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 Group I, claims 1-10 and 12, as well as substance use disorder (claim 9), and methamphetamine and opioids (claim 10) as the species, in the reply filed on 08/11/2026 is acknowledged.
Priority
The instant application filed on 02/20/2024 is a 371 of PCT/US22/75391 filed on 08/24/2022 and claims priority to U.S. Provisional application 63/236,532 filed on 08/24/2021. PRO 63/236,532 finds support for the instant application; therefore, the effective filing date of the instantly claimed invention is 08/24/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/20/2024 and 07/23/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 2 is objected to because of the following informalities: “mutations selected from the group consisting of T284S, P285I, V288I, F398I” should instead read either “mutations selected from the group consisting of T284S, P285I, V288I, and F398I” or “mutations selected from the group consisting of T284S, P285I, V288I, or F398I”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b), Indefiniteness
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 1-10 and 12 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “mutations selected from the group consisting of A199S, F227A, T284S, P285I or P285A or P285Q or P285S, S287G, V288I, A328W, Y332G, and F398I”; however, it is unclear if certain combinations of mutations are required when there are 2-6 mutations, or if there are certain singular amino acid mutations are required when there is 1 mutation. This is unclear because “or” and “and” are both used between certain mutations, while some mutations have no linking phrase (i.e., “or” or “and”) between the mutations. For the purposes of applying prior art, the Examiner has interpreted the alternatives within this Markush group to mean that 1-6 of these mutations can be present within the BChE polypeptide variant, and that there is no specific combination of mutations when 2-6 are present in the BChE polypeptide variant.
Claim 3 recites “mutations selected from the group consisting of A199S, F227A, P285A or P285Q or P285S, S287G, A328W, and Y332G”; however, it is unclear if certain combinations of mutations are required when there are 2-6 mutations, or if there are certain singular amino acid mutations are required when there is 1 mutation. This is unclear because “or” and “and” are both used between certain mutations, while some mutations have no linking phrase (i.e., “or” or “and”) between the mutations. For the purposes of applying prior art, the Examiner has interpreted the alternatives within this Markush group to mean that 1-6 of these mutations can be present within the BChE polypeptide variant, and that there is no specific combination of mutations when 2-6 are present in the BChE polypeptide variant.
Claims 2, 4-10, and 12 are included in this rejection for depending on rejected independent claim 1 and failing to rectify the noted deficiency.
Claim Rejections - 35 USC § 102, Anticipation
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.
Claims 1, 3, 5, 8, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Geng (US 2017/0051261; Date of Publication: February 23, 2017).
Geng’s general disclosure relates to wildtype and mutant butyrylcholinesterases with enhanced ability to hydrolyze acyl ghrelin, as well as “methods for administering a nucleic acid encoding a wild-type or mutant butyrylcholinesterase having the ability to hydrolyze acyl ghrelin to a mammal under conditions wherein the level of acyl ghrelin within the mammal is reduced” (see, e.g., Geng, abstract).
Regarding claim 1 pertaining to a method of inactivating ghrelin, Geng teaches administration of mutant BChE (see, e.g., Geng, Example 3 & [0010]), wherein the mutant BChE has 100% sequence identity to Geng’s SEQ ID NO: 3 (see, e.g., Geng, Figure 2 & Office Action Appendix) and wherein the mutant comprises one or more of the following amino acid substitutions: A199S, F227A, S287G, A328W, F329M, or Y332G (see, e.g., Geng, [0009] & Examples 2-3). The Examiner has interpreted the limitations following the phrase “optionally” to not be required.
Regarding claim 3 pertaining to the BChE polypeptide variant, Geng teaches a mutant BChE having 100% sequence identity to Geng’s SEQ ID NO: 3 (see, e.g., Geng, Figure 2 & Office Action Appendix) and wherein the mutant comprises one or more of the following amino acid substitutions: A199S, F227A, S287G, A328W, F329M, or Y332G (see, e.g., Geng, [0009] & Examples 2-3). The Examiner has interpreted the limitations following the phrase “optionally” to not be required.
Regarding claim 5 pertaining to SEQ ID NO: 7, Geng teaches a mutant BChE having 100% sequence identity to Geng’s SEQ ID NO: 3 (see, e.g., Geng, Figure 2 & Office Action Appendix) and wherein the mutant comprises one or more of the following amino acid substitutions: A199S, F227A, S287G, A328W, F329M, or Y332G (see, e.g., Geng, [0009] & Examples 2-3). Instant SEQ ID NO: 7 has the same amino acid sequence as instant SEQ ID NO: 2, and it also contains the following mutations: A199S, S287G, A328W, and Y332G, which are all mutations taught by Geng. Additionally, instant SEQ ID NO: 7 corresponds to Geng’s BChE mutant 10, which has 100% sequence identity to Geng’s SEQ ID NO: 3 and the A199S, S287G, A328W, and Y332G mutations (see, e.g., Geng, [0071] & Example 2).
Regarding claim 8 pertaining to administering the ghrelin hydrolase to a subject, Geng teaches administering mutant BChE polypeptides to mice, wherein administration and expression of reduces acyl ghrelin levels and increase desacyl ghrelin levels (see, e.g., Geng, Example 3).
Regarding claim 12 pertaining to administration of a pharmaceutically acceptable carrier, Geng teaches that the BChE polypeptide can be administered with a pharmaceutically acceptable carrier (see, e.g., Geng, [0053]).
Claim Rejections - 35 USC § 103, Obviousness
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 2 is rejected under 35 U.S.C. 103 as being unpatentable over Geng as applied to claims 1, 3, 5, 8, and 12 above, and further in view of Dafferner (Characterization of butyrylcholinesterase in bovine serum; 2017 – cited in the IDS filed on 02/20/2024).
Geng’s general disclosure is discussed above.
Regarding claim 2 pertaining to SEQ ID NO: 2, Geng teaches a mutant BChE having 100% sequence identity to Geng’s SEQ ID NO: 3 (see, e.g., Geng, Figure 2 & Office Action Appendix). The Examiner has interpreted the limitations following the phrase “optionally” to not be required.
However, Geng does not teach: wherein the BChE variant comprises 1, 2, 3, or 4 mutations selected from the group consisting of T284S, P285I, V288I, and F398I (claim 2).
Dafferner’s general disclosure relates to determining whether bovine serum can be used as a source of BChE by immunopurification (see, e.g., Dafferner, abstract). Moreover, Dafferner teaches “We provide mass spectrometry evidence for the presence of BoBChE in bovine plasma, though the levels of BoBChE are very low. FBS is a richer source of BoBChE than serum of the adult cow” (see, e.g., Dafferner, Introduction, pg. 2).
Regarding claim 2 pertaining to the F398I variant in BChE, Dafferner teaches production of a wild-type human BChE with the F398I mutation (see, e.g., Dafferner, Section 2.9, pg. 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Geng’s BChE polypeptide, wherein the polypeptide comprises an F398I mutation, as taught by Dafferner. One would have been motivated to do so because Dafferner teaches that the F398I mutation is in the acyl-binding pocket of the BChE polypeptide and should create more space in the active site pocket (see, e.g., Dafferner, Section 3.8, pg. 9). Additionally, the I398 should “allow a water molecule access to the diethoxyphosphate-serine in the active site. The water molecule can assume a position to attack the phosphorus atom, thus releasing diethoxyphosphate from the active site serine and reactivating the BoBChE enzyme” (see, e.g., Dafferner, Section 4.5, pg. 13). Moreover, Geng teaches production of BChE mutants wherein a series of amino acid substitutions are performed in the region of the active site in order to cause large increases in peptide hydrolyzing activity (see, e.g., Geng, Example 2, [0060], [0089]). Therefore, based on the teachings of Geng and Dafferner, it would have been obvious to produce Geng’s BChE polypeptide comprising a F398I mutation in order to increase the size of the active site pocket which could increase peptide hydrolyzing activity. One would have expected success because Geng and Dafferner both teach BChE mutants, wherein mutations are performed near the active site.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Geng as applied to claims 1, 3, 5, 8, and 12 above, and further in view of Watkins (U.S. Patent No. 6,989,261; Date of Publication: January 24, 2006).
Geng’s general disclosure is discussed above.
Regarding claim 4 pertaining to the BChE polypeptide mutant, Geng teaches a BChE mutant wherein the mutant comprises one or more of the following amino acid substitutions: A199S, F227A, S287G, A328W, F329M, or Y332G (see, e.g., Geng, [0009] & Examples 2-3).
However, Geng does not teach: wherein the BChE polypeptide variant comprises an amino acid sequence wherein residues 530 to 574 are truncated, such that the amino acid sequence has 529 amino acids (claim 4).
Watkins’ general disclosure relates to “a butyrylcholinesterase variant having increased cocaine hydrolysis activity as well as the corresponding encoding nucleic acid. The invention further provides methods of hydrolyzing a cocaine-based butyrylcholinesterase substrate as well as methods of treating a cocaine-induced condition with the invention variant” (see, e.g., Watkins, abstract).
Regarding claim 4 pertaining to the truncated BChE variant, Watkins teaches SEQ ID NO: 47, which has 100% sequence similarity to instant truncated SEQ ID NO: 2 comprising amino acids 1-529 (see, e.g., Office Action Appendix).
It would have been obvious to one of ordinary skill in the art before the effective filing date to produce Geng’s BChE polypeptide mutant, wherein the polypeptide mutant is truncated, as taught by Watkins. One would have been motivated to do so because Watkins teaches “residues important for the functional structure of a butyrylcholinesterase variant include the cysteine residues 65Cys-92Cys, 252Cys-263Cys, and 400Cys-519Cys involved in intrachain disulfide bonds. Therefore, a functional fragment can be a truncated form, region or segment of the reference butyrylcholinesterase variant designed to possess most or all of the residues critical for cocaine hydrolysis activity or functional structure so as to retain equivalent cocaine hydrolysis activity” (see, e.g., Watkins, col 13, lines 66-67 & col 14, lines 1-8)). Additionally, Watkins teaches that the truncated butyrylcholinesterase is still able to exhibit cocaine hydrolysis activity, signifying that it is still an active enzyme (see, e.g., Watkins, Figure 6). Moreover, Geng teaches wildtype and mutant butyrylcholinesterases for enhanced hydrolysis of acyl ghrelin or treatment of obesity and/or aggression (see, e.g., Geng, [0008]). Moreover, Geng teaches amino acid substitutions: A199S, F227A, S287G, A328W, F329M, or Y332G in mutant butyrylcholinesterases that enhance hydrolysis activity (see, e.g., Geng, [0009]). Therefore, based on the teachings of Geng and Watkins, it would have been obvious to produce a truncated butyrylcholinesterases because this would allow for production of a smaller butyrylcholinesterase with the same activity as a wildtype butyrylcholinesterase. Additionally, production of this smaller, truncated butyrylcholinesterase would also have increased hydrolysis activity compared to wildtype if the truncated butyrylcholinesterase comprises the amino acid substitutions taught by Geng. Additionally, the amino acid substitutions taught by Geng are still comprised within the truncated butyrylcholinesterase and do not affect the 65Cys-92Cys, 252Cys-263Cys, and 400Cys-519Cys involved in intrachain disulfide bonds, as taught by Watkins. One would have expected success because Geng and Watkins both teach production of mutant butyrylcholinesterases.
Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Geng as applied to claims 1, 3, 5, 8, and 12 above, and further in view of Hong (WO 2018/111196; Date of Publication: June 21, 2018) and Chen (Development of a Long-acting Fc-fused Cocaine Hydrolase with Improved Yield of Protein Expression; 2019).
Geng’s general disclosure is discussed above.
Regarding claim 6 pertaining to the BChE polypeptide variant, Geng teaches a mutant BChE (see, e.g., Geng, Example 3 & [0010]), wherein the mutant BChE has 100% sequence identity to Geng’s SEQ ID NO: 3 (see, e.g., Geng, Figure 2 & Office Action Appendix) and wherein the mutant comprises one or more of the following amino acid substitutions: A199S, F227A, S287G, A328W, F329M, or Y332G (see, e.g., Geng, [0009] & Examples 2-3).
However, Geng does not teach: wherein an Fc polypeptide having SEQ ID NO: 12 is joined to the N- or C-terminal end of the BChE polypeptide variant (claim 6); or wherein the Fc polypeptide is joined to the BChE polypeptide via a linker (claim 7).
Hong’s general disclosure relates to multimerization of Vascular Endothelial Growth Factor Receptors wherein the multimerization component is an “Fc portion of Human Immunoglobulin constant Fragment or wherein the amino acid of the Fc portion of Human Immunoglobulin constant Fragment has at least 90% identity to a sequence of SEQ ID NO: 7 or wherein the amino acid of the Fc portion of Human Immunoglobulin constant Fragment has a sequence of SEQ ID NO: 7” (see, e.g., Hong, [0010]). Regarding claim 6 pertaining to instant SEQ ID NO: 12, Hong teaches SEQ ID NO: 7 which has 100% sequence similarity to instant SEQ ID NO: 12 and corresponds to an the Fc portion of Human Immunoglobulin constant Fragment (see, e.g., Hong, [0010] & Office Action Appendix).
Chen’s general disclosure relates to producing active recombinant BChE mutants with sufficiently long biological half-lives by fusing an Fc protein to the N-terminus of BChE (see, e.g., Chen, abstract).
Regarding claims 6-7 pertaining to the BChE polypeptide and Fc polypeptide, Chen teaches that an Fc polypeptide was fused to the N-terminus of BChE, and wherein the Fc polypeptide can be a A1V/D142E/L144M mutant (see, e.g., Chen, Introduction, pg. 3). Additionally, Chen teaches linking the Fc polypeptide to the BChE polypeptide via linkers (see, e.g., Chen, “Optimization of Fc-fused CocH3 entity with a linker”, pg. 5).
It would have been obvious to one of ordinary skill in the art to produce Geng’s BChE polypeptide mutant, wherein the polypeptide is linked to an Fc polypeptide, as taught by Hong and Chen. One would have been motivated to do so because Chen teaches that IgG Fc polypeptide fusion to BChE prolongs the biological half-life of the protein without affecting catalytic activity (see, e.g., Chen, Introduction, pg. 3). Additionally, Chen teaches that a linker was added to fuse the BChE polypeptide to the Fc polypeptide because direct fusion of the Fc polypeptide to the N-terminus of BChE could affect the entrance of the substrate to the active site thus affecting catalytic activity (see, e.g., Chen, Introduction, pg. 3). Furthermore, Hong teaches that Hong’s SEQ ID NO: 7 corresponds to an immunoglobulin Fc polypeptide and can be used to multimerize polypeptides (see, e.g., Hong, [0011]). Moreover, Geng teaches that the BChE polypeptide can be modified to link to another polypeptide resulting in a modified polypeptide having an increased half-life, which “can result from reduced proteolytic degradation, immune recognition, or cell scavenging of the modified polypeptide” (see, e.g., Geng, [0039]-[0040]). Therefore, based on the teachings of Geng, Chen, and Hong, it would have been obvious to produce a BChE polypeptide linked to an Fc polypeptide at the N-terminus in order to increase the half-life of the BChE polypeptide. One would have expected success because Geng and Chen both teach modified BChE polypeptides. Chen and Hong both teach linkage of polypeptides to immunoglobulin Fc polypeptides to produce multimerized polypeptides.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Geng as applied to claims 1, 3, 5, 8, and 12 above, and further in view of Zallar (The Role of the Ghrelin System in Drug Addiction; 2017).
Geng’s general disclosure is discussed above.
However, Geng does not teach: wherein the subject is in need of treatment for substance use disorder (claim 9); or wherein the subject is in need of treatment for polysubstance use disorder involving methamphetamine and opioids (claim 10).
Zallar’s general disclosure relates to a review of the ghrelin system in drug addiction wherein “the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels” (see, e.g., Zallar, abstract).
Regarding claims 9-10 pertaining to the subject being in need of treatment for substance use disorder, Zallar teaches that “Intraperitoneal injection of a single dose of methamphetamine or 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy) increased blood ghrelin concentrations in rats” (see, e.g., Zallar, Section 3.1, pg.100). Additionally, Zallar teaches “a number of studies show that pharmacological blockade of GHS-R1a attenuates the biobehavioral outcomes associated with stimulants use. Indeed, injection of a GHS-R1a antagonist (JMV2959), compared with placebo, prior to intraperitoneal administration of cocaine or methamphetamine, led to decreased drug-induced conditioned place preference, hyper locomotion, and accumbal dopamine release in rats” (see, e.g., Zallar, Section 3.1, pg. 101). Furthermore, Zallar teaches that “intracerebroventricular administration of ghrelin in rats increased intravenous heroin consumption and motivation for heroin, as shown by increased breakpoints on a progressive ratio schedule, but intracerebro-ventricular administration of a GHS-R1a antagonist (D-Lys3-GHRP-6) had no effect on heroin self-administration or food deprivation-induced reinstatement of heroin seeking” (see, e.g., Zallar, Section 5.1, pgs. 104-105).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer Geng’s BChE mutant in order to treat substance abuse disorders involving methamphetamine and opioids, as taught by Zallar. One would have been motivated to do so because Zallar teaches that methamphetamine increases blood ghrelin concentrations in rats and “a number of studies show that pharmacological blockade of GHS-R1a attenuates the biobehavioral outcomes associated with stimulants use. Indeed, injection of a GHS-R1a antagonist (JMV2959), compared with placebo, prior to intraperitoneal administration of cocaine or methamphetamine, led to decreased drug-induced conditioned place preference, hyperlocomotion, and accumbal dopamine release in rats” (see, e.g., Zallar, Section 3.1, pg. 101). Additionally, Zallar teaches “intracerebroventricular administration of ghrelin in rats increased intravenous heroin consumption and motivation for heroin, as shown by increased breakpoints on a progressive ratio schedule, but intracerebroventricular administration of a GHS-R1a antagonist (D-Lys3-GHRP-6) had no effect on heroin self-administration or food deprivation-induced reinstatement of heroin seeking” (see, e.g., Zallar, Section 5.1, pgs. 104-105). Moreover, Geng teaches the production and administration of mutant BChE polypeptides with enhanced ability to hydrolyze acyl ghrelin (see, e.g., Geng, [0032]). Therefore, based on the teachings of Geng and Zallar, it would have been obvious to administer Geng’s mutant BChE to treat substance use disorders because Geng’s mutant BChE has enhanced ability to hydrolyze acyl ghrelin, and methamphetamine and heroine (i.e., illegal opioid) substance use disorder results in increased ghrelin levels, and increased ghrelin levels causes increased consumption of these substances. Therefore, hydrolyzing acyl ghrelin to desacyl ghrelin results in decreased ghrelin levels and decreased consumption of these substances. One would have expected success because both Geng and Zallar teach ghrelin’s involvement in diseases and disorders, as well as administration of products that inactive ghrelin to treat diseases and disorders.
Conclusion
Claims 1-10 and 12 are rejected.
No claims are allowed.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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