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 .
Status of Application, Amendments and/or Claims
Claims 1-15 are pending.
Election/Restrictions
Applicant’s election without traverse of (i) HSV as the species of virus and (ii) ICP47 as the species of viral protein in the reply filed on 08 June 2026 is acknowledged.
Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08 June 2026.
Claims 1-4 and 6-15 are under consideration in the instant application.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12 March 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
1. Claims 1, 9, 10, 12, and 14 are objected to because of the following informalities:
1a. Claim 1 is missing punctuation/words at the end of subpart lines (I) and (II) and in between parts (A) and (B).
For instance, in claim 1, line 5, after “nucleic acid”, a comma should be inserted.
In claim 1, line 9, after “ncRNA”, a comma and the word “and” should be inserted. Lastly, in line 11, after “(TCR)”, the comma should be deleted and a semi-colon and the word “and” inserted (“; and”).
1b. In claim 9, line 2, after “DNA binding domain”, the word “and” should be deleted and a comma inserted. Additionally, after the phrase “drug-binding domain”, a comma should be inserted (i.e., “a DNA binding domain, , and an activation domain”.
1c. In claim 10, line 4, the capital “W” in the word “Wherein” should be lowercase.
1d. In claim 10, lines 5 and 6, the two recitations of “cell” should be plural for consistency with claim 1.
1e. Claim 12 is missing punctuation/words at the end of subpart lines (I) and (II). For instance, in claim 12, line 5, after “nucleic acid”, a comma should be inserted. In claim 12, line 9, after “ncRNA”, a comma and the word “and” should be inserted.
1f. Claim 14 is missing punctuation/words at the end of subpart lines (I) and (II) and in between parts (A) and (B).
For instance, in claim 14, line 5, after “nucleic acid”, a comma should be inserted.
In claim 14, line 9, after “ncRNA”, a comma and the word “and” should be inserted. Lastly, in line 11, after “carrier”, the comma should be deleted and a semi-colon inserted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
2. Claims 1, 2, 8-12, and 14 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.
Claim 1 of the instant application is directed to a composition comprising
A) immune cells comprising
a) an inducible gene expression system comprising
I) a first nucleic acid comprising a drug-inducible promoter operably linked to a second nucleic acid
II) said second nucleic acid encoding a polypeptide or a non-coding RNA (ncRNA) which decreases cell surface expression level of major histocompatibility complex (MHC) class I relative to cell surface expression level of MHC class I of an immune cell that does not express said polypeptide or ncRNA
b) a third nucleic acid encoding a chimeric antigen receptor (CAR) or T cell receptor (TCR),
B) a drug that induces said drug-inducible promoter.
The specification of the instant application teaches that K3 and US6 encoding sequences are subcloned into a lentiviral vector under the control of a PGK promoter (page 38, lines 7-8). The specification also discloses that isolated T cells are transduced 24 h after activation with fresh or frozen, carefully resuspended VSV-G pseudotyped lentiviral particles encoding either K3 or US6 (page 38, lines 10-12). The specification indicates that on day 8, either K3-, US6, or ICP47-modified T cells are co-cultured with autologous NK cells and subsequent killing analyzed (page 38, lines 15-17).
Regarding the encoded non-coding RNA (ncRNA) which decreases cell surface expression level of major histocompatibility complex (MHC) class I, the specification teaches that the term "‘polypeptide (or protein) or ncRNA which decreases (or reduces) cell surface expression level of major histocompatibility complex (MHC) class I in an immune cell (a T cell) relative to cell surface expression level of MHC class I of an immune cell (a T cell) that does not express the polypeptide (or protein) or ncRNA’ as used herein refer to heterologous polypeptides (or proteins) or ncRNAs that are able to reduce, down-regulate, knock down or knock out the expression of MHC class I in the cell, when they are expressed in said cell” (page 14, lines 15-20). The specification continues to disclose that said polypeptide is a viral protein which decreases cell surface expression level of MHC class I in an immune cell such as a T cell relative to cell surface expression level of MHC class I of an immune cell such as T cell that does not express the viral protein (page 14, lines 21-24). The specification states that ncRNA is an RNA molecule that is not translated into a protein (page 16, line 16).
Therefore, in view of the teachings of the instant specification, the “non-coding RNA (ncRNA)” limitation is broadly interpreted by the Examiner as reading upon any ncRNA which decreases cell surface expression level of MHC class I relative to cell surface expression level of MHC class I of an immune cell that does express ncRNA. However, the specification does not teach all possible ncRNA that decrease cell surface expression of MHC class I and that can be utilized in a gene expression system.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the factors present in the claims for the second nucleic acid in the immune cells is (1) a structural characteristic of a non-coding RNA (ncRNA) and (2) functional characteristics of decreasing cell surface expression level of MHC class I and the ability of being utilized in a gene expression system. There is no identification of any particular sequence or structure of the ncRNA that must be conserved in order to provide the required functions. Thus, the claims are drawn to a genus of ncRNA.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of ncRNA and the functions of decreasing cell surface expression level of MHC class I and the ability of being utilized in a gene expression system. In other words, the specification does not teach the structure which results in a ncRNA in the claimed composition with the required characteristics. The lack of description of ncRNA that decrease cell surface expression of MHC class I in the instant specification and the prior art indicates that the instant claims contain subject matter which was not described in such a way as to reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention. Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (See page 1117). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (See Vas-Cath at page 1116). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the genus of ncRNA that decrease cell surface expression of MHC class in the claimed composition and that can be utilized in a gene expression system, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The specific ncRNA are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
3. Claims 1-4, 6-9, and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al. (Int J Mol Sci 19: 3455, 2018) and Chaparro Riggers et al. (WO 2018/193394; cited on the IDS of 12 March 2024).
Gu et al. teach that the tetracycline regulatory system is widely used to control transgene expression by a small dose of doxycycline, thus controlling the activity of chimeric antigen receptor (CAR) T cells and managing side effects (abstract; page 2, 1st full paragraph). Gu et al. disclose the generation of inducible CD19CAR (iCAR19) T cells via an inducible one-vector system for T-cell therapy that has high induction efficiency and low expression leakage, meeting the limitations of instant claims 1 and 14 (page 2, 2nd full paragraph; abstract). Gu et al. disclose that the system utilizes a CD19CAR with a Tet-on sequence (entire page 2; Figure 1A). For the construct, Gu et al. disclose that the Tet-On sequence is downstream of the human phosphoglycerate kinase 1 promoter (PGK) and the CD19CAR is transcribed in the reverse orientation under the TREalb promoter (which is the Tet-responsive promoter for albumin), meeting the limitations of instant claims 1, 12, and 14 (page 2, 2nd and 3rd full paragraphs; Figure 1A (copied below)).
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It is noted that Gu et a. disclose that the rtTA2S-M2 transactivator domain in the construct comprises a VP16 domain, meeting the limitations of instant claims 8 and 9 (page 7, 3rd full paragraph). Gu et al. state that that the construct is cloned into a pCDH-CMV-MCS-EF1α-copGFP lentiviral backbone (page 2, 3rd full paragraph; Figure 1B). Gu et al. teach compositions comprising the iCAR19 T cells and doxycycline (Dox), meeting the limitations of instant claims 1 and 14 (page 3, sections 2.3 and 2.4). Gu et al. disclose that iCAR19 T cells show dox-dependent cell proliferation, cytokine production, CAR expression, and CD19-specific cytotoxicity (page 6, discussion).
Gu et al. do not teach that a sequence for a viral protein (that decreases cell surface expression of MHC I) is linked to the TREalb promoter and anti-CD19 CAR scFv sequences in the one-vector Tet-on construct.
Chaparro Riggers et al. teach an isolated T cell comprising (i) a viral protein which decreases cell surface expression level of MHC class I relative to cell surface expression level of MHC class I of an isolated T cell that does not comprise the viral protein; and (ii) a chimeric antigen receptor (CAR), meeting the limitations of instant claims 1-3 and 12-15 (page 2, lines 9-13; page 18, lines 10-20). Chaparro Riggers et al. disclose a polynucleotide encoding (i) a viral protein which decreases cell surface expression of a MHC class I molecule and (ii) a CAR, wherein (i) and (ii) are co-expressed, meeting the limitations of instant claims 1-3 and 12-15 (page 6, lines 17-21). Chaparro Riggers et al. indicate that the coding sequence for (i) and (ii) are operably linked to the same promoter (page 6, lines 21-22; page 9). Chaparro Riggers et al. state that the viral protein includes without limitation, ICP47 (elected species), meeting the limitations of instant claims 4, 6, and 7 (page 19, lines 2-20 through page 24). Chaparro Riggers et al. teach methods of generating such cell, meeting the limitations of instant claim 12 (page 4, lines 5-10). Chaparro Riggers et al. teach a composition comprising such T cell (page 4, lines 21-28). Chaparro Riggers et al. state that the T cell may be autologous, meeting the limitations of instant claim 11 (page 41, lines 1-3; page 8, lines 12-13).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the one-vector Tet-on construct of Gu et al. by linking the TREalb promoter and anti-CD19 CAR scFv sequences to a viral protein sequence which decreases cell surface expression level of MHC class I, as taught by Chaparro Riggers et al. The person of ordinary skill in the art would have been motivated to make that modification because expression of the viral protein leads to decreased MHC class I cell surface expression, resulting in decreased T cell recognition and increased in vivo persistence and improved CAR-T cell efficacy (Chaparro Rigger et al. page 2, lines 3-7). The person of ordinary skill in the art reasonably would have expected success because co-expression of CARs and viral proteins was successfully being performed at the time the invention was made (see Chaparro Riggers et al., pages 46-49). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Conclusion
No claims are allowable.
Wang et al. (Mol Ther 29(2): 718-733, 2021; published online 22 October 2020; teach the generation of γ-retroviruses encoding K3 and/or K5 viral transgenes that efficiently transduce primary human T cells (abstract); disclose that the expression of K3 or K5 results in downregulation of MHC-IA (human leukocyte antigen [HLA]-A, -B, and -C) and MHC class II (HLA-DR) cell-surface expression (abstract; page 720, column 1, “results”); indicate that CAR-T cells are transduced with a CAR-encoding vector (iMC-PSCA-CAR.ζ-CD20stalk), a retroviral vector encoding a K3myc-Q.CD8 stalk or K5myc-Q.CD8 stalk, and a third vector encoding eGFPFfluc (page721, column 1, 2nd full paragraph);; do not teach a nucleic acid encoding a viral protein (such as K3 or K5) is linked to the nucleic acid comprising a drug-inducible promoter (iMC))
Graham et al. WO 2021/202832 (teach cells (such as CAR T cells) that comprise a genome modified to express a nucleic acid sequence encoding a viral immunoevasin protein, such as ICP47 (pages 7-8; page 13, lines 20-28; page 14, lines 16-23; page 15; page 20, lines 17-33 through page 21)
Herbring et al. Sci Reports 6: 36907, 2016 (teach that ICP47 inhibits TAP)
Drug inducible systems
Barrett et al. Cancer Gene Ther 25: 106-116, 2018
Juillerat et al. Sci Reports 6: 18950, 2016
Kallunki et al. Cell 8: 796, 2019
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BEB
Art Unit 1647
27 July 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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