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 .
Priority
The instant application, filed on 11 October 2023 is a 371 of PCT/US2022/024440 filed on 12 April 2022, which claims domestic benefit to US provisional application no. 63/173,982, filed on 12 April 2021.
Information Disclosure Statement
The two information disclosure statements (IDS) submitted on 08 March, 2024 have been considered by the examiner.
Status of Application, Amendments, and/or Claims
The response filed on 01 June, 2026 has been entered in full. The response is an amendment due to a restriction requirement of the claim set filed on 08 March 2024. In the amendment, claims 5, 6, 8, 16, 22, 23, 37, 39, 41, 42, 43, 48, 49, and 50 are amended, claims 2, 3, 7, 9-15, 17, 18, 21, 24-33, 35, 36, 38, 44-47, and 51-58 are cancelled.
The election of group 1 from the restriction requirement renders claims 19, 20, 22, 23, 34, 37, 39-43, and 48-50 as withdrawn, however upon further consideration the restriction requirement is dropped and all the claims are rejoined.
Therefore, claims 1, 4-6, 8, 16, 19, 20, 22, 23, 34, 37, 39-43, and 48-50 are pending and are the subject of this Office Action.
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 39 and 40 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.
Both claims 39 and 40 recite the engineered nucleic acid molecule of claim 37 wherein the myostatin propeptide comprises a mutation (or an Ala for claim 40) at the position corresponding to D76 in SEQ ID NO: 1. It is unclear if the myostatin propeptide has to be the propeptide of SEQ ID NO:1 or if the claim is referring to any myostatin propeptide. For the purpose of further examination, the claim will be interpreted that the nucleic acid must be that of SEQ ID NO: 1 with the specified mutation.
Claim Rejections - 35 USC § 103
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.
Claims 1, 4-6, 8, 16, 19, 20, 22, 23, 34, 37, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al. (of record, IDS 03/08/2024) in view of Eliers et al. (2020) Local myostatin inhibition improves skeletal muscle glucose uptake in insulin-resistant high-fat diet-fed mice Am J Physiol Endocrinol Metab 319: E163-E174.
In regards to claims 1 and 34 Xiong teaches a therapeutic modality which successfully treated obesity comprising administering an adeno-associated virus expressing a GDF15 protein in mice (pg.2, col 1, lines 1-5/Figure 1c – 1d).
In regards to claims 4 and 16 Xiong teaches using inserting a cDNA encoding for GDF15 into the adeno-associated virus vector (pg.7, col 1, line 52 – pg.7, col 2, line 3).
In regards to claims 5 and 6 Xiong teaches injecting 100μL of an 8 x 1012 genomic units/mL AAV solution to mice which successfully reduced the body weight of the mice (pg.7, col 2, lines 30-32/Figure 1c). Further specifically in regards to claim 6, Xiong teaches the AAV vector had no detrimental effects on skeletal muscle as well as other organs and tissues (pg.3, col 1, lines 8-13/ Table S1).
In regards to claim 19, 20, 22, and 23 Xiong teaches administering a modified fusion protein of GDF15 and an FC dimer to increase protein production while maintaining the activity of the protein (pg.3, col 2, lines 13-25). The fusion proteins were given in various concentrations which are effective at reducing weight in both obese mice and obese monkey models (pg.3, col 1, lines 14-33/ Figure 3).
Xiong fails to teach the myostatin inhibitor of claims 1, 19, and 34, the second nucleic acid molecule encoding the myostatin inhibitor of claim 4, the myostatin inhibitor being a myostatin propeptide of claims 8 and 37, the myostatin inhibitor and GDF15 polypeptide being the same composition of claim 20, and the myostatin inhibitor being in a vector of claim 16, and the prevention of muscle mass loss and/or muscle function loss of claim 23.
Eliers, however, in regard to claim 1, 19, 20, and 34 teaches delivering a myostatin inhibitor to obese high fat diet fed mice improves muscle insulin stimulated glucose disposal, as well as induces muscle hypertrophy after 10 weeks of exposure (pg.E168, col 1, line 16 – pg.E168, col 2, line 13 /Fig 3), which implies it would have beneficial effects as a treatment in patients with obesity and insulin resistance (pg.E172, col 1, lines 11-15).
In regards to claim 23 Eliers teaches inhibiting myostatin induces muscle hypertrophy (pg.E168, col 1, line 16 – pg.E168, col 2, line 13).
Further, in regards to claims 1, 4, 8, 16, and 37 Eliers teaches the myostatin being delivered in the form of an adeno-associated virus vector containing a modified propeptide sequence fussed to a mouse immunoglobulin G2a (pg.E164, col 1, lines 15-20).
In regards to claim 50 both Xiong and Eliers both teach administering the vectors encoding the GDF15 and myostatin propeptide to obese mice models to express them in the mice as outlined above.
Thus, Xiong discloses a method of treating obesity comprising administering an adeno-associated virus vector expressing the GDF15 protein or a GDF15 fusion protein wherein the treatment decreases body weight without muscle mass loss and/or muscle function loss, and Eliers teaches administering an adeno-associated virus expressing an myostatin propeptide to inhibit myostatin activity increasing muscle glucose disposal and inducing muscle hypertrophy. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try the combination of teachings from Xiong and Eliers to deliver together in the combination a adeno-associated virus vector encoding GDF15 or a GDF15 fusion protein of Xiong with the myostatin inhibitor in the form of the adeno-associated virus vector encoding the myostatin propeptide of Eliers with a reasonable expectation of success to develop a method and therapeutic which can treat obesity which induces significant weight loss while also bolstering muscle function and muscle mass.
Claims 41, 42, 48, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al. in view of Eliers et al. as applied to claims 34 and 37 above, and further in view of Fotin-Mileczek et al. (WO 2017/191274).
Xiong in view of Eliers fails to teach the nucleotide sequence encoding the GDF15 polypeptide having at least 80% to any one of SEQ ID NOs: 26-30 of claim 41, the nucleotide sequence encoding the myostatin inhibitor having at least 80% to any one of SEQ ID NOs: 16-25 of claim 42 and the engineered cells comprising the engineered nucleic acid of claims 48 and 49.
Fotin-Mileczek, however, teaches mRNA with increased stability and increased translation efficiency (pg.3 lines 12-16) through codon optimization (pg.60) and G/C content modification (pg.54).
Further, in regards to claim 41 Fotin-Mileczek teaches the nucleotide sequence of SEQ ID NO: 17455 which is a nucleotide sequence encoding GDF15 with 87.9% identity to instant application SEQ ID NO: 27 as shown below.
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1015
561
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In regards to claim 42 Fotin-Mileczek teaches the nucleotide sequence of SEQ ID NO: 20089 which is a nucleotide sequence encoding a myostatin inhibitor with 90.2% identity to instant application SEQ ID NO: 16 as shown below.
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893
559
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In regards to claims 48 and 49 Fotin-Mileczek teaches the RNA can be administered to an expression system which includes a cell, a tissue, or an organism (eukaryotic cells) in various methods including in vitro, in vivo, and ex vivo which all results in transfection of the cell to express the encoded protein for various applications including, diagnostics, research, and therapeutic purposes (pg.92, line 32 – pg.93, line 27).
Thus, Xiong in view of Eliers discloses a method of treating obesity comprising administering an adeno-associated virus vector expressing the GDF15 protein or a GDF15 fusion protein wherein the treatment decreases body weight without muscle mass loss and/or muscle function loss, and an adeno-associated virus expressing an myostatin propeptide to inhibit myostatin activity increasing muscle glucose disposal and inducing muscle hypertrophy. Fotin-Mileczek teaches mRNA sequences optimized to improve stability, translation efficiency and expression in cell systems. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings from Xiong in view of Eliers and Fotin-Mileczek to deliver together in the combination a adeno-associated virus vector encoding GDF15 of Xiong with the myostatin inhibitor in the form of the adeno-associated virus vector encoding the myostatin propeptide of Eliers and simply substituting the improved mRNA sequences of Fotin-Mileczek with a reasonable expectation of success to develop a method and therapeutic which can treat obesity which induces significant weight lose with a vector that has more efficiently translated and stable mRNA.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al. in view of Eliers et al. as applied to claim 34 above, and further in view of Domenger and Grimm (2019) Next-generation AAV vectors- do not judge a virus (only) by its cover Human Molecular Genetics 28(R1); R3-R14.
Xiong, in view of Eliers fails to teach a tissue specific promoter linked to the nucleotide sequence of claim 43. Domenger and Grimm, however, teach using tissues specific promoters in AAVs results in less inactivation in comparison to ubiquitous promoters, provide seminal possibility of spatially controlled transgene expression, and further they are being used in more and more preclinical and clinical studies (pg.R5, col 1, lines 22-25/ pg.R5, col 1, 36-48).
Thus, Xiong in view of Eliers discloses a method of treating obesity comprising administering an adeno-associated virus vector expressing the GDF15 protein or a GDF15 fusion protein wherein the treatment decreases body weight without muscle mass loss and/or muscle function loss, and an adeno-associated virus expressing an myostatin propeptide to inhibit myostatin activity increasing muscle glucose disposal and inducing muscle hypertrophy. Domenger and Grimm teach and suggest a tissue specific promoter would be beneficial in reducing the risk of inactivation, and further in support site specific transgene expression. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try the combination of teachings from Xiong and Eliers to deliver together in the combination a adeno-associated virus vector encoding GDF15 of Xiong with the myostatin inhibitor in the form of the adeno-associated virus vector encoding the myostatin propeptide of Eliers, with the teachings and suggestion of Domenger and Grimm of using a tissue specific promoter with a reasonable expectation of success to develop a method and therapeutic which can treat obesity which induces significant weight loss and has site specific transgene expression and a lower risk of inactivation using a method gaining popularity in the field.
Prior Art of Record
In regards to claims 39 and 40, the prior art of record does not disclose an engineered nucleic acid molecule of SEQ ID NO:1 comprising a mutation at D76 and further does not teach an Ala at the D76 position.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Friday from 8:30am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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