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 .
Application Status
The action is written in response to applicant’s correspondence received on 6/17/2025. Claims 1-2, 5, 7-8, 12, 14-17, 19, 22, 24-25, 28, 31, 33, 36-37, 39-41, and 192-194 are currently pending.
Priority
The instant application claims priority to US provisional application 63/271,487, with an effective filing date of 10/25/2021.
Specification
The use of the term RNAScope®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 2, 17 and 36 37 are objected to because of the following informalities:
Regarding claim 2, “comprising same” should be “comprising the same”
Regarding claim 17, sevoflurane is misspelled as “sevolurane”.
Regarding claim 36, “an intro” should be spelled “an intron”.
Regarding claim 37, applicant indicates vector genomes as 1x1010 followed by 1x1012. Applicant should consider using superscripts to remain consistent in the claim language.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Written Description
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 1-2, 5, 7-8, 12, 14-17, 19, 22, 24-25, 28, 31, 33, 36-37, 39-41, and 192-194 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s), which recites any agent that enhances glymphatic influx (including FDA approved anesthetics, AQP4 facilitators, or an α2-anrenergic agonist), contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The factors to be considered when analyzing claims for compliance with the written description requirement include: (A) actual reduction to practice; (B) disclosure of drawings or structural chemical formulas; (C) sufficient relevant identifying characteristics (e.g., complete structure, partial structure, physical and/or chemical properties, structure/function correlation); (D) level of skill and knowledge in the art; and (E) predictability in the art.
Reduction to Practice
Regarding reduction to practice, applicant discloses the use of ketamine/dexmedetomidine and Atipamezole, which is an α-2 adrenergic agonist (see example 1 of the instant specification). Applicant does not reduce to practice the use of hypertonic solutions or other FDA approved anesthetics outside of ketamine/dexmedetomidine.
Sufficient Relevant Identifying Characteristics
Regarding structure/function correlation, applicant discloses agents that can improve glymphatic influx. Applicant discloses the use of ketamine/dexmedetomidine and Atipamezole, which is an α-2 adrenergic agonist (see example 1 of the instant specification) delivered to the CNS of a subject.
Level of Skill and Knowledge in the Art
At the time of filing, the use of an agent to improve glymphatic influx was known, as evidenced by Nedergaard et al. (WO 2020/072357 A1, published 4/9/2020), where Nedergaard teaches administration of an agent to increase glymphatic influx for the delivery of a pharmaceutical composition.
Predictability in the Art
The level of unpredictability in the art is high. Applicant broadly recites any agent, including any FDA approved anesthetic. In an article published by Hu (From propofol to cipepofol, a new intravenous general anesthetic approved for adults undergoing surgery, Volume 35, pgs. 1385-1388, published 8/7/2026), Cypsedo® is a newly approved FDA anesthetic. However, the use of “one or more FDA approved anesthetics that enhance glymphatic influx” applies to future approved FDA anesthetics. In this regard, the art is silent on whether such newly approved anesthetics, such as Cypsedo®, could be used to increase glymphatic influx in a subject.
To conclude, as the applicant broadly recites “an agent” which can be read on any agent that increases glymphatic influx, including ones that are newly discovered, as well as “an FDA anesthetic” which includes present and future approved anesthetics, it is clear that the applicant cannot have possession of all agents known in the art, or to be discovered, that would increase glymphatic influx for the purpose of enhancing the delivery of a pharmaceutical composition.
In view of the foregoing, claims 1-2, 5, 7-8, 12, 14-17, 19, 22, 24-25, 28, 31, 33, 36-37, 39-41, and 192-194 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement.
Indefiniteness
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.
Regarding claims 7, 8, 12, 14, 17, 19, 22, 25, 28, 31, 36, and 40-41, the phrase "for example" “e.g.” “such as”, “in particular” or “more particularly” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Interpretation
Regarding claims that use the term “in particular”, examiner interprets this statement as “preferably”.
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)(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.
(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, 2, 5, 19, 22, and 24 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Nedergaard et al. (WO 2020/072357 A1, published 4/9/2020) or, in the alternative, under 35 U.S.C. 103.
Regarding claim 1, Nedergaard teaches methods for improving delivery of a composition to the CNS, wherein the method comprises enhancing the glymphatic system influx and the step of enhancing glymphatic influx can be administering an agent to the subject (see summary of invention, pg. 2, line 6).
Nedergaard teaches where nucleic acid molecules can be administered using techniques known in the art, including via vector (see pg. 29, line 19) and “vector” refers to a virus (e.g., AAV) particle that functions as a nucleic acid delivery vehicle (see pg. 36, line 6).
Regarding claim 2, Nedergaard teaches where the agent can be a hypertonic solution (see pg. 2, line 13), and where the therapeutic composition and hypertonic solution may be administered concurrently at the same time (see pg. 29, line 25).
Regarding claim 5, Nedergaard teaches where a composition or compound to be delivered is administered intracisternally or intrathecally (see pg. 18, line 33).
Regarding claim 19, Nedergaard teaches the agent of enhancing glymphatic system influx can be a hypertonic solution administered into the blood or plasma of the subject, wherein the hypertonic solution can comprise NaCl or mannitol (see pg. 2, line 13).
Regarding claim 22, Nedergaard teaches where mice received 0.34 M and 1M NaCl intraperitoneal injections (see Figs. 2A-D) and where hypertonic saline comprised of 1M NaCl in ddH2O (see solutions, pg. 39, line 5). 1M NaCl. A skilled artisan would recognize molarity is moles of solute/per liter of solution, where NaCl has a molecular weight of 58.44g/mol. Therefore, 58.44g of NaCl/1 liter solution, would result in a 1M NaCl solution have 5.84% (w/v).
Regarding claim 24, Nedergaard teaches where the composition can be delivered intrathecally about the same time, or after, or before the glymphatic system influx is enhanced (see pg. 3, line 12).
Regarding claim 24, Nedergaard already teaches the use of increasing glymphatic influx through the use of hypertonic saline. Nedergaard does not explicitly state the minutes before or after where the AAV can be administered in conjunction with increasing glymphatic influx. However, as Nedergaard recites about the same time, before, or after, a skilled artisan would recognize that the time frame of AAV administration is merely routine experimentation of the methods taught by the stated art.
In view of the foregoing, claims 1, 2, 5, 19, 22, and 24 are rejected.
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.
Claims 1, 7-8, 12, and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Nedergaard et al. (WO 2020/072357 A1, published 4/9/2020) in view of Huber et al. (Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood-brain barrier:[17O]H2O JJVCPE MRI study, Neuroreport, Volume 29, Issue 9, pgs. 697-703, published 5/23/2018), Hablitz et al. (Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia, Science Advances, Volume 5, Issue 2, all pages, published 2/27/2019), Tobias et al. (Dexmedetomidine-Ketamine Sedation in a Patient with Dilated Cardiomyopathy, Journal of Medical Cases, Volume 8, No. 10, pgs. 293-296, published 10/2017), Kim et al. (Effect on Dexmedetomidine on Sevoflurane Requirements and Emergence Agitation in Children undergoing Ambulatory Surgery, Yonsei Med. J., Volume 55, Issue 1, pgs. 209-215, published 11/29/2013), and Semyachkina-Glushkovskaya et al. (Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer’s Disease and the Blood-Brain Barrier, International Journal of Molecular Sciences, Volume 21, Issue 17, published 8/26/2020).
Regarding claim 1, Nedergaard teaches the method for improving delivery of a pharmaceutical composition comprising an AAV viral vector to the CNS of a subject, the method comprising administering an agent that enhances glymphatic influx in combination with the pharmaceutical composition is taught by Nedergaard (see above).
Regarding claim 14, Nedergaard teaches where the composition can be delivered about the same time, or after, or before the glymphatic system influx is enhanced (see pg. 2, line 19).
Regarding claims 7, 8, 12, and 15-17, Nedergaard does not teach wherein the agent administered is an Aquaporin 4 facilitator, where the agent is an anesthetic that enhance glymphatic influx (such as ketamine, dexmedetomidine, or a combination thereof), or a method of administering ketamine and dexmedetomidine followed by sevoflurane.
Regarding claim 7, Huber teaches TGN-073 promotes interstitial fluid circulation within the blood-brain barrier (see abstract).
Regarding claim 8, Hablitz teaches glymphatic system activity increases during sleep or ketamine/xylazine (K/X) anesthesia (see abstract).
Regarding claim 12, Tobias teaches the successful use of a combination of dexmedetomidine and ketamine to provide sedation and analgesia in a 9-month-old patient with dilated cardiomyopathy (see abstract).
Regarding claim 15 and 16, Tobias teaches where dexmedetomidine (1 ug/kg) and ketamine (2 mg/kg) were administered over 5 min followed by a dexmedetomidine infusion at 0.2ug/kg/h (see pg. 294, column 1).
Regarding claim 17, Kim teaches the combined use of dexmedetomidine and sevoflurane as an anesthetic, wherein the sevoflurane is administered via a face mask (see abstract and materials and methods, paragraph 2).
Regarding claim 25, Semyachkina-Glushkovskaya teaches pharmacological enhancements for increasing the time of slow wave sleep by the administration of tiagabine for improving quality of sleep and brain functions (see section 3, Slow Sleep Wave Enhancement is Promising Therapy of Alzheimer’s Disease). Furthermore, Semyachkina-Glushkovskaya teaches where slow wave activity plays a role of glymphatic clearance during deep sleep and contributes to the efficiency of fluid influx into the brain and the clearance of waste and Aβ from the brain (see section 1, Sleep as a potential biomarker of Alzheimer’s Disease).
It would have been obvious to one of ordinary skill in the art, before the effective filing date, to combine the teachings of Huber, Halblitz, Tobias, Kim and Semyachkina-Glushkovskaya, to modify Nedergaard to arrive at the instantly claimed invention, which is using either TGN-073, a combination of ketamine-dexmedetomidine-sevoflurane, or administering tiagabine as an agent to increase glymphatic influx prior to the delivery of a pharmaceutical composition.
One would expect a reasonable chance of success as the teachings of Huber teaches TGN-073 promotes interstitial fluid circulation within the blood-brain barrier, wherein AQP4 is a facilitates proper glymphatic flow (see title and introduction). Hablitz teaches where glymphatic system activity is increased during ketamine/xylazine anesthesia, Tobias teaches ketamine and dexmedetomidine are often administered together, and Kim teaches where sevoflurane and dexmedetomidine are also administered together. Furthermore, Semyachkina-Glushkovskaya teaches where tiagabine improves increases slow wave activity in slow wave sleep, which leads to increased glymphatic influx as well.
While Nedergaard only teaches enhancing glymphatic influx with a hypertonic agent, the use of TGN-073, anesthetic combinations comprising ketamine, or tiagabine was already well known in the art, at the time of filing, for the purpose of increasing glymphatic influx. A skilled artisan would recognize that substituting a hypertonic solution of Nedergaard with either TGN-073, a composition of ketamine-dexmedetomidine-sevoflurane, or tiagabine would be merely a substitution of known elements that have the same function to yield predictable results. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007); MPEP § 2143(i)(b).
Furthermore, while Nedergaard does not specify at what time point ketamine is administered prior to the pharmaceutical composition (see claim 14), Nedergaard teaches where the agent that improves glymphatic influx can be administered prior to, concurrently, or after administration of the pharmaceutical composition. Therefore, the different time points as recited in the instant claim would easily be determined by a skilled artisan through routine experimentation to test what time point would improve or enhance the uptake of a pharmaceutical composition.
One would be motivated to do so as Nedergaard teaches where improving glymphatic influx can further enhance the delivery of a composition to the CNS, which can comprise therapeutic compositions for the treatment of a neurological disease (see summary of invention, all of pg. 2 and 3).
In view of the foregoing, claims 1, 7-8, 12, and 14-17 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Claims 1, 28, 31, 33, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Nedergaard et al. (WO 2020/072357 A1, published 4/9/2020) in view of Castle et al. (Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion, Science Advances, Volume 4, Issue 11, all pages, published 11/14/2018).
Regarding claim 1, Nedergaard teaches the method for improving delivery of a pharmaceutical composition comprising an AAV viral vector to the CNS of a subject, the method comprising administering an agent that enhances glymphatic influx in combination with the pharmaceutical composition (see above).
Regarding claim 31, Nedergaard teaches where the term “vector” can refer to a virus (e.g. AAV) particle that functions as a nucleic acid delivery vehicle (see pg. 36, line 6).
Nedergaard does not teach where the subject is maintained in a position with hind limbs elevated with hind limbs elevated (claim 28), wherein the AAV viral vector comprises a capsid protein, in particular AAV9 (claim 31), where the AAV vector comprises a polynucleotide encoding a SMN protein (claim 33), modifications to the AAV vector (claim 36), or viral vector genomes for the pharmaceutical composition (claim 37). Furthermore, Nedergaard does not teach where the composition is administered to coincide with CSF influx during the sleep cycle (claim 39),
Regarding claim 28, Castle teaches physical position markedly enhances brain transduction after intrathecal AAV9 infusion. Castle teaches when rats were inverted in the Trendelenburg position or continuously rotated after intrathecal AAV9 infusion, they found a 15-fold increase in number of transduced neurons (see abstract).
Regarding claim 31, Castle teaches the use of AAV serotype 9 as it drives widespread CNS transduction after intrathecal administration to the cerebrospinal fluid (CSF) of nonhuman primates (see introduction).
Regarding claim 31 and 33, Jad teaches large scale production of AAV9 carrying the human survival motor neuron gene (see title). Jad further teaches an AAV cis-plasmid containing the gene of interest flanked by two ITRs in the ends (see introduction, Fig. 1) and where two plasmids bear CMV enhancer/beta-actin (CB) promoter, CMV IE enhancer, and polyadenylation signal sequences (see abstract). In other embodiments, a small intron sequence was inserted between promoter and transgene to help mRNA splicing of the transgene (see Fig.1 description).
Regarding claim 37, Castle teaches where 21 adult rats received a cisterna magna (CM) infusion of 1 x 1012 vector genomes of AAV9 containing the CAG promoter (see results). Castle further teaches where high AAV doses are used to efficiently transduce the CNS, ranging as high as 1.0 x 1014 vg/kg for rodents and 2.0 x 1014 vg/kg in humans (see discussion).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Nedergaard, Castle, and Jad to arrive at the instantly claimed invention.
One would expect a reasonable chance of success as Nedergaard already discloses increasing glymphatic influx to deliver a therapeutic composition to the CNS of a subject through an AAV vector. The combined teachings of Castle and Jad teach the composition of the AAV9 vector, including ITRs, promoters, enhancers, introns, and SMN gene. A skilled artisan would recognize that AAV9 vectors are specifically used to transduce cells in the CNS, and as Nedergaard broadly recites any AAV, a substitution of an art recognized vector for the same purpose of transducing genetic material in the CNS would yield predictable results, absent evidence to the contrary.
A skilled artisan would be motivated to do so as 1) AAV9 effectively induces the CNS, which would improve the composition of Nedergaard, (2) Castle teaches where the Trendelenburg position enhances gene transfer to the brain in addition to cervical spinal cord and where the number of transduced brain cells is significantly increased by more than 15-fold, and (3) Jad discloses that the SMN gene is associated with spinal muscular atrophy (SMA). Therefore, the combined teachings would result in an AAV9 vector that can be used to treat SMA with improved or enhanced gene/genetic material delivery.
In view of the foregoing, claims 1, 28, 31, 33, and 37 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Claims 1 and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Nedergaard et al. (WO 2020/072357 A1, published 4/9/2020) in view of Plog et al. (The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future, Annual Reviews, Volume 13, pgs. 379-394, published 1/2018) and Semyachkina-Glushkovskaya et al. (Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer’s Disease and the Blood-Brain Barrier, International Journal of Molecular Sciences, Volume 21, Issue 17, published 8/26/2020), evidenced by Castle et al. (Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion, Science Advances, Volume 4, Issue 11, all pages, published 11/14/2018).
Regarding claim 1, Nedergaard teaches the method for improving delivery of a pharmaceutical composition comprising an AAV viral vector to the CNS of a subject, the method comprising administering an agent that enhances glymphatic influx in combination with the pharmaceutical composition (see above).
Regarding claim 39, Nedergaard teaches a method of treating a neurological disorder in a subject, the method comprises (1) enhancing glymphatic system influx and (2) delivering a therapeutic composition to the CNS interstitium, brain interstitium, and/or the spinal cord interstitium (see pg. 2, line 28), wherein the therapeutic composition comprises a nucleic acid (e.g. antisense molecules and RNAi agents).
Nedergaard does not teach where the administration of the pharmaceutical composition coincides with CSF influx during the sleep cycle (claim 39), or where the pharmaceutical composition is administered when the subject goes to sleep (claim 40).
Regarding claim 39 and 40, Plog teaches where within the glymphatic pathway, CSF enters the brain via periarterial spaces, passes into the interstitium via AQP4, and then drives the perivenous drainage of ISF and its solute (see abstract). Plog also teaches where natural sleep was associated with enhanced periarterial CSF tracer influx and improved interstitial solute clearance and where sleep state resulted in increased glymphatic function (see section titled “Regulation of glymphatic flow”). Plog also teaches in a previous study of brain-wide delivery of an AAV-GFP construct, the glymphatic system was responsible for delivery wherein disruption of the glymphatic influx with AQP4 knockout led to reduced viral transduction (see section titled “Modulation of Interstitial Fluid Production to Improve Gene Therapy and Drug Delivery Within the Central Nervous System”).
Regarding claim 40, Semyachkina-Glushkovskaya teaches pharmacological enhancements for increasing the time of slow wave sleep by the administration of tiagabine for improving quality of sleep and brain functions (see section 3, Slow Sleep Wave Enhancement is Promising Therapy of Alzheimer’s Disease). Furthermore, Semyachkina-Glushkovskaya teaches where slow wave activity plays a role of glymphatic clearance during deep sleep and contributes to the efficiency of fluid influx into the brain and the clearance of waste and Aβ from the brain (see section 1, Sleep as a potential biomarker of Alzheimer’s Disease).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Nedergaard and Plog, to arrive at the instantly claimed invention.
One would have expected a reasonable chance of success as Plog teaches where sleep increases glymphatic influx through enhanced CSF influx which allows an AAV to flow freely throughout the brain to transduce genetic material. A skilled artisan would recognize that sleep is an art recognized method to improve glymphatic influx. This is further evidenced by Castle, where Castle teaches in humans, transduction may also be increased if the patient sleeps in an inverted position after recovering from anesthesia because sleep increases cortical CSF influx (see discussion of Castle). While Nedergaard teaches increasing glymphatic influx through an agent, a substitution of a functionally equivalent alternative, as described by the art, would yield predictable results. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007); MPEP § 2143(i)(b). Furthermore, enhancing sleep with a drug, such as Tiagabine, is taught in the art, as described by Semyachkina-Glushkovskaya.
One would be motivated to administrate the composition during sleep or enhanced sleep to better deliver an AAV or pharmaceutical composition to the CNS of a subject.
In view of the foregoing, claims 1 and 39-41 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Claims 192-194 are rejected under 35 U.S.C. 103 as being unpatentable over Nedergaard et al. (WO 2020/072357 A1, published 4/9/2020) in view of Huber et al. (Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood-brain barrier:[17O]H2O JJVCPE MRI study, Neuroreport, Volume 29, Issue 9, pgs. 697-703, published 5/23/2018).
Regarding claims 192 and 193, Nedergaard teaches methods and compositions for enhancing the deliver of a pharmaceutical composition to the CNS of a subject through the delivery of a pharmaceutical composition and an agent that enhances glymphatic influx (see abstract, summary of invention, pg. 30, line 23).
Regarding claim 194, Nedergaard teaches where in an embodiment, the agent can be one that prevents AQP4 depolarization (see pg. 16, line 1).
Regarding claim 194, Huber teaches where AQP4 expression in the brain is highly polarized to the end feet of astrocytes (see Fig. 1), and wherein AQP4 facilitates the flow of water in and out of the brain, and where localization of AQP4 in the brain is highly specific (see introduction). Huber also teaches TGN-073 is an AQP4 facilitator playing a role in AQP4 polarization.
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to combine the teachings of Nedergaard and Huber to arrive at the instantly claimed inventions.
One would expect a reasonable chance of success as Nedergaard teaches a method of improving the efficiency of an AAV vector, which can be in a pharmaceutical composition (see above), through enhancing glymphatic influx with an hypertonic agent or an agent that facilitates the polarization of AQP4. A skilled artisan would recognize that improving the transduction efficiency or uptake of genetic material and increasing the efficacy of an intrathecally delivered pharmaceutical composition (also taught by Nedergaard) are both an outcome of the “agent that enhances glymphatic influx”, which is fully disclosed by Nedergaard. Huber teaches specifically TGN-073 is a facilitator of AQP4, which can be substituted with the agent presented in Nedergaard, and where the polarization plays an important role of allowing the delivery of a composition to the CNS.
Furthermore, looking to the specification for guidance, applicant defines “reducing variable brain distribution as well as reduced liver and/or DRG toxicity” is an effect of enhancing glymphatic influx (see paragraph 0004), which is taught by Nedergaard. Absent evidence to the contrary, there is not an additional step where another agent is administered to reduce such toxicity and the recited effect is merely a secondary effect resulting from improving glymphatic influx, which is known in the art.
One would be motivated to do so as Nedergaard teaches where improving glymphatic influx can further enhance the delivery of a composition to the CNS, which can comprise therapeutic compositions for the treatment of a neurological disease (see summary of invention, all of pg. 2 and 3).
In view of the foregoing, claims 192-194 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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