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
The amendment of 07 July 2026 has been entered in full. Claims 6, 17, 42-44, 61, are amended. Claims 3, 5, 8-10, 14, 16, 20-30, 36, 45, 47, 49-60, 62, and 64-69 are cancelled.
Claims 1, 2, 4, 6, 7, 11-13, 15, 17-19, 31-35, 37-44, 46, 48, 61, and 63 are pending.
Election/Restrictions
Applicant’s election of Group I, claims 1, 2, 4, 6, 7, 11-13, 15, and 17 in the reply filed on 07 July 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)).
Claims 18-19, 31-35, 37-44, 46, 48, 61, and 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07 July 2026.
Claims 1, 2, 4, 6, 7, 11-13, 15, and 17 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12 March 2025 and 05 February 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
1. The drawings are objected to because the figures are missing “Figure 13D”.
The Brief Description of the Drawings (pages 13-14, [0038]) refers to a “Figure 13D” in the first line of the description. However, there is no further brief description for Figure 13D and there is no figure labeled as “Figure 13D”. It is not clear if the last unlabeled graph (“Day 4”) on the same sheet as Figures 13B and 13C is intended to be 13D. If so, the sheet should be amended to add a label, “Figure 13D”, and the Brief Description of the Drawings should be amended.
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
2. The disclosure is objected to because of the following informalities:
2a. At page 22, [0061]; page 25, [0073] the specification states that SEQ ID NO: 29 is a nucleic acid encoding a cellodextrin transporter protein. However, SEQ ID NO: 29 encodes a beta-glucosidase protein (see for instance, Figure 21; specification page 30, [0092]) and paragraphs [0061] and [0073] should be amended to recite such.
2b. The disclosure is objected to because it contains numerous embedded hyperlinks and/or other forms of browser-executable code:
Pages 38-39, [00127];
Page 39, [00128];
Pages 94-95, [00341];
Page 102, [000342];
Page 164, [00346-00347];
Page 165, [00349];
Page 166, [00350];
Page 167, [00353]; and
Page 179, [00392].
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
3. Claim 12 is objected to because of the following informalities:
3a. In claim 12, lines 5-7, recite that SEQ ID NO: 29 is a nucleic acid encoding cellodextrin transporter protein. However, SEQ ID NO: 29 encodes a beta-glucosidase protein (see for instance, claim 4, subpart (b); Figure 21; specification page 30, [0092]) and lines 5-6 should be amended to recite such. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claims 2, 4, 6, 7, 11-13, 15, and 17 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.
4a. Claims 2, 4, 6, 7, 11-13, 15, and 17 are rejected as being indefinite because claim 2, line 4 does not recite a word after the phrase “functional fragment thereof;”. It is not clear if “and” or “or” is intended and without such, it is not clear what recited limitations are encompassed by the claim. For example, does the bioengineered cell comprise the limitations recited in (a), (b), and (c)? Or, does the bioengineered cell comprise one of the limitations recited (i.e., (a), (b), or (c))? One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
4b. Claims 4 and 6 are rejected as being indefinite because claims 4 and 6 recite the phrase “the nucleic acid sequence encoding the cellodextrin transporter protein [or the beta-glucosidase protein] or a functional fragment thereof encodes a protein at least 90% identical to” SEQ ID NO: 1, 2, 17-19, 28, 4, 5, and 29. However, SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29 are nucleic acid sequences, not proteins (amino acid sequences). Several of the sequences recited in claims 4 and 6 are amino acid sequences (SEQ ID NOs: 32, 3, 37, and 6). Therefore, it is not clear if Applicant is intending the recite the nucleic acid sequences encoding the proteins or simply the amino acid sequences. Please note that this issue could be overcome by possibly amending claim 4 to remove the nucleic acid sequences (SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29) from subparts (a) and (b). Or, adding subparts (c) and (d) that specifically recite, for example:
(c) the nucleic acid sequence encoding the cellodextrin transporter protein or a functional fragment thereof, wherein the nucleic acid sequence is at least 90% identical to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 28; or
(d) the nucleic acid sequence encoding the beta-glucosidase protein or a functional fragment thereof, wherein the nucleic acid sequence is at least 90% identical to SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 29.
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.
5. Claims 1, 2, 4, 6, 7, 11-13, 15, and 17 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 is directed to a bioengineered cell modified to metabolize a xenobiotic fuel, the xenobiotic fuel not metabolized by a corresponding unmodified cell, the bioengineered cell comprising:
(a) at least one foreign nucleic acid encoding at least one transporter protein or a functional fragment thereof for transport of the xenobiotic fuel into the bioengineered cell;
(b) at least one foreign nucleic acid encoding at least one protein or a functional fragment thereof for enabling the metabolizing of the xenobiotic fuel in the bioengineered cell; or
(c) a combination of (a) and (b).
Instant claim 2 recites the bioengineered cell of claim 1, wherein: (a) the xenobiotic fuel comprises cellobiose; (b) the transporter protein comprises a cellodextrin transporter or a functional fragment thereof; (c) the protein for enabling the metabolizing of the xenobiotic fuel comprises a beta-glucosidase protein or a functional fragment thereof or a cellobiose phosphorylase protein or a functional fragment thereof.
Claim 4 recites sequences with at least 90% sequence identity to SEQ ID NOs: 1-6, 17-19, 28, 29, 32, and 37.
Claim 12 recites a bioengineered cell comprising a vector comprising a nucleic acid sequence at least 90% identical to SEQ ID NO: 28 or 29.
The specification of the instant application teaches that the transporter protein or functional fragment thereof comprises a cellodextrin transporter protein (CDT-1) or a functional fragment thereof; or (b) the protein or functional fragment thereof for enabling the metabolizing of the xenobiotic fuel in the bioengineered cell comprises a beta-glucosidase protein (GH1-1) or a functional fragment thereof or a cellobiose phosphorylase protein or a functional fragment thereof (page 28, [0084]; page 37, [00119]). The specification also teaches (a) the nucleic acid sequence encoding the cellodextrin transporter protein or a functional fragment thereof encodes a protein at least 90% identical to SEQ ID NO: 32 or SEQ ID NO: 3; or (b) the nucleic acid sequence encoding the beta glucosidase protein or a functional fragment thereof encodes a protein at least 90% identical to SEQ ID NO: 37 or SEQ ID NO: 6 (page 29, [0085]; page 32, [0096]). The instant specification discloses that in some embodiments, (a) the nucleic acid sequence encoding the cellodextrin transporter protein or a functional fragment thereof is at least 90% identical to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 17, SEQ ID NO: 18, or SEQ ID NO: 19; or (b) the nucleic acid sequence encoding the beta-glucosidase protein or a functional fragment thereof is at least 90% identical to SEQ ID NO: 4 or SEQ ID NO: 5 (page 29, [0086]; page 32, [0097]). The specification also teaches full-length CDT-1 amino acid sequences of SEQ ID NOs: 3, 32 and full-length GH1-1 amino acid sequences of SEQ ID NO: 6, 37 (Tables 1 and 3). The instant specification discloses nucleic acid sequences and vector constructs comprising specific CDT-1 and GH1-1 sequences (see Tables 1-2, pages 95-161; see SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29).
Therefore, the “functional fragment” limitations recited in the instant claims are broadly interpreted by the Examiner as reading upon (i) any fragment, as small as two amino acids in length, of any transporter protein that transports xenobiotic fuel into a bioengineered cell (including cellodextrin), and (ii) any fragment, as small as two amino acids in length, of any protein for enabling the metabolizing of the xenobiotic fuel (including beta-glucosidase or cellobiose phosphorylase) (and nucleic acids encoding such fragments). However, the specification does not teach any functional fragments of all possible transporter proteins that transport xenobiotic fuel into a bioengineered cell. The specification also does not teach all possible proteins and functional fragments thereof that metabolize xenobiotic fuel.
The “at least 90% identical” limitations recited in the instant claims are also broadly interpreted by the Examiner as reading upon sequences that have at least 90% sequence identity to the full-length amino acid sequences of SEQ ID NO: 3, 32, 6, 37 and 90% sequence identity to the full-length nucleic acid sequences of SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29. However, the specification does not teach any variants, substitutions, insertions, deletions, or fragments of the sequences recited in the instant claims, other than the full-length CDT-1 amino acid sequences of SEQ ID NOs: 3, 32; full-length GH1-1 amino acid sequences of SEQ ID NO: 6, 37; and nucleic acid sequences and vector constructs of SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29.
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 are: (1) structural characteristics of a bioengineered cell that comprises a nucleic acid encoding at least one transporter protein or fragment thereof and/or a nucleic acid encoding at least one metabolizer protein or fragment thereof (such as a beta-glucosidase or a cellobiose phosphorylase); and sequences that have at least 90% sequence identity to the full-length amino acid sequences of SEQ ID NO: 1-6, 17-19, 28, 29, 32, 37 and (2) functional characteristics that the encoded transporter protein transports xenobiotic fuel into the cell; the encoded transporter protein fragment is functional; the second encoded protein metabolizes xenobiotic fuel in the cell; and the second encoded metabolizer protein fragment is functional. There is no identification of any particular sequence or structure of the transporter protein, transporter protein functional fragment, or variants, substitutions, insertions, deletions, or fragments of the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32 that must be conserved in order to provide the required function of transporting xenobiotic fuel into a bioengineered cell. There also is no identification of any particular sequence or structure of the second encoded protein, functional fragment thereof, or variants, substitutions, insertions, deletions, or fragments of the sequences of SEQ ID NOs: 4-6, 29, and 37 that must be conserved in order to provide the required function of metabolizing the xenobiotic fuel in a bioengineered cell. Thus, the claims are drawn to a genus of encoded transporter proteins and fragments thereof and encoded “metabolizer” proteins and fragments thereof.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of encoded transporter proteins and fragments thereof and the function of transporting xenobiotic fuel into a bioengineered cell. The specification also fails to disclose and there is no art-recognized correlation between the structure of the genus of encoded “metabolizer” proteins and fragments thereof and the function of metabolizing xenobiotic fuel in a bioengineered cell. In other words, the specification does not teach the structure which results in encoded proteins with the claimed required characteristics. The description of the full-length CDT-1 amino acid sequences of SEQ ID NOs: 3, 32; full-length GH1-1 amino acid sequences of SEQ ID NO: 6, 37; and nucleic acid sequences and vector constructs of SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29 is not adequate written description of an entire genus of encoded transporter proteins and fragments thereof; an entire genus of encoded “metabolizer” proteins and fragments thereof; and the genus of sequence variants at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32.
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability.
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 encoded transporter proteins and fragments thereof; the genus of encoded “metabolizer” proteins and fragments thereof; and the sequence variants that have at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32, 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 encoded protein is 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, only a bioengineered cell comprising (a) a nucleic acid encoding the full-length CDT-1 amino acid sequence of SEQ ID NO: 3 or 32; (b) a nucleic acid encoding the full-length GH1-1 amino acid sequence of SEQ ID NO: 6 or 37; and (c) nucleic acid sequences and vector constructs of SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29, but not the full breadth of the claims meets 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).
6. Claims 1, 2, 4, 6, 7, 11-13, 15, and 17 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 bioengineered cell comprising (A) (i) a nucleic acid encoding the full-length cellodextrin transporter (CDT-1) amino acid sequence of SEQ ID NO: 3 or 32 and (ii) a nucleic acid encoding the full-length beta-glucosidase (GH1-1) amino acid sequence of SEQ ID NO: 6 or 37; or (B) (i) nucleic acid sequences and vector constructs of comprising the nucleic acid sequences of SEQ ID NOs: 1, 2, 17-19, 28, or 32 and (ii) nucleic acid sequences and vector constructs of comprising the nucleic acid sequences of SEQ ID NOs: 4, 5, and 29, does not reasonably provide enablement for a bioengineered cell that comprises all possible encoded transporter proteins and fragments thereof; all possible encoded “metabolizer” proteins and fragments thereof; and all possible sequence variants at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 1 is directed to a bioengineered cell modified to metabolize a xenobiotic fuel, the xenobiotic fuel not metabolized by a corresponding unmodified cell, the bioengineered cell comprising:
(a) at least one foreign nucleic acid encoding at least one transporter protein or a functional fragment thereof for transport of the xenobiotic fuel into the bioengineered cell;
(b) at least one foreign nucleic acid encoding at least one protein or a functional fragment thereof for enabling the metabolizing of the xenobiotic fuel in the bioengineered cell; or
(c) a combination of (a) and (b).
Instant claim 2 recites the bioengineered cell of claim 1, wherein: (a) the xenobiotic fuel comprises cellobiose; (b) the transporter protein comprises a cellodextrin transporter or a functional fragment thereof; (c) the protein for enabling the metabolizing of the xenobiotic fuel comprises a beta-glucosidase protein or a functional fragment thereof or a cellobiose phosphorylase protein or a functional fragment thereof.
Claim 4 recites sequences with at least 90% sequence identity to SEQ ID NOs: 1-6, 17-19, 28, 29, 32, and 37.
Claim 12 recites a bioengineered cell comprising a vector comprising a nucleic acid sequence at least 90% identical to SEQ ID NO: 28 or 29.
The specification of the instant application teaches that the transporter protein or functional fragment thereof comprises a cellodextrin transporter protein (CDT-1) or a functional fragment thereof; or (b) the protein or functional fragment thereof for enabling the metabolizing of the xenobiotic fuel in the bioengineered cell comprises a beta-glucosidase protein (GH1-1) or a functional fragment thereof or a cellobiose phosphorylase protein or a functional fragment thereof (page 28, [0084]; page 37, [00119]). The specification also teaches (a) the nucleic acid sequence encoding the cellodextrin transporter protein or a functional fragment thereof encodes a protein at least 90% identical to SEQ ID NO: 32 or SEQ ID NO: 3; or (b) the nucleic acid sequence encoding the beta glucosidase protein or a functional fragment thereof encodes a protein at least 90% identical to SEQ ID NO: 37 or SEQ ID NO: 6 (page 29, [0085]; page 32, [0096]). The instant specification discloses that in some embodiments, (a) the nucleic acid sequence encoding the cellodextrin transporter protein or a functional fragment thereof is at least 90% identical to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 17, SEQ ID NO: 18, or SEQ ID NO: 19; or (b) the nucleic acid sequence encoding the beta-glucosidase protein or a functional fragment thereof is at least 90% identical to SEQ ID NO: 4 or SEQ ID NO: 5 (page 29, [0086]; page 32, [0097]). The specification also teaches full-length CDT-1 amino acid sequences of SEQ ID NOs: 3, 32 and full-length GH1-1 amino acid sequences of SEQ ID NO: 6, 37 (Tables 1 and 3). The instant specification discloses nucleic acid sequences and vector constructs comprising specific CDT-1 and GH1-1 sequences (see Tables 1-2, pages 95-161; see SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29). The instant specification teaches methods of transfecting HEK-293T cells mouse T cells, Platinum-E cells, and primary T cells with the constructs (pages 164, 168-184).
Therefore, the “functional fragment” limitations recited in the instant claims are broadly interpreted by the Examiner as reading upon (i) any fragment, as small as two amino acids in length, of any transporter protein that transports xenobiotic fuel into a bioengineered cell (including cellodextrin), and (ii) any fragment, as small as two amino acids in length, of any protein for enabling the metabolizing of the xenobiotic fuel (including beta-glucosidase or cellobiose phosphorylase) (and nucleic acids encoding such fragments). However, the specification does not teach any functional fragments of all possible transporter proteins that transport xenobiotic fuel into a bioengineered cell; or any functional fragments of all possible proteins that metabolize xenobiotic fuel.
The “at least 90% identical” limitations recited in the instant claims are also broadly interpreted by the Examiner as reading upon sequences that have at least 90% sequence identity to the full-length amino acid sequences of SEQ ID NO: 3, 32, 6, 37 and 90% sequence identity to the full-length nucleic acid sequences of SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29. However, the specification does not teach any variants, substitutions, insertions, deletions, or fragments of the sequences recited in the instant claims, other than the full-length CDT-1 amino acid sequences of SEQ ID NOs: 3, 32; full-length GH1-1 amino acid sequences of SEQ ID NO: 6, 37; and nucleic acid sequences and vector constructs of SEQ ID NOs: 1, 2, 17-19, 28, 4, 5, and 29.
There are no methods or working examples in the specification that indicate all possible transporter proteins and all possible fragments thereof transport xenobiotic fuel into a bioengineered cell. There are also no methods or working examples that indicate all possible proteins or all possible fragments thereof metabolize a xenobiotic fuel in an engineered cell. Lastly, there are no methods or working examples that indicate sequence variants at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32 have the desired functions required by the claims. A large quantity of experimentation would be required of the skilled artisan to generate all possible transporter proteins and all possible fragments thereof; all possible “metabolizer” proteins or all possible fragments thereof; and all possible sequence variants at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32, and then screen such for transporting xenobiotic fuel into a bioengineered cell and/or metabolizing a xenobiotic fuel in a bioengineered cell. Such experimentation is considered undue.
Additionally, one skilled in the art would not be able to predict that all possible transporter proteins and all possible fragments thereof; all possible “metabolizer” proteins and all possible fragments thereof; and all possible sequence variants at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32 would have the desired functional activity of transporting xenobiotic fuel into a bioengineered cell and/or metabolizing a xenobiotic fuel in a bioengineered cell. A person of skill in the art would not know which amino acid residues or nucleic acids are considered essential and which are non-essential. Without detailed direction as to which amino acids/nucleic acids are essential to the function of the transporter proteins and fragments thereof; the “metabolizer” proteins and fragments thereof; and the sequence variants at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32, the skilled artisan would not be able to determine without undue experimentation which proteins, fragments, variants, and nucleic acids are encompassed by the instant claims that exhibit the desired functional characteristics of transporting xenobiotic fuel into a bioengineered cell and/or metabolizing a xenobiotic fuel in a bioengineered cell.
The problem of predicting protein and DNA structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein and DNA is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495). However, Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the proteins which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427).
See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph).
Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract).
Due to the large quantity of experimentation necessary to generate all possible transporter proteins and all possible fragments thereof; all possible “metabolizer” proteins and all possible fragments thereof; and all possible sequence variants at least 90% identical to the sequences of SEQ ID NOs: 1-3, 17-19, 28, and 32 and screen such for the desired functional activity of transporting xenobiotic fuel into a bioengineered cell and/or metabolizing a xenobiotic fuel in a bioengineered cell; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claim Rejections - 35 USC § 102
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 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.
7. Claims 1, 2, 4, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Doudna Cate et al. (US 2014/0057323 or WO 2012/109274; ‘323 cited on the IDS of 05 February 2024). It is noted that US 2014/0057323 and WO 2012/109274 have the same disclosure. Thus, for brevity, relevant portions of US 2014/0057323 will be cited below.
Doudna Cate et al. teach bioengineered host cells containing one or more or of a recombinant cellodextrin transporter, a recombinant cellodextrin phosphorylase, a recombinant β-glucosidase, a recombinant phosphoglucomutase, or a recombinant hexokinase, meeting the limitations of instant claims 1 and 2 (page 25, [0089], [0091]; page 26, [0099]). Doudna Cate et al. indicate a host cell, such as the yeast, S. cerevisiae, does not naturally ferment cellodextrins (including cellobiose), meeting the limitations of instant claims 1 and 2 (page 10, [0026]; page 43, [0260]). Doudna Cate et al. disclose host cells are genetically modified in that recombinant nucleic acids have been introduced into the host cells, and as such, the genetically modified host cells do not occur in nature, meeting the limitations of instant claim 1 (page 26, [0099]). Doudna Cate et al. teach that a host cell, such as S. cerevisiae, has been genetically modified to secrete or surface-display a f-glucosidase to hydrolyze cellodextrins to glucose extracellularly; or to import cellodextrins with a cellodextrin transporter for intracellular hydrolysis by a β-glucosidase (page 26, [0099]; page 43, [0260, 0264-0269]; page 39, [0224]). Doudna Cate et al. state that expression vectors (such as a plasmid) containing the recombinant polynucleotides are introduced or transferred into the host cells, meeting the limitations of instant claim 11 (page 39, [0225-0226]). Lastly, Doudna Cate et al. disclose that the encoded cellodextrin transporter in the host cell is 100% identical to CDT-1, comprising the amino acid sequence of SEQ ID NO: 9 (page 28, [0110]). It is noted that the amino acid sequence of SEQ ID NO: 9 of Doudna Cate et al. is 100% identical to the amino acid sequence of SEQ ID NO: 3 of the instant application, meeting the limitations of instant claim 4 (see sequence alignment, below).
Qy= instant SEQ ID NO: 3
Db= SEQ ID NO: 9 of Doudna Cate et al.
Publication No. US20140057323A1
GENERAL INFORMATION
APPLICANT: The Regents of the University of California
APPLICANT: The Board of Trustees of the University of Illinois
APPLICANT: DOUDNA CATE, James H.
APPLICANT: JIN, Yong-Su
APPLICANT: GALAZKA, Jonathan M.
APPLICANT: HA, Suk-Jin
TITLE OF INVENTION: ENHANCED CELLODEXTRIN METABOLISM
FILE REFERENCE: 677792001300
CURRENT APPLICATION NUMBER: US/13/982,248
CURRENT FILING DATE: 2013-07-26
PRIOR APPLICATION NUMBER: PCT/US2012/24186
PRIOR FILING DATE: 2012-02-07
PRIOR APPLICATION NUMBER: US 61/440,305
PRIOR FILING DATE: 2011-02-07
PRIOR APPLICATION NUMBER: US 61/566,548
PRIOR FILING DATE: 2011-12-02
NUMBER OF SEQ ID NOS: 265
SEQ ID NO 9
LENGTH: 579
TYPE: PRT
ORGANISM: Neurospora crassa
Query Match 100.0%; Score 3028; Length 579;
Best Local Similarity 100.0%;
Matches 579; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSSHGSHDGASTEKHLATHDIAPTHDAIKIVPKGHGQTATKPGAQEKEVRNAALFAAIKE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSSHGSHDGASTEKHLATHDIAPTHDAIKIVPKGHGQTATKPGAQEKEVRNAALFAAIKE 60
Qy 61 SNIKPWSKESIHLYFAIFVAFCCACANGYDGSLMTGIIAMDKFQNQFHTGDTGPKVSVIF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SNIKPWSKESIHLYFAIFVAFCCACANGYDGSLMTGIIAMDKFQNQFHTGDTGPKVSVIF 120
Qy 121 SLYTVGAMVGAPFAAILSDRFGRKKGMFIGGIFIIVGSIIVASSSKLAQFVVGRFVLGLG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SLYTVGAMVGAPFAAILSDRFGRKKGMFIGGIFIIVGSIIVASSSKLAQFVVGRFVLGLG 180
Qy 181 IAIMTVAAPAYSIEIAPPHWRGRCTGFYNCGWFGGSIPAACITYGCYFIKSNWSWRIPLI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 IAIMTVAAPAYSIEIAPPHWRGRCTGFYNCGWFGGSIPAACITYGCYFIKSNWSWRIPLI 240
Qy 241 LQAFTCLIVMSSVFFLPESPRFLFANGRDAEAVAFLVKYHGNGDPNSKLVLLETEEMRDG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LQAFTCLIVMSSVFFLPESPRFLFANGRDAEAVAFLVKYHGNGDPNSKLVLLETEEMRDG 300
Qy 301 IRTDGVDKVWWDYRPLFMTHSGRWRMAQVLMISIFGQFSGNGLGYFNTVIFKNIGVTSTS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 IRTDGVDKVWWDYRPLFMTHSGRWRMAQVLMISIFGQFSGNGLGYFNTVIFKNIGVTSTS 360
Qy 361 QQLAYNILNSVISAIGALTAVSMTDRMPRRAVLIIGTFMCAAALATNSGLSATLDKQTQR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QQLAYNILNSVISAIGALTAVSMTDRMPRRAVLIIGTFMCAAALATNSGLSATLDKQTQR 420
Qy 421 GTQINLNQGMNEQDAKDNAYLHVDSNYAKGALAAYFLFNVIFSFTYTPLQGVIPTEALET 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GTQINLNQGMNEQDAKDNAYLHVDSNYAKGALAAYFLFNVIFSFTYTPLQGVIPTEALET 480
Qy 481 TIRGKGLALSGFIVNAMGFINQFAGPIALHNIGYKYIFVFVGWDLIETVAWYFFGVESQG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TIRGKGLALSGFIVNAMGFINQFAGPIALHNIGYKYIFVFVGWDLIETVAWYFFGVESQG 540
Qy 541 RTLEQLEWVYDQPNPVKASLKVEKVVVQADGHVSEAIVA 579
|||||||||||||||||||||||||||||||||||||||
Db 541 RTLEQLEWVYDQPNPVKASLKVEKVVVQADGHVSEAIVA 579
Conclusion
No claims are allowable.
The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Ha et al. Proc Natl Acad Sci USA 108(2): 504-509, 2011 (teach S. cerevisiae expressing N. crassa cellodextrin transporters and beta-glucosidase (page 505, column 1)
Huang et al. Transgenic Res 22: 779-790, 2013 (teach engineered CHO cells comprising A. crossean cellulase (EGX) and A. niger beta-glucosidase sequences (page 780, column 2; abstract); do not teach engineered immune cells)
Miller et al. Cell 189: 1717-1730, 2026 (post-filing date publication by the instant inventors)
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BEB
Art Unit 1647
03 August 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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