DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 11/14/2025 has been entered.
Claims 1-5, 8-13, 16 and 19-23 are pending in this application.
Applicant’s amendment to the claims filed 11/14/2025 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims. Regarding canceled claims 6 and 7, applicant is reminded of the amendment practice according to MPEP 714.II.C that requires canceled claims to be listed by only the claim number and status identifier, without presenting the text of the claims.
Applicant’s Declaration under 37 CFR 1.130(a) filed 11/14/2025 is acknowledged.
Applicant’s remarks filed on 11/14/2025 in response to the final rejection mailed on 07/14/2025 is acknowledged and has been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election
The elected subject matter is:
Species A, synergistic therapeutic effect,
Species B, polyethylene glycosylated Erwinia chrysanthemi-derived asparaginase (pegcrisantaspase, PegC),
Species C, Venetoclax (Ven), and
Species D, acute myeloid leukemia (AML),
elected without traverse in the reply filed 07/15/2024.
Claims 1-5, 8-13, 16 and 19-23 are being examined on the merits only to the extent they read on the elected subject matter.
Claim Objections
The objection to claim 8 is withdrawn in view of the amendment to recite “Erwinia chrysanthemi-derived short acting asparaginase” once and to end the Markush group with the conjunction “and”.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 9 and 11 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point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention is withdrawn in view of the amendments to claims 9 and 11 to remove the term “about”.
Claim Rejections - 35 USC § 103
The rejection of claims 1-5, 8-13, 16, and 19-23 under 35 U.S.C. 103 as being unpatentable over Emadi et al. (Cancer Chemother Pharmacol, 2018, 81:217; cited on the IDS submitted 06/17/2021; herein Emadi) in view of Cambridge Innovation Technologies Consulting Limited (WO 2018/050918; cited on the IDS submitted 06/17/2021; herein Cambridge), Wilson et al. (Lancet Oncol, 2010, 11:1149; cited on the Form PTO-892 mailed 12/13/2024; herein Wilson) and Kaizer et al. (Cancer Res, 2018, 78:884; cited on the IDS submitted 06/17/2021; herein Kaizer) is withdrawn in view of Applicant’s Declaration under 37 CFR 1.130(a) to establish Kaizer as excepted under 35 USC 102(b)(1)(A).
Claims 1-5, 9-13, 16, and 20-23 are newly rejected under 35 U.S.C. 103 as being unpatentable over Emadi in view of Peirs et al. (Lymphoid Neoplasia, 2014, 124:3738; cited on the attached Form PTO-892; herein Peirs) and Leonard et al. (Sci Transl Med, 2016, 8:354ra114; cited on the attached Form PTO-892; herein Leonard).
Claim 1 is drawn to a method of treating cancer in a subject or prolonging survival of a subject having cancer, comprising administering synergistically therapeutic amount of a first agent that depletes plasma glutamine and a second agent that inhibits BCL-2 activity to a subject having cancer.
Emadi discusses asparaginase Erwinia chrysanthemi that effectively depletes plasma glutamine in patients with acute myeloid leukemia (AML) [title], and discusses the potential for the enzyme’s activity to produce glutamine deprivation as a therapeutic approach to AML via targeting the reliance of AML cells on glutamine [p 217, col 2, para 1 to p 218, col 2, para 1].
Regarding the limitation in claim 1 of an agent that depletes plasma glutamine, Emadi teaches the depletion of glutamine as a therapeutic approach to treatment of AML, and that asparaginase derived from Erwinia chrysanthemi has the greatest glutaminase activity of the available asparaginases [abstract].
Emadi further discusses that routine treatment for younger patients with AML is a combination chemotherapy with cytarabine and an anthracycline [p 217, col 2, para 1], wherein cytarabine is understood in the art to be an antimetabolite treatment, and anthracyclines are understood in the art to induce cell death. Therefore Emadi recognizes that it was routine in the field to treat AML by combining an antimetabolite treatment with a treatment to induce cell death, and suggests the use of the disclosed asparaginase above as the antimetabolite.
Emadi does not teach the use of a BCL-2 inhibitor, or a synergistic therapeutic amount of a first and a second agent in a cancer treatment.
Peirs relates to ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia [title], and discusses targeted therapeutics against hematologic malignancies such as ABT-199 can potentially improve patient prognosis and survival [p 3738, col 2, final para].
Regarding claim 1 and the limitation of a synergistically therapeutic amount of a first and second agent, Peirs teaches ABT-199 shows synergistic therapeutic effects with different chemotherapeutic agents, wherein ABT-199 is disclosed as the BCL-2 inhibitor venetoclax by Leonard [abstract] with impressive activity against hematologic malignancies such as AML by selectively inhibiting BCL-2, wherein the inhibition of the antiapoptotic BCL-2 is understood to result in the induction of cell death or apoptosis [p 1, col 2, paras 2-3 of Leonard]. Piers further discloses that the chemotherapeutic agents used in the combinatorial treatment with ABT-199 include the L-asparaginase [abstract] Erwinase, PL 01511/0272 [Peirs, p 3740, col 1, Section “Combination treatment of cells with ABT-199 and chemotherapeutic agents]. Additionally, Peirs shows the identification of synergistic combinations of ABT-199 and asparaginase concentrations against leukemia cell lines in [Figure 6B], which is considered to encompass synergistically therapeutic amounts of a first agent and a second agent recited in claim 1.
In view of Emadi, Peirs and Leonard, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Emadi by administering an asparaginase with a BCL-2 inhibitor, as taught by Peirs and Leonard, and comprising synergistically therapeutic amounts of a first agent and a second agent, as taught by Peirs, to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to modify the method of Emadi by using a BCL-2 inhibitor, because Emadi teaches it was routine in the field to treat AML by combining an antimetabolite treatment such as asparaginase with a treatment to induce cell death, Leonard teaches that venetoclax is a BCL-2 inhibitor used to induce cell death in AML treatments, and Peirs teaches a combination therapy of venetoclax and asparaginase to treat leukemia cells.
One of ordinary skill in the art would have been motivated to modify the method of Emadi by using synergistically therapeutic amounts of a first and second agent because Peirs teaches the determination of synergistic amounts of venetoclax and asparaginase for combination treatment of leukemia cells.
One of ordinary skill in the art would have had a reasonable expectation of success because Emadi and Peirs discuss combination therapy for cancer treatment comprising the administration of asparaginase and an agent to increase cell death, and Emadi, Peirs and Leonardo discuss cancer treatments with an agent to induce cell death.
Regarding claims 2-4, the combined method of Emadi, Peirs and Leonardo as described above is considered to encompass a concurrent administration of a combination of first and second agents with overlapping periods of administration, as Peirs teaches the addition of ABT-199 and chemotherapeutic (venetoclax) to cell lines [p 3740, col 1, para 5].
Regarding claim 5, Peirs teaches the asparaginase is prepared in a 0.9% NaCl solvent [p 3740, col 1, para 5], which is considered to be encompassed by the limitation of an agent formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.
Regarding claims 10, 12 and 20, Emadi teaches a method of treating AML (corresponding to claim 12), and Peirs teaches a method of treating leukemia with venetoclax (corresponding to claims 10 and 20).
Regarding claim 9, Emadi teaches a dosage of 25,000 IU/m2 asparaginase [p 219, col 1, para 2].
Regarding claim 11, Peirs teaches the administration of concentrations of venetoclax ranging approximately 1 to 20,000 nM [Figure 6B] in 100 µL volumes [p 3739, col 2, para 2]. As the molecular weight of venetoclax is understood to be approximately 868 g/mol, the range of venetoclax taught by Peirs corresponds to a range of approximately 86.8 to 173,000 mg, and according to MPEP 2144.05.I, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Regarding claim 13, the combined method of Emadi, Peirs and Leonardo as discussed above teaches the limitation of treating a subject with cancer by administering asparaginase to reduce glutamine plasma levels and a BCL-2 inhibitor to said subject [Emadi, abstract; Peirs abstract and p 3740, col 1, Section “Combination treatment of cells with ABT-199 and chemotherapeutic agents]. Therefore it would have been obvious to one of skill in the art before the effective filing date to use the asparaginase and BCL-2 inhibitor of Peirs in the combined method of Emadi, Peirs and Leonardo, to treat AML, as taught by Emadi, to arrive at the claimed invention.
Regarding claim 16, the combined method of Emadi, Peirs and Leonardo as discussed above teaches the limitation of treating a subject with cancer by administering asparaginase to reduce glutamine plasma levels and a BCL-2 inhibitor to said subject [Emadi, abstract; Peirs abstract and p 3740, col 1, Section “Combination treatment of cells with ABT-199 and chemotherapeutic agents]. Peirs additionally teaches the use of the synergistically therapeutic amounts of the BCL-2 inhibitor venetoclax with the L-asparaginase Erwinase [abstract, p 3740, col 1, Section “Combination treatment of cells with ABT-199 and chemotherapeutic agents, and Figure 6], wherein the increased synergism shown in Fig. 6 corresponds to decreased viability of leukemia cell lines, which is considered to correspond to prolonged survival of a subject. As Leonard teaches that venetoclax shows activity against hemotalogic malignancies such as AML [p 1, col 1, final para], it would have been obvious to one of skill in the art before the effective filing date to use the asparaginase and BCL-2 inhibitor of Peirs in the combined method of Emadi, Peirs and Leonard, to prolong survival of a subject having AML, as taught by Peirs and Leonard, to arrive at the claimed invention.
Regarding claim 21 (dependent from claim 13), the combined method of Emadi, Peirs and Leonard and is considered to encompass a concurrent administration of a combination of first and second agents with overlapping periods of administration, as Peirs teaches the addition of ABT-199 and chemotherapeutic (venetoclax) to cell lines [p 3740, col 1, para 5].
Regarding claim 22 (dependent from claim 16), the combined method of Emadi, Peirs and Leonard and is considered to encompass a concurrent administration of a combination of first and second agents with overlapping periods of administration, as Peirs teaches the addition of ABT-199 and chemotherapeutic (venetoclax) to cell lines [p 3740, col 1, para 5].
Regarding claim 23, the method of claim 23 limits the polyethylene glycosylated E. coli-derived asparaginase in the method of claim 8, but does not limit the method of claim 8 to comprise a polyethylene glycosylated E. coli-derived asparaginase. Therefore the method as recited in claim 23 still encompasses all of the alternatives of claim 8, including E. coli-derived short acting asparaginase, polyethylene glycosylated E. coli-derived asparaginase, Erwinia chrysanthemi-derived short acting asparaginase, and polyethylene glycosylated Erwinia chrysanthemi-derived asparaginase. Therefore the combination used to reject claim 8 is also used for claim 23. If the applicant intends to limit the method of claim 23 to comprise a polyethylene glycosylated E. coli-derived asparaginase, the applicant should consider an amendment to recite "the method of claim 8 comprising a polyethylene glycosylated E. coli-derived asparaginase".
Therefore, the invention of claims 1-5, 9-13, 16, and 20-23 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 8 and 19 are newly rejected under 35 U.S.C. 103 as being unpatentable over Emadi in view of Peirs and Leonard as applied to claims 1-5, 9-13, 16, and 20-23 above, and further in view of Chien et al. (Invest New Drugs, 2014, 32:795; cited on the attached Form PTO-892; herein Chien).
Claim 8 is drawn to the method of claim 1, wherein the agent that depletes plasma glutamine is polyethylene glycosylated Erwinia chrysanthemi-derived asparaginase (PegC, according to the instant specification at [para 14]).
Chien relates to the pharmacology and efficacy of novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase [title].
Regarding claims 8 and 19, Chien teaches bacterial L-asparaginases are an indispensable component of the treatment of acute lymphoblastic leukemia, and that pegylated recombinant crisantaspase from Erwinia chrysanthemi-derived L-asparaginase shows anti-leukemic activity [abstract]. Therefore the enzyme of Chien is considered to correspond to the polyethylene glycosylated Erwinia chrysanthemi-derived asparaginase recited in the claims.
In view of Chien, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Emadi, Peirs and Leonard by using the enzyme of Chien to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that both the asparaginase of Emadi and the enzyme of Chien are both asparaginase enzymes used for the treatment of leukemia, and as such both are capable of being incorporated into methods as by Emadi. Thus it would have been obvious to one of ordinary skill in the art to replace the asparaginase of Emadi with the asparaginase of Chien, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the Emadi and Chien discuss the use of asparaginases in leukemia treatments.
Therefore, the invention of claims 8 and 19 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to Remarks: beginning at p 5 of Applicant’s response to rejections under 35 USC 103 and Applicant’s Declaration under 37 CFR 1.130(a); Applicant in summary contends the Kaizer reference should be excepted under 35 USC 102(b)(1)(A) in reference to the 1.130(a) declaration; Applicant further reiterates remarks set forth in the response filed 03/26/2025 to the non-final rejection mailed 12/13/2024; Applicant further asserts the claimed invention displays surprising results exemplified by the instant specification at [para 0120-0121] that could not have been predicted.
Applicant’s Declaration under 37 CFR 1.130(a) has been fully considered, and the rejections under 35 USC 103 that included the Kaizer reference have been withdrawn above as a result of the prior art exception under 35 USC 102(b)(1)(A).
To the extent applicant’s remarks apply to the new rejections set forth above, applicant’s remarks are considered and found not convincing. Regarding Applicant’s remarks set forth in the previous response filed 03/26/2025, these remarks are directed to prior art combinations involving the Cambridge reference, and as said rejections have been withdrawn, Applicant’s arguments are not directed to the rejections of record.
Regarding Applicant’s assertion that the claimed invention displays surprising results exemplified by the instant specification at [para 0120-0121] that could not have been predicted, the assertion is being interpreted as an allegation of unexpected results.
According to MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention, and the results proffered by Applicant correspond to Ven-PegC treatment of a xenograft model of AML, which is not commensurate in scope with the invention of “A method of treating cancer in a subject or prolonging survival of a subject having cancer, comprising administering synergistically therapeutic amounts of a first agent that depletes plasma glutamine and a second agent that inhibits BCL-2 activity to a subject having cancer”. Therefore the requirements of MPEP 716.02(d) are not satisfied.
According to MPEP 716.02(e), unexpected results must be compared with the closest prior art. As the data proffered by Applicant is found in the instant specification, there is no comparison with any prior art. Therefore the requirements of MPEP 716.02(e) are not satisfied.
For these reasons, Applicant’s allegations of unexpected results is considered insufficient to rebut a prima facie case of obviousness.
It is noted that these allegations of unexpected results are directed to rebut the combination of Emadi, Cambridge and Kaizer, and rejections using this combination of prior art references have been withdrawn, the allegations are not relevant to the rejections of record.
Conclusion
Status of the Application:
Claims 1-5, 8-13, 16 and 19-23 are pending.
Claims 1-5, 8-13, 16 and 19-23 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656