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 .
DETAILED ACTION
Claims 1-16 are pending and under examination on their merits.
Claim Objections
Claims 6-7 are objected to because of the following informalities:
In claim 6, part (b), “comprising” in lines 4-5 is grammatically incorrect and should be replaced with comprises.
In claims 6-7, several words are randomly italicized. In claim 6, the sequence identifiers and (b) the first are italicized. In claim 7, SEQ ID NO: 4, and wherein is italicized.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7 and 9-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites the limitation, wherein the second fragment comprises amino acid residues 147-441 of SEQ ID N0:4, and wherein the second fragment has at least one mutation selected from the group consisting of K94A, N157A, Y365A, and S311A/D312A in the corresponding residues of SEQ ID NO:4. The claim has multiple reasonable interpretations, rendering it indefinite. In one interpretation, the mutations are defined according to the amino acid residue numbering of SEQ ID NO: 4. In a second interpretation, the mutations are defined according to the residues of the fragment 147-441 of SEQ ID NO4 (i.e. amino acid residue 147 of SEQ ID NO:4 is amino acid residue 1 of the fragment). The claim is further indefinite for the limitation wherein the second fragment has at least one mutation selected from the group consisting of K94A, N157A, Y365A, and S311A/D312A. It is unclear whether S311A and D312A are alternatives or whether a second fragment comprising S311A must also include D312A.
Claims 9-10 are rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
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 1-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of silencing neurons in vitro, does not reasonably provide enablement for a method of silencing neurons in vivo or a method of silencing a single neuron either in vivo or in vitro. 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 use the invention commensurate in scope with these claims.
Per MPEP 2164.01(a), the following eight factors should be considered when determining whether the person of ordinary skill in the art would face undue experimentation to make and/or use the invention: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
Nature of the invention. Claim 1 is drawn to a method of silencing a neuron comprising introducing into the neuron a first construct comprising a first fragment of a protein and a first photodimerizer molecule, introducing into the neuron a second construct comprising a second fragment of the protein and a second photodimerizer molecule and applying visible light to the neuron. Claim 1 also requires that the first photodimerizer molecule binds to the second photodimerizer molecule in the presence of visible light, thereby promoting physical contact between the first fragment and the second fragment, and inducing the neuron-silencing activity.
Breadth of the claims. Claims 1-13 encompass both in vivo and in vitro methods of silencing a neuron. Claims 14-16 are limited to in vivo methods of locally silencing a neuron in a subject. Claim 15 requires applying the visible light to the neuron or its vicinity only. Claim 16 limits the subject to a human. The neurons are not limited to any particular type of neurons and thus encompass any neuron, such as specialized light-sensing retinal neurons (e.g. rods and cones), sensory neurons, motor neurons, and interneurons.
State of the prior art and unpredictability. Kramer et al. (Nature neuroscience 16.7 (2013): 816-823) teaches a variety of optopharmacogical and optogenetic tools for neuronal control (Table 1). However, the vast majority of optogenetic tools have not been applied in vivo. The in vivo application of the optopharmacogical and optogenetic tools is limited to mice, rats, zebrafish, C. elegans, and Drosophila, with the exception of two retinal studies: one performed in ex vivo humans and another performed in primates (Table 1).
Fenno et al. (Annual review of neuroscience 34.2011 (2011): 389-412) describes the development of optogenetic tools and their application in diverse animal models (page 390, Table of Contents). Regarding primates, Fenno teaches that optogenetic modulation of primate neurons has been explored by ChR2 delivery to cortical neurons of macaques via lentiviral transduction, but behavioral responses have not yet been observed (page 45, right column, paragraph 2, “Primates”). Fenno teaches that cellular specificity can be obtained with viruses by using specific promoters, spatial targeting of virus injection, and by restriction of opsin activation to particular cells or projections of specific cells via targeted light delivery (page 398, right column, Delivering Optogenetic tools into neuronal systems). Fenno teaches that a major drawback of viral expression systems is a maximum genetic payload strength; only promoter fragments that are small, specific, and strong may be used and these are rare (page 398, bottom of right column).
Kennedy (Nature methods 7.12 (2010): 973-975; cited on the IDS filed on 12/4/2024) teaches CRY2-CreN and CIBN-CreC constructs (page 976, left column, paragraph 4). The Cry-CIB molecules induce dimerization of a split Cre recombinase: CRY2 is fused to amino acids 19-104 of Cre recombinase (“CreN”) and CIBN is fused to amino acids 106-343 of Cre recombinase (“CreC;” Fig. 3c; page 974, right column, bottom paragraph). Cells containing CRY2-CreN (“first construct”) and CIBN-CreC (“second construct”) exposed to continuously pulsed blue light for 24 h demonstrate light-dependent recombinase activity (page 975, left column, middle of first paragraph; Fig. 3d and 3e). Kennedy suggests that the split-protein approach would confer light-dependent activity to a diverse range of target proteins (page 974, right column, second paragraph). Kennedy teaches that photodimerization occurs on the subsecond time scale and also suggests the application of the photodimerization technique to in vivo whole organisms (first full paragraph on page 973). However, Kennedy’s light activation of Cre recombinase is limited to HEK293T cells transfected with the Cre reporter construct (page 977, Online Methods, Light activation of split Cre recombinase, left column, bottom paragraph) or transfected organotypic slice cultures (page 977, right column, Two-photon microscopy, bottom).
To summarize, the state of the art with respect to silencing neurons in vivo or silencing a single neuron in vitro or in vivo was highly unpredictable just before the effective filing date of the claimed invention.
Guidance in the specification and working examples. The specification does not provide any working examples in which a single neuron is silenced in vitro or vivo or in which neurons are silenced in a subject. The specification discloses measuring spontaneous quantal neurotransmitter release by recording AMPA receptor-mediated mEPSCs (miniature excitatory postsynaptic currents) in dissociated hippocampal cultures that were infected with AAVs encoding vPA-BoNT (lines 15-17 on page 31). In vesicular PA-BoNT, the SspB-fused C-terminal BoNT fragment is expressed as a soluble protein and the N-terminal BoNT-iLID fragment is fused to the synaptic vesicle protein synaptophysin (syph) along with a EGFP reporter (lines 2-6 on page 31). Neurons expressing the toxin constructs displayed a slight increase in frequency, but not amplitude of mEPSCs (lines 17-18 on page 31).
The specification also discloses co-injecting two AAVs, each encoding one of the vPA-BoNT fragments, into the hippocampal CA1 region (Fig. 4A) in order to control neurotransmission in an intact circuit (lines 24-28 on page 32). Acute slices were prepared 1.5-2 weeks following injection (line 29 on page 32). The slices were exposed to blue light for 30 min (lines 34 on page 32).
Thus, Applicant’s results are limited to in vitro dissociated hippocampal cultures or slices of the hippocampal CA1 region. No working examples are disclosed in which a single neuron is silenced either in vitro or in vivo or a group of neurons are locally silenced in a subject (in vivo).
Amount of experimentation necessary. Undue experimentation would be required for the person of ordinary skill in the art to develop a method with sufficient selectivity to locally silence neurons in a subject or to precisely silence a single neuron either in vitro or in vivo. The person of ordinary skill in the art would also face undue experimentation to practice the claimed method in vivo because the claimed method was not reduced to practice in vivo and the state of the art suggests a high degree of unpredictability with respect to locally silencing neurons in a subject.
Taking these factors into account, undue experimentation would be required by one of ordinary skill in the art to practice the full scope of the claimed invention. Thus, the claims are not fully enabled by the disclosure.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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 1-5, 8, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Aranda et al. (WO 2017/220800 A1; cited on the IDS filed on 12/4/2024) in view of Kennedy (Nature methods 7.12 (2010): 973-975; cited on the IDS filed on 12/4/2024).
Aranda silences neurotransmission (“silencing a neuron”) by expressing wild-type or modified light chain botulinum toxins from a viral expression vector (lines 22-24 on page 8). Aranda teaches infecting primary cultures of rat embryonic DRG neurons with amplicon vectors expressing A2-CMV-BoNT-A or BoNT-B (lines 29-30 on page 34). Each botulinum neurotoxin expressed by the vectors cleaves its natural target SNARE protein (lines 32-33 on page 34). Aranda teaches that BoNT-A injections suppress the formation of SNARE complex (lines 8-10 on page 3). Aranda teaches that the light chains of botulinum toxins inhibit release of the neuropeptide CGRP in primary cultures of rat embryonic DRG neurons (line 7 on page 35).
Aranda does not teach a first construct comprising a first fragment of the neurotoxin and a first photodimerizer molecule and a second construct comprising a second fragment of the protein and a second photodimerizer molecule.
Aranda does not teach that the first fragment and the second fragment are each inactive in silencing the neuron when not physically contacting each other and that the first fragment and the second fragment have a neuron-silencing activity when physically contacting each other.
Aranda does not teach that, in the absence of visible light, the first photodimerizer molecule does not bind to the second photodimerizer molecule and, in the presence of visible light, the first photodimerizer molecule binds to the second photodimerizer molecule, thereby promoting physical contact between the first fragment and the second fragment, and inducing neuron-silencing activity.
Kennedy teaches CRY2-CreN and CIBN-CreC constructs (page 976, left column, paragraph 4). The Cry-CIB molecules induce dimerization of a split Cre recombinase: CRY2 is fused to amino acids 19-104 of Cre recombinase (“CreN”) and CIBN is fused to amino acids 106-343 of Cre recombinase (“CreC;” Fig. 3c; page 974, right column, bottom paragraph). Cells containing CRY2-CreN (“first construct”) and CIBN-CreC (“second construct”) exposed to continuously pulsed blue light for 24 h demonstrate light-dependent recombinase activity (page 975, left column, middle of first paragraph; Fig. 3d and 3e). In other words, in the absence of visible light, the first photodimerizer molecule does not bind to the second photodimerizer molecule and, in the presence of visible light, the first photodimerizer molecule binds to the second photodimerizer molecule, thereby promoting physical contact between the first fragment and the second fragment, and inducing the protein activity. Kennedy suggests that the split-protein approach would confer light-dependent activity to a diverse range of target proteins (page 974, right column, second paragraph). Kennedy teaches that photodimerization occurs on the subsecond time scale and also suggests the application of the photodimerization technique to in vivo whole organisms (first full paragraph on page 973).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply the optogenetic split-protein photodimerization approach of Kennedy by splitting Aranda’s light chain botulinum toxins into two fragments encoded in two constructs and fusing Kennedy’s photodimerizer molecules, CRY2 and CIBN, to the two fragments of BoNT/A or BoNT/B. The person of ordinary skill in the art would have been motivated to attain inducible control of the activity of Aranda’s neurotoxin and hence the resulting neurotransmission inhibition. The person of ordinary skill in the art would have had a reasonable expectation of success given that Kennedy suggests that the approach was applicable to a diverse range of target proteins. Furthermore, Kennedy successfully demonstrates the approach with Cre recombinase.
Regarding claim 2¸ Kennedy teaches that cells containing the first and second constructs demonstrate light-dependent recombinase activity when exposed to continuously pulsed blue light for 24 h (page 975, left column, middle of first paragraph; Fig. 3d and 3e).
Regarding claims 3-4, Aranda teaches infecting primary cultures of rat embryonic DRG neurons with amplicon vectors expressing A2-CMV-BoNT-A or BoNT-B (lines 29-30 on page 34). BoNT-A and BoNT-B are serotypes of Clostridium botulinum neurotoxin.
Regarding claim 5, Aranda does not teach that the first fragment of the protein comprises an N-terminal portion of the neurotoxin light chain and the second fragment of the protein comprises a C-terminal portion of the neurotoxin light chain. However, applying the technique of Kennedy to the system of Aranda would have resulted in a first construct comprising a C-terminal fragment of Clostridium botulinum light chain neurotoxin fused to CRY2 or CIBN and a second construct comprising an N-terminal fragment of the Clostridium botulinum light chain neurotoxin fused to CIBN or CRY2, respectively.
Regarding claim 8(a), Kennedy teaches first and second constructs comprising CRY2 or CIBN (“CreC;” Fig. 3c; page 974, right column, bottom paragraph).
Regarding claim 12, Aranda teaches infecting primary cultures of rat embryonic DRG neurons with amplicon vectors expressing A2-CMV-BoNT-A or BoNT-B (lines 29-30 on page 34).
Regarding claim 13, in one embodiment, the viral expression vector is an adeno-associated virus (AAV) vector (page 7, lines 3-4). The light chain botulinum toxins are from Clostridium botulinum serotype A or serotype B (lines 13-16 on page 22). Thus, Aranda teaches an AAV having a nucleotide sequence encoding a construct comprising a Clostridium botulinum neurotoxin light chain protein.
Claim 8(b) is rejected under 35 U.S.C. 103 as being unpatentable over Aranda et al. (WO 2017/220800 A1; cited on the IDS filed on 12/4/2024) in view of Kennedy (Nature methods 7.12 (2010): 973-975; cited on the IDS filed on 12/4/2024), as applied to claims 1-5, 8, and 12-13 above, further in view of Zimmerman et al. (Biochemistry 55.37 (2016): 5264-5271; cited on the IDS filed on 12/4/2024).
See discussion of Aranda and Kennedy above, which is incorporated into this rejection as well.
Regarding claim 8(b), Aranda does not teach that the first photodimerizer molecule comprises a LOV domain-peptide fusion (iLID) and the second photodimerizer molecule comprises a domain of E. coli SspB.
Zimmerman teaches the light inducible dimers SspB and iLID, which are activated with blue light (Abstract). Zimmerman also teaches a low affinity switch comprising a new variant of SspB called SspBmilli that has a weaker affinity for iLID and functions at higher protein concentrations (page 5265, left column, bottom third of top paragraph). SspB is from E. coli BL21 (DE3) cells (page 5265, right column, paragraph 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to replace CIBN and CRY2 with SspBmilli and iLID, respectively, in the first and second constructs in the method of Aranda modified by Kennedy. The person of ordinary skill in the art would have been motivated to optimize the system to function at higher botulinum toxin concentrations. The person of ordinary skill in the art would have had a reasonable expectation of success given that SspBmilli and iLID dimerize upon exposure to blue light just like CIBN and CRY2.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Aranda et al. (WO 2017/220800 A1; cited on the IDS filed on 12/4/2024) in view of Kennedy (Nature methods 7.12 (2010): 973-975; cited on the IDS filed on 12/4/2024), as applied to claims 1-5, 8, and 12-13 above, further in view of Rost (Neuron 96.3 (2017): 572-603; cited on the IDS filed on 12/4/2024).
See discussion of Aranda and Kennedy above, which is incorporated into this rejection as well.
Regarding claim 11, Aranda does not teach that the first construct or the second construct further comprise a synaptic vesicle protein synaptophysin.
Rost teaches optogenetic tools such as optogenetic actuators in Figure 2. Rost teaches the split-protein approach, wherein the protein of interest is expressed as two inactive fragments that reconstitute a functional protein upon light adsorption due to the dimerization of CRY2 and CIBN (page 578, left column, paragraph 6, Cry2-CIB Dimerization Systems). Rost cites Kennedy when discussing the split-protein approach (page 578, left column, paragraph 6, Cry2-CIB Dimerization Systems). Rost teaches targeting optogenetic tools to synaptic vesicles by fusing them to vesicular proteins such as synaptophysin (see Figure 3C caption).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to add synaptophysin to the first and second construct in the method of Aranda modified by Kennedy and Rost in order to target the constructs to synaptic vesicles, as suggested by Rost. The person of ordinary skill in the art would have been motivated to target the constructs to the synaptic vesicles in order to silence synaptic transmission of the neurons. The person of ordinary skill in the art would have had a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12,162,912 (hereafter ‘912) in view of Aranda et al. (WO 2017/220800 A1; cited on the IDS filed on 12/4/2024).
Claim 1 of ‘912 is drawn to a light-controlled protein system comprising: a first construct comprising a first fragment of a protein comprising the first fragment and a second fragment, wherein the first fragment is fused to a first photodimerizer molecule; and a second construct comprising the second fragment of the protein, wherein the second fragment is fused to a second photodimerizer molecule; wherein the protein is a Clostridium botulinum neurotoxin serotype B or a biologically active fragment thereof; wherein in the absence of visible light the first photodimerizer molecule does not bind to the second photodimerizer molecule, forming a non-activated system, wherein in the presence of visible light, the first photodimerizer molecule binds to the second photodimerizer molecule thus promoting physical contact between the first fragment of the protein and the second fragment of the protein, and forming an activated system, wherein the biological activity of the protein in the activated system is higher than in the non-activated system.
Claim 1 of ‘912 does not recite a method of silencing a neuron comprising introducing into the neuron the first construct and the second construct or applying visible light to the neuron.
Aranda silences neurotransmission (“silencing a neuron”) by expressing wild-type or modified light chain botulinum toxins from a viral expression vector (lines 22-24 on page 8). Aranda teaches infecting primary cultures of rat embryonic DRG neurons with amplicon vectors expressing A2-CMV-BoNT-A or BoNT-B (lines 29-30 on page 34). Each of the botulinum neurotoxin expressed by the vectors cleaves its natural target SNARE protein (lines 32-33 on page 34). Aranda teaches that BoNT-A injections suppress the formation of SNARE complex (lines 8-10 on page 3). Aranda teaches that the light chains of botulin toxins inhibit release of the neuropeptide CGRP in primary cultures of rat embryonic DRG neurons (line 7 on page 35).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to introduce the light-controlled system of claims 1-7 of ‘912 into the primary cultures of rat embryonic DRG neurons in order to silence neurotransmission per the teaching of Aranda. The person of ordinary skill in the art would have been motivated to attain inducible control of the activity of Aranda’s neurotoxin and hence the resulting neurotransmission inhibition. The person of ordinary skill in the art would have had a reasonable expectation of success in introducing the system of claims 1-7 of ‘912 into the cultures of rat embryonic DRG neurons and subsequently activating the system with visible light.
Instant claim 2 is obvious over claim 2 of ‘912 in view of Aranda.
Instant claim 3 is obvious over claim 1 of ‘912 in view of Aranda.
Instant claims 4-5 are obvious over claim 3 of ‘912 in view of Aranda
Instant claim 6 is obvious over claim 1 of ‘912 in view of Aranda.
Instant claim 7 is obvious over claim 1 of ‘912 in view of Aranda.
Instant claim 8 is obvious over claim 4 of ‘912 in view of Aranda.
Instant claims 9-10 are obvious over claim 5 of ‘912 in view of Aranda.
Instant claim 11 is obvious over claim 6 of ‘912 in view of Aranda.
Instant claims 12-13 are obvious over claim 7 of ‘912 in view of Aranda.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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