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 .
Application Status and Election
Claims 1-12, 14 and 37 are pending.
Applicant’s election with traverse of decreasing infiltration of Type 2 immune cells in a tumor microenvironment (TME) and an IL-33 inhibitor is acknowledged. Applicant timely traversed the election requirement in the reply filed on September 8, 2026. The traversal is on the ground(s) that the present genus of 3 therapeutic outcomes and 4 therapeutic agents each represents a finite and not unreasonable number of species. This is not found persuasive because each of the genera is not just 3 and 4 species. Each “species” required for the election is actually a huge genus. As indicated below, the elected species of “IL-33 inhibitor” is itself an extremely large and diverse genus of molecules that includes nucleic acids, antibodies, peptide, aptamers and small molecules. Each class of molecules then also is a genus of molecules that in some cases like peptides may have no structural similarity to other species in the same genus. Additionally, the “therapeutic outcomes” is actually four (4) different outcomes. “Treating cancer comprising a KRAS(G12D) substitution” is completely independent from “decreasing section of IL-33 in a TME of a cancer”. One outcome is limited to specific cancers and encompasses a wide variety of means for treating (i.e., cytotoxicity) while the other is not limited to specific cancers and requires a specific mechanism involving IL-33. As such, the outcomes are not necessarily related. Nonetheless, the Application is a 371 application and as such a species restriction is based on lack of unity and not on a search burden. Applicant does provide arguments traversing the lack of unity analysis in the Restriction Requirement. The requirement is still deemed proper and is therefore made FINAL.
The restriction requirement required that if an inhibitor, such as an IL-33 inhibitor was elected, that Applicant also needed to elect a specific inhibitor, such as an antibody or shRNA. Examiner telephoned Applicant’s representative Gibson Lanier (Reg. No. 57,519) on October 6, 2026 to request an election of a specific IL-33 inhibitor. Applicant elected an IL-33 antibody. During the course of examination, an IL-33 shRNA was found. The genus of examined species now includes both IL-33 antibodies and generic shRNAs.
Claims 2-4, 7-10 and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species, there being no allowable generic or linking claim.
Claims 1, 5-6, 11-12 and 37 are under examination along with generic IL-33 antibodies and shRNAs.
Specification
The use of the term Matrigel®, ParaVision®, IVIS®, TRIzol®, RNeasy®, SYBR®, SureCell®, NextSeq®, Lipofectamine®, Pannoramic®, Nextera®, TapeStation®, MiSeq®, TALEN®, Quantikine®, and GraphPad® which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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 5 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 5 contains the trademark/trade name TALEN. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe transcription activator-like effector nucleases, accordingly, the identification/description is indefinite. Although TALEN is used as an acronym, it nevertheless is a trademarked term.
To overcome this rejection, it is suggested that “TALEN” be replaced with “TALE nuclease”.
Claim Rejections - 35 USC § 112(a)
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 1, 5-6, 11-12 and 37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species' means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
Claim 1 recites an IL-33 inhibitor, an ST2 inhibitor, and an MEK inhibitor, each of which represents a genus of molecules that are defined by their function of inhibiting a gene/protein, rather than their structure. Some such inhibitors are listed in the specification on page 2 and include antisense RNAs such as shRNA, small molecules and antibodies, and site-specific DNA modifiers such as Cas9/sgRNA and TALENs comp. Although not discussed in the Specification, the genus of inhibitors also includes aptamers, which are nucleic acids that can inhibit a protein based on a 3D folding of the DNA/RNA, and not through complementary base pairing. The Specification describes antibodies “generally” including how they are produced (pages 27-28), and also discusses antibody fragments (pages 29-30) and humanized antibodies (page 30). Although the Specification lists various characteristics of many inhibitors, the Specification does not provide any structural detail for the inhibitors. Lastly, because the inhibitors are used in a method within a tumor microenvironment (TME), any inhibitors must be able to be delivered to and work in vivo.
Regarding nucleic acid-based and CRISPR-based, TALEN-based, and ZFN-based inhibitors, the genomic and expressed transcript sequences of IL-33, ST2 and MEK are well known in the art based on GenBank entries. Because there is a known correlation between the structure of RNAi antisense molecules and/or guide RNAs and their inhibitory function, one skilled in the art could have predicted the structure of antisense inhibitory RNAs and CRISPR guide molecules that have the claimed inhibitor function. Additionally, the “code” for designing TALENs and ZFNs is known in the art such that skilled artisan could design a TALEN or ZFN that can bind the genomic sequences of IL-33, ST2 and MEK. However, for the reasons described below, Applicant has not sufficiently described the genus of antibodies, aptamers and small molecules targeting IL-33, ST2, and MEK that have the claimed inhibitory function such that one skilled in the art could have reasonably concluded Applicant had possession of the genus as claimed.
The claims recite or encompass an IL-33, ST2 or MEK inhibiting antibodies, and therefore only identify the antibody by function. No IL-33, ST2 or MEK antibody structure is recited in the claims that correlates to the claimed function of inhibiting their respective function. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. To provide adequate written description and evidence of possession of the claimed antibody inhibitor genus, the instant specification in view of the art must structurally describe representative antibodies that function as an inhibitor, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
The specification describes “general” methods and characteristics to produce inhibitory antibodies. However, Applicants do not demonstrate any antibodies capable of inhibiting IL-33 ST2 or MEK function in vivo or in cells. The only demonstration of inhibition is with shRNAs targeted to IL-33 (page 37).
The Specification identifies AF3625 and AF6326 as IL-33 antibodies, and which are produced and sold by R&D System (pages 3 and 46). However, the working examples only use the antibodies for immunohistochemistry and immunofluorescence (page 46). Indeed, the product page for the antibodies only lists diagnostic-based uses for the antibodies (i.e., ELISA, western blot, immunocytochemistry) (https://www.rndsystems.com/products/human-il-33-antibody_af3625). There is no evidence in the art that the antibodies can be used therapeutically or are capable of inhibiting IL-33 function in vivo. A few therapeutic IL-33 and ST2 antibodies are in clinical trials (e.g., tozorakimab, astegolimab and itepekimab) but these are for respiratory diseases. There is no evidence that they are effective at binding to and inhibiting IL-33 or ST2 in a TME. Additionally, there are no known therapeutic MEK antibodies because MEK is an intracellular protein.
Although Applicants may argue that it is possible to screen for IL-33, ST2 and MEK antibodies that function as claimed in a TME, the court found in that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future IL-33, ST2 or MEK antibody yet to be discovered that may function as claimed.
Regarding aptamers and small molecules, although small molecule inhibitors of MEK are known in the art, a diligent search of the prior and contemporaneous art revealed no teachings of any small molecules known to inhibit IL-33 or ST2 in any way, or aptamers that could bind to and inhibit IL-33, ST2 or MEK and the specification identifies none. Around the time of the filing date, skilled artisans understood that discovering inhibitors of proteins generally was unpredictable. Wu observes that although computer-aided protein-inhibitor discovery technology was available, there is insufficient data to predict inhibitors of many proteins (Wu et al., Molecules (2019), 24: 4428, pages 1-14). Wu writes: [U]nder many circumstances, it is hard to find a [compound] library with functionally and structurally diverse molecules with quantitative activity data for a given protein. More importantly, the lack of publications with negative results hinders the identification of inactive molecules, resulting often in the development of qualitative common feature pharmacophores only from active compounds. Finally, as LBVS applications are generally based on the properties of the known ligands, the diversity of the hits discovered are generally limited. (Page 3 of 14, second paragraph.) Wu support a finding that skilled artisans expected genera of inhibitors of a given protein to be diverse and that as of the effective filing date, they would not have concluded that applicants possessed a representative number of species of small molecule inhibitors of inflammation and immune signaling in particular.
Given the lack of representative examples to support the full scope of the IL-33, ST2 and MEK inhibitors encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown sequences of antibodies and aptamers and the structure of small molecules that provide inhibition of IL-33, ST2, and/or MEK function, the specification does not provide an adequate written description of molecules that inhibit -33, ST2, and/or MEK function that is required to practice the claimed invention.
Claims 5, 11-12 and 37 do not limit or substantially limit the genus of inhibitors or specifically IL-33 inhibitors and are rejected for the reasons recited above for claim 1.
Claim 6 limits the IL-33 inhibitor to AF3625 or AF6326, which are not antibodies that can detect IL-33 in in vitro or diagnostic assays. However, as noted above there is no evidence that AF3625 or AF6326 could be used to inhibit IL-33 in a subject.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Wang et al., Biochemical and Biophysical Research Communications (2016), 479: 461e468).
Regarding claims 1, 5, and 12 Wang teaches an shRNA inhibits the expression of IL-33 (i.e., an IL-33 inhibitor that decreases expression of IL-33) (Section 2.2). Wang teaches administering the IL-33 shRNA to non-small cell lung cancer cells isolated from patients (NSCLC), which limited the cells outgrowth and invasion capacity (Fig. 2F-H, Fig. S3A). Wang teaches that IL-33 promotes NSCLC outgrowth and metastasis in vivo (Fig. 3M, N). Wang teaches blocking IL-33 is a promising therapeutic strategy for clinical treatment of NSCLC patients (page 468, ¶1).
Wang does not teach administering the IL-33 shRNA to a subject specifically in the tumor microenvironment (TME).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered Wang’s IL-33 shRNA to a patient having NSCLC and to expect that delivering the shRNA would decrease the secretion of IL-33 in the TME. It would have amounted to the using the shRNA in an obvious way. The skilled artisan would have been motivated to administer the shRNA to a patient based on the in vitro results that the IL-33 shRNA decreases tumor cell size and invasion capacity. Additionally, Wang suggests blocking IL-33 signaling as a therapeutic strategy in the clinic. It would have been entirely predictable that the IL-33 shRNA would decrease IL-33 secretion since the shRNA reduced IL-33 expression by over 50%. Since IL-33 is a secreted protein, the skilled artisan would have predicted that a 50% decrease in IL-33 expression would result in less IL-33 protein secreted.
Claims 1, 5, 12 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Wang et al., Biochemical and Biophysical Research Communications (2016), 479: 461e468) in view of Larsen (Larsen et al., International Journal of Molecular Sciences (2018), 19: 2676) and Ercolano (Ercolano et al., Frontiers in Immunology (2019), 10: 2801, pages 1-9). This rejection is also directed to the elected method of decreasing infiltration of Type 2 immune cells in a tumor microenvironment.
Regarding claims 1, 5, 12 and 37, Wang teaches an shRNA inhibits the expression of IL-33 (i.e., an IL-33 inhibitor that decreases expression of IL-33) (Section 2.2). Wang teaches administering the IL-33 shRNA to non-small cell lung cancer cells isolated from patients (NSCLC), which limited their outgrown and invasion capacity (Fig. 2F-H, Fig. S3A). Wang teaches that IL-33 promotes NSCLC outgrown and metastasis in vivo (Fig. 3M, N).
Wang does not teach administering the IL-33 shRNA to a subject specifically in the tumor microenvironment (TME) or that the IL-33 shRNA results in reduced Th2 or ILC2 cell infiltration.
Larsen teaches IL-33 signaling through its receptor ST2 has been shown to potently invoke T helper 2 (Th2) immune response and modulates the TME by recruiting immune cells that impact tumor phenotype and malignancy (page 2, ¶1). Larsen teaches that when secreted IL-33 acts as a cytokine “alarmin” by triggering an inflammatory cascade (page 2, ¶2). Larsen teaches that ST2 is expressed in Th2 lymphocytes (page 4, ¶1). Larsen teaches that active signaling by IL-33/ST2 results in activation of immune effector cells that leads to recruitment of pro-tumorigenic cells into the TME in cancer (page 4, ¶2). Larsen teaches “[c]onsistent with a pro-tumorigenic role, IL-33 and ST2 expression in patient tumor tissues were found to correlate with tumor progression in NSCLC patients.” (page 11, ¶2). Larsen teaches additional studies showed that IL-33 blockade inhibited tumor growth by inhibiting polarization of M2 tumor-associated macrophages and reducing accumulation of Tregs in the TME (sentence spanning pages 11-12).
Ercolano teaches that group 2 innate lymphoid cells (ILC2s) play a role in tumor settings and could be a target to improve current tumor immunotherapies (Abstract). Ercolano teaches ILC2s constitute are the most prominent ILC subset in the respiratory tract and respond rapidly to alarmins like IL-33 (page 5, ¶3). Ercolano teaches expansion of ILC2s in the periphery of lung tumors was accompanied by higher levels of IL-33 (page 5, ¶3).
Regarding claims 1, 5, 12 and 37, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered Wang’s IL-33 shRNA to a patient having NSCLC and to expect that delivery of the shRNA would decrease infiltration of ILC2s and/or Th2 cells into the TME. It would have amounted to the using the shRNA in an obvious way to bring out a predictable outcome. The skilled artisan would have been motivated to administer the shRNA to a patient based on the in vitro results that the IL-33 shRNA decreases tumor cell size and invasion capacity. Additionally, Wang suggests blocking IL-33 signaling as a therapeutic strategy in the clinic. It would have been entirely predictable that the IL-33 shRNA would result in decreased ILC2 and Th2 cells in the TME based on the teachings of Larsen and Ercolano. For instance, Larsen teaches that IL-33 signaling activates pro-tumorigenic immune cells in the TME, while Ercolano provides that ILC2s respond to IL-33 and are pro-tumorigenic in NSCLC. Thus, inhibiting IL-33 secretion would predictably decrease ILC2 activation and recruitment to the TME. Likewise, Larsen provides that Th2 cells have the highest expression of ST2 and therefore are predicted to respond to increased levels of IL-33 in the TME. Conversely, their activation in the TME would predictably decrease upon a reduction of IL-33 expression in the TME.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (Wang et al., Biochemical and Biophysical Research Communications (2016), 479: 461e468), Larsen (Larsen et al., International Journal of Molecular Sciences (2018), 19: 2676) and Ercolano (Ercolano et al., Frontiers in Immunology (2019), 10: 2801, pages 1-9) as applied to claims 1, 5, 12 and 37 above, and further in view of Kumar (Kumar et al., WIREs Nanomed Nanobiotechnol (2021), 13:e1677, available November 10, 2020).
The teachings of Wang, Larsen and Ercolano are recited above and applied as for claims 1, 5, 12, and 37. Larsen also teaches that therapies targeting IL-33/ST2 could be used to enhance immunotherapies against cancer (i.e., a combination therapy) (page 19, last ¶).
Kumar teaches the standard management of advanced stages of NSCLC includes chemoradiotherapy or neoadjuvant combination therapy (page 2, ¶1). Kumar teaches that to overcome drug resistance, several studies indicated that silencing specific genes using RNAi, possibly in combination with chemotherapy will be effective (page 2, ¶2). Kumar teaches shRNAs have been used to deliver siRNAs for treatment of NSCLC and in combination with anti-cancer agents (Table 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have combined the IL-33 shRNA taught in Wang with an anti-cancer agent for the treatment of NSCLC. It would have amounted to the simple combination of known prior art elements by known means to yield predictable results. The skilled artisan would have predicted that an anti-cancer agent could be administered to a patient with the IL-33 shRNA because Kumar teaches that other shRNAs have previously been delivered in combination with anti-cancer agents for treatment of NSCLC. The skilled artisan would have been motivated to administer the combination because Kumar teaches it is often needed to overcome drug resistance.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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