DETAILED ACTION
Status of the Application
Claims 1, 3-16 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A preliminary amendment of claims 1, 3-6, 10-11, 13-15 as submitted in a communication filed on 1/20/2026 is acknowledged.
Applicant’s election without traverse of Group I, claims 1, 3-6, 13-15, drawn in part to a variant of the endonuclease V of SEQ ID NO: 1, and the election of the substitution C169Q as a single combination of substitutions, as submitted in a communication filed on 1/20/2026 is acknowledged.
In view of the election of a single combination of substitutions wherein the combination only requires the substitution C169Q, and the fact that claims 4-6 and 15 are directed to variants of the polypeptide of SEQ ID NO: 1 that have non-elected combinations of substitutions, these claims are directed to non-elected inventions.
Claims 4-12, 15-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/20/2026.
Claims 1, 3, 13-14 are at issue and will be examined to the extent they encompass the elected invention.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 5, lines 14 and 15, two instances. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01.
Priority
Acknowledgment is made of a claim for foreign priority under 35 U.S.C. 119(a)-(d) to EUROPEAN PATENT OFFICE (EPO) EP20306277 filed on 10/26/2020. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
This is the US national application which entered the national stage from PCT/EP2021/079254 filed on 10/21/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 1/20/2026 and 9/23/2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings submitted on 4/25/2023 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claim 1 is objected to due to the recitation of “has one or more amino acid substitutions as compared to SEQ ID NO: 1 at positions selected from the group consisting of…, wherein the positions are numbered by reference to the amino acid sequence set forth in SEQ ID NO: 1, and wherein one or more amino acid substitutions comprises at least one substitution selected from the group consisting of…C169Q…and C192L”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “has one or more amino acid substitutions at positions corresponding to positions in the polypeptide of SEQ ID NO: 1 selected from positions 136, 169 and 192, and wherein the one or more amino acid substitutions correspond to substitutions in the polypeptide of SEQ ID NO: 1 selected from substitutions C136W, C169Q…and C192L…”. Appropriate correction is required.
Claim 1 is objected to due to the recitation of “… has deoxyinosine-specific nucleic acid cleavage activity and ..exhibits improved residual activity under non-reducing condition as compared to endonuclease SEQ ID NO: 1”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “… has deoxyinosine-specific nucleic acid cleavage activity and ..exhibits improved residual activity under non-reducing conditions as compared to the endonuclease SEQ ID NO: 1”. Appropriate correction is required.
Claim 3 is objected to due to the recitation of “comprising at least one substitution selected from the group consisting of C169Q…and C169P”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “comprising at least one substitution that corresponds to a substitution in the polypeptide of SEQ ID NO: 1 selected from the group consisting of C169Q…and C169P”. Appropriate correction is required.
Claim 13 is objected to due to the recitation of “comprising at least one substitution selected from the group consisting of C169Q…and C169L”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “comprising at least one substitution that corresponds to a substitution in the polypeptide of SEQ ID NO: 1 selected from the group consisting of C169Q…and C169L”. Appropriate correction is required.
Claim 14 is objected to due to the recitation of “comprising the substitution C169Q”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “comprising a substitution that corresponds to the substitution C169Q in the polypeptide of SEQ ID NO: 1”. 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 1, 3 and 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to products of nature without significantly more without significantly more. The claims recite in part a protein which is a variant of the polypeptide of SEQ ID NO: 1 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, wherein said variant comprises a substitution that corresponds to the substitution C169G in the polypeptide of SEQ ID NO: 1. This judicial exception is not integrated into a practical application because claims 1, 3 and 13 are directed to a naturally occurring protein as evidenced by Arimizu et al. (GenBank accession No. GDS84708, 4/16/2019; cited in the prior Office action), who teach an E. coli endonuclease V that comprises all of SEQ ID NO: 1 except for substitutions that corresponds to the substitutions C169G and L122M in the polypeptide of SEQ ID NO: 1, thus having 99% sequence identity to the polypeptide of SEQ ID NO: 1 (99.1% = 221x100/223; SEQ ID NO: 1 has 223 amino acids). See alignment below. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claims 1, 3 and 13 fully encompass a naturally-occurring protein. Since the specification asserts that a variant of the polypeptide of SEQ ID NO: 1 having a substitution that corresponds to substitution C169G in the polypeptide of SEQ ID NO: has the recited functional properties, it follows that the protein of Arimizu et al. would have the same functional properties by virtue of having this substitution. As such, the claim encompasses subject matter which is not patent-eligible.
Query = SEQ ID NO:1
Sbjct = GDS84708
NW Score Identities Positives Gaps
1147 221/223(99%) 222/223(99%) 0/223(0%)
Query 1 MDLASLRAQQIELASSVIREDRLDKDPPDLIAGADVGFEQGGEVTRAAMVLLKYPSLELV 60
MDLASLRAQQIELASSVIREDRLDKDPPDLIAGADVGFEQGGEVTRAAMVLLKYPSLELV
Sbjct 1 MDLASLRAQQIELASSVIREDRLDKDPPDLIAGADVGFEQGGEVTRAAMVLLKYPSLELV 60
Query 61 EYKVARIATTMPYIPGFLSFREYPALLAAWEMLSQKPDLVFVDGHGISHPRRLGVASHFG 120
EYKVARIATTMPYIPGFLSFREYPALLAAWEMLSQKPDLVFVDGHGISHPRRLGVASHFG
Sbjct 61 EYKVARIATTMPYIPGFLSFREYPALLAAWEMLSQKPDLVFVDGHGISHPRRLGVASHFG 120
Query 121 LLVDVPTIGVAKKRLCGKFEPLSSEPGALAPLMDKGEQLAWVWRSKARCNPLFIATGHRV 180
L+VDVPTIGVAKKRLCGKFEPLSSEPGALAPLMDKGEQLAWVWRSKAR NPLFIATGHRV
Sbjct 121 LMVDVPTIGVAKKRLCGKFEPLSSEPGALAPLMDKGEQLAWVWRSKARGNPLFIATGHRV 180
Query 181 SVDSALAWVQRCMKGYRLPEPTRWADAVASERPAFVRYTANQP 223
SVDSALAWVQRCMKGYRLPEPTRWADAVASERPAFVRYTANQP
Sbjct 181 SVDSALAWVQRCMKGYRLPEPTRWADAVASERPAFVRYTANQP 223
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
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, 3, 13 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 1, 3, 13 and 14 are directed in part to a genus of variants of the polypeptide of SEQ ID NO: 1 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, wherein said variants have deoxyinosine-specific nucleic acid cleavage activity and improved residual activity under non-reducing conditions compared to the polypeptide of SEQ ID NO: 1, wherein said variants have a substitution at the position corresponding to position 169 of the polypeptide of SEQ ID NO: 1.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is a significant amount of structural variability with respect to the members of the genus of proteins required by the claims. While the specification in the instant application discloses the structure of a limited number of species of the recited genus of endonuclease V proteins, it provides no clue as to the structural elements required in any endonuclease V having the recited functional characteristics, nor does it teach which structural elements of the protein of SEQ ID NO: 1, are required in any endonuclease V protein having the desired functional characteristics. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of the polypeptide of SEQ ID NO: 1 having the recited % sequence identity and the recited substitution have the desired endonuclease V activity.
The claims encompass a large genus of proteins which are substantially unrelated in structure. A polypeptide having 90% sequence identity with the polypeptide of SEQ ID NO: 1 allows for any combination of 23 amino acid modifications within SEQ ID NO: 1 (23 = 0.1x223; SEQ ID NO: 1 has 223 amino acids). The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula N!x19A/(N-A)!/A!, where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. Thus, the total number of variants that result from amino acid substitutions and have at least 90% sequence identity to the polypeptide of SEQ ID NO: 1 is 223!x1923/(223-23)!/23! or 3.15x1060 variants. A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, the recited structural feature, i.e., 90% sequence identity to the polypeptide of SEQ ID NO: 1, is not representative of all the members of the genus of endonuclease V proteins recited since there is no information as to which are the structural elements within the polypeptide of SEQ ID NO: 1 that are essential for the recited activity, which are the remaining structural elements required in the recited polypeptides in addition to those recited in the claims such that the desired endonuclease V activity is displayed, or a correlation between structure and function which would provide those unknown structural features. Furthermore, while one could argue that the few species disclosed are representative of the structure of all the members of the genus, it is noted that the art teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999) teach that one conservative amino acid substitution transforms a β-ketoacyl synthase into a malonyl decarboxylase and completely eliminates β-ketoacyl synthase activity. Tang et al. (Phil Trans R Soc B 368:20120318, 1-10, 2013) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrate (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001) teach that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the few species disclosed are representative of the structure of all the endonuclease V proteins required in the claimed method.
Due to the fact that the specification only discloses a limited number of species of the genus of endonuclease V proteins required by the claims, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 1, 3, 13 and 14 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 protein which is a variant of the polypeptide of SEQ ID NO: 1 that comprises all of SEQ ID NO: 1 except for a substitution that corresponds to the substitution C169Q in the polypeptide of SEQ ID NO: 1, wherein said variant has deoxyinosine-specific nucleic acid cleavage activity and improved residual activity under non-reducing conditions as compared to the endonuclease of SEQ ID NO: 1, does not reasonably provide enablement for a variant of the polypeptide of SEQ ID NO: 1 having the recited % sequence identity and substitution, wherein said variant has deoxyinosine-specific nucleic acid cleavage activity and improved residual activity under non-reducing conditions as compared to the endonuclease of SEQ ID NO: 1. 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/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 1, 3, 13 and 14 broadly encompass variants of the polypeptide of SEQ ID NO: 1 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1 and a substitution at a position that corresponds to position 169 of the polypeptide of SEQ ID NO: 1, wherein said variants have deoxyinosine-specific nucleic acid cleavage activity and improved residual activity under non-reducing conditions as compared to the endonuclease of SEQ ID NO: 1. The enablement provided is not commensurate in scope with the claims due to the lack of information regarding the structural elements within the polypeptide of SEQ ID NO: 1 which are required and those which can be modified to obtain the extremely large number of variants having the endonuclease V activity required by the claims. In the instant case, the specification enables a protein which is a variant of the polypeptide of SEQ ID NO: 1 that comprises all of SEQ ID NO: 1 except for a substitution that corresponds to the substitution C169Q in the polypeptide of SEQ ID NO: 1, wherein said variant has deoxyinosine-specific nucleic acid cleavage activity and improved residual activity under non-reducing conditions as compared to the endonuclease of SEQ ID NO: 1
The amount of direction or guidance presented and the existence of working examples. The specification discloses the amino acid sequence of a limited number of endonuclease V proteins, including the protein of SEQ ID NO: 1, and variants of the protein of SEQ ID NO: 1 that comprise all of SEQ ID NO: 1 except for a substitution at the position corresponding to position 169 of the polypeptide of SEQ ID NO: 1, as working examples. However, the specification fails to provide any clue as to the structural elements required in any endonuclease V that has improved residual activity under non-reducing conditions as compared to the endonuclease of SEQ ID NO: 1, including which structural features within SEQ ID NO: 1 can be modified and which ones should be present for a variant having the recited % sequence identity and substitution to display the recited endonuclease V activity. No correlation between structure and function has been presented.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a polypeptide determines its structural and functional properties. While the art discloses a limited number of endonuclease V proteins, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any endonuclease V having the recited functional characteristics. In addition, the art does not provide any teaching or guidance as to which changes can be made to the protein of SEQ ID NO: 1 such that the resulting variant would display the desired functional characteristics, or the general tolerance of endonuclease V proteins to structural modifications and the extent of such tolerance. The art clearly teaches that (a) determining function based solely on structural homology, and (b) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved are highly unpredictable. For example, Singh et al. (Current Protein and Peptide Science 19(1):5-15, 2018) disclose different protein engineering approaches and state that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility and conformational changes (page 11, left column, last paragraph). Sadowski et al. (Current Opinion in Structural Biology 19:357-362, 2009) teach that much of the problem in assigning function from structure comes from functional convergence, where although a stable structure is required to perform many functions it is not always necessary to adopt a particular structure to carry out a particular function (page 357, right column, first full paragraph). Sadowski et al. further explain that the unexpected and significant difficulties of predicting function from structure show that the potential of structural models for providing novel functional annotations has not yet fully realized. Sadowski et al. also states that while a few successes have been achieved which required manual intervention, the ability to vary the requirements for specificity in prediction means that it is difficult to determine how useful the end result may be for the user (page 361, left column, first full paragraph). The teachings of Singh et al. and Sadowski et al. are further supported by the teachings of Witkowski et al., Tang et al. and Seffernick et al. already discussed above, where it is shown that even small amino acid changes result in enzymatic activity changes.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a polypeptide and enzymatic assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find an endonuclease V having the recited functional characteristics. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, and/or (ii) a correlation between structure and endonuclease V activity, one of skill in the art would have to test an essentially infinite number of proteins to determine which ones have the desired functional characteristics.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Claim Rejections - 35 USC § 102 (AIA )
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 1, 3 and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Arimizu et al. (GenBank accession No. GDS84708, 4/16/2019; cited in the prior Office action).
Claims 1, 3 and 13 are directed in part to a protein which is a variant of the polypeptide of SEQ ID NO: 1 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, wherein said variant comprises a substitution that corresponds to the substitution C169G in the polypeptide of SEQ ID NO: 1, wherein said variant has deoxyinosine-specific nucleic acid cleavage activity and improved residual activity under non-reducing conditions as compared to the endonuclease of SEQ ID NO: 1.
Arimizu et al. teach an E. coli endonuclease V that comprises all of SEQ ID NO: 1 except for substitutions that corresponds to the substitutions C169G and L122M in the polypeptide of SEQ ID NO: 1, thus having 99% sequence identity to the polypeptide of SEQ ID NO: 1 (99.1% = 221x100/223; SEQ ID NO: 1 has 223 amino acids). See alignment above. Since the specification asserts that a variant of the polypeptide of SEQ ID NO: 1 having a substitution that corresponds to substitution C169G in the polypeptide of SEQ ID NO: has the recited functional properties, it follows that the protein of Arimizu et al. would have the same functional properties by virtue of having this substitution. Therefore, the protein of Arimizu et al. anticipates the instant claims as written/interpreted.
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 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.
Conclusion
No claim is in condition for allowance.
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.
Applicant is advised that any Internet email communication by the Examiner has to be authorized by Applicant in written form. See MPEP § 502.03 (II). Without a written authorization by Applicant in place, the USPTO will not respond via Internet email to any Internet correspondence which contains information subject to the confidentiality requirement as set forth in 35 U.S.C. 122. Sample written authorization language can be found in MPEP § 502.03 (II). An Authorization for Internet Communications in a Patent Application or Request to Withdraw Authorization for Internet Communications form (SB/439) can be found at https://www.uspto.gov/patent/forms/ forms-patent-applications-filed-or-after-september-16-2012, which can be electronically filed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
February 6, 2026