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 .
Election/Restrictions
Applicant’s election without traverse of Species A3, B2 and C2 drawn to claims 1-15, 19-20, 22, 24 and 26-33 in the reply filed on 07/28/2025 is acknowledged.
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 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.
Claim 7 recites the limitation "the one or more steady-streaming fluid velocities". There is insufficient antecedent basis for this limitation in the claim, as “steady-streaming fluid velocities” are only previously recited in claim 2, from which claim 7 is not dependent from. For the purposes of examination, the steady-streaming fluid velocities in claim 7 is interpreted as the same steady-streaming fluid velocities in claim 2.
Claim 32 recites the limitation "the AAV vector RNA sequences". There is insufficient antecedent basis for this limitation in the claim, as claim 31 from which 32 depends upon, only recites “adeno-associated virus (AAV) vector DNA sequences” and not the RNA sequences. For the purposes of examination, these are interpreted as the same RNA sequences in both claims 31 and 32.
Claim Rejections - 35 USC § 102
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5-6, 8-15, 19-20, 22, 24, 28-29, 31 and 33 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Anand (US 20190160254).
Regarding claim 1, Anand discloses a method for fluid delivery to a target area in a central nervous system of a patient (para. [0013], last four sentences of paragraph, sentences 12-15), the method comprising: infusing a therapeutic bolus into an intrathecal space of a patient (para. [0013], sentence 12; para. [0277], sentence 1) in a first location (Fig. 20A: first location 122M; para. [0211], sentence 13, the drug bolus is simultaneously infused at 122M); subsequently infusing a flush fluid (para. [0211], sentences 17 & 19, flush fluid being the previously-aspirated CSF or other fluid) into the intrathecal space of the patient in a second location (Fig. 20A: second location 122P; para. [0211], sentences 16-17, advancement step) at one or more flush flow rates (para. [0211], sentence 20, the pulsatile flow and flow rate described further in “Example A,” paras. [0231], [0234], [0237]), the one or more flush flow rates based on at least one of patient anatomy or physiology data (para. [0211], sentence 20, the pulsatile manner including the flow rate in coordination with a physiological parameter of the patient; para. [0214], sentence 1).
Regarding claim 5, Anand discloses the method of claim 1, as described above, wherein the at least one of patient anatomy or physiology data comprises data obtained from patient imaging and tests, and computations performed on the patient imaging and tests (para. [0021] and para. [0228], sentences 1-5, imaging determining total CSF fluid used as a physiological parameter to impact infusion velocity of buffer or other fluid following bolus).
Regarding claim 6, Anand discloses the method of claim 1, as described above, wherein the at least one of patient anatomy or physiology data comprises one or more of: patient age, patient sex, patient size, patient CSF volume, patient CSF dynamics, patient respiration data, patient sleep data, patient anatomical geography, heart rate, or disease (para. [0224], last sentence, parameters including CSF flow, heart rate, etc.; para. [0021] and para. [0228], sentences 1-5, imaging determining total CSF fluid used as a physiological parameter to impact infusion velocity of buffer or other fluid following bolus).
Regarding claim 8, Anand discloses the method of claim 1, as described above, wherein a volume of the flush fluid corresponds to a volume of the cerebrospinal fluid between the first location and the target area (paras. [0228] and [0277], 3D modeling used to calculate CSF volume total or between any two points).
Regarding claim 9, Anand discloses the method of claim 8, as described above, further comprising imaging the patient to determine the volume of the cerebrospinal fluid between the first location and the target area (para. [0021] and para. [0228], sentences 1-5, imaging determining total CSF; para. [0277], 3D modeling used to calculate CSF volume total or between any two points).
Regarding claim 10, Anand discloses the method of claim 1, as described above, wherein the target area is the brain, the spine or combinations thereof (para. [0152], sentences 2-3).
Regarding claim 11, Anand discloses the method of claim 1, as described above, further comprising: measuring CSF pressure of the patient with a pressure sensor (para. [0329], sentence 3); and stopping the infusion of the flush fluid or reducing the one or more flush flow rates in response to determining that the CSF pressure exceeds a predetermined threshold or drops below a predetermined threshold (para. [0329], sentence 3 and para. [0192], sentence 2, the pump stopping infusions when threshold CSF pressure from pressure sensor is reached).
Regarding claim 12, Anand discloses the method of claim 1, as described above, further comprising: measuring CSF pressure of the patient with a pressure sensor (para. [0329], sentence 3); and beginning the infusion of the flush fluid in response to determining that the CSF pressure indicates an ascending or descending phase of a waveform (Figs. 21B-C; paras. [0385] and [0387], the ascending/descending waveform from sensed pressure determining injection timings).
Regarding claim 13, Anand discloses the method of claim 1, as described above, wherein the second location is spaced caudally from the first location (para. [0211], sentences 13-20, first location 122M, second location 122P; Fig. 20A: 122P spaced caudally from 122M).
Regarding claim 14, Anand discloses the method of claim 1, as described above, wherein the first location and the second location are in a same region of the intrathecal space (para. [0211], last sentence, first and second locations 122M and 122P can be located in the same discrete region of the spine).
Regarding claim 15, Anand discloses the method of claim 1, as described above, further comprising: creating an access opening into the intrathecal space of the patient in a lumbar region thereof (para. [0271], sentences 1-2); and inserting a catheter through the access opening (para. [0271], sentence 5) and threading the catheter rostrally within the intrathecal space (Fig. 26: catheter 304 threaded rostrally from access site at needle 302), wherein infusion of the therapeutic bolus and the flush fluid is performed through the catheter (para. [0271], last two sentences, and para. [0272]; Fig. 26: infusions performed by pump 310 through same catheter 304).
Regarding claim 19, Anand discloses the method of claim 15, as described above, wherein the catheter comprises a single lumen (Figs. 42A-C; para. [0297], sentence 1) with a distal fluid port (Figs. 42A-C; distal tip port 634), and threading the catheter rostrally within the intrathecal space comprises: positioning the distal fluid port at the first location within a lumbar region up to a cisterna magna region for infusion of the therapeutic bolus (para. [0213], sentences 2, 4); and withdrawing the catheter to position the distal fluid port at the second location within the lumbar region up to the cisterna magna for infusion of the flush fluid (para. [0213], 8-10).
Regarding claim 20, Anand discloses the method of claim 19, as described above, wherein threading the catheter rostrally within the intrathecal space comprises: positioning the distal fluid port at the first location within a thoracic region up to a cervical region for infusion of the therapeutic bolus (para. [0213], sentences 2, 4); and withdrawing the catheter to position the distal fluid port at the second location within the lumbar region for infusion of the flush fluid (para. [0213], 8-10).
Regarding claim 22, Anand discloses the method of claim 1, as described above, further comprising creating an access opening into the intrathecal space of the patient in a lumbar region thereof with a lumbar puncture needle (para. [0271], sentence 3), wherein infusion of the therapeutic bolus and the flush fluid is performed through the lumbar puncture needle in the lumbar region (para. [0272]; Fig. 24A: both infusions performed through the needle 302).
Regarding claim 24, Anand discloses the method of claim 1, as described above, wherein infusing the flush fluid comprises infusing an artificial cerebrospinal fluid or anti-inflammatory fluid into the intrathecal space of a patient in the second location at the one or more flush flow rates (para. [0330] and paras. [0278]-[0279], the flush fluid following the bolus may be artificial CSF instead of the patient’s own CSF).
Regarding claim 28, Anand discloses the method of claim 1, as described above, wherein the therapeutic bolus comprises a nucleic acid, a protein therapeutic, a cell therapy, a small molecule therapeutic, a viral vector encoding a therapeutic protein, or a combination thereof (para. [0346], the bolus may comprise small molecules, nucleic acids, etc.).
Regarding claim 29, Anand discloses the method of claim 28, as described above, wherein therapeutic bolus comprises the nucleic acid selected from the group consisting of an antisense oligonucleotide, a ribozyme, an miRNA, an siRNA, and shRNA, or a nucleic acid encoding a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (Cas) system, or a combination thereof (para. [0227], sentence 7, drug including an antisense oligonucleotide).
Regarding claim 31, Anand discloses the method of claim 1, as described above, wherein the therapeutic bolus comprises adeno-associated virus (AAV) vector DNA sequences, recombinant AAV particles, or combinations thereof (para. [0277], sentences 10 and 14-15, drug bolus comprising AAV).
Regarding claim 33, Anand discloses the method of claim 1, as described above, wherein the therapeutic bolus is infused according to a therapy platform comprising one of: conventional gene replacement, x- reactivation, exon skipping, or promoter modulation (para. [0277], sentences 14-15, performing gene therapy by delivering a virus AAV being conventional gene replacement therapy).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
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 2-4 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Anand (US 20190160254) in view of Khani (“Impact of Neurapheresis System on Intrathecal Cerebrospinal Fluid Dynamics: A Computational Fluid Dynamics Study,” Journal of Biomedical Engineering, Vol. 142, 2019).
Regarding claim 2, Anand discloses the method of claim 1, as described above, wherein the one or more flush flow rates are calculated using modeling from MRI imaging to calculate the volume of the cerebrospinal fluid and other sensor inputs, but fails to disclose the flush flow rates being calculated using estimated or measured steady-streaming fluid velocities of the cerebrospinal fluid.
Khani teaches an analogous method of modeling cerebrospinal fluid, in which estimated steady-streaming fluid velocities of cerebrospinal fluid within the intrathecal space of the patient between the first location and the target area divided into one or more axial sections and estimated or measured axial cross-sectional areas of the one or more axial sections (section 2.3: “Analysis of Cerebrospinal Fluid Velocities” and section 3.2, “Steady-Streaming Cerebrospinal Fluid Velocity Quantification”, the first and second locations being determined by the slices along the axis). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Anand method by incorporating into their 3D modeling of the spine, calculations for the steady-streaming velocities of the CSF, as taught by Khani, to also be used to calculate the flush flow rates, because the flow velocities of the CSF give a more precise indication of how the drug will move and diffuse through the spine to better inform the rate at which the flush fluid should be administered (Khani, Fig. 3).
Regarding claim 3, Anand in view of Khani teaches the method of claim 2, as described above, wherein the one or more flush flow rates are based on averages of the steady-streaming fluid velocities or maximum values of the steady-streaming fluid velocities in the one or more axial sections (Khani: section 3.2, “Steady-Streaming Cerebrospinal Fluid Velocity Quantification”).
Regarding claim 4, Anand in view of Khani teaches the method of claim 3, as described above, wherein the one or more flush flow rates are calculated using a predetermined percentage of the averages of the steady-streaming fluid velocities or the maximum values of the steady-streaming fluid velocities in the one or more axial sections (Khani: section 3.2, “Steady-Streaming Cerebrospinal Fluid Velocity Quantification”, calculated using the maximum values).
Regarding claim 7, Anand discloses the method of claim 6, as described above, but fails to disclose the flush flow rates being calculated using estimated or measured steady-streaming fluid velocities of the cerebrospinal fluid.
Khani teaches an analogous method of modeling cerebrospinal fluid, in which one or more steady-streaming fluid velocities are estimated by a central nervous system computational or in vitro model for the patient using the at least one of patient anatomy or physiology data as input (section 2.3: “Analysis of Cerebrospinal Fluid Velocities” and section 3.2, “Steady-Streaming Cerebrospinal Fluid Velocity Quantification”, the first and second locations being determined by the slices along the axis obtained from MRI input). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Anand method by incorporating into their 3D modeling of the spine, calculations for the steady-streaming velocities of the CSF, as taught by Khani, to also be used to calculate the flush flow rates, because the flow velocities of the CSF give a more precise indication of how the drug will move and diffuse through the spine to better inform the rate at which the flush fluid should be administered (Khani, Fig. 3).
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Anand (US 20190160254) in view of Sah (US 20190055578) in further view of Cohen (US 20130209450).
Regarding claim 26, Anand discloses the method of claim 1, as described above, for infusing the therapeutic bolus and infusing the flush fluid, but fails to disclose the patient being positioned in a head down tilt for the infusion, and that the therapeutic bolus itself comprises a buffer being colder or deter than the CSF.
Sah teaches an analogous method for infusing a drug into the cerebrospinal fluid, including positioning the patient in a head down tilt orientation prior to infusing the therapeutic bolus (para. [0470], the Trendelenburg position). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Anand method by incorporating the Sah teaching of placing the patient in the Trendelenburg position with their head tilted down, in order to further urge the bolus to the cervical region of the patient (Sah: para. [0470], sentence 2). However, Anand in view of Sah still fails to teach that the therapeutic bolus itself comprises a buffer being colder or deter than the CSF.
Cohen teaches an analogous method for administering a viral vector therapy to a patient wherein the therapeutic bolus comprises a buffer (para. [0292], a saline buffer), the buffer being at least one of: colder than a temperature of cerebrospinal fluid of the patient (para. [0424], the drug in the saline buffer is administered at room temperature, which is colder than the in vivo CSF); or more dense than the cerebrospinal fluid of the patient. It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Anand in view of Sah method by incorporating the teaching of Cohen to dilute the drug in an aqueous saline buffer solution for more precise dosing for administration, and to administer it at room temperature, in order to keep the viral vector as stable as possible prior to infusion.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Anand (US 20190160254) in view of Singh (US 20160213312).
Regarding claim 27, Anand discloses the method of claim 1, as described above, injecting a contrast agent and further comprising adjusting the one or more flush flow rates based on real-time feedback from the contrast agent (para. [0228], CSF volume may be determined with injection of contrast agent, used to determine and adjust volume of flush fluid delivered/velocity of its infusion). However, Anand fails to disclose that the therapeutic bolus or the flush fluids themselves comprise the contrast agent.
Singh teaches an analogous method for infusing a drug into the intrathecal space (para. [0082], sentence 2) wherein at least one of the therapeutic bolus or the fluish fluid comprises a contrast agent (para. [0007], sentences 1-2, the flush fluid following the drug bolus having the tracer/contrast agent) for real-time feedback from the contrast agent (para. [0119], sentence 1). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Anand method by incorporating directly into the flush fluid the tracer as taught by Singh in order to have more accurate monitoring and direct feedback of the drug delivery (Singh: para. [0119], sentence 1).
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Anand (US 20190160254) in view of Rigo (US 20200308580).
Regarding claim 30, Anand discloses the method of claim 28, as described above, wherein the therapeutic bolus comprises an antisense oligonucleotide (para. [0227], sentence 7, drug including an antisense oligonucleotide), but fails to disclose that that antisense oligonucleotide targets mRNA encoding Huntington protein (HTT) or mRNA encoding survival motor neuron-2 (SMN2).
Rigo teaches an analogous method for delivering an antisense oligonucleotide that targets mRNA encoding Huntington protein (HTT) or an antisense oligonucleotide that targets mRNA encoding survival motor neuron-2 (SMN2) (para. [0008], sentences 1 and 3-4). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Anand method by incorporating the specific SMN2 targeting antisense oligonucleotide taught by Rigo in order to be effectively used to treat patients with SMA (Rigo: para. [0007], last sentence).
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Anand (US 20190160254) in view of Gao (US 20190300904).
Regarding claim 32, Anand discloses the method of claim 31, as described above, with the AAV vector sequences, but fails to explicitly disclose that those AAV vector sequences encode miRNA sponge sequences that interfere with miRNA106a.
Gao teaches an analogous method of administering AAV gene therapy, wherein the AAV vector RNA sequences encode miRNA sponge sequences (para. [0031]) that interfere with miRNA106a and Xist (para. [0135], miR-106a being one of the possible miRNA genes). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV vector sequence in the Anand method by incorporating the teaching of Gao for the sponge miRNA to interact with RNA 106a, in order to effectively inhibit RNA 106a for more effective gene therapy (Gao: para. [0018]). Although Anand in view of Gao does not explicitly teach that this specific AAV vector works by slightly unfolding the chromosome and allowing re-expression of the silent healthy gene, this limitation is an intended result limitation for the intended outcome of the claimed method, and as such is given no patentable weight, as the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (see MPEP 2112.I.).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATERINA ANNA WITTLIFF whose telephone number is (703)756-4772. The examiner can normally be reached M-Th: 9-7ET.
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/K.A.W./Examiner, Art Unit 3783
/MICHAEL J TSAI/Supervisory Patent Examiner, Art Unit 3783