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 .
Application Status
This action is written in response to applicant’s correspondence received on 04/24/2026. Claims 1-27 are currently pending. The Election of Species requirement mailed on 02/25/2026 is still deemed proper. Applicant elected species without traverse in the reply filed on 04/24/2026, see details below.
Election of Species
Applicant's elected the following species without traverse in the reply filed on 04/24/2026:
1). An adenosine deaminase variant comprising the amino acid sequence of SEQ ID NO: 1 with the amino acid alterations E27H, 149K, and Y761; Based on the specification, the protein sequence of a CABE-1; or TADAC-1 mutant strain 1.2, with reference sequence TadA*8.20 (SEQ ID NO: 1), according to Page 69, Table 1A.
2). A guide polynucleotide or guide RNA comprising the nucleotide sequence of SEQ ID NO: 332;
3). A polynucleotide programmable DNA binding domain/protein comprising the amino acid sequence of SEQ ID NO: 198 lacking an N-terminal methionine and having a D10A amino acid alteration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a CON of PCT/US2022/022050, filed on 03/25/2022, and has PRO 63/229,057, filed on 08/03/2021 and PRO 63/166,778, filed on 03/26/2021.
Claim Objections
Claim 18 is objected to because of the following informalities: Missing period at the end of the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 27 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The recited “kit” is not defined in the specification, wherein only preferred embodiments of “kit(s)” are recited from line 8, page 308 to line 12, page 309. It is not a limitation based on the Broadest Reasonable Interpretation (BRI), hence failing to further limit claim 9 from which claim 27 depends from.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112 Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 9-23, 27 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 claims contain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The independent claim 1 directs to an extremely broad genus of enzyme variants wherein the claimed product genus relies on a functional limitation “an adenosine deaminase variant having an increased in cytidine deaminase activity and/or increase in cytidine deaminase specificity relative to a reference adenosine deaminase, …”, whereas no common structure that underlie the functional limitation is disclosed. In another word, it claims what the product does instead of what the product is. Furthermore, the recitation “wherein the adenosine deaminase variant comprises two or more amino acid alterations relative to the reference adenosine deaminase” covers an astronomical number of molecules with no structural commonality. For example, a reference adenosine deaminase TadA*8.20 (SEQ ID NO:1), a protein with 167 amino acids, has 1.87x10217 variants.
The specification demonstrates 20x CABE-1 or TADAC-1 variants based on the reference adenosine deaminase TadA*8.20 (SEQ ID NO: 1) in Table 1A (Page 70) and 199x CABE-2s or TADAC-2 variants in Table 1B (Pages 71-77) with specific sequence alternations described. The total 219 variants, while representative for select residues and local, crystal structure-guided variations, do not sufficiently represent the full scope of the genus as claimed.
Regarding the state of the art, Starr (Epistasis in protein evolution. Protein Sci. 2016 Jul;25(7):1204-18) describes the influence of a phenomenon called “epistasis” on the evolution of protein sequences, structures, and functions, and teaches high levels of unpredictability in predicting protein function based on sequence mutations (Page 1204, Abstract, lines 9-19). Miton (How mutational epistasis impairs predictability in protein evolution and design. Protein Sci. 2016 Jul;25(7):1260-72) further teaches that “The degree of unpredictability introduced by epistasis, due to the non-additivity of functional effects, strongly hinders the strategies developed in protein design and engineering” (Page 1260, Abstract, lines 3-4). These are strong evidence that there is a high degree of unpredictability in the art in predicting protein functions based on combinatorial mutations.
The disclosure of insufficient species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claim 1 is overly broad with insufficient evidence of possession at the time of filing to one skilled in the art. Thus, claim 1 does not meet the written description requirement, and the specification demonstrates a clear lack of possession of the full genus as claimed.
Claims 2-5, 9-23, 27 are also rejected for depending from the rejected claim 1 and failing to remedy the lack of written description therein.
Claims 18 and 19 are additionally 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, separately from the rejection above for failing to remedy the lack of written description regarding the extremely broad genus of variants in claim 1, from which claims 18 and 19 depends indirectly from. The claims contain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The dependent claims 18 and 19 direct to methods of treating a genetic disease or disorder in a subject. However, the specification does not teach which diseases or which genetic defects the subject suffers from. On page 32, the recitation that “"disease" is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ” (Lines 31-32) does not specify any detail. This indicates an extremely broad genus of genetic disorders.
The specification only demonstrates the base-editing capabilities using isolated synthetic targets or in vitro experiments using HEK293 cells (FIGs. 1-21). The specification is silent on the capacity of any of the claimed adenosine deaminase variant in correcting any mutation underlying any disease.
Regarding the state of the art, Rees (Nat Rev Genet. 2018 Dec;19(12):770-788) describes numerous laboratory exploration efforts in deploying base-editors for therapeutic developments targeting a variety of genetic disorders in cells or animal models, such as converting the Alzheimer disease-associated allele APOE4 to APOE3r in mouse astrocytes, correcting the cancer-associated p53 mutation Y163C in human breast cancer cells, correcting the L119P mutation in MPDU1 that causes the congenital disorder of glycosylation type 1f139, correcting the hereditary haemochromatosis-causing mutation C282Y in an immortalized patient-derived LCL, installing a mutation known to increase fetal haemoglobin (HBG) expression in adults, and correcting a mutant HBB allele in an engineered HEK293T cell line or in patient-derived primary fibroblasts, etc. (Page 783, right column, 2nd ¶). Since the claimed inventions are further engineered variants of established base-editors, the state in the art suggests that the claimed inventions could be adapted for similar therapeutic endeavors. However, there has been no base-editing-based therapeutics approved by FDA to date, and any efficacy associated with using base-editing to treat genetic disorders in subjects in need remains to be seen, hence highly unpredictable.
The disclosure of insufficient species of a broad genus of targeted genetic disorders, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claims 18 and 19 are overly broad with insufficient evidence of possession at the time of filing to one skilled in the art. Thus, claims 18 and 19 do not meet the written description requirement, and the ineffective variant examples presented in the specification demonstrate a clear lack of possession of the full genus as claimed.
Allowable Subject Matter
Claims 8, 24-26 are allowed.
Claims 6 and 7 are objected to as being dependent upon a rejected base claim 1, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 6 and 7 disclose specific mutations at defined amino acid positions in a specified reference adenosine deaminase sequence (Pages 70-77; Tables 1A & 1B). Representative variants with these mutation profiles have been shown to meet the functional limitations as claimed (Pages 310-335; FIGs. 1-55). Thus, claims 6 and 7 are able to remedy the lack of written description in claim 1 if rewritten in independent form including all of the limitations of claim 1.
The following is a statement of reasons for the indication of allowable subject matter:
Claims 8, 24-26 describe specific mutations at clearly defined amino acid positions along a specified reference adenosine deaminase sequence (SEQ ID NO: 1) that are fully described in the specification (Pages 70-77; Tables 1A & 1B). There are 219 working examples disclosed in the specification demonstrating that representative variants comprising these mutation profiles meet the functional limitation as claimed (Pages 310-335; FIGs. 1-55).
The closest prior arts are: Chen (Nat Biotechnol 2023 41, 663–672) and Jeong (Nat Biotechnol 2021 39, 1426–1433). Both prior arts describe single position amino acid mutation strategies, such as Chen’ N46L and Jeong’s P48R mutations, to augment the cytidine deaminase activity of a model adenosine deaminase. However, neither teaches the same directed evolution and structure-guided design strategies disclosed in the instant application, and none disclose variants with the claimed mutation profiles.
Sequence search for one of the elected species, i.e. An adenosine deaminase variant comprising the amino acid sequence of SEQ ID NO: 1 with the amino acid alterations E27H, 149K, and Y761 failed to reveal any 100% match (See sequence search strategy and history). Although sequence search reveals perfect 100% matches for the other two elected species, i.e. a guide RNA comprising the nucleotide sequence of SEQ ID NO: 332 and a polynucleotide programmable DNA binding domain/protein comprising the amino acid sequence of SEQ ID NO: 198 lacking an N-terminal methionine and having a D10A amino acid alteration, these species must complex with the elected adenosine deaminase variant to form a multi-molecular complex in the relevant claims. Thus, the elected complex is free of prior art.
Therefore, claims 8, 24-26 are allowable.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled "Comments on Statement of Reasons for Allowance".
Conclusion
Claims 8, 24-26 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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