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 .
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 – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Fig. 2C, 3A-3E, 5A, 15, 16D, 18C, 18E, 31, 32C, and 35B have nucleotides sequences with no SEQ ID provided in the drawing or brief description of the drawings in the specification.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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.
‘
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The following sections have paragraphs have hyperlinks: p. 28, [0083]; p. 36, [0130], and p. 264, [0462]. To overcome these objections, applicant may remove “https://” from the address.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 292 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 292 recites the limitation "the target sequence" in line 10. There is insufficient antecedent basis for this limitation in the claim. The prior claim language does not recite a target sequence.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 293 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 293 recites, “A human cell modified by the method of claim 277”. The instant specification recites, “The compositions and methods described herein may be used to treat, prevent, diagnose, or identify an infection in a subject. In some embodiments, the subject is an animal (e.g., a mammal, such as a human).” (p. 219, [0363]) Therefore, the BRI of “human cell” in Claim 293 includes a human organism. Therefore, Claim 293 is rejected under 35 USC 101 for claiming a human organism.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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)(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 277, 280, 282-284, and 286-295 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Doudna, J. et. al., The Reagents of the University of California, US 2021/0324356 A1 with a priority date of Mar. 7, 2019 from provisional application No. 62/815,173.
Regarding Claim 277, Doudna teaches “methods of modifying a target nucleic acid” (p. 1, [0003]) in a human cell, in which the method comprises contacting the human cell (p. 40, [0316]) with a lipid nanoparticle (p. 42, [0324]); a mRNA encoding a Cas12J polypeptide (p. 40, [0317]); and a guide RNA (p. 40, [0317]).
Doudna teaches the Cas12J protein, a nuclease, may have the amino acid sequence with the designation Cas12J_10000286_53, which is listed as SEQ ID NO: 120 (p. 14, [0137]; Fig. 6L). SEQ ID NO: 120 has 100% identity with SEQ ID NO: 12 of the instant application.
Doudna teaches that a guide RNA consists of a protein-binding region and a targeting segment (p. 25, [0216]). Doudna teaches the protein-binding region of Cas12J_10000286_53 in Fig. 8 listed as SEQ ID NO: 172 (p. 28, [0235]). SEQ ID NO: 172 has 100% identity to SEQ ID NO: 1531 of the instant application. Doudna teaches the targeting segment may be “over 17 or more” contiguous nucleotides with a complementary sequence to a target region (p. 26, [0223]). Doudna further teaches the PAM sequence “is immediately 5' of the target sequence if the non-complementary strand of the target DNA”, and “the PAM sequence of the non-complementary strand is 5'-NTTN-3'” (p. 25, [0210] and [0213]). Doudna also teaches a 2’ O-methyl modification “to increase stability and binding affinity” (p. 36, [0291]) and nucleotides with phosphorothioate linkages to resist nuclease degradation (p. 37, [0294]).
Doudna teaches LNPs contain the “Cas12J system of the present disclosure” (p. 42, [0324]) during contacting, and the “systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid” thereby modifying the gene (p. 1, [0002]).
Therefore, Claim 277 is anticipated by Doudna.
Regarding Claim 280, Doudna teaches the use of 2’ O-methyl modifications and phosphorothioate bonds. Therefore, Claim 280 is anticipated by Doudna.
Regarding Claim 282, Doudna teaches their method may be used with human cells (p. 40, [0316] such as “cells from tissues such as … liver” (p. 49, [0376]) Therefore, Claim 282 is anticipated by Doudna.
Regarding Claim 283, Doudna teaches Cas12J_10000286_53, which is listed as SEQ ID NO: 120 (p. 14, [0137]; Fig. 6L). SEQ ID NO: 120 has 100% identity with SEQ ID NO: 12 of the instant application. Therefore, Claim 283 is anticipated by Doudna.
Regarding Claim 284, Doudna teaches their method may be used “to treat a disease or as an antiviral, antipathogenic, or anticancer therapeutic” (p. 160, [0399]), which reads as a administering the LNP to a subject in need. Therefore, Claim 284 is anticipated by Doudna.
Regarding Claim 286, Doudna teaches, “in some cases, suitable PAMs can include GTTA, GTTG, ATTA, ATTG, CTTA, and CTTG” (p. 25, [0211]) and “some cases, suitable PAMs can include GTTT, GTTC, GTTG, ATTT, ATTC, ATTG, CTTT, CTTC, CTTG” (p. 25, [0213). Therefore, Claim 286 is anticipated by Doudna.
Regarding Claim 287, Doudna teaches their invention cleaves both strands of a target DNA (p. 1, [0017], Fig. 12A-12B). Therefore, Claim 287 is anticipated by Doudna.
Regarding Claim 288, Doudna teaches their method may compromise of “contacting the target nucleic acid with: a) a Cas12J polypeptide of the present disclosure; b) a Cas12J guide RNA; and c) a donor nucleic acid” (p. 47, [0366]). Therefore, Claim 288 is anticipated by Doudna.
Regarding Claim 289, Doudna teaches “donor sequences … can be delivered by viruses (e.g., adenovirus, AAV)” (p. 52, [0403]). Therefore, Claim 289 is anticipated by Doudna.
Regarding Claim 290, Doudna teaches “a fusion Cas12J protein … includes … a nuclear localization (e.g., in some cases 2 or more…)” positioned near the N-terminus and/or C-terminus (p. 23, [0200]). Therefore, Claim 290 is anticipated by Doudna.
Regarding Claim 291, Doudna teaches a first and second NLS fused to the N- and C-terminus respectively of the nuclease. Therefore, Claim 291 is anticipated by Doudna.
Regarding Claim 292, Claim 292 is rejected under 112(b) for improper antecedent. The “target sequence” is interpreted as “a target sequence that hybridizes the spacer sequence”.
Doudna teaches their invention in a LNP comprising a mRNA encoding SEQ ID NO: 12, taught as SEQ ID NO: 120, and a gRNA comprising of the protein-binding sequence SEQ ID NO: 1531, taught as SEQ ID NO: 172, a spacer sequence 17 or more nucleotides long, and at least one chemical modification selected from a 2’ O-methyl modification or a phosphonothioate modification in which a target sequence is adjacent to the PAM motif of NTTN. Therefore, Claim 292 is anticipated by Doudna.
Regarding Claim 293, Doudna teaches their method applied to a human cell. Therefore, Claim 293 is anticipated by Doudna.
Regarding Claim 294, Doudna teaches their method may be used to treat a subject in need by administration of the LNP to a subject: “administration can be for the purpose of treating and/or preventing a disease” including human individuals (p. 49, [0377]). Therefore, Claim 294 is anticipated by Doudna.
Regarding Claim 295, Doudna teaches a composition comprising the lipid nanoparticle of Claim 292. Therefore, Claim 295 is anticipated by Doudna.
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 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 278 and 279 are rejected under 35 U.S.C. 103 as being unpatentable over Doudna, J. et. al., The Reagents of the University of California, US 2021/0324356 A1 with a priority date of Mar. 7, 2019 from provisional application No. 62/815,173 as applied to Claim 277 above, and further in view of Kulkarni, J., et. al., Nanomedicine: Nanotechnology, Biology and Medicine, Vo. 13, No. 4, p. 1377-1387, May 2017.
Regarding Claim 278, Doudna anticipated Claim 277.
Doudna does not teach a amine group to phosphate (N/P) ratio of the LNP.
Kulkarni teaches, “LNP-pDNA systems containing DLin-KC2-DMA and SOPC were formulated at N/P ratios between 3 and 15” (p. 1379, col. 2). Figure 2(E) shows successful use of a N/P ratio of 3 (p. 1381).
It would be obvious to one skilled in the art to combine the method of Doudna, which teaches Claim 277, with the teachings of Kulkarni to create a LNP with a N/P ratio between 2 and 10. One of ordinary skill in the art could have combined the methods of Doudna and Kulkarni because Doudna does not teach a specific N/P ratio, while Kulkarni tested N/P ratios to deliver a plasmid with a lipid nanoparticle. The results would be predictable because Kulkarni provides evidence a N/P ratio between 3 and 10 successfully expressed a reporter. Therefore, Claim 277 is obvious over Doudna in further view of Kulkarni.
Regarding Claim 278, Kulkarni teaches successful delivery of a plasmid with a N/P ratio of 3, which is between 2 and 4. Therefore, Claim 278 is obvious over Doudna in further view of Kulkarni.
Claim 281 is rejected under 35 U.S.C. 103 as being unpatentable over Doudna, J. et. al., The Reagents of the University of California, US 2021/0324356 A1 with a priority date of Mar. 7, 2019 from provisional application No. 62/815,173 as applied to Claim 277 above, and further in view of Basila, M. et. al., PLOS One, Vol. Vol. 12, No. 11, p. 1-19, published November 27, 2017
Regarding Claim 281, Doudna anticipates Claim 277. Doudna also teaches the use of 2’ O-methyl and phosphorothioate linkage modifications (p. 36, [0290]). Doudna further teaches, “Phosphorothioate bonds can be introduced between the last 3-5 nucleotides at the 5'- or 3'-end of the oligo to inhibit exonuclease degradation” (p. 37, [0294]).
Doudna does not teach 2’ O-methyl modifications on any one of the first three 5’ and last three 3’ nucleotides.
Basila teaches gRNA with “one to three 2’-O-methyl modifications with 3’ phosphorothioate linkages” (p. 8, Fig. 2). Fig 2A shows 2’ O-methyl modifications on combinations of the first three 5’ and last 3’ nucleotides (p. 7). Basila teaches “that modification of the single-stranded region of crRNA and tracrRNA (5’ end of crRNA with 3’ end of tracrRNA) was important for stability and resulted in the overall highest gene editing efficiencies” (p. 14, para 2).
It would be obvious to one skilled in the art before the effective filing date to combine the teachings of Doudna, which teach the method of Claim 277 and the use of 2’ O-methyl and phosphorothioate linkage modifications, with the teachings of Basila to modify the gRNA with 2’ O-methyl on any of the first three 5’ and last three 3’ nucleotides and phosphorothioate bonds in between any one of the first three 5’ nucleotides and last two 3’ nucleotides because Doudna does not limit the locations of the modifications and Basila provides guidance on where to modify the gRNA. One skilled in the art would have a reasonable expectation of success because Basila provides data on the optimal location of gRNA 2’ O-methyl and phosphorothioate linkage modifications. One would be motivated to do so because Basila teaches the modifications improve gene editing efficiency. Therefore, Claim 281 is obvious over Doudna in view of Basila.
Claim 285 is rejected under 35 U.S.C. 103 as being unpatentable over Doudna, J. et. al., The Reagents of the University of California, US 2021/0324356 A1 with a priority date of Mar. 7, 2019 from provisional application No. 62/815,173 as applied to Claim 284 above, and further in view of Aravalli, R. and Steer, C., Journal of Cellular Biochemistry, Vol. 119, p. 4265-4278, published December 21, 2017.
Regarding Claim 285, Doudna anticipates Claim 284 including a method comprising administering the LNP containing the mRNA and gRNA to a subject in need and liver cells.
Doudna does not teach the subject comprises a mutation in a gene that is associated with a liver disease.
Aravalli teaches, “Gene editing is a logical therapeutic approach for liver diseases because many metabolic and acquired disorders are caused by mutations within a single gene” and provides an overview for therapeutic strategies using CRISPR technology (p. 4265, Abstract). Aravalli also teaches, “The most popular delivery method for LTGT [liver-targeted gene therapy] in animals has been by the hydrodynamic injection, where a nonviral vector is tagged to a carrier, such as lipid nanoparticles” (p. 4273, col. 2).
Regarding Claim 285, it would have been obvious to one skilled in the art before the effective filing date to have used the teachings of Doudna to use the method of Claim 284 to administer the LNP containing the mRNA and gRNA to a subject comprising a mutation in a gene that is associated with liver disease because Aravalli teaches using CRIPSR and lipid nanoparticles are a common strategy for delivery gene therapy for liver disease. One would have a reasonable expectation of success because Aravalli teaches LNP deliver for liver disease is a well understood method. One would be motivated to do so because Aravalli teaches many liver diseases are caused by mutations in a single gene. Therefore, Claim 285 is obvious over Doudna in further view of Aravalli.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Krishna Nuggehalli Ravindra whose telephone number is (571)272-2758. The examiner can normally be reached M-Th, alternate F, 8a-5p est.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N.R./Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636