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 the following species:
cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as the elected condition species; and
diC16-PIP2 as the elected therapeutic agent species
is maintained.
Claims 5, 14, 20 and 27 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner
discover a prior art by Raineteau et al. that anticipates the claimed invention, wherein the prior art teaches LY294002 as a therapeutic agent species; However, it is noted that the prior art does not teach the elected therapeutic agent species (diC16-PIP2). In light of this discovery, the search is expanded to the subject matter of the therapeutic agent species to include LY294002 in addition to the elected therapeutic agent species, such that it does not encompass the full scope of the claims.
Priority
The instant application 17/598,008 filed on September 24, 2021 is a 371 of PCT/US2020/023943 filed on March 30, 2020, which claims priority to, and the benefits of U.S. Provisional Application No.
62/823,378 filed on March 25, 2019.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on October 15, 2025, wherein claims 1, 5, 8-10, 14-16, 20, 22-23, 27 and 29 are amended; claims 2-4, 6-7, 11-13, 17-19 and 24-26 are unchanged; claims 21 and 28 are cancelled; and claims 33-36 are newly added.
Claims 1-20, 22-27 and 29-36 are pending. Claims 5, 14, 20, and 27 remain withdrawn.
Claims 1-4, 6-13, 15-19, 22-26 and 29-36 are under examination in accordance with the elected species along with the expanded species set forth in the Expansion of Species section above.
Action Summary
Applicant’s amendment to the claims overcome each and every objection previously sets
forth in the Non-Final Office Action mailed on April 15, 2025.
Claims 1-4, 6-13, and 15 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating CADASIL, does not reasonably provide enablement for curing all and any conditions characterized by reduced cerebral blood flow are maintained, but revisited and modified in view of the claim amendments.
Claim 1-4, 6-9, 15, 22 and 29 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 are withdrawn in view of the claim amendments.
Claims 8, 21 and 28 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 are withdrawn in view of the claim amendments.
Applicant’s argument with respect to the rection of claims 1-4, 6-13, 15-19, 21-26, and 28-29 on the basis that it contains an improper Markush grouping of alternatives are persuasive. The rejection of claims 1-4, 6-13, 15-19, 21-26, and 28-29 has been withdrawn.
Claims 16-17 and 23-24 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Raineteau et al. (WO 2018/178194 A1; cited in the IDS filed on September 24, 2021) are maintained, but revisited and modified in view of the claim amendments.
Claims 1, 2, 6, 9, 16-17, 21-24, 28 and 29 rejected under 35 U.S.C. 103 as being unpatentable over Raineteau et al. (WO 2018/178194 A1; cited in the IDS filed on September 24, 2021), as evidenced by Florida Neonatal Neurologic Network (Published Online on June 12, 2018. retrieved from Wayback Machine) are maintained, but revisited and modified in view of the claim amendments.
Claims 1-2, 6, 9, 16-17, 21-24, and 28-29 rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) are maintained, but revisited and modified in view of the claim amendments.
Claims 1-4, 6, 9, 16-19, 21-26, and 28-29 rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) as applied to claims 1-2, 6, 9, 16-17, 21-24, and 28-29 above, and further in view of Harraz et al. (Elife. 2018. Vol. 7:e38689. Published on Aug 7, 2018; cited in the IDS filed on September 24, 2021) and Sohn et al. (J Physiol. 2007. Vol. 582(Pt 3):1037-1046) are maintained, but revisited and modified in view of the claim amendments.
Claims 1-2, 6-11, 15-17, 21-24, and 28-29 rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) as applied to claims 1-2, 6, 9, 16-17, 21-24, and 28-29 above, and further in view of Ebihara et al. (Intern Med. 2018. Vol. 57(20): 3011-3014) and Joutel et al. (Nature, 1996. Vol. 383(6602): 707-710) are maintained, but revisited and modified in view of the claim amendments.
Claims 1-4, 6-10, 11-13, 15-19, 21-26, and 28-29 rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) in view of Ebihara et al. (Intern Med. 2018. Vol. 57(20): 3011-3014) and Joutel et al. (Nature 383: 707-710, 1996) as applied to claims 1-2, 6-11, 15-17, 21-24, and 28-29 above, and further in view of Harraz et al. (Elife. 2018. Vol. 7:e38689. Published on Aug 7, 2018; cited in the IDS filed on September 24, 2021) and Sohn et al. (J Physiol. 2007. Vol. 582(Pt 3):1037-1046) are maintained, but revisited and modified in view of the claim amendments.
Claim Interpretation
Instant claims recite the term “treat”, when construed in light of paragraph [0044] of the specification shown as follows:
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, is taken to include cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the cerebral blood flow or the symptoms thereof.
Instant claims recite the term "cerebral ischemia", when construed in light of paragraph [0040] of the specification, is taken to include a condition that has a reduction or cessation of blood flow to the central nervous system.
Instant claims recite the terms “a subject having reduced cerebral blood flow” and “a subject having reduced functional hyperemia”, when construed in light of paragraph [0050] of the specification, is taken to include subjects having small vessel disease, ischemic stroke, traumatic brain injury, cerebral ischemia, hypertension, hypotension, autonomic dysfunction, spinal cord injury, Alzheimer's disease, smoking, diabetes, and healthy aging.
Claim Rejections - 35 USC § 112
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 1-4, 6-13, and 15 remain rejected and claims 30-31 and 33-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating CADASIL, does not reasonably provide enablement for curing all and any conditions characterized by reduced cerebral blood flow. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims (partially newly applied as necessitated by amendments).
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
Instant claim 1 recites “[a] method of treating a subject having a condition characterized by reduced cerebral blood flow”, including the elected CADASIL.
Instant claim 10 recites “[a] method of treating cerebral autosomal-dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a subject“.
The claimed term “treating”, when construed in light of paragraph [0044] of the specification, is taken to include administration of the claimed therapeutic agent to a subject to cure, heal, alleviate, relieve, alter, remedy, ameliorate, palliate, improve or affect the cerebral blood flow, or the symptoms of the condition characterized by reduced cerebral blood flow, including the the elected CADASIL.
The claimed term “a condition characterized by reduced cerebral blood flow”, when construed in light of dependent claims 6-8, is taken to include a small vessel disease (including the elected CADASIL), ischemic stroke, traumatic brain, and cerebral ischemia. Said term is also reasonably construed in light of newly added claims 30-31 to include hypertension, hypotension, autonomic dysfunction, spinal cord injury, Alzheimer's disease, smoking, diabetes, and healthy aging.
Therefore, the breadth of claim 1 pertains to a method of treating a subject having each and every condition characterized by reduced cerebral blood flow.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack
thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the
art would have known, at the time the application was filed, about the subject matter to which the
claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art
refers to the skill of those in the art in relation to the subject matter to which the claimed invention
pertains at the time the application was filed.”
As discussed above, the scope of the claimed invention includes subject with any condition characterized by reduced cerebral blood flow, including CADASIL, with the intention to cure. According to Brownell (Wyss Institute. Retrieved online on March 26, 2025), there is currently no treatment beyond managing symptoms for people suffering from a traumatic brain injury (TBI), and there is no treatment for the damaged caused to brain tissue during TBI (see e.g., p.1-2). In addition, according to National Institute of Neurological Disorder and Stroke (retrieved online on March 26, 2025), CADASIL is a rare inherited disorder caused by a mutation in the Notch3 gene, which is characterized by thickening blood vessel walls in the brain, has no cure or effective treatment right now (see e.g., “treating CADASIL” section); therefore, to the extent that the claimed term “treating” includes subject with the condition characterized by reduced cerebral blood flow, including the elected CADASIL, with the intent to cure, these cited references demonstrate the state of the prior art with respect to curing a condition characterized by reduced cerebral blood flow and CADASIL is still underdeveloped.
Furthermore, in view of the claim amendments, the scope of “the condition characterized by reduced cerebral blood flow” comprises reduced functional hyperemia, such as diabetes. The relative skill of those in the art would have known that there is no cure for patients with type 1 diabetes according to Belsterling (University Hospital. Published online on November 20, 2025)(see e.g., 2nd paragraph). In addition, one would have also known that there’s currently no cure for Alzheimer’s disease according to National Health Service (“Alzheimer's disease”. Published online on July 4, 2024). Therefore, to the extent that the claimed term “treating” or “treat” proceeding the phrase of “the condition characterized by reduced cerebral blood flow” includes curing said condition, the cited reference demonstrate that the state of the art with respect to treating the entire scope of reduced functional hyperemia as the condition characterized by reduced cerebral blood flow, including diabetes (e.g., type 1 diabetes), is still underdeveloped.
While Applicant’s claimed invention may play a role in restoring cerebral blood flow and functional hyperemia associated with CADASIL, it is uncertain whether the claimed invention can successfully treat each and every condition characterized by reduced cerebral blood flow, including CADASIL, diabetes, to the extent that the claimed term “treating” includes “curing”.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of claimed invention. Although the instant specification discloses working examples that tested the administration of PIP2 can enhance functional hyperemia in CADASIL model mice (see e.g., paragraph [0034]); However, the activity of PIP2 in curing condition characterized by reduced cerebral blood flow, including CADASIL, has not been disclosed. The specification also fails to disclose administering a therapeutic agent that increase the level of PIP2 for treating diabetes and Alzheimer’s disease as the reduced functional hyperemia and the condition of characterized by reduced cerebral blood flow. Therefore, one of the relative skill in the art could not reasonably predict which of the hundreds or thousands of therapeutic agent that increases the level of PIP2, including the soluble PIP2 analog, as broadly encompassed by the claims could successfully cure each and every condition characterized by reduced cerebral blood flow, including CADASIL, diabetes and Alzheimer’s disease, based on the limited disclosure provided. Each of these findings demonstrate that it would require an undue experimentation to cure a condition characterized by reduced cerebral blood flow, including the elected CADASIL, for the reasons set forth herein.
Therefore, to the extent that “treating” is drawn to a medical management of a subject with the intent to cure, the claimed invention is not enabled by the instant application for the reasons set forth herein. Accordingly, claims 2-4, 6-9, 11-13, 15, 30-31, and 33-34 are rejected based on their dependency on a rejected claim. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Response to Arguments
Applicant's arguments filed on October 15, 2025 with respect to the rejection of claim 1-4, 6-13, and 15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating CADASIL, does not reasonably provide enablement for curing all and any conditions characterized by reduced cerebral blood flow have been fully considered but they are not persuasive.
Applicant amends claim 1 by changing the recitation of “treating a subject for a condition” to the recitation of “treating a subject having a condition” in the preamble, delete the recitation of “under conditions effective”, further added the limitation of “in the selected subject” in the administration step. Applicant newly added claims 30-31 and 33-34, which depends on the rejected base claims, recites species of reduced functional hyperemia as part of the condition characterized by reduced cerebral blood flow. Therefore, the rejection on the record has been revisited and modified in view of the amendments to address newly added claims.
In Summary, applicant argues the present application fully enables the claimed methods as one would have expected that administering “a therapeutic agent that increases the level of phosphatidylinositol 4,5-bisphosphate (PIP2)" would be effective to treat both (i) "a condition characterized by reduced cerebral blood flow" as recited in claim 1 and (ii) "CADASIL as recited in claim 10 based on the instant specification and the subsequent publication of Mughal et al. Applicant further argues based the results of administration of exogenous PIP2, a person of ordinary skill in the art would have likewise expected other compounds that similarly increase the level of PIP2 to have a therapeutic effect as presently claimed. Applicant further argues the disclosure of the present application, in combination with Mughal, Harraz, and Dabertrand, provide the skilled person in the art with more than sufficient guidance to carry out the claimed methods.
In response, applicant’s argument is not found persuasive, because the rejection on the record is form on the basis that the claimed term “treating” , when construed in light of paragraph [0044] of the instant specification, is taken to include curing. It is noted that the disclosure provides no guidance for “curing” a condition characterized by reduced cerebral blood flow nor CADASIL. Thus, the method of “treating” a subject having each and every condition characterized by reduced blood flow, including the elected CADASIL, is not enabled by the instant specification to the extent that the term “treating” includes curing. By presenting the cited references that demonstrate curing a condition characterized by reduced cerebral blood flow”, such as traumatic brain injury and CADASIL, is still underdeveloped, there is a question in doubt whether the administration of each and every therapeutic agent that increases the level of PIP2 can successfully cure the entire scope of “condition characterized by reduced cerebral blood flow” without any undue experimentations.
In the present case, applicant amends the claims to introduce new claims 30-31 and 33-34, in which claim 31 specifically recites diabetes and Alzheimer's disease are included as part of “the condition characterized by reduced cerebral blood flow comprises reduced functional hyperemia”. Therefore, while the rejection of 1-4, 6-13, and 15 is maintained for the same reasons on the record, the rejection has been revisited and modified to address the newly added claims for the reasons sets forth herein.
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.
(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 16-17 and 23-24 remain rejected and claims 32 and 35-36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Raineteau et al. (WO 2018/178194 A1; cited in the IDS filed on September 24, 2021)(partially newly applied as necessitated by amendments).
To the extent that the embodiment of “a subject having reduced functional hyperemia” and “a subject having a reduction in cerebral blood flow” is a healthy aging subject (see paragraph [0050] of the instant specification), then the following 35 U.S.C. 102(a)(1) rejection applies.
Raineteau et al. teaches the administration of an PI3K inhibitor LY294002 in the brain of postnatal or adult mice effectively promotes oligodendrogenesis (see e.g., p. 3, line 7-9; p. 17, line 5-7; Table 3C).
In the present case, Raineteau et al. clearly teaches the administration of PI3K inhibitor LY294002, which is a small molecule that increases the level of PIP2 according to paragraph [0060] of the specification, to the brain of adult mice, and that is a healthy aging subject. Since same compound (LY294002) cannot exert mutually exclusive properties when administered under the same or similar circumstances, the limitation of “restoring functional hyperemia” and “restoring cerebral blood flow” would necessarily present by practicing the method of Raineteau et al.
Therefore, the claimed invention is being anticipated by Raineteau et al.
Response to Arguments
Applicant's arguments filed on October 15, 2025 with respect to the rejection of claims 16-17 and 23-24 under 35 U.S.C. 102(a)(1) as being anticipated by Raineteau et al. (WO 2018/178194 A1; cited in the IDS filed on September 24, 2021) have been fully considered but they are not persuasive.
Applicant amends independent claims 16 and 23 by deleting the recitation of “under conditions effective” in the administration step. Applicant newly added claims 35-36 that recite “the therapeutic agent is LY294002”; therefore, said amendments necessitate a modification of the rejection on the record to address the newly added claims.
In Summary, applicant argues the method taught by Raineteau et al. is for the treatment of brain injuries and/or demyelinating disorders, and that is not related to a method of restoring cerebral blood flow and a method of restoring functional hyperemia instantly claimed. Applicant further argues Raineteau et al. fails to teach selecting a subject having a condition characterized by reduced cerebral blood flow or reduced functional hyperemia. Applicant further argues the PI3K inhibitor LY294002 taught by Raineteau et al. is an inhibitor of various pathways rather than a compound to impact a level of PIP2. Applicant further argues Examiner’s assertion that the PI3K inhibitor LY294002 of Raineteau et al. increases the level of PIP2 by preventing the phosphorylation of PIP2 to generate PIP3 is not supported by the prior art, and argues that “a compound that inhibits the activity of PIP3 kinase…does not necessarily equal an increase in PIP2. The overall level of PIP2 is not entirely dependent on PIP3; rather the level of PIP2 will depend on the balance between its synthesis and breakdown by other enzymes as well”.
In response, applicant’s argument is not found persuasive for the reasons set forth below:
First, it may well be true that Raineteau et al. is silent regarding “restoring cerebral blood flow in a subject” (see instant claim 16) and “restoring functional hyperemia in a subject” (see instant claim 23); However, each of these properties is an outcome of the method step(s) positively recited; therefore, by practicing the method of administering PI3K inhibitor LY294002 in the brain of postnatal or adult mice taught by Raineteau et al., each of these claimed properties would necessarily present, since the same compound (LY294002) is being administered to the same subject to the extent that the subject having reduced cerebral and/or reduced functional hyperemia is a healthy aging subject. Please note that the subjects having reduced cerebral blood flow and/or reduced functional hyperemia includes healthy aging according to paragraph [0050] of the instant specification. According to MPEP 2145, II, "[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
In response to applicant’s argument that Raineteau et al. fails to teach selecting the subject instantly calmed, in the present case, the prior art clearly teaches the administration of LY294002 in the brain of postnatal or adult mice (see page 3, line7-9; p. 5, line 22-27), and said mice is clearly a healthy aging subject. Therefore, to the extent that the claimed subject having a reduction in cerebral blood flow or reduced functional hyperemia is a healthy aging subject, a healthy aging subject would necessarily be selected when administering PI3K inhibitor LY294002 to the brain of postnatal or adult mice.
Furthermore, “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. In the present case, Raineteau et al. is clearly teaches the same compound (LY294002), which is listed as one of the exemplary therapeutic agents that increase the level of PIP2 according to paragraph [0060] of the instant specification. Although Raineteau et al. teaches LY294002 is an inhibitor of PI3K/Akt (see p. 2, line 26), said prior art also further teaches the following:
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. In other words, the PI3K inhibitor LY294002 taught by Raineteau et al. is capable of inhibiting the kinase activity of at least one member of the PI3K family, which in turn prevents the synthesis of PIP3 from PIP2. If applicant premises that the administration of the same compound (LY294002) does not necessarily lead to an increase in the level of PIP2, such statement must be supported by an appropriate affidavit or declaration. According to MPEP 716.01(c), II, “[a]rguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor”. In the absence of an appropriate affidavit or declaration, the assertion presented by the applicant (“a compound that inhibits the activity of PIP3 kinase…does not necessarily equal an increase in PIP2. The overall level of PIP2 is not entirely dependent on PIP3; rather the level of PIP2 will depend on the balance between its synthesis and breakdown by other enzymes as well”) appears to be an attorney’s argument.
Therefore, the rejection is maintained, but revisited and modified in view of the amendments for the reasons set forth herein.
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, 2, 6, 9, 16-17, 22-24, and 29 remain rejected and claims 30-33, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Raineteau et al. (WO 2018/178194 A1; cited in the IDS filed on September 24, 2021), as evidenced by Florida Neonatal Neurologic Network (Published Online on June 12, 2018. retrieved from Wayback Machine)(partially newly applied as necessitated by amendments).
Raineteau et al. teaches a method for treating brain injuries, such as hypoxic/ischemic brain injury in the adult, comprising administering to a subject in need thereof a therapeutically effective amount of PI3K inhibitors, such as LY294002 having the structure of:
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(see e.g., p. 27, line 7-10; p. 2, line 21-26; p. 19, line 2; p. 40, “In vivo procedures” section). Raineteau et al. further teaches the administration of an PI3K inhibitor LY294002 in the brain of postnatal or adult mice effectively promotes oligodendrogenesis (see e.g., p. 3, line 7-9; p. 17, line 5-7; Table 3C). Please note the PI3K inhibitor LY294002 taught by Raineteau et al. is a small molecule (see e.g., Table 3C). Raineteau et al. further teaches the term “brain injuries” refers to traumatic brain injury or other forms of acquired brain injury, including without limitation: hypoxic/ischemic brain injury in the adult, perinatal hypoxia/ischemia, or stroke (see e.g., p. 6, line 17-19). Raineteau et al. further teaches phosphoinositide 3-kinases (PI3K) are a family of enzymes that phosphorylate the 3’hydroxyl group of the onositol ring of the phosphatidylinositol, the activation of PI3K signaling pathway results in the synthesis of PIP3 from PIP2 (see e.g., p. 18, line 4-7). Raineteau et al. further teaches a compound inhibitor of PI3K is capable of inhibiting the kinase activity of at least one member of PI3K family (see e.g., p. 18, line 8-10). Please note the PI3K inhibitor LY294002 taught by Raineteau et al. prevents the phosphorylation of PIP2 to generate PIP3, and that increases the level of PIP2. Raineteau further teaches the compound inhibitor may be combined with pharmaceutically acceptable excipients to form pharmaceutical compositions for oral administration to animals and human beings (see e.g., p. 28, line 23-25; p. 29, line 3-7).
In the present case, Raineteau et al. does not specifically teach the administration of PI3K inhibitor LY294002 to a subject with brain injury; However, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to select a subject having hypoxic/ischemic brain injury, and administer PI3K inhibitor LY294002 as the therapeutic agent to said subject for treating hypoxic/ischemic brain injury, as taught by Raineteau et al. One would have been motivated to do so, because Raineteau et al. teaches the administration of an PI3K inhibitor LY294002, which is known to prevent the phosphorylation of PIP2 to generate PIP3, can effectively promotes oligodendrogenesis in a subject with hypoxic/ischemic brain injury. One would have a reasonable expectation of success, because one would have reasonably expected that by selecting the subject with traumatic brain injury, and orally administering PI3K inhibitor LY294002 would successfully increase the level of PIP2 for the treatment of brain injury, including hypoxic/ischemic brain injury. Please note the term “ischemic” in hypoxic/ischemia brain injury taught by Raineteau et al. has the definition of inadequate supply of blood to the brain, as evidenced by Florida Neonatal Neurologic Network, and that is a "cerebral ischemia" according to the definition disclosed in paragraph [0040] of the specification. Please also note according to paragraph [0060] of the instant specification, LY294002 is a small molecule and a therapeutic agent that increase the levels of PIP2.
With respect to “restoring cerebral blood flow in a subject” in claim 16, the claimed limitation would flow naturally from the fact that Raineteau et al. teaches the administration of PI3K inhibitor LY294002, which is a therapeutic agent that increases the levels of PIP2, to the same subject (a subject with hypoxic/ischemic brain injury is a subject with reduction in cerebral blood flow). Given that the same therapeutic agent cannot exert mutually exclusive properties when administered under the same or similar circumstances, by practicing the method of Raineteau et al. for the treatment of hypoxic/ischemic brain injury as set forth above, one will also be restoring cerebral blood flow in a subject with a reasonable expectation of success. MPEP 2145 II states: "[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
With respect to “restoring functional hyperemia in a subject” in claim 23, the claimed limitation would flow naturally from the fact that Raineteau et al. teaches the administration of PI3K inhibitor LY294002, which is a therapeutic agent that increases the levels of PIP2, to the same subject (a subject with hypoxic/ischemic brain injury is a subject with reduced functional hyperemia). Given that the same therapeutic agent cannot exert mutually exclusive properties when administered under the same or similar circumstances, by practicing the method of Raineteau et al. for the treatment of hypoxic/ischemic brain injury as set forth above, one will also be restoring functional hyperemia in a subject with a reasonable expectation of success. MPEP 2145 II states: "[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Regarding the limitation of “wherein the condition characterized by reduced cerebral blood flow comprises reduced functional hyperemia” in claim 30, the claimed limitation is obvious by the fact that Raineteau et al. teaches administering PI3K inhibitor LY294002 as the therapeutic agent for treating hypoxic/ischemic brain injury as sets forth above. The term “ischemic” in hypoxic/ischemia brain injury taught by Raineteau et al. has the definition of inadequate supply of blood to the brain, as evidenced by Florida Neonatal Neurologic Network. The “hypoxic/ischemic brain injury” taught in the method of Raineteau et al. is a cerebral ischemia, and therefore, it is a condition characterized by reduced cerebral blood flow and reduced functional hyperemia.
Regarding the limitation of “wherein the reduced functional hyperemia is selected from…healthy aging” in claims 31-32, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Raineteau et al. sets forth above by administering the PI3K inhibitor LY294002 to a subject having hypoxic/ischemic brain injury along with a healthy aging subject. One would have been motivated to do so, because Raineteau et al. teaches the administration of LY294002 to postnatal or adult mice can effectively promotes oligodendrogenesis. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of LY294002 to a postnatal or adult subject would successfully promote oligodendrogenesis; and said subject meets the limitation of “healthy aging” subject.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
All rejections pertaining to claims 21 and 28 are moot because the claims were cancelled in view of the amendments filed on October 15, 2025.
Applicant's arguments filed on October 15, 2025 with respect to the rejection of claims 1, 2, 6, 9, 16-17, 21-24, 28 and 29 under 35 U.S.C. 103 as being unpatentable over Raineteau et al. (WO 2018/178194 A1; cited in the IDS filed on September 24, 2021), as evidenced by Florida Neonatal Neurologic Network (Published Online on June 12, 2018. retrieved from Wayback Machine) have been fully considered but they are not persuasive.
Applicant amends independent claims 16 and 23 by deleting the recitation of “under conditions effective” in the administration step. Applicant further added new claims 33, 35-36 that recite “the therapeutic agent is LY294002”. Applicant further added new claim 30 that recites “wherein the condition characterized by reduced cerebral blood flow comprises reduced functional hyperemia”; and further added claims 31-32 that recites “the reduced functional hyperemia is healthy aging”. Therefore, said amendments necessitate a modification of the rejection on the record to address the newly added claims.
In Summary, applicant presents the same argument with respect to Raineteau et al. in the rejection under 35 U.S.C. § 102 sets forth above.
In response, applicant’s argument is not found persuasive for the same reasons sets forth in the Response to Arguments section above and are applied as before.
Claims 1-2, 6, 9, 16-17, 22-24, and 29 remain rejected and claims 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1)(partially newly applied as necessitated by amendments).
Bisset et al. teaches a method for treating or preventing neurodegenerative disease by preventing cellular apoptosis, comprising administering to said patient an agent that increases cellular levels of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) (see e.g., abstract; claims 79 and 83-85). Please note the PtdIns(4,5)P2 taught by Bisset et al. is referred to the same phosphatidylinositol-4,5-bisphosphate, but it is abbreviated as PIP2 in the instant application. Bisset et al. further teaches the agent is a small molecule activator, or an analogue of a substrate of type I PIP kinase or type II PIP kinase (see e.g., [0094]; [0176]). Bisset et al. further teaches the neurodegenerative disorder is selected from, inter alia, neurodegenerative disorders resulting from cerebral ischemia, or hereditary cerebral angiopathy (see e.g., [0017]). Please note cerebral ischemia is a condition characterized by reduced cerebral blood flow and a condition characterized by reduced functional hyperemia, which meets the limitation as claimed in claim 30. Bisset et al. further teaches the route of administration (delivery) include, inter alia, oral (see e.g., [0198]).
In the present case, Bisset et al. does not specifically teach the administration of a small molecule activator to a subject with cerebral ischemia; However, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to select a subject having cerebral ischemia, and then administer a small molecule activator that increases cellular levels of phosphatidylinositol-4,5-bisphosphate for the treatment of cerebral ischemia, as taught by Bisset et al. One would have been motivated to do so, because Bisset et al. teaches a small molecule activator that increases cellular levels of phosphatidylinositol-4,5-bisphosphate can treat neurodegenerative diseases, including cerebral ischemia, by preventing cellular apoptosis. One would have a reasonable expectation of success, because one would have reasonably expected that the oral administration of a small molecule activator taught by Bisset et al. would successfully treat cerebral ischemia in the subject with cerebral ischemia by preventing cellular apoptosis.
With respect to “restoring cerebral blood flow in a subject” in claim 16, the claimed limitation would flow naturally from the fact that Bisset et al. teaches the administration of an agent that increases the levels of PIP2 to the same subject. Given that the same therapeutic agent cannot exert mutually exclusive properties when administered under the same or similar circumstances, by practicing the method of Bisset et al. sets forth above, one will also be restoring cerebral blood flow in a subject with a reasonable expectation of success. MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
With respect to “restoring functional hyperemia in a subject” in claim 23, the claimed limitation would flow naturally from the fact that Bisset et al. teaches the administration an agent that increases the levels of PIP2, to the same subject. Given that the same therapeutic agent cannot exert mutually exclusive properties when administered under the same or similar circumstances, by practicing the method of Bisset et al. as set forth above, one will also be restoring functional hyperemia in a subject with a reasonable expectation of success. MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Regarding the limitation of “wherein the reduced functional hyperemia is selected from…healthy aging in claims 31-32, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Bisset et al. by administering the small molecule activator that increases cellular levels of phosphatidylinositol-4,5-bisphosphate to the subject having cerebral ischemia along with healthy aging subject. One would have been motivated to do so, because Bisset et al. teaches a small molecule activator that increases cellular levels of phosphatidylinositol-4,5-bisphosphate can also be used to prevent neurodegenerative diseases. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the small molecule activator of Bisset et al. would also successfully prevent neurodegenerative diseases in a subject that has not yet develop a detectable symptom of said disease, and said subject renders obvious the limitation of “healthy aging” instantly claimed.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
All rejections pertaining to claims 21 and 28 are moot because the claims were cancelled in view of the amendments filed on October 15, 2025.
Applicant's arguments filed on October 15, 2025 with respect to the rejection of claims 1-2, 6, 9, 16-17, 21-24, and 28-29 under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) have been fully considered but they are not persuasive.
Applicant amends independent claims 16 and 23 by deleting the recitation of “under conditions effective” in the administration step. Applicant newly added claims 30-32. Therefore, said amendments necessitate a modification of the rejection on the record, including addressing the newly added claims.
In Summary, applicant argues Bisset fails to teach or suggest selecting a subject having a condition characterized by reduced cerebral blood flow or reduced functional hyperemia. Applicant further argues Bisset also does not teach or suggest administering a therapeutic agent that increases the level of PIP2 to restore cerebral blood flow or restore functional hyperemia.
Please note the examiner mistakenly recites “Raineteau et al.” for claims 16 and 23 in the previous action when addressing the claimed limitation(s) would naturally present in the prior art method. Since the base rejection clearly reflects the correct name, the instant action has corrected the typographical errors present in claims 16 and 23.
In response, applicant’s argument is not found persuasive for the reasons set forth below:
First, Bisset et al. clearly teaches the administration of an agent that increases cellular levels of phosphatidylinositol-4,5-bisphosphate to the patient for treating a neurodegenerative disease (see e.g., claims 79 and 83-85), wherein the neurodegenerative disorder is selected from, inter alia, neurodegenerative disorders resulting from cerebral ischemia, or hereditary cerebral angiopathy
(see e.g., [0017]). Specifically, these teachings can be found in claims 79 and 83-85, and paragraph [0017]:
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In other words, the fact that Bisset et al. teaches the neurodegenerative disease is being treated, a subject having said disease would reasonably be selected before administering the agent that increases cellular levels of phosphatidylinositol-4,5-bisphosphate.
Second, according to the instant specification, “cerebral ischemia” is clearly a condition characterized by reduced cerebral blood flow (see e.g., [0038] of instant specification); and the subject having reduced cerebral blood flow and/or reduced functional hyperemia clearly includes a patient having cerebral ischemia (see e.g., [0050] of instant specification). In the present case, by practicing the method taught by Bisset et al. for treating cerebral ischemia as the neurodegenerative disease, one would have reasonably expected that the administration of the agent that increases cellular levels of phosphatidylinositol-4,5-bisphosphate would successfully treat cerebral ischemia in a subject with said disease by preventing cellular apoptosis. In other words, in the absence of unexpected results, treating the underlying cerebral ischemia as the neurodegenerative disease would have reasonably expected to ameliorate the associated characteristics (“reduced cerebral blood flow and/or reduced functional hyperemia”), even though the prior art was not aware of it. MPEP 2145 II states: "[t]he fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious”. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Therefore, the rejection is maintained for the same reasons of record, but revisited and modified in view of the claim amendments for the reasons set forth herein.
Claims 1-4, 6, 9, 16-19, 22-26, and 29 remain and Claims 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) as applied to claims 1-2, 6, 9, 16-17, 22-24, 29 and 30-32 above, and further in view of Harraz et al. (Elife. 2018. Vol. 7:e38689. Published on Aug 7, 2018; cited in the IDS filed on September 24, 2021) and Sohn et al. (J Physiol. 2007. Vol. 582(Pt 3):1037-1046)(partially newly applied as necessitated by amendments).
The teachings of Bisset et al. are set forth above and applied as before.
Bisset et al. does not teach the elected therapeutic agent, a soluble PIP2 analog diC16-PIP2 as claimed in claims 3-4, 18-19, and 25-26.
Harraz et al. teaches that increases in [K+]o associated with neuronal activity alter cerebral
blood flow at the capillary level, showing that extracellular K+ activates capillary Kir2.1 channels, triggering a retrograde electrical (hyperpolarizing) signal that propagates upstream to dilate feeding
arterioles and enhance blood flow to the active region (see e.g., p. 14, “Discussion” section, 1st paragraph). Harraz et al. further teaches phosphatidylinositol 4,5-bisphosphate (PIP2) is required for the Kir2.1 channel, because PIP2 depletion inhibits capillary electrical signaling (see e.g., abstract; p. 2, last paragraph, line 10-12; p. 14, “Discussion” section, 1st paragraph). Harraz et al. further teaches diC16-PIP2 is a longer-chain PIP2 analog (see e.g., p.7, “ATP-dependent suppression of TRPV4 channels is mediated by PIP2” section, 2nd paragraph). Please note the diC16-PIP2 taught by Harraz et al. is a soluble PIP2 analog and a small molecule.
Sohn et al. teaches diC16-PIP2 is more efficiently loaded to the cell membrane due to its higher partition coefficient (see e.g., p. 1042, left column, line9-11). Sohn further teaches PIP2 concentration in the membrane reaches higher levels when pipettes contain PIP2 with a longer acyl chain (see e.g., p. 1041, right column, 1st paragraph).
Even though Bisset et al. does not specifically teach the administration of diC16-PIP2 as the agent for increasing the levels of phosphatidylinositol-4,5-bisphosphate, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Bisset et al. as set forth above by selecting the PIP2 analog diC16-PIP2 of Harraz et al. as the agent for treating cerebral ischemia. One would have been motivated to do so, because Sohn et al. teaches the diC16-PIP2 taught by Harraz et al. can increases the level of PIP2 concentration in the membrane more efficiency. One would have a reasonable expectation of success, because one would have reasonably expected that the administration of diC16-PIP2 of Harraz et al. as the agent for increasing the levels of phosphatidylinositol-4,5-bisphosphate would successfully treat cerebral ischemia, absent factual evidence to the contrary.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
All rejections pertaining to claims 21 and 28 are moot because the claims were cancelled in view of the amendments filed on October 15, 2025.
Applicant's arguments filed on October 15, 2025 with respect to the rejection of claims 1-4, 6, 9, 16-19, 21-26, and 28-29 under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) as applied to claims 1-2, 6, 9, 16-17, 21-24, and 28-29 above, and further in view of Harraz et al. (Elife. 2018. Vol. 7:e38689. Published on Aug 7, 2018; cited in the IDS filed on September 24, 2021) and Sohn et al. (J Physiol. 2007. Vol. 582(Pt 3):1037-1046) have been fully considered but they are not persuasive.
Applicant amends independent claims 16 and 23 by deleting the recitation of “under conditions effective” in the administration step. Applicant newly added claims 30-32; therefore, said amendments necessitate a modification of the rejection on the record to address the newly added claims.
In Summary, applicant argues presents the same argument with respect to Bisset et al. in the rejection under 35 U.S.C. § 103 sets forth above, and argues that neither Harraz nor Sohn overcome
the deficiencies of Bisset; therefore, none of Bisset, Harraz, or Sohn, taken alone or in combination, teach or suggest the claimed methods, including the method of treating a subject having a condition characterized by reduced cerebral blood flow, the method of restoring cerebral blood flow and the method of restoring functional hyperemia in a subject.
In response, applicant presents the same arguments with respect to Bisset et al. in the rejection under 35 U.S.C. § 103 sets forth above, which has been addressed the Response to Arguments section above, and does not present new arguments specifically against Harraz and Sohn. Therefore, applicant’s argument is not found persuasive for the same reasons sets forth therein and are applied as before.
Claims 1-2, 6-11, 15-17, 22-24, and 29 remain rejected and claims 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) as applied to claims 1-2, 6, 9, 16-17, 22-24, 29, and 30-32 above, and further in view of Ebihara et al. (Intern Med. 2018. Vol. 57(20): 3011-3014) and Joutel et al. (Nature, 1996. Vol. 383(6602): 707-710)(partially newly applied as necessitated by amendments).
The teachings of Bisset et al. are set forth above and applied as before.
Bisset et al. does not teach the elected condition, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); However, Bisset et al. teaches the neurodegenerative disorder is selected from hereditary cerebral angiopathy, or vascular dementia (see e.g., [0017]).
Ebihara et al. teaches cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral angiopathy caused by mutations in the NOTCH3 gene on chromosome 19 by citing a reference written by Joutel et al. (see e.g., p. 3011, “introduction” section).
Joutel et al. teaches CADASIL causes a type of stroke and dementia whose key features include recurrent subcortical ischemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging (see e.g., p. 707, left column, abstract).
In the present case, the difference between the method of Bisset et al. and the claimed method lies on the elected condition (CADASIL). It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Bisset et al. as set forth above by selecting the subject with CADASIL as the neurodegenerative disorder. One would have been motivated by the fact that Ebihara et al. teaches CADASIL is the most common form of hereditary cerebral angiopathy, as taught by Bisset et al., and Joutel et al. teaches vascular dementia is also one of the clinical features of CADASIL. One would have a reasonable expectation of success in arriving the claimed invention, because one would have reasonably expected that the oral administration of a small molecule activator of Bisset et al. as an agent that increases cellular levels of PIP2 would successfully treat hereditary cerebral angiopathy, including CADASIL, by treating vascular dementia and preventing cellular apoptosis in said patient.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
All rejections pertaining to claims 21 and 28 are moot because the claims were cancelled in view of the amendments filed on October 15, 2025.
Applicant's arguments filed on October 15, 2025 with respect to the rejection of claims 1-2, 6-11, 15-17, 21-24, and 28-29 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) as applied to claims 1-2, 6, 9, 16-17, 21-24, and 28-29 above, and further in view of Ebihara et al. (Intern Med. 2018. Vol. 57(20): 3011-3014) and Joutel et al. (Nature, 1996. Vol. 383(6602): 707-710) have been fully considered but they are not persuasive.
Applicant amends independent claims 16 and 23 by deleting the recitation of “under conditions effective” in the administration step. Applicant newly added claims 30-32. Therefore, said amendments necessitate a modification of the rejection on the record to address the newly added claims.
In Summary, applicant argues presents the same argument with respect to Bisset et al. in the rejection under 35 U.S.C. § 103 sets forth above, and argues that neither Ebihara nor Joutel overcome the deficiencies of Bisset; therefore, none of Bisset, Ebihara, or Joutel, taken alone or in combination, teach or suggest the claimed methods, including the method of treating a subject having a condition characterized by reduced cerebral blood flow, the method of restoring cerebral blood flow and the method of restoring functional hyperemia in a subject.
In response, applicant presents the same arguments with respect to Bisset et al. in the rejection under 35 U.S.C. § 103 sets forth above, which has been addressed the Response to Arguments section above, and does not present new arguments specifically against Ebihara and Joutel. Therefore, applicant’s argument is not found persuasive for the same reasons sets forth therein and are applied as before.
Claims 1-4, 6-10, 11-13, 15-19, 22-26, and 29 remain rejected and claims 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) in view of Ebihara et al. (Intern Med. 2018. Vol. 57(20): 3011-3014) and Joutel et al. (Nature 383: 707-710, 1996) as applied to claims 1-2, 6-11, 15-17, 22-24, 29, and 30-32 above, and further in view of Harraz et al. (Elife. 2018. Vol. 7:e38689. Published on Aug 7, 2018; cited in the IDS filed on September 24, 2021) and Sohn et al. (J Physiol. 2007. Vol. 582(Pt 3):1037-1046)(partially newly applied as necessitated by amendments).
The teachings of Bisset et al., Ebihara et al., and Joutel et al. are set forth above and applied as before.
Bisset et al., Ebihara et al., and Joutel et al. does not teach the elected therapeutic agent, a soluble PIP2 analog diC16-PIP2 as claimed.
Harraz et al. teaches that increases in [K+]o associated with neuronal activity alter cerebral
blood flow at the capillary level, showing that extracellular K+ activates capillary Kir2.1 channels, triggering a retrograde electrical (hyperpolarizing) signal that propagates upstream to dilate feeding
arterioles and enhance blood flow to the active region (see e.g., p. 14, “Discussion” section, 1st paragraph). Harraz et al. further teaches phosphatidylinositol 4,5-bisphosphate (PIP2) is required for the Kir2.1 channel, because PIP2 depletion inhibits capillary electrical signaling (see e.g., abstract; p. 2, last paragraph, line 10-12; p. 14, “Discussion” section, 1st paragraph). Harraz et al. further teaches diC16-PIP2 is a longer-chain PIP2 analog (see e.g., p.7, “ATP-dependent suppression of TRPV4 channels is mediated by PIP2” section, 2nd paragraph). Please note the diC16-PIP2 taught by Harraz et al. is a soluble PIP2 analog and a small molecule.
Sohn et al. teaches diC16-PIP2 is more efficiently loaded to the cell membrane due to its higher partition coefficient (see e.g., p. 1042, left column, line9-11). Sohn further teaches PIP2 concentration in the membrane reaches higher levels when pipettes contain PIP2 with a longer acyl chain (see e.g., p. 1041, right column, 1st paragraph).
Even though Bisset et al., Ebihara et al., and Joutel et al. does not specifically teach the administration of diC16-PIP2 as the agent for increasing the levels of phosphatidylinositol-4,5-bisphosphate, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Bisset et al., Ebihara et al., and Joutel et al. as set forth above by selecting the PIP2 analog diC16-PIP2 of Harraz et al. as the agent for treating CADASIL as the neurodegenerative disorder. One would have been motivated to do so, because Sohn et al. teaches the diC16-PIP2 taught by Harraz et al. can increases the level of PIP2 concentration in the membrane more efficiency, and Harraz et al. teaches PIP2 plays a crucial role in capillary electrical signaling responsible for cerebral blood flow. One would have a reasonable expectation of success in arriving the claimed invention, because one would have reasonably expected that the administration of diC16-PIP2 of Harraz et al. as the agent would successfully treat CADASIL as the neurodegenerative disorder by increasing the levels of phosphatidylinositol-4,5-bisphosphate, absent factual evidence to the contrary.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
All rejections pertaining to claims 21 and 28 are moot because the claims were cancelled in view of the amendments filed on October 15, 2025.
Applicant's arguments filed on October 15, 2025 with respect to the rejection of claims 1-4, 6-10, 11-13, 15-19, 21-26, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) in view of Ebihara et al. (Intern Med. 2018. Vol. 57(20): 3011-3014) and Joutel et al. (Nature 383: 707-710, 1996) as applied to claims 1-2, 6-11, 15-17, 21-24, and 28-29 above, and further in view of Harraz et al. (Elife. 2018. Vol. 7:e38689. Published on Aug 7, 2018; cited in the IDS filed on September 24, 2021) and Sohn et al. (J Physiol. 2007. Vol. 582(Pt 3):1037-1046) have been fully considered but they are not persuasive.
Applicant amends independent claims 16 and 23 by deleting the recitation of “under conditions effective” in the administration step. Applicant newly added claims 30-32. Therefore, said amendments necessitate a modification of the rejection on the record, including addressing the newly added claims.
In Summary, applicant argues presents the same argument with respect to Bisset et al. in the rejection under 35 U.S.C. § 103 sets forth above, and argues that neither Ebihara, Joutel, Harraz, nor Sohn overcome the deficiencies of Bisset; therefore, none of Bisset, Ebihara, Joutel, Harraz, or Sohn, taken alone or in combination, teach or suggest the claimed methods, including the method of treating a subject having a condition characterized by reduced cerebral blood flow, the method of restoring cerebral blood flow and the method of restoring functional hyperemia in a subject.
In response, applicant presents the same arguments with respect to Bisset et al. in the rejection under 35 U.S.C. § 103 sets forth above, which has been addressed the Response to Arguments section above, and does not present new arguments specifically against Ebihara, Joutel, Harraz, and Sohn. Therefore, applicant’s argument is not found persuasive for the same reasons sets forth therein and applied as before.
Claims 1-2, 6-11, 15-17, 22-24, 29, and 30-36 are rejected under 35 U.S.C. 103 as being unpatentable over Bisset et al. (US 2010/0092456 A1) in view of Ebihara et al. (Intern Med. 2018. Vol. 57(20): 3011-3014) and Joutel et al. (Nature 383: 707-710, 1996) as applied to claims 1-2, 6-11, 15-17, 22-24, 29, and 30-32 above, and further in view of Saengsawang et al. (J Cell Sci, 2013. Vol. 126(Pt 11): 2411-2423) and Raineteau et al. (WO 2018/178194 A1; cited in the IDS filed on September 24, 2021)(newly applied as necessitated by amendments).
The teachings of Bisset et al., Ebihara et al., and Joutel et al. are set forth above and applied as before.
Bisset et al., Ebihara et al., and Joutel et al. does not teach LY294002 as claimed in claims 33-36.
Saengsawang et al. teaches PI3K inhibitor LY294002 decreases PIP3, but increases PIP2 levels (see e.g., Fig. S1).
Raineteau et al. teaches a method for treating brain injuries, such as hypoxic/ischemic brain injury in the adult, comprising administering to a subject in need thereof a therapeutically effective amount of PI3K inhibitors, such as LY294002 having the structure of:
PNG
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(see e.g., p. 27, line 7-10; p. 2, line 21-26; p. 19, line 2; p. 40, “In vivo procedures” section). Please note the PI3K inhibitor LY294002 taught by Raineteau et al. is a small molecule (see e.g., Table 3C). Raineteau et al. further teaches the administration of an PI3K inhibitor LY294002 in the brain of postnatal or adult mice effectively promotes oligodendrogenesis (see e.g., p. 3, line 7-9; p. 17, line 5-7; Table 3C). Raineteau et al. further teaches phosphoinositide 3-kinases (PI3K) are a family of enzymes that phosphorylate the 3’hydroxyl group of the onositol ring of the phosphatidylinositol, the activation of PI3K signaling pathway results in the synthesis of PIP3 from PIP2 (see e.g., p. 18, line 4-7). Raineteau et al. further teaches a compound inhibitor of PI3K is capable of inhibiting the kinase activity of at least one member of PI3K family (see e.g., p. 18, line 8-10).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Bisset et al., Ebihara et al., and Joutel et al. sets forth above by selecting LY294002 of Saengsawang et al. as the agent that increases cellular levels of phosphatidylinositol-4,5-bisphosphate. One would have been motivated to do so, because Saengsawang teaches LY294002 increases the level of PIP2; and Raineteau teaches LY294002 can successfully promote oligodendrogenesis. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the LY294002 of Saengsawang et al. would successfully treat CADASIL as the neurodegenerative disorder by increasing the levels of phosphatidylinositol-4,5-bisphosphate as well as promoting oligodendrogenesis.
Therefore, the claimed invention is prima facie obvious for one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
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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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628