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 present Application, filed July 2, 2024, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2023/060098, filed January 4, 2023, which claims the benefit of U.S. Provisional Patent Application No. 63/296,266, filed January 4, 2022.
Status of the Claims
In the amendment filed July 2, 2024, claims 2, 5, 17-20, and 24 are canceled and claims 3-4, 7, 13-16, 21-23, and 26 are amended. Claims 1, 3-4, 6-16, 21-23, and 25-27 are currently pending.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on June 2, 2024 and on March 23, 2026 are acknowledged.
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.
Claims 1, 3-4, 6-16, 21-23, and 25-27 are indefinite:
Claims 1, 3-4, 6-16, 21-23, and 25-27 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.
Claim 1 is indefinite for reciting, “one or more PARP1 inhibitors,” because a person of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. In particular, in the absence of any unifying theme of chemical structure or mechanism of action, or any baseline threshold of efficacy or specificity, one could not reasonably determine what constitutes a PARP1 inhibitor within the scope of claim 1. For example, without further definition, it would be unclear whether the phrase includes agents that indirectly diminish PARP1 activity by modulating upstream activity such as by reducing DNA strand break formation, or that decrease PARP1 expression. The claim 1 recitations of “one or more inhibitors of activated stromal/activated cancer-associated fibroblasts,” and “one or more modulators of TNFalpha, IL6 or JAK” are indefinite for substantially the same reason.
Furthermore, and with respect to “inhibitors of activated stromal/activated cancer-associated fibroblasts,” it would be unclear whether such inhibition constitutes inhibition of fibroblast reproduction, inhibition of fibroblast survival, inhibition of fibroblast activation or migration, inhibition of other fibroblast-related activities, or any or all of the above. Finally, the recitation of “activated stromal/activated cancer-associated fibroblasts” renders it unclear whether the slash corresponds to a disjunctive (“or”) or conjunctive (“and”) reading. Activated cancer-associated fibroblasts is understood as constituting a sub-category of activated stromal fibroblasts, and it would be unclear whether the recited inhibitor must inhibit activated cancer-associated fibroblasts, or may acceptably inhibit any activated stromal fibroblasts, including non-cancer-associated fibroblasts.
Claims 3-4, 6-16, 21-23, and 25-27 are indefinite for depending directly or indirectly from claim 1 without fully curing this indefiniteness.
Claim 13 is further indefinite for reciting the limitation “the Olaparib and PEGPH20” in lines 1-2. This lacks antecedent basis in the base claim, at least with respect to “the Olaparib.” It is unclear whether the definite article also applies to PEGPH20.
Claim 22 is further indefinite for reciting the limitation “the JAK inhibitor” in lines 1-2. This lacks antecedent basis in the base claim, which recites “one or more modulators of…JAK.” Claims 23 and 25 are likewise further indefinite for reciting “the IL6 inhibitor” and claim 26 is further indefinite for reciting “the TNFalpha inhibitor” because each of these similarly fails to have antecedent basis in the base claim which recites “one or more modulators of TNFalpha [or] IL6.”
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 1, 3-4, 6-12, 14-16, 21-23, and 26-27 are obvious over Sun:
Claims 1, 3-4, 6-12, 14-16, 21-23, and 26-27 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent Application Publication No. US 2021/0008053 A1 to Sun et al. (hereinafter “Sun”).
Claim 1 recites a method comprising administering to a subject in need thereof: (a) one or more PARP1 inhibitors; and (b) one or more inhibitors of activated stromal/activated cancer-associated fibroblasts or one or more modulators of TNFalpha, IL6, or JAK.
Sun teaches methods of treating a subject with a disease or condition comprising administering a first agent that inhibits poly [ADP-ribose] polymerase (administering to a subject in need thereof one or more PARP inhibitors) and a second agent that can be a regulatory T cell (Treg) inhibitory agent , an antigen specific immune response enhancer agent, or a combination thereof. Sun teaches that an exemplary PARP inhibitor for use with the method is Niraparib (paragraph [0088]), an inhibitor of both PARP1 and PARP2, and thus constitutes “one or more PARP1 inhibitors.”
Sun further teaches an exemplary second agent is siltuximab (paragraphs [0010] and [0155]). Siltuximab is a “modulator of IL6” (see, for example, the non-patent publication, Siltuximab: First Global Approval, Drugs, 74, pgs. 1147-1152 (2014 by Markham et al. (hereinafter, “Markham”), which states that siltuximab is an Interleukin-6 inhibitor that is associated with sustained reduction in IL-6 levels (pg. 1148, Features and properties of siltuximab)). More generally, Sun teaches that a combination therapy with an agent that regulates activity within the tumor microenvironment and an agent that inhibits PARP is useful to treat certain cancers (paragraph [0028]) and particularly that the combination of a PARP inhibitor with a second agent that modulates activity of TAMs (Tumor-associated macrophages) in the tumor microenvironment is useful (paragraphs [0159]-[0160]). Further, Sun teaches that anti-IL6 agents can be effective macrophage (e.g. TAM) inhibitory agents (e.g. paragraph [0021]) and lists siltuximab (paragraph [0021]), among several other alternatives, as a suitable exemplary macrophage inhibitory agent (paragraph [0021]).
In view of these teachings of Sun, it would have been at least obvious to perform the method of Sun by co-administering a PARP1 inhibitor such as niraparib with an IL-6 inhibitory agent, such as siltuximab, as second agent. Sun thus teaches, or at least renders obvious, a method comprising administering to a subject having a disease (a subject in need thereof) a PARP inhibitor such as niraparib (one or more PARP1 inhibitors) and a second agent such as siltuximab (one or more modulators of IL6).
With respect to claim 3, Sun teaches that the method is particularly applicable to the treatment of cancer (e.g. Abstract and claim 1). With respect to claim 4, Sun teaches that a suitable cancer for treatment is primary peritoneal cancer (a primary cancer – paragraph [0187]). With respect to claim 6, as noted above, Sun teaches that niraparib is an exemplary PARP inhibitor for use in the method (paragraph [0088]).
Claims 7-12 recite narrowed lists of available inhibitors of activated stromal/activated cancer-associated fibroblasts, but none of these claims require that such inhibitors be used, as opposed to using one or more modulators of IL6, for example. Thus, none of claims 7-12 excludes the method of Sun as described in reference to claim 1, and claims 7-12 are therefore obvious for the same reasons as is claim 1. Claims 22 and 26, which narrow the available options for modulators of JAK or modulators of TNFalpha, are likewise obvious according to the same reasoning; they do not require that the method employ a modulator of JAK or of TNFalpha as opposed to a modulator of IL6 and are therefore obvious for the same reason as is claim 1.
With respect to claim 14, Sun teaches that in some embodiments, the administering comprises administering the first agent (PARP1 inhibitor) before administering the second agent (e.g. siltuximab) – see paragraph [0020]. With respect to claim 15, Sun further teaches more generally that the administering comprises administering the first and second agent sequentially (paragraph [0020]). Since the only sequential administration other than administering the PARP inhibitor before the second agent is to reverse this order, the sequential administration of Sun plainly and foreseeably encompasses administration of the one or more PARP1 inhibitors after administration of the second agent, e.g. siltuximab. With respect to claim 16, Sun teaches simultaneous administration of the first and second agents (PARP1 inhibitor and, e.g. siltuximab).
With respect to claim 21, Sun teaches that administration (of the first and/or second agent) can be by any of a variety of routes, including systemic administration routes such as intravenous (paragraph [0050]).
With respect to claim 23, the siltuximab of Sun is an IL6 inhibitor that is an antibody (see, for example, Markham, Abstract). With respect to claim 27, Sun teaches pharmaceutical combinations having a first agent (PARP1 inhibitor) and second agent of the type described above (e.g. paragraph [0016]).
Claim 25 is obvious over Sun and Sukhatme:
Claim 25 is rejected under 35 U.S.C. § 103 as being unpatentable over Sun, in view of U.S. Patent Application Publication No. US 2019/0290614 A1 to Sukhatme et al. (hereinafter “Sukhatme”).
Claim 25 recites the method of claim 1 wherein the IL6 inhibitor comprises ARGX-109, FE301, or FM101. Sun is applied to claim 25 as to claim 1, above, but does not expressly teach the element wherein the IL6 inhibitor (i.e. the second agent of Sun) is ARGX-109, FE301, or FM101. It would have been obvious, however, to substitute the siltuximab of with ARGX-109, FE301, or FM101 because these were all known in the art as being anti-IL6 antibodies with IL6 inhibitory activity, with similar mechanisms of action and therapeutic utilities. See, for example, Sukhatme.
Sukhatme teaches methods of reducing the risk of cancer recurrence, involving combining a COX-1 inhibitor with a second agent such as an IL-6 inhibitor (Abstract). Sukhatme further teaches that when IL-6 inhibitor is used, it can be an anti-IL-6 antibody such as siltuximab, ARGX-109, FE301, or FM101 (among several others, see paragraph [0017]). In view of the teaching of Sun that an anti-IL6 antibody, siltuximab, functions as an effective IL6 inhibitor to inhibit macrophage recruitment in effective concert with a PARP1 inhibitor to treat cancer, and in view of the teaching of Sukhatme that siltuximab, ARGX-109, FE301, and FM101 are all anti-IL6 antibodies with IL6 inhibitory activity, it would have been obvious to try, and one would have had a reasonable expectation of success in the effort, to substitute any of ARGX-109, FE301, or FM101 for the siltuximab of Sun.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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