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
Claims 1, 2, 5-8, 10, 11, 13, 15-24, 26-29, 35-36, 42, 44, 45, 47-48, 53-56, 60-62, and 64 are pending.
Applicant’s election without traverse of Group I, claim(s) 1, 2, 5-8, 10, 11, 13, 15-24, 26-29, drawn to a modified G-protein coupled receptor (GPCR) wherein the modified GPCR has: (i) a decreased responsiveness to an endogenous activating ligand, and (ii) a retained or enhanced responsiveness to an exogenous agonist; compared to a parent which is the native GPCR, in the reply filed on 06/24/2026 is acknowledged.
Claims 35-36, 42, 44, 45, 47-48, 53-56, 60-62, and 64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 06/24/2026.
Applicants have also elected from species Group A (exogenies agonist): diphenhydramine, from species Group B (GPCR): CHRM, from species Group C (amino acid sequence of the native parent GPCR): SEQ ID NO: 1, from species Group D (the specific amino acid modification sequence of the GPCR): Y113C+ A203G and S85V+ Y416F, and from species Group E (the nucleotide sequence of the native parent GPCR): SEQ ID NO: 36.
Claims 10-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Therefore, claims 1-2,5-8,13,15-24 and 26-29 are under examination in the instant application.
Information Disclosure Statement
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.
Specification
The disclosure is objected to because of the following informalities:
The instant specification contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See for example line 40, page 6 and line 29, page 7 of the instant specification.
Appropriate correction is required.
Claim Objections
Claims 2, 19, 20, 21, and 23 are objected to because of the following informalities:
Claim 2 recites “an exogenous agonist selected from Table 1 or Table 2”. Claim 19 recites “the GPCR is selected from a GPCR identified in Table 3”. Claim 20 recites “native parent GPCR of any one of SEQ ID 1-35 of Table 8”. Claim 21 recites “the modified GPCR comprises a sequence shown in any one of Tables 3-6 comprising said modifications”. Claim 23 recites “native parent GPCR of any one of SEQ ID 36-70 of Table 8”.
Claims 2, 19, 20, 21, and 23 should be amended, such that they do not refer to tables and that the relevant limitations should be directly placed in the claims for clarity.
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.
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 21 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 21 recites “the modified GPCR comprises a sequence shown in any one of Tables 3-6 comprising said modifications”. The recitations of “Tables 3-6” introduces ambiguity and renders the claims indefinite since it refers to tables. Tables 3-6 on pages 50-52 of the instant specification are not clear and unreadable. It is unclear which modifications are actually being claimed. MPEP 2173.05(s) states “where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)”. Claim scope is not limited by claim language that suggests selecting a modified GPCR from Tables 3-6, and one of ordinary skill in the art would not be reasonably apprised of the scope of the claimed invention.
Claims 1, 2, 5-8, 10, 11, 13, 15-24, 26-29 are 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 1 recites “more preferably”. Claim 8 recites “most preferably”. Claim 16 recites “preferably”. The term “preferably” creates ambiguity and renders the claim indefinite because it is unclear whether the limitations after the term “preferably” are actually being claimed or are just being described as a better embodiment. Therefore, in the interest of compact prosecution, claims 1, 8, and 16 are interpreted as not being limited to the particular embodiments following “preferably”. Claims 2, 5-8, 10, 11, 13, 15-24, 26-29 that directly or indirectly depend from claim 1, are similarly rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, and 15-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Abdul-Ridha et al. (Abdul-Ridha et al., “Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor”. J Biol Chem. 2014 Feb 28;289(9):6067-79).
Regarding claim 1, Abdul-Ridha et al. discloses molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor (Title). Abdul-Ridha et al. specifically teaches Y3816.51A amino acid substitution at M1 muscarinic acetylcholine receptor (M1mAChRs) that is a G protein-coupled receptor (Page 6070, column 1, paragraph 2, Table 1, and Page 6067, column 2, paragraph 2). This reads on a modified G-protein coupled receptor (GPCR). Abdul-Ridha et al. discloses that the Tyr 381 residue is able to discriminate between different mAChR antagonists, such that the Y3816.51A amino acid substitution completely abolished [3H]NMS binding, although it showed unaltered affinity for [3H]QNB (Page 6070, column 1, paragraph 3). It further discloses that the most divergent effects include Y3816.51A in the orthosteric pocket, causing a marked decrease in CCh affinity but not that of [3H]QNB (Page 6071, column 1, paragraph 1 and Figure 2). This reads on that the modified GPCR has: (i) a decreased responsiveness to an endogenous activating ligand. The Tyr 381 residue in the M1mAChR corresponds to the Y416 residue in instant SEQ ID NO: 1 of the GPCR.
Regarding claim 2: Following discussion of claim 1 above, Abdul-Ridha et al. fails to specifically mention that the modified GPCR has a retained or enhanced responsiveness to an exogenous agonist, wherein the exogenous agonist is diphenhydramine.
However, Church et al. (Church et al. “Pharmacology of antihistamines”. Indian J Dermatol. 2013 May;58(3):219-24) provides evidence that diphenhydramine functions as an inverse agonist at histamine H1 receptors, a class of G-protein-coupled receptor, meaning it not only blocks histamine binding but also reduces the receptor's constitutive activity, shifting the receptor equilibrium toward the inactive state and inhibiting downstream signaling (Abstract, page 219, column 1, paragraph 2, and column 2, paragraph 1).
Therefore, having has a retained or enhanced responsiveness to diphenhydramine exogenous agonist by the modified GPCR is inherently and necessarily present in Abdul-Ridha et al. Accordingly, the mere recitation of its presence in the instant claims is not sufficient to distinguish the instant claims from prior art. “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997).
Regarding claim 15: Following discussion of claim 1 above, Abdul-Ridha et al. teaches that the GPCR is a Gi-coupled GPCR (Page 6070, column 1, paragraph 2, Table 1, and Page 6067, column 2, paragraph 2).
Regarding claim 16: Following discussion of claim 1 above, Abdul-Ridha et al. discloses in Figure 1 that the GPCR is coupled via a G-protein to an ion channel.
Regarding claim 17-19: Abdul-Ridha et al. teaches that the GPCR is cholinergic muscarinic receptor (CHRM1) (Page 6067, column 1, paragraph 1).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 2, 5-6, 15-19, 22, 24 and 26-29, is/are rejected under 35 U.S.C. 103 as being unpatentable over Abdul-Ridha et al. (Abdul-Ridha et al., “Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor”. J Biol Chem. 2014 Feb 28;289(9):6067-79), in view of Bowrey et al. (WO 2018/045178 Al, filed on 08/13/2017 and published on 03/08/2018).
Regarding claims 1, 2, and 15-19, the teachings of Abdul-Ridha et al. are set forth in detail above.
Regarding claims 5-6: Following discussion of claim 1 above, Abdul-Ridha et al. fails to teach that the modified GPCR comprises Y113C and A203G substitutions.
However, Bowrey et al. teaches DREADD, which is anengineered G-protein coupled receptor, a human muscarinic acetylcholine receptor M4 (page 31, lines 11-13, 20-25). Bowrey et al. further teaches that the DREADD is a human muscarinic acetylcholine receptor M4 comprising two mutations: a substitution at Y113 (e.g. Y113C) and a substitution at A203 (e.g. A203G) (page 31, lines 20-24). Bowrey et al. also teaches treating nervous system disease by administering an effective amount of a viral vector comprising a polynucleotide comprising a nucleic acid sequence encoding the engineered GPCR (DREADD) and at least one additional therapeutic agent for treatment of the neuropsychiatric disorder, such as diphenhydramine (claims 1, 7, 20, 21).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have created Y113C and A203G substitutions at the modified GPCR of Abdul-Ridha et al. with a reasonable expectation of success. One would have been motivated to have done so in order to have a retained or enhanced responsiveness to treat nervous system when combined with an exogenous agonist, such as diphenhydramine as taught by Bowrey et al.
Regarding claim 22: Following discussion of claim 1 above, Bowrey et al. teaches a polynucleotide comprising a nucleic acid sequence encoding the engineered GPCR (DREADD) (claims 1, 7, 20, 21, 26).
Regarding claim 24: Following discussion of claim 22 above, Bowrey et al. teaches an expression vector comprising the polynucleotide, wherein the vector is a viral vector (claims 1, 7, 13).
Regarding claim 26: Following discussion of claim 24 above, Bowrey et al. teaches that the vector is an adenovirus vector and/or an adeno-associated vector (AAV) (claim 13).
Regarding claim 27: Following discussion of claim 24 above, Bowrey et al. teaches that the vector is a herpes virus vector, a retrovirus vector, or a lentivirus vector (page 31, lines 3-5).
Regarding claim 28: Following discussion of claim 24 above, Bowrey et al. teaches that the nucleic acid encoding the engineered GPCR is operably linked to a cell specific promoter (claims 1, 7, 22).
Regarding claim 29: Following discussion of claim 28 above, Bowrey et al. teaches that the promoter is a neuronal cell type-specific promoter (page 41, Examples 5-6).
Claim(s) 1, 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abdul-Ridha et al. (Abdul-Ridha et al., “Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor”. J Biol Chem. 2014 Feb 28;289(9):6067-79), in view of Bowrey et al. (WO 2018/045178 Al, filed on 08/13/2017 and published on 03/08/2018), as applied to claim 1 above, and further in view of Gjoni et al. (US20130035256A1, filed on 04/20/2011, and published on 02/07/2013).
Regarding claim 1, the teachings of Abdul-Ridha et al. and Bowrey et al. are set forth in detail above.
Regarding claim 20: Following discussion of claim 1 above, Abdul-Ridha et al. fails to teach that the modified GPCR has at least 70% sequence identity with its native parent GPCR of instant SEQ ID NO: 1.
However, Gjoni et al. teaches a GPCR that has an amino acid sequencer of SEQ ID NO: 84 that is 100% identical to instant SEQ ID NO: 1 (please see below a screenshot of the query match).
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516
641
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Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the amino acid sequence of SEQ ID NO: 84 of the GPCR of Gjoni et al. as the use of Gjoni et al. represents nothing more than the substitution of one amino acid sequence for another
with predictable results.
Claim(s) 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abdul-Ridha et al. (Abdul-Ridha et al., “Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor”. J Biol Chem. 2014 Feb 28;289(9):6067-79), in view of Bowrey et al. (WO 2018/045178 Al, filed on 08/13/2017 and published on 03/08/2018), and Gjoni et al. (US20130035256A1, filed on 04/20/2011, and published on 02/07/2013), as applied to claims 1 and 20 above, and further in view of Alberts, et al. (Alberts, et al., "Molecular Biology of the Cell, Fifth Edition". New York:Garland Science, 2008. Pages 1-3 and 367).
Regarding claim 22, the teachings of Abdul-Ridha et al., Bowrey et al., and Gjoni et al. are set forth in detail above.
Regarding claim 23: Following discussion of claim 22 above, Abdul-Ridha et al. fails to teach that the nucleic acid has at least 70% sequence identity with its native parent GPCR of instant SEQ ID 36.
However, Alberts et al. teaches that the nucleotide sequence of a gene, through the intermediary of mRNA, is translated into the amino acid sequence of a protein by rules that are known as the genetic code (paragraph 3, page 367, lines 6-8).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the nucleic acid encoding the amino acid sequence of GPCR (SEQ ID NO: 84) as the selection of the sequence of these nucleotide sequences represents nothing more than choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
Allowable Subject Matter
Claims 7-8, 13, and 21 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Claims 7-8, 13 and 21 are considered free of prior art for the following reasons:
The closest prior art of record Abdul-Ridha et al. (Abdul-Ridha et al., “Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor”. J Biol Chem. 2014 Feb 28;289(9):6067-79) discloses molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor (Title). Abdul-Ridha et al. specifically teaches Y3816.51A amino acid substitution at M1 muscarinic acetylcholine receptor (M1mAChRs) that is a G protein-coupled receptor (Page 6070, column 1, paragraph 2, Table 1, and Page 6067, column 2, paragraph 2). Abdul-Ridha et al. discloses that the Tyr 381 residue is able to discriminate between different mAChR antagonists, such that the Y3816.51A amino acid substitution completely abolished [3H]NMS binding, although it showed unaltered affinity for [3H]QNB (Page 6070, column 1, paragraph 3). It further discloses that the most divergent effects include Y3816.51A in the orthosteric pocket, causing a marked decrease in CCh affinity but not that of [3H]QNB (Page 6071, column 1, paragraph 1 and Figure 2). The Tyr 381 residue in the M1mAChR corresponds to the Y416 residue in instant SEQ ID NO: 1 of the GPCR. However, Abdul-Ridha et al. fails to teach that the modified GPCR comprises Y113C+A203G+S85V+Y416F amino acid modifications.
Also, Bowrey et al. (WO 2018/045178 Al, filed on 08/13/2017 and published on 03/08/2018) teaches DREADD, which is an engineered G-protein coupled receptor, a human muscarinic acetylcholine receptor M4 (CHRM4) (page 31, lines 11-13, 20-25). Bowrey et al. further teaches that the DREADD is a human muscarinic acetylcholine receptor M4 comprising two mutations: a substitution at Y113 (e.g. Y113C) and a substitution at A203 (e.g. A203G) (page 31, lines 20-24). Bowrey et al. also teaches treating nervous system disease by administering an effective amount of a viral vector comprising a polynucleotide comprising a nucleic acid sequence encoding the engineered GPCR (DREADD) and at least one additional therapeutic agent for treatment of the neuropsychiatric disorder, such as diphenhydramine (claims 1, 7, 20, 21). However, Abdul-Ridha et al. fails to teach that the modified GPCR also comprises S85V+Y416F amino acid modifications.
Overall, the prior art fails to sufficiently teach or render obvious a modified G-protein coupled receptor (GPCR) wherein the modified GPCR has: (i) a decreased responsiveness to an endogenous activating ligand, and (ii) a retained or enhanced responsiveness to an exogenous agonist; compared to a parent which is the native GPCR, wherein the modified GPCR comprises Y113C+A203G+S85V+Y416F amino acid modifications as claimed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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