DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 5-19-26.
Claims 1-19, 39 are pending in the instant application.
Claims 12-14, 17-19, 39 are withdrawn as being drawn to a nonelected invention or species.
Claims 1-11, 15, 16, the Cas 7-11 polypeptide of Seq ID No. 1, the Csx29 polypeptide of SEQ ID No. 35, IL-12, steric hindrance, the linker comprising SEQ ID NO:36 have been examined on their merits as set forth below.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-11,15, 16 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the in vitro analyses of molecular interactions (e.g., Csx30-Csx31-RpoE complexes, Cas7-11-crRNA-Csx29-tgRNA), and of the in vitro inhibition of E. Coli growth does not reasonably enable methods for treating any cancer in a subject comprising administration of a Cas7-11:Csx29 complex, a guide strand specifically hybridizing a RNA target, and an apoptotic protein fused to an inhibitory peptide via a Csx30 linker for the reasons set forth in the Office action mailed 2-19-26 and as set forth below.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Applicant’s Arguments
Applicant argues the following:
The Specification Enables the Claimed RNA-Guided Activation Mechanism in Mammalian Cells
Working Examples in Mammalian Cells
The central factual premise of the rejection is incorrect: The specification is not limited to in vitro molecular interactions or bacterial growth inhibition. Example 10 expressly demonstrates programmable RNA-sensing activity of the Cas7-11-Csx29-Csx30 system in human HEK293FT cells. In that example, Cas7-11, Csx29, and Csx30 were codon-optimized for mammalian expression. The Csx30 sequence was placed between a citrine protein and a dihydrofolate reductase degron. Upon expression in mammalian cells, the system activated Csx29 in the presence of a target RNA and targeting guide, resulting in cleavage of the Csx30 linker and a three-fold increase in citrine fluorescence (Fig. 4I).
The specification further confirms this mechanism by Western blot analysis… (Fig. 4J and Fig. 21). …That result establishes target-RNA-dependent Csx29-mediated cleavage of the Csx30 linker in living human cells...
A skilled artisan would have understood from this disclosure that substituting a therapeutic effector, such as a caspase or cytokine, for the citrine reporter would be a routine implementation of the same disclosed mechanism. The Csx30 cleavage event is not dependent on the identity of the flanking reporter protein. The specification identifies the relevant cleavage site within Csx30 and teaches that activation occurs through cleavage of the Csx30 linker (Specification, page 74). Thus, once the system is shown to activate a degron-regulated fusion protein in human cells in response to target RNA, adapting the fusion to include a disclosed apoptotic effector is a predictable application of the same platform, not an independent inventive undertaking requiring undue experimentation.
The Specification Provides Concrete Guidance for Delivery and Implementation
The specification also provides ample direction regarding delivery of the system components. Example 10 reports delivery of the Cas7-11 and Csx29 expression plasmid, guide RNA, and citrine-degron reporter into HEK293FT cells using standard transfection methods (Specification, at page 93). This disclosure establishes that the components can be introduced into living mammalian cells and expressed in a form that produces the claimed RNA-guided activation mechanism.
The specification also identifies delivery modalities suitable for administration in therapeutic settings, including lipid nanoparticles (LNPs), extracellular contractile injection systems (eCIS), and engineered virus-like particles (eVLPs) (Specification, at page 27)…
The Office's Cited References Do Not Support a Conclusion of Non-Enablement
The Office cites Roberts (2020), Kobelt (2022), Osborn (2018), and Damase (2021) for the general proposition that efficient oligonucleotide or gene-therapy delivery can be challenging. Those references do not support the rejection. Instead, they address broad issues in nucleic-acid therapeutics and gene therapy. They do not touch on the Cas7-11:Csx29 system, the Csx30 linker, RNA-guided protease activation, or the specific therapeutic architecture recited in the claims. The cited references do not identify any property of the claimed system that would question the viability of delivery, expression, guide-RNA targeting, Csx30 cleavage, or effector activation in a subject.
The Specification Provides Detailed Structural and Functional Guidance
The specification supplies substantial information regarding the components of the claimed system. The specification identifies numerous Cas7-11 polypeptide sequences (SEQ ID NOs: 1-34), multiple Csx29 sequences (SEQ ID NO: 35 and 57-69), and multiple Csx30 linker sequences (SEQ ID NOs: 36-46). It also provides plasmid maps, expression protocols, and experimental guidance sufficient to produce and test the components used in the claimed methods. This disclosure would enable a skilled artisan to practice a programmable molecular system without undue experimentation.
The specification further identifies suitable therapeutic effectors. For example, it expressly discloses apoptotic proteins, including caspase 2, caspase 3, caspase 6, caspase 7, caspase 8, caspase 9, caspase 10, caspase 11, and caspase 12. It also identifies immune-activating cytokines, including IL-12, IL-7, IL-15, IL-2, and others (Specification, pages 83-84). These are well-characterized proteins. The specification also describes inhibitory mechanisms, including steric hindrance and degradation signals, such as DHFR-derived degrons (Specification, at pages 84-85). Example 10 reduces this regulatory architecture to practice in mammalian cells by demonstrating a Csx30-linked protein regulated by a degron and activated upon target-RNA-dependent cleavage.
The recitation of treating cancer is also cabined by the claim recitation that the cancer comprises cells comprising the target RNA. This limitation is an important feature. The claimed method is not an indiscriminate cancer treatment. It is a targeted approach in which activation depends on the presence of a selected RNA in the cancer cell. The specification identifies suitable tumor-associated RNA targets, including ADAR1 mRNA, FOXM1 mRNA, and H2AFX mRNA for solid tumors (Specification, at page 27). A skilled artisan would understand how to select a cancer- associated or cancer-enriched RNA target, design a guide RNA to hybridize to that target, and use the disclosed system to activate the therapeutic effector in cells expressing the target RNA.
The working examples are particularly significant. Example 10 supplies a mammalian-cell demonstration of the same RNA-guided cleavage-and-activation mechanism recited in the claims. That example materially distinguishes this case from one in which a therapeutic method is asserted based only on in vitro binding data or purely theoretical mechanism. The specification shows that the system functions in living human cells and provides a direct path for substituting disclosed therapeutic effectors into the same regulatory architecture.
Response to Applicant’s Arguments
Applicant's arguments filed 5-19-26 have been fully considered but they are not persuasive. It is understood that replacing the reporter gene with an appropriate therapeutic effector would also provide release of the therapeutic effector upon Csx30 linker cleavage in vitro, and perhaps in an appropriate target cell in vitro. But, contrary to Applicant’s assertions, the success of proper cleavage and release of therapeutics within a target cell depends on adequate delivery of all of the system components to the proper target cells in a subject. In vitro transfection is not representative or correlative of the ability to deliver the claimed system to a subject and provide therapeutic effects.
Applicant is correct that the claims require that the target cells express the desired target RNA. But this is only logical. Why would the instantly claimed system be used to target cells which do not express the desired target gene, except as a negative control? Contrary to Applicant’s arguments, in vivo delivery is still a major challenge in the field of RNA therapeutics.
And in response to applicant's argument that the citations do not support the enablement rejection because it is nonanalogous art, it has been held a reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, and as stated previously, Roberts et al (Nature Rev., Drug Discovery, Vol. 19, pages 673-694 (2020)) teaches on page 673 that “achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation.”
Kobelt et al (Cancer Gene Therapy in Gene Therapy of Cancer: Methods and Protocols, Methods in Molecular Biology, Vol. 2521, pages 1-15 (Springer Nature 2022)) teach that limitations to cancer gene therapy relate to limitations in gene transfer efficiency (see esp. pages 3-4).
In addition, Osborn et al (Nucleic Acid Therapeutics, Vol. 28, No. 3, pages 128-136 (2018)) state the following about challenges to siRNA delivery on page 128:
…The primary challenge facing the clinical development of small interfering RNAs (siRNA) has been overcoming barriers that impede in vivo delivery. siRNAs are large, polyanionic macromolecules with intrinsically poor pharmacological properties. Unmodified siRNAs have a half-life of less than 5 min in circulation, and they do not permeate intact cellular membranes…
Damase et al (Frontiers in Bioengineering and Biotechnology, Vol. 9, Article 628137, pages 1-24 (2021)) on page 13 also address the challenges of using RNA-based drugs:
Targeted delivery is a major hurdle for effective RNA therapeutics, a hurdle that must be overcome to broaden the application of clinical translation of this type of therapeutic. …There is a need for novel delivery vehicles that will deliver the RNA drug to the site of therapeutic action facilitating the entry of the RNA drug into the cytoplasm where it may exert its effect…
[Citations omitted] [Emphases added].
As stated previously, the following factors have been considered in determining that the specification does not enable the skilled artisan to make and/or use the invention over the broad scope claimed.
The breadth of the claims:
The claims are drawn to methods of treating cancer comprising administering an effective amount of a Cas7-11:Csx29 complex or a first nucleic acid encoding the Cas7-11:Csx29 complex, a guide RNA that specifically hybridizes to a RNA target, and an apoptotic protein fused to an inhibitory peptide via a Csx30 linker or a second nucleic acid encoding the apoptotic protein fused to the inhibitory peptide via the Csx30 linker, the apoptotic activity of the apoptotic protein is inhibited by the inhibitory peptide and the apoptotic activity of the apoptotic protein is activated upon cleavage of Csx3, which cancer cells comprise the target RNA; and Csx29 cleaves Csx30 when the Cas7-11:Csx29 complex binds to the target RNA, which Cas7-11 optionally comprises SEQ ID NO: 1, which Csx29 optionally comprises SEQ ID NO: 35, which guide RNA optionally comprises a mature pre-crRNA and is a single-strand RNA (ssRNA), and which linker optionally comprises Csx30 of SEQ D No. 36.
Teachings in the specification.
Teachings in the specification:
As stated previously, the specification teaches the following in vitro analyses:
Figs. 1A-1D show Cryo-EM structures of the Cas7-11-erRNA-Csx29 complexes with and without the target RNA.
Fig.1A shows domain structures of Cas711 and Csx29.
Fig.1B shows nucleotide sequences of the crRNA and its target RNA. Disordered nucleotides are indicated by dashed circles PFS protospacer flanking sequence
Figure 1B discloses SEQ ID NOS 84-85 respectively, in order of appearance.
Figs. IC-1D show overall structures of Cas7-11-crRNA-Csx29
(Fig. 1C) and Cas7-11-erRNA-Csx29-tgRNA
(Fig. 1D). The bound zinc ions are shown as spheres. The disordered L1 and L2 linkers are not shown for clarity.
Figs.2A-2E show interaction between Cas7-11 and Csx29.
Fig. 2A shows structure of Csx29 in the Cas7-11-crRNA-Csx29 complex.
Fig. 2B shows interface between Cas7-11 an Csx29 in the Cas7-11-crRNA-Csx29 complex. The Cas11 and INS domains are omitted for clarity.
Fig. 2C shows location of the Csx29 active site. The catalytic residue H615 of the Csx29 protease is shown.
Figs. 2D-2E show interfaces between Cas7-1 and Csx29 in Cas7-11-crRNA-Csx29
(Fig. 2D) and Cas7-11-erRNA-Csx29 tgRNA
(Fig. 2E). Csx29 is shown as a surface representation, except for the AR, which is shown as a ribbon representation.
The AR and APD are disordered in the Cas7-11-crRNA-Csx29-tgRNA structure in (Fig. 2E).
Figs. 3A-3E show target RNA-triggered Csx30 cleavage by Csx29.
Fig. 3 shows schematic of the RNA-triggered Csx30 cleavage of the as7-11rRNA Csx29 complex TR, target RNA without a PFS CTR cognate target RNA with a non-matching PFS NTR, non-cognate target RNA with a matching PFS.
Figure3A discloses SEQ ID NO: 86.
Fig. 3B shows RNA triggered Csx30 cleavage by the Cas7-11-erRNA-Csx29 complex. The Cas7-11-crRNA-Csx29 was incubated with Csx30 at 37°C for 1 min in the presence or absence of the target RNA (CTR). The wtype (W) and catalytically inactivated
(Fig. 3D) versions of Cas7-and Csx29 were used.
Fig 3C shows effects of the complementarity between the crRNA 5' tag and tgRNAPFS on the Csx30 cleavage. The dCas7-11-crRNA-Csx29 complex was incubated withCsx30 at 37°C for 5,10,15 min in the presence of the target RNA (TR CTR or NTR).
Fig.3D shows proteolytic cleavage site in Csx30The Csx30 site cleaved by Csx2 is indicated by a triangle. The Csx30 structure was predicted using AlphaFold2, and the Ca atoms of M427and K428at the cleavage site are indicated by spheres Figure 3D discloses SEQ ID NO: 37.
Fig. 3E shows Csx29-mediated Cleavage of the Csx30 mutants. The dCas7-11-crRNA-Csx29 complex was incubated with the Csx30 mutants at 37°C for 10min in the presence or absence of the target RNA (CTR).
In (Fig. 3B), (Fig. 3C)(Fig. 3E) the proteins were analyzed by SDS-PAGE, and gel was stained with CBB.
Figs. 4A4J show effects of Csx30 and Csx31 on bacterial cell growth.
Fig. 4A shows schematic of bacterial growth assays for studying the Csx30 and Csx31 functions
Fig.4B shows Growth curves and end-point analyses
(Fig.4C) of E.coli expressing either full-length Csx30, the N-terminal fragment (residues 1 -427) of Csx30 (Csx30-1), of the C-terminal fragment (residues 428-565) of Csx30 (Csx30-2).
Figs. 4D-4E show growth curves (Fig.4D and end-point analyses
(Fig. 4E) of E.coli expressing either Csx30-1, full-length Csx30 and Csx31, or Csx30-1 and Csx31.
In Figs 4B-4E, growth was compared between induced and uninduced expression conditions. In Figs. 4C and 4E ,,,
Fig. 4Fshows heatmap comparing the survival percentages of bacteria expressing either Csx30-1, Csx30-2, full-length Csx30 and Csx31, full-length Csx30 alone, Csx30 and Csx3, or Csx302 and Csx31, cultured at three different temperatures. …
Fig. 4H show schematic of the mammalian application of the Cas7-11-Csx29 Csx30 degron reporter system for RNA sensing in live cells.
Fig. induces cell growth inhibition as part
of anti-viral immunity. The Csx30 NTD probably binds RpoE as an anti-sigma factor, and affects cell growth and viability through unknown mechanisms.Csx31 likely functions as an antitoxin, thereby protecting the cell from the toxic effect of the Csx30 NTD
Figs. 6A-6F show Cryo-EM analysis of the Cas7-11-crRNA-Csx29 complex.
Fig. 6A shows single-particle cryo-EM image processing workflow.
Fig. 6B shows representative micrograph at a magnification of x105,000.
Fig.6C shows representative 2D averaged class images from the particles used for final reconstruction. Number of particles and resolution of reconstruction are indicated for each class.
Fig. 6D shows Fourier shell correlation (FSC) curves.
Mapmap FSC curve was calculated between the two independently refined half-maps after masking (blue line), and the overall resolution was determined by gold standard FSC = 0.143 criterion. Map-to Model FSC was calculated between the refined atomic models and maps (red line).
Fig. 6E shows directional FSC plots calculated in the 3DFSC server.
Fig. 6Fshows Euler angle distribution of particles in the final reconstruction.
Figs. 7A-7F show Cryo-EM analysis of the Cas7-11-crRNA-Csx29-tgRNA complex.
Fig. 7A shows single-particle cryo-EM image processing workflow.
Fig. 7B shows representative micrograph at a magnification of x105,000.
Fig. 7C shows representative 2D averaged class images from the particles used for final reconstruction. Number of particles and resolution of reconstruction are indicated for each class.
Fig. 7D shows FSC curves. Map-to-map FSC curve was calculated between the two independently refined halfmaps after masking, and the overall resolution was determined by gold standard FSC = 0.143 criterion. MaptoModel FSC was calculated between the refined atomic models and maps.
Fig. 7E shows directional FSC plots calculated in the 3DFSC server.
Fig. 7F shows Euler angle distribution of particles in the final reconstruction.
Figs. 8A-8D show Cryo-EM density maps.
Figs. 8A-8B show Cryo-EM density maps for Cas7-11-crRNA-Csx29 (Fig. 8A) and Cas7-11-crRNA-Csx29-tgRNA (Fig. 8B).
Figs. 8C-8D show Cryo-EM density maps for Cas7-11-erRNA-Csx29 (Fig. 8C) and Cas7-11- crRNA-Csx29-tgRNA (Fig. 8D).
Figs. 9A-9C show structural comparison of the Cas7 11 complexes in different states.
Figs. 9A-9C show structures of Cas7-11-crRNA-tgRNA (PDB ID: 7WAH) (Fig. 9A), Cas7-11- crRNA-Csx29
(Fig. 9B), and Cas7-11-crRNA-Csx29-tgRNA (Fig. 9C). The bound zinc ions are shown. The disordered L1 and L2 linkers are not shown for clarity. The disordered regions (residues 10431126) in the INS domain are indicated by dashed circles…
(Fig. 9B) and (Fig.9C). The bound RNA molecules are shown on the right of the complexes.
Figs. 10A10C show RNA recognition by Cas711.
Fig. 10A shows recognition of the crRNA 5' end by the Cas7.1 domain. The density map is shown as a gray mesh. The possible location of U(-16) and the pre-crRNA processing site are indicated by a dashed circle and a triangle, respectively.
Figs.10B-10C show recognition of the guide-target duplex by Cas7-11
(Fig.10B) and Csm (PDB ID: 6IFY)
(Fig. 10C). The catalytic residues (D429A/D654A of Cas7-11 and D33N of Csm) are depicted as space-filling models. The target RNA cleavage sites are indicated by triangles. The thumb-like ß-hairpins are indicated by circles in the schematics.
Fig. 11 shows structural comparison between Csx29 and human separase. Overall structures of Csx29 and human separase (PDB ID: 7NJ1). The catalytic residues are depicted as space-filling models. Securin (separase inhibitor) is colored gray. The close-up views of the protease active sites are shown in insets.
Figs.12A12D show interaction between Cas711 and Csx29.
Fig. 12A shows interface between Cas7-11 and Csx29 in the Cas7-11-crRNA-Csx29 complex.Cas711 and Csx29 are shown as ribbon and surface representations, respectively. The INS and CTE domains of Cas7-11 are omitted for clarity.
Fig. 12B-12D show structures of the Cas7.1-Cas7.4 domains in Cas7-11- crRNA-tgRNA (PDB ID: 7WAH)
(Fig. 12B) Cas7-11-crRNA-Csx29 (Fig. 12C) and Cas7-11- crRNA-Csx29-tgRNA
(Fig. 12D) The bound zinc ions are shown as spheres. The α-helical insertion in the Cas7.4 ZF motif is highlighted.
Figs.13A-13D show interface between Cas7-11 and Csx29.
Fig.13A shows interface between Cas7-11 Cas7.4 and Csx29 NTD.
Fig.13B shows interface between Cas7-11 Cas7.3/L2 and Csx29 NTD.
Fig.13C shows interface between Cas7-11 L2 and the Csx29 NTD/TPR.
Fig.13D shows interface between Cas7-11 Cas7.3 and Csx29 TPR1/2.
Figs. 14A14D show target RNA induced conformational change in the Cas7-11-Csx29 complex.
Figs 14A-14B show interfaces between Cas7-11 and Csx29 in Cas7-11-erRNA--Csx29
(Fig. 14A) and Cas7-11-crRNA-Csx29-tgRNA (Fig.14B).
Fig. 14C shows recognition of the tgRNA non-matching PFS by Cas711. The density map for the RNA molecules is shown as a gray mesh.
Fig. 14D shows superimposition of Cas7-11-crRNA-Csx29 and Cas7-11-crRNA- Csx29tgRNA. A potential steric clash between the tgRNA non-matching PFS and Csx29 (TPR1 and AR2) is indicated by a dashed circle.
Figs. 15A-15B show target RNA and Csx30 cleavage by theCas7-11-Csx29 complex.
Fig. 15A shows the Cas7-11-crRNACsx29 complex was incubated with a 5'-Cy5-labeled ssRNA FII11725504.1 target at 37°C for 10 min, and then analyzed by 5% TBEurea PAGE. The gels were visualized, using either Cy5 or SYBR Gold fluorescence. The wild-type (W) and catalytically inactivated (D)versions of Cas711 and Csx29 were used.
Fig. 15B shows RNA-triggered Csx30 cleavage by the Cas7-11-crRNA-Csx29 complex. The Cas7-11-crRNA Csx29 complex was incubated with Csx30 at 37°C for 5 min in the presence of the target RNA (CTR). The wild-type (W) and catalytically inactivated (D) versions of Cas7-11 and Csx29 were used.
Fig. 16 shows N-terminal analysis of Csx30. Elution profiles for N-terminal seven residues in the -15 kDa Csx30 fragment (Csx30-2) were shown.
Figs. 17A17D show effects of Csx30 and Csx31 on bacterial cell growth.
Fig. 17A shows growth curves of E. coli expressing the non-induced full-length Csx30, the N-terminal fragment (residues 1-427) of Csx30 (Csx30-1), or the C-terminal fragment (residues 428-565) of Csx30(Csx302). These curves serve as noninduced controls for the curves in Figure 4B.
Fig17B shows effects of Csx30 growth at a range concentrations End-point analysis of E. coli expressing arabinose-inducible full-length Csx30, the N-terminal fragment (residues 1-427) of Csx30 (Csx30-1), the C-terminal fragment (residues 428-565) of Csx30 (Csx30-2), or full-length and N- or C terminal Csx30 fragments conjugated to Csx31. OD600 values are shown for bacteria at concentrations ranging from 0 to 2% arabinose in the growth media, including the 1% value used for other experiments in the study.
Fig. 17C shows electrostatic surface potential of the Csx30 and Csx31 structures predicted using AlphaFold2. The predicted structures suggested that Csx30 and Csx31have negatively and positively charged surfaces, respectively.
Fig. 17D shows growth curves of E. coli expressing non-induced Csx30-1, full-length Csx30 and Csx31, or Csx30-1 and Csx31. These curves serve as non-induced controls for the curves in Figure 4D.
Figs.18A18E show interaction between Csx30, Csx31, and RpoE.
Figs.18A-18B show elution profiles of the Csx30-Csx31-RpoE complex from a gelfiltration column. Csx30, His6-tagged Csx31 ("His6" disclosed as SEQ ID NO: 83), and His6-tagged RpoE ("His6" disclosed as SEQ ID NO: 83) were co-expressed in E. coli, and purified by Ni-NTA and HiLoad16/600 Superdex 200 columns.
In (Fig.18A) the Csx30-Csx31RpoEcomplex was loaded onto a Superdex 200 Increase column
(Fig.18B) the Csx30-Csx31-RpoE complex was incubated with the Cas7-11-crRNA-Csx29-tgRNA complex, and then loaded onto a Superdex 200 Increase column. The fractions indicated by orange lines were analyzed by SDS-PAGE…
[Citations omitted] [Emphases added].
The examples provided in the instant specification, of the in vitro analyses of molecular interactions (e.g., Csx30-Csx31-RpoE complexes, Cas7-11-crRNA-Csx29-tgRNA), and of the in vitro inhibition of E. Coli growth, are not representative or correlative of the ability to treat cancer in a subject as instantly claimed. And in vitro transfections, even in human cells, are not representative of the ability to adequately deliver the system components to target cells in a subject and thereby provide therapeutic effects..
In light of the teachings in the art and the specification, one skilled in the art would not accept on its face the examples provided in the instant disclosure as being correlative or representative of the ability to provide treatment effects in a subject. Since the specification fails to provide the requisite guidance for the treatment in any subject, and since determination of the factors required for accomplishing this in any subject is highly unpredictable, it would require undue experimentation to practice the invention over the broad scope claimed.
For these reasons, the instant rejection for lacking enablement over the full scope claimed is properly maintained.
Allowable Subject Matter
SEQ ID No. 36 appears free of the prior art searched and of record.
Conclusion
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.
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Jane Zara
6-25-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
Prosecution Insights