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 .
Applicant’s amendments and response filed on 26 August 2025 have been received and entered into the case.
Priority
Foreign priority was erroneously indicated in the office action mailed 28 February 2025. The instant application claims domestic priority from US provisional application 62/881,540 filed 01 August 2019.
Election/Restrictions
Claims 24-25 and 28-29 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 1, 18, 25, and 32 are currently amended. Claims 24-25 and 28-29 have been withdrawn as being directed to a non-elected species.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, 33-36, and 39 were previously cancelled. Claims 37-38 have been cancelled. Claims 1-3, 6, 8, 10-11, 13, 16, 18-21, and 32 have been considered on their merits.
Withdrawn Rejections
The claim rejections under 35 U.S.C. § 112(a) have been withdrawn due to the instant amendments.
The claim rejections under 35 U.S.C. § 112(b) have been withdrawn due to the instant amendments.
The claim rejections under 35 U.S.C. § 102(a)(1) have been withdrawn due to the instant amendments.
The claim rejections under 35 U.S.C. § 103 have been withdrawn due to the instant amendments.
Response to Arguments
Applicant’s arguments, see Remarks, filed 26 August 2025, with respect to the rejections of claims 1, 3, 6, 10-11, 13, 16, 18, 20-21, 32 and 37-38 under 102(a)(1) and claims 2, 8 and 19 under 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Illiano et al. and Tervo et al.
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.
Claims 1, 3, 6, 8, 10-11, 13, 16, 18, 20-21, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Illiano et al. (Scientific Reports, 2017, of record) and further in view of Tervo et al. (Neuron. 2016, IDS ref.).
This is a new rejection, necessitated by applicant’s amendments to the claims.
Regarding claims 1, 3, 6, and 11, Illiano et al. teach target-specific mediated gene therapy of dopamine transporter deficiency syndrome (DTDS), which is caused by a loss-of-function mutation in dopamine transporter (DAT) gene, utilizing a combinatorial adeno-associated viral (AAV) gene therapy by expressing DAT selectively in dopamine (DA) neurons and terminals (Abstract). Two vectors were utilized, TH-iCRE-AAV (the second composition) provided improved CRE recombinase (iCre) protein (an exogenous agent) and CMV-DIO-mDAT-AAV (the first composition) is an AAV vector carrying a therapeutic gene, DAT, which is inverted relative to its promoter and activatable by iCre (Figure 1B). Illiano et al. teach the vectors were administered to DAT knockout (DAT-KO) mice (a mammal) via bilateral stereotaxic injection (local administration) of AAV particles in the substantia nigra (SN) (the central nervous system), where A9 dopaminergic cell bodies originate and send their axonal projections to the dorsal striatum (DS) (pp. 2-3, Results and Figure 3A). Illiano et al. teach the rescue of DAT protein expression in the striatum and restoration of tyrosine hydroxylase (TH) expression levels in treated KO mice. The signal for mDAT was not detectable in the KO control group (relative to a mammal not administered the first and second viral vector) (Figure 3D).
Illiano et al. is silent to one of the adeno-associated viral vectors is a retrograde vector.
However, Tervo et al. teach 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 et al. teach 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).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the retrograde vector of Tervo et al. in the method of Illiano et al. with a reasonable expectation of success because Tervo et al. teach the rAAV2-retro can be used 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. One would be motivated to utilize the retrograde vector of Tervo et al. in the method of Illiano et al. because retrograde vectors deliver genes to brain cells by entering at the axon terminal and traveling backwards along the axon to the cell body, providing a method to target specific neural circuits distant from the injection site, which is crucial for both analyzing neuronal pathways and delivering gene therapy to neurodegenerative cells.
Regarding claim 8, Illiano et al. is silent to the order of administration of the first and second vector. However, one skilled in the art would recognize administering the vectors as performing process steps and can be performed in any order, absent evidence to the contrary. MPEP § 2144.04(IV)(C) states “…In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results)…”.
Regarding claims 10, 20, and 21, Illiano et al. teach both vectors were administered via bilateral stereotaxic injection in the substantia nigra (SN), where A9 dopaminergic cell bodies originate and send their axonal projections to the dorsal striatum (DS) (pp. 2-3, Results and Figure 3A). Injecting the vectors in the SN with the intention of rescue of DAT protein expression in the striatum (Figure 3C/D) reads as targeting both the SN and striatum.
Regarding claim 13, the CMV-DIO-mDAT-AAV vector of Illiano et al. reads as the first viral vector containing recognition sites (loxP) capable of recombination and activation of the gene in the first vector and the TH-iCRE-AAV vector of Illiano et al. reads as the second vector encoding a recombinase (iCre) that is specific for the recognition sites (Figure 1B).
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 protein provided by the TH-iCRE-AAV vector of Illiano et al. reads as an exogenous agent which would activate the gene product of the CMV-DIO-mDAT-AAV vector.
Regarding claims 18 and 32, the wherein clauses recite an intended result and do not add structure to the method. 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. Although, Illiano et al. teach preclinical data demonstrating the efficacy of their target-specific mediated gene therapy which resulted in rescue of the abnormalities in dopaminergic transmission, leading to the robust amelioration of major behavioral deficits and the prevention of the development of the neurodegenerative phenotype in the DAT-KO model (p. 2, last full para.). Illiano et al. teach target-specific mediated gene therapy of dopamine transporter deficiency syndrome (DTDS) (Abstract) and DTDS is a symptom of Parkinson’s disease (p. 1).
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 2 is rejected under 35 U.S.C. 103 as being unpatentable over Illiano et al. (Scientific Reports, 2017, of record) in view of Tervo et al. (Neuron. 2016, IDS ref.) as applied to claims 1, 3, 6, 8, 10-11, 13, 16, 18, 20-21, and 32 above, and further in view of Stavarache et al. (J. Neurosurg, March 2019 (IDS ref.)).
This is a new rejection, necessitated by applicant’s amendments to the claims.
Regarding claim 2, Illiano et al. in view of Tervo et al. are silent to the first or second vector is systematically administered and focused ultrasound is employed to target the specific population of neurons.
Stavarache et al. teach 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 use the target-specific mediated gene therapy of Illiano et al. with the delivery method of Stavarache et al. with a reasonable expectation of success because Stavarache et al. teach 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 vector delivery in a noninvasive method, such as the bilateral stereotaxic injection method of Illiano et al. One would be motivated to use the target-specific mediated gene therapy of Illiano et al. with the delivery method of Stavarache et al. because Stavarache et al. teach 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 are rejected under 35 U.S.C. 103 as being unpatentable over Illiano et al. (Scientific Reports, 2017, of record) in view of Tervo et al. (Neuron. 2016, IDS ref.) as applied to claims 1, 3, 6, 8, 10-11, 13, 16, 18, 20-21, and 32 above, and further in view of Kuhlman et al. (PLoS ONE, 2008).
This is a new rejection, necessitated by applicant’s amendments to the claims.
Regarding claim 19, Illiano et al. in view of Tervo et al. are silent to the administration of the two vectors to the mammal is separated by at least 24 hours.
Kuhlman et al. teach functional manipulation of specific neuron types in Cre-recombinase knockin mice brains by Cre-activated viral gene expression (Abstract). Kuhlman et al. teach 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 et al. 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 Illiano et al. 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.
Conclusion
No claims are allowed.
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.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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