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 species of neurons of the anterodorsal (AD) thalamus (claims 1-4, 7-9, and 12-13) and promotors expressed in a neuron of the anterodorsal (AD) thalamus (claims 10-11) in the reply filed on June 3, 2026 is acknowledged. Based on evaluation of the claims and search of the prior art, the species have been rejoined.
Claims 1-13 are examined on the merits.
Priority
The present application is a continuation of the International Application No. PCT/US2022/035072, filed on December 27, 2022. The instant application claims benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) to U.S. provisional application 63/216463, filed on December 29, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 22, 2023 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objection to the Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description:
FIGs. 9J-9M are recited on Pg. 46 of the specification but do not appear in the drawings.
FIG. 9N is recited on Pg. 47 of the specification but does not appear in the drawings.
FIGs. 11N-11V are recited on Pg. 48 of the specification but do not appear in the drawings.
FIGs. 14F-14G are recited on Pg. 51 of the specification but do not appear in the drawings.
FIGs. 14H-14M are recited on Pg. 52 of the specification but do not appear in the drawings.
FIGs. S7A-S7B are recited on Pg. 52 of the specification but do not appear in the drawings.
FIGs. S7C-S7E are recited on Pg. 54 of the specification but do not appear in the drawings.
This is not intended to be a complete list. It is recommended that Applicant thoroughly review the instant disclosure for other references to figures which are not part of the disclosure.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Objection to the Specification
The disclosure is objected to because of the following informalities:
Pg. 53, 3rd para. contains typographical errors in lines 16 which recites “ the inventors xamined…”, line 21 which recites “the inventors anted…”, and line 22 which recites “The inventors ound…”, which appear to be misspellings of examined, wanted, and found, respectively.
In addition to the specification containing references to FIGs which do not appear to be supplied with the instant disclosure (See Objection to Drawings section above), it appears that some figure descriptions in the specification do not correspond with the figures and some examples of the instant disclosure reference figures which to not correspond to the subject matter. For example, the figure descriptions for the FIG. 13 do not appear to correspond to the figures provided in the drawings. Example 2 of the specification which is related to mapping of the outputs of the AD thalamus contains many references to various figures of FIG. 9A-I which appear to depict gene expression in hippocampal neurons and effects of knockdown of specific genes in hippocampal neurons on memory.
This is not intended to be a complete list. It is recommended that Applicant thoroughly review the instant disclosure for other discrepancies related to figure descriptions.
Appropriate correction is required.
Claim Objections
Claims 5, 6, 10 and 11 are objected to for use of arrows to indicate neuronal pathways. It is recommended that Applicant amend the claims to replace the arrow with language which conveys the intended pathway, such as “projecting to”.
Claim 8 is objected to because of the following informalities: Claim 8 recites the abbreviations for PTCHD1, YWHAG, and HERC1 without initially reciting the full title corresponding to the abbreviation followed by the abbreviation in parentheses.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13, which depends from claim 1, recites the limitation "the ligand". There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of a ligand.
Claim Interpretation
Claims 10 and 11 recite that the instantly claimed recombinant adeno-associated virus “comprises a promoter expressed in a neuron selected from the group consisting of neurons of the anterodorsal (AD) thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex (RSC) pathway, and neurons present in the AV thalamus projection to the RSC pathway.” Applicant’s use of “consisting of” in the Markush group of promoters is interpreted as a closed group. MPEP 2117(I) states “Claim language defined by a Markush grouping requires selection from a closed group "consisting of" the alternative members. Id. at 1280, 67 USPQ2d at 1196. See also Amgen Inc. v. Amneal Pharmaceuticals LLC, 945 F.3d 1368, 1376-78, 2020 USPQ2d 3197 (Fed. Cir. 2020) (stating that there is a strong presumption that a claim element set off with "consisting of" is closed to unrecited elements.).” Therefore, the instantly claimed methods require use of a promoter which is specific to only one of the members of the closed Markush group. That is, a promoter which is specific only for one of neurons of AD thalamus, neurons of the AV thalamus, neurons of the entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex (RSC) pathway, or neurons present in the AV thalamus projection to the RSC pathway and not to any promoters which would target other neurons, cells, or combinations of neurons and/or cells.
Claim Rejections - 35 USC § 112(a) – 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 1-13 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) 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.
Independent claim 1 encompasses a methods for increasing a genus of cognitive performance comprising administration of a genus of recombinant adeno-associated viruses (rAAV) comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit anterodorsal (AD) thalamus hyperexcitability.
Independent claim 2 encompasses a method for reducing a genus of cognitive impairment associated with a neuropsychiatric disorder in a subject, comprising administration of a genus of rAAVs comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit AD hyperexcitability.
Dependent claims 3-6 encompass a genus of neurons in which the genus of rAAV encoding the genus of engineered M4 muscarinic acetylcholine receptors is to be expressed.
Dependent claims 7-8-encompass a genus of subjects to which the rAAV is administered.
Dependent claims 9 and 13 encompasses a genus of agents which are to be administered to the subject.
Independent claim 10 encompasses a method for increasing a genus of cognitive performance comprising administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability.
Independent claim 11 encompasses a method for reducing a genus of cognitive impairment associated with a neuropsychiatric disorder administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability.
Dependent claim 12 encompasses a genus of rAAVs which comprise a polynucleotide encoding a Cre-dependent DREADD hM2Di.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
ACTUAL REDUCTION TO PRACTICE
With regard to claim 1 encompassing a methods for increasing a genus of cognitive performance comprising administration of a genus of recombinant adeno-associated viruses (rAAV) comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit anterodorsal (AD) thalamus hyperexcitability, the specification provides only a method of increasing long term memory (LTM) comprising targeted microinjection of an rAAV8 comprising a Cre-dependent hM4Di into the AD thalamus (See FIG. 6D) of PTCHD1 knockdown mice followed by administration of a “low dose” of Compound 21 (C21) which reduces AD thalamus hyperexcitability (FIG. 6E) and improves LTM performance defects caused by the PTCHD1 knockdown (FIG. 6H). It is noted that Applicant’s specification discloses that the reduction of AD hyperexcitability and improvement of LTM performance was not seen when a “regular” dose of C21 was administered (See FIGs. 6E-6H) and therefore only the low dose of C21 was used in subsequent testing. The specification provides use of this same protocol in YWHAG (FIGs. 7D-7F) and HERC1 (FIGs 7J) knockdown mice in order to reduce AD thalamus hyperexcitability and improve LTM performance deficits caused by the YWHAG and HERC1 knockdown (See Example 7). Although Applicant indicates in Example 7 (Pg. 52, 1st full para.) that improvements in spatial working memory were also seen in PTCHD1, YWHAG, and HERC1 knockdown mice upon reduction of AD hyperexcitability and references FIGS. 14K-14M, these FIGs have not been provided with the instant disclosure. The specification provides no guidance that LTM could be improved in a normal subject or a subject which is not deficient in PTCHD1, YWHAG, or HERC1, nor that AD hyperexcitability would be necessarily be present in any other subjects.
With regard to claim 2 encompassing a methods for reducing a genus of cognitive impairment associated with a neuropsychiatric disorder in a subject, comprising administration of a genus of rAAVs comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit AD hyperexcitability, similar to claim 1 above, the specification provides only a method of increasing long term memory (LTM) comprising targeted microinjection of an rAAV8 comprising a Cre-dependent hM4Di into the AD thalamus (See FIG. 6D) of PTCHD1 knockdown mice followed by administration of a “low dose” of Compound 21 (C21) which reduces AD thalamus hyperexcitability (FIG. 6E) and improves LTM performance defects caused by the PTCHD1 knockdown (FIG. 6H). It is noted that Applicant’s specification discloses that the reduction of AD hyperexcitability and improvement of LTM performance was not seen when a “regular” dose of C21 was administered (See FIGs. 6E-6H) and therefore only the low dose of C21 was used in subsequent testing. The specification provides use of this same protocol in YWHAG (FIGs. 7D-7F) and HERC1 (FIGs 7J) knockdown mice in order to reduce AD thalamus hyperexcitability and improve LTM performance deficits caused by the YWHAG and HERC1 knockdown (See Example 7). Although Applicant indicates in Example 7 (Pg. 52, 1st full para.) that improvements in spatial working memory were also seen in PTCHD1, YWHAG, and HERC1 knockdown mice upon reduction of AD hyperexcitability and references FIGS. 14K-14M, these FIGs have not been provided with the instant disclosure. The specification provides only examples using knockdown of PTCHD1 and YWHAG, genes associated with autism; and HERC1, a gene associated with schizophrenia, which the specification indicates are heavily expressed in the AD thalamus (See Example 1). The specification provides no guidance for reduction of cognitive impairment as it relates to LTM associated with other neuropsychiatric disorders, for example Parkinson’s disease, nor that AD hyperexcitability would be necessarily be present in any subjects having other neuropsychiatric disorders.
With regard to claims 3-6 encompassing a genus of neurons in which the genus of rAAVs encoding the genus of engineered M4 muscarinic acetylcholine receptors is to be expressed, the specification provides only examples of microinjection of an rAAV8 comprising an hM4Di to neurons of the AD thalamus, which project to the RSC, and in which the AD thalamus to RSC projections play a role in LTM.
With regard to claims 7-8-encompassing a genus of subjects to which the rAAV is administered, as detailed above, the instantly specification only provides examples using knockdown of PTCHD1 and YWHAG, which are genes associated with autism; and HERC1, which is a gene associated with schizophrenia.
With regard to claims 9 and 13 encompassing a genus of agents which are to be administered to the subject, the specification provides guidance only for administration of C21 and that a “low dose” of C21 (See Pg. 69, 1st full para.) is required for improvements in LTM (See Example 7, FIGs. 6D-6H, 7D-7F, and 7J). Furthermore, Applicant specification indicates that the engineered M4 muscarinic acetylcholine receptors such as hM4Di do not inhibit hyperexcitability in the absence of ligand (p. 40, last two para.)
With regard to claim 10 encompassing a method for increasing a genus of cognitive performance comprising administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability, as detailed above, the specification only provides guidance for use of an rAAV8 encoding an hM4Di polypeptide administered via microinjection to the AD thalamus and subsequent administration of a low dose of C21 in order to reduce AD thalamus hyperexcitability and improve deficits in LTM caused by knockdown of PTCHD1, YWHAG, and HERC1. As detailed above in the claim interpretation section, Applicant has claimed use of a promoter which is expressed only in neurons of the AD thalamus, neurons of the AV thalamus, neurons of the entorhinal cortex, neurons in the AD thalamus to RSC projection pathway, or neurons in the AV thalamus to RSC pathway. However, Applicant’s instant disclosure indicates that the AAV8 encoding an hM4Di polypeptide comprises a human synapsin-1 promoter (See FIGs. 6D and 7D and Pg. 57, last para.), which is essentially a pan-neuronal promoter.
With regard to claim 11 encompassing a methods for reducing a genus of cognitive impairment associated with a neuropsychiatric disorder administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability, as detailed above, the specification only provides guidance for use of an rAAV8 encoding an hM4Di polypeptide administered via microinjection to the AD thalamus and subsequent administration of a low dose of C21 in order to reduce AD thalamus hyperexcitability and improve deficits in LTM caused by knockdown of PTCHD1, YWHAG, and HERC1 which are genes associated with autism and schizophrenia (Example 1). As detailed above in the claim interpretation section, Applicant has claimed use of a promoter which is expressed only in neurons of the AD thalamus, neurons of the AV thalamus, neurons of the entorhinal cortex, neurons in the AD thalamus to RSC projection pathway, or neurons in the AV thalamus to RSC pathway. However, Applicant’s instant disclosure indicates that the AAV8 encoding an hM4Di polypeptide comprises a human synapsin-1 promoter (See FIGs. 6D and 7D and Pg. 57, last para.), which is essentially a pan-neuronal promoter.
With regard to claim 12 encompassing a genus of rAAVs which comprise a polynucleotide encoding a Cre-dependent DREADD hM2Di, the specification only provides guidance for use of an rAAV8 comprising a sequence encoding a Cre-dependent DREADD hM4Di (See FIGs. 6D, 7D).
DISCLOSURE OF STRUCTURE
The Applicant has provided no examples of a method of increasing any type of cognitive performance or reducing any type of cognitive impairment associated with a neuropsychiatric disorder other than improvements in LTM in mice having reduced expression of PTCHD1 and YWHAG, genes associated with autism, and HERC1, a gene associated with schizophrenia. Additionally, Applicant has utilized only targeted microinjection to the AD thalamus of an rAAV8 having a pan-neuronal human synapsin-1 promoter and encoding an hM4Di which was able to reduce AD thalamus hyperexcitability and improve LTM impairment caused by the knockdown of PTCHD1, YWHAG, and HERC1 following a specific “low” dose of C21 (See Example 7).
Furthermore, the prior art is silent with respect to increasing other measures of cognitive performance in any subject via administration of any engineered M4 acetylcholine receptor via any route of administration without the use of a targeted ligand as well as the ability of a promoter to specifically express the receptor in neurons that inhibit AD thalamus hyperexcitability. Likewise, the prior art is silent as to using the same method to reduce cognitive impairment associated with any neuropsychiatric disorder. Further, Although Applicant claims use of a promoter which is specific for only one neuronal population (claims 10 and 11), Applicant’s instant specification indicates use of a human synapsin-1 promoter (Pg. 57, last para.) which a skilled artisan would expect to target all neurons. Applicant provides no guidance as to which promoters could be selected in order to target only neurons of the AD thalamus, neurons of the AV thalamus, neurons of the entorhinal cortex, neurons present in the AD thalamus to RSC pathway, or neurons present in the AV thalamus to RSC pathway without targeting any other neuron or cell population and the prior art is silent as to promoters which are specific only for the AD thalamus or any of the other claimed neuronal populations.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
The role of specific acetylcholine receptors in memory and the targeting of muscarinic acetylcholine receptors, including M4 receptors, for the treatment of specific neuropsychiatric disorders such as schizophrenia is known in the art. In addition, use of targeted delivery of engineered DREADD hM4Di receptors followed by ligand administration in order to selectively inhibit certain neurons is also known in the art.
The breadth of the claims encompasses a method which improves a genus of cognitive performances or reduces a genus of cognitive impairments associated with a genus of neuropsychiatric disorders in a subject via administration of a genus of rAAVs comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors via any administration route and expressing the receptor in a genus of neurons that inhibit AD thalamus hyperexcitability with a genus of promoters that have not been described. However, the instant specification offers limited guidance and descriptions regarding the method beyond specific cognitive improvements in a specific subject population via targeted administration of a specific DREADD hM4Di to a specific neuronal population and subsequent administration of a specific dose of a specific ligand. Therefore, a skilled artisan would not know which rational approach could be used to use the genus of engineered M4 muscarinic acetylcholine receptors which are to be expressed in a genus of neurons in order to improve a genus of cognitive performance and/or reduce a genus of cognitive impairments associated with a genus of neuropsychiatric disorders in a genus of subjects. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of methods.
Regarding the engineered M4 muscarinic acetylcholine receptor, Applicant’s instant disclosure provides several examples of viral constructs comprising hM4Di receptors, both using an AAV8 serotype, two comprising a human synapsin-1 (hSyn) promoter and which are Cre-dependent but differ in their visualization tags (i.e., AAV8-hSyn-DIO-hM4Di-mCherry; AAV8-hSyn-DIO-hM4Di-mCitrine) and one which comprises a calcium/calmodulin-dependent protein kinase II promoter (CaMKIIα) promoter (i.e., AAV8-CaMKIIa-hM4Di-mCherry) (Pg. 57, last para.). Note that the CaMKIIα promoter targets multiple types of neurons in the brain. However, Applicant appears only appears to utilize a single viral construct, AAV8-hSyn-DIO-hM4Di-mCitrine, in the instantly claimed method (See Example 7, FIGs. 6D, 7D). Additionally, the instant disclosure utilizes only a single ligand for the disclosed hM4Di receptor, C21, (pg. 69, 1st full para.) and indicates that there is a limited dosage of C21 which is effective for the functional limitations of the instantly claimed method (Example 7; FIGs. 6E-6H, 7E-7F, 7J). Although Applicant’s specification provides a list of AAVs which could be used in various embodiments (Pg. 41, last para.), the viral constructs comprising the described hM4Di receptor utilize only AAV8. Similarly, although Applicant’s specification provides a list of promoters which could be used in various embodiments (Pg. 43), the viral constructs comprising the described hM4Di receptor which was utilized in the instantly claimed method utilizes only hSyn. It is noted that Applicant provides no description of promoters which could be used to specifically target the groups of neurons as recited in claims 10 and 11 and that hSyn would be known to a skilled artisan as pan-neuronal promoter.
Regarding administration of the AAV comprising the specific hM4Di responsible for the claimed functional effect, Applicant’s instant specification describes only targeted microinjections to the AD thalamus (FIG. 6D, 7D). There is no description of routes of administration other than microinjections targeted to specific brain areas and no description of microinjections to areas outside of the AD thalamus which are associated with the functional effect on cognition. Thus, it appears from the instant specification that the functional effect is dependent upon targeted delivery to only neurons in the AD thalamus.
Regarding the population of subjects and the functional effects on cognition, Applicant’s instant description indicates that the functional effects on cognition are shown in mice in which PTCHD1, YWHAG, or HERC1 genes (genes associated with autism and schizophrenia), have been knocked down and that the knockdown of these genes results in AD thalamus hyperactivity (FIGs. 6A, 7B, and 7H) and effects on LTM (FIG. 1H-I, 2B, 2K). Applicant’s disclosure indicates that this hyperactivity can be reduced via targeted microinjections of AAV8-hSyn-DIO-hM4Di-mCitrine to the AD thalamus and subsequent administration of a low dose of C21 (FIGs. 6D, 6E, 7D, 7E) which also results in improvements to LTM in PTCHD1, YWHAG, and HERC1 knockdown animals (FIGs. 6H, 7F, 7J). Although Applicant’s instant specification identifies other genes associated with autism and schizophrenia and which are highly expressed in the AD thalamus (Pg. 44-45, bridging para.) and that several of these genes result in LTM deficits (GRIA3 FIG. 2E; CACNA1G FIG. 2H), Applicant has not shown that knockdown of these genes also results in AD thalamus hyperexcitability nor that targeted microinjections of AAV8-hSyn-DIO-hM4Di-mCitrine to the AD thalamus is able to rescue LTM for these animals. Applicant has not provided any description of cognitive improvements in normal subjects, subjects suffering from neuropsychiatric disorders other than autism and schizophrenia, or subjects having autism and schizophrenia which is associated with alterations of genes which are not heavily expressed in the AD thalamus. Additionally, Applicant has only described LTM defects in this specific population, in which genes of the AD thalamus are knocked down, but indicates no effects on freezing behavior in a neutral context (FIG. 4B), which is a marker of memory specificity. Thus, it appears that the instantly claimed cognitive improvements and/or reductions in cognitive impairment are limited to LTM as well as to deficits in a specific population of subjects.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of using the claimed invention is not well established. Although the role of acetylcholine receptors in memory and targeting of muscarinic acetylcholine receptors, including M4 receptors, for the treatment of neuropsychiatric disorders such as schizophrenia and use of targeted delivery of engineered DREADD hM4Di receptors coupled with ligand administration in order to selectively inhibit certain neurons is also known in the art, one of skill in the art would neither expect nor predict a successful outcome to increase any cognitive performance or reduce any cognitive impairments associated with any neuropsychiatric disorder in any subject by administration of any rAAV comprising an engineered M4 muscarinic acetylcholine receptor and expressing the receptor in neurons that inhibit AD thalamus hyperexcitability.
As an initial matter, the contemporaneous art of Roy et al. (2021, Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models. Neuron, 109(16), 2590-2603)
discloses that deletion of PTCHD1 from the thalamic reticular nucleus does not cause memory deficits (Pg. 3, 1st para.) and references Wells et al. (2016, Thalamic reticular impairment underlies attention deficit in Ptchd1 Y/− mice. Nature, 532(7597), 58-63.) which discloses that PACHD1 is mutated in about 1% of patients with autism and intellectual disability (Pg. 58, left col., 2nd para.) and Ptchd1 knockout mice show no performance deficits in spatial learning, but show deficits in both contextual and cued-fear conditioning (Pg. 61, left col., last para.). It is noted that the results of Wells et al., in a Ptchd1 knockout model, differ from those as instantly disclosed where localized knockdown of PTCHD1 in the AD thalamus was associated with deficits in spatial memory (FIG. 1J) but not tone fear conditioning (Pg. 53, last para.) so it appears that the specific location of PTCHD1 knockdown influences the phenotype of cognitive deficit. Roy et al. discloses that the AD thalamus is “understudied” (Pg. 3, 2nd para.) and that the role of the AD thalamus in memory is unclear (Pg. 3, 3rd para.), and that the localized expression of certain autism and schizophrenia genes in the AD thalamus indicates that it may be implicated in dysfunction in a subset of disorders (Pg. 4, 1st para.). Further, Roy et al. discloses that although AD thalamus specific knockdown of several genes highly expressed in the AD thalamus and associated with autism and schizophrenia resulted in memory deficits (Pg. 3, 1st para.), memory deficits were not seen when those same genes were knocked down in the hippocampus (Pg. 3, 2nd para.) and also that the AD thalamus is specifically implicated in cognitive tasks related to LTM (Pg. 10, 3rd para.). Thus, the prior art of Wells et al. and the contemporaneous art of Roy et al. indicate that, at the time of filing, the specific subject population and the specific cognitive defects which might be able to be treated by expressing an engineered M4 muscarinic acetylcholine receptor in neurons that inhibit AD thalamus hyperexcitability were not well characterized and a skilled artisan could not have looked to the state of the art in order to appropriately predict which subjects or which cognitive deficits could be treated.
Regarding the specific engineered M4 muscarinic acetylcholine receptor, Applicant’s instant specification provides guidance for use of an inhibitory DREADD hM4Di receptor, which are known in the art. However, Applicant’s instant claims do not recite use of a specific ligand at a specific dose and Applicant’s instant disclosure indicates that the improvements in LTM in animals with AD thalamus specific knockdown of PTCHD1, YWHAG, and HERC1 were only seen after administration of C21 at a “low” dose (FIGS. 6E, 6H, 7E, 7F, 7J) which is defined in the specification as 0.6 mg/kg (Pg. 69, 1st full para.). The prior art of Goutaudier et al. (2020, Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats. Plos one, 15(9), e0238156) discloses that in a method of modulating dopaminergic neurons using a DREADD hM4Di, off target effects of the dose of C21 differed between male and female rats, with female animals being more susceptible to off-target effects of low doses (i.e., 0.5 mg/kg) than males (Abstract and Discussion Pg. 8, 2nd para.). Goutaudier et al. discloses that the ligand used is also important as another DREADD hM4Di ligand, CNO, is known to produce off-target behavioral effects which limits their use as specific DREADD ligands (Pg. 2, 1st para.). Goutaudier et al. further discloses that C21 may also have affinity for serotonergic and histaminergic receptors in addition to hM4Di (Discussion Pg. 8, 2nd para.). Thus, given the unpredictability surrounding the specific ligand for the hM4Di receptor and the specific dose of C21 which could be used to produce the claimed cognitive improvements, a skilled artisan would not have known, from the prior art, which dose of C21 to use nor which DREADD hM4Di ligand could be used in the instantly claimed method.
Regarding the specific AAV construct comprising the hM4Di receptor, Applicant’s instant specification discloses a single AAV construct, AAV8-hSyn-DIO-hM4Di-mCitrine, administered via targeted microinjection directly to the AD thalamus in order to improve AD thalamus hyperexcitability and LTM deficits following AD thalamus specific knockdown of PTCHD1, YWHAG, or HERC1. Applicant’s instant claims 10 and 11 recite use of a promoter which specifically targets only a particular neuronal subset. Although AAV serotypes are well known and well characterized in the art, the choice of AAV serotype is important for delivery to the central nervous system as well as specific areas of the brain. The prior art of Manfredsson et al. (2009, AAV9: a potential blood-brain barrier buster. Molecular Therapy, 17(3), 403-405) discloses that the blood brain barrier blocks rAAV delivery to the central nervous system when systemically administered which results in the need to use localized injections to targeted brain areas (Pg. 403, left col., 1st para.). Manfredsson et al. discloses that localized delivery is advantageous for gene therapy in neuropathology which is localized to a specific region (Pg. 403, left col., 1st para.) and that transduction of any specific rAAV is dependent on not only the local receptor population (Pg. 403, right col., 2nd para.) but also the species which is being targeted (Pgs. 403-404, bridging para., see also Table 1). Therefore, as the specific pathway which is to be targeted for the instantly claimed cognitive effects is not well characterized in the existing art, a skilled artisan would likewise not be able to appropriately determine which rAAV to use to ensure appropriate targeting to neurons which inhibit AD thalamus hyperexcitability and would understand that selection of the rAAV would depend on the route of administration, area to be targeted, and species.
Further, the viral construct used in Applicant’s disclosure contains a hSyn promoter, which is known to be pan-neuronal. Although Applicant claims use of a promoter which is specific for only a subset of neurons, the art is silent as to a promoter which is specifically able to target only neurons of the AD thalamus, AV thalamus, entorhinal cortex, neurons in the AD thalamus to RSC pathway, or neurons in the AV thalamus to RSC pathway and these promoters are not described in the instant disclosure, therefore a skilled artisan would not be able to determine based on the state of the art which promoter could be used to directly target only the claimed neuronal populations.
Applicant has claimed a method of increasing a genus of cognitive performance and/or reducing cognitive impairment associated with a genus of neuropsychiatric disorders in a genus of subjects comprising administering a genus of rAAVs comprising a genus of engineered M4 muscarinic acetylcholine receptors and expressing the receptor in a genus of neurons which inhibit AD thalamus hyperexcitability, yet the specification has only disclosed administration of a specific AAV comprising a specific hM4Di via microinjection to the AD thalamus in a specific subject population which is able to reduce impairments in LTM in that population only in response to a specific dose of a receptor ligand. Therefore, Applicant’s specification is not considered to be sufficiently detailed to show that Applicant was in possession of the claimed genus of methods. Furthermore, the state of the art indicating that practicing the claimed method is not well established and that the claimed function on cognitive improvement would require undue experimentation, and one of ordinary skill in the art would neither expect nor predict the claimed method would be successful according to the claimed genuses of cognitive effects, routes of administration, AAVs comprising engineered M4 muscarinic acetylcholine receptors and promoters, neurons inhibiting AD thalamus hyperexcitability, and subject populations.
CONCLUSION
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus of methods of increasing a genus of cognitive performance and/or reducing a genus of cognitive impairment associated with a neuropsychiatric disorder in a genus of subjects comprising administration of a genus of rAAVs encoding a genus of engineered M4 muscarinic acetylcholine receptors and expressing the receptor in a genus of neurons which inhibit AD thalamus hyperexcitability. Specifically, there is limited description of the structure-function relationship between the claimed genus of rAAVs comprising the genus of engineered M4 muscarinic acetylcholine receptors delivered by the genus of routes of administration to the genus of neuronal populations and the ability to improve cognitive performance and/or reduce cognitive impairment in the genus of subjects. Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed genus of methods.
Claim Rejections - 35 USC § 112(a) – Enablement/Scope of Enablement
Claims 1-13 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 improvements in LTM in subjects having reduced AD thalamus expression of PTCHD1, YWHAG, and HERC1 via targeted microinjection to the AD thalamus of an rAAV8 comprising a human synapsin-1 promoter and sequence encoding a DREADD hM4Di and subsequent administration of a “low” dose of C21, does not reasonably provide enablement for improvements in other types of cognitive performance in other subjects via administration of other engineered M4 muscarinic acetylcholine receptors via other routes of administration to other brain areas (or systemically) or subsequent administration of other doses of ligands. 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.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of methods for increasing a genus of cognitive performance and/or a genus of reducing cognitive impairment associated with a neuropsychiatric disorder in a genus of subject comprising administration of a genus of rAAVs comprising a genus engineered M4 muscarinic acetylcholine receptors and expressing the receptors in a genus of neurons that inhibit AD thalamus hyperexcitability. As discussed supra, the specification fails to describe the genus of cognitive effects, subjects, engineered M4 muscarinic acetylcholine receptors, rAAVs, and neurons where the receptor is to be expressed and would require undue experimentation to discover these cognitive effects, subjects, engineered M4 receptors, rAAVs, and targeted neurons. The specification only discloses and provides guidance for a method of increasing LTM comprising administration of an AAV8 hM4Di via targeted microinjection to the AD thalamus in animals having AD thalamus specific knockdown of PTCHD1, YWHAG, and HERC1 and subsequent administration of a low dose of C21.
Independent claim 1 encompasses a method for increasing a genus of cognitive performance comprising administration of a genus of recombinant adeno-associated viruses (rAAV) comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit anterodorsal (AD) thalamus hyperexcitability.
Independent claim 2 encompasses a methods for reducing a genus of cognitive impairment associated with a neuropsychiatric disorder in a subject, comprising administration of a genus of rAAVs comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit AD hyperexcitability.
Dependent claims 3-6 encompass a genus of neurons in which the genus of rAAV encoding the genus of engineered M4 muscarinic acetylcholine receptors is to be expressed.
Dependent claims 7-8-encompass a genus of subjects to which the rAAV is administered.
Dependent claims 9 and 13 encompasses a genus of agents which are to be administered to the subject.
Independent claim 10 encompasses a method for increasing a genus of cognitive performance comprising administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability.
Independent claim 11 encompasses a method for reducing a genus of cognitive impairment associated with a neuropsychiatric disorder administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability.
Dependent claim 12 encompasses a genus of rAAVs which comprise a polynucleotide encoding a Cre-dependent DREADD hM2Di.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
ACTUAL REDUCTION TO PRACTICE
The specification does not provide guidance for or a working example for use of the method in normal subjects, subjects who are suffering from a neuropsychiatric disorder other than autism or schizophrenia, or even subjects who have alterations in genes other than PTCHD1, YWHAG, and HERC1 in areas of the brain other than the AD thalamus. Likewise, no working examples are provided for improvements in cognition beyond long term memory. The absence of working examples directed to the specific subject population and the specific improvements in cognitive performance for which the method can be used necessitates further experimentation. Additionally, no working examples were provided that utilize viral constructs other than AAV8-hSyn-DIO-hM4Di-mCitrine, delivery other than targeted microinjection to the AD thalamus, nor that utilize promoters which are specific for only a narrow subset of neurons. Further, the instantly claimed method requires subsequent administration of only a low dose of C21 for the claimed functional effects. Therefore, the specification does not provide sufficient guidance on how to make and use the full scope of the instantly claimed methods.
With regard to claim 1 encompassing a genus of methods for increasing cognitive performance comprising administration of a genus of recombinant adeno-associated viruses (rAAV) comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit anterodorsal (AD) thalamus hyperexcitability, the specification provides only a method of increasing long term memory (LTM) comprising targeted microinjection of an rAAV8 comprising a Cre-dependent hM4Di into the AD thalamus (See FIG. 6D) of PTCHD1 knockdown mice followed by administration of a “low dose” of Compound 21 (C21) which reduces AD thalamus hyperexcitability (FIG. 6E) and improves LTM performance defects caused by the PTCHD1 knockdown (FIG. 6H). It is noted that Applicant’s specification discloses that the reduction of AD hyperexcitability and improvement of LTM performance was not seen when a “regular” dose of C21 was administered (See FIGs. 6E-6H) and therefore only the low dose of C21 was used in subsequent testing. The specification provides use of this same protocol in YWHAG (FIGs. 7D-7F) and HERC1 (FIGs 7J) knockdown mice in order to reduce AD thalamus hyperexcitability and improve LTM performance deficits caused by the YWHAG and HERC1 knockdown (See Example 7). Although Applicant indicates in Example 7 (Pg. 52, 1st full para.) that improvements in spatial working memory were also seen in PTCHD1, YWHAG, and HERC1 knockdown mice upon reduction of AD hyperexcitability and references FIGS. 14K-14M, these FIGs have not been provided with the instant disclosure. The specification provides no guidance that LTM could be improved in a normal subject or a subject which is not deficient in PTCHD1, YWHAG, or HERC1, nor that AD hyperexcitability would be necessarily be present in any other subjects.
With regard to claim 2 encompassing a genus of methods for reducing cognitive impairment associated with a neuropsychiatric disorder in a subject, comprising administration of a genus of rAAVs comprising a sequence encoding a genus of engineered M4 muscarinic acetylcholine receptors to a subject and expressing the receptor in a genus of neurons of the subject that inhibit AD hyperexcitability, similar to claim 1 above, the specification provides only a method of increasing long term memory (LTM) comprising targeted microinjection of an rAAV8 comprising a Cre-dependent hM4Di into the AD thalamus (See FIG. 6D) of PTCHD1 knockdown mice followed by administration of a “low dose” of Compound 21 (C21) which reduces AD thalamus hyperexcitability (FIG. 6E) and improves LTM performance defects caused by the PTCHD1 knockdown (FIG. 6H). It is noted that Applicant’s specification discloses that the reduction of AD hyperexcitability and improvement of LTM performance was not seen when a “regular” dose of C21 was administered (See FIGs. 6E-6H) and therefore only the low dose of C21 was used in subsequent testing. The specification provides use of this same protocol in YWHAG (FIGs. 7D-7F) and HERC1 (FIGs 7J) knockdown mice in order to reduce AD thalamus hyperexcitability and improve LTM performance deficits caused by the YWHAG and HERC1 knockdown (See Example 7). Although Applicant indicates in Example 7 (Pg. 52, 1st full para.) that improvements in spatial working memory were also seen in PTCHD1, YWHAG, and HERC1 knockdown mice upon reduction of AD hyperexcitability and references FIGS. 14K-14M, these FIGs have not been provided with the instant disclosure. The specification provides only examples using knockdown of PTCHD1 and YWHAG, genes associated with autism; and HERC1, a gene associated with schizophrenia, which the specification indicates are heavily expressed in the AD thalamus (See Example 1). The specification provides no guidance for reduction of cognitive impairment as it relates to LTM associated with other neuropsychiatric disorders, for example Parkinson’s disease, nor that AD hyperexcitability would be necessarily be present in any subjects having other neuropsychiatric disorders.
With regard to claims 3-6 encompassing a genus of neurons in which the genus of rAAVs encoding the genus of engineered M4 muscarinic acetylcholine receptors is to be expressed, the specification provides only examples of microinjection of an rAAV8 comprising an hM4Di to neurons of the AD thalamus, which project to the RSC, and in which the AD thalamus to RSC projections play a role in LTM.
With regard to claims 7-8-encompassing a genus of subjects to which the rAAV is administered, as detailed above, the instantly specification only provides examples using knockdown of PTCHD1 and YWHAG, which are genes associated with autism; and HERC1, which is a gene associated with schizophrenia.
With regard to claims 9 and 13 encompassing a genus of agents which are to be administered to the subject, the specification provides guidance only for administration of C21 and that a “low dose” of C21 (See Pg. 69, 1st full para.) is required for improvements in LTM (See Example 7, FIGs. 6D-6H, 7D-7F, and 7J). Furthermore, Applicant specification indicates that the engineered M4 muscarinic acetylcholine receptors such as hM4Di do not inhibit hyperexcitability in the absence of ligand (p. 40, last two para.)
With regard to claim 10 encompassing a genus of methods for increasing cognitive performance comprising administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability, as detailed above, the specification only provides guidance for use of an rAAV8 encoding an hM4Di polypeptide administered via microinjection to the AD thalamus and subsequent administration of a low dose of C21 in order to reduce AD thalamus hyperexcitability and improve deficits in LTM caused by knockdown of PTCHD1, YWHAG, and HERC1. As detailed above in the claim interpretation section, Applicant has claimed use of a promoter which is expressed only in neurons of the AD thalamus, neurons of the AV thalamus, neurons of the entorhinal cortex, neurons in the AD thalamus to RSC projection pathway, or neurons in the AV thalamus to RSC pathway. However, Applicant’s instant disclosure indicates that the AAV8 encoding an hM4Di polypeptide comprises a human synapsin-1 promoter (See FIGs. 6D and 7D and Pg. 57, last para.), which is essentially a pan-neuronal promoter.
With regard to claim 11 encompassing a genus of methods for reducing cognitive impairment associated with a neuropsychiatric disorder administration to a subject a genus of recombinant adeno-associated viruses (rAAV) comprising a genus of promoters expressed in a neuron selected from the group consisting of neurons of the AD thalamus, anteroventral (AV) thalamus, entorhinal cortex, neurons present in the AD thalamus projection to the retrosplenial cortex pathway, and neurons present in the AV thalamus projection to the RSC pathway, wherein the promoter is operably linked to a polynucleotide encoding an hM4Di polypeptide such that the hM4Di polypeptide expression inhibits AD thalamus hyperexcitability, as detailed above, the specification only provides guidance for use of an rAAV8 encoding an hM4Di polypeptide administered via microinjection to the AD thalamus and subsequent administration of a low dose of C21 in order to reduce AD thalamus hyperexcitability and improve deficits in LTM caused by knockdown of PTCHD1, YWHAG, and HERC1 which are genes associated with autism and schizophrenia (Example 1). As detailed above in the claim interpretation section, Applicant has claimed use of a promoter which is expressed only in neurons of the AD thalamus, neurons of the AV thalamus, neurons of the entorhinal cortex, neurons in the AD thalamus to RSC projection pathway, or neurons in the AV thalamus to RSC pathway. However, Applicant’s instant disclosure indicates that the AAV8 encoding an hM4Di polypeptide comprises a human synapsin-1 promoter (See FIGs. 6D and 7D and Pg. 57, last para.), which is essentially a pan-neuronal promoter.
With regard to claim 12 encompassing a genus of rAAVs which comprise a polynucleotide encoding a Cre-dependent DREADD hM2Di, the specification only provides guidance for use of an rAAV8 comprising a sequence encoding a Cre-dependent DREADD hM4Di (See FIGs. 6D, 7D).
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of practicing the claimed invention is not well established. Although the role of acetylcholine receptors in memory and targeting of muscarinic acetylcholine receptors, including M4 receptors, for the treatment of neuropsychiatric disorders such as schizophrenia and use of targeted delivery of engineered DREADD hM4Di receptors coupled with ligand administration in order to selectively inhibit certain neurons is also known in the art, one of skill in the art would neither expect nor predict a successful outcome to increase any cognitive performance or reduce any cognitive impairments associated with any neuropsychiatric disorder in any subject by administration of any rAAV comprising an engineered M4 muscarinic acetylcholine receptor and expressing the receptor in neurons that inhibit AD thalamus hyperexcitability.
As an initial matter, the contemporaneous art of Roy et al. (2021, Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models. Neuron, 109(16), 2590-2603)
discloses that deletion of PTCHD1 from the thalamic reticular nucleus does not cause memory deficits (Pg. 3, 1st para.) and references Wells et al. (2016, Thalamic reticular impairment underlies attention deficit in Ptchd1 Y/− mice. Nature, 532(7597), 58-63.) which discloses that PACHD1 is mutated in about 1% of patients with autism and intellectual disability (Pg. 58, left col., 2nd para.) and Ptchd1 knockout mice show no performance deficits in spatial learning, but show deficits in both contextual and cued-fear conditioning (Pg. 61, left col., last para.). It is noted that the results of Wells et al., in a Ptchd1 knockout model, differ from those as instantly disclosed where localized knockdown of PTCHD1 in the AD thalamus was associated with deficits in spatial memory (FIG. 1J) but not tone fear conditioning (Pg. 53, last para.) so it appears that the specific location of PTCHD1 knockdown influences the phenotype of cognitive deficit. Roy et al. discloses that the AD thalamus is “understudied” (Pg. 3, 2nd para.) and that the role of the AD thalamus in memory is unclear (Pg. 3, 3rd para.), and that the localized expression of certain autism and schizophrenia genes in the AD thalamus indicates that it may be implicated in dysfunction in a subset of disorders (Pg. 4, 1st para.). Further, Roy et al. discloses that although AD thalamus specific knockdown of several genes highly expressed in the AD thalamus and associated with autism and schizophrenia resulted in memory deficits (Pg. 3, 1st para.), memory deficits were not seen when those same genes were knocked down in the hippocampus (Pg. 3, 2nd para.) and also that the AD thalamus is specifically implicated in cognitive tasks related to LTM (Pg. 10, 3rd para.). Thus, the prior art of Wells et al. and the contemporaneous art of Roy et al. indicate that, at the time of filing, the specific subject population and the specific cognitive defects which might be able to be treated by expressing an engineered M4 muscarinic acetylcholine receptor in neurons that inhibit AD thalamus hyperexcitability were not well characterized and a skilled artisan could not have looked to the state of the art in order to appropriately predict which subjects or which cognitive deficits could be treated.
Regarding the specific engineered M4 muscarinic acetylcholine receptor, Applicant’s instant specification provides guidance for use of an inhibitory DREADD hM4Di receptor, which are known in the art. However, Applicant’s instant claims do not recite use of a specific ligand at a specific dose and Applicant’s instant disclosure indicates that the improvements in LTM in animals with AD thalamus specific knockdown of PTCHD1, YWHAG, and HERC1 were only seen after administration of C21 at a “low” dose (FIGS. 6E, 6H, 7E, 7F, 7J) which is defined in the specification as 0.6 mg/kg (Pg. 69, 1st full para.). The prior art of Goutaudier et al. (2020, Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats. Plos one, 15(9), e0238156) discloses that in a method of modulating dopaminergic neurons using a DREADD hM4Di, off target effects of the dose of C21 differed between male and female rats, with female animals being more susceptible to off-target effects of low doses (i.e., 0.5 mg/kg) than males (Abstract and Discussion Pg. 8, 2nd para.). Goutaudier et al. discloses that the ligand used is also important as another DREADD hM4Di ligand, CNO, is known to produce off-target behavioral effects which limits their use as specific DREADD ligands (Pg. 2, 1st para.). Goutaudier et al. further discloses that C21 may also have affinity for serotonergic and histaminergic receptors in addition to hM4Di (Discussion Pg. 8, 2nd para.). Thus, given the unpredictability surrounding the specific ligand for the hM4Di receptor and the specific dose of C21 which could be used to produce the claimed cognitive improvements, a skilled artisan would not have known, from the prior art, which dose of C21 to use nor which DREADD hM4Di ligand could be used in the instantly claimed method.
Regarding the specific AAV construct comprising the hM4Di receptor, Applicant’s instant specification discloses a single AAV construct, AAV8-hSyn-DIO-hM4Di-mCitrine, administered via targeted microinjection directly to the AD thalamus in order to improve AD thalamus hyperexcitability and LTM deficits following AD thalamus specific knockdown of PTCHD1, YWHAG, or HERC1. Applicant’s instant claims 10 and 11 recite use of a promoter which specifically targets only a particular neuronal subset. Although AAV serotypes are well known and well characterized in the art, the choice of AAV serotype is important for delivery to the central nervous system as well as specific areas of the brain. The prior art of Manfredsson et al. (2009, AAV9: a potential blood-brain barrier buster. Molecular Therapy, 17(3), 403-405) discloses that the blood brain barrier blocks rAAV delivery to the central nervous system when systemically administered which results in the need to use localized injections to targeted brain areas (Pg. 403, left col., 1st para.). Manfredsson et al. discloses that localized delivery is advantageous for gene therapy in neuropathology which is localized to a specific region (Pg. 403, left col., 1st para.) and that transduction of any specific rAAV is dependent on not only the local receptor population (Pg. 403, right col., 2nd para.) but also the species which is being targeted (Pgs. 403-404, bridging para., see also Table 1). Therefore, as the specific pathway which is to be targeted for the instantly claimed cognitive effects is not well characterized in the existing art, a skilled artisan would likewise not be able to appropriately determine which rAAV to use to ensure appropriate targeting to neurons which inhibit AD thalamus hyperexcitability and would understand that selection of the rAAV would depend on the route of administration, area to be targeted, and species.
Further, the viral construct used in Applicant’s disclosure contains a hSyn promoter, which is known to be pan-neuronal. Although Applicant claims use of a promoter which is specific for only a subset of neurons, the art is silent as to a promoter which is specifically able to target only neurons of the AD thalamus, AV thalamus, entorhinal cortex, neurons in the AD thalamus to RSC pathway, or neurons in the AV thalamus to RSC pathway and these promoters are not described in the instant disclosure, therefore a skilled artisan would not be able to determine based on the state of the art which promoter could be used to directly target only the claimed neuronal populations.
Since the prior art at the effective filing date of the present application did not provide guidance for improvement of any cognitive performance or reduction of any cognitive impairment associated with any neuropsychiatric disorder in any subject by administrating any rAAV encoding any engineered M4 muscarinic acetylcholine receptor via any route of administration and expressing the receptor in any neuronal population that inhibits AD thalamus hyperexcitability, it is incumbent upon the instant specification to do so.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that success of said method is prone to influence by multiple factors, and is highly unpredictable with respect to increasing any type of cognitive performance and/or reducing any type of cognitive impairment associated with any neuropsychiatric disorder via administration of an rAAV comprising an engineered M4 muscarinic acetylcholine receptor which is expressed in neurons which inhibit AD thalamus hyperexcitability, and the specification does not provide ample guidance with respect to achieving the unexpected results, one would be burdened with undue experimentation to use the claimed invention in order to increase any cognitive performance and/or reduce cognitive impairment associated with any neuropsychiatric disorder via the instantly claimed methods. Given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to make and use the invention beyond the scope of improvements in LTM in subjects having reduced AD thalamus expression of PTCHD1, YWHAG, and HERC1 via a method comprising targeted microinjection to the AD thalamus of an rAAV8 comprising a human synapsin-1 promoter and sequence encoding a DREADD hM4Di and subsequent administration of a “low” dose of C21.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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