CTNF 18/517,417 CTNF 98213 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION Claim Status The claims filed November 22, 2023 have been received and entered. Claims 1-20 are currently pending and under consideration. Priority Applicant’s claim for the 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) is acknowledged. This application claims priority to U.S. Provisional Application 63/427,309 filed November 22, 2022. Information Disclosure Statement 06-49-06 AIA 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. Claim Objections 07-29-01 AIA Claim s 1-2, 12, 16-17 and 20 are objected to because of the following informalities: Claims 1-2 - the RIMS protein name “regulating synaptic membrane exocytosis protein” should not be capitalized. Claim 12 - should read “adeno - associated”. Claim 12 - delete “vector” after lentivirus. Claim 16 (line 6) - should read across the “blood-brain barrier (BBB)” as this is the first use of the term “BBB”. Claim 17 - delete the term “blood-brain barrier (BBB)” so claim reads “across the BBB”. Claim 20 - should read “administration” . Appropriate correction is required. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. Claims 4-5, -, and 16 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Claim 4 recites the zinc finger domain of the fusion protein comprises a sequence selected from 1-4 and 38-41. However, the instant specification discloses that the recited sequences correspond to full-length human and rat RIMS1 and RIMS2 amino acid and nucleotide sequences as shown below. SEQ ID NO: 1 - human RIMS1 protein sequence SEQ ID NO: 2 - human RIMS2 protein sequence SEQ ID NO: 3 - human RIMS1 nucleic acid sequence SEQ ID NO: 4 - human RIMS2 nucleic acid sequence SEQ ID NO: 40 - rat RIMS1 protein sequences SEQ ID NO: 41 - rat RIMS2 protein sequence SEQ ID NO: 38 - rat RIMS1 nucleic acid sequence SEQ ID NO: 39 - rat RIMS2 nucleic acid sequence Although the instant specification underlines the amino acid residues comprising the zinc finger domain in SEQ ID NOs 1 and 2, the claim language recites the zinc finger “ comprises ” the recited sequences, which indicates that the entire sequence is incorporated into the fusion protein construct. As such, one of ordinary skill in the art would not know what amino acid residues or nucleotides comprise the recited zinc finger domain from the recited full length sequences. Claims 4-5 are drawn to the first domain and the second domain, respectively, however, the claims depend from claim 1 which does not refer to different domains. To overcome the rejection, the claims should be amended to read “ a first domain” and “ a second domain”. Claim 9 is drawn to a promoter that is operatively linked to the nucleic acid . However, the claim depends from claim 7, which does not provide antecedent basis for this limitation. The claim should be amended to depend from claim 6, which refers to the nucleic acid. Claim 16 recites “the formulation of the pharmaceutical composition”, however there is no antecedent basis for “the formulation” in the claims”. The claim should be amended to read “…wherein the pharmaceutical composition comprises the formulation selected from the group consisting of…”. Appropriate correction is required. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-15 AIA Claim s 1-3, 6-14, and 18-19 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Tan et al. ( Neuron , 2022; 110:1498-1515) (“Tan”) . The instant claims are drawn to a fusion protein comprising a zinc-finger domain (ZNF) of regulating synaptic membrane exocytosis protein (RIMS) and a Cav b Ca 2+ channel subunit, wherein the RIMS is RIMS1 or RIMS2 selected from SEQ ID NOs: 1-4 and 38-41 and the Cav b Ca 2+ channel subunit is Cav b 1, Cav b 2, Cav b 3, or Cav b 4 selected from SEQ ID NOs: 5-8 and 42-47. Also claimed is a synthetic nucleic acid encoding the fusion protein of claim 1, a lentivirus vector encoding the fusion protein, wherein the vector is a DNA or RNA nucleic acid vector comprising a nervous tissue-specific promoter that is operatively linked to the nucleic acid, and a neuronal cell comprising said fusion protein. The recited fusion protein is for use in a method of repairing or enhancing synaptic function in a subject or treating a neurological or secretory disorder in a subject. Tan discloses fusion proteins of the RIM zinc finger domain with Cav b Ca +2 channel subunits ( instant claim 1 ). Tan selected the RIM1 zinc finger fused to Cav b 4 for characterization studies ( b 4-Zn protein), finding b 4-Zn recruits Munc13-1 to the target membrane and mediates vesicle docking close to Ca +2 channels for recovery of extent and temporal precision of release ( instant claims 2-3 ). Tan explains the fusion protein targets the priming complex of the RIM zinc finger and Munc13 to Ca +2 channels [pg. 1507]. Tan discloses the zinc finger fusion protein cDNA constructs were subcloned into a lentiviral vector and expression was driven by a synapsin promoter that restricts expression to neurons ( instant claims 6-11 ). The fusion protein comprises the zinc finger domain of human RIM1 and a rat derived Cav b subunit. Neurons were transduced with the subsequent lentiviral vectors [Method Details, pg. e4] ( instant claims 13-14 ). Tan further discloses the small Cav b 4-RIM zinc finger fusion is only 80 kDa, which allows it to be packaged in an adeno-associated virus (AAV) for use in treating brain disorders by restoring neurotransmitter secretion [pg. 1513] ( instant claims 12, 18-19 ). In addition, the zinc finger fusion protein construct taught by Tan (Figure S5A below) is the exact same zinc finger fusion protein construct depicted in the disclosure (Figure 13A). PNG media_image1.png 124 724 media_image1.png Greyscale Therefore, absent a showing of any difference, the zinc finger fusion protein fusion disclosed by the prior art is deemed to anticipate the claimed product . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-20-aia AIA 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. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-21-aia AIA Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. ( Neuron , 2022; 110:1498-1515) (“Tan”) as applied to claims 1-3, 6-14, and 18-19 above . Claim 5 recites the Cav b Ca 2+ channel subunit domain of the fusion protein comprises a sequence selected from 5-8 and 42-47. The instant specification discloses that the recited sequences correspond to Cav b subunits amino acid and nucleotide sequences as shown below. SEQ ID NO: 5 - human Cav b 4 protein sequence SEQ ID NO: 6 - human Cav b 3 protein sequence SEQ ID NO: 7 - human Cav b 2 protein sequence SEQ ID NO: 8 - human Cav b 1 protein sequence SEQ ID NO: 42 - mouse Cav b 4 nucleotide sequence SEQ ID NO: 43 - modified mouse Cav b 4 nucleotide sequence SEQ ID NO: 44 - modified human Cav b 1 nucleotide sequence SEQ ID NO: 45 - mouse Cav b 4 protein sequence SEQ ID NO: 46 - modified mouse Cav b 4 protein sequence SEQ ID NO: 47 - modified human Cav b 1 protein sequence Tan teaches the fusion protein comprises the zinc finger domain of human RIM1 and a rat derived Cav b subunit, not a Cav b construct derived from a human or mouse sequence as recited in the instant claims. It would have been obvious to one of ordinary skill in the art to design a fusion protein based on a mouse Cav b sequence as rat and mouse genes share a high degree of homology. Accordingly, using a mouse Cav b sequence instead of a rat Cav b sequence is a simple substitution of one known element for another to obtain predictable results. KSR Int’l Co. v. Teleflex Inc. , 550 U.S. 398 (2007). Therefore, the invention as a whole was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention . 07-21-aia AIA Claim s 15-17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. ( Neuron , 2022; 110:1498-1515) (“Tan”) as applied to claims 1-3, 6-14, and 18-19 above, and in further view of Dimidschstein et al. (US 2022/0195457) (“Dimidschstein”) . The instant claims are drawn to a pharmaceutical composition comprising a fusion protein comprising a zinc-finger domain (ZNF) of regulating synaptic membrane exocytosis protein (RIMS) and a Cav b Ca 2+ channel subunit, wherein the formulation of the pharmaceutical composition is as a nanoparticle or as a liposome, wherein the pharmaceutical composition is formulated for delivery to the brain via intracranial injection. The teachings of Tan are set forth above, including the use of AAV viral vectors to deliver the fusion protein to the target on the neuronal membrane surface. Tan does not explicitly teach pharmaceutical compositions comprising the fusion protein or routes of administration. Dimidschstein teaches pharmaceutical compositions or formulations for treating subjects who are afflicted with, or who are at risk of developing, a neurological or neurogenetic disease, disorder , or pathology comprising a recombinant adeno-associated virus (rAAV) ( instant claim 15 ) [0253]. The therapeutic agent is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the agent in a controlled manner, such as nanoparticles or liposomes [0256]. Dimidschstein teaches routes of administration include for the pharmaceutical composition including intracranial administration by injection, that optimally provide continuous, sustained levels of the agent in the patient [0258]. For direct delivery to the brain , rAAV vectors are administered by focal injection in order to bypass the blood-brain barrier , to temporally and spatially restrict transgene expression, and to target specific areas of the brain, e.g., interneuron cells and brain tissue comprising these cells [0246]. The teachings of Tan differ from the present invention in that although a fusion protein comprising a RIMS1 zinc finger domain and a Cav b Ca 2+ channel subunit delivered in a lentiviral vector targeting neuronal membranes that restores synaptic activity as a treatment for a neurological disorder is taught, the method does not explicitly teach a pharmaceutical composition comprising the fusion protein or that the lentiviral vector can be delivered in a manner to bypass the blood-brain barrier BBB. Given that Dimidschstein teaches methods of treating neurological disorder by administering a formulation comprising rAAV carrying therapeutic peptides that can be delivered directly to the brain to bypass the BBB via intracranial injection, the skilled artisan would have a reasonable expectation of success in delivering the Cav b 4-RIM zinc finger fusion taught by Tan in the same manner because Tan teaches that the small 80 kDa fusion protein allows it to be packaged in an adeno-associated virus (AAV) for use in treating brain disorders by restoring neurotransmitter secretion. Therefore it would have been obvious to one of ordinary skill in the art to administer the fusion protein in an rAAV directly to the brain via intracranial injection in order to bypass the BBB and directly target neuronal cells. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300. 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If you would like assistance from a USPTO Customer Service Representative, call (800) 786-9199 (IN USA OR CANADA) or (571) 272-1000. /MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642 /SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642 Application/Control Number: 18/517,417 Page 2 Art Unit: 1642 Application/Control Number: 18/517,417 Page 3 Art Unit: 1642 Application/Control Number: 18/517,417 Page 4 Art Unit: 1642
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