponding to SEQ ID NO: 1.
Regarding Applicant’s allegations of hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. So long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The obviousness rejection of record takes into account only the knowledge of the ordinarily skilled artisan, and relies solely upon the prior art, not upon knowledge gleaned only from Applicant’s disclosure. The obviousness rejection of record is based on an “obvious to try” rationale. The examiner has met each of the criteria to establish a prima facie case of obviousness under this rationale set forth in MPEP 2143(I)(E). It is noted that motivation to arrive at a specific solution amongst the identified, predictable solutions is not required to render the claims obvious under this rationale. The rejection also provides motivation to target the natural antisense transcript of COL1A2 described by Nanjing (see paragraph 21 of the prior action, and paragraph 12 above). There is no apparent deficiency in the rejections with respect to the limitations of the claims (e.g., lengths of strands, or specific sequences), or the requirements to establish a prima facie case of obviousness under the rationale applied.
Applicant also alleges that Collard and Nanjing do not teach or suggest a dsRNA which “is effective in reducing at least one of THSD7A expression or Focal Adhesion Kinase (FAK) phosphorylation in medulloblastoma cells” as recited in instant claim 25. The limitations referred to by Applicant recite properties of the dsRNA. As described in paragraph 8 above, the specification teaches that inhibiting MB3 lincRNA using a combination of siRNAs (“siRNA SEQ ID NOs: 2-7”), one of which is encompassed by the instant claims (i.e., “siRNA1,” or “si1,” corresponding to SEQ ID NOs: 2-3), reduces THSD7A expression and Focal Adhesion Kinase (FAK) phosphorylation in medulloblastoma cells (Example 7; Figs. 7, and 10-11). As evidenced by the specification, the properties recited in instant claim 25 are achieved by a dsRNA having the structure recited in instant claim 25. Examiner has rendered obvious each structural element of the dsRNA of claim 25 over Collard and Nanjing. The properties are presumed to be inherent to the obvious structure based on the specification. The prior art does not need to disclose such inherent properties. See MPEP 2112.
Applicant also relies upon alleged “unexpectedly superior results” disclosed in Example 2 and Fig. 2C, in which “the claimed dsRNA (identified as siRNA1 in the Examples section) was particularly effective in silencing MB3 lincRNA and had the highest silencing effect amount three different siRNAs….” Examiner has reviewed the results in Example 2 and Fig. 2C. Example 2 and Fig. 2C describe the effects of an siRNA (“siRNA1” or “si 1”) which consists of SEQ ID NOs: 2-3, and which based on Fig. 2C, decreases MB3 lincRNA expression by 86% in vitro. Applicant’s evidence is not commensurate with the instant claims, which are directed to a genus of dsRNAs comprising a sense and antisense strand, wherein each strand is between 19-25 nts in length, and the sense strand comprises SEQ ID NO: 2, and the antisense strand comprises SEQ ID NO: 3. In addition, it is not evident that Applicant’s proffered results are unexpected, because the effect of the siRNA consisting of SEQ ID NOs: 2-3 (i.e., 86% reduction in MB3 lincRNA expression) is similar to two other siRNAs, which result in 79% and 83% reduction in vitro, and siRNAs which reduce target RNA levels to 86% or more are not unexpected based on the prior art, which demonstrates that greater than 50% of siRNAs designed to a target RNA reduce expression by more than 80% (see pg. 326, Fig. 1 and description of Reynolds et al., 2004, Nature Biotechnology, Vol. 22, No. 3, pg. 326-330). Thus, at present, Applicant’s evidence of alleged unexpected results is not sufficient to overcome the rejections of record.
Regarding the § 103 rejections raised in further view of Su, Anderton, and Ivanov, Examiner acknowledges Applicant’s observations that downregulating MB3 lincRNA using an inhibitory nucleic acid results in reduction in THSD7A expression and/or FAK phosphorylation in medulloblastoma cells. Examiner also acknowledges Applicant’s intended use for the claimed methods, i.e., as a “personalized” treatment for medulloblastoma, as well as Applicant’s assertion that the claimed methods are of “great clinical significance.” In making these statements, it is not entirely clear if Applicant is attempting to rely on secondary considerations to overcome these rejections. Examiner notes that Applicant’s remarks of “great clinical significance” and “a particularly beneficial, personalized, treatment strategy,” are, at present, unsupported by evidence. The specification describes in vitro studies, which in view of the prior art, including the references cited herein under § 103, provides a reasonable expectation that the claimed treatment methods could be performed. However, the specification does not provide any working examples of treating a subject with medulloblastoma as claimed. Applicant may submit evidence to support their assertions of “great clinical significance” and “a particularly beneficial, personalized, treatment strategy” should Applicant wish to rely upon such assertions to overcome the obviousness rejections of record. Applicant’s arguments alone cannot take the place of evidence, and are not sufficient to overcome the rejections of record.
Applicant’s remarks regarding the alleged lack of motivation to combine Collard and Nanjing, as well as the properties of the structure recited in claim 25 are addressed above in paragraph 27 above. These remarks are not found convincing to overcome the rejections of claims 28 and 33 for the reasons described therein.
Applicant also alleges that Collard and Nanjing “do not relate to any diagnostic aspects, in particular with respect to levels of natural antisense polynucleotides in biological samples as being indicative of any condition, let alone cancer and specifically medulloblastoma.” Examiner respectfully disagrees. As noted in the rejection of record, which is maintained above, Collard teaches that the expression of COL1A2 is increased by administering antisense compounds which knockdown expression of COL1A2-AS1 (Fig. 2; [0018]). Collard teaches that administration of the antisense compounds is applicable to diseases associated with defective Collagen gene expression, including cancer and specifically, medulloblastoma (claims 14, 35-36, pg. 45; wherein ""cancer" refers to all types of cancer or neoplasm or malignant tumor... including... medulloblastoma," [0058]; [0216]). Thus, Collard does, indeed, pertain to modulating the levels of natural antisense polynucleotides in biological samples, in the context of cancer and medulloblastoma. Furthermore, the rejection of record does not rely on Collard alone to establish the obviousness of claims 28 and 33. The rejection relies upon Su, Anderton, and Ivanov in combination with Collard and Nanjing. Applicant’s remarks with respect to Collard and Nanjing are not found persuasive.
Applicant alleges that Collard and Nanjing only illustrate an inverse relationship between COL1A2 and its antisense polynucleotides in “normal, non-cancer cells.” Applicant then alleges that “the methylation level of COL1A2 is presumably normal (as hypermethylation is associated with cancer according to Anderton and Ivanov),” and therefore, “[t]he inverse relationship between COL1A2 and its antisense polynucleotides therefore does not appear to be related to methylation based on Collard and Nanjing, or at least indicates that additional mechanisms may be involved.” Applicant, referring to Su, alleges that “there is no evidence or teaching that [natural antisense transcripts can directly impact CpG methylation of their corresponding gene] in medulloblastoma or COL1A2. Applicant then alleges that “there are various mechanisms by which DNA methylation is regulated,” and Ivanov and Anderton “do not mention any causative explanation to the hypermethylation of COL1A2 in medulloblastoma.” Applicant concludes that there would have been no motivation to arrive at “high MB3 lincRNA expression as a diagnostic marker, much less with a reasonable expectation of success.”
First, Collard demonstrates that there is an inverse relationship between COL1A2 and its natural antisense transcript, which can be modulated by antisense molecules targeting the natural antisense transcript. Neither Collard nor Nanjing were not relied upon to establish the relationship between COL1A2 and its natural antisense transcript in medulloblastoma cells, specifically. Neither Collard nor Nanjing appear to teach or suggest a mechanism for the inverse relationship between COL1A2 and its natural antisense transcript. Applicant’s conclusions based on Collard and Nanjing (i.e., that methylation is not involved, or additional mechanisms are involved, in the inverse relationship) are unsupported by any evidence.
Applicant appears to argue that there could be other mechanisms through which COL1A2 becomes hypermethylated and/or silenced in medulloblastoma. However, the burden is not on Examiner to determine the causative mechanism(s). A mechanism is established by the prior art, upon which Examiner has established a prima facie case of obviousness. Specifically, the cited art establishes that there is a well-known inverse relationship between natural antisense transcripts and their corresponding sense transcript. Collard demonstrates such an inverse relationship between COL1A2 and its natural antisense transcript, using antisense compounds similar to those instantly claimed. Mechanistically, Su teaches that natural antisense transcripts can promote methylation of CpG islands within the sense gene (in this instance, COL1A2) which leads to sense gene inactivation (sections 3-4, pg. 178-179; Fig. 1). Su proposes using natural antisense transcripts as diagnostic tools, and targeting natural antisense transcripts as an effective, alternative strategy to poorly tolerated DNA methyltransferase inhibitors, in diseases or disorders associated with aberrant gene silencing (section 5, pg. 179-180). This applies directly to COL1A2 in the context of medulloblastoma, because Anderton teaches that COL1A2 is frequently methylated and epigenetically silenced in medulloblastoma (pg. 982, left col.; Figs. 2-3, pg. 986-988). Anderton also demonstrates that methylated medulloblastoma cell lines and primary samples have less COL1A2 expression (Fig. 4), and treatment of COL1A2-methylated cell lines with a DNA methyltransferase inhibitor increases COL1A2 expression (Fig. 1B, 4A).
Thus, there is evidence that COL1A2 is aberrantly methylated and silenced in medulloblastoma based on Anderton, and that targeting its natural antisense transcript (as opposed to using a DNA methyltransferase inhibitor) would be an effective, alternative strategy to reverse aberrant silencing of COL1A2 in medulloblastoma. Su strongly suggests such a strategy, and Collard demonstrates that COL1A2 expression can, indeed, be increased by inhibiting its natural antisense transcript using antisense molecules. Finally, in contrast to Applicant’s remarks, there is motivation to use the natural antisense transcript of COL1A2 as a diagnostic marker, not least of which because Su explicitly states that the levels of natural antisense transcripts could “serve as molecular markers for monitoring tumor development” (section 5, pg. 180). Applicant’s remarks regarding the alleged deficiencies with respect to the mechanistic relationship underlying COL1A2 and its natural antisense transcript are not found persuasive.
Finally, Regarding the § 103 rejections raised in further view of Li, Applicant asserts that Li fails to cure the alleged deficiencies of Collard, Nanjing, Su, Anderton, and Ivanov. Examiner has not found Applicant’s remarks regarding the alleged deficiencies of the aforementioned references convincing for the reasons described in the preceding paragraphs. Furthermore, Li was not relied upon for the limitations met by the aforementioned references. Applicant’s remarks regarding Li are not found convincing to overcome the rejection of claim 29, which is maintained above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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