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 the species of Adiponectin in the reply filed on 7/20/2026 is acknowledged.
Adiponectin Receptor Agonists (ARA) are the non-elected species.
Claims 22, 24, 29-30, and 31 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of Adiponectin and Adiponectin Receptor Agonists is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: These are structurally different compounds. At least for example, Adiponectin is a 244 amino acid polypeptide hormone and Adiporon (a specific Adiponectin Receptor Agonist) is a small organic molecule. See at least page 2 of the restriction requirement mailed 5/19/2026.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
The claims should be amended so that they are directed to the elected embodiment only.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the figures are not numbered in accordance with 37 CFR 1.84(u)(1). The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear. At least for example, FIG. 1a, FIG. 2EA and FIG. S1a do not meet these numbering requirements. Applicant should review the numbering for all of the figures. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Pages 94-95 disclose nucleic acid sequences but do not reference the required sequence identifiers.
Appropriate correction is required.
Claim Objections
Applicant is advised that should claim 33 be found allowable, claim 39 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Both claims depend upon claim 32 and recite the same limitations.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 22-41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods as discussed below, does not reasonably provide enablement for all methods encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 22 is directed to a method of treating immune checkpoint blockade (ICB)-induced immune related adverse events (irAEs) in a subject, comprising administering a therapeutically effective amount of Adiponectin or Adiponectin Receptor Agonist (ARA) to the subject.
by the checkpoint blockade therapy.
Claim 31 is directed to a method for treating a subject with ICB-induced irAEs, the method comprising: administering a combination of a therapeutically effective amount of Adiponectin or ARA with an anti-tumor immunotherapy comprising administering lymphocytes to the subject.
Claims 22 and 31 treat ICB-induced immune related adverse events (irAEs). While the specification provides some examples of such adverse events (such as ICB-induced colitis), it does not provide a clear definition of what is included or excluded. Paragraph [0367] of the specification states that “the term ‘Immune-related adverse events’ (irAE) relates any side
effect specific that specifically occur in the context of an immune checkpoint inhibitor
treatment, for example in the context of a cancer therapy. IrAEs are unique and are
different to adverse events occurring in the context of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or
system.” This definition is ambiguous and does not clearly set forth the biological conditions that must be treated. See also claim 27 which is directed to the method of claim 22, wherein the irAEs affect the gastrointestinal tract, lungs, endocrine glands, skin, liver, or any combination thereof. This claim does not clearly set forth the biological conditions that must be treated.
Paragraph [0444] defines a "therapeutically effective amount" as referring to a quantity of a specified compound sufficient to achieve a desired effect in a subject being treated with said compound. This definition is ambiguous and does not clearly set forth the therapeutic effects that must be achieved. Claims 22 and 31 do not require any particular therapeutic effect and as such, all therapeutic effects encompassed by the claims must be enabled for all adverse effects encompassed by the claims. Only claims 29 and 41 recite the specific therapeutic effect of reducing ICB-induced colitis.
Example 1 of the specification evaluates the severity of irAE before initiation of extracorporeal photopheresis. The DSS-induced colitis model experiment described in paragraph [0457] administers adiponectin. Dextran sodium sulfate (DSS) is administered to induce colitis. Acute colitis was induced in mice and the mice were injected with an immune checkpoint inhibitor. Treatment with extracorporeal photophoresis (ECP) treated splenocytes was performed where in some cases adiponectin was also administered. See also paragraph [0494]. Example 1 also discloses the experiment where splenic T-0cells treated with adiponectin were injected into mice with colitis. These mice had received DSS to induce colitis and had been injected with anti-PD1 (this is assumed to mean an anti-PD1 antibody but the example does not disclose this). Note that the colitis is not induced by the checkpoint inhibitor.
Page 107 of the specification discloses that mice were treated with 3% DSS and anti-PD1 to induce colitis (Figures Sla). Anti-PD1 treatment increased colitis severity compared to the isotype (Figures S1b and S1c) indicating ICI-induced colitis. DSS and anti-PD1 treatment reduced the body weight of the mice consistent with the development of colitis (Figure 1a). Transfer of ECP-treated donor splenocytes reduced weight loss (Figure 1a) and prevented inflammation-induced colon shortening compared to the group treated with anti-PD1 alone (Figures 1b and 1c). Colon length was reported as a surrogate parameter for the severity of ICI-induced colitis and colon length and bodyweight were found to correlate (Figure S1d). In agreement with reduced colitis severity, reduced infiltration of neutrophil granulocytes (neutrophils) and lymphocytes in the colon wall of mice treated with ECP compared to the group treated with anti-PD1 was observed (Figures 1d-f). Transfer of untreated splenocytes (see instant claim 31) was not protective (Figures S1e-S1h) and improvement of colitis by ECP was comparable to steroid treatment (Figures Sli-S11). Comparable to splenocytes the use of PBMCs for the ECP-procedure induced protection from colitis (Figures S1m-S1p), indicating the comparability to the application of ECP in patients, where PBMCs are used. Transplantation of ECP-treated splenocytes showed similar results with DSS/anti-CTLA4-induced colitis (Figures S2a- S2d), which is frequently applied in combination with anti-PD1 as a treatment in metastatic melanoma.
ECP reduces ICI-induced colitis in mice by causing production of adiponectin in recipient cells. See paragraph [0501].
Paragraph [0502] of the specification discloses that ECP-treated leukocytes underwent rapid apoptosis in vitro, and only the combination of ultraviolet A light (UVA) and 8-Methoxypsoralen (8-MOP), which is ECP, induced cell death (Figures S4a and S4b). (See instant claims 32-35 and 38-39.)
Paragraph [0508] of the specification discloses application of an adiponectin receptor agonist (AdipoRon, ARA) or recombinant adiponectin in mice with DSS/anti-PD1-induced colitis (Figures 4a-h). Both treatments synergized with ECP to reduce ICI-induced colonic inflammation (Figures 4i-p). ARA-treatment was not only effective in anti-PD1-mediated colitis, but also in DSS/anti-CTLA4-induced intestinal inflammation (Figures S10a-S10d). This data showed that adiponectin signaling can reduce the severity of colitis induced by ICI-therapy and that it acts synergistically with ECP.
The results from these examples cannot be extrapolated to support the breadth of the claims with respect to all irAEs embraced by the claims and all therapeutic effects embraced by the claims. At least for example the DSS-induced colitis model would not have been a known model for the treatment of the irAEs in Table S3 on page 119 such as iron deficiency, dry eye, bronchitis, unsteady gait, disorientation, and infections (e.g. bacterial, viral, fungal). At least for example, there is no evidence of record nor reason to believe that administration of adiponectin would cure, improve, or reverse any of these conditions. The specification and prior art of record do not provide examples or guidance for treating these conditions with adiponectin. These conditions have different biological mechanisms as compared to ICB-induced colitis.
The scope of the claims is not enabled.
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.
Claims 22-41 are 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.
Claims 22 and 31 treat ICB-induced immune related adverse events (irAEs). While the specification provides some examples of such adverse events (such as ICB-induced colitis), it does not provide a clear definition of what is included or excluded. Paragraph [0367] of the specification states that “the term ‘Immune-related adverse events’ (irAE) relates any side
effect specific that specifically occur in the context of an immune checkpoint inhibitor
treatment, for example in the context of a cancer therapy. IrAEs are unique and are
different to adverse events occurring in the context of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or
system.” This definition is ambiguous and does not clearly set forth the metes and bounds of the claims for irAEs. In addition, claims 22 and 31 recite a “therapeutically effective amount” without specifically the specific therapeutic effect that must be achieved. The metes and bound of the claims cannot be determined.
Claim 25 is confusing in reciting “wherein the checkpoint blockade therapy comprises administration of at least one antibody.” The claim does not clearly identify which checkpoint protein is being blockaded and the antibody is not required to be directed against that checkpoint protein. Applicants are cautioned against introducing new matter.
Claim 26 is directed to the method of claim 25, “wherein the at least one antibody is selected from the group comprising cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and/or programmed cell death ligand-1 (PD-L1) or Lymphocyte-activation gene 3 (LAG-3).” This language is confusing. The language “selected from the group consisting of A, B, or C” is conventional language. The language “selected from A, B, and C” is conventional language. The group of this claim is open-ended (“comprising”) and the “and/or programmed cell death ligand (PD-L1) or Lymphocyte-activation gene 3 (LAG03)” language does not clearly identify the choices. Furthermore, the claim as written refers to targets of the antibodies and not antibodies themselves. For example, CTLA-4 is not an antibody. Applicant may have intended to recite an anti-CTLA-4 antibody. Applicants are cautioned against introducing new matter.
Claim 27 is confusing in reciting “wherein the irAEs affect the gastrointestinal tract, lungs, endocrine glands, skin, liver, or any combination thereof.” The specification and claims do not provide a limiting definition for the “affects” encompassed. For example, while the specification and claim 28 disclose ICB-induced colitis (which would affect the gastrointestinal tract), it is not known what other effects are included or excluded. The metes and bounds of the claim cannot be determined.
Claim 30 is confusing as it lacks antecedent basis in claim 22 for “does not interfere with an anti-tumor response induced by the checkpoint blockade therapy. Claim 22 does not recite that any checkpoint blockade therapy has been administered or that any anti-tumor response is induced or required by any such therapy.
Claim 31 is confusing in reciting “with an anti-tumor immunotherapy.” The subject of claim 31 is not required to have a tumor/cancer.
Claim 32 is confusing as to whether the lymphocytes present in the sample derived from an isolated blood sample of the subject and treated as set forth in claim 32 are isolated and administered (see claim 31) or whether the entire treated blood sample (containing lymphocytes) is administered.
Claim 36 is confusing in reciting “wherein the anti-tumor immunotherapy is extracorporeal photopheresis.” This lacks clear antecedent basis in claim 31 as claim 31 recites that the anti-tumor immunotherapy comprises administering lymphocytes to the subject.
Claim 38 is confusing as to whether the immunoregulatory T cells present in the sample derived from an isolated blood sample of the subject and treated as set forth in claim 38 are isolated and administered (see claims 31 and 37) or whether the entire treated blood sample (containing immunoregulatory T cells) is administered.
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 (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.
Claims 22-41 are rejected under 35 U.S.C. 103 as being unpatentable over Zeiser et al. (WO 2021/122969, of record, published 24 June 2021) in view of Nishihara et al. (2006) and Matsuzawa et al. (U.S. Patent No. 7,863,243).
Zeiser et al. (WO 2021/122969, of record, published 24 June 2021) discloses providing a sample derived from a blood sample of a subject that has received a checkpoint-inhibitor therapy and is suspected of developing or has developed symptoms of immune-related adverse events (irAE), adding a photosensitizing agent to the sample, and subjecting the sample to irradiation, which preferably generates immunoregulatory NK cells in said sample and then administering those immunoregulatory NK cells (a type of lymphocyte, see at least page 22) to treat irAE in a subject that has received a checkpoint-inhibitor therapy. T cells and regulatory T cells are disclosed. See also page 12, third and fourth full paragraphs, and instant claims 37-38. The photosensitizing agent can be 8-methoxypsoralen and/or the irradiation can be UVA irradiation. Checkpoint inhibitors such as anti-CTLA4 antibodies and anti-PD-1 antibodies are disclosed. See at least abstract and claims. Colitis is an immune related adverse effect from checkpoint-inhibitor therapy such as administering anti-CTLA4 and anti-PD-1 antibodies. See at least page 2. The steps of instant claims 32-35 are disclosed in at least the claims. Using checkpoint inhibitors to treat cancer is disclosed. See at least claims 8, 10, and 13-15 and pages 1-2. The reference does not disclose administering adiponectin.
Nishihara et al. (2006) discloses that adiponectin is protective against DSS-induced colitis. See at least abstract.
Matsuzawa et al. (U.S. Patent No. 7,863,243) discloses that adiponectin is an anti-tumor agent that can be used to treat cancer. The intravenous injection dosage is 1 to 100 mg/kg/day, preferably 3 to 20 mg/kg/day. See at least abstract; claims; column 3, and column 4, lines 15-22.
It would have been obvious to administer adiponectin in combination with electrocorporeal photopheresis (ECP) in a subject with ICB-induced colitis where the subject was being treated or had been treated with a checkpoint inhibitor such as an anti-CTLA-4 antibody or an anti-PD-1 antibody to treat cancer as taught by Reiser et al. in order to reduce colitis. Nishihara et al. discloses that administration of adiponectin also reduces colitis and Matsuzawa et al. discloses that administration of adiponectin treats cancer. One would have been motivated to do so in order to provide additional therapies that reduced irAEs. Note that the preferred dosage range disclosed by Matsuzawa et al. is within the dosage range for adiponectin disclosed in the instant application at paragraph [0445].
With respect to instant claim 22, the claim encompasses administering adiponectin while performing ECP therapy in view of the “comprising” language.
With respect to instant claim 24, administering adiponectin during administration of the checkpoint inhibitor is fairly suggested by the prior art.
With respect to instant claim 30, there would have been no expectation that adiponectin interfered with the anti-tumor response induced by the checkpoint blockade therapy. Checkpoint inhibitors and adiponectin act by different mechanisms.
The prior art of record and not relied upon is considered pertinent to applicant's disclosure.
U.S. Patent No. 12,491,248 (of record) is the 371 filing of Zeiser et al. (WO 2021/122969, of record, published 24 June 2021).
The Qin Zhao et al. publication (2018, of record) suggests that adiponectin administration alleviates DSS-induced colonic inflammation in mice. It has an anti-inflammatory effect on intestinal epithelial cells. See at least abstract and discussion. This publication was retracted on 31 March 2022.
Campbell et al. (of record, 2005, Abstract S1380) discloses extracorporeal photopheresis (ECP) using 8-methoxypsoralen (8-MOP) and UVA light. Administration of ECP-treated cells promotes the generation of regulatory T cells that are capable of modulating immune responses. Regulatory T cells have shown protective effects in an animal model of colitis.
Conclusion
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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