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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/08/2026 has been entered.
Election/Restrictions
The requirement for restriction between Groups of inventions, Groups I-III, was withdrawn in the Official Action mailed on 28 February 2025.
Claims 24-25 and 28-29 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. The species election of striatum for the first vector target and substantia nigra for the second vector target was made without traverse in the reply filed on 31 January 2025.
Claim Status
Claims 24-25 and 28-29 have been withdrawn as being directed to a non-elected species, claims 4-5, 7, 9, 12, 14-15, 17, 22-23, 26-27, 30-31, and 33-39 were previously cancelled, claim 10 is newly cancelled, claim 1 is currently amended, and claims 1-3, 6, 8, 11, 13, 16, 18-21, and 32 have been considered on their merits.
Response to Arguments
Applicant’s arguments, see Remarks, filed 09 February 2026, with respect to the rejection of the claims under § 103 have been fully considered and are persuasive. Specifically, the amendments to claim 1 has overcome the rejections as it pertains to the primary reference, Illiano. Therefore, the 103 rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Tervo.
Applicant’s arguments with respect to Illiano have been considered but are moot because the new ground of rejection does not rely on Illiano.
Applicant’s arguments with respect to Tervo have been considered, however, upon further consideration it was found that Tervo teaches and/or suggests all of the limitations of the claims.
Regarding the arguments directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
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 1-3, 6, 8, 11, 13, 16, 18-21, and 32 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.
This is a new rejection, necessitated by Applicant’s amendment to the claims.
Claim 1 recites “wherein the viral vectors are adeno-associated viral vectors”, in the first line; “wherein one of the vectors” in the second line; and “the other vector” in the fourth line of the last paragraph of the claim. It is unclear to which viral vectors these limitations are referring, the vectors of the first composition, the second composition, or both. For the purpose of clarity, it is recommended to amend these instances associated with the vectors as either the first vector or the second vector. For example, change “wherein the viral vectors are adeno-associated viral vectors” to “wherein the first and second viral vectors are adeno-associated viral vectors” and “wherein one of the vectors” to “wherein the first or second vector”. For the purpose of compact prosecution, claim 1 is interpreted as requiring at least one of the compositions to comprise an AAV vector.
The dependent claims are included in the rejection because they do not remedy the clarity of claim 1.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 and 11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
This is a new rejection.
Claim 6 recites the limitation, wherein the first viral vector or the second viral vector is a retrograde viral vector. Claim 1, from which claim 6 depends, recites in the last paragraph of the claim, wherein one of the adeno-associated viral vectors is a retrograde vector. Since claim 1 already requires one of the vectors to be a retrograde vector claim 6 does not further limit the claim from which it depends.
Claim 11 recites the limitation, wherein at least one of the viral vectors comprises an adeno-associated virus, adenovirus, canine adenovirus, herpes simplex virus, or lentivirus vector. Claim 1, from which claim 11 depends, recites in the last paragraph of the claim, wherein the viral vectors are adeno-associated vectors. This limitation in claim 1 is narrower than the limitations in claim 11 because claim 1 requires both vectors to be adeno-associated vectors, thus, does not further limit the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 6, 8, 11, 13, 16, 18, 20, and 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tervo et al. (Neuron. 2016, IDS ref., of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims.
Regarding claims 1, 3, 6, and 11, Tervo teaches the variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers, and enable sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations (Abstract). Tervo teaches the rAAV2-retro gene delivery system can be used on its own or in conjunction with Cre recombinase driver lines to achieve long-term, high-level transgene expression that is sufficient for effective functional interrogation of neural circuit function, as well as for genome editing in targeted neuronal populations (p. 3, Introduction). Tervo teaches to eliminate the possible confound of cell-to-cell variability in transgene expression level, the AAV was used to deliver Cre recombinase to Rosa26-Lox-STOP-Lox-H2B-EGFP transgenic mice (p. 4). Tervo teaches low concentrations of the Cre enzyme was sufficient to turn on the expression of the Cre-dependent cassette (Fig. 2). Tervo teaches a dense layer of GFP-positive layer V projection neurons could be observed throughout the rostro-caudal axis of the cortex in rAAV2-retro-injected animals (Fig. 2B). Tervo teaches rAAV2-retro exhibits up to two orders of magnitude enhancement over existing serotypes in retrograde access to corticopontine projection neurons (p. 5). Tervo teaches quantitative analysis revealed that strong retrograde labeling was found in the vast majority of regions that have been previously reported to send prominent projections to the striatum (Fig. 3B-C and p. 5). Tervo suggests rAAV2-retro was an effective reagent to genetically access projection neurons for functional interrogation of neural circuits and for possible therapeutics for disorders of the nervous system characterized by progressive large-scale network dysfunction (p. 7).
Tervo teaches rAAV2-retro was sufficient to deliver Cre recombinase (second composition comprising a product which activates the gene product of the first vector) to cell bodies to direct high-level expression for locally delivered Cre-dependent payloads (p. 8). Tervo teaches, in low efficiency circuits, corticothalamic and corticocollicular projections, labeling of projection neurons following local delivery (claim 3) of high-copy number Cre-dependent payloads to projection neurons cell bodies (first composition comprising a conditionally activatable gene) were used to determine labeling efficiency of rAAV2-retro (Table S2 description). Tervo teaches the injection location of the rAAV2-retro vector (claim 6 and claim 11) in the superior colliculus and the projection neurons were located in layer 5 of the visual cortex (Table S2). The projection neurons of Tervo read as axons from regulatory neurons since projection neurons are defined by their long axons that transmit signals over significant distances between brain regions or between the brain and the body. The superior colliculus reads as targeting a structure in the brain of a mammal and the visual cortex reads as a different region.
Regarding claim 8, Tervo teaches, in low efficiency circuits, corticothalamic and corticocollicular projections, labeling of projection neurons following local delivery of high-copy number Cre-dependent payloads to projection neurons cell bodies were used to determine labeling efficiency of rAAV2-retro (Table S2 description). The phrase “following local delivery” reads as the first vector was administered before the second vector and not coadministered.
Regarding claim 13, Tervo teaches rAAV2-retro was sufficient to deliver Cre recombinase to cell bodies to direct high-level expression for locally delivered Cre-dependent payloads (p. 8). The Cre-Lox system described by Tervo reads on the limitation of the claim.
Regarding claim 16, the phrase “is activatable by an exogenous agent” at the end of the claim is not limiting because it does not require an active step. Therefore, claim 16 reads as having the same limitations as claim 1. However, if the exogenous agent was required by the limitations of the claim, the Cre recombinase of Tervo reads as an exogenous agent.
Regarding claims 18 and 32, the wherein clauses recite an intended result and do not add structure to the method for targeting a specific population of mammalian neurons. MPEP § 2111.04 states “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). Therefore, the limitations of claims 18 and 32 are the same as claim 1 and are rejected for the same reason.
Regarding claim 20, Tervo teaches rAAV2-retro expressing EGFP was injected in the striatum of an adult Long Evans rat (Fig. S1 description). Injection in the striatum reads as targeting.
Thus, the reference anticipates the subject matter of the claims.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Tervo et al. (Neuron. 2016, IDS ref., of record) as applied to claims 1, 3, 6, 8, 11, 13, 16, 18, 20, and 32 above, and further in view of Stavarache et al. (J. Neurosurg, March 2019, IDS ref., of record).
This is a new rejection, necessitated by applicant’s amendments to the claims.
Tervo anticipates the subject matter of claims 1, 3, 6, 8, 11, 13, 16, 18, 20, and 32, and thus, also render them obvious.
Regarding claim 2, Tervo is silent to the first or second vector is systematically administered and focused ultrasound is employed to target the specific population of neurons.
Stavarache teaches focused ultrasound under the control of MRI (MRgFUS), in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker (Abstract).
It would have been obvious to one of ordinary skill in the art to utilize the ultrasound delivery method of Stavarache with the method of Tervo with a reasonable expectation of success because Stavarache teaches the non-invasive ultrasound delivery demonstrated ongoing gene expression 16 months following delivery via this method (p. 992 2nd column). This demonstrates an effective method of targeted vector delivery in a noninvasive method to a specific population of neurons, i.e., the striatum of a subject. One would be motivated to utilize the ultrasound delivery method of Stavarache with the method of Tervo because Stavarache teaches transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of AAV vectors to the intended brain target, raising the potential for noninvasive focal human gene therapy for neurological disorders (Abstract and p. 990 1st column).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Tervo et al. (Neuron. 2016, IDS ref., of record) as applied to claims 1, 3, 6, 8, 11, 13, 16, 18, 20, and 32 above, and further in view of Kuhlman et al. (PLoS ONE, 2008, of record).
This is a new rejection, necessitated by applicant’s amendments to the claims.
Tervo anticipates the subject matter of claims 1, 3, 6, 8, 11, 13, 16, 18, 20, and 32, and thus, also render them obvious.
Regarding claim 19, Tervo is silent to the administration of the two vectors to the mammal is separated by at least 24 hours.
Kuhlman teaches functional manipulation of specific neuron types in Cre-recombinase knockin mice brains by Cre-activated viral gene expression (Abstract). Kuhlman teaches expression of AAV-LSL-GFP is stable after AAV transfection in Pv-cre mice and the GFP signal was prominent as early as 6 days post-injection with expression levels increasing further at 15 days post-injection (p. 2, Expression of AAV-LSL-GFP is stable for months).
The teachings of Kuhlman indicate viral transfection can be done at any time period as the transfected genes continue to express well after 24 hours post injection.
It would have been obvious to one of ordinary skill in the art to select the timing for injecting the vectors as a matter of routine optimization through routine experimentation. MPEP § 2144.05(II)(A) states “…In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").” There would have been a reasonable expectation of success because regardless of the timing of vector administration, the end result would be conditional activation of the desirable gene product. Therefore, the it would be obvious to administer the vectors taught by Tervo at least 24 hours apart because the results would be the same whether the vectors were administered simultaneously or separated by 24 hours.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Tervo et al. (Neuron. 2016, IDS ref., of record) as applied to claims 1, 3, 6, 8, 11, 13, 16, 18, 20, and 32 above, and further in view of Pan et al. (Frontiers in Neuroanatomy, December 2010, Volume 4, Article 147).
This is a new rejection, necessitated by applicant’s amendments to the claims.
Tervo anticipates the subject matter of claims 1, 3, 6, 8, 11, 13, 16, 18, 20, and 32, and thus, also render them obvious.
Regarding claims 20 and 21, Tervo teaches rAAV2-retro expressing EGFP was injected (targeted) in the striatum of an adult rat (Fig. S1 description) and is silent to a vector targeting the substantia nigra.
However, if this vector were not administered in conjunction with a different vector, Tervo teaches quantitative analysis revealed that strong retrograde labeling was found in the vast majority of regions that have been previously reported to send prominent projections to the striatum (Fig. 3B-C and p. 5). Tervo suggests rAAV2-retro was an effective reagent to genetically access projection neurons for functional interrogation of neural circuits and for possible therapeutics for disorders of the nervous system characterized by progressive large-scale network dysfunction (p. 7). Tervo teaches rAAV2-retro was sufficient to deliver Cre recombinase to cell bodies to direct high-level expression for locally delivered Cre-dependent payloads (p. 8).
Pan teaches retrograde labeling via injections in the striatum of mice wherein the dopaminergic input to the dorsal striatum originated from neurons with somata located predominantly in the substantia nigra pars compacta (SNc) (p. 3, Results and Fig. 5). Pan provided suggestive evidence for the convergence of projections from specific nuclei across the nigro-striatal pathway (p. 10). Thus, providing motivation to target the striatum and/or substantia nigra.
Therefore, it would have been obvious to one of ordinary skill in the art to target the striatum as suggested by Pan with one of the vectors of Tervo with a reasonable expectation of success because vectors injected into the striatum of mammals was well known in the art, which reads as targeting the vector to the striatum. One would be motivated to target the striatum as suggested by Pan with one of the vectors of Tervo because Pan teaches the striatum is connected to various regions of the brain, to include the substantia nigra, which is a well-known pathway involved with neurological disease, such as Parkinson’s disease. Additionally, Tervo suggests the rAAV2-retro vector as a therapeutic for disorders of the nervous system characterized by progressive large-scale network dysfunction and Tervo teaches rAAV2-retro was sufficient to deliver Cre recombinase to cell bodies to direct high-level expression for locally delivered Cre-dependent payloads. Thus, suggesting targeting the striatum (claim 20) with a vector comprising a therapeutic payload via a retrograde vector could be utilized activate a gene product to the substantia nigra which could targeted with a vector (claim 21) comprising a Cre-dependent payload.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gomph et al. (Front. Behav. Neurosci., 01 July 2015, Volume 9, Article 152)
Gomph teaches neuron subtype specific gene expression in wildtype animals utilizing a combinatorial AAV targeting system that drives, in combination, subtype specific Cre-recombinase expression with a strong but non-specific Cre-conditional transgene. Gomph teaches combinatorial strategies have been designed to express circuit-manipulating constructs in adult brains by delivering recombinase-dependent viruses into discrete brain regions of recombinase-expressing transgenic animals. Gomph teaches a combinatorial dual AAV vector approach to achieve specificity while maintaining high expression levels in wildtype animals, wherein the first AAV incorporates the gene of interest in a double-inverted open (DIO) reading frame, driven by a strong neuron specific or generalized promoter. Gomph teaches small amounts of Cre are needed to reorient the transgene for expression, thus a significantly weaker, but neuronal subtype specific promoter, tyrosine hydroxylase, can drive sufficient Cre expression.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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