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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 25th, November, 2025 has been entered.
Claim Status
Claims 1-11 and 13-20 are pending.
Claims 1-10, and 19-20 are withdrawn.
Claims 11 and 13-18 are under examination.
Claim Rejections - 35 USC § 112(a)
Written Description
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 11 and 13-18 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 purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include a disclosure of a representative number of species to describe the complete structure of the claimed genus and/or disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
Scope of the Invention
In the instant case, the genus is
Mutations in the gene CISH , where “the one or more mutations comprise (1) an insertion and/or a deletion or (2) a conversion of one nucleobase to another” (claim 11 and dependents).
The broadest reasonable interpretation of the scope of this genus is insertions or deletions or all possible lengths in the CISH gene, and conversions of one nucleobase to another in all possible locations of the CISH gene which may be nonsense, missense, or silent and further includes all possible combinations of these mutations. Additionally, the mutations may be in any region of the recited gene including coding and non-coding sequences.
Point mutations in the CISH gene (claim 16)
The broadest reasonable interpretation of the scope of this genus is all possible point mutations in all possible locations of the CISH gene that may be nonsense, missense, or silent. Additionally, the mutations may be in any region of the recited gene including coding and non-coding sequences. The scope also includes all possible all possible combinations of all types of these mutations in the CISH gene.
Importantly, the mutations are required to have the functional result of “expression of CISH is decreased in the genome-edited γδ T cell.”
To illustrate the breadth of the claimed mutations, Applicant is directed to the gene of CISH, which is more than 1000 bp long. As an exemplary estimation of the breadth of these mutations, the embodiment of a conversion of one nucleobase to another, for each position there can be up to 4 options (each of the three other nucleotides or no change), which amounts to 41000 distinct sequences. Since the breadth of the claims is even broader than this and encompasses insertions or deletions or all possible lengths in the CISH gene, and conversions of one nucleobase to another in all possible locations of the CISH gene which may be nonsense, missense, or silent, the breadth of the claims encompasses an unfathomably large number of structurally distinct sequences.
Disclosure of Complete or Partial Structure
In regards to the mutations, Applicant describes Specific Gene knock-ins made by CRISPR/Cas9 (para. [0086]) using guide RNAs for specific regions. Specific RNA guides to target the CISH mutations are disclosed as SEQ ID NO: 9 in Figure 6. Specific mutations were confirmed to be present in CISH in Figures 10A-E. The sequences and specific lengths of these mutations do not appear to be disclosed. Specific point mutations do not appear to be disclosed.
Structure/Function correlation
Regarding the mutations, as stated above, Applicants claims encompasses insertions or deletions or all possible lengths in the CISH gene, and conversions of one nucleobase to another in all possible locations of the CISH gene which may be nonsense, missense, or silent and for point mutations encompasses all possible point mutations in all possible locations of the CISH gene that may be nonsense, missense, or silent.
Collectively, these mutations are drawn to an unfathomable number of distinct functional embodiments that could result in an increase, decrease, or no change in the function of CISH. Non-limiting examples of these embodiments are described below.
Single Nucleotide Substitutions
Single nucleotide substitutions may result in:
a silent mutation in which a single nucleotide is changed, but the amino acid is encodes remains the same due to codon redundancy.
a missense mutation, which occurs when the nucleotide changes the amino acid it encodes, but the transcript then codes for a very similar amino acid, such as a leucine to an isoleucine change, which does not meaningfully affect the function of the encoded protein
a nonsense mutation, which occurs when the substitution results in the production of a stop codon, which shortens the protein. Depending on the relative location of the premature stop codon, it may or may not affect the function of the protein. In the case where the majority of the protein is lost, then the nonsense mutation will likely result in loss of function.
In other words, a single nucleotide substitution, without further structure, encompasses functional affects from no changes in the protein, to a loss of function, and could also result an increase in function.
Nucleotide Insertions and Deletions
Insertions and deletions may result in:
A premature stop codon causing a nonsense mutation. Depending on the relative location of the premature stop codon, it may or may not affect the function of the protein. In the case where the majority of the protein is lost, then the nonsense mutation will likely result in loss of function.
A frameshift mutation, which occurs when the mutation disrupts the reading frame of the gene. This can result in an entirely different set of amino acids produced due to the change in the codons read, and may change the end of the transcript as the location of the stop codon may change. Furthermore, a frameshift may introduce a new start codon that may affect alternative splicing.
Deletions specifically may remove a start or stop codon, which can affect the whether the protein is encoded at all and its length, which may result in a non-functional protein.
Importantly, Applicant does not claim a specific insertion or deletion size. Clearly, a large insertion could entirely change the protein encoded by the transcription, with unpredictable results in function.
In other words, insertions and deletions, without further structure, encompasses functional affects from no changes in the protein, to a loss of function, and could also result an increase in function.
For discussions regarding types of mutations and their effects on protein transcripts, Applicant is directed to the art of Brown (Brown TA. Genomes. 2nd edition. Oxford: Wiley-Liss; 2002. Chapter 14, Mutation, Repair and Recombination.).
Written Description - Conclusion
Therefore, the examiner concludes there is insufficient written description support for the instantly claimed genera. Specifically, there is insufficient support for mutations in the CISH gene. The specification describes only a few mutations that would be targeted by SEQ ID NO:9 (Figure 6). As stated above, the claimed mutations of combinations of mutations encompasses an unfathomably large amount of potential mutations or combinations of mutations. Because the breadth of the claims in unfathomably large, encompasses many different possible outcomes in terms of the function of the mutated CISH gene, and the specification has not provided sufficient structural-functional relationship between the breadth of the claimed derivative and the functional result of the genome-edited γδ T cell that has a decreased expression of CISH, a person of ordinary skill in the art cannot envision such mutations and combinations of mutation from the instant disclosure. Accordingly, the mutations and combinations of mutations of the CISH gene have not been described in sufficient detail, and Applicant has not shown possession of the claimed invention at the time of effective filing.
Response to Arguments
Applicant’s arguments, filed 25th, November, 2025 have been fully considered but are not found persuasive.
Applicant argues “A person of ordinary skill in the art would reasonably conclude that the inventors had possession of the claimed invention, as recited in amended claim 11, at the time of filing based on the specification. Furthermore, the genus of insertions, deletions, and base conversions leading to reduced CISH expression would be clearly understood by a person of skill in the art by structure alone, e.g., by the introduction of a premature stop codon. Thus, specification provides a person of ordinary skill in the art with sufficient detail to reasonably conclude that the inventors had
possession of the claimed invention” (pg. 5).
In response, as discussed above, the present claims encompass an unfathomably large genus of structurally distinct sequences, while the instant specification describes a small number of specific mutations (see “Disclosure of Complete or Partial Structure”). The specific mutations were confirmed be present in CISH in Figures 10A-E are not representative of the unfathomably large genus of mutations encompassed by instant claims. Furthermore, the specification provides no nexus between the structure of the mutation and the required function of a decrease in the expression of CISH in the γδ T cell and therefore one of ordinary skill would not be able to envision the requisite structural elements at the time of filing.
Applicant is directed to MPEP 2163.02 which states that the test for sufficiency of support in a parent application is whether the disclosure of the application relied upon "reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter." Ralston Purina Co. v. Far-Mar-Co., Inc., 772 F.2d 1570, 1575, 227 USPQ 177, 179 (Fed. Cir. 1985) (quoting In re Kaslow, 707 F.2d 1366, 1375, 217 USPQ 1089, 1096 (Fed. Cir. 1983)).
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 (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., 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 inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) (MPEP 2163). A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In the instant case, for the reasons set forth above, the few species disclosed by Applicant are not a “representative number of species" to provide possession for the full breadth of the claimed genus which encompasses an unfathomably large number of structurally and functionally distinct sequences. The instant specification has not provided a nexus for one of ordinary skill to be able to arrive at which of these species arrive in the required functional result of decreased CISH expression and therefore the claims do not have adequate written description support.
Withdrawn Claim Rejections - 35 USC § 112b
The rejection of claims 13-14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New Claim Rejections - 35 USC § 112b
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 11 and 13-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 recites “the gene comprises CISH (Cytokine-inducible SH2-containing protein).” Since CISH is a protein and not a gene, it is unclear what the scope of the gene encompasses.
By nature of their ultimate dependency on claim 11, claims 13-18 are also rejected because they do not clarify the issue.
To overcome this issue, it is recommended that Applicant amend from “comprising one or more mutations in a gene wherein the gene comprises CISH” to “comprising one or more mutations in a gene encoding CISH.”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 11, 13-15 and 17-18 remain rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. (US-2022/0211756-A1; Priority to 29th, April, 2016; henceforth “Anderson”) in view of Conway et al. (US-2019/0136261-A1; Benefit to 9th, November, 2017; henceforth “Conway”).
Regarding claim 11, Anderson discloses a genome-edited γδ T cell (“T cell which expresses a gamma-delta T cell receptor (TCR) and a chimeric antigen receptor (CAR)” abstract; see also Figure 2; para. [0001-0002, 0006-0008, 0030-0031, 0044-0050, 0052, 0057, 0059-0063, 0065-0068, 0070-0074, 0077-0082, 0088-0091, 0108-0109, 0118, 0151-0155, 0157-0158, 0160-0174, 0177-0179, 0185-0186, 0190, 0193-0195, 0198]; Examples 1-4; claims 1, 18-20, 24-26). Anderson discloses the cell further comprises a chimeric antigen receptor comprising an extracellular domain capable of binding to an antigen, a transmembrane domain, and at least one intracellular domain (abstract; para. [0002, 0010, 0016-0018, 0021-0023, 0079, 0108, 0110, 0126, 0128, 0132-0136, 0183-0184] ; SEQ ID NO: 25; claims 4, 8, 10, 12 and 26).
However, regarding claim 11, Anderson does not disclose the genome-edited γδ T cell comprises a mutation in CISH (Cytokine inducible SH2-containing protein).
Nevertheless, regarding claims 11 and 21, Conway teaches targeted genetic modifications of a CISH gene in T cells including “one or more insertions and/or deletions of an endogenous CISH gene” (para. [0016]; see also abstract; para. [0002, 0005-0011, 0015-0016, 0019-0024, 0029-0031, 0033-0039, 0041-0042, 0044-0045, 0048-0055, 0139, 0150-0151, 0175, 0177, 0182, 0189, 0194, 0197, 0223-0224, 0227-0228, 0231-0237]; Examples 1-4; claims 1, 3, 6 and 7-18; see in particular Example 1). Conway teaches the genetic modifications in CISH can be in CD3 positive T cells (para. [0044, 00196]).
Therefore, regarding claim 11, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the genome-edited γδ T cell of Anderson, and combine the known prior art element of the targeted genetic modifications of a CISH gene of Anderson to yield the predictable result of a genome-edited T cell (see MPEP 2143 Exemplary Rationale (A). One of ordinary skill would have been motivated to do so as taught by Conway because reducing CISH expression in human T cells enhanced the functionality of co-transduced tumor-specific TCRs (para. [0011]), and resulted in increased immunostimulatory function, upregulation of TNFα (para. [0053]) (see MPEP 2143 Exemplary Rationale (G)). Regarding the reasonable expectation of success, Conway evidences editing the CISH gene in T cell (Examples 1-4). Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in editing the CISH gene in the γδ T cells of Anderson.
Regarding claim 11, as stated above, Conway suggests a mutation in CISH that reduced CISH expression in human T cells (para. [0011]). Therefore, it would naturally follow that this CISH mutation would result in decreased expression of CISH in the genome-edited γδ T cell as suggested by Anderson in view of Conway.
Regarding claim 13, further to the discussion of claim 11 above, Anderson teaches the antigen is a tumor antigen (“Tumour-Associated Antigen (TAA)” Table 1; see also para. [0013, 0045, 0076, 0114-0118).
Regarding claim 14, further to the discussion of claim 11 above, Anderson teaches the extracellular domain capable of binding to an antigen is a single chain variable fragment of an antibody that binds to the antigen (para. [0109-0110, 0183-0184]; Figure 3).
Regarding claim 15, further to the discussion of claim 11 above, the mutation in the CISH gene as suggested by Conway above includes the gene is deleted (“knockout of CISH” para. [0053] or “deletions” claim 2; see also para. [0016-0017, 0029, 0033, 0038, 0067, 0139, 0143, 0159, 0178]).
Regarding claim 17, further to the discussion of claim 11 above, Anderson teaches the cell further comprises an exogenous gene (CAR; abstract; Figures 2, 5-6, 9-11, 13; para. [0001-0004, 0006-0008, 0012, 0016-0018, 0020-0026, 0044, 0048-0052, 0055-0058, 0068-0073, 0076-0082, 0085-0088, 0091, 0111, 0115-0116, 0118-0120, 0128, 0132, 0137-0139, 0144, 0156, 0158, 0160, 0170-0174, 0180]; Examples 1-4; claims 1, 7-8, 10-13, 15 and 18).
Regarding claim 18, further to the discussion of claim 11 above, as stated above (see claims 11 and 15 rejection above) the cell as suggested by Anderson in view of Conway above includes a deletion in CISH. Conway teaches the reduction of CISH enhanced the functionality of the cells (para. [0011]), and resulted in increased immunostimulatory function, upregulation of TNFα, due to the loss of CISH (para. [0053]). Therefore, the T cell as suggested by Anderson in view of Conway would have increased immunostimulatory function and would exhibit an increased capacity to kill cancer cells relative to a non-genome edited γδ T cell because it would comprise a reduction of CISH which Conway teaches results in increased immunostimulatory function. Furthermore, as stated above, the γδ T cell suggested by Anderson in view of Conway comprises a CAR and therefore would have an increased capacity to kill cancer cells relative to a non-genome-edited γδ T cell.
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 25th, November, 2025 have been fully considered but are not found persuasive.
Applicant argues the combination is not predictable (pg. 7-8). Specifically, Applicant argues “A person of ordinary skill in the art would not have recognized that the results of the combination of Anderson and Conway were predictable because the function of cytokine inducible sh2- containing protein (CISH) in γδ T cells was not known and genetic modifications to T cell signaling may have different, or even opposite, results between αβT cells γδ T cells. For example, Ribiero et al., 2015 ("Five Layers of Receptor Signaling in γδ T-Cell Differentiation and Activation" Front Immunol. 2015 Jan 26:6: 15, provided with Information Disclosure Statement filed March 19, 2024, hereinafter "Ribiero") discusses unexpected differences between signaling in αβ T cells and γδ T cells:
Mutations on the binding site of PLCγ1 on LAT resulted in a severe block in murine αβ thymocyte development while γδ T-cell numbers were only modestly reduced in the thymus, intestine, and liver, and remained normal in the skin. Unexpectedly, a population of γδ T-cells in the secondary lymphoid organs in these mice underwent uncontrolled expansion and caused autoimmune pathology, suggesting distinct functions for LAT /PLCγδ-mediated signaling in subpopulations of γδ T-cells.
Ribiero, p. 2, left column, second paragraph. Thus, genetic modifications that affect T cell signaling, as in the claimed modifications to CISH, can have distinct, or even opposite, effects between αβ and γδ T cells.” (pg. 7).
Applicant argues “Gamma delta T cells exhibit inherently stronger TCR signals compared to alpha beta T cells. As noted in Ribiero "[t]he 'strong' signals stemming from the γδ TCR (when compared to the 'weaker' pre-TCR signaling) drive γδ/αβ common precursors into the γδ lineage. These stronger gamma delta TCR signals are characterized by "increased phosphorylation of ERK 1/2, abundant calcium release and induction of early growth response (Egr) transcription factors." Ribiero, p. 1, right column, last paragraph. Thus, signaling in γδ T cells differs from that in αβ T cells, which complicates predicting the effects of mutations that would alter endogenous signaling pathways, such as mutations in CISH.
Furthermore, γδ T cells, unlike alpha beta T cells, do not express CD4 or CD8 co-receptors.
As discussed in Ribiero:
The TCR complex does not present intrinsic kinase activity but the intracellular signaling is initiated after phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 cytoplasmic domains by the Src-family kinases (SFKs) Lek and Fyn. The recruitment of these SFKs to the TCR complex in γδ T-cells remains obscure since these cells do not express the CD4 or CD8 co-receptors.
Ribiero, p. 1, final paragraph bridging p. 2. In other words, there are aspects of γδ T cell signaling that are poorly understood, e.g., recruitment of SFKs to the TCR complex in γδ T-cells in the absence of CD4 or CD8 co-receptors, as of the publication of Ribiero, which further complicates predicting the effects of mutations that would alter endogenous signaling pathways in γδ T cells, based upon data in αβ T cells.
Thus, the results of the combination of Anderson and Conway were not predictable because the function of cytokine inducible sh2-containing protein (CISH) in γδ T cells was not known at the time of filing of the application and could not have been predicted based solely upon data collected in αβ T cells.” (pg. 7-8).
In response, Applicant is directed to MPEP 2143.02 which states that where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). In other words, while the prior art suggests the reason for modification, it is the preparation of the modification that requires a reasonable expectation of success. Achievement of the desired result, is not necessarily required. In the instant case, instant claims are drawn to a product, and therefore the reasonable expectation of success is required for preparation of the product, which a genome-edited γδ T cell comprising one or more mutations in CISH, where expression of CISH is decreased, and further comprising a CAR. Based on the combination of art above, one of ordinary skill would have had a reasonable expectation of success in preparing the genome-edited γδ T cell because it merely requires combining a CISH mutation from Conway with the genome-edited γδ T cell of Anderson. Conway provides a reasonable expectation of success in editing the CISH gene in effector T cells by providing specific guidance in the specification as well as Example 1 that would lead one or ordinary skill to be able to perform the suggested mutation in a T cell, which would include the γδ T cell of Anderson (para. [0016]; see also abstract; para. [0002, 0005-0011, 0015-0016, 0019-0024, 0029-0031, 0033-0039, 0041-0042, 0044-0045, 0048-0055, 0139, 0150-0151, 0175, 0177, 0182, 0189, 0194, 0197, 0223-0224, 0227-0228, 0231-0237]; Examples 1-4; claims 1, 3, 6 and 7-18; see in particular Example 1). Since Conway specifically evidences a result of decrease of CISH expression in effector T cells, one of ordinary skill would have a reasonable expectation of success in arriving at this result in the suggested γδ T cell.
Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). In the instant case, as discussed above, Conway provides a reasonable expectation of success in combining the CISH mutation with the γδ T cell of Anderson by providing specific guidance in the specification as well as Example 1 that would lead one or ordinary skill to be able to perform the suggested mutation in a T cell, which would include the γδ T cell of Anderson (para. [0016]; see also abstract; para. [0002, 0005-0011, 0015-0016, 0019-0024, 0029-0031, 0033-0039, 0041-0042, 0044-0045, 0048-0055, 0139, 0150-0151, 0175, 0177, 0182, 0189, 0194, 0197, 0223-0224, 0227-0228, 0231-0237]; Examples 1-4; claims 1, 3, 6 and 7-18; see in particular Example 1).
Regarding claim 18 specifically, which requires a functional result of the genome-edited γδ T cell exhibits increased capacity to kill cancer cells relative to a non-genome-edited γδ T cell, this result is also obvious with a reasonable expectation of success for the following reasons. Conway teaches the reduction of CISH enhanced the functionality of the cells (para. [0011]), and resulted in increased immunostimulatory function, upregulation of TNFα, due to the loss of CISH (para. [0053]) and therefore there would have been a reasonable expectation of success that the T cell as suggested by Anderson in view of Conway would have increased immunostimulatory function and would exhibit an increased capacity to kill cancer cells relative to a non-genome edited γδ T cell because it would comprise a reduction of CISH which Conway teaches results in increased immunostimulatory function. Furthermore, as stated above, the γδ T cell suggested by Anderson in view of Conway comprises a CAR and therefore there would also be a reasonable expectation of success that the suggested T cell would have an increased capacity to kill cancer cells relative to a non-genome-edited γδ T cell that does not comprise a CAR which also meets the functional requirements of instant claims.
Applicants arguments are drawn to data in αβ T cells and cites the alleged differences in these cells with γδ T cells. However, the art of record of Conway, which is used above to render the CISH mutation obvious, is not drawn only to αβ T cells. While Conway specifically teaches examples in human T effector cells which include CD4 and CD8 positive cells (Figures 5-6), Conway teaches the mutation can be performed generally immune cells and generally in T cells (para. [0044]), including CD3+ T cells which include γδ T cells.
Applicant argues “the function of cytokine inducible sh2-containing protein (CISH) in γδ T cells was not known at the time of filing of the application and could not have been predicted based solely upon data collected in αβ T cells”
In response, for the reasons discussed above, there would have been a reasonable expectation of success in creating the mutation in CISH in the γδ T cell of Anderson. As discussed above, conclusive proof of efficacy is not required to show a reasonable expectation of success, and furthermore, while the prior art suggests the reason for modification, it is the preparation of the modification that requires a reasonable expectation of success. Achievement of the desired result, is not necessarily required.
The experimental data of Conway in the examples, which is used above to render the CISH mutation obvious, is drawn to human T effector cells which do include CD4 and CD8 positive cells (Figures 5-6). These teachings still appear to be applicable to other types of T cells because Conway teaches the mutation can be performed generally in immune cells and generally in T cells (para. [0044]), including “(e.g., CD4+, CD3+, CD8+, etc.)” T-cells (para. [0044]). Since γδ T cell are CD3+, they would be included in this taught genus. Conway provides a motivation to make the claimed combination by teaching that reducing CISH expression in human T cells enhanced the functionality of co-transduced tumor-specific TCRs (para. [0011]), and resulted in increased immunostimulatory function and upregulation of TNFα (para. [0053]). Although this teaching is from results in human effector T cells that are CD4 or CD8 positive, this would be expected to motivate a person of ordinary skill to make the claimed combination because Conway specifically teaches the mutation can be made in other immune cells including CD3 positive T cells. CD3 positive T cells include γδ T cells.
Claim Rejections - 35 USC § 103
Claim 16 remains rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. (US-2022/0211756-A1; Priority to 29th, April, 2016; henceforth “Anderson”) in view of Conway et al. (US-2019/0136261-A1; Benefit to 9th, November, 2017; henceforth “Conway”) as applied to claim 11 above, and in further view of Zhao et al. (Cell Biochem Biophys. 2014 Apr;68(3):529-34.; henceforth “Zhao”) and Wu et al. (US-20170096638-A1; see IDS filed 19th, March, 2024; henceforth “Wu”).
Regarding claim 16, further to the discussion of claim 11 above, although Conway teaches an
mutations that inactivates a CISH gene (para. [0033]) in T cells, Conway is silent to a point mutation in the CISH gene that reduces the expression of CISH In a T cell.
Nevertheless, regarding claim 16, Zhao teaches a point mutation in CISH that results in decreased CISH expression (rs414171 SNP pg. 533 col. 1 2nd para.).
Therefore, regarding claim 16, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the genetically modified γδ T cell as suggested by Anderson in view of Conway, and simply substitute the known prior art element of the rs414171 point mutation of Zhao for the deletion of Conway to obtain the predictable result of decreased CISH expression. One of ordinary skill would have been motivated to do so because Wu teaches deletions and point mutations and known alternatives for reducing gene function (Figure 1). Regarding the reasonable expectation of success, Wu evidences making a T cell with a point mutation in a gene (T-ires-point mutation PD1 in Figure 1; see also para. [0011, 0029, 0108, 0115, 0017, 0152, 0152-0163] ; Table 1; Example 2).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632