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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 3/5/2026 has been considered. Claim 20 has been canceled. Claims 1-14, 19 and 21-22 are pending. Claims 19, 21 and 22 have been amended. Claims 1-14 are currently withdrawn without traverse from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking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. Claims 19 and 21-22 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Priority
Applicant’s claim for the benefit of a prior-filed application CN202010591468.8 and 371 of PCT/CN2020/105381 filed on 6/24/2020 and 7/29/2020, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 6/24/2020.
Withdrawn Rejections and Objections
The objection of claim 19 is withdrawn due to applicants’ amendments which import the claim limitations from withdrawn claim 1.
The 35 U.S.C. 103 rejection of claim 19-22 as obvious over Hoffman in view of Zhang has been withdrawn in light of applicants claim amendments which add new limitations including that the exogenous MEGL gene consists of SEQ ID NO: 1.
Reply to Applicants Arguments
Applicant traverses the previous rejections by pointing to new claim amendments which specify that the method is for treating malignant tumors comprising administering a viral vector encoding an exogenous MEGL gene that is a methionine y-lyase gene consisting of SEQ ID NO: 1 and wherein the vector uses an EF1A promoter. Applicant argues that Hoffman treats a metabolic disorder and does not teach treating tumors. Applicant argues that the cited prior art does not teach a methionine y-lyase gene consisting of SEQ ID NO: 1. Applicant argues that Hoffman discloses an enucleated cell and not a viral vector. Applicant argues that Zhang does not cure the deficiencies of Hoffman.
This argument has been fully considered, but is not found persuasive since the rejection is newly applied in view of Harrison and Wang who teach a methionine y-lyase gene consisting of SEQ ID NO: 1 and EF1A promoter. Furthermore, it is emphasized that one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145.
New Claim Objections
Claim 19 is objected for reciting “a viral vector where an exogenous” rather than “a viral vector wherein an exogenous”. Claim 19 is objected for reciting “consists of a sequence of SEQ ID NO.1” rather than “consists of SEQ ID NO.1”. Claim 19 is objected for reciting “SEQ ID NO.1, wherein the vector” rather than “SEQ ID NO.1 and wherein the vector”.
New 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 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.
Claims 19, 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffman et al. US 2019/0309271, published 10/10/2019 (hereinafter Hoffman, reference of record) in view of Zhang et al. "Symphony of epigenetic and metabolic regulation—interaction between the histone methyltransferase EZH2 and metabolism of tumor." Clinical Epigenetics 12.1 (2020): 72 (hereinafter Zhang, reference of record), Harrison et al. US 2005/0036984, published 2/17/2005 (hereinafter Harrison) and Wang et al. "The EF‐1α promoter maintains high‐level transgene expression from episomal vectors in transfected CHO‐K1 cells." Journal of cellular and molecular medicine 21.11 (2017): 3044-3054 (hereinafter Wang). This rejection is newly applied to address applicants claim amendments filed on 3/5/2026.
Claim 19: Hoffman describes a lentiviral vector into which an exogenous polypeptide comprising methionine γ- lyase is inserted (Hoffman, para 11, 21). Hoffman presents this as a method for treating homocystinuria (a metabolic disorder) using engineered erythroid cells that express methionine γ- lyase which helps degrade homocysteine (Hoffman, para 11, 60). Hoffman provides alternative embodiments wherein the vector is administered directly into a tumor (Hoffman, para 599). Hoffman does not describe treating malignant tumors, gliomas, killing cancer cells directly or inhibiting histone methyltransferase EZH2.
Claims 19 and 21-22: Zhang describes the interaction of histone methyltransferase EZH2 and tumor metabolism (Zhang, abstract). Zhang shows that methionine γ- lyase expression inhibits histone methyltransferase EZH2 by depleting the cellular pool of methionine, which in turn reduced the production of methyl donor s-adenosylmethionine (SAM) (Zhang, pg 7 and Fig 3). By reducing methionine levels, methionine γ- lyase effectively restricts the cell’s ability to produce SAM. EZH2 is a specific histone methyltransferase that uses SAM as a substrate to catalyze the trimethylation of histone H3 on lysine 27 (H3K27me3) (Zhang, pg 8 col 1). When the intracellular SAM concentration drops due to methionine γ- lyase activity, EZH2’s catalytic activity is significantly impaired because it cannot access its necessary methyl donor. The methylation reaction catalyzed by EZH2 produces S-adenosylhomocysteine (SAH) as a byproduct. Methionine depletion disrupts the methionine cycle, which can lead to SAH accumulation and further inhibit EZH2 (Zhang, pg 7 and Fig 3).
Claim 20: Zhang states that in glioma cells, inhibition of EZH2 activity suppresses aerobic glycolysis which is critical for glioma growth and proliferation since glioma cells primarily rely on this metabolic pathway even when oxygen is available (Zhang, col 1 pg 5). Thus, Zhang shows that methionine γ- lyase expression leads to histone methyltransferase EZH2 inhibition which can selectively and directly kill malignant tumor cells like gliomas.
It would have been prima facie obvious to one of ordinary skill in the art to administer the methionine γ- lyase expressing lentiviral vector described by Hoffman as a cancer treatment in light of the disclosure of Zhang. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Zhang shows that methionine γ- lyase expression inhibits histone methyltransferase EZH2 by depleting the cellular pool of methionine, which in turn leads to SAH accumulation and further inhibition of EZH2 which is known to suppresses aerobic glycolysis in glioma cells. One would have been motivated to make this combination since Zhang shows that methionine γ- lyase expression leads to histone methyltransferase EZH2 inhibition which can selectively and directly kill malignant tumor cells like gliomas. One would have a reasonable expectation of success given that Hoffman provides embodiments wherein the vector is administered directly into tumors, showing that there are predictable administration pathways.
Neither Hoffman nor Zhang describe an exogenous MEGL gene consisting of a sequence of SEQ ID NO: 1.
Claim 19: However, the sequence of this particular MEGL gene was known in the art and used as an anticancer agent as shown by Harrison (Harrison, abstract). Harrison discloses SEQ ID NO: 8 which encodes for L-methioninase from Pseudomonas putida and shares 100% local similarity to instant SEQ ID NO: 1 (Harrison, para 85).
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Sequence search results between SEQ ID NO: 8 and instant SEQ ID NO: 1
Furthermore, the collection of cited art does not disclose the use of a EF1A promoter.
Claim 19: However, the EF1A promoter is a known constitutively active promoter that is active in a broad range of cell types. In particular, it is resistant to silencing by DNA methylation, which is particularly relevant when delivering MEGL genes (Wang, pg 3045 col 1). Wang states that CMV promoters are often transcriptionally silenced via DNA methylation (Wang, pg 3045 col 1).
It would have been prima facie obvious to one of ordinary skill in the art to deliver thar particular MEGL gene disclosed by Harrison using the EF1A promoter disclosed by Wang as a glioma cancer treatment in light of the disclosures of Zhang and Hoffman. It would have been a matter of simple substitution of one known element for another to obtain predictable results for one of ordinary skill to use a EF1A rather than a CMV promoter and the MEGL gene encoded by SEQ ID NO: 1. One would have been motivated to make this substitution since the EF1A promoter is a known constitutively active promoter that is resistant to silencing by DNA methylation when compared to CMV promoters like the ones used by Hoffman. Furthermore, the exogenous MEGL gene encoded by SEQ ID NO: 1 from Pseudomonas putida is a known L-methioninase variant and shown to be therapeutically effective against cancer. Thus, one would have a reasonable expectation of success given that all elements of the therapeutic vector were known in the art and shown to be effective in targeting glioma cancers. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the invention to have been prima facie obvious to at the time the invention was made.
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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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