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 .
This Office action is responsive to Applicant’s supplemental preliminary amendment and remarks, filed 10 June 2026.
This application is a domestic application, filed 24 Oct 2023; and claims benefit of provisional application 63/380,678, filed 24 Oct 2022.
Claims 1-18 are pending in the current application. Claims 14-18, drawn to non-elected inventions, are withdrawn. Claims 1-13 are examined on the merits herein.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13, in the reply filed on 24 April 2026 is acknowledged.
Claims 14-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24 April 2026.
Applicant’s election of species of conjugate of PARP1 and the effector molecule GCSF comprising SEQ ID no 1 in the reply filed on 24 April 2026 is acknowledged.
Search and examination has expanded to include the species of conjugate of PARP1 with anti-human epidermal growth factor receptor 2 (HER2) antibodies as the effector molecule and the species of conjugate of PARP1 with monomethyl auristatin F (MMAF) as the effector molecule; and include the species of conjugate of PARP1 and thee effector molecule comprises an interleukin, an interferon, a tumor necrosis factor, a granulocyte colony stimulating factor (GCSF), or a granulocyte-macrophage colony stimulating factor (GM-CSF).
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 11 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 11 recites “The conjugate of claim 1 wherein a ratio of the effector molecule conjugated to the automodified PARP is about 5:1 to about 100:1.” The claim is indefinite because it is unclear how the ratio is defined, such as a molar ratio or a weight ratio. For example, the specification in example 2 at paragraph 96 as published describes the embodiment of a GCSF-alkyne conjugated onto PARylated PARP1 with a molar ratio of 20:1, however the specification does not clearly define the term “ratio” to mean a molar ratio.
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.
Claims 1-7 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shi et al. (Chem. Sci., 2020, 11, p9303-9308, provided by Applicant in IDS filed 15 March 2024, first published 17 Aug 2020, Electronic Supplementary Information cited in PTO-892).
Shi et al. discloses generation of an auto-PARylated PARP1 with 3’-azido ADP-riboses and subsequent conjugations of anti-human epidermal growth factor receptor 2 (HER2) antibodies and monomethyl auristatin F (MMAF) payloads (page 9303, abstract), meeting limitations of claim 1 and 6-7, where the antibody and/or the drug MMAF is interpreted as an effector molecule. In the design of the conjugate at least one of the plurality of 3’-azido ADP-riboses is not conjugated to an effector molecule, the 3’-azido ADP-riboses have the structure of claimed Formula I, the antibody is linked to the automodified PARP1 through an alkyne-containing linking group NHS-PEG4-BCN, and the MMAF is linked to the automodified PARP1 through an alkyne-containing linking group DBCO (page 9304, figure 1), meeting limitations of claims 1-7. The PARP1 conjugates were prepared at a molar ratio of 1:20 PARylated PARP1:payload (Supplementary Information page S9, paragraph 4), meeting limitations of claim 11.
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.
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 8 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Chem. Sci., 2020, 11, p9303-9308, provided by Applicant in IDS filed 15 March 2024, first published 17 Aug 2020, Electronic Supplementary Information cited in PTO-892) as applied to claims 1-7 and 11, in view of List et al. (Molecular Cancer Therapeutics, 2014, 13(11), p2641-2652, cited in PTO-892).
Shi et al. teaches as above. Shi et al. further teaches antibody-drug conjugates (ADCs) are one of the fast-growing classes of therapeutics that exploit monoclonal antibodies for cell- and tissue-specific drug delivery (page 9303, right column, paragraph 2). Similar to ADCs with pyrophosphate diester-derived linkers, poly-ADP-ribose (PAR) polymer–drug conjugates may allow to stably carry payloads in plasma and rapidly release drugs upon internalization into target cells. Collectively, PAR polymer-based ADCs may provide improved physicochemical properties, therapeutic efficacy, and safety profiles (page 9304, left column, paragraph 2). Trastuzumab and MMAF were selected as a model targeting antibody and cytotoxic payload for synthesizing the PAR polymer-based ADC (page 9304, right column, paragraph 2).
Shi et al. does not specifically disclose the conjugate wherein the effector molecule comprises an interleukin, an interferon, a tumor necrosis factor, a granulocyte colony stimulating factor (GCSF), or a granulocyte-macrophage colony stimulating factor (GM-CSF) (claim 8). Shi et al. does not specifically disclose a composition comprising the conjugate and a pharmaceutically acceptable carrier (claim 12).
List et al. teaches the combination of immunostimulatory agents with cytotoxic drugs is emerging as a promising approach for potentially curative tumor therapy. List et al. teaches a multipayload class of targeted drugs, the immunocytokine-drug conjugates (IDC), which combine a tumor-homing antibody, a cytotoxic drug, and a proinflammatory cytokine in the same molecular entity. In particular, the IL2 cytokine and the disulfide-linked maytansinoid DM1 microtubular inhibitor could be coupled to the F8 antibody (page 2641, abstract). Antibody–drug conjugates (ADC) are armed versions of monoclonal antibodies, which may deliver a highly potent cytotoxic agent at the tumor site, thus helping spare normal tissues. Similarly, a large number of proinflammatory cytokines have been genetically fused to tumor-targeting recombinant antibodies, yielding fusion proteins (termed "immunocytokines") which display a potent therapeutic activity in mouse models of the disease and encouraging results in patients with cancer (page 2641, right column, paragraph 3). List et al. teaches in vivo experiments wherein the conjugates were injected compared to a control group of saline solution (page 2648, right column, paragraph 2), implying the conjugate formulated in a pharmaceutically acceptable carrier of saline. In principle, the IDC strategy should be broadly applicable to a variety of antibodies, cytokines, and cytotoxic agents. Examples of cytokines for use in this strategy include IL2, TNF, GM-CSF, IFNα, and IFNβ (page 2649, left column, paragraph 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Shi et al. in view of List et al. in order to combine the PAR polymer-based ADCs of Shi et al. with the immunocytokine taught by List et al. One of ordinary skill in the art would have been motivated to combine Shi et al. in view of List et al. with a reasonable expectation of success because List et al. teaches the IDC strategy as an improvement over the ADC strategy such as taught by Shi et al., Shi et al. teaches the specific embodiment serves as a model of the, and List et al. teaches the IDC strategy should be broadly applicable to a variety of antibodies, cytokines, and cytotoxic agents, suggesting it would have been obvious to combine Shi et al. in view of List et al. in order to improve similar ADC compounds in the same way with a reasonable expectation of success.
Claims 9 and 13 is rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Chem. Sci., 2020, 11, p9303-9308, provided by Applicant in IDS filed 15 March 2024, first published 17 Aug 2020, Electronic Supplementary Information cited in PTO-892) in view of List et al. (Molecular Cancer Therapeutics, 2014, 13(11), p2641-2652, cited in PTO-892), further in view of Metcalf (Nature Reviews Cancer, 2010, 10, p425-434, cited in PTO-892).
Shi et al. in view of List et al. teaches as above.
Shi et al. in view of List et al. does not specifically teach the effector molecule comprises granulocyte colony stimulating factor (GCSF) (claim 9 and 13).
Metcalf teaches four colony-stimulating factors (CSFs) are glycoproteins that regulate the generation and some functions of infection-protective granulocytes and macrophages. Recombinant granulocyte-CSF (G-CSF) and granulocyte–macrophage-CSF (GM-CSF) have now been used to increase dangerously low white blood cell levels in many millions of cancer patients following chemotherapy (page 425, abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Shi et al. in view of List et al. further in view of Metcalf in order to select the cytokine to be GCSF. One of ordinary skill in the art would have been motivated to combine Shi et al. in view of List et al. further in view of Metcalf with a reasonable expectation of success because List et al. teaches the IDC strategy should be broadly applicable to a variety of antibodies, cytokines, and cytotoxic agents, and examples of cytokines for use in this strategy include GM-CSF, and Metcalf suggests recombinant G-CSF and GM-CSF are known for the same purpose regarding treatment of cancer, and it would have been obvious to substitute equivalents known for the same purpose with a reasonable expectation of success because the strategy should be broadly applicable to a variety of cytokines.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Chem. Sci., 2020, 11, p9303-9308, provided by Applicant in IDS filed 15 March 2024, first published 17 Aug 2020, Electronic Supplementary Information cited in PTO-892) in view of List et al. (Molecular Cancer Therapeutics, 2014, 13(11), p2641-2652, cited in PTO-892) and Metcalf (Nature Reviews Cancer, 2010, 10, p425-434, cited in PTO-892) as applied to claims 1-9 and 11-13 above, and further in view of DeFrees et al. (US 7,956,032, issued 07 June 2011, cited in PTO-892).
Shi et al. in view of List et al. and Metcalf teaches as above.
Shi et al. in view of List et al. and Metcalf does not specifically teach the GCSF comprises SEQ ID No 1. (claim 10).
DeFrees et al. teaches conjugates between Granulocyte Colony Stimulating Factor and PEG moieties (abstract). DeFrees et al. teaches GCSF can be used to accelerate neutrophil recovery from myelosuppressive treatments, and G-CSF decreases the morbidity of cancer chemotherapy by reducing the incidence of febrile neutropenia (column 1, line 35). The commercially available forms of recombinant human G-CSF have a short-term pharmacological effect. A molecule with a longer circulation half-life would decrease the number of administrations necessary to alleviate the leukopenia and prevent consequent infections (column 1, line 65 to column 2, line 5). DeFrees et al. teaches embodiments of the G-CSF peptide sequence for use in the conjugates of the invention such as SEQ ID no 5 (column 21, lines 55-60), which is the same peptide sequence as claimed SEQ ID no 1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Shi et al. in view of List et al. and Metcalf further in view of DeFrees et al. in order to select the GCSF to have the SEQ ID no 5 taught by DeFrees et al. One of ordinary skill in the art would have been motivated to combine Shi et al. in view of List et al. and Metcalf further in view of DeFrees et al. with a reasonable expectation of success because Shi et al. in view of List et al. and Metcalf teach the PAR polymer-based ADC further modified with recombinant G-CSF as taught above, and DeFrees et al. teaches G-CSF peptide sequence suitable for use in forming conjugates, making obvious selection of the G-CSF to have the SEQ ID no 5 taught by DeFrees et al. based on its suitability for its intended use. See also MPEP 2144.07.
Conclusion
No claim is found to be allowable.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693
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