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 .
DETAILED ACTION
The amendment filed on January 2, 2026 has been entered.
Election/Restrictions
Applicant’s election of Group I with a species election of the circularly permutated variant having the amino acid sequence of SEQ ID NO:913 (amino acids 122-297 of SEQ ID NO:1 - GSSGGGSSGGEPTTENLYFQSDNGSSGGGSSGG – amino acids 1-121 of SEQ ID NO:1, TEV cleavage site underlined) in the reply filed on January 2, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 22-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on January 2, 2026.
Status of Claims
Claims 1, 3, 5-7, 17, and 20-29 are pending.
Claims 22-28 are withdrawn.
Claims 1, 3, 5-7, 17, 20-21, and 28 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 10, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim for Domestic Priority
Applicants' claim for domestic priority under 35 USC 119(e) to US provisional application 63/338,364, filed 05/04/2022, is acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c), see the linker amino acid sequence at page 62.
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 sequence identifiers, 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 Objections
Claims 1, 6, 21, and 29 are objected to due to the recitation of “cp”. Abbreviation/acronym unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation/acronym is used.
Appropriate correction is required.
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 1 and claims depending therefrom are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “C-terminal-most position of SEQ I NO:1 is connected…to N-terminal-most position of SEQ ID NO:1”. The metes and bounds of the limitation in the context of the above claim are not clear. (1) It is unclear which amino acid position is considered as a “C-terminal-most” and “N-terminal-most”. (2) The amino acid at the C-terminus of SEQ ID NO:1 is a Gly residue and the amino acid at the N-terminus of SEQ ID NO:1 is a Met residue. However, for a first sequence and second sequence each having at least 70% but less than 100% sequence identity to SEQ ID NO:1, the amino acid position at the C-terminus and N-terminus can be any amino acid. Clarification is requested.
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 7 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.
Claim 7 recites that the first and second sequences comprise sequence corresponding to at least 70% of the sequence of SEQ ID NO:1. Claim 7 depends from claim 1. Claim 1 recites that the first and second sequences have at least 70% sequence identity to SEQ ID NO:1. Therefore, claim 7 fails to further limit claim 1.
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.
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, 5-7, 17, 20-21, and 29 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.
MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' In this case, claims 1, 3, 5-7, 17, and 20-21 encompass a composition comprising any circularly permutated variant of a polypeptide comprising (A) a first and second sequence each having at least 70% sequence identity to SEQ ID NO:1, (B) wherein the circularly permutated variant has a cp (circularly permutated) site at a position corresponding to a position between 104 and 130 or a cp site at position 121 of SEQ ID NO:1, (C) wherein any amino acid at the C-terminus of the first sequence is connected directly or by any linker, any cleavable linker, or linker comprising cleavage site for TEV protease to any amino acid at the N-terminus of the second sequence, and (D) wherein the circularly permutated variant is capable of forming a covalent bond with a haloalkane substrate. Claim 29 encompasses a composition comprising any split circularly permutated variant comprising (A) any deletions of up to 40 at the N-terminus of SEQ ID NO:1, C-terminus of SEQ ID NO:1, or either side of the cp site, wherein (B) any first peptide or polypeptide comprising (i) any segment having at least 70% sequence identity to SEQ ID NO:1 and (ii) a segment comprising a first portion of a linker segment, (C) any second peptide or polypeptide comprising (i) a segment having at least 70% sequence identity to SEQ ID NO:1 and (ii) a segment comprising a second portion of a linker segment, wherein the first and second portion of a linker segment compress the results of cleave of the linker segment at a cleavage site, (D) wherein the split circularly permutated variant comprises a cp site at a position corresponding to a position between positions 104 and 130, and (E) wherein the function of the split circularly permutated variant is not recited. Therefore, the claims are directed to a genus of circularly permutated variant having unknown structure expect having a cp site at the position corresponding to position 121 or a position between 104-130 of SEQ ID NO:1 and having the function of forming a covalent bond with a haloalkane substrate and a genus of split circularly permutated variant circularly permutated variant having unknown structure expect having a cp site at a position between 104-130 of SEQ ID NO:1 and having unknown unction.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The recitation of “circularly permutated”, “forming a covalent bond with a haloalkane substrate”, and “split circularly permutated” fails to provide a sufficient description of the genus of the variants as it merely describes the functional features of the genus without providing any definition of the structural features of the species within the genus. The specification does not specifically define any of the species that fall within the genus. The specification does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
Rhodococcus rhodochrous haloalkane dehalogenase was known in the prior art. Kulakova (The plasmid-located haloalkane dehalogenase gene from Rhodococcus rhodochrous NCIMB 13064. Microbiology (Reading). 1997 Jan;143 ( Pt 1):109-115 – form PTO-892) discloses a Rhodococcus rhodochrous haloalkane dehalogenase having 92.1% sequence identity to SEQ ID NO:1 of the instant application (Fig. 2 and see the sequence alignment below). A modified Rhodococcus rhodochrous haloalkane dehalogenase (known as HaloTag) having 100% sequence identity to SEQ ID NO:1 of the instant application was also known in the art, see Darzin (US Patent No. 8,420,367 – form PTO-892, see SEQ ID NO:27 and the sequence alignment below). A few circularly permutated variants of Rhodococcus rhodochrous haloalkane dehalogenase (HaloTag) were known in the prior art but are limited to a circularly permutated HaloTag having a cp site at position 143, see Deo (The HaloTag as a general scaffold for far-red tunable chemigenetic indicators. Nat Chem Biol. 2021 Jun;17(6):718-723. Epub 2021 Apr 1 – form PTO-1449, page 719) or at position 141, see Schreiter (WO 2019/133976 – form PTO-1449. SEQ ID NO:4).
Fransceus (J Ind Microbiol Biotechnol. 2017 May;44(4-5):687-695. – form PTO-892) reviews protein engineering techniques, such as random mutagenesis and recombination, directed evolution and iterative or combinatory saturation “hotspots”. Fransceus states that “a recurring problem, however, is choosing which amino acid positions should be targeted. Answering this question is not an easy feat and requires substantial insight in the relationship between an enzyme’s sequence or structure and its properties.” Sanavia (Computational and Structural Biotechnology Journal, Volume 18, 2020, Pages 1968-1979. – form PTO-892) discloses challenges in the prediction of protein stability in the occurrence of multiple mutations. “Multiple-point mutations are common variations of the protein sequence that may be needed in protein engineering when a single-point mutation is not enough to yield the desired stability change. Dealing with multiple-site variations adds another level of complexity beyond the prediction of the effect of a single variant on protein stability, since it requires the learning of many types of combinatorial effects”.
The specification is limited to specific circularly permutated variants and split circularly permutated variants having the amino acid sequence of SEQ ID NO:119 (cpHT(122)), SEQ ID NO:870 (cpHT(122)-TEV linker), SEQ ID NO:855 (sp/cpHT(122)-TEV linker), and SEQ ID NO:913 (cpHT(121)-TEV linker), wherein the variants form a covalent bond with a haloalkane substrate. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the four variants described above are not enough and does not constitute a representative number of species to describe the whole genus. Therefore, the specification fails to describe a representative species of the claimed genus.
Further, one of skill in the art could circularly permutate a polypeptide having at least 70% sequence identity to SEQ ID NO:1 at a cp site located at a position between 104-130 of SEQ ID NO:1. However, there is no teaching regarding which 30% of the amino acids of SEQ ID NO:13 can be modified and circularly permutated resulting in a polypeptide having the function of forming a covalent bond with a haloalkane substrate.
An important consideration is that structure is not necessarily a reliable indicator of function. In the instant case, there is no disclosure relating similarity of structure to conservation of function. Conservation of structure is not necessarily a surrogate for conservation of function.
Regarding claim 29, the claim encompasses many functionally unrelated polypeptides encompassed within the scope of these clams, including partial sequences, resulting in a substantial variation within the genus. The genus of these polypeptides comprises a large variable genus with the potentiality of having different function or no function. The specification is limited to a split circularly permutated variant having the amino acid sequence of SEQ ID NO:855 (sp/cpHT(122)-TEV linker), wherein the variant forms a covalent bond with a haloalkane substrate. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the one example described above is not enough and does not constitute a representative number of species to describe the whole genus polypeptides having any function or unknown function. The specification also fails to describe additional representative species of the polypeptides by any identifying characteristics or properties of the polypeptides, for which no predictability of function is apparent. Therefore, one skilled in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 1, 3, 5-7, 17, 20-21, and 29.
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.
Claim(s) 1, 3, 5-7, 17, 20, and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Urh (HaloTag, a Platform Technology for Protein Analysis. Curr Chem Genomics. 2012;6:72-8. – form PTO-892), Darzin (US Patent No. 8,420,367 – form PTO-892, Deo (The HaloTag as a general scaffold for far-red tunable chemigenetic indicators. Nat Chem Biol. 2021 Jun;17(6):718-723. Epub 2021 Apr 1 – form PTO-1449, page 719), and Binkowski (WO 2012/061530 – form PTO-1449),
Regarding claims 1, 3, 5-7, 17, 20-21, and 29, Urh discloses a HaloTag protein (haloalkane dehalogenase) forming a covalent bond with a haloalkane (abstract, 2nd full paragraph at page 74). The amino acid sequence of the HaloTag protein has 100% sequence identity to the haloalkane dehalogenase mutant having the amino acid sequence of SEQ ID NO:1 of the instant application, see Darzin (US Patent No. 8,420,367 – form PTO-892, see SEQ ID NO:27 and the sequence alignment below). Urh discloses that HaloTag protein provides a single tag that meets different experimental needs, which is more efficient than using multiple tags such as auto-fluorescent and affinity tags (page 72). Urh discloses that the HaloTag protein allows the function of which can be altered by attaching various chemical moieties (fluorescent labels, affinity handles, etc.) and allows for specificity and ease of using one genetically encoded protein tag with the functional diversity and adaptability supplied by synthetic chemistry (page 72).
Regarding claims 1, 3, and 7, Deo discloses a circularly permutated (cp) HaloTag having a cp site at position 143 (abstract, 1st full paragraph at page 719, and Fig. 2 at page 720). Deo discloses introducing a circularly permutated HaloTag protein to create new N and C termini in close spatial proximity to the bound fluorophore (1st full paragraph at page 719). Deo discloses that further engineering of the protein scaffold (comprising HaloTag) to modulate existing bioavailable dyes will enable a large portfolio of sensors useful in a variety of biological contexts. (1st full paragraph at page 723).
Neither Urh nor Deo disclose a circularly permutated HaloTag protein having a cp site at positions 104-430 and having the linker of SEQ ID NO:912. However, circularly permutating enzymes and linker of SEQ ID NO:912 were known in the prior art, as discussed below.
Regarding claims 1 and 6, Binkowski discloses circularly permutated luciferases by making a circular permutation at every 1-3 sites ([00509] and pages 183-203).
Regarding claims 1, 5, 17, and 20, Binkowski discloses the circularly permutated lucifererases have linker comprising the amino acid sequence of SEQ ID NO:328 in between the permutated fragments ([00509]). The linker of SEQ ID NO:328 (GSSGG-GSSGG-EPTT-ENLYFOS-DN-GSSGG-GSSGG) is identical to the linker of SEQ ID NO:912 of the instant application, is 33 amino acids in length, and comprises a cleavage site for TEV protease ([00509] and see the sequence alignment below). Binkowski discloses that linker provides a long enough tether between the two variant frames (first and second sequence) so that they can associate in a way that produces a functional luciferase ([00509]). Binkowski discloses that the TEV protease recognition site provides a means to disrupt the tether (in the presence of TEV protease) so that its importance to maintaining activity could be investigated ([00509]). The use of the TEV protease recognition site created a mode to predict which CP sites would be useful for protein complementation assays (PCA) or for biosensor applications (e.g., insertion of a response element between the CP sites) ([00509]).
Regarding claim 29, Binkowski discloses a split circularly permutated luciferase which can be used in a general complementation system ([00198], [00527]).
Therefore, in combining the teachings of the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to make a circularly permutated or split circularly permutated HaloTag proteins comprising a cp site at every position of HaloTag, which includes positions 104-130 or 121, and comprising the GSSGG-GSSGG-EPTT-ENLYFOS-DN-GSSGG-GSSGG linker. One having ordinary or art would have been motivated to do so in order to make HaloTag proteins that can accommodate more bioavailable dyes, enabling a large portfolio of sensors useful in a variety of biological contexts. One having ordinary or art would have been motivated use the linker of Binkowski in order to provide a long enough tether between the two first and second sequence so that they can associate in a way that produces a functional HaloTag and use of the TEV protease recognition site comprised in the linker provides a mode to predict which CP sites would be useful for protein complementation assays (PCA) or for biosensor applications. One having ordinary skill in the art would have had a reasonable expectation of success since Urh discloses a HaoTag protein, Deo discloses a circularly permutated HaloTab, and Binkowski discloses making circularly permutated luciferases having a cp site at every 1-3 positions and split circularly permutated luciferases. The rationale to support a conclusion that the claim would have been obvious is that a method of enhancing a particular class of devices (circular permutation of proteins) has been made part of the ordinary capabilities of one skilled in the art based upon the teaching of such improvement in other situations. One of ordinary skill in the art would have been capable of applying this known method of enhancement to a “base” device (HaloTag) in the prior art and the results would have been predictable to one of ordinary skill in the art. See MPEP 2143.
Therefore, the above references render claims 1, 3, 5-7, 17, 20, and 29 prima facie obvious.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 29 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 9, 12-23, 32-34, and 44 of copending Application No. 18/312,117 (reference application) in view of Binkowski (WO 2012/061530 – form PTO-1449). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 29 of the instant application and the claims of the reference application directed to split circularly permutated variant of SEQ ID NO:1. SEQ ID NO:1 of the instant application is identical to SEQ ID NO:1 of the reference application.
Regarding claim 29 of the instant application, claim 3 of the reference application recites a composition comprising a split circularly permutated variant of a polypeptide comprising (i) a first fragment of the polypeptide comprising at least 70% sequence identity similarity with a first portion of SEQ ID NO: 1, and (ii) a second fragment of the polypeptide comprising at least 70% sequence identity similarity with a second portion of SEQ ID NO: 1, claim 12 of the reference application recites that the split variant comprises a cp site at a position between positions 104 and 130, and claim 13 of the reference application recites that the split variant comprises deletions of up to 40 amino acids at the N-terminus of SEQ ID NO:1, C-terminus of SEQ ID NO:1, and either side of the cp site.
The claims of the reference application do not recite a linker.
However, use of a linker in making circularly permutated protein was known in the prior art. Binkowski discloses circularly permutated lucifererases have linker comprising the amino acid sequence of SEQ ID NO:328 in between the permutated fragments ([00509]). The linker of SEQ ID NO:328 (GSSGG-GSSGG-EPTT-ENLYFOS-DN-GSSGG-GSSGG) is identical to the linker of SEQ ID NO:912 of the instant application, is 33 amino acids in length, and comprises a cleavage site for TEV protease ([00509] and see the sequence alignment below). Binkowski discloses that linker provides a long enough tether between the two variant frames (first and second sequence) so that they can associate in a way that produces a functional luciferase ([00509]). Binkowski discloses that the TEV protease recognition site provides a means to disrupt the tether (in the presence of TEV protease) so that its importance to maintaining activity could be investigated ([00509]). The use of the TEV protease recognition site created a mode to predict which CP sites would be useful for protein complementation assays (PCA) or for biosensor applications (e.g., insertion of a response element between the CP sites) ([00509]).
Therefore, it would have been obvious to one having ordinary skill in the art to modify the claims of the reference application by inserting the linker of Binkowski into the split circularly permutated HaloTag. One having ordinary or art would have been motivated use the linker of Binkowski in order to provide a long enough tether between the two first and second sequence so that they can associate in a way that produces a functional HaloTag and use of the TEV protease recognition site comprised in the linker provides a mode to predict which CP sites would be useful for protein complementation assays (PCA) or for biosensor applications. One having ordinary skill in the art would have had a reasonable expectation of success since the claim of the reference application recites a split circularly permutated HaoTag protein and Binkowski discloses using a linker comprising a TEV cleavage site.
Therefore, the conflicting claims are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 3, 5-7, 17, and 20-29 are pending.
Claims 22-28 are withdrawn.
Claims 1, 3, 5-7, 17, 20-21, and 29 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on 408-918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YONG D PAK/Primary Examiner, Art Unit 1652
Sequence alignment between SEQ ID NO:1 of the instant application (“Qy”) and the Rhodococcus rhodochrous haloalkane dehalogenase of Kulakova (“Db”)
DHAA_RHORH
ID DHAA_RHORH Reviewed; 293 AA.
AC P0A3G2; Q53042;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 1.
DT 18-JUN-2025, entry version 74.
DE RecName: Full=Haloalkane dehalogenase;
DE EC=3.8.1.5;
GN Name=dhaA;
OS Rhodococcus rhodochrous.
OG Plasmid pRTL1.
OC Bacteria; Bacillati; Actinomycetota; Actinomycetes; Mycobacteriales;
OC Nocardiaceae; Rhodococcus.
OX NCBI_TaxID=1829;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=NCIMB 13064;
RX PubMed=9025284; DOI=10.1099/00221287-143-1-109;
RA Kulakova A.N., Larkin M.J., Kulakov L.A.;
RT "The plasmid-located haloalkane dehalogenase gene from Rhodococcus
RT rhodochrous NCIMB 13064.";
RL Microbiology 143:109-115(1997).
CC -!- FUNCTION: Catalyzes hydrolytic cleavage of carbon-halogen bonds in
CC halogenated aliphatic compounds, leading to the formation of the
CC corresponding primary alcohols, halide ions and protons. Expresses
CC halogenase activity against 1-chloroalkanes of chain length C3 to C10,
CC and also shows a very weak activity with 1,2-dichloroethane.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-haloalkane + H2O = a halide anion + a primary alcohol +
CC H(+); Xref=Rhea:RHEA:19081, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15734, ChEBI:CHEBI:16042, ChEBI:CHEBI:18060; EC=3.8.1.5;
CC -!- PATHWAY: Xenobiotic degradation; haloalkane degradation.
CC -!- SUBUNIT: Monomer.
CC -!- INDUCTION: By 1-haloalkanes.
CC -!- SIMILARITY: Belongs to the haloalkane dehalogenase family. Type 2
CC subfamily. {ECO:0000305}.
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DR EMBL; AF060871; AAC15838.1; -; Genomic_DNA.
DR PDB; 2V9Z; X-ray; 3.00 A; A=1-293.
DR PDB; 3FBW; X-ray; 1.23 A; A=1-293.
DR PDB; 3RK4; X-ray; 1.31 A; A=1-293.
DR PDB; 3SK0; X-ray; 1.78 A; A=1-293.
DR PDB; 4E46; X-ray; 1.26 A; A=1-293.
DR PDB; 4F5Z; X-ray; 1.20 A; A=1-293.
DR PDB; 4F60; X-ray; 1.45 A; A=1-293.
DR PDB; 4FWB; X-ray; 1.26 A; A=4-293.
DR PDB; 4WCV; X-ray; 1.69 A; A=1-293.
DR PDB; 5FLK; X-ray; 0.99 A; A=1-293.
DR PDB; 5UXZ; X-ray; 1.92 A; A/B=4-290.
DR PDB; 5UY1; X-ray; 1.35 A; A/B=4-290.
DR PDB; 5VNP; X-ray; 2.23 A; A/B=4-293.
DR PDB; 6SP5; X-ray; 1.60 A; A/B=3-293.
DR PDB; 6SP8; X-ray; 1.55 A; A/B=3-293.
DR PDB; 6TY7; X-ray; 1.50 A; A/B=1-293.
DR PDB; 6XT8; X-ray; 1.70 A; A/B/C/D=1-293.
DR PDB; 6XTC; X-ray; 2.54 A; A/B/C/D=1-293.
DR PDB; 7O3O; X-ray; 1.25 A; A=1-293.
DR PDB; 7O8B; X-ray; 1.75 A; A=4-293.
DR PDBsum; 2V9Z; -.
DR PDBsum; 3FBW; -.
DR PDBsum; 3RK4; -.
DR PDBsum; 3SK0; -.
DR PDBsum; 4E46; -.
DR PDBsum; 4F5Z; -.
DR PDBsum; 4F60; -.
DR PDBsum; 4FWB; -.
DR PDBsum; 4WCV; -.
DR PDBsum; 5FLK; -.
DR PDBsum; 5UXZ; -.
DR PDBsum; 5UY1; -.
DR PDBsum; 5VNP; -.
DR PDBsum; 6SP5; -.
DR PDBsum; 6SP8; -.
DR PDBsum; 6TY7; -.
DR PDBsum; 6XT8; -.
DR PDBsum; 6XTC; -.
DR PDBsum; 7O3O; -.
DR PDBsum; 7O8B; -.
DR AlphaFoldDB; P0A3G2; -.
DR SMR; P0A3G2; -.
DR ESTHER; rhoso-halo1; Haloalkane_dehalogenase-HLD2.
DR BRENDA; 3.8.1.5; 5395.
DR SABIO-RK; P0A3G2; -.
DR UniPathway; UPA00007; -.
DR EvolutionaryTrace; P0A3G2; -.
DR GO; GO:0016020; C:membrane; IEA:TreeGrafter.
DR GO; GO:0018786; F:haloalkane dehalogenase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0009636; P:response to toxic substance; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.1820; alpha/beta hydrolase; 1.
DR HAMAP; MF_01231; Haloalk_dehal_type2; 1.
DR InterPro; IPR000073; AB_hydrolase_1.
DR InterPro; IPR029058; AB_hydrolase_fold.
DR InterPro; IPR050266; AB_hydrolase_sf.
DR InterPro; IPR000639; Epox_hydrolase-like.
DR InterPro; IPR023594; Haloalkane_dehalogenase_2.
DR NCBIfam; NF002938; PRK03592.1; 1.
DR PANTHER; PTHR43798:SF24; CIS-3-ALKYL-4-ALKYLOXETAN-2-ONE DECARBOXYLASE; 1.
DR PANTHER; PTHR43798; MONOACYLGLYCEROL LIPASE; 1.
DR Pfam; PF00561; Abhydrolase_1; 1.
DR PRINTS; PR00412; EPOXHYDRLASE.
DR SUPFAM; SSF53474; alpha/beta-Hydrolases; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Detoxification; Hydrolase; Plasmid.
FT CHAIN 1..293
FT /note="Haloalkane dehalogenase"
FT /id="PRO_0000216775"
FT DOMAIN 34..158
FT /note="AB hydrolase-1"
FT /evidence="ECO:0000255"
FT ACT_SITE 106
FT /note="Nucleophile"
FT /evidence="ECO:0000250"
FT ACT_SITE 130
FT /note="Proton donor"
FT /evidence="ECO:0000250"
FT ACT_SITE 272
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT STRAND 13..17
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 20..28
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 30..32
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 35..38
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 45..48
FT /evidence="ECO:0007829|PDB:5FLK"
FT TURN 49..51
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 52..55
FT /evidence="ECO:0007829|PDB:5FLK"
FT TURN 56..58
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 61..64
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 81..94
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 99..105
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 106..118
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 120..122
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 123..130
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 135..137
FT /evidence="ECO:0007829|PDB:3RK4"
FT HELIX 138..140
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 143..145
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 146..152
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 154..156
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 157..162
FT /evidence="ECO:0007829|PDB:5FLK"
FT TURN 163..165
FT /evidence="ECO:0007829|PDB:6XTC"
FT HELIX 167..170
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 172..175
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 177..179
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 183..190
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 191..193
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 196..199
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 200..208
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 216..231
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 236..243
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 245..247
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 249..258
FT /evidence="ECO:0007829|PDB:5FLK"
FT STRAND 262..272
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 274..277
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 279..289
FT /evidence="ECO:0007829|PDB:5FLK"
FT HELIX 291..293
FT /evidence="ECO:0007829|PDB:5FLK"
SQ SEQUENCE 293 AA; 33246 MW; 2B637C53E36BE9F3 CRC64;
Query Match 92.1%; Score 1489; Length 293;
Best Local Similarity 92.5%;
Matches 271; Conservative 9; Mismatches 13; Indels 0; Gaps 0;
Qy 1 MAEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYVWRNIIPHVAPTHR 60
|:||||||||||||||||||||||||||||||||||||||||||||:||||||||||:||
Db 1 MSEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYLWRNIIPHVAPSHR 60
Qy 61 CIAPDLIGMGKSDKPDLGYFFDDHVRFMDAFIEALGLEEVVLVIHDWGSALGFHWAKRNP 120
||||||||||||||||| ||||||||::||||||||||||||||||||||||||||||||
Db 61 CIAPDLIGMGKSDKPDLDYFFDDHVRYLDAFIEALGLEEVVLVIHDWGSALGFHWAKRNP 120
Qy 121 ERVKGIAFMEFIRPIPTWDEWPEFARETFQAFRTTDVGRKLIIDQNVFIEGTLPMGVVRP 180
||||||| |||||||||||||||||||||||||| ||||:|||||| |||| || ||||
Db 121 ERVKGIACMEFIRPIPTWDEWPEFARETFQAFRTADVGRELIIDQNAFIEGALPKCVVRP 180
Qy 181 LTEVEMDHYREPFLNPVDREPLWRFPNELPIAGEPANIVALVEEYMDWLHQSPVPKLLFW 240
|||||||||||||| |||||||||||||||||||||||||||| ||:|||||||||||||
Db 181 LTEVEMDHYREPFLKPVDREPLWRFPNELPIAGEPANIVALVEAYMNWLHQSPVPKLLFW 240
Qy 241 GTPGVLIPPAEAARLAKSLPNCKAVDIGPGLNLLQEDNPDLIGSEIARWLSTL 293
||||||||||||||||:|||||| |||||||: ||||||||||||||||| |
Db 241 GTPGVLIPPAEAARLAESLPNCKTVDIGPGLHYLQEDNPDLIGSEIARWLPAL 293
Sequence alignment between SEQ ID NO:1 of the instant application (“Qy”) and the HaloTag of Darzins (“Db”)
US-11-978-950-27
Sequence 27, US/11978950
Patent No. 8420367
GENERAL INFORMATION
APPLICANT: Darzins, Aldis
APPLICANT: Encell, Lance P.
APPLICANT: Friedman Ohana, Rachel
APPLICANT: Otto, Paul
APPLICANT: Vidugiris, Gediminas
APPLICANT: Wood, Keith V.
APPLICANT: Wood, Monika G.
APPLICANT: Zimmerman, Kris
APPLICANT: Promega Corporation
TITLE OF INVENTION: Mutant Hydrolase Proteins with Enhanced Kinetics and Functional Expression
FILE REFERENCE: 341.048US1
CURRENT APPLICATION NUMBER: US/11/978,950
CURRENT FILING DATE: 2007-11-07
PRIOR APPLICATION NUMBER: US 60/855,237
PRIOR FILING DATE: 2006-10-30
PRIOR APPLICATION NUMBER: US 60/930,201
PRIOR FILING DATE: 2007-05-15
NUMBER OF SEQ ID NOS: 73
SEQ ID NO 27
LENGTH: 297
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: A synthetic DhaA mutant
Query Match 100.0%; Score 1617; Length 297;
Best Local Similarity 100.0%;
Matches 297; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYVWRNIIPHVAPTHR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYVWRNIIPHVAPTHR 60
Qy 61 CIAPDLIGMGKSDKPDLGYFFDDHVRFMDAFIEALGLEEVVLVIHDWGSALGFHWAKRNP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CIAPDLIGMGKSDKPDLGYFFDDHVRFMDAFIEALGLEEVVLVIHDWGSALGFHWAKRNP 120
Qy 121 ERVKGIAFMEFIRPIPTWDEWPEFARETFQAFRTTDVGRKLIIDQNVFIEGTLPMGVVRP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ERVKGIAFMEFIRPIPTWDEWPEFARETFQAFRTTDVGRKLIIDQNVFIEGTLPMGVVRP 180
Qy 181 LTEVEMDHYREPFLNPVDREPLWRFPNELPIAGEPANIVALVEEYMDWLHQSPVPKLLFW 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LTEVEMDHYREPFLNPVDREPLWRFPNELPIAGEPANIVALVEEYMDWLHQSPVPKLLFW 240
Qy 241 GTPGVLIPPAEAARLAKSLPNCKAVDIGPGLNLLQEDNPDLIGSEIARWLSTLEISG 297
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GTPGVLIPPAEAARLAKSLPNCKAVDIGPGLNLLQEDNPDLIGSEIARWLSTLEISG 297
Sequence alignment between SEQ ID NO:912 of the instant application (“Qy”) and the linker of SEQ ID NO:328 of Binkowski (“Db”)
AZW25871
ID AZW25871 standard; peptide; 33 AA.
XX
AC AZW25871;
XX
DT 05-JUL-2012 (first entry)
XX
DE Circularly permuted luciferase variants related linker peptide, SEQ 328.
XX
KW enzyme engineering; enzyme production; luminescence; protein interaction.
XX
OS Synthetic.
XX
CC PN WO2012061530-A2.
XX
CC PD 10-MAY-2012.
XX
CC PF 02-NOV-2011; 2011WO-US059018.
XX
PR 02-NOV-2010; 2010US-00140922.
XX
CC PA (PRMG ) PROMEGA CORP.
XX
CC PI Binkowski B, Encell LP, Hall M, Robers MB, Slater MR, Wood KV;
CC PI Wood MG;
XX
DR WPI; 2012-F44135/40.
XX
CC PT New isolated polynucleotide encoding OgLuc variant polypeptide useful
CC PT e.g. in a vector, a cell, a non-human transgenic animal and for measuring
CC PT the enzymatic activity of a luminogenic protein.
XX
CC PS Example 48; SEQ ID NO 328; 401pp; English.
XX
CC The present invention relates to novel Oplophorus gracilirostris derived
CC luciferase (OgLuc), its variants, novel coelenterazines (luciferase
CC generates light in the presence of a coelenterazine) and their uses. The
CC invention also provides a polynucleotide encoding an Oplophorus
CC gracilirostris luciferase variant; a vector comprising the polynucleotide
CC ; a host cell comprising the vector; a non-human transgenic animal
CC comprising the cell; a fusion protein comprising the luciferase variant;
CC a method for producing the luciferase variant; a kit comprising the
CC luciferase variant encoding polynucleotide; a kit comprising the
CC luciferase variant polypeptide; a bioluminescence resonance energy
CC transfer (BRET) system and a method for measuring the enzymatic activity
CC of a luminogenic protein. The polynucleotide, vector, cell, luciferase
CC variant polypeptide or the fusion protein is useful for measuring
CC bioluminescence and in protein complementation assays to detect the
CC interaction of biomolecules. The luciferase variant protein of the
CC invention has enhanced luminescence; signal stability and signal duration
CC ; enzyme stability; resistance to elevated temperature; altered substrate
CC specificity and enhanced biocompatibility. The present sequence is linker
CC peptide used in the circularly permuted luciferase variants of the
CC invention.
XX
SQ Sequence 33 AA;
Query Match 100.0%; Score 175; Length 33;
Best Local Similarity 100.0%;
Matches 33; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GSSGGGSSGGEPTTENLYFQSDNGSSGGGSSGG 33
|||||||||||||||||||||||||||||||||
Db 1 GSSGGGSSGGEPTTENLYFQSDNGSSGGGSSGG 33