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 .
Response to Amendment/Status of Claims
Receipt of Remarks filed on 01/14/2026 is acknowledged. Claims 1-4,6-9,13,18,19,23,24,27-29,31 and 32 were cancelled. Claims 30,34,37,39 and 40 were amended. Claims 30,34,37 and 39-55 are pending.
Election/Restrictions
Applicant’s election of Group III (Claims 30-32,34,37,39 and 40) and A20 Variant 1, N102S as Species C in the reply filed on 01/14/2026 is acknowledged. 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)). Applicant has also added new claims 41-55 defining the use of the products defined in Group III claims, and has canceled claims of Group I and II, thereby rendering the Restriction moot.
Claims 30,34,37 and 39-55 are under examination
Priority
This application is a 371 of PCT/AU2020/050155, filed 02/21/2020, and claims foreign priority to Australia 2019900574, filed 02/22/2019 and Australia 2019900607, filed 02/26/2019, as reflected by the most recent filing receipt.
Drawings
The drawings are objected to because all of the drawings are not labeled correctly. For example, “Figure 1a”. See 37 CFR 1.84(u) Numbering of views.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
In addition, some of the figures are not clear and legible. Figures 3,8,15,17 are difficult to make out a lot of the numbers and words.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term “TALEN”, which is a trade name or a mark used in commerce, has been noted in this application (see pages 4 and 38). The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 30,34,37,39,41,42 and 52 are objected to because of the following informalities: the instant claims recite the abbreviations “NF-κB” and “JNK”. For clarity, at least the first recitation in the claims should recite the full name rather than just the acronym. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 30 and 34 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Regarding Step 1 of the Eligibility Analysis for 35 USC 101, claims 30 and 34 recite “an isolated nucleic acid molecule” and “an isolated A20 variant protein”, respectively, and are therefore directed to a product, which is one of the statutory categories of invention.
Regarding Step 2A Prong One of the Eligibility Analysis, claims 30 and 34 recite at least one judicial exception that is a product of nature, which is an isolated nucleic acid molecule comprising a polynucleotide sequence encoding an A20 variant protein comprising an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 1 and comprising an asparagine (N) to serine (S) substitution at a position corresponding to amino acid 102 in the sequence set forth in SEQ ID NO: 1; and claim 34 recites an isolated A20 variant protein comprising an amino acid sequence which is at least 90% identical to the sequence set forth in SEQ ID NO: 1 and comprising an asparagine (N) to serine (S) substitution at a position corresponding to amino acid 102 in the sequence set forth in SEQ ID NO: 1. Based on the broadest reasonable interpretation, the isolated nucleic acid molecule and the isolated A20 variant protein reads on a product of nature as the A20 variant has the rs number rs146534657 (Table 2 on page 24 of the instant specification). According to Zhu et al. (“Journal of Translational Medicine, Vol. 13, No. 1, 5 July 2015, page 215), cited on an IDS, SNPs of the A20 gene, include the SNP, rs146534657 and was detected for the first time in RA patients, and that this SNP is a non-synonymous variant located in exon 3 of A20 and results in an amino acid at position 102 substitution from asparagine to serine (Table 1 page 3; page 8, left column). Therefore, Zhu et al. shows the recited SNP occurs in the A20 gene in RA patients and is therefore a product of nature. Claims 30 and 34 do not have markedly different characteristics from the A20 variant protein and nucleic acid encoding the A20 variant protein found in nature as there are no modifications recited in the compound.
Next then, Step 2A Prong Two is analyzed to determine if the claim recites additional elements that integrate the judicial exception into a practical application. Regarding claims 30 and 34, no additional elements are recited. Therefore the claims do not recite additional elements that integrate the judicial into a practical application.
Next, Step 2B of the Eligibility Analysis on whether a claim amounts to significantly more than the judicial exception is evaluated. Claims 30 and 34 do not include any additional elements in addition to the isolated nucleic acid molecule comprising a polynucleotide sequence encoding an A20 variant protein, or isolated A20 variant protein. The claims do not add significantly more because of generally linking the use of the judicial exception to a particular technological environment or field of use. See MPEP 2106.05(h).
Therefore, it is concluded that claims 30 and 34 fail all of the steps of the test for subject matter eligibility under 35 USC 101.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 45 and 48 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 45 and 48 contain the trademark/trade name “TALEN”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a transcription activator-like effector-based nuclease and, accordingly, the identification/description is indefinite.
Claim Rejections-Scope of Enablement
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 54 and 55 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of increasing the strength of an immune response in a subject comprising delivering the A20 variant protein of claim 34 to the subject by administering one or more of (i) an isolated nucleic acid molecule comprising a polynucleotide sequence encoding the A20 variant protein of claim 34 or an expression vector comprising same; (ii) the A20 variant protein of claim 34; (iii) an isolated T cell modified to express the A20 variant protein of claim 34 and/or (iv) a pharmaceutical composition comprising any one or more of (i)-(iii) by way of the prior art, does not reasonably provide enablement for a method of treating a genus of cancers in a subject in need thereof comprising increasing a subject’s immune response by performing the method of claim 51 by any route of administration and administering to the subject an immunotherapeutic agent. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Claim 54 encompasses treating any cancer in a subject in need thereof, including solid tissue cancers and blood cancers, by administering one or more of (i) an isolated nucleic acid molecule comprising a polynucleotide sequence encoding the A20 variant protein of claim 34 or an expression vector comprising same; (ii) the A20 variant protein of claim 34; (iii) an isolated T cell modified to express the A20 variant protein of claim 34 and/or (iv) a pharmaceutical composition comprising any one or more of (i)-(iii), and administering to the subject any immunotherapeutic agent, including those that are not enabled for treating cancer. The instant specification even discloses on page 47 that “The cancer to be treated may be any cancer, including, but not limited to, lymphoblastic leukemia (ALL), acute myeloid leukemia, adrenocortical carcinoma, basal-cell carcinoma, bile duct cancer, bladder cancer, bone tumor, osteosarcoma/malignant
fibrous histiocytoma, brainstem glioma, brain tumor, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, breast cancer, bronchial adenomas/carcinoids, Burkitt's lymphoma, carcinoid tumor, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, glioma, childhood visual pathway and hypothalamic, Hodgkin lymphoma, melanoma, islet cell carcinoma, Kaposi sarcoma, renal cell cancer, laryngeal cancer, leukaemias, lymphomas, mesothelioma, neuroblastoma, non-Hodgkin lymphoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary adenoma, plasma cell neoplasia, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma, testicular cancer, thyroid cancer, or uterine cancer”.
Claim 55 adds the immunotherapeutic agent is selected from the group consisting of checkpoint inhibitors, monoclonal antibodies, chimeric antigen receptor (CAR) T cells, and small molecule immune agonists, but still encompass many immunotherapeutic agents as many of the recited immunotherapeutic agents are just functionally recited and not chemically recited, and may or may not be enabled for treating cancer.
The State of the Prior Art
Zhu et al., (“Journal of Translational Medicine, Vol. 13, No. 1, 5 July 2015, page 215), cited on an IDS, teach A20, also known as TNFAIP3, is a TNF primary response transcript encoding a 790 amino acid protein with a unique zinc finger motif and is a ubiquitin-editing enzyme that is an essential negative regulator of inflammation and acts as a negative-feedback regulator of NF-kB activation (page 2, left column). Zhu et al. teach peripheral blood mononuclear cells and synovial fluid was collected from RA patients and RNA and DNA extraction from the PBMCs were performed, and different domains of genomic DNA that cover A20 exons 2-9 and exon/intron junctions were amplified, subjected to PCR and analyzed for mutation analysis (page 2, right column). Zhu et al. teach SNPs of the A20 gene, including the SNP, rs146534657 detected for the first time in RA patients, and that this SNP is a non-synonymous variant located in exon 3 of A20 and results in an amino acid at position 102 substitution from asparagine to serine (Table 1 page 3; page 8, left column).
Chang et al. (Oncology Reports, Vol. 35, 206, pages 2936-2942), cited on an IDS, also teach tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) which encodes a ubiquitin-modifying enzyme (A20), acts as a negative regulator of the NF-kB pathway (Abstract), and is one of the major inhibitors of the NF-kB signaling pathway (page 2937, left column).
Das et al. (Frontiers in Immunology, vol. 9, Article 104, Published 21 Feb 2018), cited on an IDS, taught stimulation of the nuclear factor-kB (NF- κB) signaling pathway leads to transcription of numerous pro-inflammatory and cell-survival genes, and several mechanisms tightly control NF-kB activity, including the key regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor alpha-induced protein 3 (TNFAIP3), and that SNPs in the vicinity of the TNFAIP3 gen are associated with a spectrum of chronic systemic inflammatory diseases, and when immune cells involved in the adaptive immune response are targeted for A20/TNFAIP3 deletion, mice development spontaneous inflammation the resembles human autoimmune disease (Abstract).
Das et al. taught A20/TNFAIP3 is a protein that terminates NF-kB signaling and regulates protein ubiquitination (page 2, left column). Das et al taught reduced TNFAIP3 mRNA expression was observed in peripheral blood mononuclear cells in SLE and RA patients, and that SNPs near the TNFAIP3 gene can result in reduced A20/TNFAIP3 mRNA and consequently protein concentrations (page 6, left page). Das et al. taught knowledge from cell-specific targeting studies in mice illustrate that loss of A20/TNFAIP3 results in either autoinflammation or autoimmunity (page 8, left column). Therefore Das et al. suggests a defective A20 mutation that causes loss of function of A20 would increase NF- κB signaling resulting in increased immune response.
Ventola (P&T, Vol. 42, No. 8, August 2017, pages 514-521) taught that obstacles still exist for the field of cancer immunotherapy, and that a major challenge for cancer immunotherapies is the need to develop agents that are consistently effective in a majority of patients and cancer types (Page 514, left column). Ventola taught many immunotherapy treatments have demonstrated efficacy only in a select group of cancers and usually in a minority of patients with those cancers, and reasons for the variability in patient response include cancer pathways, tumor heterogeneity, variability of cancer type and stage, treatment history, and underlying immunosuppressive biology of cancer (page 514, left column). Ventola taught that tumor heterogeneity and development of resistant cancer cell clones are both issues contributing to therapeutic failures observed with cancer immunotherapy in clinical practice (pages 516-517). Ventola taught work must still be done to establish immunotherapy as the standard of care for immune-sensitive tumors, to broaden its applicability across a variety of cancers, and to enhance its efficacy in a wider range of patients (page 518, right column).
Therefore, the state of the art provides support that the A20 protein is a negative regulator of NF-kB activation and signaling, and that the instant claimed A20(TNFAIP3) protein variant (rs146534657) was detected in RA patients, as well as reduced mRNA expression of TNFAIP3 in SLE and RA patients, and loss of A20/TNFAIP3 results in autoinflammation and autoimmunity which suggests a defective A20 mutations that causes loss of function would increase NF-kB signaling and therefore an increased immune response. The state of the art does not provide support that the instant claimed A20 variant would be capable of treating a genus of cancers in combination with an immunotherapeutic agent.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to the claims encompassing that the recited method treats a genus of cancers in a subject. The immunotherapeutic agent in claim 54 can be any immunotherapeutic, and the immunotherapeutic agents in claim 55 are still generic and not specific checkpoint inhibitors or specific small molecule immune agonists for example, that would be enabled for treating a specific type of cancer in a subject. While the state of the art and specification supports increasing NK-kB signaling which would increase the subject’s immune response, it is not predictable that this would result in treating any cancer in a subject. The instant specification even discloses on page 47 the numerous types of cancers that are encompassed by “cancer”. Ventola cited above supports the lack of predictability and challenges with regards to cancer immunotherapy, citing variability in patient response include cancer pathways, tumor heterogeneity, variability of cancer type and stage, treatment history, and underlying immunosuppressive biology of cancer.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 54 and 55, the specification does not enable any person skilled in the art to which it pertains to make and/or use the invention commensurate in scope with the claims. The instant specification discloses the variants, including the N102S variant, in Figure 5A showed an induction in NF-kB activity upon hTNFalpha stimulation (Example 3, page 60).
PNG
media_image1.png
362
557
media_image1.png
Greyscale
Page 62 and Figure 6B discloses that that the N102S variant scored higher than the NTC and suggests the complete inability of this variant to suppress NF-kB.
Therefore, there is in vitro data supporting the ability of the N102S variant as having increased NF-kB signaling activity.
The in vivo experiments of A20 variants in mice of Examples 6-8, do not pertain to the N102S variant. There are no examples, either in vitro or in vivo that pertain to any of the A20 variants and their ability to treat cancer including administering an immunotherapeutic agent. Therefore, there is a lack of information provided by the specification and examples regarding treating a genus of cancers in a subject in need thereof, comprising increasing a subject’s immune response by performing the method of claim 51 and administering to the subject an immunotherapeutic agent.
The Quantity of Experimentation Necessary
Regarding claims 54 and 55, in light of the unpredictability surrounding the breadth of the claimed method, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Therefore, given the lack of guidance present in the specification for the recited method of treating a genus of cancers by the recited method, further experimentation would be required and would be considered undue as one would have to perform experiments in various cancer models. Ventola taught work must still be done to establish immunotherapy as the standard of care for immune-sensitive tumors, to broaden its applicability across a variety of cancers, and to enhance its efficacy in a wider range of patients (page 518, right column).
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 54 and 55, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 54 and 55 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Claim Interpretation
Regarding the “wherein clause” recited in claims 30,34,37,39,41,42, “wherein the A20 variant protein exhibits increased NF-kB and/or JNK signaling activity relative to an A20 protein comprising the sequence set forth in SEQ ID NO: 1”, and in claims 51-53 regarding “wherein, following administration, the strength of an immune response in the subject is increased relative to the strength of the immune response in the absence of the A20 variant protein being delivered to the subject”, the increased NF-kB and/or JNK signaling activity and the increased strength of the immune response are unappreciated properties that would flow from the structure of the recited A20 variant protein. Therefore, art that teaches the recited A20 variant protein comprising an asparagine (N) to (S) substitution at a position corresponding to amino acid 102 in the sequence set forth in SEQ ID NO: 1, would have the property of increased NF-kB and/or JNK signaling activity relative to an A20 protein comprising the sequence set forth in SEQ ID NO:1, and would result in the strength of an immune response in the subject being increased relative to the strength of an immune response in the absence of the A20 variant protein being delivered to the subject.
In addition, instant SEQ ID NO: 1 is disclosed as the amino acid sequence for reference human A20 protein on page 17 of the specification. Table 2 on page 24 of the instant specification discloses that the instantly claimed variant has the rs number rs146534657. Therefore, art that teaches this rs number (rs146534657) teaches the instantly claimed A20 protein variant that corresponds to the identity and positions of human A20 protein sequence of SEQ ID NO: 1.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 30 and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhu et al., (“Journal of Translational Medicine, Vol. 13, No. 1, 5 July 2015, page 215), cited on an IDS.
Regarding claims 30 and 34, Zhu et al. teach A20, also known as TNFAIP3, is a TNF primary response transcript encoding a 790 amino acid protein with a unique zinc finger motif and is a ubiquitin-editing enzyme that is an essential negative regulator of inflammation and acts as a negative-feedback regulator of NF-kB activation (page 2, left column). It is noted that instant SEQ ID NO: 1 is the amino acid sequence for human A20 protein, and is also 790 amino acids. Zhu et al. teach peripheral blood mononuclear cells and synovial fluid was collected from RA patients and RNA and DNA extraction from the PBMCs were performed, and different domains of genomic DNA that cover A20 exons 2-9 and exon/intron junctions were amplified, subjected to PCR and analyzed for mutation analysis (page 2, right column). Zhu et al. teach SNPs of the A20 gene, including the SNP, rs146534657 detected for the first time in RA patients, and that this SNP is a non-synonymous variant located in exon 3 of A20 and results in an amino acid at position 102 substitution from asparagine to serine (Table 1 page 3; page 8, left column).
Therefore, Zhu et al. teach an isolated nucleic acid molecule comprising a polynucleotide sequence encoding an A20 variant protein of 790 amino acids that corresponds to instant SEQ ID NO: 1 (a human A20 protein that is 790 amino acids in length), and an isolated A20 variant protein comprising an amino acid sequence with the recited asparagine to serine substitution at amino acid position 102 that would correspond to position 102 in instant SEQ ID NO: 1, as it teaches the rs146534657 SNP that is the same rs SNP defined in Table 2 on page 24 of the instant specification that corresponds to the instantly claimed variant, and would therefore have the property of increased NF-kB and/or JNK signaling activity due to the structure of the variant (see Claim Interpretation above).
Claims 30 and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chang et al. (Oncology Reports, Vol. 35, 206, pages 2936-2942), cited on an IDS.
Regarding claims 30 and 34, Chang et al. teach tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) which encodes a ubiquitin-modifying enzyme (A20), acts as a negative regulator of the NF-kB pathway (Abstract), and is one of the major inhibitors of the NF-kB signaling pathway (page 2937, left column). Chang et al. teach DNA was extracted from peripheral blood samples from normal controls, and identified five SNPs in 50 normal Taiwanese individuals, and two of them, including N102S (rs146534657) were not found in oral squamous cell carcinoma tissue (Abstract). Chang et al. teach human genome-wide association studies have linked germline single nucleotide polymorphisms of the TNFAIP3 gene with susceptibility to human inflammatory and autoimmune pathologies (page 2937, left column).
Therefore, as stated in the above claim interpretation section, Chang et al. teach the same rs146534657 SNP as the instant A20 variant protein and polynucleotide sequence thereof that corresponds to instant SEQ ID NO:1, as it teaches the rs146534657 SNP with the substitution N102S that would correspond to position 102 in instant SEQ ID NO: 1, which is the same rs SNP defined in Table 2 on page 24 of the instant specification that corresponds to the instantly claimed variant, and would therefore have the property of increased NF-kB and/or JNK signaling activity due to the structure of the variant (see Claim Interpretation above).
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 37 and 39-53 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. as applied to claims 30 and 34 above, and further in view of Das et al. (Frontiers in Immunology, vol. 9, Article 104, Published 21 Feb 2018) and the English translation of Kim et al. (WO2018030874, Published 15 Feb 2018), both cited on an IDS.
The teachings of Zhu et al. as applicable to claims 30 and 34 have been described above.
Zhu et al. do not teach an isolated T cell modified to express an A20 variant protein comprising the recited substitution, or a pharmaceutical composition comprising one or more isolated nucleic acid molecules encoding the A20 variant protein and a pharmaceutically acceptable carrier, diluent or excipient, or a method of administering an isolated nucleic acid molecule encoding the A20 variant; the A20 variant protein, an isolated T cell modified to express the A20 variant protein; and/or a pharmaceutical composition comprising any one or more of the isolated nucleic acid molecule, the A20 variant protein or isolated T cell modified to express the A20 variant protein.
Before the effective filing date, Das et al. taught stimulation of the nuclear factor-kB (NF- κB) signaling pathway leads to transcription of numerous pro-inflammatory and cell-survival genes, and several mechanisms tightly control NF-kB activity, including the key regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor alpha-induced protein 3 (TNFAIP3), and that SNPs in the vicinity of the TNFAIP3 gen are associated with a spectrum of chronic systemic inflammatory diseases, and when immune cells involved in the adaptive immune response are targeted for A20/TNFAIP3 deletion, mice development spontaneous inflammation the resembles human autoimmune disease (Abstract).
Das et al. taught A20/TNFAIP3 is a protein that terminates NF-kB signaling and regulates protein ubiquitination (page 2, left column), and that resting T-cells constitutively express high levels of A20/TNFAIP3 protein, which is degraded after activation by paracaspase MALT1 to facilitate NF-κB translocation (Page 4, left column), and A20/TNFAIP3 is highly expressed in naïve T cells (page 5 left column). Das et al taught reduced TNFAIP3 mRNA expression was observed in peripheral blood mononuclear cells in SLE and RA patients, and that SNPs near the TNFAIP3 gene can result in reduced A20/TNFAIP3 mRNA and consequently protein concentrations (page 6, left page). Das et al. taught knowledge from cell-specific targeting studies in mice illustrate that loss of A20/TNFAIP3 results in either autoinflammation or autoimmunity (page 8, left column). Therefore Das et al. suggests a defective A20 mutation that causes loss of function of A20 would increase NF- κB signaling resulting in increased immune response.
Kim et al. taught an artificially manipulated immune system having an improved immune effect, and an immunomodulatory element that may function related to activation or deactivation of immune cells, and can function to suppress or promote the immune response, and pertains to genetically engineered or modified TNFAIP3 (A20) gene as immunoregulatory genes (page 2 of translation). Kim et al. taught modifications can occur in the exon region of the gene, and including substitution with one or more nucleotides that is different from the wild type gene (page 3 of translation). Kim et al. taught immune growth regulatory elements may be genes or proteins involved in the expression pathway of NF-kB (page 9 of translation).
Kim et al. taught the invention provides artificially engineered immune cells comprising said artificially engineered immunomodulatory gene, and the immune cell can be a T cell or a CAR-T cell (pages 4 and 13 of translation). Kim et al. taught the modified cell population may be further formulated with a pharmaceutically acceptable carrier, diluent or carrier (page 96 of translation).
Kim et al. taught an immune therapy approach including administration of an artificially engineered cell such as genetically engineered immune cells to a subject, and the effective immune cell therapeutic agent can be obtained by artificially manipulated immune modulating factor (page 6 of translation)
Kim et al. taught the therapeutic method provides for use of a population of cells manipulated or modified recombinantly in vitro, for example, via viral vectors, and the modified cell is an allogenic or autologous cell (page 96 of translation). Kim et al. taught methods of treating a disease using an immunotherapeutic approach comprising administration of an artificially engineered cell such as a genetically engineered immune cell to the subject, and the subject being treated includes humans, primates and rodents (page 93 of translation). Kim et al. taught immune enhancement in patients with significantly decreased immunity, and may include treatment of viral infectious diseases or bacterial diseases (page 95 of translation).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to provide an isolated T cell including CAR-T cells, autologous T cells, or allogenic T cells, which are modified to express the variant A20 protein of Zhu et al., based on the teachings of Das et al. and Kim et al. with a reasonable expectation of success to arrive at the instant claims. There would be a reasonable expectation of success, because Zhu et al. teach A20/TNFAIP3 is a negative-feedback regulator of NF-kB activation, Das et al. taught A20/TNFAIP3 terminates NF-kB signaling and Kim et al. taught genetically engineered or modified TNFAIP3 (A20) gene, including substitutions as immunoregulatory genes. One of ordinary skill in the art would have been motivated to provide an isolated T cell, including a CAR-T cell, autologous T cell, or allogenic T cell which is modified to express an A20 variant protein which is rs146534657 and has an amino acid at position 102 substitution from asparagine to serine, because Zhu et al. taught A20/TNFAIP3 is a negative-feedback regulator of NF-kB activation and Das et al. taught A20/TNFAIP3 terminates NF-kB signaling and that resting T-cells and naïve T cells express high levels of A20/TNFAIP3 protein and that SNPs near the TNFAIP3 gene can result in reduced A20/TNFAIP3 mRNA and knowledge from cell-specific targeting studies in mice illustrate that loss of A20/TNFAIP3 results in either autoinflammation or autoimmunity. Therefore Das et al. suggests a defective A20 mutation that causes loss of function of A20 would increase NF- κB signaling resulting in increased immune response. Additionally, one of ordinary skill in the art would have been motivated to do so because Kim et al. taught genetically engineered or modified TNFAIP3 (A20) gene as immunoregulatory genes (page 2 of translation) and taught modifications can occur in the exon region of the gene, and including substitution with one or more nucleotides that is different from the wild type gene (page 3 of translation), and taught immune growth regulatory elements may be genes or proteins involved in the expression pathway of NF-kB (page 9 of translation). Kim et al. taught artificially engineered immune cells comprising said artificially engineered immunomodulatory gene, and the immune call can be a T cell or a CAR-T cell, allogenic or autologous cells and taught therapeutic methods provides for use of a population of cells manipulated or modified recombinantly in vitro for methods of treating a disease using an immunotherapeutic approach comprising administration of an artificially engineered cell such as a genetically engineered immune cell to the subject.
Accordingly, the limitations of claims 37 and 48-50 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide a pharmaceutical composition comprising an isolated nucleic acid molecule encoding the A20 variant protein, an isolated A20 variant protein, or an isolated T cell modified to express the A20 variant of Zhu et al. in a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent or excipient based on the teachings of Das et al. and Kim et al. There would be a reasonable expectation of success, because Zhu et al. teach A20/TNFAIP3 is a negative-feedback regulator of NF-kB activation, Das et al. taught A20/TNFAIP3 terminates NF-kB signaling and Kim et al. taught genetically engineered or modified TNFAIP3 (A20) gene, including substitutions as immunoregulatory genes. One of ordinary skill in the art would have been motivated to provide a pharmaceutical composition comprising an isolated nucleic acid molecule encoding the A20 variant protein, an isolated A20 variant protein, or an isolated T cell modified to express the A20 variant of Zhu et al. in a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent or excipient because Das et al. taught knowledge from cell-specific targeting studies in mice illustrate that loss of A20/TNFAIP3 results in either autoinflammation or autoimmunity and Kim et al. taught the invention provides artificially engineered immune cells comprising said artificially engineered immunomodulatory gene, and the immune cell can be a T cell or a CAR-T cell and the modified cell population may be further formulated with a pharmaceutically acceptable carrier, diluent or carrier (page 96 of translation) and used in an immune therapy approach. Regarding claim 40, the recitation “vaccine” does not add any structure or additional elements to the pharmaceutical composition that is recited in claim 39, and therefore art that reads on claim 39 also applies to claim 40.
Accordingly, the limitations of claims 39-47 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art, to administer the isolated variant A20 nucleic acid molecule or protein of Zhu et al. or administer an isolated T cell modified to express the A20 variant protein of Zhu et al. to a subject for the purpose of enhancing the immune response of a subject with a reasonable expectation of success. There would be a reasonable expectation of success because both Zhu et al. and Das et al. teach A20/TNFAIP3 is a negative-feedback regulator of NF-kB activation and Das et al. suggests a defective A20 mutation that causes loss of function of A20 would increase NF-κB signaling resulting in increased immune response. One of ordinary skill in the art would be motivated to administer the isolated variant A20 nucleic acid molecule or protein of Zhu et al. or administer an isolated T cell modified to express the A20 variant protein of Zhu et al. to a subject because Kim et al. taught an artificially manipulated immune system having an improved immune effect, and can function to promote the immune response, including genetically engineered or modified TNFAIP3 (A20) gene as immunoregulatory genes and immune growth regulatory elements may be genes or proteins involved in the expression pathway of NF-kB, and taught an immune therapy approach including administration of an artificially engineered cell such as genetically engineered immune cells to a subject, and the effective immune cell therapeutic agent can be obtained by artificially manipulated immune modulating factor, and taught immune enhancement in patients with significantly decreased immunity, and may include treatment of viral infectious diseases or bacterial diseases.
Accordingly, the limitations of claims 51-53 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 37 and 39-53 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al. as applied to claims 30 and 34 above, and further in view of Das et al. (Frontiers in Immunology, vol. 9, Article 104, Published 21 Feb 2018) and the English translation of Kim et al. (WO2018030874, Published 15 Feb 2018), both cited on an IDS.
The teachings of Chang et al. as applicable to claims 30 and 34 have been described above.
Chang et al. do not teach an isolated T cell modified to express an A20 variant protein comprising the recited substitution, or a pharmaceutical composition comprising one or more isolated nucleic acid molecules encoding the A20 variant protein and a pharmaceutically acceptable carrier, diluent or excipient, or a method of administering an isolated nucleic acid molecule encoding the A20 variant; the A20 variant protein, an isolated T cell modified to express the A20 variant protein; and/or a pharmaceutical composition comprising any one or more of the isolated nucleic acid molecule, the A20 variant protein or isolated T cell modified to express the A20 variant protein.
Before the effective filing date, Das et al. taught stimulation of the nuclear factor-kB (NF- κB) signaling pathway leads to transcription of numerous pro-inflammatory and cell-survival genes, and several mechanisms tightly control NF-kB activity, including the key regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor alpha-induced protein 3 (TNFAIP3), and that SNPs in the vicinity of the TNFAIP3 gen are associated with a spectrum of chronic systemic inflammatory diseases, and when immune cells involved in the adaptive immune response are targeted for A20/TNFAIP3 deletion, mice development spontaneous inflammation the resembles human autoimmune disease (Abstract).
Das et al. taught A20/TNFAIP3 is a protein that terminates NF-kB signaling and regulates protein ubiquitination (page 2, left column), and that resting T-cells constitutively express high levels of A20/TNFAIP3 protein, which is degraded after activation by paracaspase MALT1 to facilitate NF-κB translocation (Page 4, left column), and A20/TNFAIP3 is highly expressed in naïve T cells (page 5 left column). Das et al taught reduced TNFAIP3 mRNA expression was observed in peripheral blood mononuclear cells in SLE and RA patients, and that SNPs near the TNFAIP3 gene can result in reduced A20/TNFAIP3 mRNA and consequently protein concentrations (page 6, left page). Das et al. taught knowledge from cell-specific targeting studies in mice illustrate that loss of A20/TNFAIP3 results in either autoinflammation or autoimmunity (page 8, left column). Therefore Das et al. suggests a defective A20 mutation that causes loss of function of A20 would increase NF- κB signaling resulting in increased immune response.
Kim et al. taught an artificially manipulated immune system having an improved immune effect, and an immunomodulatory element that may function related to activation or deactivation of immune cells, and can function to suppress or promote the immune response, and pertains to genetically engineered or modified TNFAIP3 (A20) gene as immunoregulatory genes (page 2 of translation). Kim et al. taught modifications can occur in the exon region of the gene, and including substitution with one or more nucleotides that is different from the wild type gene (page 3 of translation). Kim et al. taught immune growth regulatory elements may be genes or proteins involved in the expression pathway of NF-kB (page 9 of translation).
Kim et al. taught the invention provides artificially engineered immune cells comprising said artificially engineered immunomodulatory gene, and the immune cell can be a T cell or a CAR-T cell (pages 4 and 13 of translation). Kim et al. taught the modified cell population may be further formulated with a pharmaceutically acceptable carrier, diluent or carrier (page 96 of translation).
Kim et al. taught an immune therapy approach including administration of an artificially engineered cell such as genetically engineered immune cells to a subject, and the effective immune cell therapeutic agent can be obtained by artificially manipulated immune modulating factor (page 6 of translation)
Kim et al. taught the therapeutic method provides for use of a population of cells manipulated or modified recombinantly in vitro, for example, via viral vectors, and the modified cell is an allogenic or autologous cell (page 96 of translation). Kim et al. taught methods of treating a disease using an immunotherapeutic approach comprising administration of an artificially engineered cell such as a genetically engineered immune cell to the subject, and the subject being treated includes humans, primates and rodents (page 93 of translation). Kim et al. taught immune enhancement in patients with significantly decreased immunity, and may include treatment of viral infectious diseases or bacterial diseases (page 95 of translation).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to provide an isolated T cell including CAR-T cells, autologous T cells, or allogenic T cells, which are modified to express the variant A20 protein of Chang et al., based on the teachings of Das et al. and Kim et al. with a reasonable expectation of success to arrive at the instant claims. There would be a reasonable expectation of success, because Chang et al. teach A20/TNFAIP3 is a negative regulator of NF-kB activation, Das et al. taught A20/TNFAIP3 terminates NF-kB signaling and Kim et al. taught genetically engineered or modified TNFAIP3 (A20) gene, including substitutions as immunoregulatory genes. One of ordinary skill in the art would have been motivated to provide an isolated T cell, including a CAR-T cell, autologous T cell, or allogenic T cell which is modified to express an A20 variant protein which is rs146534657 and has an amino acid at position 102 substitution from asparagine to serine, because Chang et al. taught A20/TNFAIP3 is a negative regulator of NF-kB activation and Das et al. taught A20/TNFAIP3 terminates NF-kB signaling and that resting T-cells and naïve T cells express high levels of A20/TNFAIP3 protein and that SNPs near the TNFAIP3 gene can result in reduced A20/TNFAIP3 mRNA and knowledge from cell-specific targeting studies in mice illustrate that loss of A20/TNFAIP3 results in either autoinflammation or autoimmunity. Therefore Das et al. suggests a defective A20 mutation that causes loss of function of A20 would increase NF- κB signaling resulting in increased immune response. Additionally, one of ordinary skill in the art would have been motivated to do so because Kim et al. taught genetically engineered or modified TNFAIP3 (A20) gene as immunoregulatory genes (page 2 of translation) and taught modifications can occur in the exon region of the gene, and including substitution with one or more nucleotides that is different from the wild type gene (page 3 of translation), and taught immune growth regulatory elements may be genes or proteins involved in the expression pathway of NF-kB (page 9 of translation). Kim et al. taught artificially engineered immune cells comprising said artificially engineered immunomodulatory gene, and the immune call can be a T cell or a CAR-T cell, allogenic or autologous cells and taught therapeutic methods provides for use of a population of cells manipulated or modified recombinantly in vitro for methods of treating a disease using an immunotherapeutic approach comprising administration of an artificially engineered cell such as a genetically engineered immune cell to the subject.
Accordingly, the limitations of claims 37 and 48-50 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide a pharmaceutical composition comprising an isolated nucleic acid molecule encoding the A20 variant protein, an isolated A20 variant protein, or an isolated T cell modified to express the A20 variant of Chang et al. in a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent or excipient based on the teachings of Das et al. and Kim et al. There would be a reasonable expectation of success, because Chang et al. teach A20/TNFAIP3 is a negative regulator of NF-kB activation, Das et al. taught A20/TNFAIP3 terminates NF-kB signaling and Kim et al. taught genetically engineered or modified TNFAIP3 (A20) gene, including substitutions as immunoregulatory genes. One of ordinary skill in the art would have been motivated to provide a pharmaceutical composition comprising an isolated nucleic acid molecule encoding the A20 variant protein, an isolated A20 variant protein, or an isolated T cell modified to express the A20 variant of Chang et al. in a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent or excipient because Das et al. taught knowledge from cell-specific targeting studies in mice illustrate that loss of A20/TNFAIP3 results in either autoinflammation or autoimmunity and Kim et al. taught the invention provides artificially engineered immune cells comprising said artificially engineered immunomodulatory gene, and the immune cell can be a T cell or a CAR-T cell and the modified cell population may be further formulated with a pharmaceutically acceptable carrier, diluent or carrier (page 96 of translation) and used in an immune therapy approach. Regarding claim 40, the recitation “vaccine” does not add any structure or additional elements to the pharmaceutical composition that is recited in claim 39, and therefore art that reads on claim 39 also applies to claim 40.
Accordingly, the limitations of claims 39-47 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art, to administer the isolated variant A20 nucleic acid molecule or protein of Chang et al. or administer an isolated T cell modified to express the A20 variant protein of Chang et al. to a subject for the purpose of enhancing the immune response of a subject with a reasonable expectation of success. There would be a reasonable expectation of success because both Chang et al. and Das et al. teach A20/TNFAIP3 is a negative regulator of NF-kB activation and Das et al. suggests a defective A20 mutation that causes loss of function of A20 would increase NF- κB signaling resulting in increased immune response. One of ordinary skill in the art would be motivated to administer the isolated variant A20 nucleic acid molecule or protein of Chang et al. or administer an isolated T cell modified to express the A20 variant protein of Chang et al. to a subject because Kim et al. taught an artificially manipulated immune system having an improved immune effect, and can function to promote the immune response, including genetically engineered or modified TNFAIP3 (A20) gene as immunoregulatory genes and immune growth regulatory elements may be genes or proteins involved in the expression pathway of NF-kB, and taught an immune therapy approach including administration of an artificially engineered cell such as genetically engineered immune cells to a subject, and the effective immune cell therapeutic agent can be obtained by artificially manipulated immune modulating factor, and taught immune enhancement in patients with significantly decreased immunity, and may include treatment of viral infectious diseases or bacterial diseases.
Accordingly, the limitations of claims 51-53 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 30,34,37 and 39-55 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R Shukla can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636