DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on September 18, 2025 have been received and entered. Claims 1 and 38 have been amended, while claims 2-11, 13, 22-24 and 28-37 have been canceled.
Claims 1, 12, 14-21, 25, 27 and 38 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 22-25, 38 (group IV) in the reply filed on May 30, 2025 was acknowledged. Claims 1, 7 14-17 link the invention of groups I-IV. Examiner further acknowledge the revised group corresponding to the four group and linking claim is as follows: Group I, claim(s) 8-9, 12, 18-21, 27; Group II, claim(s) 18-21, 27; Group III, claim(s) 22- 25, 38; Group IV, claim(s) 22-25, 38; and Linking claims, 1, 7, and 14-17.
Claims 8, 12, 18-21, 26, 27 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 30, 2025.
Priority
This application is a 371 of PCT/US20/46976 filed on 08/19/2020, which claims priority from US provisional application no 62/889,111 filed on 08/20/2019.
Claims 1, 14-17, 25 and 38 are under consideration.
Maintained-Claim Rejections - 35 USC § 112-in modified form
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, 14-17 and 25 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
A method for replenish Atp23 level in CA2 area of the hippocampus of a subject, said method comprising directly injecting into the CA2 area of the hippocampus of the subject a therapeutically effective amount of an adeno-associated viral vector comprising a nucleic acid encoding Atp23 consisting of the amino acid sequence of SEQ ID NO: 2, wherein the nucleic acid is operably linked to a neuron specific promoter and wherein said injection replenishes Atp23 level in the interneuron of CA2 area of the hippocampus of the subject,
does not reasonably provide enablement for using (i) delivering the vector via any other route and (iv) treating any social memory deficit in a subject with a neuropsychiatric disease that comprises 22q11 deletion syndrome. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Response to arguments
Applicant disagree with the rejection arguing a skilled artisan can replace CamKII alpha promoter to any other promoter and the administration by injection with other methods, e.g., transcranial surgical injection or internasal administration, without undue experimentation, as claim 1 now requires that the vector is administered to the CA2 area of the hippocampus of the subject. Paragraphs [0079]-[0083] provide a detailed description of each administration method. Hence, a skilled artisan, combining the teachings in paragraphs [0079]-[0083] with the common knowledge in the field, can achieve administration of the vector to the recited area of the hippocampus. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to Applicant’s argument, it should be noted that previous office action explicitly stated that claims are not enabling for (i) delivering the vector via any other route and (iv) treating any social memory deficit in a subject with a neuropsychiatric disease that comprises 22q11 deletion syndrome as broadly claimed.
In the instant case, claims broadly encompasses AAV of any serotype administered to the CA2 area of the hippocampus of the subject. The specification contemplated administering AAV to the CA2 area of the hippocampus by direct injection to CA2, intranasal, central, peripheral , intrathecal or intracranial , implant or epidural administration (see page 21, para. 4 and 5 of the specification). The AAV vector may have a capsid from any serotype including one selected from AAV1, AAV2, AAV5, AAV8, or AAV9 (see page 20, para. 3). It is further relevant to note that claims as such do not even require expression of Atp23 in any part of CNS or in CA2 area of the hippocampus of a subject to replenish any deficiency of Atp23. The claims continue to read on delivering AAV of any serotype comprising a nucleic acid encoding any Atp23 via any route that includes subcutaneous, intradermal, intramuscular, intranasal, peripheral to make and use the invention. The guidance provided in the specification is limited to direct injection of AAVs expressing Atp23 fused under control of pan- GABAergic interneuron promoter into the CA2 area. The previous office action indicated that claims are enabled for a direct injection of AAV encoding Atp23 under control of neuron specific promoter into the CA2 region of the hippocampus that replenish Atp23 levels. To achieve a therapeutic concentration of administered gene in the CNS, the gene delivery system must be administered at a very high dose. It is known that high amounts of a gene delivery vector in the blood stream, however, it is known to initiate an immune or cytotoxic response (page 3, last para. Puhl et al Brain Res Bull. 2019 150: 216–230). In the instant case, neither specification nor prior art provided adequate guidance of delivering AAV of any serotype via any parenteral or any other route that includes subcutaneous, intradermal, intramuscular. While it is known in prior art that intravenous injection of AAV9 crosses the BBB, however, AAV2/9 systemic distribution also makes it challenging to be specifically contained expression in a small, critical area like the CA2 region in a without potential off-target effects or overexpression in other tissues. There is no evidence on record that intravenous injection or intradermal or intramuscular injection of AAV of any serotype enables the method as claimed. Shevtsova et al (Exp Physiol. 90.1, 53-59 2005) emphasized that selecting a right vector with an appropriate combination of promoters and serotypes remains an important issue to consider for any gene therapy (pp 58, col. 1, para. 2). Barkats et al (USPGPUB 20100240739, dated 09/23/2010) discloses unpredictability in targeting cells of CNS using conventional viral vectors as they do not pass blood brain barrier. It is further disclosed that gene transfer strategies via intrathecal delivery or direct injections of the vectors into the spinal cord parenchyma also failed to produce efficient widespread CNS transduction (see para. 3). Maguaire et al (Neurotherapeutics (2014) 11:817–839) report challenges for treating CNS disease involves (i) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier (abstract). Maguaire et al continue to teach that “locale at which a delivery vehicle is administered greatly impacts its ability to transfer its genetic payload to the CNS. Due to the constraints imposed by the blood-brain barrier (BBB), the most common delivery route is direct injection into the target region in the brain, which bypasses this barrier” (see page 818, col. 1, para. 2) (emphasis added). One of ordinary skill in the art would have to perform undue experimentation to first characterize of AAV of different serotype from different species with respect to testing their ability to infect neurons in the CA2 region of the hippocampus such that therapeutic protein in expressed in these cells at a therapeutic level in predictable animal model of treating a social memory deficit in a subject with a neuropsychiatric disease comprising 22q1 deletion syndrome in a subject, to make use of the invention without a reasonable expectation of success.
In response to applicants’ argument that one of ordinary skill in the art would have used any of other known route to deliver the AAV to the CA2 region of CNS, it should be noted that prior art teaches that the transduction of target cells represents the first critical step in any gene delivery, which not only depends upon the type of target cells but also on the choice and/or characteristics of delivery vectors. In addition, besides the limitations in gene transfer the problem to selectively target cells (CA2 region) in vivo is still one of the most difficult obstacles to overcome (as discussed before, supra). For example, upon systemic administration the viral particle may bind to many cells they encounter in vivo and therefore would be diluted before reaching their targets. The claims merely require administering the AAV to the CA2 region of a subject without providing any specifics or showing that any routes of administration would result in expression in target cells other than direct injection into CA2 region of the hippocampus. For instance, Hsich et al. (Hum. Gene Ther. 13: 579-604, art of record) discloses the difficulty in gene delivery to the CNS that is overcome by direct intraparenchymal injections (see page 586, col. 1, para. 2). The specification fails to provide an enabling disclosure for the claimed invention because the specification fails to provide sufficient guidance as to how an artisan of skill would have practiced the claimed method in any subject by administering AAV vector to CA2 region via any route to treat a social memory deficit comprising C22q11 deletion in a subject with a neuropsychiatric disease. In reviewing the above-discussed problem, it is evident that the artisan would require making and/or using a new invention in the field. A showing that enough of transgenes reach the target cell in the CA2 region by introducing a nucleic acid encoding Atp23, enough nucleic acid is incorporated into neuronal cells from, that such nucleic acid is properly incorporated into such cells as DNA, enough mRNA is produced therefrom, and enough make protein is produced to treat a social memory deficit in a subject with a neuropsychiatric disease as broadly encompassed by the claims.
In response to applicant’s argument that claims have been amended to limit the scope to a social memory deficit in a subject with a neuropsychiatric disease comprising 22q11 deletion syndrome, it should be noted that instant specification discloses that the 22q11.2 deletion syndrome (22q11DS) is associated with high risk of developing schizophrenia symptoms, including psychosis. The specification broadly defines the term “schizophrenia” (see page 12 of the specification) and symptoms of schizophrenia may appear in a range of related disorders including classical schizophrenia as well as dementia, bipolar disorder, obsessive compulsive disorder (OCD), panic disorder, phobias, acute stress disorder, adjustment disorder, agoraphobia without history of panic disorder, alcohol dependence (alcoholism), amphetamine dependence, brief psychotic disorder, cannabis dependence, cocaine dependence, cyclothymic disorder, delirium, delusional disorder, dysthymic disorder, generalized anxiety disorder, hallucinogen dependence, major depressive disorder, nicotine dependence, opioid dependence, paranoid personality disorder, Parkinson's disease, schizoaffective disorder, schizoid personality disorder, schizophreniform disorder, schizotypal personality disorder, sedative dependence, shared psychotic disorder, smoking dependence and social phobia (see page 12 of the specification).
As stated in previous office action, the specification lacks to establish nexus between cellular pathology associated with plurality of social memory deficit in a subject with a neuropsychiatric disease comprising 22q11 deletion in a mammal and therapeutic Atp23 level in any cells of CNS for the treatment of said social memory deficit in a subject with genu of neuropsychiatric disease comprising 22q11 deletion. The specification does not provide any guidance on the resulting outcome in different species of rodent, mammal and/or gender. It is emphasized that neuropsychiatric disease could be have aggregate of symptoms and signs associated with any other process and constituting together the picture of the disease. In the instant case, the specification only teaches injecting AAV encoding Atp23 directly into CA region of CNS. Prior to instant invention, Weitzer et al (J. Vis. Exp. 2015, (100), e52706, 1-11) reported that the Morris water maze (MWM) is a commonly used task to assess hippocampal-dependent spatial learning and memory in transgenic mouse models of disease. However, the background strain of the mouse model used can have a substantial effect on the observed behavioral phenotype, with some strains exhibiting superior learning ability relative to others (abstract). For example, BALB/c mice exhibit superior performance in learning and memory tasks compared to other strains, such as the C57BU6 (see page 1, last para.). Bernstein et al (Physiol Behav. 2024 Sep 1:283:114595, 1-10) in a post filing art reported sex differences in performance on the learning and reversal procedure raise concern for interpretation of behavior differences between sexes due to the attribution of these differences to motor activity rather than cognition (see abstract). Moy et al (Behavioral Brain Research 191 (2008) 118–129) who reported Inbred strain distributions using social choice tasks have shown that levels of social approach and preference are dependent upon genetic background, with some strains (AKR/J, C57BL/6J, C3H/HeJ, FVB/NJ) demonstrating high affiliation, and other strains (A/J, BALB/c, BALB/cByJ, BTBR T + tf/J, 129S1/SvImJ) having low preference or even avoidance (see page 119, col. 1, para. 1). Nestler and Hyman (Nat Neurosci. 2010; 13(10): 1161–1169) while reviewing animal model of neuropsychiatric disorder states “many of the symptoms used to establish psychiatric diagnoses in humans (e.g., hallucinations, delusions, sadness, guilt) cannot be convincingly ascertained in animals. When there are reasonable correlates in animals, (eg., abnormal social behavior, motivation, working memory, emotion, and executive function), the correspondence may only be approximate. A further complication is determining how symptoms in an animal add up to a recognized human disorder, a seemingly critical issue if the animal is to be used for the development of therapeutics. For the vast majority of pathological states contained within the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IVTR)6 , knowledge of pathophysiology remains scant, and objective diagnostic tests lacking. Consequently, diagnoses are based solely on phenomenology, i.e., on symptoms, signs, and course of illness (Box 1). As a result, the boundaries between DSM-IVTR disorders, and the boundaries between disorder and normal variation, are often arbitrary or hazy. This state of affairs creates enormous hurdles for the development and validation of animal models (see box 1, 2 and page 2). Therefore, because an artisan does not know any known relationship of plurality of different symptoms that could be extrapolated to different neuropsychiatric disease comprising 22q11 deletion in a mammal, an artisan would not know how to treat a social memory deficit in a subject with a plurality of neuropsychiatric disease comprising 22q11 deletion embraced by the breadth of the claim. Furthermore, for an artisan to use or make the instant method for its intended use an artisan would have to determine the specificity of the functional phenotype and if there are any disease or specific conditions associated with this animal model. It is apparent that art suggested strain, gender and breeding specific alteration in neurobehavioral traits. (Emphasis added). It is clear that the effect on behavioral phenotype seen after overexpression of Atp23 in a C57BL/6 and the phenotype could not be generally extrapolated to any other gender, strain or genetic background. An artisan would have to carry out extensive experimentation to make and use the invention, and such experimentation would have been undue because art of the autism associated cognitive dysfunction in a mammalian model was not routine rather it was unpredictable and specification fails to provide any guidance as to how the claimed mouse and method would have been practiced to achieve a specific phenotype correlating as contemplated in the instant application.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments are not compelling and do not overcome the rejection of record.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 1, 7, 14-17, 22-24 and 38 were 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. Applicant’s amendment to the claims 1 obviates the basis of the rejection. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 102
Claim 38 was rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Yue et al (WO2001/10903, dated 02/15/2001). In view of Applicants’ amendment of base claim 38, introducing the limitation “wherein the vector is an AAV vector”, the previous rejections of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below:
Claim 38 was rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Weckbecker et al (EMBO J, 2012 Vol. 31, Pgs. 4348-4358, IDS). In view of Applicants’ amendment of base claim 38, introducing the limitation “wherein the vector is an AAV vector”, the previous rejections of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below:
New Claim Rejections - 35 USC § 102- necessitated by amendments
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.
Claim 38 is rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Rosen et al (WO/2001/054474, dated 08/02/2001).
Claims are directed to a pharmaceutical composition comprising a vector encoding a protein encoded by said Atp23 gene and a pharmaceutically acceptable carrier or excipient and wherein the vector is an AAV vector.
Rosen teaches a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide comprising the amino acid sequence as set forth in SEQ IDN O: 647 that has 100% sequence identity to SEQ ID NO: 2 (atp23 protein) (see claim 11 and sequence search report), wherein the recombinant nucleic acid may be part of a an AAV vector and the composition may be generally comprises along with an active ingredient formulated with a pharmaceutically acceptable excipient (see para. 285, 293, 295, 302, 900). Accordingly, Rosen anticipates claim 38.
New-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Yue et al (WO2001/10903, dated 02/15/2001, art of record) in view of Bueler (Biol. Chem., 1999, 380, 613 -622).
Claims are directed to a pharmaceutical composition comprising a vector encoding a protein encoded by said Atp23 gene and a pharmaceutically acceptable carrier or excipient and wherein the vector is an AAV vector.
Yue teaches a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide consisting of amino acid sequence as set forth in SEQ IDN O: 8 that has 100% sequence identity to SEQ ID NO: 2 (atp23 protein) (see claim 1, 3, and 6 and sequence search report), wherein the recombinant nucleic acid may be part of a vector such as any viral vector including adenoviral vector and the composition may be generally comprises along with an active ingredient formulated with a pharmaceutically acceptable excipient. (see page 19, lines 34-35 to page 20, lines 1-2, page 28, line 29, page 29, line 17, and page 41, line 1). Yue differs from claimed invention by not disclosing viral vector is an AAV vector.
Bueler cure the deficiency by disclosing a defective nonpathogenic human AAV vector as gene delivery vector. It is disclosed that rAAV shows long-term gene expression in vivo with minimal immune response as compared to adenovirus vector (See abstract and page 617, col. 2, para. 1). It is further disclosed that these properties make AAV vector attractive for therapeutic application in animal model of human disease (see abstract, page 619, col. 1, para. 2).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the composition of Yue by substituting adenoviral vector with AAV as suggested Bueler, as instantly claimed, with a reasonable expectation of success, before the effective date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so prior art specifically recognized advantage of using rAAV over other viral vectors including adenovirus vector (see above) . Absent evidence of any unexpected results, one of skill in the art would have been expected to have a reasonable expectation of success in using rAAV over other viral vector because it was routine to substitute one vector over other to minimize immune response and exert long term expression of gene of interest in vivo . It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Conclusion
No claims 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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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632