Arity
DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The preliminary amendments filed 8/12/2024 and 03/07/2025 are acknowledged and have been entered. Claims 22, 24, and 26 are amended. Claims 1-15 are cancelled. Claims 16-30 are pending and are being examined on the merits.
Priority
The application is a 371 PCT of EP2022/067351 filed 06/24/2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement filed 12/22/2023 has been considered.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show colors as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
In the event Color photographs and color drawings are submitted, they are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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 - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in 0126, 0130, 0136, 0142, 0149, 0158, 0166, 0169, 0174, 0184, 0192, 0201, 0209, 0218, and Table 2.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
The disclosure is objected to because of the following informalities:
The specification contains references to colored drawings that are not depicted by the indicated color [507-514; 0024].
Table 5 is missing numbers from the last “SEQ ID NO:” recitations
Appropriate correction is required.
Claim Objections
Claims 6, 16, 19, 24-26, and 29 are objected to because of the following informalities:
Claim 6 end in a comma versus a period.
Claim 16 has the grammatical error of reciting “molecules” in line 2. It would be remedial to replace ‘molecules’ with ‘molecule’.
In claim 16, the wording that describes the relationship between the recited “complementary sequence” and the previously recited “second sequence for recognizing the transposase” in lines 21-27 is confusing. It would be remedial to amend the claims to explicitly identify the sequence to which the complementary sequence corresponds. For example, “the second single-stranded nucleic acid molecule comprising or consisting essentially of a sequence complementary to the second sequence located at the 3’ end of the first-stranded nucleic acid molecule…”.
Regarding claim 16, although “the first molecule” has antecedent basis back to the “first nucleic acid molecule” the claim is difficult to follow due to the repeated alternatives. It would be remedial to rephrase lines 21-24 to recite “the first single-stranded nucleic acid molecule comprises at its 5’ end a first transposase recognition sequence and at its 3’ end a second transposase recognition sequence, and the second single-stranded nucleic acid molecule comprises at its 5’ end a sequence complementary to the second transposase recognition sequence of the first single-stranded nucleic acid molecule…” Additionally, it would be remedial to rename the “sequence…for recognizing the transposase” as the “transposase recognition sequence”.
In claim 16, it would also be remedial to replace “double-stranded binding site(s) of a transposase” with “double-stranded transposase binding site(s)”.
Regarding claim 16 and 25, although it is clear that the A sequence is functioning as an insertion site, the wording could be improved by reciting “an A sequence that comprises an insertion site for a complementary sequence of a nucleic acid of interest…”
Claim 19 recites “wherein said the molecule comprises”. This is grammatically incorrect and it would be remedial to change this phrase to “wherein said molecule comprise”.
Claim 24 and 26 recites “183-184 et 201 a 288 of table”. There appears to be typos in this recitation.
Claim 25 recites “the complementary sequence binding at 5' to a first T-rich sequence”. The article (“the”) appears to be omitted after “at”.
Claim 25 recites “the A sequence being positioned at 5' end”. The article (“the”) appears to be omitted after “at”.
Claim 25 recites “a region located between complementary sequence”. The article (“the”) appears to be omitted after “at”.
Claim 25 recites “in its 5' part” and “in its 3' part”. It would be remedial to replace these phrases with “at it’s 5’ (3’) end”.
Claim 29 recites “at 5'” and “at 3'”. It would be remedial to replace these phrases with “at the 5’ (3’) end”.
Claim 29 is missing a period at the end of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(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.
Claims 16-30 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 16 recites that “the first and second single stranded nucleic acid molecules are partially paired according to the base complementarity defined by Watson and Crick so as to define a first AND a second double-stranded binding sites of a transposase”. The claim further defines the first double-stranded binding site as being constituted by a first sequence for recognizing the transposase and a complementary sequence of the first sequence, and defines the second double-stranded binding site of the transposase is constituted by a second sequence for recognizing the transposase and complementary sequence of said second sequence. However, the claim only affirmatively recited that the first single-stranded nucleic acid molecule comprises the first sequence and the second sequence, and that the second single-stranded nucleic acid molecule comprises at least the complementary sequence of the second sequence. The claim does not identify the location of the complementary sequence of the first sequence that is required to form the first double-stranded binding site. Consequently, it is unclear how the first and second single-stranded acid molecules, as recited, define both the first and second double-stranded binding sites, and one of ordinary skill in the art cannot determine the metes and bounds of the claimed complex with reasonable certainty. There seems to be a contradiction between the functional requirement (“the two molecules define both binding sites”) and the structural recitations (only one complementary sequence is actually assigned to a molecule).
Claim 19 depends from claim 16, which requires that “first and second single-stranded nucleic acid molecules are partially paired according to the base complementarity defined by Watson and Crick so as to define a first and a second double-stranded binding sites of a transposase.” However, claim 19 recites that the first molecule comprises, in sequence, the first sequence for recognizing the transposase, the second sequence for recognizing the transposase, and the complementary sequence of the first sequence for recognizing the transposase, while the second molecule comprises only the complementary sequence of the second sequence. As drafted, both the first transposase-recognition sequence and its complementary sequence are located on the first molecule. Therefore, it is unclear how the first and second molecules are “partially paired…so as to define” the first-double stranded binding site as required by claim 16. Instead, claim 19 appears to permit the first double- stranded binding site to be formed entirely within the first molecule. Consequently, it is unclear whether claim 19 remains within the scope of claim 16 or instead defined a different molecular architecture. Accordingly, the metes and bounds of claim 19 cannot be determined with reasonable certainty.
Claim 22 recites that “the first molecule comprises one of the following sequences” and thereafter lists numerous expressions containing SEQ ID NOs together with undefined variables including “X,” “R1,” and “R2.” The claim does not clearly define the meaning of these variables or how the listed expressions correspond to the nucleotide sequence of the claimed first molecule. In addition, the recitation that “R1 is SEQ ID NO:n and R2 is SEQ ID NO:n+1” where n is an even or odd number within specified ranges does not clearly identify the resulting claimed sequence combinations. Accordingly, one of ordinary skill in the art cannot determine the scope of claim 22 with reasonable certainty.
Claims 23 recites “the first and the second molecules comprising the sequences as defined in table 2” Incorporation by reference to a table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words” MPEP 2173.05(s). In this case, Applicant may refer to the SEQ ID NOs in the table, rather than referring to the tables themselves.
Claims 24 recites “comprising one of the pairs of the first and the second molecules as defined in lines 1-166, 171-172, 177-178, 183-184 et 201 a 288 of table 4”. Incorporation by reference to a table or line numbers in a table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words” MPEP 2173.05(s). In this case, Applicant may refer to the SEQ ID NOs in the table, rather than referring to the tables themselves.
Claim 24 recites “the pairs of the first and the second molecules” and depends from claim 16. There is insufficient antecedent basis for this limitation in the claim as claim 16 only mentions a pair of first and second molecules, not multiple pairs. It is not clear whether “the pairs” refers to pairs of first and second molecule, pairs od nucleoside sequences, complementary sequence pairs, etc. Accordingly, the metes and bounds of the claim cannot be determined with reasonable certainty.
Claim 25 internally defines inconsistent numbers of double-stranded binding sites. The claim initially recites that pairing of the first and third single-stranded nucleic acid molecules defines “a first and a second double-stranded binding sites” and that pairing of the second and third single-stranded nucleic acid molecules defines “the first and the second double-stranded binding sites.” However, the claim later recites first, second, third, and fourth double-stranded binding sites. Accordingly, it is unclear whether the claimed ensemble contains two or four double-stranded binding sites, and the metes and bounds of the claim cannot be determined with reasonable certainty. Furthermore, if the claimed ensemble requires only two double-stranded binding sited it is unclear how both the first and third single-stranded nucleic acid molecules and the second and third single-stranded nucleic acid molecules can form the the first and the second double-stranded binding sites of a transposase.
Claim 25 recites “the third double-stranded binding site of the transposase” and “the fourth double-stranded binding site of the transposase”. This is insufficient antecedent basis for these limitations in the claim.
Claim 25 recitation of a “B sequence” is described inconsistently as (i) allowing insertion of a complementary sequence of a nucleic acid of interest, (ii) comprising a complementary sequence of a nucleic acid of interest, and (iii) being a complementary sequence of the nucleic acid of interest. The claim does not clearly distinguish these alternatives or define whether they describe the same or different structures, such that the scope of the claim cannot be determined with reasonable certainty.
Claims 26 recites “comprising one of the pairs of the first and the second molecules as defined in lines 1-166, 171-172, 177-178, 183-184 et 201 a 288 of table 5”. Incorporation by reference to a table or line numbers in a table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words” MPEP 2173.05(s). In this case, Applicant may refer to the SEQ ID NOs in the table, rather than referring to the tables themselves.
Claim 27 recites “the first, second, and third molecules of the ensemble”. It is unclear if this recitation is referring to the first single-stranded nucleic acid molecule, second single-stranded nucleic acid molecule, and third single-stranded nucleic acid molecule.
Claim 28 recites “placing the replacement complex in the presence of a transposase recognizing the double-stranded binding sites the said transposase contained in the ensemble”. It cannot be determined whether the transposase is contained in the ensemble, whether the double-stranded binding sites are contained in the ensemble, or what relationship is untended between the transposase and the ensemble.
Claim 28 recites “recombining the combination complex”. There is insufficient antecedent basis for this limitation in the claim. The claim previously introduces a “replacement complex” and a “recombination complex,” but does not introduce a “combination complex.” Therefore, it is unclear which complex is being recombined, and the metes and bounds of the claim cannot be determined with reasonable certainty.
Claim 28 recites “recombining the combination complex.” This phrase does not clearly identify what nucleic acid components undergo recombining or what is actually required. Accordingly, the metes and bounds of claim 28 cannot be determined with reasonable certainty.
Claim 29 recites “the adjacent region” and depends from claim 25. There is insufficient antecedent basis for this limitation in the claim as there is no earlier recitation of “adjacent region.”
Claim 29 recites “said complementary region” and depends from claim 25. There is insufficient antecedent basis for this limitation in the claim as there is no earlier recitation of “complementary region.”
Claim 29 recites “the third sequence”. It is unclear if this recitation refers back to the third molecule (single-stranded nucleic acid molecule), the third transposase-recognition sequence, or something else.
Claim 29 recites “preparing a second ensemble” and further define specific components of the ensemble. The claim fails to recite what the second ensemble comprises that aids in method as claimed. Therefore, the metes and bounds of the claim cannot be determined with reasonable certainty.
Claim 29 recites obtaining “a recombination complex” without reciting the steps by which the complex is formed. The claim merely recites preparation of first and second ensembles before stating that a recombination complex is obtained. Consequently, the scope of the claimed recombination complex cannot be determined with reasonable certainty.
Claim 29 recites “cell ready to be edited”. This is a subjective characterization lacking objective boundaries. The claim does not define the structural or functional characteristics that distinguish a cell that is “ready to be edited” from one that is not.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
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 16-21, 25, and 27-29 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 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.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Independent claim 16 broadly recites a complex comprising first and second single-stranded nucleic acid molecules that define first and second double-stranded transposase-binding sites, wherein the binding sites comprise first and second sequences “for recognizing a transposase.” The claim is not limited to any particular transposase-recognition sequence or any particular transposase. Accordingly, the claim encompasses any nucleotide sequence capable of recognition by any transposase.
The specification, however, primarily describes specific transposases and particular transposase-recognition sequences associated with those systems. For example, the specification identifies the transposases of Tn5, Tn9, Tn10, Tn903, Tn602, and Tc1/mariner, and further provides specific nucleotide sequences and variants for selected transposase-recognition sequences (e.g., Tn5 mosaic-end sequences identified by specific sequence listings and embodiments) [0098-00112; example 1].
The specification does not identify structural characteristics common to the entire genus of transposase-recognition sequences that would permit one of ordinary skill in the art to recognize members of the claimed genus, nor does it disclose a representative number of species commensurate with the full breadth of “first” and “second” sequences capable of recognizing a transposase. Likewise, although multiple transposases are identified by name, the specification does not provide representative disclosure demonstrating possession of the full genus of transposase systems encompassed by the claims.
The art recognized that transposition requires highly specific transposase-DNA interactions and that different transposases possess distinct DNA-recognition domains, synaptic architectures, and substrate requirements Reznikoff (Reznikoff et al. Annu. Rev. Genet. 2008. 42:269–86) teaches that Tn5 activity depends on highly specific interactions between transpose and mosaic end sequences and that small changes significantly affect activity [pg. 281]. Reznikoff also teaches that synaptic complex formation is structurally constrained [pg. 277-278]. These teachings support the notion that success cannot be predicted mererly from knowing the sequence. Nesmelova (Nesmelova and Hackett Advanced Drug Delivery Reviews 62 (2010) 1187–1195) explain that although DD(E/D) transposases share a catalytic fold, their DNA-binding domains differ substantially in sequence, structure, and organization, and that synaptic complexes vary among different transposases [see section 3.1; 3.2, 4 and 6]. Davies (Davies et al. Science Vol 289. 2000) further teach that Tn5 transposition requires precise recognition of terminal DNA sequences, formation of a synaptic complex prior to catalysis, and extensive protein-DNA interactions necessary for coordinated cleavage and strand transfer [Fig. 1, pg. 84].
The disclosure therefore does not reasonably convey possession of the full scope of the claimed genus of transposase-recognition sequences and transposase systems, but instead demonstrates possession of specific disclosed recognition sequences and associated embodiments. Accordingly, in view of the limited amount of guidance provided by the specification and the art, one of ordinary skill in the art would conclude that Applicant was not in possession of the claimed invention.
Claims 16-21, 25, and 27-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a complex, ensemble, and method for replacement/editing of a target region according to example 1 in the specification, does not reasonably provide enablement for any complex, ensemble, and method for replacement/editing of a target region according to the full scope of the claimed invention. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention
The claims are directed to a complex, ensemble, and methods using the complex or ensemble for genome editing comprising first and second single-stranded nucleic acid molecules that define first and second double-stranded transposase-binding sites, wherein the binding sites comprise first and second sequences “for recognizing a transposase.”
State of the Art
The art recognized that transposition requires highly specific transposase-DNA interactions and that different transposases possess distinct DNA-recognition domains, synaptic architectures, and substrate requirements Reznikoff (Reznikoff et al. Annu. Rev. Genet. 2008. 42:269–86) teaches that Tn5 activity depends on highly specific interactions between transpose and mosaic end sequences and that small changes significantly affect activity [pg. 281]. Reznikoff also teaches that synaptic complex formation is structurally constrained [pg. 277-278]. These teachings support the notion that success cannot be predicted mererly from knowing the sequence. Nesmelova (Nesmelova and Hackett Advanced Drug Delivery Reviews 62 (2010) 1187–1195) explain that although DD(E/D) transposases share a catalytic fold, their DNA-binding domains differ substantially in sequence, structure, and organization, and that synaptic complexes vary among different transposases [see section 3.1; 3.2, 4 and 6]. Davies (Davies et al. Science Vol 289. 2000) further teach that Tn5 transposition requires precise recognition of terminal DNA sequences, formation of a synaptic complex prior to catalysis, and extensive protein-DNA interactions necessary for coordinated cleavage and strand transfer [Fig. 1, pg. 84].
Breadth of the claims
Independent claim 16 broadly encompasses complexes comprising first and second single-stranded nucleic acid molecules that partially hybridize to define first and second double-stranded transposase-binding sites. The claims are not limited to any particular:
• transposase;
• transposase-recognition sequence;
• transposase-binding site architecture;
• nucleic acid of interest;
• target-complementary sequence;
• genomic target;
• inserted sequence;
• first and second A/T-rich sequences within the recited length ranges;
• G/C-rich domains within the recited length ranges; or
• spacing between the A sequence and the G/C-rich domains.
Instead, the claims encompass virtually any combination of these variables provided that the resulting complex is capable of forming the recited transposase-binding sites.
Guidance of the Specification
The specification primarily describes specific transposases and particular transposase-recognition sequences associated with those systems. For example, the specification identifies the transposases of Tn5, Tn9, Tn10, Tn903, Tn602, and Tc1/mariner, and further provides specific nucleotide sequences and variants for selected transposase-recognition sequences (e.g., Tn5 mosaic-end sequences identified by specific sequence listings and embodiments) [0098-00112; example 1]. The specification contains only a limited number of representative embodiments compared with the breadth of the claimed genus. Although the specification provides examples of particular constructs and sequence arrangements, it does not provide sufficient guidance that would permit one of ordinary skill in the art to reliably identify or design functional complexes across the full breadth of the claimed genus without substantial experimentation.
In particular, successful practice of the claimed invention depends upon numerous interacting variables including:
1. Selection of functional transposase-recognition sequences. The claims encompass any first and second sequences capable of recognizing a transposase, whereas the specification primarily discloses particular recognition sequences and variants associated with selected transposase systems. The specification does not provide predictive guidance identifying structural features common to all functional transposase-recognition sequences or teaching how to design additional functional recognition sequences throughout the claimed scope.
2. Selection of transposases. The claims encompass numerous transposases having different DNA-recognition requirements and mechanisms of synaptic complex formation. The specification does not demonstrate that the disclosed molecular architecture predictably functions across the full breadth of transposase systems encompassed by the claims.
3. Formation of functional paired transposase-binding sites. The claims broadly require partially paired single-stranded nucleic acid molecules that define two functional double-stranded transposase-binding sites. The specification does not provide sufficient guidance establishing which combinations of recognition sequences, complementary sequences, hybridization lengths, or sequence arrangements will successfully form functional synaptic complexes throughout the claimed scope.
4. Broad sequence variables. The claims broadly encompass numerous combinations of A sequences, nucleic acids of interest, A/T-rich regions, G/C-rich domains, and spacing relationships without providing predictive guidance demonstrating that all such combinations will retain functional transposition activity.
Experimentation Required
Accordingly, a person of ordinary skill in the art seeking to practice the full scope of the claimed invention would be required to determine which transposase-recognition sequences remain functional, which transposases function with the claimed architecture, which combinations of A/T-rich regions and G/C-rich domains preserve activity, which hybridization architectures successfully form functional transposase-binding sites, and which combinations maintain transposition activity across different target sequences and nucleic acids of interest. Accordingly, one of ordinary skill would be required to engage in extensive screening and empirical optimization to determine which combinations of transposase, recognition sequences, hybridization architectures, sequence compositions, and spacing relationships produce functional complexes across the entire scope of the claims.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Claim Interpretation and Effect of Indefiniteness on Examination
The claims presently under examination contain numerous ambiguities, inconsistent recitations, missing antecedent basis, internally conflicting limitations, and unclear structural relationships. As discussed in the rejections under 35 U.S.C. § 112(b), these deficiencies prevent the claims from particularly pointing out and distinctly claiming the subject matter regarded as the invention. Consequently, the metes and bounds of the claimed invention cannot be determined with reasonable certainty.
For purposes of examination, the Examiner interpreted the claims in light of the specification to the extent reasonably possible. Based upon the claim language and disclosure, the Examiner’s present understanding is that the claimed invention is generally directed to nucleic acid complexes or ensembles, and methods using such, comprising multiple partially paired single-stranded nucleic acid molecules that cooperate through Watson-Crick base pairing to form double-stranded transposase-recognition sites while positioning a replacement nucleic acid sequence for transposase-mediated replacement of a target nucleic acid sequence. However, this interpretation is necessarily provisional because numerous claim limitations fail to clearly define the structural relationships among the recited molecules, transposase-recognition sequences, complementary sequences, binding sites, and replacement nucleic acid regions.
Notwithstanding these deficiencies, the Examiner conducted a prior art search based upon the broadest reasonable interpretation of the claims that could be derived from the claim language and the disclosure. Under the Examiner’s present understanding of the claimed invention, the search did not identify prior art that teaches or suggests the specific claimed molecular architecture of multiple partially paired single-stranded nucleic acid molecules that cooperatively generate the recited transposase-binding sites while simultaneously arranging a replacement nucleic acid region in the structural relationship presently understood from the claims.
Nevertheless, because the claims presently lack reasonably certain metes and bounds, this search was necessarily directed to multiple reasonable interpretations of the claimed subject matter, including transposase donor constructs, transposase-recognition site architectures, CRISPR-associated transposase systems, recombination substrates, split nucleic acid assemblies, and related genome-editing technologies.
Closest Prior Art
The closest prior art found is, Klompe et al., who teaches CRISPR-associated transposase (CAST) systems that employ a CRISPR-Cas targeting complex together with a Tn7-like transposition machinery to achieve RNA-guided integration of donor DNA into a target genomic site. Klompe teaches programmable transposition using transposase recognition sequences located at the ends of a donor transposon and transposase proteins acting in conjunction with a Cascade targeting complex.
However, Klompe (Klompe et al. Nature 571.7764 (2019): 219-225), nor the prior art, teach or suggest a molecular architecture comprising multiple partially paired single-stranded nucleic acid molecules that cooperatively form the recited double-stranded transposase-binding sites through Watson-Crick base pairing. Nor does Klompe, or the prior art, disclose or suggest positioning a replacement nucleic acid region between complementary transposase-recognition sequences carried on separate single-stranded molecules to generate the claimed replacement ensemble or complex.
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.
Claims 16-19, 25, 28 and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 8 and 15 of copending Application No. 19/143,616 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1, 3-5, 8 and 15 of the copending application anticipates the current rejected claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
Absence of prior art rejections under 35 U.S.C. §§ 102 and 103 in this Office Action should not be construed as a determination that the pending claims are patentable. Rather, the numerous deficiencies under 35 U.S.C. § 112(b) materially affect the ability to determine the precise scope of the claimed invention and, consequently, the scope of the prior art search.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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