Patent Application 18941441 - INTERLEUKIN-18 VARIANTS AND METHODS OF USE

Title: INTERLEUKIN-18 VARIANTS AND METHODS OF USE

Application Information

Invention Title: INTERLEUKIN-18 VARIANTS AND METHODS OF USE
Application Number: 18941441
Submission Date: 2025-05-13T00:00:00.000Z
Effective Filing Date: 2024-11-08T00:00:00.000Z
Filing Date: 2024-11-08T00:00:00.000Z
Examiner Employee Number: 89569
Art Unit: 1674
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 2

Cited Patents

No patents were cited in this rejection.

Office Action Text

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 of Group I in the reply filed on 4/24/25 is acknowledged. As Applicant indicated, a typographical error appeared in the restriction mailed 4/24/25 that excluded claim 22 from the listed groups. Claim 22 is included in Group I, and will be examined as indicated below. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).

Claim Status
Claims 1-23 are pending.
Claim 23 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/1/25.
Claims 1-22 are currently under consideration for patentability under 37 CFR 1.104.

Specification
Lengthy Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.

Claim Objections
Claims 1-3 are objected to because of the following informalities: the claims contain acronyms and/or abbreviations that should be spelled out upon first occurrence. Appropriate correction is required.

Claims 13 and 17 are objected to because of the following informalities: the claims contain the abbreviation and/or acronym “WT” that should be spelled out upon first occurrence. Appropriate correction is required.

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 1-10 and 20-21 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “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.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy-resistant IL-18 variant polypeptide and a chimeric antigen receptor or “engineered” T cell receptor. The claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. There is no requirement for any particular parent polypeptide sequence in claims 1-10. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates possible locations of the mutations, without defining the parent polypeptide sequence. See also rejection under 35 USC 112(b) below. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable.
The specification does not adequately describe the modified IL-18 polypeptide. As a result, the polynucleotide that encodes the polypeptide is also not adequately described. The polypeptides are modified from a parent sequence that is not given in the claims. The specification provides one example base sequence as set forth in SEQ ID NO:30, but the claims are not limited to this parent sequence. The modifications must produce polypeptides with specific functions including acting as an IL-18 polypeptide (claim 1), having the functions of a “decoy resistant” IL-18 (claim 1), and having a Kd for IL-18BP of 10 nM or greater (claim 10). Notably, there is no specific definition for the term “decoy resistant” in the instant specification, which prevents any attempt at envisaging the encompassed genus of nucleic acids. The specification indicates that the polypeptide must act as a pro-inflammatory cytokine that can increase the number and/or activity of immune cells in vitro, in vivo or ex vivo, such as the number and/or activity of T cells, NK cells, and/or myeloid cells (see e.g. paragraph [0077] of the instant published application), and the IL-18 polypeptide can actively signal through IL-18R (see e.g. paragraph [0068] of the instant published application). The IL-18 variant polypeptide can have other functions including binding IL-18 receptor (IL-18R) and having decreased binding to IL-18BP compared to the wild type protein as set forth in SEQ ID NO:30. Species of mutations within the modified IL-18 proteins are presented in the dependent claims, although there is no base sequence required in which the mutations would occur. While the dependent claims present a set of 18 locations for the substitutions, of which as few as one site may be selected for substitution, the mutations are not limited to these sites. Further, specific substitutions, with defined alternative amino acids, are not identified for the mutation locations. The encompassed mutants number in the millions. The sequence of SEQ ID NO:30, which is just one possible parent sequence, has 157 amino acids, any of which can be mutated to any of the other 19 amino acids, creating a virtually unlimited number of possible single mutations and combinations of mutations within this one example parent sequence. There are also many other IL-18 proteins and homologs that could be the parent sequence for the mutation, which contributes to creating an even larger genus of variant proteins that are encoded by the nucleic acids of the instant claims. The specification does not define any corresponding structures for the required functionality, and permits any mutation of any residue, or any combination of mutations of any combination of residues, within the modified IL-18 polypeptide. There is no description of the specific structures that must be maintained or modified to create the required functions. One of skill in the art would not conclude from that identification of a few closely related species that Applicant had possession of the entire recited immune cell and nucleic acid genus. The variability is only increased when considering the redundancy of nucleic acid sequences encoding various amino acids. The specification provides no guidance regarding which variants are capable of the required functions. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Additionally, several claims recite an “engineered T cell receptor.” Neither the specification nor the claims adequately describe the criteria that a T cell receptor must meet to be considered “engineered”, and a representative number of species are not presented in the disclosure. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the recited “decoy-resistant” IL-18 polypeptides or the corresponding nucleic acids encoding the IL-18 polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The agent itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Regarding the encompassed modified IL-18 proteins, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Regarding nucleic acid based therapeutics, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al (Advanced Drug Delivery Reviews 59 (2007) 75–86), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13). Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications under the 35 USC §112 paragraph 1, “Revision 1” of Written Description Requirement (66 FR 1099-1111, March 25, 2008) state, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention (ld. At 1104). Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.

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.

Claims 1-16 and 20-21 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 1, 6-7, and 9-12 recite the term “decoy-resistant”, which renders the claim scope indefinite. The specification neither defines the term, nor identifies specific criteria by which an IL-18 variant polypeptide could be evaluated to determine whether it was “decoy-resistant”. It is also unclear what is meant by the term “decoy”, or to what the “decoy” is compared. The dependent claims are also rejected because they do not remedy the deficiencies.
Claims 7-9 recite mutations described as “relative to WT IL-18” or “relative to wildtype IL-18 as set forth in SEQ ID NO:30.” In the claims that reference SEQ ID NO:30, it is unclear if the sequence of SEQ ID NO:30 is required, or if the sequence can be used only to demonstrate relative sequence locations. The dependent claims are also rejected because they do not remedy the deficiencies.
Claims 7-8 recite “five or more mutations” without defining a parent sequence to which the “mutations” can be identified. It is impossible to confirm “five or more mutations” without knowing the parent sequence to which the “mutations” can be compared. For example, it is impossible to determine if a mutation has occurred at position 53, causing mutation of a lysine to another amino acid, if the original parent sequence is not known. There is no way to determine whether the parent sequence originally had another amino acid at position 53 without having a described parent sequence. The dependent claims are also rejected because they do not remedy the deficiencies.
Claims 1, 4-5, 13-15 and 20-21 recite the term “engineered,” which renders the claim indefinite. The term is not defined in the specification, except to reference it as “altered” (see e.g. page 76 of the instant specification). The specification does not define the type of alterations that are encompassed, and it is unclear which alterations would be encompassed by the claims. The dependent claims are also rejected because they do not remedy the deficiencies.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation “an immune cell”, and the claim also recites “an engineered immune cell” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.

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.

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.
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.
Claim(s) 1-2, 4, 6-7, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Avanzi et al (Blood (2016) 128 (22): 816) in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02), as evidenced by Yeku (Biochem Soc Trans. 2016 April 15; 44(2): 412–418).
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. There is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
Avanzi does not teach a modified IL-18 protein, including one that has 5 mutations compared to SEQ ID NO:30.
Kim et al provide mutants of IL-18 with lower affinity to IL-18BP than wild type (see e.g. abstract, page 5, lines 15-20). A preferred embodiment is SEQ ID NO:7 (see e.g. page 6). SEQ ID NO:6 comprises an identical sequence to instant SEQ ID NO:30, except with a mutation of E6A (see sequence below and continued on next page, arrow pointing to mutation). SEQ ID NO:7 comprises an identical sequence to instant SEQ ID NO:30, except with a mutation of K53A (see sequence below and continued on next page, arrow pointing to mutation). The IL-18M can be modified with “one or more amino acid residues”, which include E42, I85, M87, K89, M96, D130, K132, P143, M149, and L189 (see e.g. claims 1-4). The mutations are labeled at different location numbers, but as shown in the sequences below, these sites correspond to E6, I49, M51, K53, M60, D94, K96, P107, M113, and L153. The language “one or more” encompasses proteins that have all of the mutations listed, and therefore would comprise more than 5 mutation sites. The IL-18 modified (IL-18M) can be administered to treat disease such as cancer or viral disease in patients (see e.g. page 6, lines 5-15; page 8, lines 15-25; page 9, lines 5-15 ). Tumor cells can be isolated and genetically modified to be given to the same patient for local vaccination (see e.g. page 8, lines 25-30), and these patients are human (see e.g. page 14, lines 15-25, and Example 7). The IL-18M has the same structure and mutation at the required site, and therefore inherently would possess the required functions of the claims.
E6A mutant (SEQ ID NO:6):
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K53A mutant (SEQ ID NO:7):
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It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in Kim to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of Kim exhibit higher stability, likely as a result of decreased neutralization by IL-18BP, which results from lower binding between IL-18 and IL-18BP (see e.g. page 5, entire page). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of Kim would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of Avanzi, based on the teachings of Kim, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-2-7, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Avanzi et al (Blood (2016) 128 (22): 816) in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02), and further in view of Klingemann (OncoImmunology 2014; 3:e28147), as evidenced by Yeku (Biochem Soc Trans. 2016 April 15; 44(2): 412–418).
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. There is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
Avanzi does not teach a modified IL-18 protein, including one that has 5 mutations compared to SEQ ID NO:30.
Kim et al provide mutants of IL-18 with lower affinity to IL-18BP than wild type (see e.g. abstract, page 5, lines 15-20). A preferred embodiment is SEQ ID NO:7 (see e.g. page 6). SEQ ID NO:6 comprises an identical sequence to instant SEQ ID NO:30, except with a mutation of E6A (see sequence below and continued on next page, arrow pointing to mutation). SEQ ID NO:7 comprises an identical sequence to instant SEQ ID NO:30, except with a mutation of K53A (see sequence below and continued on next page, arrow pointing to mutation). The IL-18M can be modified with “one or more amino acid residues”, which include E42, I85, M87, K89, M96, D130, K132, P143, M149, and L189 (see e.g. claims 1-4). The mutations are labeled at different location numbers, but as shown in the sequences below, these sites correspond to E6, I49, M51, K53, M60, D94, K96, P107, M113, and L153. The language “one or more” encompasses proteins that have all of the mutations listed, and therefore would comprise more than 5 mutation sites. The IL-18 modified (IL-18M) can be administered to treat disease such as cancer or viral disease in patients (see e.g. page 6, lines 5-15; page 8, lines 15-25; page 9, lines 5-15 ). Tumor cells can be isolated and genetically modified to be given to the same patient for local vaccination (see e.g. page 8, lines 25-30), and these patients are human (see e.g. page 14, lines 15-25, and Example 7). The IL-18M has the same structure and mutation at the required site, and therefore inherently would possess the required functions of the claims.

E6A mutant (SEQ ID NO:6):
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K53A mutant (SEQ ID NO:7):
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702
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Neither Avanzi nor Kim teach the use of a CAR-NK cell.
Klingemann teaches the use of natural killer cells as alternatives to T cells for CAR-based immunotherapy (see e.g. page e28147-2, left column).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in Kim to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of Kim exhibit higher stability, likely as a result of decreased neutralization by IL-18BP, which results from lower binding between IL-18 and IL-18BP (see e.g. page 5, entire page). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of Kim would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of Avanzi, based on the teachings of Kim, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al containing the constructs of Kim et al, specifically to use a natural killer cell for CAR therapy instead of a T cell. As taught by Klingemann, while T cells are only able to kill targets by CAR-specific mechanisms, NK cells are endowed with spontaneous cytotoxic activity and can trigger demise of target cells in a tumor antigen unrestricted manner via specific natural cytotoxicity receptors (see e.g. e28147-2, left column). Additional features make them better and potentially safer CAR drivers than T cells (see e.g. e28147-2, middle column). For example, NK cells produce cytokines different from those produced by T cells, which could be important for preventing cytokine storm initiated by CAR-T cells (see e.g. e28147-2, middle and right columns). Further, NK cells are capable of killing multiple targets over time, i.e. “serial killing”, while evidence for serial killing by T cells is lacking (see e.g. e28147-2, right column). Further, NK cells have a limited lifespan, and there is no concern about persisting CAR-associated side effects that are often seen in CAR-T cells when “off target” effects are present (see e.g. Table 1). It would be expected, absent evidence to the contrary, that use of CAR-NK cells as presented by Klingemann would decrease off-target effects, lower side effects, and produce more effective tumor cell killing. These advantages provide the motivation to make the aforementioned modification of the cells of Avanzi as modified with the constructs of Kim, based on the teachings of Klingemann, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.

Claim(s) 1-2, 4, 6-18, 20, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28, 30-32, and 34 of copending Application No. 18/055,581 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of enhancing IL-18 signaling comprising administering a composition comprising a nucleic acid encoding a modified IL-18, where in the IL-18 polypeptide comprises at least one mutation, wherein the sequence of the parent IL-18 is SEQ ID NO: 30, which is identical to instant SEQ ID NO:30 (see e.g. claim 28). The mutations can be the same as the mutations of the instant claims (see e.g. copending claims 28 and 30-32). The IL-18 protein can exhibit reduced binding to IL-18BP (see e.g. claim 28).
The copending claims do not require that the nucleic acid is present in an immune cell or engineered immune cells, such as a CAR-T cell or CAR-NK cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28, 30-32, and 34 of copending Application No. 18/055,581 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02) and further in view of Klingemann (OncoImmunology 2014; 3:e28147). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of enhancing IL-18 signaling comprising administering a composition comprising a nucleic acid encoding a modified IL-18, where in the IL-18 polypeptide comprises at least one mutation, wherein the sequence of the parent IL-18 is SEQ ID NO: 30, which is identical to instant SEQ ID NO:30 (see e.g. claim 28). The mutations can be the same as the mutations of the instant claims (see e.g. copending claims 28 and 30-32). The IL-18 protein can exhibit reduced binding to IL-18BP (see e.g. claim 28).
The copending claims do not administer an immune cell or engineered immune cells, such as a CAR-T cell or armored CAR-T cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
Neither Avanzi nor the copending application teach the use of a CAR-NK cell.
Klingemann teaches the use of natural killer cells as alternatives to T cells for CAR-based immunotherapy (see e.g. page e28147-2, left column).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al containing the constructs of the copending application, specifically to use a natural killer cell for CAR therapy instead of a T cell. As taught by Klingemann, while T cells are only able to kill targets by CAR-specific mechanisms, NK cells are endowed with spontaneous cytotoxic activity and can trigger demise of target cells in a tumor antigen unrestricted manner via specific natural cytotoxicity receptors (see e.g. e28147-2, left column). Additional features make them better and potentially safer CAR drivers than T cells (see e.g. e28147-2, middle column). For example, NK cells produce cytokines different from those produced by T cells, which could be important for preventing cytokine storm initiated by CAR-T cells (see e.g. e28147-2, middle and right columns). Further, NK cells are capable of killing multiple targets over time, i.e. “serial killing”, while evidence for serial killing by T cells is lacking (see e.g. e28147-2, right column). Further, NK cells have a limited lifespan, and there is no concern about persisting CAR-associated side effects that are often seen in CAR-T cells when “off target” effects are present (see e.g. Table 1). It would be expected, absent evidence to the contrary, that use of CAR-NK cells as presented by Klingemann would decrease off-target effects, lower side effects, and produce more effective tumor cell killing. These advantages provide the motivation to make the aforementioned modification of the cells of Avanzi as modified with the constructs of the copending application, based on the teachings of Klingemann, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-2, 4, 6-18, 20, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-31 and 34-39 of copending Application No. 18/157,385 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of comprising administering a nucleic acid encoding a modified IL-18 polypeptide, wherein the sequence of the base IL-18 is SEQ ID NO:30, which is identical to instant SEQ ID NO:30 (see e.g. claim 27). The mutations can be the same as the mutations of the instant claims (see e.g. copending claims 27-31). The protein can exhibit reduced binding to IL-18BP (see e.g. claim 27). The IL-18 can comprise at least 5 of the named mutations (see e.g. claim 38).
The copending claims do not administer an immune cell or engineered immune cells, such as a CAR-T cell or armored CAR-T cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-31 and 34-39 of copending Application No. 18/157,385 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02) and further in view of Klingemann (OncoImmunology 2014; 3:e28147). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of comprising administering a nucleic acid encoding a modified IL-18 polypeptide, wherein the sequence of the base IL-18 is SEQ ID NO:30, which is identical to instant SEQ ID NO:30 (see e.g. claim 27). The mutations can be the same as the mutations of the instant claims (see e.g. copending claims 27-31). The protein can exhibit reduced binding to IL-18BP (see e.g. claim 27). The IL-18 can comprise at least 5 of the named mutations (see e.g. claim 38).
The copending claims do not administer an immune cell or engineered immune cells, such as a CAR-T cell or armored CAR-T cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
Neither Avanzi nor the copending application teach the use of a CAR-NK cell.
Klingemann teaches the use of natural killer cells as alternatives to T cells for CAR-based immunotherapy (see e.g. page e28147-2, left column).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al containing the constructs of the copending application, specifically to use a natural killer cell for CAR therapy instead of a T cell. As taught by Klingemann, while T cells are only able to kill targets by CAR-specific mechanisms, NK cells are endowed with spontaneous cytotoxic activity and can trigger demise of target cells in a tumor antigen unrestricted manner via specific natural cytotoxicity receptors (see e.g. e28147-2, left column). Additional features make them better and potentially safer CAR drivers than T cells (see e.g. e28147-2, middle column). For example, NK cells produce cytokines different from those produced by T cells, which could be important for preventing cytokine storm initiated by CAR-T cells (see e.g. e28147-2, middle and right columns). Further, NK cells are capable of killing multiple targets over time, i.e. “serial killing”, while evidence for serial killing by T cells is lacking (see e.g. e28147-2, right column). Further, NK cells have a limited lifespan, and there is no concern about persisting CAR-associated side effects that are often seen in CAR-T cells when “off target” effects are present (see e.g. Table 1). It would be expected, absent evidence to the contrary, that use of CAR-NK cells as presented by Klingemann would decrease off-target effects, lower side effects, and produce more effective tumor cell killing. These advantages provide the motivation to make the aforementioned modification of the cells of Avanzi as modified with the constructs of the copending application, based on the teachings of Klingemann, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-19 of copending Application No. 18/501,206 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a composition comprising a cell expressing a human decoy resistant modified IL-18 polypeptide, comprising at least 5 substitutions, at the same locations as mutations of the instant claims, wherein the substitutions are relative to wildtype IL-18 of SEQ ID NO:30 (see e.g. claim 14). The expression of the mutant IL-18 in the copending claims inherently requires a nucleic acid to be present in the cell to generate the expression of the protein. SEQ ID NO:30 of the copending claims is identical to instant SEQ ID NO:30. The composition can further comprise an immune cell (see e.g. claim 12) wherein the cell can be a T-cell, NK cell or myeloid cell (see e.g. claim 18-19). The copending claims further recite a cell expressing the decoy IL-18 polypeptide, and the cell can be an immune cell, a CAR-T cell, a CAR-NK cell, or a cell with an engineered T cell receptor (see e.g. claims 18-19). The term “at least five substitutions” in reference claim 14 encompasses all possible combinations that can be envisaged from the list. One combination of mutations that is encompassed by reference claim 14 includes mutations at Methionine-51, Methionine-60, Serine-105, Aspartic acid-110, and Asparagine-111. Notably, this exact species is identified as a “decoy-resistant” IL-18 polypeptide in instant claim 8, indicating that the copending claims are directed to compositions that express “decoy-resistant” IL-18 that is identical to the instant claims. The copending claims recite additional mutations at Cysteine-38 and Cysteine-68. This brings the total number of mutations for this species of the copending claims, which recites otherwise identical residue locations for substitutions compared to the instant claims, to seven mutations. The amino acid sequence of SEQ ID NO:30 consists of 157 amino acids, 150 amino acids of which are not mutated. This combination yields a protein that is 95.5% identical to SEQ ID NO:30, which would fall within the genus of the instant claims.
The copending claims therefore anticipate the instant claims.
The copending claims differ in scope from the instant claims by reciting species encompassed by the instant claims, wherein the copending claims recite additional mutations that are not recited in the instant claims, including mutations at C38 and C68.

Claim(s) 1-2, 4, 6-18, 20, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/501,210 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of promoting IL-18 signaling activity comprising administering a nucleic acid encoding a decoy-resistant modified IL-18 polypeptide to a subject in need thereof (see claims 1-5), and a composition comprising a nucleic acid encoding the modified IL-18 or a cell comprising the nucleic acid (see e.g. claims 6-20), wherein the polypeptide comprises “one or more substitution mutations”, at the exact locations of the instant claims, wherein the substitutions are relative to wildtype IL-18 of SEQ ID NO:30 (see e.g. claim 1-20). The modified IL-18 can have five or more substitutions at the sites of the instant claims (see e.g. claim 18). The cell comprising the nucleic acid can be an immune cell (see e.g. claim 17). The composition can comprise an immune cells comprising the nucleic acid (see e.g. claim 17).
The copending claims do not administer an immune cell or engineered immune cells, such as a CAR-T cell or armored CAR-T cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/501,210 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02) and further in view of Klingemann (OncoImmunology 2014; 3:e28147). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of promoting IL-18 signaling activity comprising administering a nucleic acid encoding a decoy-resistant modified IL-18 polypeptide to a subject in need thereof (see claims 1-5), and a composition comprising a nucleic acid encoding the modified IL-18 or a cell comprising the nucleic acid (see e.g. claims 6-20), wherein the polypeptide comprises “one or more substitution mutations”, at the exact locations of the instant claims, wherein the substitutions are relative to wildtype IL-18 of SEQ ID NO:30 (see e.g. claim 1-20). The modified IL-18 can have five or more substitutions at the sites of the instant claims (see e.g. claim 18). The cell comprising the nucleic acid can be an immune cell (see e.g. claim 17). The composition can comprise an immune cells comprising the nucleic acid (see e.g. claim 17).
The copending claims do not administer an immune cell or engineered immune cells, such as a CAR-T cell or armored CAR-T cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
Neither Avanzi nor the copending application teach the use of a CAR-NK cell.
Klingemann teaches the use of natural killer cells as alternatives to T cells for CAR-based immunotherapy (see e.g. page e28147-2, left column).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al containing the constructs of the copending application, specifically to use a natural killer cell for CAR therapy instead of a T cell. As taught by Klingemann, while T cells are only able to kill targets by CAR-specific mechanisms, NK cells are endowed with spontaneous cytotoxic activity and can trigger demise of target cells in a tumor antigen unrestricted manner via specific natural cytotoxicity receptors (see e.g. e28147-2, left column). Additional features make them better and potentially safer CAR drivers than T cells (see e.g. e28147-2, middle column). For example, NK cells produce cytokines different from those produced by T cells, which could be important for preventing cytokine storm initiated by CAR-T cells (see e.g. e28147-2, middle and right columns). Further, NK cells are capable of killing multiple targets over time, i.e. “serial killing”, while evidence for serial killing by T cells is lacking (see e.g. e28147-2, right column). Further, NK cells have a limited lifespan, and there is no concern about persisting CAR-associated side effects that are often seen in CAR-T cells when “off target” effects are present (see e.g. Table 1). It would be expected, absent evidence to the contrary, that use of CAR-NK cells as presented by Klingemann would decrease off-target effects, lower side effects, and produce more effective tumor cell killing. These advantages provide the motivation to make the aforementioned modification of the cells of Avanzi as modified with the constructs of the copending application, based on the teachings of Klingemann, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-2, 4, 6-18, 20, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-30 and 34 of copending Application No. 18/626,930 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of increasing the activity of immune cells in vivo in a subject, comprising administering a nucleic acid encoding a modified IL-18 polypeptide to a subject in need thereof (see claims 27), and a composition comprising a nucleic acid encoding the polypeptide (see e.g. claims 34). The modified IL-18 has a plurality of mutations relative to wild-type human IL-18 of SEQ ID NO:30, and those mutations impart functions of binding to the IL-18 receptor and a Kd for IL-18BP of 10 nM or greater (see e.g. reference claim 16, and claim 27), which is identical to the Kd required by instant claim 10.
The copending claims do not recite an immune cell or engineered immune cells, such as a CAR-T cell or armored CAR-T cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Claim(s) 1-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-30 and 34 of copending Application No. 18/626,930 (reference application) in view of Avanzi et al (Blood (2016) 128 (22): 816) and further in view of Kim et al (WO 02/101049 A2; filed 3/8/02; published 12/19/02) and further in view of Klingemann (OncoImmunology 2014; 3:e28147). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to a composition comprising an immune cell comprising a nucleic acid encoding a decoy resistant IL-18 variant polypeptide and a CAR or engineered T cell. The engineered cell can be a CAR-T or CAR-NK cell. The engineered cell can comprise a T cell transduced with an engineered T cell receptor. Additionally, the claims read on a variant IL-18 polypeptide that has substitutions “relative to wild-type human IL-18 as set forth in SEQ ID NO:30”. In claims 1-12, there is no requirement for any particular parent polypeptide sequence. The requirement for mutations “relative to” a particular sequence, when given the broadest reasonable interpretation, only indicates locations of the mutations, without defining the parent polypeptide sequence. The dependent claims recite that the polypeptide has “five or more”, indicating that potentially every site on the protein could be substituted, with no limitation according to sequence or amino acid location. In other words, the entire sequence of the IL-18 protein is completely variable. In claims 13-22, the claims recite a requirement for sequence identity with SEQ ID NO:30, as well as a number of mutations at various amino acid residues.
The copending claims are directed to a method of increasing the activity of immune cells in vivo in a subject, comprising administering a nucleic acid encoding a modified IL-18 polypeptide to a subject in need thereof (see claims 27), and a composition comprising a nucleic acid encoding the polypeptide (see e.g. claims 34). The modified IL-18 has a plurality of mutations relative to wild-type human IL-18 of SEQ ID NO:30, and those mutations impart functions of binding to the IL-18 receptor and a Kd for IL-18BP of 10 nM or greater (see e.g. reference claim 16, and claim 27), which is identical to the Kd required by instant claim 10.
The copending claims do not recite an immune cell or engineered immune cells, such as a CAR-T cell or armored CAR-T cell.
Avanzi teaches CAR-T cells that constitutively secrete IL-18 (see entire reference). Human and mouse T cells were transduced with polynucleic acid constructs, including one encoding IL-18 (see e.g. first page). The IL-18 secreting CAR-T cells were tested in xenograft and syngeneic mouse models (see e.g. first page). The secretion of IL-18 improved the anti-tumor efficiency in mice, and increased interferon-gamma and TNF-alpha cytokines (see e.g. second page). The engineering to secrete IL-18 creates a cell that is “armored” with IL-18 (See Yeku, abstract, which states “Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported…Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence.”
Neither Avanzi nor the copending application teach the use of a CAR-NK cell.
Klingemann teaches the use of natural killer cells as alternatives to T cells for CAR-based immunotherapy (see e.g. page e28147-2, left column).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al to use a modified IL-18 polypeptide as described in the copending application to increase the effectiveness of the CAR-T cell when administered. Avanzi teaches that cells that secrete IL-18 significantly increase cytokine secretion, enhance CAR-T cell persistence in the body, induce long-term B cell aplasia and improve survival, even without preconditioning (see e.g. Avanzi, second page). This induces high levels of T cell proliferation and anti-tumor cytotoxicity, which increases the effectiveness of the administered CAR-T cell therapy (see e.g. Avanzi, second page). Kim et al teach that if IL-18 is used locally, as adjuvant in tumor immunotherapy, the ability of the constitutive levels of IL-18BP to neutralize IL-18 in the local environment would still be exerted and consequently the IL-18 effectiveness is greatly diminished (see e.g. page 4, last paragraph). The mutants of the copending application exhibit decreased binding to IL-18BP (see e.g. copending specification page 1). It would be expected, absent evidence to the contrary, that use of the mutant IL-18 proteins of the copending application would produce increased stability of the IL-18 when expressed and secreted by the cells of Avanzi because the IL-18 mutants have decreased binding to IL-18BP. The advantages of more stable IL-18 produced by decreased interaction with IL-BP, which can increase effectiveness of the CAR-T therapy, provide the motivation to make the aforementioned modification of the cells of the copending application combined with Avanzi, and based on the teachings of Kim, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the cells of Avanzi et al containing the constructs of the copending application, specifically to use a natural killer cell for CAR therapy instead of a T cell. As taught by Klingemann, while T cells are only able to kill targets by CAR-specific mechanisms, NK cells are endowed with spontaneous cytotoxic activity and can trigger demise of target cells in a tumor antigen unrestricted manner via specific natural cytotoxicity receptors (see e.g. e28147-2, left column). Additional features make them better and potentially safer CAR drivers than T cells (see e.g. e28147-2, middle column). For example, NK cells produce cytokines different from those produced by T cells, which could be important for preventing cytokine storm initiated by CAR-T cells (see e.g. e28147-2, middle and right columns). Further, NK cells are capable of killing multiple targets over time, i.e. “serial killing”, while evidence for serial killing by T cells is lacking (see e.g. e28147-2, right column). Further, NK cells have a limited lifespan, and there is no concern about persisting CAR-associated side effects that are often seen in CAR-T cells when “off target” effects are present (see e.g. Table 1). It would be expected, absent evidence to the contrary, that use of CAR-NK cells as presented by Klingemann would decrease off-target effects, lower side effects, and produce more effective tumor cell killing. These advantages provide the motivation to make the aforementioned modification of the cells of Avanzi as modified with the constructs of the copending application, based on the teachings of Klingemann, with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.

Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674

Patent Application 18941441 - INTERLEUKIN-18 VARIANTS AND METHODS OF USE - Rejection

Patent Application 18941441 - INTERLEUKIN-18 VARIANTS AND METHODS OF USE

Application Information

Rejection Summary

Cited Patents

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