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 .
Election/Restrictions
Applicant’s election without traverse of Group I of invention (claims 1-11, and 15-22) in the reply filed on May 05, 2026 is acknowledged. Further, Applicant submits that “Matthews does not teach or suggest a TdT variant wherein a glutamine at position 4 of such amino acid sequence is substituted with a stabilizing amino acid, as required by claim 1 and claims dependent therefrom” (pg. 6 of Remarks received on May 05, 2026). This is found persuasive; thus, the provisional restriction has been withdrawn.
Applicant’s election without traverse of SEQ ID NO: 42, with an “E” as the stabilizing amino acid at position 5 with respect to SEQ ID NO: 42, as the single specific terminal deoxynucleotidyl transferase specie in the reply filed on May 05, 2026 is acknowledged.
Claims 1-7, 15, 19-20, and 22 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected terminal deoxynucleotidyl transferase (TdT) variants, and claims 12-14 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a method and a kit directed to nonelected TdT variants of claim 1, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 05, 2026.
Claims 8-11, 16-18, and 21 are currently pending and under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The instant application claims priority based on an EPO Application No. 20306079.3, filed on 09/22/2020. The EPO Application describes instant claims 8-9 ([0008], SEQ ID NO: 42), instant claim 10 (claim 10), instant claim 11 (claim 11). Accordingly, the effective filling date of instant claims 8-11 is 09/22/2020.
Support for the recitation of “wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region” in instant claim 16 could not found in EPO Application No. 20306079.3. Disclosure of exemplary histidine affinity tags including MASSHHHHHHSSGSENL YFQTGSSG incorporated at the N-terminus of TdT variants ([0062]) do not provide sufficient written description support for insertion of a peptide affinity tag into the loop 2 region of TdT variant, required in instant claim 16.
The instant application also claims priority based on an EPO Application No. 21305341.6, filed on 03/19/2021. This EPO Application describes instant claim 16 (claim 16), instant claim 17 (claim 17), instant claim 18 (claim 18), and instant claim 21 (claim 21). Accordingly, the effective filling date of instant claims 16-18, and 21 is 03/19/2021.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: the specification discloses “a template-free polymerase, such as a TdT or variant thereof…under conditions (140) effective for the enzymatic incorporation…” ([0036]) (emphasis added); however, reference label (140) is not included in FIG. 1. 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. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink ([0073], [0076]) and/or other form of browser-executable code. 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.
The use of the term GelRed ([0024]) and HaloTag ([0032]), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because of the following informalities: the specification discloses “46-737 were both tested (A) for stability using the termal stability assay” (pg. 28, line 26) which appears to be a typographical error.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objection
Claims 8, 9, and 16 are objected to because of the following informalities:
In claim 8, line 2, the recitation of “an amino acid sequence at least ninety percent identical…” is grammatically incorrect. It is recommended to amend claim to recite “an amino acid sequence having at least ninety percent sequence identity to an amino acid sequence selected from SEQ ID NO: 42”.
In claim 9, line 3, a comma is missing between recitation “SEQ ID NO: 80” and “and”.
In claim 16, line 1, the acronym “TdT” is defined as being “terminal deoxynucleotidyl transferase”. However, the acronym has previously been defined in claim 8. An acronym should only be defined the first time it appears in an independent claim or in the group of claims under an independent claim.
Appropriate correction is required.
Claim Interpretation
Regarding claim 11, the recitation of “wherein the stabilizing amino acid is selected from the group consisting of E, S, D, and N” is referring to the stabilizing amino acid at position 4 in claim 9 from which it depends. However, claim 9 is of improper form as it fails to include all of limitations from claim 8 which it depends (see discussion below in 35 USC 112d rejection). In the interest of compact prosecution, the Examiner is interpreting this recitation in claim 11 to further limit the stabilizing amino acid at position 5 of SEQ ID NO: 42 in claim 8, and this interpretation is supported by Applicant’s election of species, specifically “Applicant hereby elects a TdT variant comprising the amino acid sequence set forth in SEQ ID NO: 42 with an “E” as the stabilizing amino acid at position 5 with respect to SEQ ID NO: 42” (pg. 7 of Remarks received on May 05, 2026).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 is 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.
Claim 10 contains the incomplete trademark/trade name “SYPRO” of US serial number 74685583. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a fluorescent dye; thus, the claim relies on commercial product designation rather than reciting structure or other defined characteristics of the fluorescent dye. The commercial identifiers, including structure of the dye and catalog number, may change over time, be discontinued, or vary between suppliers and lots. Further, the claim does not provide any structural features that would allow one of ordinary skilled in the art to determine whether a given fluorescent dye would fall within the scope of the claim. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention it relies on potentially changeable information.
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 9 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. 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 9 depends from claim 8 which recites a terminal deoxynucleotidyl transferase (TdT) variant comprising an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 42 (elected species), wherein the amino acid sequence comprises a stabilizing amino acid at position 5. However, claim 9 recites “comprises the stabilizing amino acid at position 4”. Thus, the dependent claim substitutes the position of the stabilizing amino acid from position 5 to position 4, and fails to include all of the limitations of the claim from which it depends.
In addition, claim 9 recites the TdT variant is at least 90% identical to the amino acid sequence of SEQ ID NO: 78 or SEQ ID NO: 80, and comprises the stabilizing amino acid at position 4. This claim limitation is already included in claim 8. Thus, claim 9 also fails to further limit the claim from which it depends.
Claim Rejections - 35 USC § 112
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 8-11, and 21 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.
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”.
Claim 8 is drawn to a genus of terminal deoxynucleotidyl transferase (TdT) variants having at least 90% sequence identity to SEQ ID NO: 42 (elected sequence). Further, the genus encompasses members required to have three functional characteristics: (1) an amino acid residue at position 5 with stability function, (2) template-independent synthesis of oligonucleotides, and (3) ability to incorporate a 3’-O-protected nucleotide onto a free 3’-hydroxyl of a polynucleotide. Therefore, the breadth of the claims encompasses a genus of TdT variants defined by both structure and function.
SEQ ID NO: 42 consists of 362 amino acids, specifically a glutamic acid at position 5. The claimed minimum sequence identity threshold allows variation up to 36 amino acids (10% of 362 is 36 amino acids) while satisfying the requirement of at least 90% sequence identity to SEQ IDNO: 42. Therefore, the claimed genus encompasses an enormous number of species comprising up to 36 amino acids substitutions, insertions, and deletions, while maintaining the claimed functions.
The specification defines “a stabilizing amino acid” substitution to increase the melting temperature of the TdT variant by at least 1°C ([0029]). The only disclosure provided for SEQ ID NO: 42 is found with recitations of “SEQ ID NO: 43 (M77) is the same as SEQ ID NO: 42 with a His tag conjugated to its N-terminus” ([0067]), and that SEQ ID NO: 42 is a N-terminally truncated TdT ([0006]). Although the specification discloses SEQ ID NO: 1 to SEQ ID NO: 32 as TdT variants derived from natural TdTs, with a number of consistent substitutions (Table 1). The specification fails to identity the natural TdT from which SEQ ID NO: 42 is derived or explain its relationship to the numerous TdT variants. Further, TdT variants listed on Table 1 comprises a stabilizing amino acid substitution at position 4, whereas SEQ ID NO: 42 comprises a stabilizing amino acid substitution at position 5. The specification fails to identify key structural features in SEQ ID NO: 42, and recognize whether any additional substitutions, insertions or deletions can be tolerated in SEQ ID NO: 42.
Sequence alignment of SEQ ID NO: 42 to natural bovine TdT variant SEQ ID NO: 3 shows they share 90.5% sequence identity (alignment reproduced below), which indicate that approximately 10% of the natural bovine TdT was altered to SEQ ID NO: 42. However, the specification does not identify which of these amino acid differences, besides position 5, are essential for the claimed functions. The specification does not distinguish which of the substitutions are structurally neutral. Accordingly, the specification fails to disclose the correlation between structure and function of why SEQ ID NO: 42 possess the claimed properties. The specification fails to disclose which amino acid modifications encompassed by the “at least 90% sequence identity” limitation may be introduced while retaining the claimed properties.
The specification further discloses examples of two TdT variants, one of them referred to as 46-737 or SEQ ID NO: 58, which comprises a Q12E substitution ([0071]), and shares 96.8% sequence identity to SEQ ID NO: 42 with residues around the loop 2 region substituted to a histidine affinity tag (a portion highlighting the sequence difference is reproduced below). Although SEQ ID NO: 58 and SEQ ID NO: 42 contain the same substitution Q5E, the specification does not attribute functional significance to this substitution nor compare TdT variants differing at this residue to demonstrate that this substitution indeed increases melting temperature by at least 1°C. The specification provides no guidance of whether two additional residue difference between SEQ ID NO: 42 and SEQ ID NO: 58 attributes to any function. Further, stability and coupling activity assays are demonstrated for SEQ ID NO: 58, not SEQ ID NO: 42, with no data shown. These two assays focus on evaluating TdT variants’ ability to extend an oligonucleotide using a dGTP or dCTP ([0024]), not a 3’-O-protected nucleotide as required by the claims. Although the specification states that “in some embodiments, the nucleoside triphosphate is a 3’-O-blocked nucleoside triphosphate” (pg. 12, line 30), no results or statement indicate incorporation of 3’-O-protected nucleotide by SEQ ID NO: 42 is indeed achieved. In addition, disclosure of one member that differs by substitution of an affinity tag does not represent members in the entire claimed genus.
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State of the art does not recognize position 5 as a residue linked to stability or melting temperature of TdT. Delarue et al (Crystal structures of a template-independent DNA polymerase: murine terminal deoxynucleotidyltransferase; The EMBO Journal; 2002, 21(3):427-439; IDS received on 05/05/2023, NPL Cite No. 17) provides the crystal structure of the catalytic core of TdT comprising residues 130-15 (Fig. 1B). Delarue et al further shows that Gln152, corresponding to position 5 in SEQ ID NO: 42, resides within an N-terminal region and it is a conserved residue among different TdT species (Fig. 2) that forms hydrogen bonding with another conserved residue Arg462 (pg. 430, col. 2, para. 3). Delarue et al further recognize this residue is upstream and adjacent to conserved catalytic site CQR (Fig. 2), in addition to two more conserved catalytic motifs at positions 446-454 and 331-337 that are responsible in dNTP-binding (pg. 430, col. 1, para. 2). However, Delarue et al do not identify Gln152 as a key residue for thermostability or associate this region with altered substrate specificity to incorporate 3’-O-protected nucleotides.
Prior art studies establish mutagenesis of TdT for the ability to incorporate 3’-modified nucleotides centers around catalytic sites. Champion et al (WO 2019/135007 A1; Published Date: July 11, 2019; IDS received on 07/05/2023, Foreign Patent Cite No. 7) discloses 918 mouse TdT variants comprising numerous substitutions including M192R, L260P, C302R, R336L, D379V, R454P, and E457L, with respect to SEQ ID NO: 2 (Table 1). Champion et al further discloses these substitutions in wild-type mouse TdT confers TdT variants capable of performing two instantly claimed functions (2) template-independent synthesis of an oligonucleotide and (3) incorporation of a 3’-modified nucleotide into the oligonucleotide (abstract). It is noted that these substitutions disclosed by Champion et al are also present in TdT variants listed on Table 1 of instant specification, and SEQ ID NO: 42 contains some of the key substitutions, for example C302R and R336L. However, instant SEQ ID NO: 42 and Champion’s SEQ ID NO: 2 only shares 83.4% sequence identity (sequence alignment reproduced below). Champion et al do not establish the 16.6% sequence difference is associated with thermostability or altered substrate specificity.
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Similarly, Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14) disclose a TdT variant, named TdT3-2, that is 10°C more thermostable than wild-type TdT (pg. 1730, col. 2, last paragraph). Chua et al discloses TdT3-2 variant is obtained through site-directed mutagenesis and screening of about 10,000 TdT mutants (pg. 1727, col. 1, para. 2 and col. 2, para. 1-2), and comprises numerous residue substitutions throughout different regions of the enzyme (Table 1). Further, SEQ ID NO: 42 and TdT3-2 only shared 88.1% sequence identity (see alignment below), and Chua et al also do not establish the 11.9% sequence difference is associated with thermostability or altered substrate specificity.
In summary, the state of the art provides no predictability on whether additional substitutions present in SEQ ID NO: 42 are functionally equivalent, structurally neutral, or abolishes enzymatic activity. The state of the art does not recognize position 5 of SEQ ID NO: 42, or Gln152 in wild-type TdTs, to as a key residue for thermostability.
Further, dependent claims 9-11 are also rejected because they define the outcome and identity of the stabilizing amino acid without remedying the lack of written description in claim 8.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of TdT’s structural features and mutagenesis of TdT variants to increase thermostability, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of TdT variants comprising at least 90% sequence identity to SEQ ID NO: 42 with the claimed functions.
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Claim 16 is drawn to a genus of TdT variants with the same functional characteristics: (i) capable of temple-independent synthesis of an oligonucleotide, and (ii) capable of incorporating a 3’-O-protected-nucleotide onto a free 3’-hydroxyl of a polynucleotide. This genus is further defined by a structural feature wherein a peptide affinity tag is inserted into the loop 2 region.
The teachings of the specification regarding TdT variants capable of performing the required functions are discussed above as applied to claim 8, particularly TdT variants across diverse species disclosed in Table 1. Further, teachings from Champion et al regarding representative species of TdT variants capable of performing the claimed functions are discussed above as applied to claim 8, particularly 918 TdT variants disclosed in Table 1. In addition, the state of the art establishes that loop 2 region is predictable for modifications of peptide affinity tags. Delarue et al (cited supra) teaches loop 2 is recognized as an external loop adjacent to residues 421-423, and is distant from the active site (pg. 428, col. 2, para. 2). Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) further demonstrate loop 2 region is a suitable point for inserting exogenous sequences (i.e., peptide affinity tag) as this region is highly tolerable for substitutions (brief description of FIG. 14A, para. 47). Magyar et al demonstrate that a click reactive group could be installed on loop 2 region of the TdT for subsequent reaction with another click reactive group comprising a peptide that functions as a tag for affinity purifications ([00232]).
Based on the preponderance of the evidence, including the relevant teachings of the specification and the state of prior art including the knowledge of TdT’s structural features and representative species of TdT variants with alter substrate specificity, one skilled in the art would conclude that Applicant was in possession of the claimed genus of TdT variants comprising the two claimed functions and the structural feature of a peptide affinity tag inserted into the loop 2 region.
On the other hand, the breath of the dependent claim 21 is different. It encompasses a genus of TdT variants comprising at least 90% sequence identity to SEQ ID NO: 42 (elected sequence) while retaining the claimed functions and structural feature of a peptide affinity tag inserted into the loop 2 region. Considering the state of prior art including knowledge of TdT’s loop 2 region, discussed above as applied to claim 16, one skilled in the art would conclude that it is predictable to insert exogenous sequences in this region. However, the state of prior art does not provide predictability for one skilled in the art to know which amino acid residues could be substituted, inserted, and/or deleted into SEQ ID NO: 41 within the “at least 90% sequence identity” limitation while retaining the claimed functions. See discussion above as applied to claim 8. Thus, one skilled in the art would conclude Applicant was not in possession of the claimed genus of TdT variants comprising at least 90% sequence identity to SEQ ID NO: 42 and encompassing the claimed functions.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 16 is rejected under 35 U.S.C. 103 as being unpatentable over Champion et al (WO 2019/135007 A1; Published Date: July 11, 2019; IDS received on 07/05/2023, Foreign Patent Cite No. 7), as evidenced by NP_001036693.1 (DNA nucleotidylexotransferase isoform 2 [Mus musculus], NCBI Reference Sequence, ROD Feb 17, 2019, 3 pages), in view of Delarue et al (Crystal structures of a template-independent DNA polymerase: murine terminal deoxynucleotidyltransferase; The EMBO Journal; 2002, 21(3):427-439; IDS received on 05/05/2023, NPL Cite No. 17) and Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6).
Regarding claim 16, Champion et al discloses terminal deoxynucleotidyl transferase (TdT) variants comprising numerous substitutions with respect to SEQ ID NO: 2 (Table 1). As evidenced by NP_001036693.1, SEQ ID NO: 2 matches 100% to mus musculus TdT (see a portion of sequence alignment reproduced below). Further, Champion et al teach the disclosed TdT variants are capable of synthesizing a nucleic acid fragment without a template and incorporate a 3’-O-modified nucleotide into a nucleic acid fragment (i.e., polynucleotide) (pg. 37, lines 6-10).
In addition, Delarue et al teach TdT homologs share highly conserved sequences (Fig 2), and loop 2 is recognized as an external loop adjacent to residues 421-423, and is distant from the active site (pg. 428, col. 2, para. 2). In view of teachings of Delarue et al and 100% sequence alignment of Champion’s SEQ ID NO: 2 to NP_001036693.1, it is inherent that SEQ ID NO: 2 comprises a loop 2 region.
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However, Champion et al teach the TdT variants comprise histidine affinity tags on N-terminal end and/or C-terminal end for purification, identification, and increasing expression (claim 8; pg. 38, lines 1-4). Champion et al do not teach wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
Magyar et al teach TdT variants comprising photoswitches, including an azobenzene photoswitch that can controllably block entry or binding of nucleotides into the active site of the TdT enzyme ([0008]). Magyar et al also teach the loop 2 region is a suitable point for inserting exogenous photoswitches as this region is highly tolerable for substitutions (brief description of FIG. 14A, para. 47). Magyar et al further demonstrate that a click reactive group could be installed on loop 2 region of the TdT for subsequent reaction with another click reactive group comprising a peptide that functions as a tag for affinity purifications ([00232]).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the insertion site of the peptide affinity tag from terminal ends of TdT to the loop 2 region as taught by Magyar et al. This modification would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The substituted component (affinity tag insertion site from terminal ends to the loop 2 region) and its function (exogenous sequence insertion point without affecting catalytic function of TdT) were known in the art. One would have been motivated to have done so for the advantage of inserting attachment points or affinity tags at different region of the protein for modulation of expression yield, purification, and tagging to introduce additional modifications to TdT as taught by Magyar et al. One would have had a reasonable expectation of success in doing because Magyar et al demonstrate TdT variants tolerate modifications at the loop 2 region.
Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Champion et al (WO 2019/135007 A1; Published Date: July 11, 2019; IDS received on 07/05/2023, Foreign Patent Cite No. 7), as evidenced by NP_001036693.1 (DNA nucleotidylexotransferase isoform 2 [Mus musculus], NCBI Reference Sequence, ROD Feb 17, 2019, 3 pages), in view of Delarue et al (Crystal structures of a template-independent DNA polymerase: murine terminal deoxynucleotidyltransferase; The EMBO Journal; 2002, 21(3):427-439; IDS received on 05/05/2023, NPL Cite No. 17) and Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) as applied to claim 16 above, and further in view of Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding claims 17 and 18, the obviousness to substitute the peptide affinity tag insertion point from terminal ends of TdT variants to the loop 2 region as taught by Magyar et al is discussed above as applied to claim 16. Champion et al discloses the affinity tag is a histidine-tag (claim 8)
However, Champion et al nor Magyar et al explicitly teach wherein the peptide affinity tag is H2-H10 or H4-H8.
Chua et al teach TdT variants that exhibit improved thermostability to wild-type TdT, particularly, variant named TdT3-2 is 10°C more thermostable than wild-type TdT (pg. 1730, col. 2, last paragraph). Chua et al teach TdT3-2 has a histidine affinity tag on the N-terminus that comprises six histidine residues (i.e., H2-H10 or H4-H8) to improve solubility and expression (pg. 1726, col. 2, para. 2; Table S3).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified histidine tag of Champion et al to the histidine affinity tag comprising six histidine residues as taught by Chua et al because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Substitution of a histidine affinity tag to another histidine affinity tag is merely swapping similar features that serve the same purpose. One would have been motivated to have done so for the advantage of selecting an affinity tag that has been demonstrated to successfully express soluble TdTs. One would have had a reasonable expectation of success in doing because Chua et al demonstrate over 10,000 TdT variants comprising this histidine affinity tag can be expressed in cells and purified via affinity chromatography.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 8-11, 16-18, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5 of U.S. Patent No. 12,618,092 in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘092 recites a TdT variant having an amino acid sequence at least 90% sequence identical to SEQ ID NO: 25, which shares 99.4% sequence identity to instantly claimed SEQ ID NO: 42 (claim 6). Accordingly, the full-length sequence of SEQ ID NO:42 is encompassed by the recited genus. As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘092 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
Chua et al teach TdT variants that exhibit improved thermostability to wild-type TdT, particularly, variant named TdT3-2 is 10°C more thermostable than wild-type TdT (pg. 1730, col. 2, last paragraph). Chua et al teach TdT3-2 has a histidine affinity tag on the N-terminus that comprises six histidine residues (i.e., H2-H10 or H4-H8) to improve solubility and expression (pg. 1726, col. 2, para. 2; Table S3).
In addition, Magyar et al teach TdT variants comprising photoswitches, including an azobenzene photoswitch that can controllably block entry or binding of nucleotides into the active site of the TdT enzyme ([0008]). Magyar et al also teach the loop 2 region is a suitable point for inserting exogenous photoswitches as this region is highly tolerable for substitutions (brief description of FIG. 14A, para. 47). Magyar et al further demonstrate that a click reactive group could be installed on loop 2 region of the TdT for subsequent reaction with another click reactive group comprising a peptide that functions as a tag for affinity purifications ([00232]).
Thus, it would have been obvious to one of ordinary skill in the art to have modified the TdT variant of ‘092 to comprise a six-residue histidine affinity tag as taught by Chua et al at the loop 2 region as taught by Magyar et al because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each element in the combination merely performs the same function as it does separately (TdT synthesizes a nucleic acid fragment without a template while histidine residues serve as a tag for identification and purification). One would have been motivated to have done so for the advantage of selecting an affinity tag that has been demonstrated to successfully express soluble TdTs and inserting the affinity tag at a region known to tolerate modifications as taught by Chua et al and Magyar et al, respectively. One would have had a reasonable expectation of success in doing because Magyar et al demonstrate TdT variants tolerate modifications at the loop 2 region and Chua et al demonstrate over 10,000 TdT variants comprising this histidine affinity tag can be expressed in cells and purified via affinity chromatography.
Claims 8-11, 16-18, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 and 4 of U.S. Patent No. 10,752,887 in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘887 recites a TdT variant having an amino acid sequence at least 90% sequence identical to SEQ ID NO: 11, which shares 90.8% sequence identity to instantly claimed SEQ ID NO: 42. Accordingly, the full-length sequence of SEQ ID NO:42 is encompassed by the recited genus. ‘887 further recites wherein the TdT variant (i) is capable of synthesizing a nucleic acid fragment without a template and (ii) is capable of incorporating a 3’-O-modified (i.e., 3’-O-protected) nucleotide onto a free 3’-hydroxyl of the nucleic acid fragment (claims 2 and 4). As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘887 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘887 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
Claims 8-11, 16-18, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 3 of U.S. Patent No. 12,071,638 in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘638 recites a TdT variant having an amino acid sequence at least 90% sequence identical to SEQ ID NO: 11, which shares at least 90% sequence identity to instantly claimed SEQ ID NO: 42 (claim 1). Accordingly, the full-length sequence of SEQ ID NO:42 is encompassed by the recited genus. ‘638 further recites wherein the TdT variant (i) is capable of synthesizing a nucleic acid fragment without a template and (ii) is capable of incorporating a 3’-O-modified (i.e., 3’-O-protected) nucleotide onto a free 3’-hydroxyl of the nucleic acid fragment (claims 1 and 3). As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
However, ‘638 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘638 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
Claims 8-11, 16-18, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,371,680 in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘680 recites a TdT variant having an amino acid sequence at least 90% sequence identical to SEQ ID NO: 27, which shares 93.7% sequence identity to instantly claimed SEQ ID NO: 42 (claim 1). Accordingly, the full-length sequence of SEQ ID NO:42 is encompassed by the recited genus. ‘680 further recites wherein the TdT variant (i) is capable of synthesizing a nucleic acid fragment without a template and (ii) is capable of incorporating a 3’-O-modified (i.e., 3’-O-protected) nucleotide onto a free 3’-hydroxyl of the nucleic acid fragment (claim 1). As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘680 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘887 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
Claims 8-11, 16-18, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12 and 13 of U.S. Patent No. 12,428,668 in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘668 recites a TdT variant having an amino acid sequence at least 90% sequence identical to SEQ ID NO: 3, which shares 90.8% sequence identity to instantly claimed SEQ ID NO: 42 (claim 13). Accordingly, the full-length sequence of SEQ ID NO:42 is encompassed by the recited genus. ‘668 further recites wherein the TdT variant (i) is capable of synthesizing a nucleic acid fragment without a template and (ii) is capable of incorporating a 3’-O-modified (i.e., 3’-O-protected) nucleotide onto a free 3’-hydroxyl of the nucleic acid fragment (claim 12). As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘668 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘668 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
Claims 8-11, 16-18, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/581,124 (claims filed on 04/23/2026) in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘124 recites a TdT variant having an amino acid sequence at least 70% sequence identical to SEQ ID NO: 1, which is 100% identical to instantly claimed SEQ ID NO: 42 (claim 1). As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘124 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘124 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
This is a provisional nonstatutory double patenting rejection.
Claims 8-11, 16-18, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/709,291 (claims filed on 01/10/2025) in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘291 recites a TdT variant having an amino acid sequence at least 70% sequence identical to SEQ ID NO: 2, which shares 99.5% sequence identity to instantly claimed SEQ ID NO: 42 (claim 1). Accordingly, the full-length sequence of SEQ ID NO:42 is encompassed by the recited genus. As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘291 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘291 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
This is a provisional nonstatutory double patenting rejection.
Claims 8-11, 16-18, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/783,186 (claims filed on 11/21/2025) in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘291 recites a TdT variant having an amino acid sequence of SEQ ID NO: 23, which shares 99.8% sequence identity to instantly claimed SEQ ID NO: 42 (claim 1). As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘186 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘186 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
This is a provisional nonstatutory double patenting rejection.
Claims 8-11, 16-18, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/709,292 (claims filed on 06/22/2026) in view of Magyar et al (WO 2018/217689; Published on November 29, 2018; IDS received on 07/05/2023, Foreign Patent Cite No. 6) and Chua et al (Evolving a Thermostable Terminal Deoxynucleotidyl Transferase; ACS Synthetic Biology, 2020, 9(7): 1725-1735; IDS received on 07/05/2023, NP Cite No. 14).
Regarding instant claims 8-11, 16-18, and 21, ‘292 recites a TdT variant having an amino acid sequence at least 90% sequence identical to SEQ ID NO: 2, which shares 99.5% sequence identity to instantly claimed SEQ ID NO: 42 (claim 1). Accordingly, the full-length sequence of SEQ ID NO: 42 is encompassed by the recited genus. As the TdT variant sequences of the patented claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the recited functions and stability in the instant claims as inherent properties.
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However, ‘292 does not recite wherein the TdT variant comprises a peptide affinity tag inserted into the loop 2 region.
The obviousness to modify the TdT variant of ‘292 to comprise a histidine affinity tag into the loop 2 region is discussed above as applied to claim 16 in discussion regarding U.S. Patent No. 12,618,092.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights