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
This action is written in response to applicant’s correspondence received 7/31/2023. Claims 1-3,5,8-12,14-18 and 21-24 are currently pending. Claims 4, 6, 7, 13 and 19-20 were cancelled and claims 23-24 were newly added by the Applicant in the amendments filed on 05/04/2026. Accordingly, claims 1-3,5,8-12,14-18 and 21-24 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/04/2026 was filed after the mailing date of the non-final rejection on 02/04/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 8-12, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication 2015/168149 A1 to Edge (of record, applicant’s submission, hereinafter ‘Edge’) in view of Samarajeewa (Samarajeewa et al. Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration. Mol Ther. 2019 May 8;27(5):904-911.) and Yan (Yan et al. miR-155 contributes to the progression of glioma by enhancing Wnt/β-catenin pathway. Tumor Biol. (2015) 36:5323–5331.)
Regarding claim 1:
Edge teaches a method for reprogramming an adult mammalian inner ear for hair cell regeneration (i.e., modulating the epigenetic status and expression of certain genes to promote progenitor cell proliferation and hair cell differentiation) (see below; underlines added to emphasize the most relevant passages):
The present disclosure is based, at least in part, on the surprising discovery that epigenetic modulation results in supporting cell division and increases Atohl expression, which is expected to increase generation of hair cells and support cells. As shown herein, Sox2 and Pax2 interact with each other and the three prime (3 ') enhancer for Atohl, a transcription factor required for hair cell differentiation, at a compound consensus sequence, and these interactions lead to hair cell differentiation. Stimulation of the Wnt pathway also results in cell division and hair cell differentiation. In addition, modulating the epigenetic state of Atohl lead to an increase in Atohl expression. As increased Atohl leads to an increase in generation of hair cells, these epigenetic modifiers are expected to increase generation of hair cells from progenitors. (p. 6 ln 17-27)
The present disclosure provides that the epigenetic status of cochlear genes can
be modulated to promote sensory epithelial cell proliferation and hair cell differentiation. (p. 10 ln 8-10)
Edge teaches the method comprising: contacting an adult mammalian inner ear with an effective amount of a histone deacetylase (HDAC) inhibitor and one or more siRNAs targeting inhibitors of c-Myc and/or Wnt:
The compounds and methods described herein are appropriate for the treatment of mammalian (e.g., human) subjects who have or are at risk of developing hearing 25 disorders resulting from cochlear hair cell loss, preferably post-neonatal ( e.g., child, adolescent or adult, e.g., above the age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 years) subjects. (p. 16 ln 23-7)
The methods include administering to the subject, e.g., to the inner ear of the subject, a
pharmaceutical composition comprising one or more of the following: a Histone Deacetylase (HDAC) inhibitor; a histone methyltransferase (HMT) inhibitor; a DNA
methyltransferase (DNMT) inhibitor; a Histone Lysine Demethylase (KDM) inhibitor;
an R-spondin; activators of c- and n-myc or Wnt agonists; and/or an inhibitory nucleic
acid that specifically reduces expression of Hic1. (p. 1 ln 27-29, p. 2 ln 1-4)
Hicl RNAi has been shown to increase the basal expression and Wnt-responsiveness of the Axin2 gene, which is another Wnt target. (p. 12 ln 12-14)
Downstream targets of the Wnt pathway, such as c-myc and n-myc, are mediators of many of the effects of Wnt signaling and are also useful targets for cochlear cell regeneration. Activators of c- and n-myc or Wnt agonists that increase the level of these proteins can therefore be used in the present methods as well, e.g., Wnt agonists…and inhibitors of Wnt inhibitors, e.g., interfering RNA (siRNA, shRNA) directed against DIckopf, WIF-1, shisa, kremen, SOST. sFRP, or axin. (p. 12 ln 25-31)
Edge claims the method comprising administration of HDAC inhibitors (claims 1-3) and provides working examples showing that HDAC inhibitors increase expression of Atoh1 and would be expected to lead to generation of new hair cells (Fig. 15, Example 10). Edge also claims the method comprising administration of anti-Hic1 siRNA and shows that reducing Hic1 activity results in a dramatic increase in Atoh1 expression (claims 13-14, 16, Fig. 17A-B, Example 11). While Edge does not provide a working example of administering both of these elements together, Edge’s teachings that the combination of HDAC inhibitors and Wnt activators are effective at reprogramming hair cells in the adult mammalian inner ear are supported by Samarajeewa, which describes the successful application of the approach in adult mice and human inner ear tissue:
There is a growing consensus that combinational strategies may be able to synergistically enhance the regenerative capacity in neonatal and adult cochleae. For example, the in vitro hair cell yield from Lgr5-positive cells isolated from neonatal mice and grown as organoids can be further improved by treatment with the Wnt activator CHIR99021 (CHIR) and the histone deacetylase (HDAC) inhibitor valproic acid (VPA; which is thought to enhance histone H3K9 acetylation)…These findings were successfully reproduced in Lgr5-positive cells isolated from adult mice, as well as non-human primates and healthy human inner ear tissue. (p. 907 §Combinational Strategies for Hair Cell Regeneration)
Samarajeewa also notes that “there are no biological therapies for hearing loss” (Abstract), and that, “Although modulation of signaling pathways can promote hair cell regeneration in the neonatal cochlea, this regenerative response is lost or limited in adult stages…Use of Wnt and Notch modulators in combination with drugs targeted against chromatin-remodeling enzymes, such as HDAC inhibitors…highlights the positive effects that altering access to target genes can have on the regenerative response of mature inner ear tissue.” (p.907). Therefore, Samarajeewa establishes that there was a known and largely unmet need in the art for therapies for hearing loss in adult subjects, and further suggests combined therapies using Wnt modulators and HDAC inhibitors as a solution.
In summary, Edge teaches a method of reprogramming an adult mammalian inner ear for hair cell regeneration, the method comprising administration of a HDAC inhibitor in combination with a Wnt activator (i.e., RNAi agents against c-myc, n-myc and/or Wnt inhibitors, such as Hic-1). Edge provides a teaching, suggestion or motivation to use RNAi agents against c-myc and/or Wnt inhibitors with a HDAC inhibitor. Samarajeewa supports Edge’s teachings, providing the ordinary artisan with additional reasonable expectations of success by further showing that the combination of HDAC inhibitors and Wnt activators was known to be effective at reprogramming hair cells in the adult mammalian inner ear, and provides a motivation to pursue these types of combinational strategies by stating that they may synergistically enhance the regeneration of adult inner ear hair cells.
While Edge teaches the method comprising administration of nucleic acid inhibitors of Hic-1, itself a known inhibitor of the Wnt pathway, Edge does not teach the method comprising administration of nucleic acid inhibitors of Mxi1.
Yan teaches a nucleic acid inhibitor of Mxi1, miR-155, and that miR-155 activates the Wnt pathway:
miR-155 contributes to the progression of glioma by enhancing Wnt/β-catenin pathway (Title)
The suppression of miR-155 attenuated the proliferation of glioma cells and the activation of Wnt pathway…miR-155 level was inversely correlated with the abundance of HMG-box transcription factor 1 (HBP1), a strong Wnt pathway inhibitor…miR-155 promoted the progression of glioma by enhancing the activation of Wnt pathway. (Abstract)
miR-155 promoted the proliferation and invasion of glioblastoma cells through suppressing…MXI1 (p. 5330 §Discussion)
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention, absent evidence of secondary considerations of non-obviousness, to have combined the method of reprogramming adult inner ear hair cells via administration of an HDAC inhibitor and c-myc and/or Wnt-pathway-activating RNAi, as taught by Edge and supported by Samarajeewa, with Yan’s teachings that administration of a nucleic acid inhibitor of Mxi1, miR-155, enhanced activation of the Wnt pathway. The ordinary artisan would have been motivated by Edge’s teachings regarding combined HDAC and RNAi therapies/Wnt activators to seek out RNAi agents for activating Wnt (by targeting Wnt inhibitors for silencing). This motivation would have been encouraged by Samarajeewa’s teachings that such combinational therapies using Wnt activators and HDAC inhibitors together are more effective for inducing regeneration of hair cells in the adult inner ear than either one alone, and further that there was a recognized need for more such therapies. The search for additional RNAi agents for activating Wnt would have led them to Yan, which teaches that miR-155 (a nucleic acid inhibitor of Mxi1) is a Wnt activator, and would thus have been suitable for use in the therapies suggested by Edge and Samarajeewa. Based on the combination of those teachings, the ordinary artisan would have had a reasonable expectation that a combinational strategy combining a known HDAC inhibitor with a known Wnt-activating nucleic acid inhibitor, miR-155, would have successfully induced hair cell proliferation and regeneration (i.e., reprogramming) in the adult inner ear.
Regarding claims 10 and 21-22, Edge teaches the same methods for treating vestibular dysfunction in a human subject having hearing loss (hearing problems) from vestibular dysfunction (see p. 18 ln 1-8), the method also comprising administration of an Atoh1 activator (Sox2 and Pax2 cDNA; see FIG. 5 and p. 29 ln 27-30, which describe increased activation of Atoh1 by administration of “equal amounts of Pax2 and Sox2 cDNA.)
Regarding claims 2-3 and 11-12, Edge teaches wherein the HDAC inhibitor is valproic acid (see Edge claim 3).
Regarding claim 8, Edge teaches that expression of Sox2 is an inherent characteristic of undifferentiated progenitor inner ear stem cells:
Both Pax2 and Sox2 are expressed during development of the otocyst and are important for the development of the cochlea during tissue morphogenesis. Pax2 and Sox2 are both expressed in inner ear stem cells…Their level of expression decreases when inner ear stem cells are transferred from a proliferative self-renewing culture (as floating neurospheres in growth factors) to a differentiating culture (p. 23 ln 31-33, p 24. ln 1-4)
Regarding claim 9, Edge teaches wherein the contact occurs in the inner ear of the subject (e.g., claims 1, 4).
Claims 5 and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over Edge, Samarajeewa and Yan, as applied to claims 1-3, 8-12, and 21-22 above, further in view of Cukier (Cukier eta l. Molecular basis of FIR-mediated c-myc transcriptional control. Nat Struct Mol Biol. 2010 Sep;17(9):1058-64.)
Edge, Samarajeewa and Yan render obvious the methods of reprogramming inner ear hair cells/treating a human subject having vestibular dysfunction, comprising administering a composition comprising an HDAC inhibitor, Mxi1 nucleic acid inhibitor, and an Atoh1 activator to upregulate Atoh1 expression, as recited in claims 1 and/or 10, from which claims 5 and 14 depend, as discussed above.
Edge, Samarajeewa and Yan do not teach administration of inhibitory acids targeting Fir, as recited in the alternative in claims 1 and 10 and required by claims 5 and 14-15.
However, Edge does teach compositions comprising nucleic acid inhibitors for downregulation of c-myc inhibitors (i.e., activation of c-myc). Additionally, Samarajeewa teaches therapies for hearing loss which comprise administration of an Atoh1 adenoviral expression vector to adult human subjects, and that the combination of this approach with HDAC inhibition and Wnt activation can produce a more robust regenerative response:
Novartis Pharmaceuticals is currently conducting a clinical trial on the use of CGF166, a recombinant adenovirus 5 (Ad5) vector encoding the human Atonal transcription factor, in patients with severe-to-profound bilateral hearing loss for safety, tolerability, and changes in vestibular and auditory functions. (p. 906)
In addition to VPA, the combination of Wnt activation with other forms of pharmacological and genetic manipulation can also produce a more robust regenerative response in the neonatal cochlea. For instance, the combination of b-catenin stabilization with ectopic Atoh1 expression in vivo in Lgr5-positive cells of the neonatal cochlea promotes a synergistic increase in supporting cell proliferation and hair cell induction (p. 907)
Cukier teaches that FIR shuts off transcription of c-myc via its interactions with FUSE and the FUSE-binding protein (FBP):
The far upstream element (FUSE) upstream of the c-myc promoter mediates a fast transcription-responsive mechanism responsible for an upsurge of c-Myc levels during the cell cycle…FUSE-based c-Myc upregulation is mediated by the unwinding and opening of an AT-rich stretch (the FUSE sequence) located about 1.7 kb upstream of the c-myc promoter…The FUSE DNA noncoding strand (henceforth referred to as ssFUSE or ssFUSE DNA) recruits the FUSE-binding protein (FBP), which in turn interacts with transcription factor IIH (TFIIH)…and increases the rate of productive c-myc transcription…The FBP–FUSE complex recruits the FBP-interacting repressor (FIR) protein that interacts with both FBP and ssFUSE DNA. Upon binding FBP and ssFUSE, FIR interacts with TFIIH7, reducing FBP-mediated transcription (p. 1058)
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of reprogramming inner ear hair cells/treating vestibular dysfunction via a combinational therapy comprising a combination of HDAC inhibitors, c-myc and/or Wnt pathway activators such as a nucleic acid inhibitor of Mxi1, and Atoh1 expression vectors, as taught by Edge, Samarajeewa and Yan, with Cukier’s teachings that FIR is a transcriptional repressor of c-myc. The ordinary artisan would have recognized that FIR offered a target for RNAi to activate c-myc, as suggested by Edge, and would have been motivated to add it to the pre-existing combinational therapy to produce a more robust regenerative response.
Claims 1-3, 8-12, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication 2015/168149 A1 to Edge (of record, applicant’s submission, hereinafter ‘Edge’) in view of Samarajeewa (Samarajeewa et al. Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration. Mol Ther. 2019 May 8;27(5):904-911.) and Jiang (Jiang et al. Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting β-catenin for degradation in pancreatic cancer. Tumor Biol. (2016) 37:13893–13902.)
Regarding claim 1:
Edge and Samarajeewa teach the limitations of claims 1-3, 8-12, and 21-22 as far as they pertain to the method comprising an inhibitory nucleic acid targeting Mxi1, a known inhibitor of the Wnt pathway. Edge and Samarajeewa also suggest combining HDAC inhibitors with agents to activate the c-myc and/or Wnt pathways, including agonists and inhibitory nucleic acid molecules targeting inhibitors of those pathways.
Edge does not teach the method comprising administration of nucleic acid inhibitors of Fbxw7.
Jiang teaches that Fbxw7 is a Wnt antagonist, and that RNAi knockdown of Fbxw7 activates both c-myc and Wnt (see Abstract). Jiang also teaches a specific short hairpin RNA inhibitor of Fbxw7 (p. 13894 § Fbxw7 and β-catenin knockdown).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention, absent evidence of secondary considerations of non-obviousness, to have combined the method of reprogramming adult inner ear hair cells via administration of an HDAC inhibitor and c-myc and/or Wnt-pathway-activating RNAi, as taught by Edge and supported by Samarajeewa, with Yan’s teachings that administration of a nucleic acid inhibitor of Fbxw7 enhanced activation of both the c-myc and Wnt pathways. The ordinary artisan would have been motivated by Edge’s teachings regarding combined HDAC and RNAi therapies/c-myc and/or Wnt activators to seek out RNAi agents for activating c-myc and/or Wnt (by targeting c-myc and/or Wnt inhibitors for silencing). This motivation would have been encouraged by Samarajeewa’s teachings that such combinational therapies using Wnt activators and HDAC inhibitors together are more effective for inducing regeneration of hair cells in the adult inner ear than either one alone, and further that there was a recognized need for more such therapies. The search for additional RNAi agents for activating c-myc and/or Wnt would have led them to Jiang, which teaches a shRNA inhibitor of Fbxw7, and further teaches that silencing of Fbxw7 activates those pathways, and would thus have been suitable for use in the therapies suggested by Edge and Samarajeewa. Based on the combination of those teachings, the ordinary artisan would have had a reasonable expectation that a combinational strategy combining a known HDAC inhibitor with a known shRNA inhibitor of Fbxw7, with a known ability to activate Wnt and c-myc via Fbxw7 knockdown, would have successfully induced hair cell proliferation and regeneration (i.e., reprogramming) in the adult inner ear.
Regarding the other claims named in the rejection, Edge teaches those limitations as already discussed above.
Response to Arguments
Applicant's arguments filed 05/04/2026 have been fully considered but they are not persuasive for the reasons that follow.
Applicant argues that, “The Office has not established a prima facie case because the rejection does not identify substantial evidence that a person of ordinary skill in the art would have had a reasonable expectation of success in achieving the results shown by the claimed methods by combining the teachings in the references cited.” (Remarks, 05/04/2026, p. 9/12). Applicant further argues that, “neither the claims nor the cited Example disclose or suggest the combination of an HDAC inhibitor with one or more inhibitory nucleic acids targeting Fir, Mxi1, Fbxw7, or combinations thereof” (Id.). Respectfully, this argument is not persuasive for the following reasons.
First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed in the above rejection, “Edge teaches a method of reprogramming an adult mammalian inner ear for hair cell regeneration, the method comprising administration of a HDAC inhibitor in combination with a Wnt activator (i.e., RNAi agents against c-myc, n-myc and/or Wnt inhibitors, such as Hic-1). Edge provides a teaching, suggestion or motivation to use RNAi agents against c-myc and/or Wnt inhibitors with a HDAC inhibitor. Samarajeewa supports Edge’s teachings, providing the ordinary artisan with additional reasonable expectations of success by further showing that the combination of HDAC inhibitors and Wnt activators was known to be effective at reprogramming hair cells in the adult mammalian inner ear, and provides a motivation to pursue these types of combinational strategies by stating that they may synergistically enhance the regeneration of adult inner ear hair cells.”. As also discussed above, the successes disclosed by Edge and Samarajeewa, combined with their express suggestions to combine HDAC inhibitors with other Wnt and/or c-myc activators beyond those tried, would have motivated the ordinary artisan to seek out and try other activators, with a reasonable expectation of success.
Second, per MPEP 2143.02.I., the courts have held that, “the expectation of success need only be reasonable, not absolute”. As discussed in the above rejection, both Edge and Samarajeewa show that various combinatorial strategies using both HDAC inhibitors and inhibitory nucleic acids targeting Wnt/c-myc inhibitors were effective at reprogramming hair cells in the adult mammalian inner ear. Coupled with a known need in the art for further therapies, as discussed above, this would have provided the ordinary artisan with a motivation to apply the same strategy to other target genes using other inhibitors, with a reasonable expectation that it would have led to the same outcome of increased Wnt/c-myc signaling.
Applicant further argues that, “FIR, Mxi1, and FBXW7 are known be [sic] effectors of MYC and are not direct regulators of the Wnt pathway.” (Remarks, 05/04/2026, p. 9/12). Respectfully, this is not persuasive because Applicant has not supported the arguments with any citations to, evidence from, or explanations of the prior art or specification. As such, Applicant's remarks have been considered in accordance with MPEP 716.01(C) ("The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)."). In contrast, as discussed above, Edge teaches that, “Downstream targets of the Wnt pathway, such as c-myc and n-myc, are mediators of many of the effects of Wnt signaling and are also useful targets for cochlear cell regeneration…Activators of c- and n-myc or Wnt agonists that increase the level of these proteins can therefore be used in the present methods as well.”. Therefore, Edge discloses that c-myc and Wnt operate in a feedback loop (i.e., c-myc is both a target and mediator of Wnt signaling), that they are useful targets for cochlear cell regeneration, and Edge thereafter directs the ordinary artisan to try other Wnt/c-myc activators to achieve the same outcome of cochlear cell regeneration (see the rejection above). While Applicant notes that, “as shown in FIG. 2A of the application as filed, the Wnt modulator LiCl was evaluated in combination with VPA and was unable to induce reprogramming or hair cell regeneration in cultured cochleae”, based on the preponderance of evidence in the prior art and Edge’s and Samarajeewa’s disclosures, as discussed above, the ordinary artisan would nonetheless have had a reasonable expectation that a combination of HDAC inhibiton and Wnt/c-myc activation would have led to the outcome of cochlear regeneration.
Applicant further argues that, “Jiang appears to disclose that Fbxw7 is a novel regulator of Wnt/3-catenin signaling-dependent regulation of pancreatic cancer cell growth and invasion… As with Yan, which relates to glioma progression, the teachings of Jiang also pertain to cancer biology (specifically pancreatic cancer biology). These references concern fundamentally different cellular contexts from adult cochlear supporting cells, which are known to be highly refractory to regeneration. A person of ordinary skill would not reasonably expect that mechanisms identified in cancer systems would translate to reprogramming of mature inner ear cells.” (Remarks, 05/04/2026, p. 10/12). Respectfully, this argument is not persuasive because, as discussed above, Edge and Samarajeewa teach that activation of the Wnt pathway induces reprogramming of adult inner ear cells. Edge and Samarajeewa further suggest combining HDAC inhibitors with Wnt activators to achieve that outcome, also as discussed above. Given the suggestion to seek out other Wnt activators (particularly inhibitors of Wnt pathway inhibitors) to induce reprogramming of adult inner ear cells as part of a combinatorial therapy, as taught by Edge and Samarajeewa, the ordinary artisan would have been motivated to search for other Wnt antagonists. This search would have led them to Jiang, which discloses Fbxw7, a Wnt antagonist which binds B-catenin, and a method of inhibiting it with a shRNA to activate the Wnt pathway. Given that the interactions between the shRNA and Fbxw7 (i.e., complementary base pairing) and Fbxw7 and B-catenin (protein-ligand binding) are based on the structures of the interacting moieties, then, absent evidence to the contrary, the ordinary artisan would have predicted that the same structures would also have the same binding interactions in other cellular contexts. This is supported by Lu, which teaches that, “some miRNAs have important roles in reprogramming somatic cells to induced pluripotent stem cells (iPSCs)…over-expressing miR-25or introducing miR-25 mimics enhanced production of iPSCs” (Abstract), and that, “miR-25 directly regulated…Fbxw7, which is known to regulate c-Myc, Klf5 and other important factors.” (p. 2)(Lu et al. MiR-25 Regulates Wwp2 and Fbxw7 and Promotes Reprogramming of Mouse Fibroblast Cells to iPSCs. PLoSONE7(8):e40938.) Based on this, the prior art evidences that Fbxw7 interacts with the Wnt pathway via c-myc regulation in other cellular contexts, and inhibition of these interactions results in the induction of cellular reprogramming.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But 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).
Applicant has also provided rebuttal evidence to demonstrate non-obviousness (p. 11/12). Per MPEP 716.02(d), “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”. Respectfully, Applicant’s evidence is not persuasive because the evidence is not commensurate in scope with what the claims.
Applicant points out that, “numerous alternative combinations comprising small molecules and siRNAs targeting pathways including Notch, Myc, mTOR, Wnt, Tgfb, FGF, retinoic acid, BMP4, and Alk5 were evaluated, yet none achieved hair cell regeneration comparable to that observed with the combination of the HDAC inhibitor VPA and siFIR, and siMxil (see e.g., FIG. 1B and 1C)”. Applicant further notes that, “treatment with a combination of the HDAC inhibitor VPA and siFbxw7 alone or in combination with siFIR and siMxil followed by Ad-Atohl infection induced robust hair cell regeneration in the cochlea (see FIG. 7B and 7C)…the combination exhibits a synergistic effect, as neither HDAC inhibition nor inhibition of Mxil/Fir/Fbxw7 alone is sufficient to induce regeneration.”. This evidence is acknowledged. However, claim 1 is more broadly drawn to a method comprising administration of any HDAC inhibitor and a siRNA, shRNA, or antisense oligonucleotide targeting any one or more of Fir, Mxi1, or Fbxw7. This encompasses embodiments such as VPA + siFir or VPA siMxi1, the effects of which are not shown in FIGs. 7B-C, as well as embodiments using other HDAC inhibitors with those siRNAs or equivalent shRNAs/ASOs. . It is not clear that all of the combinations would have led to the superior synergistic effect demonstrated by the VPA + siFbxw7 and VPA + siFbxw7 + siF/M combinations shown in FIGs. 7B-C. While, as argued above in the rejections under 35 U.S.C. 103, the ordinary artisan would have predicted that combining an HDAC inhibitor with one or more siRNAs targeting Fir, Fbxw7 and/or Mxi1 would have led to some amount of hair cell regeneration, Applicant has argued that the superior synergistic effect shown by the VPA + siFbxw7 and VPA + siFbxw7 + siF/M combinations would not have been predictable. If that is the case, then the ordinary artisan would not be able to extrapolate the superior results of those combinations to the other combinations encompassed by the claims.
Conclusion
No claim is allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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