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 .
Claims 1-17 are pending in this application, and are under examination.
Information Disclosure Statement
The Information Disclosure Statement filed May 2, 2024 has been considered.
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:
via EFS-Web (see Section I.1 of the Legal Framework for EFS-Web (https://www.uspto.gov/patents-application-process/filing-online/legal-framework-efs-web), 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 identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
on compact disc(s) in duplicate according to 37 CFR 1.52(e)(1)(ii) and (4), labeled according to 37 CFR 1.52(e)(6), together with a statement that the duplicate compact discs are identical and an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(5) 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;
via EFS-Web as a PDF (not recommended); or
on paper.
37 CFR 1.821(e) requires that a copy of the "Sequence Listing" must also be submitted in computer readable form (CRF) in accordance with the requirements of 37 CFR 1.824.
If a "Sequence Listing" ASCII text file submitted via EFS-Web on the application filing date complies with the requirements of 37 CFR 1.824(a)(2) - (6) and (b), and applicant has not filed a "Sequence Listing" as a PDF, the text file will serve as both the "Sequence Listing" required by 37 CFR 1.821(c) and the CRF required by 37 CFR 1.821(e), and the statement of identity under the "Legal Framework" is not required.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web as a PDF, then the "Legal Framework" requires submission of a statement that the "Sequence Listing" content of the PDF copy and the ASCII text file copy submitted via EFS-Web are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or compact disc, then 37 CFR 1.821(f) requires submission of a statement that the "Sequence Listing" content of the paper or compact 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 is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
An amendment correcting the size of the ASCII text file. In this instance, the specification lists the size of the ASCII text file as 174,571 bytes, whereas the ASCII text file itself lists the size as 174,612 bytes.
Specification
The use of the terms VYBRANT at paragraphs [0133], [0134], [0146], and [0147]; EASYCYTE at paragraphs [0135] and [0148]; LIPOFECTAMINE at paragraphs [0136], [0143], and [0149]; GENOMEWALKER at paragraphs [0137], [0152], and [0162]; GENEWIZ at paragraphs [0141] and [0150]; ALEXAFLUOR at paragraph [0144]; TRITON at paragraphs [0144] and [0145]; LEICA at paragraph [0144]; SEEBLUE at paragraph [0145]; TWEEN at paragraph [0145]; IRDYE at paragraph [0145]; ODYESSEY at paragraph [0145]; ARCHIVEPURE at paragraph [0150]; NUCLEOSPIN at paragraphs [0152] and [0156]; PHUSION at paragraph [0152]; NEBNEXT at paragraph [0156]; and HISEQ at paragraph [0156]; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear 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.
Claim Objections
Claim 11 is objected to because of the following informalities:
At claim 11, line 1, “comprising” should be inserted after “composition.”
Appropriate correction is required.
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 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention.
The claims recite a method of excising all or part of a viral sequence from a cell comprising cutting the viral sequence at a first and second target sequence, which results in all or part of the viral sequence being excised from the cell. The rejected claim thus comprises a genus of enzymes defined as belonging to a group proteins, to function to cleave a target nucleic acid. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. There are numerous types of CRISPR enzymes that will provide for cleavage of a viral sequence in a cell.
However, the specification states that “that we could eliminate the integrated HIV-1 genome from HIV-1 infected cells by using the RNA-guided Clustered Regularly Interspace Short Palindromic Repeat (CRISPR)-Cas9 nuclease system (Cas9/gRNA).” See paragraph [0028]. However, it is impossible for one to extrapolate from the generic recitation of broad classes of nuclease proteins, much less the broad classes of CRISPR proteins, the structure of any enzyme, or any CRISPR enzyme whose application to a nucleic acid molecule would be useful for detection of target nucleic acids. The prior art does not appear to offset the deficiencies of the instant specification. The prior art teaches that CRISPR Type I, II, and III enzymes each have different structures and function in different pathways (Sorek et al., 82 Annual Review of Biochemistry 237-266 (2013), and cited in the Information Disclosure Statement filed May 2, 2024). The prior art further discloses additional CRISPR systems, which also have different structures and function in yet different pathways (Koonin et al., 37 Current Opinion in Microbiology 67-78 (2017), and cited in the Information Disclosure Statement filed May 2, 2024). Thus, the specification is not sufficient to support the broadly claimed genus of CRISPR enzymes, which are variants having different structures and functions.
The description of the limited Cas9 CRISPR system is not sufficient to support the genus of claimed CRISPR systems. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See Vas-Cath at page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is now is claimed." (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of CRISPR systems, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation or identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18USPQ2d 1016. Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-12.
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 1-10 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.
At claim 1, line 1, it is not clear how much of the retroviral sequence must be excised to be considered “part” of the retroviral sequence. Can “part” be as little as one or two nucleotides?
Claims 2-5 depend from claim 1, and are therefore included in this rejection
At claim 6, line 1, it is not clear how much of the retroviral sequence must be excised to be considered “part” of the retroviral sequence. Can “part” be as little as one or two nucleotides?
Claims 7-10 depend from claim 1, and are therefore included in this rejection
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-17 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Howell et al. (U.S. Patent Application Publication No. 2016/0040165, published February 11, 2016, and claiming priority to PCT Patent Application Publication No. WO 2014/165349, filed March 25, 2014 and U.S. Provisional Patent Application No. 61/808,437, filed April 4, 2013, and cited in the Information Disclosure Statement filed May 2, 2024), see the entire document.
Regarding claim 1, Howell discloses methods for excision of part or all of HIV-1 proviral DNA using a CRISPR-Cas system that employs more than one guide RNA that hybridizes to targets of the HIV-1 DNA (abstract). Howell discloses that more than one guide RNA can be used to target multiple sites within the HIV-1 DNA, which is interpreted as multiplexing guide RNAs, including use of two guide RNAs (paragraphs [0019]-[0020]). Howell discloses that bioinformatics analyses are available that generated extensive databases of CRISPR loci, and which can be used to determine protospacer adjacent motifs (PAMs) and identifying targetable DNA of HIV-1 sequences (paragraph [0019].
Regarding claims 2-5, Howell discloses a variety of sequences in the long terminal repeat (LTR)s at both the 5’ and 3’ LTRs of the HIV-1 sequence (Table 1). Howell further discloses that the U3 region of the LTR can be targeted with a CRISPR-Cas guide RNA (Table 1).
Regarding claim 6, Howell discloses methods for excision of part or all of HIV-1 proviral DNA using a CRISPR-Cas system that employs more than one guide RNA that hybridizes to targets of the HIV-1 DNA (abstract). Howell discloses that more than one guide RNA can be used to target multiple sites within the HIV-1 DNA, which is interpreted as multiplexing guide RNAs, including use of two guide RNAs (paragraphs [0019]-[0020]). Howell discloses that bioinformatics analyses are available that generated extensive databases of CRISPR loci, and which can be used to determine protospacer adjacent motifs (PAMs) and identifying targetable DNA of HIV-1 sequences (paragraph [0019].
Regarding claims 7-10, Howell discloses a variety of sequences in the long terminal repeat (LTR)s at both the 5’ and 3’ LTRs of the HIV-1 sequence (Table 1). Howell further discloses that the U3 region of the LTR can be targeted with a CRISPR-Cas guide RNA (Table 1).
Regarding claim 11, Howell discloses a composition that provides for a CRISPR endonuclease and two or more guide RNAs, where each of the guide RNAs complexes with the proviral HIV-1 DNA and provides for cleaving the double strand of the DNA in two places, which results in the excision of the proviral HIV-1 DNA, which is also further interpreted as the mutation providing for the excision of the proviral HIV-1 sequences and inactivation of the proviral DNA (paragraphs [0015], [0019], and [0057]). Howell further discloses that the CRISPR-Cas composition can be a vector comprising nucleic acids encoding the CRISPR enzyme and the guide RNAs, where the cell is able to express the CRISPR-Cas system, assemble a CRISPR-Cas complex, and providing for the expressed CRISPR-Cas system to cleave the double stranded DNA in two places, again resulting in the excision of the proviral HIV-1 DNA (paragraphs [0015], [0019]-[0020], [0026]-[0029], and [0057]). Howell discloses that the CRISPR associated protein can be Cas9, which can be codon-optimized for use in human cells (paragraphs [0005] and [0019]-[0021]).
Regarding claims 12-15, Howell discloses a variety of sequences in the long terminal repeat (LTR)s at both the 5’ and 3’ LTRs of the HIV-1 sequence (Table 1). Howell further discloses that the U3 region of the LTR can be targeted with a CRISPR-Cas guide RNA (Table 1).
Regarding claims 16-17, Howell discloses that the nucleic acids encoding the CRISPR-Cas enzyme and protein can be present in an expression vector, which may be a viral vector, such as a retrovirus, an adenovirus, or an adeno-associated virus (paragraphs [0026]-[0033]). Howell discloses that the guide RNAs can comprise a crRNA and a tracrRNA, expressed by either separate nucleic acids or as a fusion between the crRNA and the tracrRNA (paragraph [0017]).
Howell discloses each and every limitation of claims 1-17, and therefore Howell anticipates the claimed invention.
Claims 1-15 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ebina et al. (3 Scientific Reports 2510, 1-7 (August 23, 2013), and cited in the Information Disclosure Statement filed May 2, 2024).
Regarding claim 1, Ebina discloses a method of disrupting latent HIV-1 provirus (abstract). Ebina discloses that CRISPR/Cas9 may be used to simultaneously cleave both LTRs to remove a region of proviral DNA from a host cell genome (page 2, column 2, second full paragraph). Ebina discloses that the method comprises contacting the cell with a CRISPR-associated endonuclease (Cas9) and guide RNAs (Figure 4).
Regarding claims 2-5, Ebina discloses targeting the 3’ and 5’ LTRs at the U3 region of the LTR (page 2, column 2, second full paragraph and Figure 4).
Regarding claim 6, Ebina discloses a method of disrupting latent HIV-1 provirus (abstract). Ebina discloses that CRISPR/Cas9 may be used to simultaneously cleave both LTRs to remove a region of proviral DNA from a host cell genome (page 2, column 2, second full paragraph). Ebina discloses that the method comprises contacting the cell with a CRISPR-associated endonuclease (Cas9) and guide RNAs (Figure 4).
Regarding claims 7-10, Ebina discloses targeting the 3’ and 5’ LTRs at the U3 region of the LTR (page 2, column 2, second full paragraph and Figure 4).
Regarding claim 11, Ebina discloses a composition that can be used in a method of disrupting latent HIV-1 provirus (abstract). Ebina discloses that CRISPR/Cas9 may be used to simultaneously cleave both LTRs to remove a region of proviral DNA from a host cell genome (page 2, column 2, second full paragraph). Ebina discloses that the method comprises contacting the cell with a CRISPR-associated endonuclease (Cas9) and guide RNAs (Figure 4).
Regarding claims 11-15, Ebina discloses targeting the 3’ and 5’ LTRs at the U3 region of the LTR (page 2, column 2, second full paragraph and Figure 4).
Regarding claims 17, Ebina discloses that the composition can provide nucleic acids encoding the CRISPR endonuclease and the guide RNAs on different vectors (Figure 1, legend and Figure 3, legend).
Ebina discloses each and every limitation of claims 1-15 and 17, and therefore, Ebina anticipates the claimed invention.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2014/0357530, published December 4, 2014, and claiming priority to U.S. Provisional Patent Application No. 61/736,527, filed December 12, 2012, and cited in the Information Disclosure Statement filed May 2, 2024), see the entire document, in view of Howell et al. (U.S. Patent Application Publication No. 2016/0040165, published February 11, 2016, and claiming priority to PCT Patent Application Publication No. WO 2014/165349, filed March 25, 2014 and U.S. Provisional Patent Application No. 61/808,437, filed April 4, 2013), and cited in the Information Disclosure Statement filed May 2, 2024, see the entire document.
Regarding claim 1, Zhang I discloses a methods for inactivating proviral DNA that has been integrated into the genome of a host cell comprising treating the host cell comprising the CRISPR enzyme and two or more guide RNAs (paragraphs [0043], [0079], [0148], [0202], [0271], [0296], [0579] and [0649], and Figure 51). Zhang I discloses that the two gRNAs are complementary to different target proviral nucleic acid sequences (paragraphs [0061], [0271], [0296], and [0581]). Zhang I discloses a composition that comprises an isolated nucleic acid sequence encoding the CRISPR enzyme and the two guide RNAs, which are complementary to first and second protospacer sequences in a proviral DNA (paragraphs {0043], [0202], [0296], [0581], [0649]). Zhang I discloses expression of the polynucleotides in a cell (paragraphs [0036], [0043]-[0044], [0148], [0500], and [0649]). Zhang I further discloses assembling the gene editing complexes in the host cell (paragraph [0271]). Zhang I discloses that the first and second gene editing complexes are directed to the first and second target protospacers by complementary base pairing (paragraph [0271]). Zhang I discloses that the CRISPR enzyme will then cleave the proviral DNA at the first and second target sequences (paragraph [0067]).
Regarding claim 6, Zhang I discloses a methods for inactivating proviral DNA that has been integrated into the genome of a host cell comprising treating the host cell comprising the CRISPR enzyme and two or more guide RNAs (paragraphs [0043], [0079], [0148], [0202], [0271], [0296], [0579] and [0649], and Figure 51). Zhang I discloses that the two gRNAs are complementary to different target proviral nucleic acid sequences (paragraphs [0061], [0271], [0296], and [0581]). Zhang I discloses a composition that comprises an isolated nucleic acid sequence encoding the CRISPR enzyme and the two guide RNAs, which are complementary to first and second protospacer sequences in a proviral DNA (paragraphs {0043], [0202], [0296], [0581], [0649]). Zhang I discloses expression of the polynucleotides in a cell (paragraphs [0036], [0043]-[0044], [0148], [0500], and [0649]). Zhang I further discloses assembling the gene editing complexes in the host cell (paragraph [0271]). Zhang I discloses that the first and second gene editing complexes are directed to the first and second target protospacers by complementary base pairing (paragraph [0271]). Zhang I discloses that the CRISPR enzyme will then cleave the proviral DNA at the first and second target sequences (paragraph [0067]).
Regarding claim 11, Zhang I discloses a compositions for inactivating proviral DNA that has been integrated into the genome of a host cell comprising treating the host cell comprising the CRISPR enzyme and two or more guide RNAs (paragraphs [0043], [0079], [0148], [0202], [0271], [0296], [0579] and [0649], and Figure 51). Zhang I discloses that the two gRNAs are complementary to different target proviral nucleic acid sequences (paragraphs [0061], [0271], [0296], and [0581]). Zhang I discloses a composition that comprises an isolated nucleic acid sequence encoding the CRISPR enzyme and the two guide RNAs, which are complementary to first and second protospacer sequences in a proviral DNA (paragraphs {0043], [0202], [0296], [0581], [0649]). Zhang I discloses expression of the polynucleotides in a cell (paragraphs [0036], [0043]-[0044], [0148], [0500], and [0649]). Zhang I further discloses assembling the gene editing complexes in the host cell (paragraph [0271]). Zhang I discloses that the first and second gene editing complexes are directed to the first and second target protospacers by complementary base pairing (paragraph [0271]). Zhang I discloses that the CRISPR enzyme will then cleave the proviral DNA at the first and second target sequences (paragraph [0067]). Zhang I disclosed that the retrovirus can be HIV-1 (paragraph [0584]).
Regarding claims 16-17, Zhang I discloses that the components of the CRISPR complex can be on the same or separate vectors, which can be a plasmid, lentiviral, adenoviral, or adeno-associated virus vectors (paragraphs [0259] and [0304]). Zhang I further discloses that the vector can comprise a CRISPR RNA (crRNA) and a tracrRNA (trRNA), and that the guide RNAs can be a fusion of a crRNA and a trRNA (paragraph [0655]). Zhang I discloses a composition comprising CRISPR enzyme and two or more guide RNAs (column 11, line 45, column 12, line 55, column 15, lines 27-32, and column 34, lines 45-52).
Zhang I fails to explicitly disclose or suggest that the target sequences are in the long terminal repeats (LTRs) of the proviral DNA, or specifically within the U3 region of the LTR.
Regarding claims 2-5, 7-10, and 12-15, Howell discloses compositions for excision of all or part of HIV-1 proviral DNA using a CRISPR-Cas system that employs more than one guide RNA that hybridizes to targets of the HIV-1 DNA (abstract). Howell discloses that more than one guide RNA can be used to target multiple sites within the HIV-1 DNA, which is interpreted as multiplexing guide RNAs, including use of two guide RNAs (paragraphs [0019]-[0020]). Howell discloses that bioinformatics analyses are available that generated extensive databases of CRISPR loci, and which can be used to determine protospacer adjacent motifs (PAMs) and identifying targetable DNA of HIV-1 sequences (paragraph [0019]. Howell discloses a variety of sequences in the long terminal repeat (LTR)s at both the 5’ and 3’ LTRs of the HIV-1 sequence (Table 1). Howell further discloses that the U3 region of the LTR can be targeted with a CRISPR-Cas guide RNA (Table 1). Howell discloses a composition that provides for a CRISPR endonuclease and two or more guide RNAs, where each of the guide RNAs complexes with the proviral HIV-1 DNA and provides for cleaving the double strand of the DNA in two places, which results in the excision of the proviral HIV-1 DNA, which is also further interpreted as the mutation providing for the excision of the proviral HIV-1 sequences and inactivation of the proviral DNA (paragraphs [0015], [0019], and [0057]). Howell further discloses that the CRISPR-Cas composition can be a vector comprising nucleic acids encoding the CRISPR enzyme and the guide RNAs, where the cell is able to express the CRISPR-Cas system, assemble a CRISPR-Cas complex, and providing for the expressed CRISPR-Cas system to cleave the double stranded DNA in two places, again resulting in the excision of the proviral HIV-1 DNA (paragraphs [0015], [0019]-[0020], [0026]-[0029], and [0057]). Howell discloses that the CRISPR associated protein can be Cas9, which can be codon-optimized for use in human cells (paragraphs [0005] and [0019]-[0021]). Howell discloses that the nucleic acids encoding the CRISPR-Cas enzyme and protein can be present in an expression vector, which may be a viral vector, such as a retrovirus, an adenovirus, or an adeno-associated virus (paragraphs [0026]-[0033]). Howell discloses that the guide RNAs can comprise a crRNA and a tracrRNA, expressed by either separate nucleic acids or as a fusion between the crRNA and the tracrRNA (paragraph [0017]).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Howell’s methods and compositions disclosing first and second sequences complementary to the first and sequences of the target sequence in Zhang I’s and Howell’s HIV-1 proviral sequence because these sequences are highly conserved between strains of HIV-1, and as such one of ordinary skill in the art would look to such sequences in order to cleave proviral DNA at the desired sequences, thus inactivating the HIV-1 proviral DNA . Because the sequence is highly conserved, it would be well within the purview of one of ordinary skill in the art to determine the most effective sequences, and could do so using predictable and reproducible methodology.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Zhang II, U.S. Patent Application Publication No. 2015/0020223, published January 15, 2015, and claiming priority to U.S. Provisional Patent Application No. 61/736,527, filed December 12, 2012, and cited in the Information Disclosure Statement filed May 2, 2024), see the entire document in view of Howell et al. (U.S. Patent Application Publication No. 2016/0040165, published February 11, 2016, and claiming priority to PCT Patent Application Publication No. WO 2014/165349, filed March 25, 2014 and U.S. Provisional Patent Application No. 61/808,437, filed April 4, 2013), and cited in the Information Disclosure Statement filed May 2, 2024, see the entire document.
Regarding claim 1, Zhang II discloses methods by which the CRISPR complex is able to modify genomes by deleting, inserting, activating, inactivating, repressing altering methylation and transferring specific moieties, which is interpreted as the CRISPR complex being able to excise all or part of the proviral DNA in the genome of a host cell (paragraphs [0013], [0074], [0327], [0339], [0581] and [0620]). Zhang II discloses that the CRISPR enzyme is Cas9 or codon-optimized Cas9 (paragraphs [0291] and [0293]).
Regarding claim 6, Zhang II discloses methods comprising contacting the host cell with a CRISPR composition comprising the CRISPR enzyme and two or more guide RNAs (paragraphs [0043], [0079], [0148], [0202], [0271], [0296], [0579] and [0649], and Figure 51). Zhang II discloses that the two gRNAs are complementary to different target proviral nucleic acid sequences (paragraphs [0061], [0271], [0296], and [0581]). Zhang II discloses a composition that comprises an isolated nucleic acid sequence encoding the CRISPR enzyme and the two guide RNAs, which are complementary to first and second protospacer sequences in a proviral DNA (paragraphs {0043], [0202], [0296], [0581], [0649]).
Regarding claim 11, Zhang II discloses a compositions for inactivating proviral DNA that has been integrated into the genome of a host cell comprising contacting the host cell with a CRISPR composition comprising the CRISPR enzyme and two or more guide RNAs (paragraphs [0043], [0079], [0148], [0202], [0271], [0296], [0579] and [0649], and Figure 51). Zhang II discloses that the two gRNAs are complementary to different target proviral nucleic acid sequences (paragraphs [0061], [0271], [0296], and [0581]). Zhang II discloses a composition that comprises an isolated nucleic acid sequence encoding the CRISPR enzyme and the two guide RNAs, which are complementary to first and second protospacer sequences in a proviral DNA (paragraphs {0043], [0202], [0296], [0581], [0649]).
Regarding claims 16-17, Zhang II discloses that the components of the CRISPR complex can be on the same or separate vectors, which can be a plasmid, lentiviral, adenoviral, or adeno-associated virus vectors (paragraphs [0259] and [0304]). Zhang II further discloses that the vector can comprise a CRISPR RNA (crRNA) and a tracrRNA (trRNA), and that the guide RNAs can be a fusion of a crRNA and a trRNA (paragraph [0655]).
Zhang II ails to explicitly disclose or suggest that the target sequences are in the long terminal repeats (LTRs) of the proviral DNA, or specifically within the U3 region of the LTR.
Regarding claims 2-5, 7-10, and 12-15, Howell discloses methods for excision of HIV-1 proviral DNA using a CRISPR-Cas system that employs more than one guide RNA that hybridizes to targets of the HIV-1 DNA (abstract). Howell discloses that more than one guide RNA can be used to target multiple sites within the HIV-1 DNA, which is interpreted as multiplexing guide RNAs (paragraphs [0019]-[0020]). Howell discloses that bioinformatics analyses are available that generated extensive databases of CRISPR loci, and which can be used to determine protospacer adjacent motifs (PAMs) and identifying targetable DNA of HIV-1 sequences (paragraph [0019]. Howell discloses a variety of sequences in the long terminal repeat (LTR)s at both the 5’ and 3’ LTRs of the HIV-1 sequence (Table 1). Howell further discloses that the U3 region of the LTR can be targeted with a CRISPR-Cas guide RNA (Table 1). Howell discloses that the cell can be contacted with a composition that provides for a CRISPR endonuclease and two or more guide RNAs, where each of the guide RNAs complexes with the proviral HIV-1 DNA and provides for cleaving the double strand of the DNA in two places, which results in the excision of the proviral HIV-1 DNA, which is also further interpreted as the mutation providing for the excision of the proviral HIV-1 sequences (paragraphs [0015], [0019], and [0057]). Howell further discloses that the CRISPR-Cas composition can be a vector comprising nucleic acids encoding the CRISPR enzyme and the guide RNAs, where the cell is able to express the CRISPR-Cas system, assemble a CRISPR-Cas complex, and providing for the expressed CRISPR-Cas system to cleave the double stranded DNA in two places, again resulting in the excision of the proviral HIV-1 DNA (paragraphs [0015], [0019]-[0020], [0026]-[0029], and [0057]). Howell discloses that the CRISPR associated protein can be Cas9, which can be codon-optimized for use in human cells (paragraphs [0005] and [0019]-[0021]). Howell discloses that the nucleic acids encoding the CRISPR-Cas enzyme and protein can be present in an expression vector, which may be a viral vector, such as a retrovirus, an adenovirus, or an adeno-associated virus (paragraphs [0026]-[0033]). Howell discloses that the guide RNAs can comprise a crRNA and a tracrRNA, expressed by either separate nucleic acids or as a fusion between the crRNA and the tracrRNA (paragraph [0017]).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Howell’s CRISPR compositions and methods to determine first and second sequences complementary to the first and sequences of the target sequence in Zhang II’s HIV-1 proviral sequence because these sequences are highly conserved between strains of HIV-1, and as such one of ordinary skill in the art would look to such sequences in order to cleave proviral DNA at the desired sequences, thus excising inactivating the HIV-1 proviral DNA . Because the sequence is highly conserved, it would be well within the purview of one of ordinary skill in the art to determine the most effective sequences, and could do so using predictable and reproducible methodology.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over by Ebina et al. (3 Scientific Reports 2510, 1-7 (August 23, 2013), and cited in the Information Disclosure Statement filed May 2, 2024), as applied to claims 1-15 and 17 above, and in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2014/0357530, published December 4, 2014, and claiming priority to U.S. Provisional Patent Application No. 61/736,527, filed December 12, 2012, and cited in the Information Disclosure Statement filed May 2, 2024).
Ebina discloses excision of retroviral (HIV) sequences from a host cell genome, as discussed above.
Ebina fails to disclose or suggest that the nucleic acids encoding the CRISPR endonuclease and guide RNAs can be on a single vector
Regarding claims 16-17, Zhang II discloses that the components of the CRISPR complex can be on the same or separate vectors, which can be a plasmid, lentiviral, adenoviral, or adeno-associated virus vectors (paragraphs [0259] and [0304]). Zhang II further discloses that the vector can comprise a CRISPR RNA (crRNA) and a tracrRNA (trRNA), and that the guide RNAs can be a fusion of a crRNA and a trRNA (paragraph [0655]).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to incorporate Ebina’s nucleic acids encoding all of the CRISPR endonuclease and guide RNAs in a single vector because this provides a more simple and streamlined transfection/transformation of the host cell. One of ordinary skill in the art would have been motivated to use a single vector system because this will provide a predictable and accurate method of transfection/transformation in order for the host cell to express the CRISPR endonuclease and both guide RNAs, which will then cleave the proviral sequence and excise it from the host cell genome.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 7-13 of U.S. Patent No. 9,925,248.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘248 patent and the instant application claim a method of inactivating a proviral DNA integrated in a host genome. It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that excising the proviral DNA according to the ‘248 patent using the instantly claimed method and composition would both result in the excision of the viral sequences, thus inactivating the virus.
Claims 1, 6, and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,981,020.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘020 patent claims a composition for excising a viral sequence from a cell and the instant application claims are directed to methods and compositions for excising a viral sequence from a cell. It would be obvious to one of ordinary skill in the art at the time the invention was made that the composition of U.S. Patent No. 9,981,020 in the method of the instant application because the composition will result in the recited excision of the viral sequence from the cell. The instant case is analogous to Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010), where the courts ruled that obviousness-type double patenting exist between previously-disclosed, but newly-claimed utility. Therefore, the instant claims are not patentably distinct from the issued claims.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,273,209.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘209 patent and the instant application claim methods of excising viral sequence from a cell. While the instant application does not claim use of a CRISPR/Cas9 endonuclease, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the ‘209 CRISPR method would function to be able to excise a viral sequence as required by the instant claims. In addition, the methods of the ‘209 patent provide for use of the instantly claimed method and composition. Therefore, the claims are not deemed to be patentably distinct.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-8 of U.S. Patent No. 11,285,193.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘193 patent and the instant application claim methods of excising viral sequence from a cell. While the instant application does not claim use of a CRISPR/Cas9 endonuclease, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the ‘193 CRISPR composition would be able to excise a viral sequence as required. In addition, the methods of the ‘193 patent provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,291,710.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘710 patent claims a composition which can be used for deletion of an HIV sequence from a cell and the instant application claims a method and composition for excising a viral sequence from a cell. Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the CRISPR compositions of the ‘710 patent could be used in the instant compositions, which would be able to delete/excise the retroviral sequence from the genome of the cell. The instant case is analogous to Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010), where the courts ruled that obviousness-type double patenting exist between previously-disclosed, but newly-claimed utility. Therefore, the instant claims are not patentably distinct from the issued claims. In addition, the methods of the ‘710 patent provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-6 of U.S. Patent No. 11,298,410.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘410 patent and the instant application claim method and compositions of excising viral sequence from a cell. While the instant application does not claim use of a CRISPR/Cas9 endonuclease, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the ‘410 CRISPR composition would be able to excise a viral sequence as required. In addition, the methods of the ‘410 patent provide for use of the instantly claimed method and composition. The instant case is analogous to Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010), where the courts ruled that obviousness-type double patenting exist between previously-disclosed, but newly-claimed utility. Therefore, the instant claims are not patentably distinct from the issued claims. Therefore, the claims are not deemed to be patentably distinct.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6-7, and 28-31 of U.S. Patent No. 11,298,411.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘411 patent and the instant application claim method and compositions of excising viral sequence from a cell. While the instant application does not claim use of a CRISPR/Cas9 endonuclease, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the ‘411 CRISPR composition would be able to excise a viral sequence as required. In addition, the methods of the ‘411 patent provide for use of the instantly claimed method and composition. Therefore, the claims are not deemed to be patentably distinct.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,122,997.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘997 patent claims a vector composition and method for deletion of an HIV sequence from a cell and the instant application claims a method and composition for excising a viral sequence from a cell. Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the CRISPR vectors of the ‘997 patent could be used as the instant compositions and methods for deletion/excision of the retroviral sequence from the genome of the cell. The instant case is analogous to Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010), where the courts ruled that obviousness-type double patenting exist between previously-disclosed, but newly-claimed utility. Therefore, the instant claims are not patentably distinct from the issued claims. In addition, the methods of the ‘997 patent provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
Claims 1, 6, and 11 are ejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,251,429.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘429 patent and the instant application claim a method for excising part or all of a viral sequence from the cell, where the instant application required deletion of an HIV sequence, where each method claims that the target sequences are in the LTR regions of the viral sequence. Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the methods of the ‘429 patent and the instant application would result in the deletion/excision of the retroviral sequence from the genome of the cell. In addition, the methods of the ‘429 patent provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
Claims 1, 6, and 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 26-27 of copending Application No. 16/605,922 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ’922 application and the instant application each claim methods of eradicating a viral sequence from a cell. While the ‘922 application does not explicitly claim excision of the viral sequence, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that excision of the viral sequence would eradicate the virus from a cell. In addition, the methods of the ‘922 application provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. It is noted that the ‘922 patent has been allowed. Upon issuance of the ‘922 application as a patent, this rejection will no longer be provisional.
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 1-14 of copending Application No. 16/812,140 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ’140 application and the instant application each claim methods of eradicating a viral sequence from a cell. While the ‘140 application does not explicitly claim excision of the viral sequence, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that excision of the viral sequence would eradicate the virus from a cell. In addition, the methods of the ‘140 application also provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 11-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, and 22 of copending Application No. 18/566,468 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘468 application and the instant application each claim compositions of eradicating a viral sequence from a cell. While the ‘468 application does not explicitly claim excision of the viral sequence, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that excision of the viral sequence would eradicate the virus from a cell. In addition, the compositions of the ‘468 application also provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 19/382,825 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ’825 application and the instant application each claim methods of eradicating a viral sequence from a cell. While the ‘825 application does not explicitly claim excision of the viral sequence, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that excision of the viral sequence would eradicate the virus from a cell. In addition, the methods of the ‘825 application provide for use of the instantly claimed composition. Therefore, the claims are not deemed to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mcintyre et al. (6 Retrovirology 55 1-15 (2009)), and cited in the Information Disclosure Statement filed May 2, 2024) discloses that RNA interference (RNAi) is a mechanism of gene suppression that may be useful in gene therapy applications for treating viral diseases, such as HIV-1 (abstract). Mcintyre 2014discloses the preparation of a variety of shRNAs based on the HIV-1 sequences, including those sequences found in the LTRs of HIV-1, which is interpreted as including the U3 region of the LTR (page 2 column 2, second paragraph, page 3, paragraph bridging columns 1 and 2, and page 4, column 2, second full paragraph).
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636